Conditions: Acute Myeloid Leukemia
Keywords: Midostaurin PKC412 FMS-like tyrosine kinase receptor FLT3 Acute Myeloid Leukemia AML 7+3 chemotherapy 5+2 chemotherapy Daunorubicin Idarubicin Cytarabine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 301
Healthy volunteers: no

Brief summary:
The purpose of this study was to gather and evaluate additional safety and efficacy data on the combination of midostaurin and standard of care for adult patients with newly diagnosed Fms-like tyrosine kinase receptor (FLT3) mutated Acute Myeloid Leukemia (AML) who were eligible for standard induction and consolidation

Detailed description:
This Phase IIIb study was designed as a single arm study and allowed the assessment of variation of the "7+3" regimen in an extended patient population compared to RATIFY (higher dose of daunorubicin (60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), and lower dose of cytarabine (100-200 mg/m2/day) and the "5+2" reduced dose regimen). Safety was the primary endpoint. Complete Response (CR)/Complete remission with incomplete hematological recovery (CRi) in induction, consolidation and maintenance therapy was collected as secondary endpoint.

Patients who were newly diagnosed with AML, had a known FLT3 ITD (Internal tandem duplication) or TKD (Tyrosine kinase domain)(, mutation and had recently started on "7+3" or "5+2" in induction and high dose of cytarabine in consolidation were consented and screened for the clinical study.

.

The protocol treatment allowed the following treatment phases:

* Induction Phase: cytarabine with anthracycline (idarubicin or daunorubicin) sequentially per HCP choice, followed by midostaurin on day 8. In the first Induction phase, a bone marrow aspiration was performed in all subjects on Days 21- 28 (according to local standard of care) to determine the need for a second induction cycle. If the marrow aspirate was inadequate to make a determination, the bone marrow assessment was repeated within one week. If the Day 21-28 (according to local standard of care) bone marrow aspiration reveals ≥ 5% leukemic blasts in a cellular marrow (\> 20%) a second induction was given. For subjects requiring a second induction, treatment began at least 3 days after completing midostaurin. Bone marrow aspiration was performed within one week after recovery of ANC ≥ 1000/μL and platelets ≥ 100,000/μL to assess for response. Subjects in CR proceeded to consolidation therapy. Subjects not achieving a marrow remission (or with persistent blasts) were to be removed from protocol therapy. Subjects with CRi proceeded to consolidation therapy as per investigator's discretion. 1 or 2 cycles of "7+3" or "5+2" regimens (switching between regimens was not allowed).
* Consolidation Phase (for subjects in CR/CRi after consolidation therapy) (up to four cycles of cytarabine consolidation per investigator's discretion, with midostaurin given sequentially during each cycle): Based upon the superior results reported for AML subjects less than 60 years old with normal karyotypes in prospective clinical trials and RATIFY, who achieved a CR/CRi after induction received further therapy with midostaurin. Subjects received up to four cycles of consolidation therapy. Each consolidation cycle was four weeks in duration, and was to begin within two weeks following hematologic recovery (ANC ≥ 1000/μL, platelet count ≥ 100,000/μL), but not sooner than 31 days from the beginning of the previous cycle. A bone marrow aspiration was to be performed prior to the first consolidation cycle (C1D1) and later could be performed if necessary per investigator's decision at any time during Consolidation Phase.
* Maintenance Phase (for subjects in CR/CRi after consolidation therapy): Subjects who continued in CR/CRi (by bone marrow aspiration and blood evaluation) after four cycles of consolidation therapy received midostaurin. Prior to maintenance therapy, all significant acute toxicity from consolidation therapy was to be resolved to ≤ grade 2. Subjects with CRi proceeded to maintenance therapy as per investigator's discretion and for CR subjects maintenance therapy began after hematologic recovery (ANC ≥ 1000/μL, platelet count ≥ 100,000/μL) from remission consolidation, and at least 3 days after the last dose of midostaurin during consolidation. Subjects who were unable to complete four courses of HiDAC consolidation because of toxicity could still be eligible for maintenance therapy at the discretion of the principal investigator after the last dose of consolidation after recovery from hematologic and other significant acute toxicity. A bone marrow examination was to be performed prior to the first maintenance and every 3 months during Maintenance phase. Maintenance phase was up to 12 cycles of maintenance therapy with single-agent midostaurin or until relapse, unacceptable toxicity, or death, physician's decision, subject/guardian's decision, protocol deviation, study termination by sponsor, lost to follow-up, technical problems, pregnancy, subject withdrew consent or until the end of study, whichever event occured first.

Arms:
arm 1: Patients went through 3 phases:

Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles

Interventions: intervention 1: Midostaurin intervention 2: Cytarabine intervention 3: anthracycline ((daunorubicin or idarubicin): Induction Phase only
Intervention descriptions: intervention 1: Induction Phase: 50 mg (two 25 mg capsules) twice a day by mouth on days 8-28, for 1 - 2 cycles; a cycle = 28 days; Consolidation Phase: 50 mg (two 25 mg capsules) twice a day by mouth on days 8-28, for up to 4 cycles; Maintenance Phase: Continuous dosing (days 1 - 28) for up yo 12 cycles or until relapse, unacceptable toxicity, death, physician's decision, subject/guardian decision, protocol deviation, study termination by Sponsor, lost to follow-up, technical problems, pregnancy, subject withdrew consent, or until the end of study, whichever event occurred first. intervention 2: Induction Phase (standard dose) (7 + 3 arm): 100-200 mg/m2/day by Continuous intravenous infusion (CIVI) days 1-7 (168 hours infusion); Induction Phase (5 + 2 arm): 100 mg/m2/day by CIVI days 1-5; Consolidation Phase: 1-3 g/m2 infusion over 3 hours every 12 h on days 1, 3 and 5, up to 4 cycles based on age and per investigator discretion intervention 3: daunorubicin (7 + 3 arm): 60-90 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); daunorubicin (5 + 2 arm): 60 mg/m2/day by IV push on days 1-2; idarubicin (7 + 3 arm): 12 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); idarubicin (5 + 2 arm): 12 mg/m2/day by IV push on days 1-2

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................12
1
Background........................................................................................................................15
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............15
1.2
Introduction to investigational treatment(s) and other study treatment(s).............16
1.2.1
Overview of midostaurin.......................................................................16
2
Rationale............................................................................................................................21
2.1
Study rationale and purpose...................................................................................21
2.2
Rationale for the study design ...............................................................................22
2.3
Rationale for dose and regimen selection..............................................................22
2.4
Rationale for choice of combination drugs............................................................25
2.5
Rationale for choice of comparators drugs............................................................25
2.6
Risks and benefits..................................................................................................25
3
Objectives and endpoints...................................................................................................26
4
Study design ......................................................................................................................27
4.1
Description of study...............................................................................................27
4.2
Timing of interim analyses and design adaptations...............................................29
4.3
Definition of end of study......................................................................................29
4.4
Early study termination..........................................................................................29
5
Population..........................................................................................................................30
5.1
Patient population..................................................................................................30
5.2
Inclusion criteria ....................................................................................................30
5.3
Exclusion criteria...................................................................................................30
6
Treatment...........................................................................................................................32
6.1
Study treatment......................................................................................................32
6.1.1
Dosing regimen.....................................................................................32
6.1.2
Ancillary treatments..............................................................................33
6.1.3
Rescue medication ................................................................................33
6.1.4
Guidelines for continuation of treatment ..............................................33
6.1.5
Treatment duration................................................................................33
6.2
Dose escalation guidelines.....................................................................................34


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6.2.1
Starting dose rationale...........................................................................34
6.2.2
Provisional dose levels..........................................................................34
6.2.3
Guidelines for dose escalation and determination of midostaurin........34
6.3
Dose modifications................................................................................................34
6.3.1
Dose modification and dose delay ........................................................34
6.3.2
Dose modifications and management of toxicity during induction, 
consolidation therapy ............................................................................34
6.3.3
Dose modifications and management of toxicity during 
maintenance therapy..............................................................................35
6.3.4
Daunorubicin- dose modifications for hepatotoxicity...........................36
6.3.5
Cytarabine - dose modifications for neurotoxicity................................36
6.3.6
Dose modification for obese patients....................................................36
6.3.7
Anticipated risks and safety concerns of the study drug.......................36
6.3.8
Follow-up for toxicities.........................................................................37
6.4
Concomitant medications ......................................................................................38
6.4.1
Permitted concomitant therapy .............................................................38
6.4.2
Permitted concomitant therapy requiring caution and/or action...........39
6.4.3
Prohibited concomitant therapy ............................................................41
6.4.4
Use of bisphosphonates (or other concomitant agents).........................41
6.5
Patient numbering, treatment assignment or randomization .................................41
6.5.1
Patient numbering .................................................................................41
6.5.2
Treatment assignment ...........................................................................41
6.5.3
Treatment blinding................................................................................41
6.6
Study drug preparation and dispensation...............................................................41
6.6.1
Study treatment packaging and labeling ...............................................42
6.6.2
Drug supply and storage........................................................................42
6.6.3
Study drug compliance and accountability ...........................................42
6.6.4
Disposal and destruction .......................................................................43
7
Visit schedule and assessments .........................................................................................43
7.1
Study flow and visit schedule................................................................................43
7.1.1
Molecular pre-screening........................................................................48
7.1.2
Screening...............................................................................................48
7.1.3
Run-in period ........................................................................................49
7.1.4
Treatment period...................................................................................49
7.1.5
Discontinuation of study treatment .......................................................51
7.1.6
Withdrawal of consent ..........................................................................52
7.1.7
Follow up for safety evaluations...........................................................52


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7.1.8
Lost to follow-up...................................................................................53
7.2
Assessment types...................................................................................................53
7.2.1
Efficacy assessments.............................................................................53
7.2.2
Safety and tolerability assessments.......................................................55
7.2.3
Pharmacokinetics ..................................................................................57
7.2.4
Biomarkers............................................................................................58
7.2.5
Resource utilization...............................................................................58
58
8
Safety monitoring and reporting........................................................................................59
8.1
Adverse events.......................................................................................................59
8.1.1
Definitions and reporting ......................................................................59
8.1.2
Laboratory test abnormalities................................................................60
8.1.3
Adverse events of special interest.........................................................61
8.2
Serious adverse events...........................................................................................61
8.2.1
Definitions.............................................................................................61
8.2.2
Reporting...............................................................................................61
8.3
Emergency unblinding of treatment assignment ...................................................62
8.4
Pregnancies............................................................................................................62
8.5
Warnings and precautions......................................................................................63
8.6
Data Monitoring Committee..................................................................................63
8.7
Steering Committee ...............................................................................................63
9
Data collection and management.......................................................................................63
9.1
Data confidentiality ...............................................................................................63
9.2
Site monitoring ......................................................................................................64
9.3
Data collection.......................................................................................................64
9.4
Data management and quality control ...................................................................64
10 Statistical methods and data analysis ................................................................................65
10.1
Analysis sets ..........................................................................................................65
10.1.1
Full Analysis Set ...................................................................................65
10.1.2
Safety set ...............................................................................................65
10.1.3
Per-Protocol set .....................................................................................65
10.1.4
Dose-determining analysis set...............................................................65
10.1.5
Pharmacokinetic analysis set.................................................................66
10.1.6
Other analysis sets.................................................................................66
10.2
Patient demographics/other baseline characteristics .............................................66
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................66


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10.4
Primary objective...................................................................................................66
10.4.1
Variable.................................................................................................66
10.4.2
Statistical hypothesis, model, and method of analysis..........................67
10.4.3
Handling of missing values/censoring/discontinuations.......................67
10.4.4
Supportive and sensitivity analyses ......................................................67
10.5
Secondary objectives .............................................................................................67
10.5.1
Key secondary objective(s)...................................................................67
10.5.2
Other secondary efficacy objectives .....................................................67
10.5.3
Safety objectives ...................................................................................67
10.5.4
Pharmacokinetics ..................................................................................69
10.5.5
Biomarkers............................................................................................69
10.5.6
Resource utilization...............................................................................69
69
10.6
Exploratory objectives...........................................................................................69
69
10.6.2
Resource utilization...............................................................................70
10.7
Interim analysis......................................................................................................70
10.7.1
Progression free survival (PFS) ............................................................70
10.7.2
Key secondary endpoint: Overall survival (OS)...................................70
10.8
Sample size calculation..........................................................................................70
10.9
Power for analysis of key secondary variables......................................................70
11 Ethical considerations and administrative procedures ......................................................71
11.1
Regulatory and ethical compliance........................................................................71
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................71
11.3
Informed consent procedures.................................................................................71
11.4
Discontinuation of the study..................................................................................72
11.5
Publication of study protocol and results...............................................................72
11.6
Study documentation, record keeping and retention of documents.......................72
11.7
Confidentiality of study documents and patient records .......................................73
11.8
Audits and inspections...........................................................................................73
11.9
Financial disclosures..............................................................................................73
12 Protocol adherence ............................................................................................................73
12.1
Amendments to the protocol..................................................................................74
13 References (available upon request)..................................................................................75
14 Appendices ........................................................................................................................77


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List of figures
Figure 4-1
Study design..........................................................................................28
Figure 4-2
Recovery periods...................................................................................29
List of tables
Table 3-1
Objectives and related endpoints ..........................................................27
Table 6-1
Dose and treatment schedule – Induction .............................................32
Table 6-2
Dose and treatment schedule – Consolidation ......................................32
Table 6-3
Dose and treatment schedule – Maintenance........................................33
Table 6-4
Daunorubicin hepatoxicity dose modifications.....................................36
Table 6-5
Preparation and dispensing ...................................................................42
Table 6-6
Supply and storage of study treatments ................................................42
Table 7-1
Visit evaluation schedule ......................................................................44
Table 7-2
ECOG Performance status ....................................................................55
Table 7-3
Local clinical laboratory parameters collection plan ............................56
Table 10-1
Probability to detect at least one patient with an AE for different 
sample sizes and different true AE incidences......................................70




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NCCN
National Comprehensive Cancer Network
NOEL
No observable effect level
NPM1
Nucleophosmin (nucleolar phosphoprotein B23)
NYHA
New York Heart Association
ORR
Overall Response Rate
OS
Overall survival
P-gp
P glycoprotein
PHI
Protected Health Information
QTc
Corrected QT Interval
R Value
ALT / ALP in x ULN
REB
Research Ethics Board
RT
Radiation therapy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCT
Stem Cell Transplantation
TBIL
Total Bilirubin
TKD
Tyrosine kinase domain
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, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
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
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Patient Number (Patient No. 
NOVDD) Subject Number 
(Subject No. NCDS)
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
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, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not want any further visits or assessments, 
and does not want any further study related contact


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Amendment 1 (26-Mar-2018)
Amendment rationale 
The primary purpose of this amendment is 3 folds.
The first is to allow the use of historical bone marrow aspiration (BMA) result performed for 
AML diagnosis if available within 15 days before C1D1 of the first chemotherapy, in order to 
limit the repetition on this invasive assessment.
The second is an adaptation of the recovery periods in induction phase and the first cycle of 
consolidation based on the RATIFY study results analysis (Figure 4-2).
The third is to align between Section 5.3 exclusion criteria #8 and Section 6.4.1.2 
Contraceptives with midostaurin, the duration of the post study contraception to 4 months, as 
per approved midostaurin labeling information.
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.

Section 2.2: Rationale for the study design. To explain the change of administration of 
Midostaurin in comparison with the label (Day 21 --> Day 28). This change is considered 
as non-substantial.

Table 6-2: Dose and treatment schedule – Consolidation. Cytarabine dose, route and 
frequency has been updated with infusion over 3 hours every 12h on days 1, 3 and 5, up to 
4 cycles based on age and per investigator discretion. This change is considered as non-
substantial.

Section 6.3.4.1: Cytarabine – dose modifications for neurotoxicity section number has 
been updated to 6.3.5. This change is considered as non-substantial.

Section 6.3.4.2.: Dose modification for obese patients: section number has been updated to 
6.3.6. This change is considered as non-substantial.

Section 6.3.5: Anticipated risks and safety concerns of the study drug section has been 
updated to 6.3.7. This change is considered as non-substantial.

Section 6.3.6: Follow-up for toxicities: section number has been updated to 6.3.8. This 
change is considered as non-substantial.

Section 6.3.6.1: Follow up on potential drug-induced liver injury (DILI) cases: section 
number has been updated to 6.3.8.1. This change is considered as non-substantial.

Section 6.4.1.2: Contraceptives with midostaurin. The duration of the post study 
contraception has been increased from 3 months to 4. This change is considered as 
substantial.

Table 7-1: Visit evaluation schedule. A screening period has been defined within the 
screening/baseline visit between C1D1-C1D7. This change is considered as non-
substantial.


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
Section 7.1.2: Screening. To allow investigators to use the BMA result used for AML 
diagnosis if available within 15 days before C1D1 of the first chemotherapy. This change 
is considered as substantial.

Section 7.2.1: Efficacy assessments. During the first induction therapy a period window of 
7 days has been added for the bone marrow assessment. This change is considered as
substantial.

Section 7.2.1: Efficacy assessments. Within the second induction therapy paragraph the 
notion of “if applicable” has been added for a better understanding. This change is 
considered as non-substantial.

Section 7.2.2.5.3: Pregnancy and assessments of fertility. Paragraph aligned with safety 
follow up requirement, pregnancy test requires day 1 of every cycles in maintenance 
phase. This change is considered as substantial. 

Section 11.3: Informed consent procedures. The last paragraph starting with; “Women of 
child bearing potential...” has been updated mentioning that: “the patients must adhere to 
the contraception requirement for the duration of the study, and after treatment stop.” This 
change is considered as non-substantial.
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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Protocol summary
Title
An open-label, multi-center, Phase IIIb study to assess the safety and efficacy of 
midostaurin (PKC412) in patients 18 years of age or older with newly-diagnosed 
FLT3-mutated Acute Myeloid Leukemia who are eligible for “7+3” or “5+2” 
chemotherapy
Brief title
Study to assess the safety and efficacy of midostaurin (PKC412) in combination 
with standard chemotherapy during induction and consolidation followed by 12 
months of monotherapy in patients with newly-diagnosed FLT3-mutated Acute 
Myeloid Leukemia
Sponsor and
Clinical Phase
Novartis Pharma AG
Phase IIIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to gather and evaluate additional safety and efficacy 
data on the combination of midostaurin and standard of care for adult patients with 
newly diagnosed Fms-like tyrosine kinase receptor (FLT3) mutated Acute Myeloid 
Leukemia (AML) who are eligible for standard induction and consolidation
Primary Objective(s) and 
Key Secondary Objective
To further assess the safety of midostaurin in induction, consolidation and 
maintenance therapy, including, the “7+3” regimen, daunorubicin (60-
90mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day) and 
cytarabine (100-200 mg/m2/day) and allowing the “5+2” reduced dose regimen
Secondary Objectives
To assess the clinical efficacy of midostaurin in combination with chemotherapy 
regimens in induction and consolidation and the clinical efficacy of midostaurin in 
maintenance phase (measured by CR/CRi rate)
Study design
A global, open-label, single arm, multicenter, Phase IIIb study to assess the safety 
and efficacy of midostaurin (PKC412)
Population
Approximately 300 patients will be enrolled. This protocol is intended for patients 
(male and female) 18 years of age or older with newly-diagnosed FLT3-mutated 
AML who are eligible for “7+3” or “5+2” chemotherapy
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1.
Written informed consent must be obtained prior to any screening procedures
2.
Patients must be 18 years of age or older at the time of signing informed 
consent
3.
Patients must have a documented unequivocal diagnosis of AML according to 
WHO 2008 classification. A bone marrow or blood blast count of ≥20% is 
required, except for AML with t(15;17), t(8;21), inv(16) or t(16;16) where blast 
count may be <20%,and excluding M3 (acute promyelocytic leukemia)
4.
Patients with secondary AML are eligible, e.g. patients with antecedent history 
of treatment for prior malignancy. AML patients with a history of antecedent 
treatment for myelodysplasia (MDS), e.g. azacitidine or decitabine, remain 
eligible for treatment on this study. These agents must have been 
discontinued for a period of at least 30 days or 5 half-lives of the drug 
(whichever is greater) before midostaurin can be administered
5.
Patients must have started “7+3” or “5+2” first induction chemotherapy 
regimen
6.
Patients must have a documented FLT3 mutation (ITD or TKD)
7.
Patients must have an ECOG Performance Status of ≤ 2
8.
Patients requiring intrathecal chemotherapy must have a minimum washout of 
48 hours prior to the first dose of midostaurin
9.
Patients must have Total Bilirubin ≤ 2.5 x ULN
10. Patients must have Serum Creatinine ≤ 2.5 x ULN
11. Patients must be able to communicate well with the investigator to understand 
and comply with the requirements of the study


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12. Women of child-bearing potential must have a negative pregnancy test before 
starting use of midostaurin.
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1.
Prior therapy for AML with the following exceptions:
a.
emergency leukapheresis
b.
emergency treatment for hyperleukocytosis with hydroxyurea for ≤7 days
c.
cranial RT for CNS leukocytosis (one dose only)
d.
growth factor/cytokine support
2.
Patients with Left Ventricular Ejection Fraction (LVEF) less than 45% (by 
echocardiogram or MUGA) or symptomatic congestive heart failure (Class III 
or IV) according to New York Heart Association (NYHA) classification
3.
Patients with any pulmonary infiltrate including those suspected to be of 
infectious origin (unless resolved to < Grade 1 within screening timeframe)
4.
Patients with any uncontrolled illness, including, but not limited to, acute or 
chronic pancreatitis or uncontrolled infection
5.
QTc >470 msec on screening ECG
6.
History of hypersensitivity to any drugs or metabolites of similar chemical
classes as the study treatment
7.
Participation in a prior investigational interventional (drug) study with 
administration of the investigational product within 30 days or 5 half-lives of 
the investigational product, whichever is longer
8.
Pregnancy statements and contraception requirements:
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and for at least 4 months after stopping medication. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle 
of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy), total hysterectomy, or tubal ligation at least six 
weeks before taking study treatment. In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow 
up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized
male partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device or intrauterine system, 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 also add a barrier method of 
contraception, particularly as it is currently unknown whether midostaurin may 
reduce the effectiveness of hormonal contraceptives
Sexually-active males unless they use a condom during intercourse with females of 
reproductive potential or pregnant women and for at least 4 months after stopping 
treatment to avoid conception or embryo-fetal harm
9.
Patients enrolled in this study are not permitted to participate in additional 
parallel study drug or device studies
Investigational and 
reference therapy
Midostaurin (PKC412)
Efficacy assessments
Efficacy of midostaurin used with chemotherapy regimens in induction, 
consolidation and maintenance phases will be assessed by CR/CRi rate.




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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults, with an 
estimated incidence in the United States of 4.1 per 100,000 (approximately 20,000 new cases 
per year) (SEER 2016). The incidence increases with age, with more than 50% of AML patients 
being over 60 years old. The majority of patients with AML die from the disease, with an 
estimated 10,000 AML-related deaths occurring annually in the United States, i.e. 
approximately 2% of cancer deaths. In the European Union, based on data from 
RARECARE.net, the number of cases collected in the RARECAREnet database from 2000-
2007 was 54,789 and the crude incidence rate was 3.5 per 100,000 (RARECARE.net October 
2015). Acute Myeloid Leukemia shows heterogeneous molecular characteristics with the 
presence of acquired mutations as well as cytogenetic and epigenetic alterations that influence 
disease prognosis.
Mutations in the FMS-like tyrosine kinase-3 (FLT3) gene are found in approximately one third 
of patients with newly diagnosed AML, and these comprise internal tandem duplications (ITD) 
in 20% of patients, point mutations in the tyrosine kinase domain (TKD) in 6-8% of patients, 
and very rarely point mutations in the juxtamembrane domain (Kayser and Levis 2014). 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 precursor cells. FLT3-ITD 
and FLT3-TKD mutations constitutively activate its receptor tyrosine kinase activity and 
thereby activate downstream signaling pathways (Meshinchi and Appelbaum 2009). FLT3-ITD 
mutations, particularly when they are present at a high allelic ratio relative to wild-type FLT3, 
are associated with poor prognosis (Thiede et al 2002, Gale et al 2008, Schlenk et al 2014).
For the past three decades, the standard therapy for younger patients with newly diagnosed 
AML, regardless of their cytogenetic and molecular markers, has been the “7+3”remission-
induction regimen with cytarabine and daunorubicin followed by high-dose cytarabine for 
remission-consolidation. Studies showed that modification of the induction chemotherapy 
regimen resulted in little additional benefit for patients with high-risk AML, including patients 
with FLT3-mutations. Patients with poor prognostic features, including those with FLT3-ITD 
mutations, are recommended to enroll into clinical studies and/or to undergo stem cell 
transplantation (SCT) following achievement of remission with standard induction 
chemotherapy. Significant improvements in overall survival (OS) and disease-free survival 
(DFS) for AML patients harboring FLT3-ITD mutations have been reported with allo-SCT 
compared to consolidation with chemotherapy or autologous SCT (Kayser et al 2009), 
especially for patients with FLT3-ITD mutations with a high allelic ratio (Schlenk et al 2014). 
Because of the adverse prognostic impact of FLT3 gene mutations and the lack of effective 
therapy, there is a significant unmet need in patients with FLT3-mutated AML.


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1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of midostaurin
Midostaurin, also known as PKC412 or CGP41251, is an orally administered inhibitor of 
multiple tyrosine kinases, including the wild-type (WT) and mutated fms-like tyrosine kinase-
3 (FLT3) and others implicated in the pathogenesis of AML, including the KIT tyrosine kinase 
(KIT), and tyrosine kinase receptors such as the vascular endothelial growth factor receptor 
(VEGFR), and Platelet-derived growth factor receptor (PDGFR).
1.2.1.1
Non-clinical experience
1.2.1.1.1 Non-clinical pharmacokinetics
Midostaurin is an inhibitor of several protein kinase C (PKC) isoforms, of the tyrosine kinase 
VEGFR and most importantly of the class III tyrosine protein kinases FLT3 and KIT which are 
involved in hematopoiesis and play a key role in certain hematopoietic disorders. Midostaurin 
binds to the catalytic domain of these kinases and inhibits the mitogenic signaling of the 
respective growth factors in cells and results in growth arrest. Midostaurin is equally active 
against ITD- and TKD-mutated FLT3, and has been shown to exert inhibitory activity over 
mutated protein kinases implicated in other types of diseases, such as the proto-oncogene 
encoding KIT in aggressive systemic mastocytosis (ASM).
The oral absorption of [14C]midostaurin in all species was moderate to high and the 
bioavailability was low to moderate. Given midostaurin’s low aqueous solubility (<0.001 
mg/mL) and its high absorption in human (>90%), midostaurin is classified as a 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 indicating that midostaurin was 
distributed to tissues. The half-life was relatively short in animals (3.2-7.3 h). In human the 
apparent terminal half-life was relatively long (~20 h) following a single oral dose.
Radioactivity derived from [14C]midostaurin was extensively distributed into tissues in the rat.
The concentrations in most tissues were higher than that in blood, 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, indicating no potential protein binding replacement in vivo with its metabolites.
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 


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a major human circulating metabolite and detectable in the dog and rabbit. The total recovery 
of radioactivity was high in the rat, rabbit, dog and human (81.5% - 99.4%). In all these species, 
radioactivity was mainly excreted via fecal excretion. Renal excretion was apparently very 
minor (<4%).
Based on recombinant enzymes and human liver microsomes, cytochrome P450 3A4 enzyme
(CYP3A4) is the major enzyme involved in midostaurin oxidative metabolism. Midostaurin 
appears to have little inhibitory effect on in-vitro activities associated with CYP enzymes, 1A2, 
2C8, 2C9, 2C19, 2D6, and 2E1. However, inhibition of CYP3A4 (probe substrate: midazolam 
1’-hydroxylation) is observed with a half maximal inhibitory concentration (IC50) value of 
approximately 1.5 μM. With estimated clinical plasma concentrations being above the present 
IC50 concentrations, it is possible that midostaurin and/or the main metabolites could inhibit the 
metabolic clearance of comedications metabolized by CYP3A4. Midostaurin is a P-
glycoprotein (P-gp) inhibitor with IC50 value of 1.7 μM thus its concomitant use with P-gp 
substrates could lead to clinical drug-drug interactions. Midostaurin drug transport inhibition 
experiments indicated that midostaurin is not likely to be a substrate of P-gp, (multidrug 
resistance associated protein 2), and is not actively taken up into the liver.
1.2.1.1.2 Toxicology
Midostaurin has been extensively evaluated in various in vitro systems and in vivo models.
Studies relevant to clinical dosing of midostaurin include repeat dose toxicology studies with 
durations of up to 52 weeks, genetic toxicology, reproductive and developmental toxicity, 
juvenile toxicity and safety pharmacology studies. Additional toxicology studies have been 
performed with the combination of midostaurin and daunorubicin/Ara-C (cytarabine). No 
carcinogenicity studies have been performed.
Overall, the effects of treatment with midostaurin observed in the toxicology studies have been 
essentially limited to those expected from an inhibitor of cell proliferation. The no observable 
effect level (NOEL) in the 12-month toxicity studies was 3 mg/kg in rat and 1 mg/kg in dog. In
vitro and in vivo mutagenicity tests revealed no genotoxicity. There was no teratogenic effect 
noted from embryo-fetal development studies in rats and rabbits.
Developmental toxicity was seen at 10 mg/kg or higher. NOEL for fertility and general 
reproductive toxicity was defined at 30 mg/kg.
Treatment with midostaurin at doses ≥3 mg/kg in dogs and ≥10 mg/kg in rats at durations up to 
12 months was associated with effects on proliferating tissues, especially the intestine (mucosal 
alteration), testes (degenerated spermatogonia), and bone marrow (hypocellularity).
The effect on the bone marrow was accompanied by hematological changes (decreased total 
white cells, lymphocytes and erythrocytic parameters).
In conclusion, preclinical safety data obtained from various toxicology studies performed with 
midostaurin support further clinical development of midostaurin.


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1.2.1.2
Clinical experience
1.2.1.2.1 Pharmacokinetics and drug metabolism in humans
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 (99L) 
is higher than that of total body water (42 L), indicating a high tissue distribution. Midostaurin 
is mainly eliminated by metabolism via fecal excretion. Midostaurin is predominantly 
metabolized by CYP3A4 into two major active circulating metabolites, CGP62221 (via O-
demethylation) and CGP52421 (via hydroxylation).
The major circulating components in plasma are CGP52421, CGP62221 and midostaurin, 
accounting for 38, 28, and 22% of AUC0-168h, respectively with geometric mean terminal 
half-lives of midostaurin, CGP62221 and CGP52421 in plasma after a single dose, are 19.6, 
32.2 and 482 h.
The compound related materials are mainly distributed to plasma, and minimally to red blood 
cells. The mean apparent plasma clearance of midostaurin is low (3.71 L/h). The recovery in 
excreta is 81.6% of the dose.
The in-vivo drug-drug interaction studies indicated that midostaurin and its metabolites are 
metabolized by CYP3A4.
1.2.1.2.2 Clinical studies
Overall 502 healthy 
volunteers and 1902 patients have been enrolled into the 
Novartis-sponsored midostaurin clinical program, of which 383 of healthy volunteers and 
1462 patients (includes 294 patients who were enrolled and received midostaurin in the 
integrated Third Party study, [CPKC412ADE02T] - AMLSG 16-10) have received midostaurin 
as a single agent and in combination with standard antineoplastic chemotherapeutic regimens.
The clinical development of midostaurin is currently focused on two indications:

As a single agent in patients with ASM or mast cell leukemia (MCL) with or without an
associated hematologic non-mast cell lineage disorder

In combination with standard chemotherapy in patients with newly diagnosed FLT3 
mutated AML
Study [CPKC412D2201], the largest clinical trial performed in ASM/MCL, enrolled 116 
patients. In 89 patients who were eligible for response assessments, the ORR was 60%; most 
responses were major responses (40/53, 75%). With a median follow-up of 43 months (range 
29-70m), the median duration of response and median OS were 31.4 and 26.8 months 
respectively. Median OS in responders was 33.9 months. Of 16 MCL patients, 8 responded, 
including 7 MRs (44%). Median OS was 9.4 months among all patients with MCL and not yet 
reached among responders.
Midostaurin demonstrated single agent activity in AML/MDS patients with FLT3 mutations 
(Study A2104).
In a phase Ib trial (Study [CPKC412A2106]), promising data for complete remissions (CRs) in 
AML patients, particularly those with FLT3-mutated AML, were observed with midostaurin. 


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The study investigated different doses and schedules of midostaurin in combination with 
daunorubicin and cytarabine induction and high-dose cytarabine consolidation therapy in 
younger (age 18-60) patients with newly-diagnosed AML. At the best tolerated dose of 50 mg 
b.i.d. on days 8-21, CRs occurred in 32/40 (80%) of all patients, 20/27 (74%) of FLT3-WT 
patients, and 12/13 (92%) of FLT3-mutant patients. One and 2 year overall survival for the 
patients with FLT3-mutant AML were 85% and 62%, respectively; these values were 
comparable to those of the FLT3-WT subgroup (81% and 59%, respectively), suggesting that 
the addition of midostaurin to chemotherapy may improve outcomes for newly diagnosed 
younger patients with FLT3-mutant AML (Stone et al 2012). Overall, the tolerability of the 
midostaurin 50 mg b.i.d dosing regimen was better than that of the 100 mg b.i.d dosing regimens 
in both treatment arms. In addition to a lower rate of discontinuation with the lower midostaurin 
dose, certain AEs were less severe with 50 mg b.i.d dose; there were no GI toxicity SAEs 
(nausea, vomiting, diarrhea) in the 50 mg b.i.d dose cohort in either arm, nor were there SAEs 
associated with increases in liver function test results (ALT, AST, bilirubin)
Furthermore, sequential administration of chemotherapy and midostaurin appeared to be better 
tolerated overall than concomitant administration. Based on these data, the sequential 
administration schedule with midostaurin 50 mg b.i.d is considered to be the recommended 
regimen for subsequent clinical investigation in patients with AML.
This data inspired the phase III RATIFY pivotal trial (CPKC412A2301) in this patient 
population.
RATIFY study (CPKC412A2301/CALGB 10603)
The efficacy and safety of midostaurin in combination with standard chemotherapy has been 
further investigated in newly diagnosed AML with FLT3 mutation patients in the pivotal phase 
III, randomized, placebo-controlled RATIFY trial (Stone et al 2015).
The primary end point of the study is overall survival (OS), not censored for stem cell 
transplantation (SCT). The key secondary endpoint is event-free survival (EFS). Other 
secondary endpoints include OS censored for SCT, complete remission (CR) rate, disease-free 
survival (DFS), DFS rate one year after completing the planned therapy, safety, and population 
pharmacokinetics.
719 patients were randomized in RATIFY Study. 717 patients were included in the analyses, 
360 patients were randomized to the midostaurin arm, 357 to the placebo arm. The primary 
endpoint, OS non-censored at the time of SCT, showed a statistically significant difference 
(p=0.0078) at a one-sided alpha level of 0.0239 that favored midostaurin treatment. Midostaurin 
reduced the risk of death vs placebo by 23% (HR, 0.774 [95% CI, 0.629-0.953]). The estimated 
probability of being alive at 3 years (36 months) was higher in the midostaurin arm compared 
to the placebo arm (54% [95% CI: 0.49, 0.59] vs 47% [95% CI: 0.41, 0.52]). The protocol-
defined CR rate within 60 days of initiation of protocol therapy was 58.9% in the midostaurin 
arm and 53.5% in the placebo arm (p=0.073, one-sided p-value). In the midostaurin arm, more 
patients had a CR after induction Cycle 1 (51.7%) than in the placebo arm (43.1%). In a 
sensitivity analysis that considered an expanded CR definition of all CRs occurring during the 
induction phase (including CRs that occurred outside of the 60-day window), the CR rate was 
65.0% in the midostaurin arm and 58.0% in the placebo arm (p=0.027, one-sided p-value). The 


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primary DFS analysis was aligned with the key secondary EFS endpoint analysis and included 
patients who achieved a CR by Day 60 after study treatment initiation. DFS was measured from 
the date of first CR to the date of relapse or death from any cause, whichever occurred first. 
Median DFS was 26.7 months (19.35, NE) in the midostaurin arm and 15.5 months (11.33, 
23.46) in the placebo arm (HR=0.71; 95% CI: 0.55, 0.92; p=0.0051 one-sided).
The sensitivity analysis considering all CRs during induction reflects more accurately the 
benefit of midostaurin. The median DFS was 28.1 months in the midostaurin arm and 14.1 
months in the placebo arm (HR=0.66; 95% CI: 0.52, 0.85; p=0.0006 one-sided).
Remission duration was measured from the date of first CR to relapse or death due to AML 
(CR within 60 days of study treatment start, uncensored at the time of SCT), whichever occurred 
first. Patients who died from other causes without relapse were censored. The median duration 
of remission for midostaurin was 61.0 months (95% CI: 21.68, NE) and 22.2 months (95% CI: 
14.13, NE) for the placebo arm. The risk of relapse or death due to AML for patients in the 
midostaurin arm who had achieved a CR was reduced by 26% (HR=0.74; 95% CI: 0.56, 0.99) 
compared to those who had achieved a CR in the placebo arm.
Censoring for SCT, the median remission duration was 20.27 months (16.43, NE) in the 
midostaurin arm versus 17.58 months (9.63, NE) in the placebo arm, a reduction of 20% 
(HR=0.80; 95% CI: 0.58, 1.11) in the risk of relapse or death due to AML.
Anti-fungal agents are commonly administered to AML patients receiving intensive induction 
and consolidation therapy; 61%, 46% and 11% of patients in this study received antifungal 
agents during the induction, consolidation and continuation phase, respectively.
Because midostaurin is metabolized by CYP3A4, potent CYP3A4 inhibitors (e.g., some 
antifungal medications) may represent a potential for drug-drug interactions. Upon co-
administration with CYP3A4 inhibitors, an increase in concentration of 1.44-fold is observed 
for midostaurin exposure in RATIFY (CPKC412A2301).
This increase of exposure did not impact the benefit-risk balance of midostaurin in AML 
treatment, and therefore are deemed not clinically relevant. Based on these data, no change in 
dose is required when midostaurin is co-administered with CYP3A4 inhibitors.
Midostaurin was generally well tolerated. Most of the AEs, AEs suspected to be related to study 
drug, SAEs, and AEs leading to study discontinuation occurred due to the underlying disease 
at similar frequencies in both treatment groups. Adverse events not related to hematological 
toxicities were generally of grade 1 or 2 severity. Grade 3/4 exfoliative dermatitis and grade 3/4 
device related infections occurred more frequently (>5%) in the midostaurin group than in the 
placebo group. Fewer patients in the midostaurin group than in the placebo group died on 
treatment due to causes other than disease progression (15 patients vs 21 patients, respectively).
On treatment deaths suspected to be related to study drug were balanced between the treatment 
groups (2.6% and 2.1%), and included sepsis (2 patients), multi-organ failure, infectious colitis, 
acute respiratory failure, colitis, myocardial infarction, neutropenic sepsis, pulmonary 
hemorrhage and septic shock in the midostaurin treatment group (one patient each).
The results of this study indicate that the addition of midostaurin 50 mg b.i.d to standard 
chemotherapy followed by up to one year of single-agent continuation treatment significantly 
decreases mortality in patients aged 18 to <60 years with newly-diagnosed FLT3-mutated AML.


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Although more than 50% of patients in both arms underwent SCT, survival analyses censored 
for SCT, as well as analyses of survival post-CR1 SCT demonstrated a significant benefit for 
these patients.
These outcomes support a positive benefit-risk profile for midostaurin 50 mg b.i.d, both, in 
combination with standard induction/consolidation chemotherapy and as a subsequent single-
agent continuation therapy for up to 12 months for patients in remission.
Elderly study data
Study [CPKC412ADE02T] (AMLSG 16-10) conducted in Germany, a Phase-II third party 
study, evaluated midostaurin in induction, consolidation and maintenance therapy also after 
allogeneic blood stem cell transplantation in patients with newly diagnosed acute myeloid 
leukemia (AML) exhibiting FLT3 internal tandem duplication. The preliminary data from this 
study of 149 patients (patients ≥18 and ≤70 year, median age 54 years, 32% ≥ 60 years)
demonstrated that the addition of midostaurin to intensive induction therapy and as maintenance 
after Allogeneic Hematopoietic Stem Cell Transplantation or High Dose Ara-Cytarabine 
(HiDAC) is feasible and seems to be effective without an impact of age in comparison to 
historical group. This study is the most relevant experience in elderly patients demonstrating a 
favorable benefit/risk profile (Schlenk et al 2016).
2
Rationale
2.1
Study rationale and purpose
AML is amongst the most challenging hematological malignancies to treat, and patients with 
activating FLT3 mutations have a particularly poor prognosis and often relapse or are refractory 
to current treatment options. There is a high unmet medical need in this patient population. 
Initial therapy for AML to induce remission has changed little in the past 25 years, and for 
patients with an adequate performance status, it comprises cytarabine and an anthracycline, 
followed by post-remission therapy with additional intensive chemotherapy or with SCT. AML 
patients carrying FLT3 mutations, particularly ITD mutations, have a poor prognosis with a 
high risk of relapse. Midostaurin is a novel tyrosine kinase inhibitor that has been studied in a 
large, randomized, double-blind study of midostaurin 50 mg b.i.d vs placebo in combination 
with standard induction/consolidation chemotherapy conducted in patients with newly 
diagnosed, FLT3-mutated (ITD or TKD) AML (Study [CPKC412A2301]/RATIFY). The 
primary endpoint of RAFITY study was overall survival (OS). With positive Phase III data 
supporting the efficacy of midostaurin in newly-diagnosed FLT3-mutated AML, the purpose of 
this new Phase IIIb is to further evaluate the safety and efficacy of midostaurin in induction, 
consolidation and maintenance therapy in patients 18 years of age or older with newly 
diagnosed FLT3 mutated AML.
The age limit for patients in the Phase III RATIFY trial (CPKC412A2301) was 60 years old. 
This protocol allows enrollment of patients beyond age 60, and the “5+2” regimen will permit 
per physician’s decision inclusion of patients above 70 years old.


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2.2
Rationale for the study design
Considering the limited safety impact and the significant clinical benefit of the addition of 
midostaurin to the standard “7+3” regimen in the RATIFY study (CPKC412A2301), this Phase 
IIIb study is designed as a single arm study and allows the assessment of variation of the “7+3” 
regimen in an extended patient population compared to RATIFY (higher dose of daunorubicin 
(60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), and lower 
dose of cytarabine (100-200 mg/m2/day) and the “5+2” reduced dose regimen). Safety is the 
primary endpoint. CR/CRi (see Section 7.2.1) in induction, consolidation and maintenance 
therapy is collected as secondary endpoint.
Patients who are newly diagnosed with AML, have a known FLT3 ITD or TKD, mutation and 
have recently started on “7+3” or “5+2” in induction and high dose of cytarabine in 
consolidation will be consented and screened for the clinical study.
While standard chemotherapy may be initiated at the investigator’s discretion during screening, 
the patient must be enrolled prior to completion of induction chemotherapy (by day 8) and 
midostaurin added on day 8.
No age limitation:
Based on Walter (2015), Klepin (2013), Klepin (2014), and Ossenkoppele (2015), this protocol 
allows enrollment of patients beyond age 60 for both “7+3” and “5+2”, as it is common real-
world practice to offer standard induction therapy to elderly patients. As there is not a standard 
definition of fitness, the decision depends on the clinical judgement of the investigator 
according to the local guidelines.
Preliminary data from [CPKC412ADE02T - AMLSG 16-10] clinical study (patients ≥18 and 
≤70 years, 34% ≥60 years) demonstrated that in patients with AML FLT3 ITD positive the 
combination of midostaurin to intensive induction therapy and as maintenance after Allo HSCT 
or HiDAC is feasible and more effective in comparison to AML historical group (Schlenk et al 
2016).
Additionally, patients who can’t tolerate the intensive chemotherapy due to age or toxicity can 
receive “5+2” regimen per the investigator’s discretion.
2.3
Rationale for dose and regimen selection
The dosing regimen in this study is midostaurin 50 mg b.i.d, in combination with standard 
chemotherapy sequentially in induction and consolidation therapy and as a single-agent in 
maintenance therapy.
In a Phase 1, open-label, dose-escalation study [CPKC412A0002], midostaurin was evaluated 
in adult patients with non-hematologic malignancies.
The maximum tolerated dose could not be reached. However, based on the drop-outs at 225-
300 mg daily dose due to gastrointestinal (GI) toxicity, and the maximum acceptable number 
of 12 capsules for the dosing of 300 mg/day, the maximum feasible dose for practical purposes 
in this population was regarded as 225-300mg/day even though no dose-limiting toxicity was 
observed.


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In two single-agent clinical studies with midostaurin [CPKC412A2104] (75 mg, three times 
daily) and [CPKC412A2104E1] (50 mg b.i.d or 100 mg b.i.d), bone marrow or peripheral blood 
blast responses ≥50% were observed in 70% and 42% of patients with FLT3-mutant (N=55) 
and FLT3–wild-type (N=60) AML, respectively.
Overall survival was similar for the 50 mg b.i.d and 100 mg b.i.d doses. Overall, there was a 
similar level of biological activity of midostaurin in the mutated FLT3 and wild-type FLT3 
patients at either the 50 mg b.i.d or 100 mg b.i.d doses and in the FLT3-mutated patients treated 
at either 100 mg b.i.d (200 mg daily) or 75 mg three times daily (225 mg daily) doses.
Furthermore, the study [CPKC412A2104E2]
indicated that there were no obvious 
improvements in clinical response in patients with AML receiving midostaurin doses higher 
than 50 mg b.i.d, suggesting that increasing midostaurin exposure beyond 50 mg b.i.d would 
not necessarily produce discernable evidence of increased efficacy.
In Study [CPKC412A2106], a total of 69 AML/MDS patients (n=34 in arm 1; n=35 in arm 2) 
were enrolled to explore the safety, tolerability, PK and preliminary clinical efficacy of the two 
arms/regimens below:

Sequential administration of midostaurin with daunorubicin and cytarabine

Concomitant administration of midostaurin with daunorubicin and cytarabine
The choice of the sequential regimen, rather than simultaneous regimen of midostaurin, was 
based on the following:

Cell culture data showed that simultaneous administration of a FLT3 inhibitor with or 
after cytarabine enhanced cytotoxic effects, whereas exposure of cells to FLT3 inhibitors 
before cytarabine (i.e. midostaurin followed by cytarabine) had antagonistic effects on 
cytotoxicity (Levis et al 2003). Therefore, the simultaneous regimen would have the 
potential for an antagonistic interaction that the sequential regimen clearly avoids.

Study PKC412A2106 investigated the administration of midostaurin 50 mg b.i.d or 100 
mg b.i.d, sequentially or concomitantly with induction chemotherapy. The midostaurin 50 
mg b.i.d sequential regimen was the preferred investigational regimen for AML in the 
current study based on the favorable safety and tolerability profile.
Based on the initial activity and the acceptable safety and tolerability profile, a dose of 50 mg 
b.i.d midostaurin in combination with standard chemotherapy was believed to provide a 
reasonable risk-benefit balance, and was selected for the Phase III Study [CPKC412A2301]
(RATIFY).
In order to achieve IC50 values at steady state and allow the most tolerable dosing, the dose for
patients receiving midostaurin on this current study will be 50mg b.i.d, i.e., the same dose used 
in the RATIFY trial (Stone et al 2015). For patients unable to tolerate the proposed dose, dose 
adjustments are outlined in Section 6.3.
Choice of chemotherapy – (“7+3” or “5+2”)
Standard chemotherapy 7+3 or 5+2 includes induction and consolidation therapies


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“7+3”
RATIFY study demonstrated that the addition of midostaurin to standard chemotherapy “7+3” 
followed by 12 cycles of maintenance therapy with midostaurin alone significantly improved 
EFS and OS in both uncensored and censored for transplant analyses.
In this Phase IIIb study, newly diagnosed AML patients will receive “7+3” induction therapy 
with cytarabine (100-200mg/m2) and daunorubicin (60-90mg/m2) (or idarubicin 12 mg/m2/day) 
as defined by NCCN treatment guidelines.
“5+2”
The “5+2” regimen consists of similar regimen as “7+3” with reduced duration to 5 and 2 days, 
respectively. “5+2” is used in advanced age to prevent toxicity and/or increase tolerability.
The “5+2” regimen will be allowed for patients who were not able to receive the 7+3, per 
physician’s decision.
Midostaurin treatment between Day 8 to Day 28
Enrolled patients will subsequently receive oral midostaurin 50 mg (two 25 mg capsules) twice 
a day on days 8-28 of a 28 day cycle. Midostaurin treatment is extended to D28, the end of each 
cycle, compared with RATIFY dose regimen ending at D21.
In Study [CPKC412ADE02T] (AMLSG 16-10), patients received midostaurin 50 mg, orally 
twice daily in addition to standard induction and consolidation and as single agent in 
maintenance therapy also after allogeneic blood cell transplantation, midostaurin demonstrate 
acceptable toxicity and confirmed a similar safety profile and a high rate of complete remission.
In this study the use of midostaurin was extended until 48 hours before the start of the next 
cycle, demonstrating that an increase in the exposure to midostaurin increases the potential 
response. 
In [CPKC412A2408] study, the use of midostaurin was therefore extended to day 28 of each 
cycle in induction and consolidation phases (midostaurin administration from day 8 to day 28 
of each cycle).
No new safety findings have been revealed in the study.
Maintenance therapy
Standard therapy of adults with AML does not routinely involve a maintenance phase after 
completion of consolidation. However, published data suggested that the detection of minimal 
residual disease in AML patients with FLT3 mutations predicted rapid relapse once 
chemotherapy was completed (Kottaridis et al 2001). Therefore, the continued administration 
of an oral, non-cytotoxic drug such as midostaurin post-chemotherapy could continue to inhibit 
growth or even kill residual FLT3-mutated blasts present at the end of a routine course of 
chemotherapy, thereby potentially prolonging OS and DFS. In RATIFY, when assessed from 
the start of maintenance therapy, a benefit of midostaurin treatment on OS was seen (HR 0.80). 
Similarly, DFS was assessed from the start of the maintenance phase. Prior to one year, the 
Kaplan-Meier curves remain superior in the midostaurin arm however after one year (when all 
patients would no longer be receiving midostaurin) the curves cross, and DFS events occur 


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more frequently on the midostaurin arm. Although the relapse rate was similar in the two arms 
during continuation therapy, the secondary endpoint of DFS one year after completion of 
maintenance therapy demonstrated that patients on the midostaurin arm relapsed quickly once 
maintenance therapy was stopped. This data may support maintenance of midostaurin until 
relapse (particularly given the good tolerability and safety).
Approval by the US Food and Drug Administration has been received in April 2017 for using 
midostaurin in newly diagnosed AML patients who are FLT3 mutation positive in combination 
with standard cytarabine and daunorubicin induction and cytarabine consolidation (Rashidi et 
al 2016).
2.4
Rationale for choice of combination drugs
For patients’ ≤ 60 years of age with newly diagnosed AML, the standard chemotherapy 
induction regimen for the past two decades has been an anthracycline and cytarabine, followed 
by consolidation with high-dose cytarabine. More details on the cytarabine/anthracycline 
induction and cytarabine consolidation regimens can be found in the NCCN guidelines 
(Updated version 1.2017: NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid 
Leukemia). The induction regimen of cytarabine and daunorubicin/idarubicin used in this Phase 
IIIb study is similar to that used in the clinical studies with midostaurin, the Phase 1b study 
[CPKC412A2106] (Stone et al 2012) and the Phase 3 study (RATIFY ([CPKC412A2301]) 
(Stone et al 2015)
A placebo will not be used in this study.
2.5
Rationale for choice of comparators drugs
Not Applicable
2.6
Risks and benefits
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, and close clinical monitoring. There may be unforeseen risks with study 
treatment which could be serious.
The risk and benefit have been identified in the [PKC412A2106] and RATIFY’ studies 
([CPKC412A2301]).
The phase Ib study (A2106) investigated different doses and schedules of midostaurin in 
combination with daunorubicin and cytarabine induction and high-dose cytarabine 
consolidation therapy in 69 patients with newly-diagnosed AML. At the best tolerated dose of 
50 mg b.i.d CRs occurred in 32/40 (80%) of all patients, 20/27 (74%) of FLT3-WT patients, 
and 12/13 (92%) of FLT3-mutant patients. One and 2-year overall survival (OS) for the patients 
with FLT3–mutant AML were 85% and 62%, respectively, and were comparable to those of 
the FLT3–WT subgroup (81% and 59%, respectively). These data were based on small numbers 
and were not stratified for type of FLT3 mutation (i.e. TKD vs ITD, ITD length, location, or 
allelic ratio) (Stone et al 2009, Stone et al 2012).
With the recommended sequential treatment schedule (where midostaurin is started on day 8 
after the completion of chemotherapy), AEs reported in ≥ 50% of patients included 


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hematological AEs (thrombocytopenia, neutropenia, febrile neutropenia) and nausea, diarrhea, 
vomiting, pyrexia, hypokalemia, chills, and headache. The most frequent grade 3 and grade 4 
AEs were hematological AEs (thrombocytopenia, neutropenia, febrile neutropenia, anemia, and 
leukopenia). Grade 3 non-hematological AEs reported in >10% of patients in either arm were 
those associated with GI toxicity (nausea, vomiting), increases in liver function test results 
(ALT, AST, bilirubin), electrolyte imbalance (hypocalcemia, hypokalemia, hypophosphatemia), 
and pyrexia, hypoxia, and device-related infection. One on-treatment death was reported in the 
study. The patient died due to fungal infection associated with multi-organ failure that was not 
considered to be related to study drug by the Investigator. AEs that led to discontinuation were 
reported for 8.8% of patients (5% with 50 mg b.i.d, and 14% with 100 mg b.i.d).
The data available for midostaurin in acute myeloid leukemia (AML), taken from early stage 
single agent and combination trials, indicates a favorable benefit- risk profile that was 
confirmed in the randomized phase III RATIFY trial ([CPKC412A2301]; CALGB 10603). 
RATIFY data confirm the significant improvement of the overall survival for the midostaurin 
arm and the safety profile identified in the A2106 study. (RATIFY data summary Section 
1.2.1.2).
It should be recognized that the assessment of causality is challenging in AML patients given 
the combination with standard chemotherapy, the complexity of the clinical presentation of the 
disease, and the use of multiple concomitant medications.
In summary, the expected benefit (with an improvement of overall survival) support a positive 
benefit-risk profile for midostaurin 50 mg b.i.d, both, in sequential combination with standard 
induction/consolidation chemotherapy and as a subsequent single agent maintenance therapy 
for up to 12 months for patients in remission.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.




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problems, pregnancy, subject withdrew consent or until the end of study, whichever event 
occurs first.
The estimated study duration is about 3.5 years, including about 18 months for recruitment and 
around 18 to 25 months for completion of the induction, consolidation and maintenance therapy.
Figure 4-1
Study design


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Figure 4-2
Recovery periods
4.2
Timing of interim analyses and design adaptations
Not Applicable
4.3
Definition of end of study
The study will end around 18 to 25 months after LPFV depending on number of cycles and 
recovery durations. Study treatment will be provided until disease progression, death, 
unacceptable toxicities, physician’s decision, subject/guardian’s decision, protocol deviation, 
study termination by sponsor, lost to follow-up, technical problems, pregnancy, patient 
withdrew consent or until the end of study, whichever event occurs first. Patients will be 
contacted for safety evaluations. All patients must have safety evaluations for 30 days, after the 
last dose of study treatment except if consent was withdrawn. Patients who present CR/CRi 
may be eligible for transplant. Patients who undergo SCT will have midostaurin discontinued 
prior to conditioning for transplantation, and will be removed from the study following 
completion of scheduled safety monitoring.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 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. Patients who discontinue study 
treatment, including those who refuse to return for a final visit will be contacted for safety 
evaluations during 30 days following the end of treatment. All patients must have safety 
evaluations for 30 days, after the last dose of study treatment except if consent was withdrawn.


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5
Population
5.1
Patient population
The patient population will consist of male or female individuals, aged 18 years or older with 
newly diagnosed AML and must have documented FLT3 mutations (ITD or TKD) and have 
started “7+3” or “5+2” first induction chemotherapy to be eligible for the study. 300 patients 
are expected to be enrolled into this trial.
5.2
Inclusion criteria
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.
Inclusion Criteria:
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Patients must be 18 years of age or older at the time of signing informed consent.
3. Patients must have a documented unequivocal diagnosis of AML according to WHO 2008 
classification. A bone marrow or blood blast count of ≥20% is required, except for AML 
with t(15;17), t(8;21), inv(16) or t(16;16) where blast count may be <20%, and, excluding 
M3 (acute promyelocytic leukemia).
4. Patients with secondary AML are eligible, e.g., patients with antecedent history of 
treatment for prior malignancy. AML patients with a history of antecedent treatment for 
myelodysplasia (MDS), e.g., azacitidine or decitabine, remain eligible for treatment on 
this study. These agents must have been discontinued for a period of at least 30 days or 5 
half-lives of the drug (whichever is greater) before midostaurin can be administered.
5. Patients must have started “7+3” or “5+2” first induction chemotherapy regimen.
6. Patients must have a documented FLT3 mutation (ITD or TKD).).
7. Patients must have an ECOG Performance Status of ≤ 2
8. Patients requiring intrathecal chemotherapy must have a minimum washout of 48 hours 
prior to the first dose of midostaurin
9. Patients must have Total Bilirubin ≤ 2.5 x ULN
10. Patients must have Serum Creatinine ≤ 2.5 x ULN
11. Patients must be able to communicate well with the investigator to understand and comply 
with the requirements of the study
12. Women of child-bearing potential must have a negative pregnancy test before starting use 
of midostaurin.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Prior therapy for AML with the following exceptions:
a. emergency leukapheresis
b. emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days


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c. cranial RT for CNS leukostasis (one dose only)
d. growth factor/cytokine support
2. Patients with LVEF less than 45% (by echocardiogram or MUGA) or symptomatic 
congestive heart failure (Class III or IV) according to New York Heart Association 
(NYHA) classification
3. Patients with any pulmonary infiltrate including those suspected to be of infectious origin 
(unless resolved to ≤Grade 1 within screening timeframe)
4. Patients with any uncontrolled illness, including, but not limited to, acute or chronic 
pancreatitis or uncontrolled infection
5. QTc >470 msec on screening ECG (Fridericia’s formula)
6. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the 
study treatment.
7. Participation in a prior investigational interventional (drug) study with administration of 
the investigational product within 30 days or 5 half-lives of the investigational product, 
whichever is longer.
8. Pregnancy statements and contraception requirements:
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for at least 4 months after stopping medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device or intrauterine system, 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 also add a barrier method of contraception, 
particularly as it is currently unknown whether midostaurin may reduce the effectiveness of 
hormonal contraceptives.
Sexually-active males unless they use a condom during intercourse with females of 
reproductive potential or pregnant women and for at least 4 months after stopping treatment to 
avoid conception or embryo-fetal harm.
9. Patients enrolled in this study are not permitted to participate in additional parallel study 
drug or device studies.


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6
Treatment
6.1
Study treatment
Patients will have started first induction chemotherapy with cytarabine (Days 1-7) and 
daunorubicin (or idarubicin) (Days 1-3) or cytarabine (Day 1-5), daunorubicin (or idarubicin) 
(Days 1-2). Patients will start midostaurin on Day 8 up to Day 28, for 1-2 cycles, consolidation 
with cytarabine (Days 1, 3, 5) plus midostaurin (Days 8-28) for up to 4 cycles, and continuous 
dosing of midostaurin (Days 1-28) for up to 12 cycles (maintenance phase) or until relapse, 
unacceptable toxicity, death physician’s decision, subject/guardian’s decision, protocol 
deviation, study termination by sponsor, lost to follow-up, technical problems, pregnancy, 
subject withdrew consent or until the end of study, whichever event occurs first.
Patients treated with 7+3 or 5+2 per investigator’s discretion may not be switched from 7+3 to 
5+2 and vice versa.
Investigational drug refers to any Novartis study drug(s) whose properties are being tested in 
the study. For this study, the term “Investigational drug” refers to midostaurin (PKC412) 
supplied in 25 mg soft gelatin capsules which are packaged in blister packs.
Study treatment includes any drug or combination of drugs administered to the patient (subject) 
as part of the required study procedures.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule – Induction
Treatment
Dose, route and frequency (based on 28-day cycles)
Standard-dose cytarabine* 
with anthracycline* 
(idarubicin or daunorubicin) 
(7+3)
Ara-C:100-200 mg/m2/day by CIVI days 1-7 (168 hours infusion)
daunorubicin: 60-90 mg/m2/day by IV push on days 1-3
Or idarubicin: 12 mg/m2/day by IV push on days 1-3
Cytarabine* with 
anthracycline* (idarubicin or 
daunorubicin) (5+2)
Ara-C:100 mg/m2/day by CIVI days 1-5
daunorubicin 60 mg/m2/day by IV push on days 1-2
Or idarubicin: 12 mg/m2/day by IV push on days 1-2
Midostaurin
50 mg (two 25 mg capsules) twice a day by mouth on days 8-28
Patients should take their doses at approximately the same time each day, and 
approximately 12 hours should elapse between doses. Each daily 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 
before the next scheduled dose.
Table 6-2
Dose and treatment schedule – Consolidation
Treatment
Dose, route and frequency (based on 28-day cycles)
Cytarabine*
1-3 g/m2 infusion over 3 hours every 12 h on days 1, 3 and 5, up to 4 cycles based 
on age and per investigator discretion
Midostaurin
50 mg (two 25 mg capsules) twice a day by mouth on Days 8-28.
Patients should take their doses at approximately the same time each day, and 
approximately 12 hours should elapse between doses. Each daily 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 
before the next scheduled dose.


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Table 6-3
Dose and treatment schedule – Maintenance
Treatment
Dose, route and frequency (based on 28-day cycles)
Midostaurin
50 mg (two 25 mg capsules) twice a day by mouth on days 1-28, for 12 cycles or 
until relapse, unacceptable toxicity, or death. Patients should take their doses at 
approximately the same time each day, and approximately 12 hours should elapse 
between doses. 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.
*Treatment formulation availabilities depend on countries marketing authorization as a local 
commercial supply is used.
6.1.2
Ancillary treatments
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, allopurinol, etc., when appropriate. The use of aprepitant is not 
permitted.
Treatment with hormones or other chemotherapeutic agents may not be administered except for 
steroids given for adrenal failure; and hormones administered for non-disease-related 
conditions (e.g., insulin for diabetes). Steroids may be used to treat and/or prevent 
hypersensitivity reactions or transfusion reactions.
Brief use of corticosteroids as anti-emetics is permitted but not recommended in these 
immunocompromised patients. Their use must be reported in patient records.
Myeloid growth factors should not be used routinely or prophylactically, but are permitted as 
indicated by the ASCO guidelines for neutropenic patients with prognostic factors that are 
predictive of clinical deterioration such as pneumonia, hypotension, multi-organ dysfunction 
(sepsis syndrome) or fungal infection (Smith 2015). The use of CSF (filgrastim, PEG-filgrastim, 
or sargramostim) must be documented and reported in the patient’s records. The use of epoetin 
or darbepoetin (EPO) in this protocol is permissible but not recommended.
6.1.3
Rescue medication
Not Applicable
6.1.4
Guidelines for continuation of treatment
Not Applicable
6.1.5
Treatment duration
The study treatment may last approximately 18 months; in addition there are recover periods, 
and up to 30 days follow-up for safety evaluation. The study may last up to 25 months after 
LPFV depending on number of cycles and recovery durations.
Patients may receive up to 3 phases of treatment:

Induction: up to 2 cycles (28 days of treatment/cycle and recovery periods)

Consolidation: up to 4 cycles (28 days of treatment/cycle and recovery periods)

Maintenance: up to 12 cycles (28 days of treatment/cycle )


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Patients may receive treatment as outlined in the study schema (Figure 4-1 and Figure 4-2).
6.2
Dose escalation guidelines
Not Applicable
6.2.1
Starting dose rationale
Not Applicable
6.2.2
Provisional dose levels
Not Applicable
6.2.3
Guidelines for dose escalation and determination of midostaurin
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 adjustments are 
permitted in order to allow the patient to continue the study treatment. The following guidelines 
may be applied:
A patient must discontinue treatment with midostaurin (PKC412) if, after treatment is resumed 
at a lower dose, the toxicity recurs with the same or worse severity.
Patients who discontinue the study for a study related adverse event or an abnormal laboratory 
value must be followed as described in Section 7.1.5.
These changes must be recorded on the Dosage Administration Record eCRF.
6.3.2
Dose modifications and management of toxicity during induction, 
consolidation therapy
6.3.2.1
Hematologic toxicity
There will be no dose modifications for hematologic toxicity due to midostaurin.
6.3.2.2
Pulmonary toxicity >/= grade 3
For ≥ grade 3 pulmonary infiltrate, interrupt midostaurin and resume with midostaurin 50 mg 
twice daily when infiltrates resolve to ≤ grade 1. Missed doses of midostaurin will not be made 
up.
6.3.2.3
Cardiac toxicity
For QTc interval >470 ms and ≤ 500 ms, check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medication, which may prolong the QTc interval. 
Decrease midostaurin to 50 mg once daily until QTc interval improves to ≤ 470 ms, and then 
resume midostaurin with 50 mg twice daily.


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For QTc interval > 500 ms, immediately stop midostaurin, check magnesium and potassium 
levels and correct any abnormalities. If possible, stop any medication, which may prolong the 
QTc interval Re-start with midostaurin 50 mg once daily if QTc interval is between >470ms 
and ≤ 500 ms. Once QTc interval improves to ≤ 470 ms, resume midostaurin with 50mg twice 
daily. If QTc interval remains > 470 ms for more than three weeks, discontinue midostaurin 
until QTc improves to < 470 ms, then resume midostaurin with 50 mg twice daily.Missed doses 
of midostaurin will not be made up.
6.3.2.4
Other non-hematologic toxicities
If a patient experiences other grade 3/4 non-hematologic toxicity, which is considered to be at 
least possibly related to midostaurin, midostaurin must be interrupted until toxicity resolves to 
≤ grade 1. Missed doses of midostaurin will not be made up.
6.3.3
Dose modifications and management of toxicity during maintenance 
therapy
6.3.3.1
Hematologic toxicity
In the presence of grade 4 neutropenia during maintenance therapy, midostaurin must be held 
until ANC ≥ 1000/μL. Once ANC ≥ 1000/μL, then resume midostaurin at the previous dose. If 
neutropenia persists for more than two weeks, then discontinue midostaurin protocol.
6.3.3.2
Pulmonary toxicity >/= grade 3
For ≥ grade 3 pulmonary infiltrate, interrupt midostaurin and resume with midostaurin 50 mg 
twice daily when infiltrates resolve to ≤ grade 1. Missed doses of midostaurin will not be made 
up.
6.3.3.3
Cardiac toxicity
For QTc interval >470ms and ≤ 500 ms, check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medication, which may prolong the QTc interval. 
Decrease midostaurin to 50 mg once daily until QTc interval improves to ≤ 470 ms, and then 
resume midostaurin with 50 mg twice daily.
For QTc interval > 500 ms, immediately stop midostaurin, check magnesium and potassium 
levels and correct any abnormalities. If possible, stop any medication, which may prolong the
QTc interval Re-start with midostaurin 50 mg once daily if QTc interval is between >470ms 
and ≤ 500 ms. Once QTc interval improves to ≤ 470 ms, resume midostaurin with 50 mg twice 
daily. If QTc remains > 470 ms for more than three weeks, discontinue midostaurin until QTc 
improves to < 470 ms, then resume midostaurin with 50 mg twice daily. Missed doses of 
midostaurin will not be made up.
6.3.3.4
Other non-hematologic toxicities
If a patient experiences other grade 3/4 non-hematologic toxicity, which is considered to be at 
least possibly related to midostaurin, midostaurin must be interrupted until toxicity resolves to 


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≤ grade 2. If midostaurin is held for more than 28 days, then discontinue midostaurin. Missed 
doses of midostaurin will not be made up.
Persistent grade 1 or 2 toxicities during maintenance therapy that patients may deem 
unacceptable may prompt drug holidays of as long as 28 days. No drug holidays longer than 28 
days are allowed. Missed doses of midostaurin will not be made up.
6.3.4
Daunorubicin- dose modifications for hepatotoxicity
Initial and subsequent doses of daunorubicin should be modified as follows for hepatotoxicity:
Table 6-4
Daunorubicin hepatoxicity dose modifications
Total bilirubin (mg/dl)
Daunorubicin Dose Modification
Grade < 2
None
Grade ≥ 2 and ≤ 3
25% dose reduction
Grade > 3
50% dose reduction
6.3.5
Cytarabine - dose modifications for neurotoxicity
For neurotoxicity ≥ grade 2 due to cytarabine during consolidation therapy, discontinue 
cytarabine for the remainder of the cycle. Cytarabine may be considered at the next 
consolidation therapy cycle with a dose modification from 3 g/m2 to 2 mg/m2 or from 2 g/m2 to 
1 g/m2 if the toxicity has resolved to ≤ grade 1.For patient receiving 1 g/m2, cytarabine may be 
discontinued at the discretion of the Investigator.
For a second occurrence of neurotoxicity ≥ grade 2, high-dose cytarabine should be permanently 
discontinued.
Contributions of other concomitant medications to neurotoxicity should be assessed and 
medications discontinued if possible.
6.3.6
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. The calculation is by 
the DuBois and DuBois formula: = 0.20247 x height (m)0.725 x weight (kg)0.425
Failure to use actual body weight in the calculation of drug dosages will be considered a major 
protocol deviation. Investigators who are uncomfortable with administering chemotherapy dose 
based on actual body weight should not enroll obese patients on this study.
6.3.7
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this study. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities are provided in Section 6.3.2 Refer 
to preclinical toxicity and or clinical data found in the [Investigator’s Brochure Section 4.3 and 
Section 5].


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6.3.8
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
laboratory abnormality above must be followed at least once a week (or more frequently if 
required by institutional practices, or if clinically indicated) during drug-hold and for 4 weeks, 
and subsequently at 4-week intervals, until resolution or stabilization of the event, or until the 
adverse event is considered permanent per investigators discretion, whichever comes first.
For adverse events and serious adverse events, patients will continue to be followed for toxicity 
for 30 days following the end of study treatment period.
6.3.8.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with Total Bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
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.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. 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.


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All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly
documented.
6.4
Concomitant medications
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. All medications taken within 28 days prior to 
enrollment and all concomitant medications/therapies must be recorded on the Prior and 
Concomitant Medications eCRF. Anticancer agents (e.g. chemotherapy, radiation therapy, or 
biologic response modifiers or FLT3 inhibitors) other than those agents specified in this 
protocol are not permitted.
6.4.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed on the Prior and Concomitant 
Medications or the Surgical and Medical Procedures eCRF.
6.4.1.1
Supportive care
In general, the use of any concomitant medication/therapies deemed necessary for patient 
supportive care and safety are permitted provided they are documented in the patient records.
6.4.1.1.1 Anti-emetic treatment with midostaurin
Nausea and vomiting are commonly reported in studies with midostaurin administration. These 
events are more frequent during combination therapy and are dose-dependent.
Prophylaxis for the prevention of nausea and vomiting is highly recommended. The kind and 
dose of anti-emetic drug should be chosen as per investigator discretion. Patients may be given 
ondansetron hydrochloride or granisetron. Other anti-emetics such as metoclopramide, 
methotrimeprazine, cyclizine, prochlorperazine or tropisetron may be used at the discretion of 
the investigator.
Since nausea (and in some cases vomiting) may still occur 1-3 hours after the dose, additional 
anti-emetics after midostaurin dosing may be required. In these cases, promethazine 
(phenergan), prochlorperazine (compazine), lorazepam (ativan) or other anti-emetics can be 
used ½ hour to 1 hour after midostaurin as per investigator discretion.
If patients suffer from Grade 3 or 4 severe nausea and/or vomiting, refer to Section 6.3.
6.4.1.1.2 Anti-diarrheal treatment with midostaurin
For the management of diarrhea, oral loperamide can be administered. An initial dose of 4 mg 
followed by 2 mg every 4 hours or after every unformed stool (maximum of 16 mg/day) is 


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suggested. However, the kind and dose of anti-diarrheal should be chosen per investigator 
discretion.
6.4.1.1.3 Liver toxicity management with midostaurin
As midostaurin is extensively metabolized by the liver, patients with significantly impaired liver 
function or with hepatic failure should not receive midostaurin. Monitoring of LFTs 
(transaminases and bilirubin) is recommended particularly when used in combination with 
chemotherapeutic regimens that are known to be associated with increased hepatic risk. Labels 
for both daunorubicin and cytarabine contain hepatotoxicity warnings.
6.4.1.1.4 Ocular toxicity management during consolidation
For the management of ocular toxicity during consolidation administer 0.1% Dexamethasone 
or other corticosteroid ophthalmic solution 2 drops to each eye 4 times a day to begin 6-12 hours
prior to the initiation of the cytarabine infusion and to continue for at least 24 hours after the
last cytarabine dose.
6.4.1.2
Contraceptives with midostaurin
Women must avoid breast-feeding during study treatment, and all women of childbearing 
potential will be required to employ a highly effective method of birth control, refer to Section 
5.3, which is defined as a birth control which results in a low failure rate (i.e. less than 1% per 
year) when used consistently and correctly. This has to be employed for the duration of the 
study and for 4 months post study because of the long half-life of the metabolite, CGP52421.
6.4.2
Permitted concomitant therapy requiring caution and/or action
6.4.2.1
Concomitant medications with potential for CYP3A4 interactions
6.4.2.1.1 Midostaurin can be impacted by CYP3A4 inhibitors and inducers:
Midostaurin is a sensitive substrate of CYP3A4. This indicates that the pharmacokinetics of 
midostaurin may be influenced by drugs that are inducers or inhibitors of CYP3A4.
6.4.2.1.2 Interactions with inhibitors of cytochrome P450 3A4
In a healthy volunteer drug-drug interaction study (A2109) where midostaurin was co-
administrated with the potent CYP450 3A4 inhibitor ketoconazole, at steady-state of 
ketoconazole, midostaurin Cmax increased by 1.8-fold, AUCinf by 10-fold.
Another study, [CPKC412A2104E2], evaluated two midostaurin dosing regimens with an intra-
patient dose escalation of midostaurin up to 600 mg/day (300mg b.i.d, N=12) and concomitant 
administration of midostaurin 50 mg b.i.d with itraconazole as an inhibitor of CYP3A4 
enzymatic activity in a subset of patients (N=12). The study could not establish a maximum 
tolerated dose, suggesting that exposure to a midostaurin dose of up to 600mg/day was deemed 
tolerable. Moreover, the itraconazole cohort of the study did not indicate overt increase in 
midostaurin steady-state concentration, as only three patients showed a 2-3 fold increase in their 
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Taken together, the data indicates that co-administration of strong CYP3A4 inhibitors with 
midostaurin has the potential to increase exposure of midostaurin.
Based on the above data, administration of concomitant strong CYP3A4 inhibitors with 
midostaurin should be avoided and alternative therapeutics, which does not strongly inhibit 
CYP450 3A4 activity, should be considered.
Please see Section 6.4.2.2 for the suggested antifungal regimens.
Here below is a list of strong CYP3A4 inhibitors:
clarithromycin, telithromycin, troleandomycin, indinavir, lopinavir, nelfinavir, ritonavir, 
saquinavir, tipranavir, itraconazole, ketoconazole, posaconazole, voriconazole, boceprevir, 
telaprevir, cobicistat, conivaptan, nefazodone.
A list of moderate CYP450 3A4 can be found on:
//medicine.iupui.edu/clinpharm/ddis/main-table/
6.4.2.1.3 Interactions with moderate and strong inducers of cytochrome P450 3A4
In a healthy volunteer drug-drug interaction study (A2110) where midostaurin was co-
administrated with the potent CYP450 3A4 inducer rifampicin, the Cmax and AUC of 
midostaurin decreased by 73% and 94%, respectively. To avoid sub-therapeutic exposure to 
midostaurin, moderate or potent CYP450 3A4 inducers should not be co-administered.
Strong CYP3A4 inducers: avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin), St. John's wort (hypericum perforatum).
Moderate CYP3A4 inducers: bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, 
ritonavir, talviraline, thioridazine, tipranavir.
6.4.2.1.4 Midostaurin not expected to affect the pharmacokinetics of other CYP3A4 
substrates:
In study A2112, Midostaurin at a single dose of 100 mg was administered concomitantly with 
midazolam on Day 3 and, then 50 mg twice daily from Day 4 to Day 6. Overall, the PK of 
midazolam (sensitive CYP34A probe) or its metabolite 1’-hydroxymidazolam were not affected 
in a clinically meaningful manner following four dosing days of midostaurin in healthy subjects.
As a result, midostaurin is neither a CYP3A4 inhibitor nor a CYP3A4 inducer in vivo in humans 
at clinically relevant conditions. Therefore, midostaurin is not expected to affect the 
pharmacokinetics of other CYP3A4 substrates.
6.4.2.2
Concomitant anti-infective prophylaxis and treatment
It is highly recommended to avoid concomitant strong CYP3A4 inhibitors (e.g. ketoconazole, 
itraconazole, voriconazole, posaconazole). The suggested antifungal regimens from a drug 
metabolism perspective are described below:
Prophylaxis

Fluconazole (moderate CYP3A4 inhibitor)


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
Micafungin
If a patient requires active treatment for a fungal or mold infection and the only treatment 
options is an azole that is a strong CYP3A4 inhibitor, then the suggested agents from a drug 
metabolism and safety perspective include:
Treatment

Voriconazole

Posaconazole
These are both strong CYP3A4 inhibitors and will likely increase midostaurin concentrations; 
therefore, patients should be monitored closely for signs of increased toxicity.
6.4.3
Prohibited concomitant therapy
There is no prohibited concomitant therapy, however, as described in Section 6.4.2, it is highly 
recommended to avoid concomitant strong CYP3A4 inhibitors.
6.4.4
Use of bisphosphonates (or other concomitant agents)
Not Applicable
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface.
Once assigned, the Patient No. must not be reused for any other patient and the Patient No. for 
that individual must not be changed, even if the patient is re-screened. If the patient fails to be 
dosed, the reason will be entered into the Screening Log page.
6.5.2
Treatment assignment
Patients who fulfill all entry criteria will receive midostaurin (investigational drug) on day 8 of 
the first induction cycle.
6.5.3
Treatment blinding
Not Applicable
6.6
Study drug preparation and dispensation
The Investigator or responsible site personnel must instruct the patient or caregiver to take the 
study treatment as per protocol. Study treatment will be dispensed to the patient by authorized 


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site personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
Table 6-5
Preparation and dispensing
Study treatments
Dispensing
Preparation
Midostaurin (PKC412)
Soft Gelatin Capsules (SGC) including 
instructions for administration are dispensed by 
study personnel on an outpatient basis.
Patients will be provided with adequate supply of 
study treatment for self-administration at home 
until at least their next scheduled study visit.
Not applicable
Daunorubicin
Not applicable
Refer to local product information
Idarubicin
Not applicable
Refer to local product information
Cytarabine
Not applicable
Refer to local product information
6.6.1
Study treatment packaging and labeling
Midostaurin will be provided as global supply by Novartis Drug Supply Management. 
Midostaurin will be supplied via a blister pack, with a study specific label. Labeling of these 
supplies will be done at global level under the responsibility of Novartis DSM.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and study number but no information 
about the patient.
6.6.2
Drug supply and storage
Study drug (midostaurin) 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, midostaurin should be stored according to 
the instructions specified on the drug labels and in the [Investigator’s Brochure].
Table 6-6
Supply and storage of study treatments
Study treatments
Supply
Storage
Midostaurin (PKC412)
Centrally supplied by Novartis
Per label requirements
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 Treating 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 


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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.
Please do not destroy any study drug until your monitor has had the opportunity to review your 
inventory and complete drug accountability reconciliation. If your site cannot destroy the drug 
locally, you can return it to a designated Novartis vendor for safe destruction. Please discuss 
this process with your monitor.
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.
Note: If treatment with midostaurin is withheld at any time, all study visits, and safety 
assessments should continue according to the appropriate study days from Day 1 of each cycle 
as per the schedule of assessments.
All data obtained from these assessments must be supported in the patient’s source 
documentation. No eCRF will be used as a source document. The table indicates which 
assessments produce data to be entered into the database (D) or remain in the source documents 
(S).
The number of cycles in each phase (induction, consolidation and maintenance) is decided on 
at the discretion of the investigator, based on the patient’s clinical status.


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Table 7-1
Visit evaluation schedule
Category
Protocol
Section
Screening 
/ Baseline
Induction Phase
Up to 2 cycles
(Pre-dose/cycle)
Consolidation Phase
Up to 4 Cycles
(pre-dose/cycle)
Maintenance 
Phase
Up to 12 Cycles
(pre-dose/cycle)
End of 
Study 
Treatment
30 Day 
Safety 
Follow 
up
Visit Name
(C1D1 -
C1D7)
C1D8 
Enrollment
C2D1
C2D8
C1D1
C1D8
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
C1D1 up to 
C12D1
Study day(s)
-1
1
Cycle Days
7
8
1
8
1
8
1
8
1
8
1
8
1
Last
Obtain 
Informed 
Consent
D
11.7.
X
Patient history
S
7.1.2.3.
X
Interactive 
Response 
Technology
9.4.
X
X
X
X
X
End of 
disposition
D
7.1.4.1. 
7.1.4.2.
Done prior C1D1 of this phase
Done prior C1D1 
of this phase
X
Demography
D
7.1.2.3.
X
Inclusion 
/exclusion 
criteria
D
5.2 and 
5.3.
X
Medical History
D
7.1.2.3.
X
Prior 
Antineoplastic 
/ Chemotherapy
D
7.1.2.3.
X
Diagnosis and 
extent of cancer
D
7.1.2.3.
X


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Category
Protocol
Section
Screening 
/ Baseline
Induction Phase
Up to 2 cycles
(Pre-dose/cycle)
Consolidation Phase
Up to 4 Cycles
(pre-dose/cycle)
Maintenance 
Phase
Up to 12 Cycles
(pre-dose/cycle)
End of 
Study 
Treatment
30 Day 
Safety 
Follow 
up
Visit Name
(C1D1 -
C1D7)
C1D8 
Enrollment
C2D1
C2D8
C1D1
C1D8
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
C1D1 up to 
C12D1
Study day(s)
-1
1
Cycle Days
7
8
1
8
1
8
1
8
1
8
1
8
1
Last
FLT3 mutation 
status known 
(ITD/TKD )
D
7.1.2.
X
NPM1 mutation
D
4.1.
NPM1 mutation status will be collected if available
Prior and 
Concomitant 
Medications
D
7.1.2.3.
X
X
X
X
X
Surgical and 
Medical 
Procedures
D
7.1.2.3.
X
X
X
X
X
Physical 
examination
S
7.2.2.1.
X
X
X
X
X
Height
D
7.2.2.3.
X
X
Weight
D
7.2.2.3.
X
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
ECOG 
Performance 
status
D
7.2.2.4.
X
X
Laboratory assessments (local lab)
Hematology
D
7.2.2.5.1
.
X
For CR/CRi assessments and when justified for the assessment of a treatment related AE or SAE and at 
physician’s discretion


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Category
Protocol
Section
Screening 
/ Baseline
Induction Phase
Up to 2 cycles
(Pre-dose/cycle)
Consolidation Phase
Up to 4 Cycles
(pre-dose/cycle)
Maintenance 
Phase
Up to 12 Cycles
(pre-dose/cycle)
End of 
Study 
Treatment
30 Day 
Safety 
Follow 
up
Visit Name
(C1D1 -
C1D7)
C1D8 
Enrollment
C2D1
C2D8
C1D1
C1D8
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
C1D1 up to 
C12D1
Study day(s)
-1
1
Cycle Days
7
8
1
8
1
8
1
8
1
8
1
8
1
Last
Chemistry
D
7.2.2.5.
X
When justified for the assessment of a treatment related AE or SAE and at physician’s discretion
Urinalysis
D
7.2.2.5.
X
Coagulation
D
7.2.2.5.
X
Blood 
transfusion
D
6.4.1.
To be captured in the eCRF during the study
Pregnancy 
test
D
7.2.2.5.3
Within 2 days prior to midostaurin dosing in induction and consolidation phase.
X
X
Chest x-ray
D
7.2.2.6.
X
ECG
D
7.2.2.7.1
X
X
X
X
X
X
X
X
Cardiac 
Imaging (LVEF)
D
7.2.2.7.2
X
When justified for the assessment of a treatment related AE or SAE and at physician discretion
X
Safety
Adverse events
D
8.1.
To be recorded continuously
Study treatment
Study treatment 
administration
D
6.6.
X
X
X
X
Other assessments


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Category
Protocol
Section
Screening 
/ Baseline
Induction Phase
Up to 2 cycles
(Pre-dose/cycle)
Consolidation Phase
Up to 4 Cycles
(pre-dose/cycle)
Maintenance 
Phase
Up to 12 Cycles
(pre-dose/cycle)
End of 
Study 
Treatment
30 Day 
Safety 
Follow 
up
Visit Name
(C1D1 -
C1D7)
C1D8 
Enrollment
C2D1
C2D8
C1D1
C1D8
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
C1D1 up to 
C12D1
Study day(s)
-1
1
Cycle Days
7
8
1
8
1
8
1
8
1
8
1
8
1
Last
Resource 
utilization
D
7.2.5.
X
X
Bone marrow 
aspiration
D
Please 
refers to 
Section 
7.1.2
To be performed between 
Day 21 to Day 28 at each 
cycle
Prior to first consolidation cycle C1D1, and if 
necessary per investigator’s decision during 
the consolidation phase
Prior to first 
maintenance 
cycle C1D1 and 
every 3 months
X
CR/CRi
D
7.2.1.
Day 21-28 for each 
induction cycle.
CR/CRi in induction, consolidation and 
maintenance therapy is collected as 
secondary endpoint. Prior to first consolidation 
cycle and If necessary per investigator’s 
decision during the consolidation phase
Prior to first 
maintenance 
cycle C1D1 and 
every 3 months
X


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7.1.1
Molecular pre-screening
Not Applicable
7.1.2
Screening
Patients who are newly diagnosed with AML, have a known FLT3 ITD or TKD mutation and 
who have already started a “7+3” or “5+2” chemotherapy regimen in first induction will be 
consented and screened during the screening/baseline period (between C1D1 (chemotherapy 
already started) to C1D7) at least all the activities should be completed at Day 7 of the first 
chemotherapy (at Day -1). Re-screening is not allowed in this study.
The historical BMA result used to diagnose AML to the patients can be considered a part of 
inclusion criteria in the study.
If an historical BMA is available within 15 days before C1D1 of the first chemotherapy there 
is no need to repeat this assessment during the screening/baseline period. 
If in case an historical BMA is not available within the 15 days before C1D1 of the first 
chemotherapy, a BMA should be performed during the screening/baseline period of the study.
7.1.2.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
Screening assessments should be performed at the time of the screening except for pregnancy 
test if result is available and negative within 7 days prior to screening, or for cardiac imaging 
and chest x ray if results are within 14 days prior to screening.
7.1.2.2
Information to be collected on screening failures
Patient who signed an Informed Consent Form but failed to start on midostaurin for any reason 
will be considered as a screen failure. The reason for not being started on midostaurin will be 
entered on the Screening Phase Disposition eCRF. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for Screen Failure patients. No 
other data will be entered into the clinical database for patients who are screen failures, unless 
the patient has a Serious Adverse Event during the Screening Phase (see Section 8.2 for SAE 
reporting details). The following eCRFs must be completed for screening failure patients:

Screening Phase Disposition page

Informed consent

Demography

Adverse Events (only if an SAE occurs. Refer to Section 8.2.)

Inclusion/Exclusion Criteria


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7.1.2.3
Patient demographics and other baseline characteristics
Baseline patient data pertaining to demographic information and relevant medical history 
related to study indication should be documented accordingly in the eCRFs including, but not 
limited to, the following information:

Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations)

Relevant medical history

Date of diagnosis

Physical Examination (Height, Weight, Vital Signs)

Performance status

FLT3 mutation status (ITD or TKD)

Bone marrow aspiration

Any additional mutation information, if known

Prior and Concomitant Medications

Surgical and Medical Procedures

Chemotherapy information from induction cycle 1 day 1 to day 7
Additionally all other medications and significant non-drug therapies taken within 28 days prior 
to the first dose of midostaurin being administered must be recorded on the eCRF page and 
updated on a continual basis if there are any new changes to the medication. Medications 
include Investigator prescriptions and over-the-counter medications, vitamins, and herbal and 
alternative therapies.
Information to be collected on concomitant medications/significant non-drug therapies will 
include the following:

Medication/Non-drug therapy trade name

Reason for medication

Start/End date and if continuing at time of examination
7.1.3
Run-in period
Not Applicable
7.1.4
Treatment period
Patients will begin midostaurin after completing all screening procedures and fulfilling all of 
the eligibility criteria. The study design is outlined in Figure 4-1 and Figure 4-2 by treatment 
phase; induction; consolidation; maintenance. Patients achieving CR/CRi following 1 to 2 
cycles of induction will continue to consolidation therapy for up to 4 cycles. Patients who 
maintain a CR/CRi following consolidation may continue to the maintenance phase up to 12 
cycles. The duration of each phase may vary based on investigator discretion. Patients will be 
treated on protocol for about 18 months. Patients may be removed from treatment due to 
unacceptable toxicity, disease progression, at the discretion of the Investigator, withdrawal of 
consent, or as explained in Section 7.1.3, whichever comes first.


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For details of assessments, refer to Table 7-1.
7.1.4.1
Induction phase
Newly diagnosed AML patients will receive “7+3” or “5+2” induction therapy with cytarabine 
and daunorubicin (or idarubicin) as defined by NCCN treatment guidelines (NCCN Guidelines 
v1.2017). Enrolled patients will subsequently receive oral midostaurin 50 mg (two 25 mg 
capsules) twice a day on days 8-28 (see Table 6-1). Patients should take their doses at 
approximately the same time each day, and approximately 12 hours should elapse between the 
morning and evening doses. Each daily dose should be given with food and a glass of water 
(~240 mL). Patients should be instructed to swallow capsules whole and not chew capsules. If 
vomiting occurs, no re-dosing is allowed prior to the next scheduled dose.
A switch between regimens is not allowed.
Refer to Table 6-1 for Induction treatment schedule.
Patients who achieved a CR/CRi after the first cycle may continue with the consolidation phase, 
all other patients may get a second induction cycle as per investigator’s discretion.
Second induction cycle
For patients requiring a second induction cycle, treatment will begin at least 3 days and no later 
than 42 calendar days after completing midostaurin. The treatment regimen must also adhere to 
the guidelines specified above for the first induction. Please refer to Section 7.2.1.
Patients who have achieved a CR/CRi after the second cycle may continue with the 
consolidation phase; all other patients should be removed from protocol.
Patients may start consolidation treatment at least 3 days and no later than 42 calendar days 
after the last midostaurin dose of induction.
An end phase disposition will be completed prior the C1D1 of the consolidation phase.
7.1.4.2
Consolidation phase
Patients who achieved a CR/CRi after either one or two induction cycles will receive 
consolidation therapy with cytarabine as defined by NCCN treatment guidelines plus 
subsequent midostaurin during each cycle. Patients will receive up to four cycles of 
consolidation therapy. Fewer cycles are accepted as per investigator’s discretion.
Each consolidation cycle is 28 days treatment. It is recommended that subsequent cycle start at 
least 3 days after the previous cycle is completed and no later than 70 calendar days from the 
start of the first cycle of consolidation. For the other consolidation cycles a recovery periods of 
21 days maximum will be applied. Refer to Table 6-2 for consolidation treatment schedule.
An end phase disposition will be completed prior the C1D1 of the maintenance phase.
7.1.4.3
Maintenance phase
Patients who continue to achieve CR/CRi after (up to) four cycles of consolidation therapy will 
receive midostaurin maintenance therapy. Prior to initiation of midostaurin maintenance 


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therapy, all significant acute toxicity from consolidation therapy must have resolved to < grade 
2.
For CR patients, midostaurin maintenance therapy will begin after hematologic recovery 
(ANC ≥1 000/μL, platelet count ≥100 000/μL) occurs and for CRi patients per investigator 
discretion and at least 3 days and no later than 28 calendar days after the last dose of 
consolidation midostaurin.
Each maintenance cycle is 28 days treatment. Subsequent cycles start on the day after the 
previous cycle is completed. In other words, subsequent cycles start 29 calendar days from the 
start of the previous cycle.
Patients who are unable to complete the cytarabine consolidation cycles because of toxicity or 
insufficient hematologic recovery may still be eligible for maintenance therapy. Discuss this 
situation in advance with the Novartis Study Team.
Refer to Table 6-3 for maintenance treatment schedule.
7.1.5
Discontinuation of study treatment
At the time patients discontinue study treatment; a visit should be scheduled as soon as possible, 
at which time all of the assessments listed for the End of Treatment visit will be performed. An 
End of Treatment eCRF page should be completed, giving the date and reason for stopping the 
study treatment.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a study withdrawal occurs, or if the patient fails to return for visits, the Investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information in eCRF.
At minimum, patients who discontinue study treatment, including those who refuse to return 
for a final visit will be contacted for safety evaluations. All patients must have safety evaluations 
for 30 days, after the last dose of study treatment unless they have withdrawn consent.
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 eCRF 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 should discontinue study treatment for a given patient if; he/she believes that
continuation would be detrimental to the patient’s well-being.
Patients may be withdrawn from study treatment under the following circumstances:

Adverse events

Pregnancy

Subject withdrew consent


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
Lost to follow up

Technical problems

Death

Progressive disease*

Protocol deviation

Study terminated by sponsor

Investigator decision

Subject/guardian decision
*The progressive disease refers to CR/CRi not achieved at the end of induction and/or 
consolidation therapy and relapse.
7.1.5.1
Replacement policy
Not Applicable
Escalation part:
Not Applicable
Expansion part:
Not Applicable
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 any
longer, and does not want any further visits or assessments, and does not want any further study
related contact.
Novartis will continue to retain and use all research results that have already been collected for
the study evaluation. All biological samples that have already been collected may be retained
and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, 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.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.7
Follow up for safety evaluations
All patients must have safety evaluations for 30 days, after the last dose of study treatment 
except if a patient withdraws consent.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF.


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7.1.8
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 contact the patient, the family or the 
family physician, as agreed in the informed consent and document in the source documents all 
the steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. A
patient should not be considered lost to follow-up until due diligence has been completed. 
Patients lost to follow up should be recorded as such on the appropriate Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Induction therapy
FLT3 mutated patients will receive induction therapy (cytarabine with anthracycline (idarubicin 
or daunorubicin) (for details refer to Section 6.1.1) sequentially followed by midostaurin.
In the first Induction phase, a bone marrow aspiration will be performed in all patients on Day 
21-28 (according to local standard of care) to determine the need for a second induction cycle. 
If the marrow aspirate is inadequate to make a determination, repeat the bone marrow 
assessment within one week.
If the Day 21-28 (according to local standard of care) bone marrow aspiration reveals <5% 
blasts in a cellular marrow (> 20%), then a bone marrow aspiration must be performed within 
one week after recovery of ANC ≥1 000/μL and platelets ≥ 100 000/μL to document complete 
remission. Patients in CR will proceed to consolidation therapy. Patients with CRi will proceed 
to consolidation therapy as per investigator discretion.
If the Day 21-28(according to local standard of care) bone marrow aspiration reveals ≥ 5% 
leukemic blasts in a cellular marrow (> 20%) a second induction will be given.
Second Induction therapy (if applicable)
For patients requiring a second induction, treatment will begin at least 3 days after completing 
midostaurin.
Bone marrow aspiration will be performed within one week after recovery of ANC ≥1000/μL 
and platelets ≥100,000/μL to assess for response.
Patients in CR will proceed to consolidation therapy. Patients who have residual AML at this 
time after a second remission induction should be removed from protocol therapy. Patients with 
CRi will proceed to consolidation therapy as per investigator’s discretion.
Consolidation therapy (up to four cycles per investigator’s discretion)
Based upon the superior results reported for AML patients less than 60 years old with normal 
karyotypes in prospective clinical trials (Farag et al 2005) and RATIFY, who achieve a CR/CRi 
after induction will receive further therapy with midostaurin. Patients will receive up to four 
cycles of consolidation therapy. Each consolidation cycle is four weeks in duration, and should 
begin within two weeks following hematologic recovery (ANC ≥1000/μL, platelet count 
≥100,000/μL), but not sooner than 31 days from the beginning of the previous cycle. If a 


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remission consolidation cycle is delayed > 8 weeks (56 days) from the start of the previous 
course due to slow resolution of toxicity or slow recovery of complete blood counts (CBC), 
please contact Novartis. A bone marrow aspiration must be performed prior to the first 
consolidation cycle C1D1 and later can be performed if necessary per investigator’s decision at 
any time during consolidation phase.
Maintenance therapy (for patients in CR/CRi after consolidation therapy)
Patients who continue in CR/CRi (by bone marrow aspiration and blood evaluation) after four 
cycles of remission consolidation therapy will receive midostaurin. Prior to maintenance 
therapy, all significant acute toxicity from consolidation therapy must have resolved to ≤grade 
2.
Patients with CRi will proceed to maintenance therapy as per investigator’s discretion and for 
CR patients maintenance therapy will begin after hematologic recovery (ANC ≥1000/μL, 
platelet count ≥ 100,000/μL) from remission consolidation, and at least 3 days after the last dose 
of midostaurin during consolidation. Patients who are unable to complete four courses of 
HiDAC consolidation because of toxicity may still be eligible for maintenance therapy at the 
discretion of the principal investigator after the last dose of consolidation after recovery from 
hematologic and other significant acute toxicity. A bone marrow examination should be 
performed prior to the first maintenance and every 3 months during maintenance phase.
Based on the results of this bone marrow examination (during maintenance phase) the physician 
will decide if the patient pursues the study treatment.

Complete remission (CR): Bone marrow blasts <5% with spicules; absence of blasts with 
Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) 
≥1000/μL; platelet count ≥100,000/μL; independent of transfusions.
Transfusion independence is defined as at least 7 days transfusion free prior to CR/CRi 
assessments.

CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia 
(<1000/μL) or thrombocytopenia (<100,000/μL) with transfusion independence but 
persistent cytopenia.

Partial remission (PR) is designated by normalization of blood values but with a decrease 
from baseline of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow 
aspirate. A value of ≤ 5% blasts may also be considered a PR if Auer rods are present.

Treatment failure includes patients for whom treatment that failed to achieve a CR/CRi or 
equal or less than a PR.

Relapse/recurrence following complete response is a reappearance of leukemic blasts in 
the peripheral blood or finding of ≥5% blasts in the bone marrow not attributable to 
another cause. The appearance of new dysplastic changes should also be considered 
relapse. The reappearance or development of cytologically proven extramedullary disease 
also indicates relapse. Molecular and/or genetic relapse is characterized by reappearance 
of a cytogenetic or molecular abnormality.


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7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing proportion of patients with AEs, Grade 3 and 4 AEs, 
SAEs, AEs leading to discontinuation, and deaths as well as collecting of the adverse events at 
every visit. For details on AE collection and reporting, refer to Section 8.
7.2.2.1
Physical examination
A physical examination must be performed as per Table 7-1 and on the day of 
discontinuation/End of Treatment.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF.
7.2.2.2
Vital signs
Vital signs include blood pressure (supine position preferred), pulse measurement, and body 
temperature. Data on vital signs will be tabulated and listed, notable values will be flagged.
7.2.2.3
Height and weight
Height in centimeters and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but 
without shoes) will be measured. Height will be measured at Screening and on the day of 
discontinuation/ end of treatment as per Table 7-1.
Body weight will be measured at screening and at subsequent time points as specified in Table 
7-1.
7.2.2.4
Performance status
The ECOG Performance status scale will be used, as described in the Table 7-2.
Table 7-2
ECOG Performance status
Grade
ECOG
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, e.g. light house work, 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
Laboratory evaluations must be performed according to the Table 7-1. Analyses and 
assessments are to be done locally and results transcribed to the eCRF. When abnormal 
laboratory values or test results constitute an adverse event (i.e., induces clinical 
signs/symptoms or requires therapy), they must be recorded on the Adverse Events eCRF.
All laboratory samples must be drawn PRIOR to the first dose of midostaurin.


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All other laboratory evaluations should be performed when justified for the assessment of a 
treatment related AE or SAE and at physician discretion.
All efforts should be made to collect the labs prior to dosing. Fasting is not required.
If administration of midostaurin is interrupted due to Grade 3 non-hematologic laboratory 
parameters, refer to Section 6.3, for instructions.
The following laboratory assessment will be done by the local laboratory:
Table 7-3
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Red blood cells, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase (LDH), Calcium, 
Magnesium, Phosphorus, Sodium, Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Total Bilirubin, Total Cholesterol, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Amylase, Lipase, Glucose (fasting) or Glucose (non fasting)
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation
International normalized ratio [INR]), Activated partial thromboplastin time or Activated 
thromboplastin time %
Pregnancy Test
When effective contraception is required pregnancy testing is mandated at screening 
and/or pre-dose and at the end of the trial. A serum pregnancy test should be performed; 
while at the end of trial urinary pregnancy tests are sufficient.
Note: All efforts should be made to collect the labs prior to dosing. Fasting is not required.
7.2.2.5.1 Hematology
Hemoglobin, white blood cell count with differential, and platelet count will be measured.
7.2.2.5.2 Chemical chemistry
Blood urea, creatinine, total bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, 
calcium, phosphorous, albumin, and uric acid will be measured.
7.2.2.5.3 Pregnancy and assessments of fertility
For women of childbearing potential, pregnancy testing is mandatory at screening, and within 
2 days prior to midostaurin dosing in induction and consolidation phases, day 1 of every cycle
in maintenance and at the end of the study. At screening, a serum pregnancy test should be 
performed, while during and at the end of study urinary pregnancy tests are sufficient.
U-HCG or serum HCG: Women of childbearing potential must have a negative serum or urine 
pregnancy test within 2 days prior to administration of the first dose of midostaurin.
Women are considered post-menopausal and not of childbearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms).
When effective contraception is required pregnancy testing is recommended at screening and/or 
pre-dose and at the end of the study.


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7.2.2.6
Radiological examination
A screening chest image; Chest x-ray (CXR) must be performed to assess study eligibility. If a 
CXR was done within 14 days of screening assessments then it does not need to be repeated.
7.2.2.7
Cardiac assessment
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as indicated in Table 7-1. All initial ECG assessment 
must be done PRIOR to the first dose of midostaurin.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. 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 when the patient signed informed consent should 
be reported on the Medical History CRF page. Clinically significant findings must be discussed 
with Novartis prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events CRF page.
For dose modifications for cardiac toxicity refer to Section 6.3.2.3 for induction and 
consolidation, and Section 6.3.3.3 for maintenance.
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
An echocardiogram or MUGA scan must be performed as indicated in the Table 7-1. The 
baseline left ventricular ejection fraction (LVEF) must be > 45% for eligibility and the patient 
must not meet the criteria for congestive heart failure NYHA classification grade III or IV to 
be eligible for the study.
The modality chosen at screening (echocardiogram or MUGA) must remain constant 
throughout the study. These assessments may be repeated at the investigator’s discretion if there 
are signs or symptoms of cardiotoxicity through the study between the above mentioned time-
points including an additional mandatory test at the end of treatment to verify cardiac safety.
Should the investigator determine that there is an ejection fraction decrease which is clinically 
relevant, the study drug must be withheld and Novartis informed. A discussion will take place 
with the sponsor to determine the necessary steps to be taken to safeguard the patient.
7.2.2.7.3 Cardiac enzymes
Not Applicable
7.2.2.8
Tolerability
Not Applicable
7.2.3
Pharmacokinetics
Not Applicable






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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
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.
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.


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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 may 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:

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
For patients with known FLT3 mutation status who sign the main study ICF, SAE collection 
starts at time of main study informed consent whether the patient is a screen failure or not.
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 


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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 (whichever is longer) 
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, to inform all investigators involved in any study with the 
same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Not Applicable
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 CMO&PS. Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to midostaurin for any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form.


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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 (as per local requirements).
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
Not Applicable
8.7
Steering Committee
Not Applicable
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 


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place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the 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 Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
9.4
Data 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 staffs are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities terminology.


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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. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
Novartis or a designated Contract Research Organization will perform all analyses. Any data 
analysis carried out independently by the investigator should not be presented or published 
before the final analysis is completed. The data from all centers that participate will be 
combined in the analyses.
Final analyses will be performed when all patients have been followed for 30 days after they 
have either prematurely discontinued or been discontinued from the study after completing 
treatment as per protocol.
Data will be summarized with respect to demographic and baseline characteristics including 
FLT3 (ITD&TKD) and NPM1 mutation (when available), and safety and efficacy observations 
and measurements. Data may be summarized by different chemotherapy regimens (i.e. the “7+3” 
and the “5+2” induction regimens) and treatment phases (induction, consolidation and 
maintenance).
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
10.1
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting.
The ‘All enrolled patients’ set comprises all screened patients who are not screening failures.
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of 
midostaurin and have a documented FLT3 mutation (ITD or TKD).
10.1.2
Safety set
The Safety Set comprises all patients who received at least one dose of midostaurin.
10.1.3
Per-Protocol set
Not applicable
10.1.4
Dose-determining analysis set
Not applicable


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10.1.5
Pharmacokinetic analysis set
Not Applicable
10.1.6
Other analysis sets
Not Applicable
10.1.6.1 Efficacy/evaluable set
Not Applicable
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be summarized descriptively for the safety set.
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term for all patients.
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, 25th and 
75th percentiles, minimum, and maximum will be presented.
Duration of midostaurin treatment exposure in days and cumulative dose and dose intensity will 
be summarized overall and by period and induction chemotherapy regimen by means of 
descriptive statistics using the safety set.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for all patients 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, for all patients.
10.4
Primary objective
The primary objective is to further assess the safety of midostaurin in induction, consolidation 
and maintenance therapy including the ‘7+3’ regimen, daunorubicin (60-90mg/m2/day), the 
substitution of daunorubicin by idarubicin (12 mg/m2/day) and cytarabine (100-200 mg/m2/day) 
and also allowing the “5+2” reduced dose regimen.
The safety set will be used for the analysis of clinical safety data.
10.4.1
Variable
The analysis of the primary objective is described in Section 10.5.3.


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10.4.2
Statistical hypothesis, model, and method of analysis
No statistical hypotheses are being tested in this study.
10.4.3
Handling of missing values/censoring/discontinuations
No imputation will be applied for any missing data.
10.4.4
Supportive and sensitivity analyses
Not Applicable
10.5
Secondary objectives
The secondary objectives in this study are to assess the clinical efficacy of midostaurin in 
sequential combination with chemotherapy regimens in induction and consolidation and the 
clinical efficacy of midostaurin in maintenance phase (measured by CR/CRi rate).
Clinical efficacy rate is defined as the proportion of patients with complete remission (CR) or 
complete remission with incomplete hematologic recovery (CRi) as per local assessment, in 
induction, consolidation and maintenance. CR and CRi are defined according to the 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, described in the ELN recommendations 2017 (Dohner et al 2016) 
(ENL).
Clinical efficacy rate will be calculated based on the FAS. Clinical efficacy rate and its 95% 
confidence interval will be presented by induction regimen and age category as described in 
Section 10.5.3.1.
10.5.1
Key secondary objective(s)
Not Applicable
10.5.2
Other secondary efficacy objectives
Not Applicable
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.
The overall observation period may be summarized into the following mutually exclusive 
periods:
1. Pre-treatment period: prior to first dose of midostaurin
2. On-treatment period (includes 3 mutually exclusive periods):
a. Induction period: From day of first dose of midostaurin to the day before start of 
consolidation period (i.e. end of induction phase plus any rest/recovery days)


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b. Consolidation period: From day of first dose of study treatment in consolidation phase 
to the day before start of maintenance (i.e. end of consolidation phase plus any 
rest/recovery days)
c. Maintenance period: From day of first dose of midostaurin in the maintenance phase 
to the date of last dose of midostaurin + 30 days
It is noted that if a patient permanently discontinues study treatment during any of these 
periods, on-treatment is considered until the date of last dose of study treatment + 30 days 
(unless patient died before then, then it is till the death date)
3. Post-treatment period: from last date of study treatment + 31 days to end of study
Each period will contain all patients who entered that period (including withdrawal, drop-outs 
etc.).
Data may also be summarized by different chemotherapy regimens (i.e. the “7+3” and the “5+2” 
induction regimens) and by age category (i.e. patients younger than 60 years old and patients 
60 years old or older).
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 adverse events (new or worsening from baseline) will be 
summarized by system organ class, preferred term, severity (based on CTCAE grades), type of 
AE, relation to study treatment, periods and regimens as specified above and overall. AEs with 
different starts dates in different periods will be counted within each period.
AEs leading to discontinuation, serious AEs (SAE) and non-SAEs during the on-treatment 
period will be tabulated by type of AE.
All deaths (on-treatment and post-treatment) reportable as SAEs and non-fatal SAEs will be 
listed by patient and tabulated by type of AE.
All AEs, deaths and SAEs (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
Not Applicable
10.5.3.4 Other safety data
Other safety data (including vital signs and weight) will be summarized and listed, notable 
values will be flagged, and any other information collected will be listed as appropriate.
ECG
A standard 12-lead ECGs including PR, QRS, QT and QTcF intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted locally.
Listing will be provided with notable values flagged.




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10.6.2
Resource utilization
Similarly descriptive statistics will be applied to assess resource utilization, e.g. on the reason 
for hospitalization, number of hospital days by ward type, discharge reason, and the 
concomitant medications used during hospital stay.
10.7
Interim analysis
No formal interim analysis is planned for this study. Analyses may be performed periodically 
(e.g. annually), if needed, to fulfill regulatory requests, safety updates or for publication 
purposes.
10.7.1
Progression free survival (PFS)
Not Applicable
10.7.2
Key secondary endpoint: Overall survival (OS)
Not Applicable
10.8
Sample size calculation
Approximately 300 patients will be enrolled in this study. The planned sample size is based on 
the average expected accrual rate (17 patients per month) and the planned recruitment duration 
(18 months) of the trial. The actual sample size may differ from this planned number. A sample 
size of 300 patients provides a 95% probability of observing at least one patient with an adverse 
event (AE) assuming a true probability of occurrence of 1%.
Table 10-1 provides probabilities to detect at least one patient with an AE for different sample 
sizes and different true AE incidences.
Table 10-1
Probability to detect at least one patient with an AE for different 
sample sizes and different true AE incidences
Incidence of an 
adverse event
Sample size
N=200
N=250
N=300
0.4%
0.5514
0.6329
0.6995
0.5%
0.6330
0.7144
0.7777
0.6%
0.6999
0.7779
0.8356
0.8%
0.7994
0.8657
0.9102
1.0 %
0.8660
0.9189
0.9510
1.3%
0.9270
0.9620
0.9803
10.9
Power for analysis of key secondary variables
Not Applicable


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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, and after treatment stop. If there is any question that the patient will not 
reliably comply, they should not be entered in the study.
Additional consent/information forms
Additional consent forms include:

Information for female partners of male study participants

Pregnancy follow-up for pregnant participants

Pregnancy follow-up for the pregnant partner of participants


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Male participants will be requested to provide the Information for female partners of male study 
participants form to their partners.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 7.1.5.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., 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.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 


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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.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 


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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
References (available upon request)
American Cancer Society. Leukemia–acute myeloid (myelogenous). 
https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html.
Döhner H, Estey E, Grimwade D, et al (2016). Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood, pp.blood-2016.
Farag SS, et al (2005). Outcome of Induction and Post remission Therapy in Younger Adults 
With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B 
Study Journal of Clinical Oncology 23:3, 482-493.
Gale RE, Green C, Allen C, et al (2008). The impact of FLT3 internal tandem duplication 
mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young 
adult patients with acute myeloid leukemia. Blood; 111:2776-2784.
Kayser S, Levis MJ (2014). FLT3 tyrosine kinase inhibitors in acute myeloid leukemia: 
clinical implications and limitations. Leukemia & Lymphoma, 55(2), 243–255.
http://doi.org/10.3109/10428194.2013.800198.
Kayser S, Schlenk RF, Londono MC, et al (2009). Insertion of FLT3 internal tandem 
duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and 
inferior outcome. Blood; 114:2386-2392.
Klepin HD (2014). Geriatric perspective: how to assess fitness for chemotherapy in acute 
myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2014; 2014(1):8-13.
Klepin HD, Geiger AM, Tooze JA, et al (2013). Geriatric assessment predicts survival for 
older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 
Blood. 2013; 121(21): 4287-4294.
Kottaridis PD, Gale RE, Frew ME, et al (2001). The presence of a FLT3 internal tandem 
duplication in patients with acute myeloid leukemia (AML) adds important prognostic 
information to cytogenetic risk group and response to the first cycle of chemotherapy: 
analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 
trials. Blood; 98:1752-1710.
Levis M, Pham R, Small D (2003). CEP-701, a selective FLT3 tyrosine kinase inhibitor that is 
cytotoxic to FLT3/ITD-expressing leukemia cells, is synergistic with chemotherapeutic agents 
in vitro when used in time-sequential fashion. Blood: 102.66a.
Meshinchi, Appelbaum (2009). Structural and functional Alterations of FLT3 in Acute 
Myeloid Leukemia. Clin Cancer Res. 15(13): 4263–4269
NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 1.2017, 
https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf, last accessed on 27 March 
2017.
Ossenkoppele G, Lowenberg B (2015). How I treat the older patient with acute myeloid 
leukemia. Blood. 2015; 125(5):767-774.
RARECAREnet, http://www.rarecarenet.eu/rarecarenet/index.php/cancerlist, last accessed 7 
February 2017.


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Rashidi A, et al (2016). The effect of FLT3-ITD and NPM1 mutation on survival in 
intensively treated elderly patients with cytogenetically normal acute myeloid leukemia. Aug; 
57(8):1977-9.
Schlenk, et al (2014). Differential impact of allelic ratio and insertion site in FLT3-ITD 
positive AML with respect to allogeneic hematopoietic stem cell transplantation. Blood 2014 
124:3441-3449.
Schlenk, et al (2016). Midostaurin in Combination with Intensive Induction and As Single 
Agent Maintenance Therapy after Consolidation Therapy with Allogeneic HematopoieticStem 
Cell Transplantation or High-Dose Cytarabine (NCT01477606) Blood; 128:449.
SEER (2016). https://seer.cancer.gov/statfacts/html/amyl.html.
Smith TJ, et al (2015). Recommendations for the Use of WBC Growth Factors: American 
Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical 
Oncology 33:28, 3199-3212.
Stone RM, DeAngelo DJ, Klimek V, et al (2005). Patients with acute myeloid leukemia and 
an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, 
PKC412. Blood. 105:54–60.
Stone RM, et al (2012). Phase IB study of the FLT3 kinase inhibitor midostaurin with 
chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. 
Leukemia 26(9): 2061–2068.
Stone RM, Fischer T, Paquette R, et al (2009). A phase 1b study of midostaurin (PKC412) in 
combination with daunorubicin and cytarabine induction and high-dose cytarabine 
consolidation in patients under age 61 with newly diagnosed de novo acute myeloid leukemia: 
Overall survival of patients whose blasts have FLT3 mutations is similar to those with wild-
type FLT3. Blood 114:634.
Stone RM, Mandrekar S, Sanford BL, et al (2015). The multi-kinase inhibitor midostaurin 
(M) prolongs survival compared with placebo (P) in combination with daunorubicin 
(D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance 
(maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 
with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled 
double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood 126:6.
Thiede C, Steudel C, Mohr B, et al (2002). Analysis of FLT3-activating mutations in 979 
patients with acute myelogenous leukemia: association with FAB subtypes and identification 
of subgroups with poor prognosis. Blood; 99(12):4326-4335.
Walter RB, Estey EH (2015). Management of older or unfit patients with acute myeloid 
leukemia. Leukemia, 29(4), pp.770-775.









SAP_001.pdf: 
Clinical Development 
PKC412/Midostaurin/Rydapt® 
CPKC412A2408 / NCT03379727 
An open-labeled, multi–center, Phase IIIb study to assess 
the safety and efficacy of midostaurin (PKC412) in patients 
18 years of age or older with newly-diagnosed  
FLT3-mutated Acute Myeloid Leukemia who are eligible for 
“7+3” or “5+2” chemotherapy 
Statistical Analysis Plan (SAP) – Amendment 3 
Author: 
 (Trial Statistician) 
Document type: 
SAP Documentation 
Document status: 
V4.0 
Release date: 
09-Nov-2021
Number of pages: 
30 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
 
For business use only 
Page 2 
SAP Amendment III 
 
CPKC412A2408 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
22-Aug-2017 
Prior to 
FPFV 
N/A – Initial version 
N/A 
N/A 
14-Jan-2020 
Prior to 
database 
lock 
Rules to select one 
assessment among 
several assessments in 
the same visit 
Time windows for 
unplanned visits 
Selection of assessment to 
analyze among multiple 
values in the same visit 
 
Time windows to assign 
unplanned visits in 
scheduled ones 
2.1.5 
 
 
Added rules to assign 
patients to 7+3 and 5+2 
groups 
Patients who do not have 
exactly 7+3 or 5+2 are 
assigned 
2.1.8 
 
 
 
Category/Value 
missing 
Added treatment exposure 
category “>28”.Cardiac 
imaging changed “>” to  
“>-“ for 20 
2.4.2 
2.8.4.2 
 
 
Change in CSR 
template 
Concomitant medications 
will be analyzed with FAS 
instead of SAF 
2.4.3 
 
 
Clinical efficacy 
response derivation and 
subgroup analyses 
Selection of best response 
among several assessment 
in the same period. 
Response analyzed by sex 
2.6.1 
 
 
AEs by subgroup 
AEs to be analyzed by age 
category 
2.8.1 
 
 
Resource utilization 
updated to CRF 
Updated with variables only 
included in CRF 
2.13.3 
 
 
Additional details on 
imputation rules 
Derivation rules updated 
6.1 
 
 
BUN/Urea imputation 
rules 
To impute BUN or Urea 
missing values 
6.2 
26-Jun-2020 
 
Study treatment 
exposure 
Rules od study treatment 
exposure clarified. 
2.1.1 
 
 
 
Analysis set  
All enrolled subjects added 
2.2 
 
 
 
 
 
 
 
Subgroups analyses 
added : type of 
induction drugs 
Efficacy and safety outputs 
provided by Idarubicin and 
Daunorubicin. 
2.3 
 
 
Age subgroups 
<= 60 vs. >60 instead of 
<60 vs. >=60 
2.3 and 2.4.2 


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Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
 
Efficay  
If patient discontinued prior 
to first efficacy assessment 
then ‘unknown’ is assigned 
as best response 
2.7.1 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
15-Jun-2021 
Prior to 
database 
lock 
PD 
The number (%) of protocol 
deviations with COVID-19 
relationship will be 
presented by type of 
deviation for all enrolled 
subjects. 
2.5.4 
09-Nov-2021 
Post to 
database 
lock 
Subgroups analysis 
amended for a new 
agesubgroup/category. 
Included the following age 
subgroup/category:  
<= 60 / >60 to <=70 / > 70 
years old 
 
2.3, 2.4.2, 2.5.2 and 
2.7.1 
FPFV: First patient first visit 
 


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Table of contents 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions .................................................................................. 9 
2.1.2 
Baseline ................................................................................................. 13 
2.1.3 
On-treatment assessment/event ............................................................. 13 
2.1.4 
Definition of months and years ............................................................. 14 
2.1.5 
Time windows ....................................................................................... 14 
2.1.6 
Definition of end of study ..................................................................... 15 
2.1.7 
Early study termination ......................................................................... 15 
2.1.8 
Chemotherapy group assignment .......................................................... 15 
2.2 
Analysis sets .......................................................................................................... 15 
2.2.1 
All enrolled patients .............................................................................. 15 
2.2.2 
Full analysis set ..................................................................................... 15 
2.2.3 
Safety set ............................................................................................... 15 
2.3 
Subgroup analysis .................................................................................................. 16 
2.4 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.4.1 
Patient disposition ................................................................................. 16 
2.4.2 
Patient demographics and other baseline characteristics ...................... 16 
2.5 
Treatments (study treatment, concomitant therapies, compliance) ....................... 16 
2.5.1 
Dosing regimen ..................................................................................... 16 
2.5.2 
Study treatment and tolerability ............................................................ 17 
2.5.3 
Prior, concomitant and post therapies ................................................... 18 
2.5.4 
Protocol deviations ................................................................................ 18 
2.6 
Analysis of the primary objective .......................................................................... 18 
2.6.1 
Primary endpoint ................................................................................... 18 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 18 
2.6.4 
Supportive analyses ............................................................................... 18 
2.7 
Analysis of the secondary objectives ..................................................................... 19 
2.7.1 
Secondary endpoints ............................................................................. 19 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 19 


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2.8 
Analysis of secondary efficacy objective(s) .......................................................... 19 
2.9 
Safety analyses ....................................................................................................... 19 
2.9.1 
Adverse events (AEs) ............................................................................ 19 
2.9.2 
Deaths .................................................................................................... 21 
2.9.3 
Laboratory data ..................................................................................... 21 
2.9.4 
Other safety data ................................................................................... 22 
2.10 
Pharmacokinetic endpoints .................................................................................... 23 
2.11 
PD and PK/PD analyses......................................................................................... 24 
 
 24 
2.13 
Biomarkers ............................................................................................................. 24 
2.14 
Other Exploratory analyses .................................................................................... 24 
 
 24 
 
 25 
2.14.3 
Resource utilization ............................................................................... 25 
2.15 
Interim analysis ...................................................................................................... 25 
3 
Sample size calculation ..................................................................................................... 25 
4 
Change to protocol specified analyses .............................................................................. 26 
5 
References ......................................................................................................................... 26 
6 
Appendix ........................................................................................................................... 27 
6.1 
Imputation rules ..................................................................................................... 27 
6.1.1 
AE, CM date imputation ....................................................................... 27 
6.1.2 
Prior therapies date imputation ............................................................. 28 
6.2 
Laboratory parameters derivations ........................................................................ 28 
 
 28 


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List of abbreviations 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
aspartate aminotransferase 
AML 
acute myeloid leukemia 
Ara-C 
cytarabine, also known as cytosine arabinoside 
AST 
alanine aminotransferase 
ATC 
anatomical therapeutic chemical classification 
CIVI 
continuous intravenous infusion 
CR 
complete remission 
CRi 
complete remission with incomplete recovery 
CRS 
case retrieval sheet 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
DI 
dose intensity 
ECG 
electrocardiogram 
ECOG 
eastern cooperative oncology group 
eCRF 
electronic case report form 
 
 
FAS 
full analysis set 
FLT3 
fms-like tyrosine kinase receptor 
GPS 
global programming & statistical environment 
IV 
intravenous 
LPLV 
last patient last visit 
LVEF 
left ventricular ejection fraction 
MedDRA 
medical dictionary for drug regulatory affairs 
MUGA 
multi gated acquisition scan 
NCCN 
national comprehensive cancer network 
NCDS 
Novartis clinical data standards 
PD 
pharmacodynamics 
PDS 
programming data specifications 
 
 
PK 
pharmacokinetics 
 
 
PT 
preferred term 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
international system of units 
SOC 
system organ class 
TFLs 
tables, figures, listings 
WHO 
world health organization 


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1 
Introduction 
This statistical analysis plan (SAP) provides detailed statistical methodology for the analyses 
of data which will be used for preparation of the PKC412A2408 clinical study report (CSR) 
and is based on the study protocol Amendment 1, dated 26-Mar-2018. At the time of this 
amendment, enrollement was completed with 301 patients. 
The shells for the in-text tables and figures as well as the post-text tables, figures and listings 
(TFLs) are in the TFL shells document. Programming specifications for datasets, including 
derivation of variables, are given in the programming data specifications (PDS) document. 
All data will be analyzed by Novartis using Novartis clinical data standards (NCDS). Analysis 
data sets and statistical outputs will be produced using the SAS system Version 9.4 or higher 
(UNIX environment) in the global programming & statistical (GPS) environment. 
1.1 
Study design 
This is an open-label, single arm, multicenter, Phase IIIb study of midostaurin (PKC412 or 
CGP41251) in adults with newly-diagnosed fms-like tyrosine kinase receptor (FLT3)-mutated 
acute myeloid leukemia (AML) who have started on “7+3” or “5+2” induction chemotherapy.  
The purpose of this study is to gather and evaluate additional safety and efficacy data on the 
combination of midostaurin and standard of care. 
Midostaurin is used in combination with chemotherapy sequentially in induction and 
consolidation phase and as a single agent in maintenance phase as outlined in Figure 1-1. 
Approximately 300 patients are planned to be enrolled. 
No formal interim analyses are planned. 
The final (primary) analysis will be performed after database lock when all patients have either 
completed the study as per protocol (including their safety evaluation 30 days after the last dose 
of study treatment) or they have prematurely discontinued. 
 


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Figure 1-1 
Study design 
 
Complete remission (CR): Bone marrow blasts <5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count (ANC) >1.0 x109/L; platelet count >100 x 109/L; 
independence of red cell transfusions 
CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (<1.0 x109/L) or 
thrombocytopenia (<100 x 109/L) 
Figure 1-2 
Recovery periods 
 


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1.2 
Study objectives and endpoints 
Objective 
Endpoint 
Primary 
 
To further assess the safety of midostaurin in 
induction, consolidation and maintenance 
therapy, including, the “7+3” regimen, 
daunorubicin (60-90mg/m2/day), the substitution 
of daunorubicin by idarubicin (12mg/m2/day), 
cytarabine (100-200 mg/m2/day) and also 
allowing the “5+2” reduced dose regimen. 
Proportion of patients with AEs, Grade 3&4 
AEs, SAEs, AEs leading to discontinuation, and 
deaths. 
Secondary 
 
To assess the clinical efficacy of midostaurin in 
combination with chemotherapy regimens in 
induction and consolidation and the clinical 
efficacy of midostaurin maintenance phase 
(measured by CR/CRi rate). 
Proportion of patients with CR/CRi as per local 
assessment 
Exploratory 
 
 
 
 
 
 
 
 
To assess resource utilization 
Proportion of patients by reason for 
hospitalization, number of hospital days, 
discharge reason and concomitant medications 
taken during hospital stay 
AE: adverse event 
 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Categorical data will be presented as frequencies and percentages. For continuous data, n, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
The data from all centers that participate will be combined in the analyses. 
Final (primary) analysis will be performed after database lock has occurred (after last patient 
last visit (LPLV)).   
2.1.1 
General definitions  
The overall observation period is divided into the following mutually exclusive periods: 
1. Pre-treatment: from day of patient’s informed consent to the day before first dose of 
midostaurin 


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2. On-treatment: from start date of midostaurin to last date of study treatment + 30 days. 
Further details provided in Section 2.1.3. 
On-treatment includes 3 mutually exclusive periods: 
a. Induction period: From day of first dose of midostaurin to the day before start of 
consolidation period (i.e. end of induction phase plus any rest/recovery days). 
Up to 2 cycles (28 days of treatment/cycle and a recovery period) 
b. Consolidation period: From day of first dose of study treatment in consolidation 
phase to the day before start of maintenance (i.e. end of consolidation phase plus any 
rest/recovery days). 
Up to 4 cycles (28 days of treatment/cycle and a recovery period) 
c. Maintenance period: From day of first dose of midostaurin in the maintenance phase 
to the date of last dose of midostaurin + 30 days. 
Up to 12 cycles (28 days of treatment/cycle) 
It is noted that if a patient permanently discontinues study treatment during any of these 
periods, on-treatment is considered until the date of last dose of study treatment + 30 days 
(unless patient withdraws study informed consent or dies before then, then it is till the 
withdrawal/death date) 
3. Post-treatment: from last date of study treatment + 31 days to end of study 
Each period will contain all patients who entered that period (incl. withdrawal, drop-outs etc.) 
Study drug and study treatment 
Study drug refers to the individual drugs used in the study after signing of informed consent, 
i.e. the Novartis investigational drug midostaurin, or its partners, cytarabine and daunorubicin 
(or idarubicin). 
Study treatment refers to any component of the study drugs, midostaurin, cytarabine and 
daunorubicin (or idarubicin).  
Date of first administration of study drug 
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study drug is administered. The date of first administration of study drug is also referred to 
as start date of study drug. Start date of study drug is defined for each drug which is part of 
study treatment, by period (induction, consolidation, maintenance, where applicable) and 
overall.  
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered. This date is also referred to as last date of study drug. Last date of 
study drug is defined for each drug which is part of study treatment, by period (induction, 
consolidation, maintenance, where applicable) and overall. 
Date of first administration of study treatment 
The date of first administration of study treatment (will be midostaurin for all patients) is 
derived as the first date when a nonzero dose of any component of study treatment is 
administered. It is derived by period (induction, consolidation, maintenance) and overall. 


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For example, if the 1st dose of midostaurin is taken on 08-Feb-2016, and 1st dose of a 
combination partner (e.g. cytarabine), is taken on 01-Feb-2016, then the date of first 
administration of study treatment is 01-Feb-2016. The date of first administration of study 
treatment is also referred to as start date of study treatment. 
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 is administered. It is derived by period (induction, 
consolidation, maintenance) and overall.  
For example if the last dose of midostaurin is taken on 21-Mar-2016, and the last dose of a 
combination partner is taken on 03-Apr-2016, then the date of last administration of study 
treatment is on 03-Apr-2016. This date is also referred to as last date of study treatment. 
Duration of exposure 
Daunorobucin, Idarubicin and Cytarabine 
The duration of exposure for the study drugs will be calculated by cycle, period (induction, 
consolidation, maintenance, when applicable) and overall as: 
• Duration of study drug exposure (days) in a cycle = [(date of last administration of study 
drug in that cycle) – (date of first administration of study drug in that cycle) + 1]  
• Duration of study drug exposure (days) in a period = sum of durations of study drug 
exposure (days) in each cycle of that period  
• Overall duration of study drug exposure (days) = sum of durations of study drug exposure 
(days) in each cycle  
Study treament and Midostaurin 
The duration of exposure for the study treatment and Midostaurin will be calculated by cycle, 
period (induction, consolidation, maintenance) and overall as: 
• Duration of study treatment/Midostaurin exposure (days) in a cycle = [(date of last 
administration of study treatment/Midostaurin in that cycle) – (date of first administration 
of study treatment/Midostaurin in that cycle) + 1]  
• Duration of study treatment exposure (days) in a period = sum of durations of study 
trt/Mido exposure (days) in each cycle of that period. 
• Overall duration of study treatment exposure (days) = [(date of last administration of 
study treatment/Midostaurin) – (date of first administration of study 
treatment/Midostaurin) + 1]  
• If the start or end date of a study drug is missing, the duration will be missing. The 
durations will include periods of temporary interruption (planned or actual) for any reason. 
Dose interruption 
For midostaurin: An interruption is defined as a zero dose on one or more days between two 
non-zero dosing records. Any rest period as part of the regimen/schedule is not considered as 
an interruption e.g. Days 1 to 7 at the start of a cycle in the induction and consolidation phases 
is not considered as an interruption. 


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For daunorubicin (or idarubicin) and cytarabine: An interruption is defined as a zero dose 
administered on one or more scheduled days of administration e.g. a zero dose on Days 1, 3 or 
5 for cytarabine in the consolidation phase. 
Note: The last zero dose of a study drug (followed by permanent discontinuation) is not 
considered as a dose interruption. Additionally, two consecutive zero doses will be counted as 
one interruption if the reasons for these two consecutive dose interruptions are the same. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption are entered on consecutive days with different reasons these will be counted as 
separate interruptions. However, if the reason is the same in these multiple entries on 
consecutive days, then it will be counted as one interruption. 
Dose reduction 
A dose reduction is where the prescribed dose is lower than the previous prescribed dose or 
where the actual dose administered/total daily dose is lower than the prescribed dose. Any dose 
change to correct a dosing error will not be considered a dose reduction, e.g. if due to a dosing 
error, a patient receives higher than protocol planned starting dose and moves down to the 
planned starting dose then this is not counted as a reduction, however if they move directly from 
a higher than planned starting dose down to a lower than protocol planned starting dose, then 
this is counted as a reduction. 
Note: It is assumed that if there is a dose reduction, then the ‘Dose changed’ box was ticked on 
the dose administration electronic case report form (eCRF) page. 
If dose is recorded by regimen is missing or entered as ‘none’, it is assumed that the study drug 
was taken as per-protocol. 
Actual cumulative dose 
Cumulative doses will be derived for each of the study drugs: midostaurin, daunorubicin and 
idarubicin. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on study drug as documented in the dose administration eCRF.  
For patients who did not take any study drug, the actual cumulative dose is by definition equal 
to zero. 
The actual cumulative dose is the sum of the non-zero doses recorded over the study drug dosing 
periods. Rest periods are not included.  
Actual dose intensity (DI) 
Dose intensity (DI) will be derived for each of the study drugs: midostaurin, daunorubicin and 
idarubicin. 
DI for patients with non-zero duration of exposure is defined as follows:  
DI (dosing unit / unit of time) = Actual cumulative dose (dosing unit) / Duration of exposure 
(unit of time). 


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For example, DI (mg/day) 
= Actual cumulative dose (mg) / Duration of exposure (day) 
 
 
 
 
= 1300 mg / 14 days 
 
 
 
 
= 92.9 mg/day 
For patients who did not take any study drug the DI is by definition equal to zero.  
Study day 
The study day describes the relative day of the event related to the start date of midostaurin. 
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes 
Day 1. Study Day 0 is not defined.  Study day is not to be used in numerical computations, for 
example in calculating exposure. 
The study day will be calculated 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 assessments (adverse events (AEs), laboratory etc.) will be the 
start date of 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 in the listing will be negative. 
2.1.2 
Baseline 
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient, 
defined as the period from the date of signing any informed consent document to the start date 
of midostaurin.  
The last non-missing assessment, including unscheduled assessments on or before the first dose 
of midostaurin is defined as “baseline value” or “baseline assessment”. Assessments, specified 
to be collected post-dose on the first date of midostaurin are not considered for baseline.  
Where electrocardiogram (ECG) replicates are provided, the average of the ECG parameters at 
that assessment will be used in the analyses. 
If patients have no value as defined above, the baseline value will be missing.  
2.1.3 
On-treatment assessment/event 
The definition of on-treatment is given below, depending on the context. 
For safety summary tables (over the entire duration of the study) an on-treatment AE is defined 
as any AE reported in the following time interval (including the lower and upper limits):  
• <date of first administration of midostaurin; date of last administration of study treatment 
+ 30 days> 
This corresponds to the definition of treatment-emergent AEs given in the protocol, i.e. AEs 
which are newly reported or worsening from baseline.  


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An on-treatment assessment is defined as any assessment performed after the date of first 
administration of midostaurin (except for assessments specified to be collected post-dose on 
that day), i.e. assessments performed in the following time interval (including the lower and 
upper limits):  
• <date of first administration of midostaurin + 1; date of last administration of study 
treatment + 30 days> 
For patients whose last date of study treatment is missing, on-treatment assessments/events 
include any assessment/event present in the database occurring after the start date of study 
treatment.  
Listings will contain all data, flagging assessments/events outside of the on-treatment period 
where applicable. 
2.1.4 
Definition of months and years 
A month will be calculated as (365.25 / 12) = 30.4375 days. If duration is to be reported in 
months, duration in days will be divided by 30.4375.  If duration is to be reported in years, 
duration in days will be divided by 365.25. 
2.1.5 
Time windows 
Time windows for assessments are based on protocol specified windows, see protocol Table 7-
1. 
If more than one assessment is done within the same time window, the assessment performed 
closest to the target date will be used. For two assessments within a time window are equidistant 
from the target date then the earlier of the two assessments will be used. If there are multiple 
assessments for the same date, then the worst case will be used. 
 
For unplanned visits, will be classified as follows: 
Assessment Target day of assessment 
Time Interval 
Baseline  
Date when visit = IND C1D8 (or 
Day1) 
Last date <= date of IND C1D8 
INDC1 
Date when visit = INDC1D8 
Date of IND C1D8 - 7 <= date < date of 
IND C2D1 
INDC2 
Date when visit = INDC2D8 
Date of IND C2D1 <= date < date of CON 
C1D1 
CONC1 
Date when visit =  CONC1D8 
Date of CON C1D1 <= date < date of 
CON C2D1 
CONC2 
Date when visit =  CONC2D8 
Date of CON C2D1 <= date < date of 
CON C3D1 
CONC3 
Date when visit =  CONC3D8 
Date of CON C3D1 <= date < date of 
CON C4D1 
CONC4 
Date when visit = CONC4D8 
Date of CON C4D1 <= date < date of 
MAIN C1D1 
MAINC1 
Date when visit = MAIN C1D1 
Date of MAIN C1D1 <= date < date of 
MAIN C2D1 


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…  
… 
… 
MAINC12 
Date when visit = MAIN C12D1 
Date of MAIN C12D1 <= date <= date of 
last non-zero dose +30 
End Of 
Treatment 
Date when visitnum =399 
Date when visitnum  in (399, 
399.001,399.002,…) 
2.1.6 
Definition of end of study 
The study will end around 18 to 25 months (mo) after LPFV depending on number of cycles 
and recovery durations (2mo induction + 2mo recovery + 4mo consolidation + 4mo recovery + 
12mo maintenance + 1mo safety follow-up). Study treatment will be provided until disease 
progression, death, unacceptable toxicities, physician’s decision, patient/guardian’s decision, 
protocol deviation, study termination by sponsor, lost to follow-up, technical problems, 
pregnancy, patient withdrew consent or until the end of study, whichever event occurs first. All 
patients must have safety follow-up for 30 days, after the last dose of study treatment except if 
study consent was withdrawn. 
2.1.7 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as for a discontinued or withdrawn patient. 
2.1.8 
Chemotherapy group assignment 
Patients will be assigned to ‘7+3’ or ‘5+2’ chemotherapy groups considering the following rules 
of the first induction cycle: 
• If cytarabine duration is ≥ 7 days, ‘7+3’ group will be assigned, without considering the 
duration of daunorubicin/idarubicin. 
• If cytarabine duration is < 7 days, ‘5+2’ group will be assigned, without considering the 
duration of daunorubicin/idarubicin. 
2.2 
Analysis sets 
2.2.1 
All enrolled patients 
The ‘All enrolled patients’ set comprises all screened patients who are not screening failures. 
2.2.2 
Full analysis set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of 
midostaurin and have a documented FLT3 mutation (ITD or TKD). 
2.2.3 
Safety set 
The safety set comprises all patients who received at least one dose of midostaurin.  


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Screening failures 
Patients who sign an informed consent form but fail to start on midostaurin for any reason. 
2.3 
Subgroup analysis 
Safety and efficacy data will be repored for the following subgroups: 
• Age [(i) <= 60 / > 60 years old and/or (ii) <= 60 / >60 to <=70 / > 70 years old] 
• Gender (female / male) 
• Chemotherapy groups (‘7+3’ / ‘5+2’) 
• Type of induction drugs (Daunorubicin (<60 mg/m2), daunorubicin (>= 60 mg/m2) and 
Idarubicin) 
2.4 
Patient disposition, demographics and other baseline 
characteristics 
2.4.1 
Patient disposition 
Disposition data will be listed and summarized descriptively by screening and period 
(induction, consolidation and maintenance) for the FAS.  
Summaries will also include the number of patients who did not receive any dose of study 
treatment, having received at least one dose of study treatment, treatment completed as per 
protocol criteria or treatment permanently discontinued with reason, as reported in the dose 
administration record eCRF pages. 
Informed consent and inclusion/exclusion criteria data will be listed. Screening data for screen 
failure patients will be listed. 
2.4.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data (e.g. medical history, diagnosis and extent of cancer, 
eastern cooperative oncology group (ECOG) performance status, FLT3 mutation status etc.) 
will be summarized descriptively or listed as appropriate for the FAS. 
Age will also be categorized as:  
• <=60, > 60 years and/or   
• <= 60 / >60 to <=70 / > 70 years old. 
Demographic data for screen failure patients will also be listed. 
2.5 
Treatments (study treatment, concomitant therapies, 
compliance) 
2.5.1 
Dosing regimen 
All patients on study will receive standard chemotherapy plus midostaurin. 
The protocol treatment allows 1-2 cycles of standard induction therapy with cytarabine and 
daunorubicin (or idarubicin) and up to 4 cycles of cytarabine consolidation, with midostaurin 


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given sequentially during each cycle, and up to 12 cycles of maintenance therapy with single-
agent midostaurin as given in Figure 1-1.  
Table 2-1 
Dose and treatment schedule – Induction 
Treatment 
Dose, route and frequency (based on 28-day cycles) 
Cytarabine (Ara-C) with 
anthracycline (Idarubicin or 
Daunorubicin) (7+3) 
Ara-C:100-200 mg/m2/day by CIVI days 1-7 (168 hour infusion) 
Daunorubicin: 60-90 mg/m2/day by IV push on days 1-3 
or Idarubicin: 12 mg/m2/day by IV push on days 1-3 
Cytarabine with 
anthracycline (Idarubicin or 
Daunorubicin) (5+2) 
Ara-C:100 mg/m2/day by CIVI days 1-5 
Daunorubicin: 60 mg/m2/day by IV push on days 1-2 
or Idarubicin: 12 mg/m2/day by IV push on days 1-2 
Midostaurin 
50 mg (two 25 mg capsules) twice a day by mouth on days 8-28 
Table 2-2 
Dose and treatment schedule – Consolidation 
Treatment 
Dose, route and frequency (based on 28-day cycles) 
Cytarabine  
1-3 g/m2 every 12 h on days 1, 3, 5 x up to 4 cycles based on age and per 
investigator discretion  
Midostaurin 
50 mg (two 25 mg capsules) twice a day by mouth on days 8-28 
Table 2-3 
Dose and treatment schedule – Maintenance 
Treatment 
Dose, route and frequency (based on 28-day cycles) 
Midostaurin 
50 mg (two 25 mg capsules) twice a day by mouth on days 1-28 
2.5.2 
Study treatment and tolerability 
Study treatment 
Duration of exposure (days), actual cumulative dose and actual dose intensity will be 
summarized by period and overall for each of the study drugs: midostaurin, daunorubicin and 
idarubicin for the safety set. Duration of exposure (days), actual cumulative dose and actual 
dose intensity will be summarized also by cycle. The number of patients with midostaurin dose 
changes, interruptions and permanent discontinuations will be presented by age category and 
overall, along with reasons for the dose change/interruption/permanent discontinuation.   
Duration of midostaurin treatment exposure (days) will also be categorized and summarized by 
period and overall for the safety set using the following intervals: 
• ≤ 20; >20; >40; >60; >120; >180; >240; >300; >360 
Duration of study treatment exposure (days) will be summarized by period and overall for the 
safety set using the following intervals: 
• ≤ 28; >28; >56; >84; >112; >196; >280; >364; >448; >532 
Duration include  the rest/recovery days between cycles and will be derived as the following: 


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Last intake of any study treatment component – first intake of any study treatment component 
+1  
If there are more than 10 patients in each regimen exposure will be further summarized by 
regimen (“7+3” and “5+2”). 
Data will be listed for all patients in the safety set. 
Tolerability 
Tolerability of midostaurin will be evaluated in terms of dose reductions or dose interruptions 
due to an AE. 
2.5.3 
Prior, concomitant and post therapies 
Medications and significant non-drug therapies prior to and after the start of the study treatment 
will be coded according to the world health organization (WHO) Drug Reference List and 
summarized by anatomical therapeutic chemical (ATC) classification and preferred term.  
A summary table and listing for prior antineoplastic therapies will be provided for the full 
analysis set. 
Summary tables for concomitant medications and concomitant non-drug therapies by treatment 
period and overall for the full analysis set will be provided. Prior, concomitant and post study 
treatment medications and non-drug therapies will be listed for the safety set. Records outside 
of on-treatment period will be flagged. 
2.5.4 
Protocol deviations 
Protocol deviations will be listed for all screened patients. In addition, the number (%) of 
protocol deviations with COVID-19 relationship will be presented by type of deviation for all 
enrolled subjects. 
2.6 
Analysis of the primary objective 
2.6.1 
Primary endpoint 
The analysis of the primary endpoint is described in Section 2.8. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Not applicable. 
2.6.3 
Handling of missing values/censoring/discontinuations 
See Section 2.8. 
2.6.4 
Supportive analyses 
Not applicable. 


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2.7 
Analysis of the secondary objectives 
2.7.1 
Secondary endpoints 
The secondary objectives in this study are to assess the clinical efficacy of midostaurin in 
combination with chemotherapy regimens in induction and consolidation and the clinical 
efficacy of midostaurin in maintenance phase. 
Clinical efficacy rate will be presented for the FAS. All assessments before the last available 
on-treatment assessment will be included. Listings will include all data and will be based on the 
FAS. Records outside of on-treatment period will be flagged. For patients who discontinued 
prior to the first efficacy assessment, the response will be reported as ‘unknown’. 
Clinical efficacy rate is defined as the proportion of patients with complete remission (CR) or 
complete remission with incomplete hematologic recovery (CRi) as per local review. The CR 
and CRi are defined by the national comprehensive cancer network (NCCN) guidelines version 
1.2017 for AML.  
Clinical efficacy rate and its 95% confidence interval will be presented by period (induction, 
consolidation and maintenance) and overall as described in Section 2.1.1. The best overall 
response will be analyzed in each period and overall. If there are more than 10 patients in each 
regimen and age category, the clinical efficacy rate will be further summarized by regimen 
(“7+3” and “5+2”) and age category (e.g. <=60, >60 years and/or <= 60 / >60 to <=70 / > 70 
years old) and by sex.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
Not applicable. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Not applicable. 
2.8 
Analysis of secondary efficacy objective(s) 
Not applicable. 
2.9 
Safety analyses 
The primary objective is to further assess the safety of midostaurin in induction, consolidation 
and maintenance therapy including the ‘7+3’ regimen, daunorubicin (60-90mg/m2/day), the 
substitution of daunorubicin by idarubicin (12 mg/m2/day) and cytarabine (100-200 mg/m2/day) 
and also allowing the “5+2” reduced dose regimen. 
Except for baseline values, safety summary tables will only include on-treatment assessments 
(up to 30 days after study treatment discontinuation) and will be based on the safety set. Listings 
will include all data and will be based on the safety set.  
2.9.1 
Adverse events (AEs) 
The AEs will be re-coded using the latest version of the medical dictionary for regulatory 
activities (MedDRA) at the time of the analysis. 


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AEs will be graded using the common toxicity criteria for adverse events (CTCAE) 
Version 4.03. AEs will be summarized by period and overall for the safety set. AEs tables will 
be provided by age category. AEs with different starts dates in different periods will be counted 
within each period. If a patient reported more than one AE with the same preferred term (PT), 
the AE with the greatest severity will be presented. If a patient reported more than one AE 
within the same primary system organ class (SOC), the patient will be counted only once with 
the greatest severity at the SOC level, where applicable. An AE with missing CTCAE grade 
will be included in the ‘All grades’ column of the summary tables. 
In AE summaries, the primary SOC will be presented alphabetically and the PTs will be sorted 
within the primary SOC in descending frequency. 
Summary tables will be provided for: 
• Overview of AEs and age category 
• In-text table 
• All AEs regardless of relationship to study treatment by primary system organ class 
(SOC), preferred term (PT) and maximum severity and age category 
• In-text table by SOC and maximum severity 
• In-text table by PT and maximum severity 
• AEs suspected to be related to study treatment by SOC, PT and maximum severity and 
age category 
• In-text table by PT and maximum severity 
• AEs leading to treatment discontinuation regardless of relationship to study treatment by 
SOC, PT and maximum severity and age category 
• In-text table by PT and maximum severity 
• AEs leading to treatment reduction or interruption regardless of relationship to study 
treatment by SOC, PT and maximum severity and age category 
• In-text table by PT and maximum severity 
• Serious AEs (SAEs) regardless of relationship to study treatment by SOC, PT and 
maximum severity and age category 
• In-text table by PT and maximum severity 
• On-treatment deaths by SOC and PT and age category 
• In-text table by SOC and PT 
• All deaths by SOC, PT and age category 
• *Non-SAEs regardless of relationship to study treatment (threshold=5%) by SOC and PT 
• *On treatment deaths and SAEs by SOC and PT 
*(For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> AEs which are not SAEs with an incidence greater than 5% and 
on <on-treatment/treatment emergent> SAEs and SAE suspected to be related to study 
treatment will be provided by SOC and PT on the safety set. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 


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• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Listings will be provided for all AEs, SAEs and AEs leading to discontinuations (including 
those from the pre and post-treatment periods). Records outside of on-treatment period will be 
flagged. 
2.9.1.1 
Adverse events of special interest / grouping of AEs 
The adverse events of special interest (AESI) are maintained and updated on a regular basis in 
the project case retrieval sheet (CRS) and the latest version at the time of the analyses will be 
used. The CRS to produce AESI outputs will be stated in listing 14.3.2-8.  
A summary table for AESIs will be provided by period and overall for the safety set.  
2.9.2 
Deaths 
See Section 2.8.1. A listing will be provided of all deaths. Deaths outside of the on-treatment 
period will be flagged. 
2.9.3 
Laboratory data 
Laboratory values are converted to the international system of units (SI). 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 results where grades are not defined by CTCAE v4.03, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for key hematology and biochemistry by 
period and overall for the safety set: 
• Shift tables by grade (or low/normal/high if grades not available) to compare baseline to the 
worst on-treatment value: 
• Hematology: Neutrophils (absolute) and platelets 
• Chemistry: Creatinine, total bilirubin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) and alkaline phosphatase 
Listing of all laboratory data (including urinalysis, coagulation, thyroid panel, pregnancy test 
etc.) will be provided with the corresponding CTCAE grades, if applicable, and the 
classifications relative to the laboratory normal ranges. Records outside of on-treatment period 
will be flagged. 


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2.9.4 
Other safety data 
2.9.4.1 
Electrocardiogram (ECG) 
Electrocardiogram (ECG) data will be listed. Listing will include date of assessment, 
position=supine, any new clinically significant abnormalities (yes/no), QTcF (Fridericia’s 
correction), mean heart rate and mean PR, QT and QRS durations. Notable values and records 
outside of on-treatment period will be flagged. 
Where ECG replicates are provided for an assessment, the average of the ECG parameters at 
that assessment will be used in the analyses. 
Table 2-4 
Notable criteria for ECG parameters1 
Parameter 
 Notable low value  
Notable high value 
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 ≤ 60 ms 
Increase from baseline of >60 ms 
Heart rate 
Decrease  >25% from 
baseline and to a  
value <50 bpm 
Increase >25% from baseline and to a value >100 bpm 
PR 
-- 
Increase >25% from baseline and to a value >200 ms 
New value of >200 ms 
QRS 
-- 
Increase >25% from baseline and to a value >120 ms 
New value of >120 ms 
2.9.4.2 
Cardiac imaging 
The left ventricular ejection fraction (LVEF) data will be summarized for change from baseline 
to the worst on-treatment value by period and overall for the safety set. A listing will be 
provided showing the imaging method (multi gated acquisition scan (MUGA) or 
echocardiogram), date of assessment, LVEF percentage, the overall interpretation (normal, 
clinically insignificant abnormality or clinically significant abnormality) and the corresponding 
ejection fraction CTCAE v4.03 grades. Records outside of on-treatment period will be flagged. 
Grades: 
• Grade 0: Non missing value below Grade 2 
• Grade 1: NA 
• Grade 2: 50-40% or 10-19% drop from baseline i.e.  
• 40% ≤ LVEF ≤ 50% or  -20% < absolute change from baseline ≤ -10%  
• Grade 3: 39-20% or ≥20% drop from baseline i.e. 
• 20% ≤ LVEF <40% or absolute change from baseline ≤-20%  
• Grade 4: <20% i.e. 
• LVEF < 20% 


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2.9.4.3 
Chest X-ray 
Chest x-ray data will be listed showing date of assessment and the overall interpretation (normal, 
clinically insignificant abnormality or clinically significant abnormality). Records outside of 
on-treatment period will be flagged. 
2.9.4.4 
Vital signs 
Vital signs (height, weight, body surface area, temperature, position, pulse and systolic/diastolic 
blood pressure) will be summarized by period and overall for the safety set. Listings will be 
provided with notable values and records outside of on-treatment period flagged. 
Table 2-5 
Notable criteria for vital signs1 
Vital sign (unit) 
 Notable low value  
Notable high value 
Weight (kg) 
decrease ≥ 10% from baseline 
increase ≥ 10% from baseline 
Body temperature ( o C) 
-- 
≥ 39.1 
Pulse rate (bpm) 
≤ 50 and  
decrease from baseline of >25% 
≥ 100 and  
increase from baseline of >25% 
Systolic blood pressure 
(mmHg) 
≤ 90 and  
decrease from baseline of ≥ 20 
≥ 180 and  
increase from baseline of ≥ 20 
Diastolic blood pressure 
(mmHg) 
≤ 50 and  
decrease from baseline of ≥ 15 
≥ 105 and  
increase from baseline of ≥ 15  
2.9.4.5 
ECOG performance status 
ECOG performance status data will be listed. Records outside of on-treatment period will be 
flagged. Baseline summary will be provided as part of the demographics table. 
Table 2-6 
ECOG Performance Status 
Grade 
ECOG 
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, e.g. light house work, 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 
2.10 
Pharmacokinetic endpoints   
Not applicable.  


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2.11 
PD and PK/PD analyses 
Not applicable.  
 
 
 
 
2.13 
Biomarkers 
Not applicable. 
2.14 
Other Exploratory analyses 
 
 
 resource utilization will be used to evaluate the impact on 
symptom burden, overall quality of life and change in status of a patient’s overall satisfaction 
with. 
The safety set will be used for analyzing 
 resource 
utilization data unless otherwise specified. 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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2.14.3 
Resource utilization 
Descriptive statistics will be used to summarize resource utilization, e.g. the reason for 
hospitalization due to AE or not, if number of hospital days by facility/ward type and discharge 
status used during hospital stay(s). Listings will flag records outside of the on-treatment period. 
2.15 
Interim analysis 
No formal interim analysis is planned for this study. Analyses may be performed periodically 
(e.g. annually), if needed, to fulfill regulatory requests, safety updates or for publication 
purposes. 
3 
Sample size calculation 
Approximately 300 patients will be enrolled in this study. The planned sample size is based on 
the average expected accrual rate (17 patients per month) and the planned recruitment duration 
(18 months) of the trial. The actual sample size may differ from this planned number. A sample 
size of 300 patients provides a 95% probability of observing at least one patient with an adverse 
event (AE) assuming a true probability of occurrence of 1%. 
Table 3-1 provides probabilities to detect at least one patient with an AE for different sample 
sizes and different true AE incidences. 


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Table 3-1 
Probability to detect at least one patient with an AE for different 
sample sizes and different true AE incidences  
Incidence of an 
adverse event 
Sample size 
N=200 
N=250 
N=300 
0.4% 
0.5514 
0.6329 
0.6995 
0.5% 
0.6330 
0.7144 
0.7777 
0.6% 
0.6999 
0.7779 
0.8356 
0.8% 
0.7994 
0.8657 
0.9102 
1.0 % 
0.8660 
0.9189 
0.9510 
1.3% 
0.9270 
0.9620 
0.9803 
4 
Change to protocol specified analyses 
None. 
5 
References 
1. Oncology guideline for safety analysis, v1.0, dated 09-Jun-2016 
2. Oncology standard outputs TFL v3.1, dated 03-Aug-2017  
3. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 
1.2017, https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf, last accessed on 
27 March 2017 
4. Cheson 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. Journal of Clinical 
Oncology 21:24, 4642-4649 


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6 
Appendix 
6.1 
Imputation rules 
6.1.1 
AE, CM date imputation 
Table 6-1 
Imputation of start dates (AE, CM)  
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  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY  
o 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  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY.  
o 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 6-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal 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 *  
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* 
In the case of the imputed end date is before than start date, then the end date will be imputed 
equals to start date. 
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 an imputed end date provided. 


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6.1.2 
Prior therapies date imputation 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan for start and end dates in ZT domain. 
6.2 
Laboratory parameters derivations 
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. 
For missing Blood Urea Nitrogen (BUN) or urea values the following formulae will be applied: 
Urea (mg/dL) = BUN (mg/dL) / 0.357 
BUN (mg/dL) = Urea (mg/dL) / 2.1428 


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