Clinical trial NCT01883362
Conditions: Acute Myeloid Leukemia
Keywords: acute myeloid leukemia AML FLT3-ITD midostaurin PKC412 allogeneic hematopoeitic stem cell tranplant SCT HSCT CR1 adult
Sponsor: Novartis Pharmaceuticals
Start date: 2014-02-06; Completion date: 2018-04-30
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine if the addition of midostaurin (PKC412) to Standard of Care (SOC) therapy reduces relapse in FLT3-ITD mutated AML patients receiving an allogenetic hematopoietic stem cell transplant,

Detailed description:

Arms: arm 1: Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles). arm 2: Patients received standard of care alone in the post SCT setting
Interventions: intervention 1: Midostaurin intervention 2: Standard of Care
Intervention descriptions: intervention 1: Midostaurin was supplied in 25mg soft gelatin capsule taken orally twice a day for 28 days of each cycle. Patients will be treated for 12 cycles. intervention 2: Standard of Care was not defined per protocol. The investigator prescribed based on the commonly used medications given in the post SCT setting.

Protocol documents:
Prot_000.pdf: 
Oncology Clinical Development & Medical Affairs
PKC412, MIDOSTAURIN
Protocol CPKC412AUS23 / NCT01883362
A Phase II, randomized trial of standard of care, with or 
without midostaurin to prevent relapse following allogeneic 
hematopoietic stem cell transplantation in patients with 
FLT3-ITD mutated acute myeloid leukemia
Authors
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
02 (Clean)
Development phase
II
Document status
Final
Release date
02-Jul-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 15-Feb-2012
 


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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
Amendment 2 ....................................................................................................................11
Amendment 1 ....................................................................................................................14
Protocol summary:.............................................................................................................20
1
Background........................................................................................................................24
1.1
Overview of acute myeloid leukemia, epidemiology and current treatment.........24
1.1.1
FMS-like tyrosine kinase 3 mutations...................................................24
1.1.2
Allogeneic hematopoietic stem cell transplantation in AML ...............25
1.2
Introduction to investigational treatment(s) and other study treatment(s).............28
1.2.1
Overview of midostaurin.......................................................................28
2
Rationale............................................................................................................................31
2.1
Study rationale and purpose...................................................................................31
2.2
Rationale for the study design ...............................................................................32
2.3
Rationale for dose and regimen selection..............................................................32
2.4
Rationale for choice of drugs.................................................................................33
3
Objectives and endpoints...................................................................................................33
4
Study design ......................................................................................................................36
4.1
Description of study design ...................................................................................36
4.2
Definition of end of the study................................................................................37
4.3
Early study termination..........................................................................................37
5
Population..........................................................................................................................37
5.1
Patient population..................................................................................................37
5.2
Inclusion criteria ....................................................................................................38
5.3
Exclusion criteria...................................................................................................39
6
Treatment...........................................................................................................................40
6.1
Study treatment......................................................................................................40
6.1.1
Midostaurin dosing regimen .................................................................41
6.1.2
Treatment duration................................................................................41
6.2
Dose escalation guidelines.....................................................................................41
6.3
Dose modifications................................................................................................41
6.3.1
Dose modification and dose delay ........................................................41
 


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6.3.2
Follow-up for toxicities.........................................................................46
6.3.3
Anticipated risks and safety concerns of the study drug.......................46
6.4
Concomitant medications ......................................................................................46
6.4.1
Permitted concomitant therapy .............................................................46
6.4.2
Permitted concomitant therapy requiring caution and/or action...........48
6.5
Patient numbering, treatment assignment or randomization .................................50
6.5.1
Patient numbering .................................................................................50
6.5.2
Treatment assignment or randomization...............................................50
6.5.3
Treatment blinding................................................................................51
6.6
Study drug preparation and dispensation...............................................................51
6.6.1
Study drug packaging and labeling.......................................................51
6.6.2
Drug supply and storage........................................................................52
6.6.3
Study drug compliance and accountability ...........................................52
6.6.4
Disposal and destruction .......................................................................53
7
Visit schedule and assessments .........................................................................................53
7.1
Study flow and visit schedule................................................................................53
7.1.1
Screening...............................................................................................57
7.1.2
Treatment and study period...................................................................58
7.1.3
End of treatment visit including study completion and premature 
withdrawal.............................................................................................59
7.1.4
Follow up for survival and RFS............................................................60
7.2
Assessment types...................................................................................................61
7.2.1
Efficacy assessments.............................................................................61
7.2.2
Safety and tolerability assessments.......................................................62
7.2.3
Pharmacokinetics (PK)..........................................................................67
7.2.4
Biomarkers............................................................................................68
72
8
Safety monitoring and reporting........................................................................................73
8.1
Adverse events.......................................................................................................73
8.1.1
Definitions and reporting ......................................................................73
8.1.2
Laboratory test abnormalities................................................................74
8.2
Serious adverse events...........................................................................................74
8.2.1
Definitions.............................................................................................74
8.2.2
Reporting...............................................................................................75
8.3
Emergency unblinding of treatment assignment ...................................................76
8.4
Pregnancy prevention requirements ......................................................................76
 


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8.5
Pregnancy reporting...............................................................................................76
8.6
Warnings and precautions......................................................................................76
8.7
Data Monitoring Committee..................................................................................77
8.8
Independent Review committee ............................................................................77
9
Data collection and management.......................................................................................77
9.1
Data confidentiality ...............................................................................................77
9.2
Site monitoring ......................................................................................................78
9.3
Data collection.......................................................................................................78
9.4
Database management and quality control............................................................78
10 Statistical methods and data analysis ................................................................................79
10.1
Analysis sets ..........................................................................................................79
10.1.1
Full Analysis Set ...................................................................................79
10.1.2
Safety Set ..............................................................................................79
10.1.3
Per-Protocol Set ....................................................................................79
10.1.4
Pharmacokinetic Analysis Set...............................................................80
10.2
Patient demographics/other baseline characteristics .............................................80
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................80
10.3.1
Study medication...................................................................................80
10.3.2
Concomitant therapies...........................................................................80
10.4
Primary objective...................................................................................................80
10.4.1
Relapse free survival.............................................................................80
10.4.2
Statistical hypothesis, model, and method of analysis..........................81
10.4.3
Handling of missing values/censoring/discontinuations.......................81
10.4.4
Supportive analyses...............................................................................81
10.5
Secondary objectives .............................................................................................81
10.5.1
Key secondary efficacy evaluation .......................................................81
10.5.2
Safety objectives ...................................................................................82
10.5.3
Pharmacokinetics ..................................................................................84
10.5.4
Biomarkers............................................................................................84
.84
10.7
Interim analysis......................................................................................................84
10.8
Sample size calculation..........................................................................................84
11 Ethical considerations and administrative procedures ......................................................85
11.1
Regulatory and ethical compliance........................................................................85
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................85
11.3
Informed consent procedures.................................................................................85
 


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11.4
Discontinuation of the study..................................................................................86
11.5
Publication of study protocol and results...............................................................86
11.6
Study documentation, record keeping and retention of documents.......................86
11.7
Confidentiality of study documents and patient records .......................................87
11.8
Audits and inspections...........................................................................................87
11.9
Financial disclosures..............................................................................................87
12 Protocol adherence ............................................................................................................88
12.1
Amendments to the protocol..................................................................................88
13 References (available upon request)..................................................................................89
 


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List of figures
Figure 1-1
Probability of overall survival and relapse according to post 
remission therapy ..................................................................................27
Figure 1-2
Outcome after allogeneic transplantation in first CR for patients 
with AML and normal cytogenetics according to the presence or 
absence of FLT3-ITD............................................................................28
Figure 4-1
Study design..........................................................................................37
List of tables
Table 3-1
Objectives and related endpoints ..........................................................34
Table 6-1
Dose and drug schedule ........................................................................41
Table 6-2
Criteria for interruption and re-initiation of midostaurin treatment......43
Table 6-3
Preparation and dispensing ...................................................................51
Table 6-4
Packaging and labeling .........................................................................52
Table 6-5
Supply and storage of study treatments ................................................52
Table 7-1
Visit evaluation schedule ......................................................................54
Table 7-2
Treatment visit frequency and windows ...............................................59
Table 7-3
Follow up assessment frequency and windows ....................................61
Table 7-4
Bone marrow collection plan ................................................................62
Table 7-5
ECOG Performance Status....................................................................63
Table 7-6
Local clinical laboratory parameters collection plan ............................64
Table 7-7
ECG collection plan..............................................................................66
Table 7-8
Routine pharmacokinetic blood collection log .....................................67
68
70
71
72
 


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List of abbreviations
AE
Adverse event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AML
Acute Myeloid Leukemia
ASM
Aggressive Systemic Mastocytosis
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BR
Blast reduction
b.i.d.
bis in die / twice a day
BM
Bone Marrow
CBC
Complete Blood Count
CRF
Case Report/Record Form
CR
Complete Remission/Response
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events v4.0
CYP3A4
Cytochrome P 450 3A4
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DSE&E
Drug Safety and Epidemiology
DFS
Disease Free Survival
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
FLT3-ITD
fms-like tyrosine kinase 3, internal tandem duplication
FAS
Full Analysis Set
GVHD
Graft versus host disease
HSCT
Hematopoietic Stem Cell Transplant
HR
Hazard Ratio
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IWRS
Interactive Web Response System
kg
Kilograms
KM
Kaplan-Meier
MA
Medical Affairs
MCL
Mast cell leukemia
MDS
Myelodysplastic syndrome
mg
Milligrams
MTD
Maximum Tolerated Dose
MUGA
Multi Gated Acquisition scan
NRM
Non-relapse mortality
OS
Overall Survival
 


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p.o.
per os/by mouth/orally
PPS
Per Protocol Set
PD
Pharmacodynamics
PFS
Progression Free Survival
PHI
Protected Health Information
Pgp
P-glycoprotein
PK
Pharmacokinetics
PR
Partial Response
REB
Research Ethics Board
RFS
Relapse Free Survival
SS
Safety Set
SAE
Serious adverse event
SOP
Standard Operating Procedure
SOC
Standard of Care
TD-PCR
Tandem Duplication Polymerase Chain Reaction
t.i.d.
Three times per day
TKD
Tyrosine Kinase Domain
TRM
Treatment Related Mortality
ULN
Upper limit of normal
WT
Wild-type
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
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, for this study cycles are 28 days in 
length
Complete Remission
Patients are considered to be in Complete Remission (CR) when the 
following levels are detected in the Peripheral Blood (PB); ANC ≥ 
1000/uL; Platelet count ≥ 100K and no circulating leukemic 
myeloblasts in peripheral blood and Bone Marrow (BM) has adequate 
cellularity, BM blast count ≤ 5% and no auer rods detected
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 drug, midostaurin in this case, 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. 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
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.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival
Randomization number
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment
Relapse
Recurrence of disease (≥ 5% blasts in peripheral blood or bone 
marrow) applies to patient transplanted after achieving a complete 
remission and for whom relapse of disease can be recorded.
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.
 


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Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints
 


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Amendment 2
Amendment rationale
This study is actively enrolling in 23 centers with 35/60 patients enrolled to date. Based on 
feedback from various investigators the decision was made to change the inclusion criteria. 
The changes proposed in this amendment will primarily influence the eligibility criteria for 
this study changing the eligibility from age 18-60 to age 18-70 years. There were additional 
changes to dose interruption, visit schedule, 
 IRC and drug destruction.
Changes to the protocol
Administrative and Formatting changes are present throughout the document.
Throughout the document the D30-100 time points were amended to specify that D30-100 is 
from time of HSCT, “Day 30-100 Post HSCT”
Section 5.2: Inclusion Criteria:
Change to inclusion criteria 1: Age changed from between 18 and 60 to “between 18 and 70 
years of age”
Section 5.3: Exclusion Criteria:
Updated language in exclusion criteria 10: “Patient requires treatment with (a) strong 
CYP3A4 inhibitors other than those required for GVH or infection prophylaxis or treatment 
or (b) moderate or strong CYP3A4 inducer regardless of prophylaxis or treatment.”
Section 6.2: Update Criteria for interruption and re-initiation of Midostaurin treatment
Updated Nausea and Vomiting language from:
Grade 2
If this develops despite use of standard anti-emetic therapy, hold midostaurin for 3 
days (6 doses) and resume midostaurin as tolerated;
Grade 3 or 4
If this develops despite use of prophylactic anti-emetic therapy, hold midostaurin until 
recovery to Grade 2 (or at least 3 days) then restart. If this is felt to be related to study 
drug and the re-challange results in a subsequent Grade 3 or 4 toxicity then the patient 
should be discontinued from treatment.
Updated Nausea and Vomiting language to:
Grade 2
If this develops despite use of prophylactic anti-emetic therapy, hold midostaurin for 3 
days (6 doses) and resume midostaurin as tolerated
Grade 3 or 4
If this develops despite use of prophylactic anti-emetic therapy, hold midostaurin until 
recovery to Grade 2 (or at least 3 days) then restart. If this is felt to be related to study 
drug and the re-challange results in a subsequent Grade 3 or 4 toxicity then the 
midostaurin dose may be reduced (e.g from 50mg b.i.d to 25mg b.i.d).
In the event of additional toxicity requiring dose modification refer to “Grade 3 or 4 -
Other adverse events (Non-Hematologic) below.
Section 6.3.1: Added language referencing “the dose modification table”
 


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Section 6.4.2.2: Concomitant anti-infective prophylaxis and treatment:
Corrected the language to allow use of the suggested prophylaxis and spelling errors. 
Gramatical changes applied.
Section 6.6.4: Disposal and destruction:
Updated language to, “The study drug supply should be destroyed at the designated Novartis 
facility or third party, as appropriate. On site disposal or destruction is permitted upon 
Novartis review and agreement with the local policy/SOP.”
Table 7-1: Visit evaluation schedule
Updated language to allow CT scan, Chest x-ray/CT Scan
Removed, 
Section 7.2.2.6: Radiological examinations
Updated language to allow CT scan: “A screening chest image; Chest x-ray (CXR) or CT 
scan must be performed to assess study eligibility. If a CXR or CT scan was done within 14 
days of screening assessments then it does not need to be repeated.”
Section 7.2.2.7.2: Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
Added: “Cycle 3, 6 and at the EOT visit”
Table 7-7: ECG collection plan
Removed, “placebo”
Table 7-8: Routine pharmacokinetic blood collection log
Removed, “Unscheduled”
 


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Section 8.8: Independent Review committee
Updated language to allow for additional patients at the discretion of the IRC
Section 9.4: Database management and quality control
Removed language, “by joint written agreement between US Oncology Medical Affairs 
Franchise 
 and the US Oncology Medical Affairs Franchise 
.”
 


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Amendment 1
Amendment rationale
This trial is in study start-up with 14 sites opened and 3 patients have been randomized into 
the study. During the study start-up phase, feedback has been received from various 
investigators and EC/IRBs on areas where clarifications/Amendments could be made to the 
protocol - these have been incorporated in the current amendment.
The changes proposed in this amendment will influence the eligibility criteria, drug supply 
and storage, data monitoring and capturing, addition of assumption for study size calculation 
and change of study steering committee to independent review committee.
Changes to the protocol
Administrative and Formatting changes are present throughout the document.
Glossary of Terms:
Update definition of relapse to include 5% blasts in peripheral blood or bone marrow
Section 2.2, 2.4 and 4.1:
Deleted “Comparative” or “Comparator” language throughout the document. This trial is not 
a comparative trial.
Section 2.3 and 4.1:
Replaced “Study Steering Committee” with “Independent Review Committee”
Section 3: Objective and End Points
Table 3-1:
Section 5.1: Patient Population
Addition of “Enrollment criteria will be evaluated at both Visit 1 (screening) and Visit 2 
(C1D1), prior to randomization.”
Section 5.2: Inclusion Criteria:
Addition to inclusion criteria 4: “Peripheral blood”
Addition to inclusion criteria 7:
“Patients must have received a myeloablative conditioning regimen prior to HSCT. The 
following regimens are considered to be myeloablative. Alternative myeloablative regimens 
must be approved by Novartis prior to enrollment.”
 


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“Busulfan dosing based on individual PK parameters is allowed as long as myeloablative 
dosing is used (e.g., target AUC at least 4000 µM x min for 4 days).
Section 5.3: Exclusion Criteria
Addition to Exclusion criteria 3:
“haploidentical or cord blood”
Addition to Exclusion criteria 4:
“uncontrolled diabetes and chronic active pancreatitis”
Deletion from Exclusion criteria 6 and added as separate criteria:
“Patients with any pulmonary infiltrate including those suspected to be of infectious origin 
(unless resolves to ≤ Grade 1 within screening timeframe)”
Addition to Exclusion criteria 8:
“(For GVHD prophylaxis refer to Section 6.4.1.2)”
Addition to Exclusion criteria 9:
“GVHD related biopsy”
Updated Exclusion criteria 15:
Changed 3 to “5” months for male contraception.
Section 6.3.1: Dose modification and dose delay
Updated this language “. It is anticipated that dose interruption will be common during the 
early post-transplant period and the intent is to allow time to assess whether events are due to 
midostaurin, GVHD or other causes and to allow patients to remain on study.”
Addition to Table 6-2:
Pulmonary Infiltrates
Grade 3 or 4
Pulmonary infiltrate interruption of midostaurin for the 
remainder of the cycle until the infiltrate resolves to ≤ 
grade.
Deletion from other adverse events (Non-Hematologic): “if the toxicities occurred in the first 
2 months of treatment. Patients who tolerate this resumption of 50 mg b.i.d dose may remain 
on this dose.”
Addition to table notes: “Investigator discrection to continue study drug (midostaurin) may be 
used for the following if it is felt that the AE is not study drug related:
Cytopenias, AST/ALT elevation, Nausea or Vomiting. All of other AEs require dose 
modification per Table 6-2.”
Section 6.4: Concomitant medications
Addition of “Sorafenib” to prohibited drugs
Section 6.4.2.1:
Title updated to “Concomitant medications with potential for CYP3A4 interactions”
 


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Deleted this language “Midostaurin is primarily metabolized by CYP3A4 enzymes. Drugs 
which are substrates of CYP3A4 only (not inhibitors nor inducers) are not likely to interact 
with midostaurin. The recommendation is to avoid the co-administration of a strong CYP3A4 
inhibitor or a strong or moderate CYP3A4 inducer with midostaurin.”
Section 6.4.2.1.1 and 6.4.2.1.3: Updated with study codes
Section 6.4.2.1.2:
Deleted “strong” from title
Addition of “Moderate CYP3A4 inhibitors: Caution should be exercised for patients receiving 
moderate CYP450 3A4 inhibitors. A list of moderate CYP450 3A4 can be found on:
http://medicine.iupui.edu/clinpharm/ddis/main-table/”
Section 6.4.2.1.4:
Deleted this information from other section and updated here
Section 6.6.1: Study drug packaging and labelling:
Addition of “The drug should be stored in the blister pack until use and no further preparation 
of the study drug is needed.”
Deleted due to duplication of information already captured in subcategories Section 6.6
“Midostaurin will be provided as soft gelatin capsules to be taken orally. No further 
preparation of the study drug is needed. Two capsules of midostaurin 25 mg should be taken 
orally twice a day and a sufficient amount of study drug has to be dispensed to the patient at 
each visit.
Important: The storage conditions for study drug have to be maintained as described on the 
medication label.”
Section 6.6.2: Drug supply and storage
Addition to storage “Do not store above 25° C”
Section 6.6.4: Disposal and destruction
Addition to disposal language “Patients must return any remaining capsules should to the 
clinical site for proper disposal. Contact of the product with the skin should be avoided.”
Section 7.1: Study flow and visit schedule
Changes in Table 7-1
Screening labs must be drawn within 14 days before randomization instead of 21 days before 
randomization.
Addition of physical exam to be performed in cycle1 Day 3 visit.
Deletion of optional gene expression sample to be taken at Day 30 -100, C6D1 and C12D1
Updated language to “Study Drug dispensation and review”
 


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Addition of “archived stored frozen mononuclear cells/DNA” from Historical samples.
Section 7.1.1: Screening
Updated Gene Expression language to 
Patients are only required to complete failed assessments as long as the patient is re-screened 
within 14 days of the initial screening and have met eligibility by Day 60
Section 7.1.1.2: Information to be collected on screening failures
Updated language to “. All data for screen failures are entered into the IWRS system, 
including the reason for not being started on treatment”
Addition of “All screen failure data from the IWRS will be exported to a SAS dataset for final 
data review and archiving.”
Section 7.1.3.2: Study Evaluation Completion (SEC)
Updated language from Disease progression to “Relapse”
Table 7-4: Bone marrow collection plan
Updated language from Historical to “Results from initial diagnosis required for eligibility”
Section 7.2.2.5: Laboratory evaluations
Updated screening laboratory test should be drawn with 14 days of study entry instead of 7 
days
Table 7-6: Local clinical laboratory parameters collection plan
Serum “Lipase and Amylase” to be included in labs (chemistry) to be drawn at regular visits
Addition of “All efforts should be made to collect the labs prior to dosing. Fasting is not 
required for them.”
Section 7.2.2.5.1: Pregnancy and assessments of fertility
Updated child bearing potential language here are per exclusion criteria no. 14
Section 7.2.2.6: Radiological examinations
Addition of “If a CXR was done within 14 days of screening assessments then it does not 
need to be repeated”
Section 7.2.4.1: Central determination of FLT3 ITD status
Deletion of “Both results will be used in the analysis. If the results are discordant, the results 
will be summarized” and updated in Section 10.5.4
 


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Section 8.4: Pregnancy prevention requirements
Addition of this new title here and added a link for these requirements
Section 8.8: Independent Review committee
Updated independent review committee members selection criteria to those transplant expert 
physicians who are not participating in the trial
Section 10.5.4: Biomarkers
Addition of “The FLT3 results from the centralized assay using archived material will be 
compared to the local result, and differences will be described
In addition, the clinical outcome of RFS and DFS based on the FLT3 ITD result from the 
centralized assay compared to the local FLT3 ITD status will also be described.”
Section 10.8: Sample size calculation
Addition of sample size calculation assumption
“The sample size for the trial was chosen 30 patients per treatment arm to get separate 
estimates of the primary endpoint relapse free survival”
“If the two arms were compared, the following gives the power that could be achieved under 
2 scenarios of relapse rate with 30 patients per treatment arm.
Scenario 1: Assuming a 30% relapse rate in the SOC arm
Scenario 2: Assuming a 50% reduction with midostaurin (experimental arm)
i.e., 15% relapse rate in the experimental arm, a sample size of 30 patients in each arm will 
detect the reduction with 71% power. This calculation is based on one-sided type I error rate 
of 20%. The power would be 81% if we assume relapse rate to be even lower at 12% keeping 
everything else the same.”
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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. In addition, if 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 amended protocol.
 


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Protocol summary:
Protocol number
CPKC412AUS23
Title
A Phase II, randomized trial of standard of care, with or without 
midostaurin to prevent relapse following allogeneic hematopoietic stem 
cell transplantation in patients with FLT3-ITD mutated Acute Myeloid 
Leukemia
Brief title
Study to prevent relapse in FLT3-ITD mutated AML patients treated with 
standard of care (SOC) with or without midostaurin (PKC412) post 
allogeneic hematopoietic stem cell transplant.
Sponsor and Clinical 
Phase
Novartis
Investigation type
Drug
Study type
Interventional
Purpose and rationale
To determine if the addition of midostaurin (PKC412) to Standard of Care 
(SOC) therapy reduces relapse in FLT3-ITD mutated AML patients 
receiving allogeneic hematopoietic stem cell transplantation.
Primary Objective(s)
To determine if the addition of midostaurin to standard of care (SOC) 
therapy reduces relapse after at least 18 months of follow-up following 
allogeneic HSCT in FLT3-ITD mutant AML patients in first complete 
remission (CR1)
Secondary Objectives

To evaluate disease free survival (DFS)

To evaluate relapse free survival (RFS) all along the study

To evaluate non-relapse mortality (NRM)

To evaluate overall survival (OS)

To evaluate safety and tolerability of midostaurin in patients FLT3-ITD 
AML in the post-transplant setting

To evaluate pharmacokinetics (PK) of midostaurin

To assess FLT3-ITD mutation status centrally in archived material 
from diagnosis (if available) including the mutant:wild type ratio
Study design
This is a randomized, open label Phase II study to investigate the efficacy 
and safety of 50mg twice daily midostaurin in patients with FLT3 ITD 
mutated AML after HSCT.
Population
60 patients, randomized to Standard of Care +/- Midostaurin; (30 patients 
per treatment arm)
Male and Female patients, aged 18 to ≤ 70 years old, FLT3-ITD mutated 
AML patients receiving allogeneic hematopoietic stem cell transplantation
 


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Inclusion criteria

Patients must be between 18 and 70 years of age

Patients must have an ECOG Performance Status of ≤ 2

Patients must have a documented Unequivocal diagnosis of AML 
according to WHO 2008 classification (>20% blasts in the bone 
marrow and/or peripheral blood), excluding M3 (acute promyelocytic 
leukemia).

Patients must have a documented FLT3 ITD mutation, determined by 
local laboratory for eligibility (historical tissue will be requested for 
central analysis confirmation)

Patients who have undergone allogeneic HSCT in CR1 from a 
matched related or matched unrelated donor. All of the following 
criteria must also be met:
HLA typing to include available 8/8 or 7/8 allele HLA matched donor 
(at A,B,C, DRB1) Single allelic mismatch allowed

Patients who received one of the following conditioning regimens 
Alternative regimens must be approved by Novartis prior to enrollment:
Busulfan*/Fludarabine (Bu/Flu)
Busulfan (16 mg/kg PO or 12.8 mg/kg IV)
Fludarabine (120-180 mg/m2)
Fludarabine / Melphalan (Flu/Mel)
Fludarabine (120-180 mg/m2)
Melphalan (≤ 150 mg/m2)
Busulfan*/Cyclophosphamide (Bu/Cy)
Busulfan (16 mg/kg PO or 12.8 mg/kg IV)
Cyclophosphamide (120 mg/kg)
Cyclophosphamide/Total Body Irradiation (Cy/TBI)
Cyclophosphamide (120 mg/kg)
TBI (1200-1420 cGy)

Note: Busulfan dosing based on individual PK parameters is 
allowed as long as myeloablative dosing is used (e.g., target AUC 
at least 4000µM x min for 4 days)

Recovery of counts by day 42 and able to start midostaurin by day 60 
post-HSCT (first dose of midostaurin to start no earlier than 28 days 
post-HSCT); ANC >1000µL, platelets ≥20,000 without platelet 
transfusion

Patients must have the following laboratory values:
AST and ALT ≤ 3 x Upper Limit of Normal (ULN)
Serum Bilirubin ≤ 3 x ULN
Serum Creatinine ≤ 2.5 x ULN
Exclusion criteria

Patients whom have failed prior attempts at allogeneic HSCT

Patients who have received an autologous transplant, haploidentical or 
cord blood.

Patients with Acute GVHD Grade III-IV

Patients with any other known concurrent severe/and or uncontrolled 
medical condition (expect carcinoma in-situ), which could compromise 
participation in the study (e.g. uncontrolled infection, uncontrolled 
diabetes, chronic active pancreatitis)

Patients with a known confirmed diagnosis of HIV infection or active 
viral hepatitis.
 


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
Impaired cardiac function including any of the following:
-Screening ECG with a QTc > 450 msec. If QTc > 450 and electrolytes are 
not within normal ranges, electrolytes should be corrected and then the 
patient rescreened for QTc.
-Patients with congenital long QT syndrome
-History or presence of sustained ventricular tachycardia
-Any history of ventricular fibrillation or torsades de pointes
-Bradycardia defined as HR. < 50 bpm
-Right bundle branch block + left anterior hemiblock (bifascicular block)
-Patients with myocardial infarction or unstable angina < 6 months prior to 
starting study
-Congestive Heart Failure NY Heart Association class III or IV
-Patients with an ejection fraction < 45% assessed by MUGA or ---ECHO 
within 21 days prior to starting study cycle 1 (of midostaurin or control 
group)

Patients with any pulmonary infiltrate including those suspected to be 
of infectious origin (unless resolves to ≤ Grade 1 within screening 
timeframe)

Antineoplastic chemotherapy or radiotherapy, within 21 days prior to 
study cycle 1.

Patients who have had any surgical procedure, excluding central 
venous catheter placement or other minor procedures (e.g. skin 
biopsy) within 14 days prior to study cycle 1.

Patient requires treatment with strong CYP3A4 inhibitors or moderate 
or strong CYP3A4 inducers other than those required for GVH or 
infection prophylaxis or treatment

Known sensitivity to study drug(s) or class of study drug(s)

Participation in a prior investigational study within 30 days prior to 
enrollment or within 5-half lives of the investigational product, 
whichever is longer

Pregnant or nursing (lactating) women, or women of child-bearing 
potential, must use highly effective methods of contraception during 
dosing and for 30 days after treatment period

Sexually active males unless they use a condom during intercourse 
while taking drug and for 5 months after stopping midostaurin 
medication. They should not father a child in this period. A condom is 
required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.

Not able to understand and to comply with study instructions and 
requirements
Investigational and 
reference therapy
Midostaurin (PKC412)
Efficacy assessments

Relapse Free Survival (RFS),

Disease Free Survival (DFS),

Overall Survival (OS)
 


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Safety assessments

Adverse Events (AEs)

Physical examination

Vital Signs and weight

Performance status

Laboratory evaluations

ECGs

Non-Relapse Mortality (NRM)
Other assessments

Pharmacokinetics (PK) of midostaurin

FLT3-ITD mutation status in archived material from diagnosis



Data analysis
The primary efficacy criterion is the relapse free survival (RFS). The 
primary objective is related to the Kaplan-Meier estimate at 18 months.
Efficacy variables will be analyzed using Kaplan-Meier and Cox methods. 
For more details refer to Section 10.4.2.
Safety endpoints will be assessed using descriptive statistics.
Key words
acute myeloid leukemia, FLT3-ITD; midostaurin; PKC412; allogeneic stem 
cell transplant; hematopoietic stem cell transplantation (HSCT)
 


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1
Background
1.1
Overview of acute myeloid leukemia, epidemiology and current 
treatment
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells. It is 
characterized by differentiation arrest and malignant proliferation of clonal myeloid 
precursors of the bone marrow. AML represents about 30% of the forms of adult leukemia 
and the incidence is estimated at 13,000 new cases per year in the U.S. and incidence 
increases with age. The American Cancer Society also estimates the number of deaths due to 
AML as 9,000 per year. (American Cancer Society 2011)
The diagnostic workup of acute leukemia is multifaceted and may include bone marrow 
biopsy, flow cytometry, cytogenetics, and gene mutation analysis. The 2008 WHO 
classification categorizes myeloid leukemia into numerous subtypes and prognostic groups. 
The presence of abnormal cytogenetics, or the presence of leukemia-associated gene 
mutations (FLT3, NPM1, CEPBA) are important prognostic indicators. (Estey 2010) 
Treatment approaches in AML vary for patients with APL (M3) but have remained relatively 
unchanged for the past three decades for all other types of AML.
Combination chemotherapy regimens commonly used in treatment of non-APL AML have 
typically included induction with an anthracycline and nucleoside analog. Complete remission 
(CR) rates of 65-90% in younger AML patients can be observed with daunorubicin or 
idarubicin given in conjunction with cytarabine for one to two cycles. (Ravandi 2007) 
Recently, higher doses of daunorubicin have shown better results in younger AML patients 
although this benefit did not extend to the FLT3 ITD patients (Fernandez 2009). 
Consolidation therapy typically involves high dose cytarabine and duration is debated 
although typically includes three to four cycles of post-remission therapy. (Estey 2010)
Despite the high CR rate, the majority of adults with AML will relapse within 3 years with 
only 40-45% of younger patients achieving cure. (Burnett 2011) There are subsets of AML 
patients with very poor outcomes, including intermediate or poor risk by cytogenetics or 
molecular analysis. In such cases, approaches including stem cell transplantation (HSCT) are 
recommended in CR1. (NCCN Guidelines v1.2012, Estey 2010)
1.1.1
FMS-like tyrosine kinase 3 mutations
The FMS-like tyrosine kinase 3 (FLT3) belongs to the group of class III receptor tyrosine 
kinases. It belongs to a family of important signaling receptors that include c-KIT, c-FMS, 
and PDGFR. FLT3 is a growth factor receptor involved in hematopoietic cell growth and 
differentiation. FLT3 receptor and its ligand (FL) also play an important role in survival and 
self-renewal of early hematopoietic progenitors, monocytic precursors and in lymphoid 
development. Activation of FLT3 results in receptor auto-phosphorylation leading to 
downstream signaling of the RAS/MAPK, JAK/STAT5, and PI3K/AKT pathways. In normal 
bone marrow (BM), FLT3 is expressed on progenitor cells and regulates stem cell 
proliferation. As hematopoietic progenitor cells differentiate and mature, FLT3 expression is 
normally lost.
 


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In AML, signaling of FLT3 pathway is often activated and leads to malignant blast cell 
proliferation, in part due to over expression of FLT3 receptor in leukemia cells. However, a 
major research advance was the identification of mutations occurring in the FLT3 gene in 
AML patients. It is the most common somatic mutation identified in AML, with an incidence 
of about 25% (Kindler 2010, Kottaridis 2001). Two major types of FLT3 gene mutation have 
been identified: 1) internal tandem duplication (ITD) and 2) tyrosine kinase domain (TKD) 
point mutations (PM) and ITDs make up a majority of FLT3 mutations in newly diagnosed 
patients (Thiede 2002). These duplications are the result of 3 to > 400 base pairs inserted into 
the receptor in-frame (Schnittger 2002). The ITDs promote ligand-independent FLT3 receptor 
dimerization and signal activation, culminating in cellular proliferation (Kiyoi 1998, 
Hayakawa 2000).
The presence of FLT3-ITDs has been found in certain studies to be the strongest predictor of 
patient outcome (Kottaridis 2001, Kiyoi 1999). AML patients harboring FLT3 ITD mutations 
are characterized by certain pretreatment features like higher levels of white blood cell counts 
and blood and bone marrow blasts (Frohling 2002, Thiede 2002). FLT3 ITD has been 
reported consistently as an unfavorable prognostic marker for relapse-free (RFS) and overall 
survival (OS) (Kottaridis 2001, Frohling 2002, Thiede 2002, Gale 2008). In a study of 854 
AML patients, an ITD was present in 27% of the patients. Although presence of FLT3 
mutation did not impact CR rate, long term clinical outcomes varied based on the presence of 
FLT3 ITD. The relapse rate at 5 years was 64% in patients with the mutation versus 44% in 
those without. Disease free survival at 5 years was 30% compared to 46% in patients without 
a mutation and overall survival of 32% compared to 44% of patients without the mutation. 
(Kottaridis 2001)
Furthermore, additional factors of the FLT3 ITD mutation may impact outcome, including 
size of the base pair insertion, higher allelic ratio (mutant: wild-type FLT3) and insertion site 
(Stirewalt 2006, Thiede 2002, Kayser 2009) As details of FLT3 ITD mutations continue to be 
evaluated, it remains clear that AML with a FLT3 ITD mutation results in higher relapse,
shorter DFS and shorter OS which has led to an increased focus on HSCT in CR1 in this 
group.
1.1.2
Allogeneic hematopoietic stem cell transplantation in AML
It has long been recognized that despite achieving CR, undetectable leukemic cells are often 
present leading to relapse in most patients and post remission treatment is warranted. Post 
remission treatment options include intensive conventional chemotherapy (often high dose 
cytarabine), prolonged maintenance treatment, or intensive therapy followed by autologous or 
allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high-risk AML are 
typically evaluated for HSCT early as the chance of long-term cure with chemotherapy alone 
is low. Allogeneic HSCT is a highly effective treatment for AML, with improved progression 
free survival (PFS) and OS for patients with intermediate and high-risk disease. 
(Yanada 2005, Estey 2011)
In the subset of patients with FLT3 ITD mutations whom achieve complete remission, 
outcomes of HSCT have so far only been reported in three large retrospective analyses. The 
MRC group compared outcomes in FLT3 ITD+ and FLT3 ITD- patients (Gale 2005) This 
intent to treat analysis (donor versus no donor) failed to show a statistically significant 
 


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difference between HSCT and no HSCT in FLT3 ITD patients; however the small sample size 
of 35 FLT3 ITD allograft patients limits the power in the analysis (Gale 2005, Gale 2007). 
The observed OS in the allograft patients at 5 years was 58% and 44% in the FLT3 ITD- and 
ITD+ groups, respectively. The rate of relapse over 5 years was 31% in FLT3 ITD+ and 25% 
in FLT3 ITD- patients whom were allograft recipients.
An AMLSG analysis also compared outcomes for patients with FLT3 ITD versus FLT3 wild 
type (WT) in groups given post-remission chemotherapy, autologous HSCT or allogeneic 
HSCT. (Bornhauser 2007) The 376 younger, intermediate risk patients included 176 patients 
with FLT3 ITD. Overall, there were 103 matched sibling allogeneic transplants, 141 
autologous transplants and 132 chemotherapy recipients without transplant. Kaplan Meier 
analyses show that transplant increased OS in the FLT3 ITD+ patients to similar levels as 
FLT3 WT patients who underwent allogeneic or autologous transplant (approximate median 
OS 72 months for allogeneic and 36 months for autologous). The group of FLT3 ITD patients 
whom received chemotherapy had a much shorter OS than FLT3 WT. While this study shows 
benefit with HSCT in FLT3 ITD, the OS is double that of other literature reports in FLT3 WT 
AML. Discussions amongst researchers point to likely exclusion of early TRM and/or 
censoring the early relapse events in FLT3 ITD which could introduce bias and magnify the 
difference between the arms (Schlenk 2008, Bornhauser 2007, Meshinchi 2006). Following 
allogeneic HSCT, relapse occurred in about 35% of patients in the FLT3 ITD group (N=40) 
which was much higher than in the FLT3 wild type (N=60) patients at a median follow-up of 
53 months. (Bornhauser 2007)
 


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Figure 1-1
Probability of overall survival and relapse according to post remission 
therapy
Probability of overall survival and relapse according to postremission therapy. After a median 
follow-up of 53 months for surviving patients, the probability of overall survival and relapse (from 
remission) are shown for patients having received either chemotherapy (n = 132), autologous 
transplant (n = 141), or allogeneic transplant (n = 103) as postremission therapy. Tx indicates 
transplantation. (Bornhauser 2007)
These findings were corroborated by data recently published from the EBMT group. Of 206 
patients whom underwent matched sibling or matched unrelated HSCT with myeloablative 
conditioning, FLT3 ITD was observed in 120 (58%) patients. This is the largest group of FLT 
ITD patients undergoing allogeneic transplant and was the most clearly defined patient group 
of the three retrospective analyses. The incidence of relapse at two years was higher in the 
FLT3 ITD positive group at a rate of 30% compared to 16% in the negative group. Disease 
free survival was also negatively impacted by FLT3 positive status (DFS at 2 years of 58% vs. 
71% in FLT3 ITD negative) (Brunet 2012). Despite the intervention of HSCT, patients with 
FLT3 ITD relapsed at a much higher rate than patients without the mutation. Most relapses in 
the FLT3 ITD group occurred by 18 months after HSCT. Despite differences in the three 
retrospective analyses, they report a similarly high rate of relapse of 30-35% in patients with 
FLT3 ITD undergoing allogeneic HSCT.
 


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Figure 1-2
Outcome after allogeneic transplantation in first CR for patients with 
AML and normal cytogenetics according to the presence or absence 
of FLT3-ITD
Outcome after allogeneic transplantation in first CR for patients with AML and normal cytogenetics 
according to the presence (dashed line) or absence (solid line) of ITD of FLT3 gene. (A) Estimated 
probability of 2 years of cumulative incidence of relapse; (B) leukemia-free survival after 
transplantation at 2 years. (Brunet 2012)
Due to the poor prognosis conferred with a FLT3 ITD mutation, many centers are prioritizing 
allogeneic HSCT for these patients who remain at high risk for relapse. (Levis 2011, 
Van den Brink 2010) New treatments which could improve relapse rates after HSCT would be 
a significant benefit. Clinical trials are now launching to understand whether maintenance 
therapy targeting FLT3 ITD shortly after allogeneic transplantation can delay or prevent 
relapse in this high risk subset of AML patients (Metzelder 2009, Sora 2011, Levis 2010).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of midostaurin
Midostaurin is an inhibitor of several protein kinase C (PKC) isoforms, of the tyrosine kinase 
of the vascular endothelial growth factor receptor (VEGFR) and most importantly of the class 
III tyrosine protein kinases FLT3 (fms-like tyrosine kinase-3) 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 signaling of the respective growth factors in 
cells and results in growth arrest. The anti-proliferative effects of midostaurin were easily 
detectable in FLT3-ITD, FLT3-TKD and FLT3 WT cells (Weisberg 2002, Barry 2007). 
Midostaurin has also been found to revert the P-glycoprotein (Pgp) mediated MDR (multidrug 
resistance) phenotype by inhibiting the function of Pgp (Utz 1998).
Midostaurin is currently in Phase II/Phase III clinical development including:
 


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
Two phase II single arm single agent studies in patients with aggressive systemic 
mastocytosis / Mast Cell Leukemia

One phase III randomized, double-blind study (CALGB 10603; RATIFY) in patients with 
FLT3-mutated AML.
1.2.1.1
Clinical experience
1.2.1.1.1 Pharmacokinetic and pharmacodynamic data
The clinical pharmacology of midostaurin has been extensively studied in healthy volunteers 
as well as patients with AML and diabetes mellitus (Yin 2008; Stone 2012). Midostaurin is 
rapidly absorbed following oral administration with peak plasma concentrations observed 1-3 
hours post-dose. Upon daily oral dosing, midostaurin concentrations accumulated in a time 
linear manner in the first 3-8 days. Thereafter, the PK becomes non-linear with an apparent 
large increase in CL/F. This relatively high apparent oral clearance necessitates a high dosing 
rate (e.g. bid administration) to maintain target drug levels in the long term. Midostaurin 
concentrations reach steady-state after 28 days of daily dosing. (Yin 2008) In vitro studies 
have shown that midostaurin, CGP62221, and CGP52421 inhibit mutant FLT3 at low 
nanomolar concentrations, with IC50s of 10-36 nM, 26 nM and 584nM, respectively. 
(Manley 2003; Stone 2012)
Midostaurin is predominantly metabolized by CYP3A4 iso-enzymes to form two major, 
pharmacologically active metabolites which may contribute to in vivo activity: CGP62221 
(half-life ~ 30 hours, comparable to midostaurin’s half-life of ~25 hours) and CGP52421 
(half-life of ~28 days). Phase I studies in healthy volunteers evaluated the effects of a strong 
CYP3A4 inhibitor (ketoconazole) and a strong CYP3A4 inducer (rifampin) on concentrations 
of midostaurin and its metabolites and the effect of midostaurin on midazolam (a sensitive 
CYP3A4 substrate). Concomitant administration with strong CYP3A4 inhibitors or inducers 
significantly alters midostaurin concentrations. Midostaurin does not cause a drug-drug 
interaction with CYP3A4 substrates.
For additional pharmacokinetic information, please refer to the Investigators Brochure.
1.2.1.1.2 Overview of efficacy with midostaurin
Midostaurin 
has demonstrated 
activity 
in 
patients with relapsed or 
refractory 
AML/myelodysplastic 
syndrome 
(MDS) 
in 
Studies 
CPKC412A2104 
(2104) 
and 
CPKC412A2104E1 (2104E1). In Study 2104E1, the rate of BR (blast reduction) for the 
efficacy population (n=92) was 71% in FLT3-mutant patients and 42% in FLT3-WT patients. 
One partial response (PR) occurred in a FLT3-mutant patient on the 100 mg b.i.d. dose 
regimen. Both doses levels evaluated in this trial (50 mg b.i.d., and 100 mg b.i.d.) were well 
tolerated; the toxicity profiles and response rates were similar for the two doses of 
midostaurin. The results suggest that midostaurin has hematologic activity in both FLT3-
mutant and wild-type patients. The degree of clinical activity observed supports further 
studies in earlier stage disease and that combine midostaurin with other agents such as 
chemotherapy especially in FLT3-mutant AML (Fischer et al 2010).
 


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Preliminary data from the phase Ib, CPKC412A 2106 (2106), study of midostaurin in 
combination with standard daunorubicin and cytarabine therapy in patients with newly 
diagnosed AML patients indicate that midostaurin at 50 mg p.o. b.i.d. can be given with 
tolerable side effects in this patient population (Stone 2012). Efficacy data for the 50 mg b.i.d. 
population was presented at the American Society of Hematology (ASH) in 2009. The 
investigator assessment of Complete response (CR) occurred in 32/40 (80%) of all patients 
(20/27 [74%] of FLT3–WT patients, 12/13 [92%] of FLT3–mutant patients). One and 2 year 
overall survival (OS) for the patients with FLT3–mutant AML was 85% and 62%, 
respectively, and was comparable to that of the FLT3–WT subgroup (81% and 59%, 
respectively). This data was based on small numbers and not stratified for type of FLT3 
mutation (TKD, ITD, or allelic ratio) (Stone 2009). This study supported the ongoing double 
blind, placebo controlled, phase III study, CPKC412A2301 (CALGB 10603, Ratify), in newly 
diagnosed FLT3 mutated AML. Enrollment in that trial is complete (N=717) and awaiting the 
Overall Survival (OS) events required for final analysis.
In addition to the AML programs described above, an ongoing single arm, phase II study, 
CPKC412D2201 (2201) in aggressive systemic mastocytosis / mast cell leukemia has 
completed enrollment with stage I (N=40) and extension (N=40) to determine the efficacy and 
safety of 100 mg twice daily oral midostaurin as a single agent. The Overall Response Rate, 
per Valent criteria, for stage I is 60% (24/40 eligible patients) including a major response rate 
of 52.5%. (Gotlib 2012)
1.2.1.1.3 Overview of safety with midostaurin
Overall, approximately 1746 subjects have received midostaurin including ~650 patients with 
AML / MDS. In AML patients, doses of up to 600 mg per day have been given, but the 50 mg 
twice daily dose is recommended based upon reaching the IC50 and showing acceptable 
tolerability. Safety data in AML are based upon three studies: monotherapy in FLT3 mutated 
patients (2104 Core; N=20), monotherapy in relapsed AML or ineligible for chemotherapy 
(2104E1; N=95) and front-line combination therapy with daunorubicin and cytarabine (2106; 
N=69). (Stone 2005, Fischer 2010, Stone 2012). Data from the maintenance phase of the 
Phase III (2301, CALGB 10603 Ratify) study would also be very informative but the ongoing 
trial remains blinded at this time. Single agent safety data from 2104E1 will be discussed.
In study 2104E1, patients were randomized to receive midostaurin at doses of 50 mg b.i.d. or 
100 mg b.i.d. Of the patients enrolled, 73% were relapsed/refractory and 61% were greater 
than 60 years of age. Six patients had previously undergone HSCT. Midostaurin was 
generally well tolerated at both dose levels. All 95 patients experienced at least one AE 
regardless of relationship to study drug. The most frequent events were grades 1 or 2 nausea 
(61%; Grade 3 was 1%), vomiting (49%; Grade 3 was 1%), diarrhea (44%; Grade 3 or 4 was 
5%), fatigue (38%; Grade 3 was 3%), pyrexia (35%; Grade 3 was 7%) and dyspnea (29%; 
Grade 3 or 4 9%). The most commonly reported grade 3 / 4 AEs were febrile neutropenia 
(21%), thrombocytopenia (19%), neutropenia (12%), anemia (13%) and pneumonia (12%). 
[Inv Brochure ed 16, Table 6-20] The decreases observed in the hematology parameters were 
as expected for this patient population. Only one patient discontinued treatment due to a 
hematologic abnormality (grade 3 febrile neutropenia). The majority of new or worsened 
biochemistry abnormalities were of CTC grade 1-2. There were grade 3 or 4 abnormalities in 
 


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AST/ALT in 13% patients (2 were Grade 4, both receiving 100 mg b.i.d.), amylase 7% and 
albumin 5%. The full table of newly occurring or worsening hematology and chemistry 
abnormalities is shown in the Investigators Brochure Version 16. [Tables 6-21 and 6-22]
SAEs were reported for 71 (75%) patients and most commonly included: febrile neutropenia 
(20 patients), pneumonia (17 patients), pyrexia (13 patients), dyspnea (8 patients), 
thrombocytopenia (7 patients) and anemia (6 patients). The incidence of SAEs was similar for 
both dose groups. SAEs were mostly considered to be due to disease progression. Eighteen 
(19%) patients had SAEs that were considered related to study drug, with grade 3/4 anemia 
and thrombocytopenia being the most frequently reported.
In 2011, a pooled safety analysis was performed using data available from 14 solid tumor or 
AML/MDS studies. Trials included combinations with 5-FU, paclitaxel, gemcitabine, 
carboplatin, cisplatin, daunorubicin, and cytarabine. The pooled analysis included 542 
subjects (213 with AML/MDS) and the most common drug related toxicities (> 20%) in these 
phase I/II trials were nausea, vomiting and diarrhea, general disorders / administration site, 
nervous system disorders (including headache, dizziness, syncope), metabolism and nutrition 
disorders, and decreased appetite. AEs occurring less frequently (10-19%) included fatigue, 
headache, anemia, AST/ALT elevations, thrombocytopenia and constipation. (Investigators 
Brochure, ed 15) In the pooled analysis, frequencies of cardiac events were consistent with the 
investigated populations.
A Phase I trial evaluated the effect of midostaurin on the QTc interval in healthy volunteers in 
a thorough QTc study. The mean maximum change from baseline (QTcF) for midostaurin 
compared with placebo demonstrated a lack of QTcF prolongation effects. (DelCorral 2012) 
This trial evaluated midostaurin and the short acting metabolite but could not investigate 
effects of the long-acting metabolite at steady state. The long acting metabolite information 
cannot be attained from a healthy volunteer study thus will be provided from the CALGB 
10603 (Ratify) dataset.
Overall, AEs suspected to be related to midostaurin treatment were mostly Grade 1 and 2 
gastrointestinal events requiring little or no intervention. These were considered related to 
midostaurin, as the frequency increased at higher dose levels. At the 100mg twice daily dose 
in AML patients with chemotherapy, patients discontinued treatment more frequently due to 
nausea and vomiting despite addition of antiemetic therapy which contributed to selection of a 
50mg twice daily dose which was found to be well tolerated. In addition to prophylactic anti-
emetics, administering the doses with meals can reduce gastrointestinal AEs. These AEs are 
most common in the early cycles of administration. In the ongoing ASM/MCL studies, 
patients are tolerating the 100 mg twice daily dose for up to 4 years; however, prophylactic 
anti-emetics are given to all patients.
2
Rationale
2.1
Study rationale and purpose
Midostaurin is an oral agent that has been shown to inhibit FLT3 kinase in preclinical in vitro 
and in vivo studies, as well as clinically in patients with both ITD and TKD FLT3 mutations 
(FLT3mut). Both directly and indirectly, midostaurin also potently inhibits multiple other 
 


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molecular targets thought to be important for the pathogenesis of AML. These targets include 
VEGFR-1, a VEGF receptor; c-kit; H- and K-ras; as well as the multidrug resistant gene, 
MDR. Midostaurin, a staurosporine derivative, has been identified as an inhibitor of both 
mutated and wild type FLT3 kinase. Midostaurin potently inhibits recombinant FLT3 kinase 
in an in vitro kinase assay, and inhibits tyrosine phosphorylation of mutant FLT3, both ITD 
mutants and D835Y point mutants in vitro. These data suggest that midostaurin directly 
blocks the kinase activity of mutant FLT3, thereby interfering with its transforming functions. 
Expression of a mutant FLT3 receptor (FLT3-ITD or the TKD D835Y) in vivo in murine 
marrow cells results in a lethal myeloproliferative syndrome which can be successfully cured 
with the administration of midostaurin. (Weisberg 2002)
2.2
Rationale for the study design
This is a phase II, randomized, open label trials of standard of care, with or without 
midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplantation 
(HSCT) in patients with FLT3-ITD acute myeloid leukemia. The intent of this study is to 
evaluate whether the addition of midostaurin to standard of care (SOC) following allogeneic 
HSCT improves Relapse Free Survival (RFS) in FLT3-ITD AML patients in first complete 
remission (CR1). This trial will not be powered to detect a difference between the two arms. 
Powering of the trial is not feasible considering the rare nature of FLT3-ITD mutant AML 
receiving a HSCT. With a 22-25% FLT3-ITD mutation rate and approximately 25% rate of 
HSCT, estimated from the ongoing Phase III study (2301, CALGB 10603 Ratify), more than 
1050 newly diagnosed AML patients would need to be evaluated to identify 60 patients 
undergoing HSCT in CR1. The control arm, SOC, in this study provides the first prospective 
set of subjects treated at the same centers in the same timeframe which will allow an estimate 
of treatment effect which can be used to design a larger trial. There are no published sets of 
prospective, FLT3-ITD AML outcomes after transplantation.
2.3
Rationale for dose and regimen selection
Patients receiving midostaurin on this trial will receive 50mg b.i.d for 28 consecutive days of 
each cycle.
In adults, the maximum tolerated dose (MTD) of the single agent was 75 mg t.i.d. in relapsed 
AML. Preliminary PK/PD analysis from this study showed that the plasma level of 
midostaurin seems to be well above the IC50 value for FLT3 ITD/D835 inhibition. 
(Stone 2005) In this study, it was also demonstrated that single agent treatment up to 100 mg 
b.i.d. was most tolerable. Doses of at least 50 mg b.i.d. still demonstrated presence of blast 
activity.
In relapsed/refractory AML patients, average trough concentrations observed at the 50- and 
100-mg doses showed that steady-state levels of midostaurin and the metabolites reached the 
50% inhibitory concentration. This supports a minimum dose of 50 mg twice daily in FLT3 
mutated AML. (Fischer 2010). Currently the 100 mg b.i.d. dose is only used in Aggressive 
Systemic Mastocytosis patients which targets c-KIT rather than FLT3.
In order to achieve IC50 values at steady state and allow the most tolerable dosing, the dose 
for patients receiving midostaurin on this trial will be 50mg b.i.d daily. For patients unable to 
 


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tolerate the proposed dose, dose adjustments are outlined in Section 6.3. An Independent 
Review committee (IRC) will additionally review safety information after 10, 20, and 30 
patients, regardless of treatment assignment, have completed at least 3 cycles or discontinued.
2.4
Rationale for choice of drugs
All patients on study will receive Standard of Care (SOC) therapy and half of these patients 
will be randomized to receive midostaurin in addition to this. Currently, SOC therapy varies 
per treating institution in the post HSCT setting but includes anti-infective prophylaxis and 
treatment and GVHD prophylaxis and treatment.
A placebo will not be used in this trial. While a placebo was considered, it can limit 
enrollment which is already expected to be the largest challenge for the trial. In addition, the 
primary endpoint of the trial is relapse and clinical relapse in patients with AML is not 
expected to be impacted by the open label design. The frequency of relapse assessments is the 
key component and is the same for both arms.
All SOC treatment while on study must be captured for all patients on the Concomitant 
Medications / Significant Non-drug Therapies eCRF page.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
 


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
To determine if the addition of midostaurin to standard of care 
(SOC) therapy reduces relapse after at least 18 months of 
follow-up following allogeneic HSCT in FLT3-ITD mutant AML 
patients in first complete remission (CR1)
Relapse Free Survival (RFS) is defined as the time from 
transplant to relapse or death due to the disease 18 
months post transplant
Key secondary
Refer to Section 10.5.
To evaluate disease free survival (DFS)
DFS is defined as the time from transplant to relapse or 
death from any cause
To evaluate relapse free survival (RFS) all along the study
Relapse Free Survival (RFS) is defined as the time from 
transplant to relapse or death due to the disease
To evaluate non-relapse mortality (NRM)
NRM is calculated from the date of transplant to date of 
patient death due to reasons other than 
relapse/progressive AML.
To evaluate overall survival (OS)
OS is defined as the time from transplant to the date of 
death from any cause
To evaluate safety and tolerability of midostaurin in patients with 
FLT3 –ITD AML in the post-transplant setting
Safety will be assessed by the Common Toxicity Criteria 
for Adverse Events (CTCAE) version 4.0. Incidence of 
adverse events (AEs), serious adverse events (SAEs), 
changes from baseline in clinically notable changes in 
vital signs and CTC grading for laboratory results 
(hematology, blood chemistry, ECGs) will be reported.
To evaluate pharmacokinetics (PK) of midostaurin in the post-
transplant
PK concentration-steady state levels
To assess FLT3-ITD mutation status centrally in archived 
material from diagnosis, if available
FLT3-ITD mutation status, including the mutant:wild type 
ratio
 


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Objective
Endpoint
Analysis
 


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4
Study design
4.1
Description of study design
This is a randomized, open label Phase II study to investigate the efficacy and safety of twice 
daily midostaurin in patients with FLT3 ITD AML after HSCT.
Patients will be treated with the Standard of Care (SOC) treatment with or without (+/-) 
midostaurin in a 1:1 randomization. All patients who have engrafted and recovered counts by 
day 42 after HSCT will be eligible for randomization no later than 60 days after transplant 
(may occur as early as day 28 post transplant), regardless of treatment assignment. Based on 
other tyrosine kinase inhibitor data, it is anticipated that starting midostaurin shortly after 
transplant will offer the best chance to improve relapse rates. Most relapses after transplant in 
FLT3-ITD patients occur by day 100 so an earlier treatment start (days 28 to 60) is targeted in 
this trial. Midostaurin will be given at a dose of 50mg twice daily continuously in cycles of 4 
weeks (28 days) each for up to 12 cycles or disease relapse or withdrawal due to any cause, 
whichever occurs earlier.
Patient visits will occur monthly for one year during the Treatment Phase (Cycles 1-12). 
Visits will continue in the Follow-up Phase thru 24 months post HSCT. Hematology Lab 
Panels will be collected every two months to assess relapse in addition to survival status. 
Patients that have not relapsed, died or withdrawn at 24 months will be asked to provide 
quarterly hematology panels until the study ends.
The study will end when all patients have been followed for 24 months post HSCT, unless all 
patients have died or withdrawn from the study prior to this time point. Prior to database lock, 
an additional OS and RFS update will be requested for all living patients.
Patients will have bone marrow aspirate performed early (between days 30 and 100 post-
HSCT), at Cycle 6, at Cycle 12, at relapse or more frequently if clinically indicated. All 
patients will begin treatment, regardless of treatment assignment, upon recovery of counts as 
listed in the eligibility criteria. Patients who do not meet recovery eligibility criteria by day 42 
post allogeneic HSCT will not be eligible for this trial. Safety will be evaluated by an
independent review committee after 10, 20, and 30 patients, regardless of treatment arm, have 
completed at least 3 cycles or discontinued. An independent review committee of 3 to 5 study 
investigators will review safety information to include (but not limited to) adverse events, 
serious AEs, lab parameters, bone marrow results 
.
 


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Figure 4-1
Study design
1Standard of Care (SOC), 2Relapse Free Survival (RFS), 3Disease Free Survival, 4Non Relapse 
Mortality, 5Overall Survival, 6 Pharmacokinetics, 7End of Treatment
Midostaurin Group
SOC1 + Midostaurin
(50mg BID)
Control Group
SOC1
12 cycles
Primary :
•18 month RFS2
Secondary: 
•DFS3
•RFS
•NRM4
•OS5
•Safety and Tolerability
•PK6
•FLT3 mutational status
AML Patients
FLT-ITD+ in CR1
Recovery Post-
HSCT 
(MUD/MRD)
Count Recovery 
by D42 
Treatment starts 
by D28-D60 
post SCT
Randomize 
1:1 
n = 60
Screening
Treatment
Follow up  
Endpoints
Adverse Event 
Reporting 
30 days post 
EOT7
Relapse and 
Survival 
Assessments 
24 months post 
HSCT and/or 
until end of study
4.2
Definition of end of the study
The study will end when all planned patients have either been followed for 24 months post 
HSCT, died or have withdrawn from the study. Prior to database lock, an additional OS and 
RFS update will be requested from all living patients.
4.3
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 7.1.3 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Patients with acute myeloid leukemia (AML) must have documented FLT3-ITD mutation and 
have undergone allogeneic HSCT in first complete remission (CR1) to be eligible to enter the 
study.
Sixty (60) patients will be enrolled during the study. The investigator or his/her designee must 
ensure that all patients who meet the following inclusion/exclusion criteria are offered 
 


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enrollment into the study. Enrollment criteria will be evaluated at both Visit 1 (screening) and 
Visit 2 (C1D1), prior to randomization.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. Patients who have completed the study may not be re-
enrolled for a second course of treatment.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained prior to any screening procedures. If consent 
cannot be expressed in writing, it must be formally documented and witnessed, ideally via an 
independent trusted witness.
1. Patients must be between 18 and 70 years of age
2. Patient must give written informed consent
3. Patients must have an ECOG Performance Status of ≤2
4. Patients must have a documented Unequivocal diagnosis of AML according to WHO 
2008 classification (>20% blasts in the bone marrow and/or peripheral blood), excluding 
M3 (acute promyelocytic leukemia).
5. Patients must have a documented FLT3 ITD mutation, determined by local laboratory for 
eligibility (historical tissue will be requested for central analysis confirmation)
6. Patients who have undergone allogeneic HSCT in CR1 from a matched related or matched 
unrelated donor. All of the following criteria must also be met:

HLA typing to include available 8/8 or 7/8 allele HLA matched donor (at A,B,C, 
DRB1) Single allelic mismatch allowed
7. Patients must have received one of the following conditioning regimens prior to HSCT.
Alternative regimens must be approved by Novartis prior to enrollment:
Busulfan*/Fludarabine (Bu/Flu)
Busulfan (16 mg/kg PO or 12.8 mg/kg IV)
Fludarabine (120-180 mg/m2)
Fludarabine / Melphalan (Flu/Mel)
Fludarabine (120-180 mg/m2)
Melphalan (≤ 150 mg/m2)
Busulfan*/Cyclophosphamide (Bu/Cy)
Busulfan (16 mg/kg PO or 12.8 mg/kg IV)
Cyclophosphamide (120 mg/kg)
Cyclophosphamide/Total Body Irradiation (Cy/TBI)
Cyclophosphamide (120 mg/kg)
TBI (1200-1420 cGy)
*
Note: Busulfan dosing based on individual PK parameters is allowed as long as 
myeloablative dosing is used (e.g., target AUC at least 4000µM x min for 4 days)
8. Recovery of counts by day 42 and able to start Standard of Care +/- midostaurin by day 60 
post-HSCT (first dose of midostaurin to start no earlier than 28 days post-HSCT)
 


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
ANC >1000 perµL, platelets ≥20,000 perµL without platelet transfusion
9. Patients must have the following laboratory values:

AST and ALT ≤3 x Upper Limit of Normal (ULN)

Serum Bilirubin ≤3 x ULN

Serum Creatinine ≤2.5 x ULN
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients whom have failed prior attempts at allogeneic HSCT
2. Patients who have received an autologous transplant, haploidentical or cord blood.
3. Patients with Acute GVHD Grade III-IV
4. Patients with any other known concurrent severe/and or uncontrolled medical condition 
(expect carcinoma in-situ), which could compromise participation in the study (e.g. 
uncontrolled infection, uncontrolled diabetes, chronic active pancreatitis)
5. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis.
6. Impaired cardiac function including any of the following:

Screening ECG with a QTc > 450 msec. If QTc > 450 and electrolytes are not within 
normal ranges, electrolytes should be corrected and then the patient rescreened for 
QTc.

Patients with congenital long QT syndrome

History or presence of sustained ventricular tachycardia

Any history of ventricular fibrillation or torsades de pointes

Bradycardia defined as HR. < 50 bpm

Right bundle branch block + left anterior hemiblock (bifascicular block)

Patients with myocardial infarction or unstable angina < 6 months prior to starting 
study

Congestive Heart Failure NY Heart Association class III or IV

Patients with an ejection fraction < 45% assessed by MUGA or ECHO within 21 days 
prior to starting study cycle 1 (of midostaurin or control group)
7. Patients with any pulmonary infiltrate including those suspected to be of infectious origin 
(unless resolves to ≤ Grade 1 within screening timeframe)
8. Antineoplastic chemotherapy or radiotherapy, within 21 days prior to study cycle 1 (For 
GVHD prophylaxis refer to Section 6.4.1.2)
9. Patients who have had any surgical procedure, excluding central venous catheter 
placement or other minor procedures (e.g. skin biopsy/GVHD related biopsy) within 14 
days prior to study cycle 1
10. Patient requires treatment with (a) strong CYP3A4 inhibitor other than those required for 
GVH or infection prophylaxis or treatment or (b) moderate or strong CYP3A4 inducer
regardless of prophylaxis or treatment
11. Known sensitivity to study drug(s) or class of study drug(s)
 


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12. Participation in a prior investigational study within 30 days prior to enrollment or within 
5-half lives, if known, of the investigational product, whichever is longer.
13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test within 48 hours of beginning study treatment.
14. 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 3 months after treatment completion. 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) 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). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms).
15. Sexually active males unless they use a condom during intercourse while taking drug and 
for 5 months after stopping midostaurin medication. They should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.
16. Not able to understand and to comply with study instructions and requirements
6
Treatment
6.1
Study treatment
Study Treatment refers to the treatment assigned upon randomization;

Standard of Care (SOC) or

Standard of Care (SOC) with midostaurin.
 


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Study drug refers to any Novartis investigational drug(s) being used for an unapproved 
indication. For this study, the term “Study drug” refers to midostaurin (PKC412) supplied in 
25 mg soft gelatin capsules which are packaged in blister packs.
6.1.1
Midostaurin dosing regimen
Table 6-1
Dose and drug schedule
Study drug
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Midostaurin (PKC412)
25mg Soft gelatin capsule; 
oral administration
50mg
(2 x 25mg) capsules)
Twice Daily
(28 day cycles)
The standard dose of midostaurin is listed in Table 6-1 and should be followed unless patients 
meet criteria for dose modifications Section 6.3.
6.1.2
Treatment duration
The treatment phase is defined as Cycles 1 – 12. Patients will be randomized to SOC +/-
midostaurin. Patients receiving midostaurin will receive study drug for 12 cycles (max) or 
until patient experiences unacceptable toxicity, disease progression and/or treatment is 
discontinued at the discretion of the investigator or withdrawal of consent, whichever comes 
first.
6.2
Dose escalation guidelines
Not applicable
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment as listed in Table 6-2.
The toxicities listed will require treatment interruption of midostaurin treatment until recovery 
to ≤ Grade 2 or for a maximum of up to 21 consecutive days (a modification to this rule for 
nausea/vomiting is noted below). In addition, dosing interruption is allowed to up to 1 week at 
a time to assess if it is related to GVHD or midostaurin. It is anticipated that dose interruption 
will be common during the early post-transplant period and the intent is to allow time to 
assess whether events are due to midostaurin, GVHD or other causes and to allow patients to 
remain on study. Patients may be re-challenged per the dose modification table. Any patient 
requiring a longer delay than 21 days will be discontinued from the study.
Until durable engraftment has occurred, cytopenias may require transfusion support and/or 
growth factors and are permitted as per standard of care. If the cytopenia(s) are not considered 
related to midostaurin, the cause should be documented and dose holding and reduction of 
midostaurin is not required. If the cytopenia(s) is determined to be possibly attributable to 
midostaurin, the dose modification guidelines should be followed.
 


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Dose adjustments are required for patients taking concomitant strong CYP3A4 inhibitors with 
midostaurin, refer to Section 6.4.2 for details.
These changes must be recorded on the Dosage Administration Record eCRF.
 


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Table 6-2
Criteria for interruption and re-initiation of midostaurin treatment
Recommended dose modifications for CPKC412AUS23
Investigations (Hematologic)
Neutropenia (ANC)
Grade 4 (ANC < 500/mm3)
First event, hold midostaurin dose until recovery to Grade 2 then restart at 50mg b.i.d
Second event, hold midostaurin until recovery to Grade 2, then restart at 25mg b.i.d for 2 weeks 
and then re-escalate to 50mg b.i.d as tolerated
Third event, patient should be discontinued if neutropenia is attributable to midostaurin
Febrile Neutropenia
Grade 4
First event, hold midostaurin dose until recovery to Grade 2 then restart at 50mg b.i.d
Second event, hold midostaurin until recovery to Grade 2, then restart at 25mg b.i.d for 2 weeks 
and then re-escalate to 50mg b.i.d as tolerated
Third event, patient should be discontinued if neutropenia is attributable to midostaurin
Thrombocytopenia
Platelet count < 15,000/mL
First event, hold midostaurin dose until recovery to ≥ 20,000 per microliter then restart at 50mg 
b.i.d
Second event, hold midostaurin dose until recovery to ≥ 20,000 per microliter then restart at 25mg 
b.i.d for 2 weeks and then re-escalate to 50mg b.i.d as tolerated
Third event, patient should be discontinued if other causes for the thrombocytopenia cannot be 
determined
Other Hematologic Adverse Events
Grade 3 or 4
If a patient has not recovered from a new or worsening grade 3 or 4 hematologic toxicity 
(suspected relationship to midostaurin) to grade ≤ 2 within 21 days, he/she must be discontinued 
from the study.
 


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Recommended dose modifications for CPKC412AUS23
Investigations (Hepatic)*
Bilirubin, AST or ALT
Grade 3 (> 3.0 - 10.0 x ULN) related to midostaurin 
(rather than VOD, GVH)
If alternate causes of liver dysfunction have been managed, but liver dysfunction persists, hold 
midostaurin until recovery to Grade 2 then restart.
If this is felt to be related to study drug and the re-challenge results in a subsequent Grade 3 or 4 
elevation, then patient should be discontinued from treatment.
Pulmonary Infiltrates
Grade 3 or 4
Pulmonary infiltrate interruption of midostaurin for the remainder of the cycle until the infiltrate 
resolves to ≤ grade.
Investigation (Gastro intestinal)
Nausea or Vomiting
Grade 2
If this develops despite use of prophylactic anti-emetic therapy, hold midostaurin for 3 days (6 
doses) and resume midostaurin as tolerated; e.g. reduce the dose to 25mg b.i.d; if the event 
continues hold for 3 days (6 doses), resume at 25mg qd. If the event continues the patient should 
be discontinued from treatment,
Grade 3 or 4
If this develops despite use of prophylactic anti-emetic therapy, hold midostaurin until recovery to 
Grade 2 (or at least 3 days) then restart at 50mg b.i.d. If this is felt to be related to study drug and 
the re-challange results in a subsequent Grade 3 or 4 toxicity then the midostaurin dose may be 
reduced to 25mg b.i.d (50mg/day).
In the event of additional toxicity requiring dose modification refer to “Grade 3 or 4 -Other adverse 
events (Non-Hematologic) below.
 


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Recommended dose modifications for CPKC412AUS23
Other adverse events (Non-Hematologic)
Grade 3 or 4
If a patient has recovered to ≤ Grade 2 within 21 days of interrupting treatment, the midostaurin 
dose will be reduced to 25mg b.i.d (50mg/.day). In the event of additional toxicity requiring dose 
modification, further dose reductions of midostaurin below 25mg b.i.d (50mg/day) will not be 
allowed. If the patient tolerates the lower dose of midostaurin (25 mg b.i.d) and considering the 
nature of the PK profile of midostaurin (concentration drops following multiple doses), a dose 
increase back to 50mg b.i.d may be attempted as tolerated.
If a patient has not recovered from any grade 3 or 4 non-hematologic toxicity to < Grade 2 within 
21 days of interrupting treatment (with the exception of the dose modification stated above for 
Grade 2-4 nausea and vomiting) will be discontinued from the study.
QTc Prolongation
Refer to Table 7-7.
All dose modifications should be based on the worst preceding toxicity. Common Toxicity Criteria for Adverse Events (CTCAE Version 4.0)
Investigator discrection to continue study drug (midostaurin) may be used for the following if it is felt that the AE is not study drug related:
Cytopenias, AST/ALT elevation, Nausea or Vomiting. All of other AEs require dose modification per Table 6-2.
 


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6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value must be followed at least once a week during drug-
hold and be followed for 4 weeks, and subsequently at 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. If a patient requires a dose delay of > 21 
days from the intended day of the next scheduled dose, then the patient must be discontinued 
from the study. However, the patient will continue to be followed for toxicity as previously 
described. All patients will be followed for adverse events and serious adverse events for 30 
days following the end of study treatment period.
For collection of survival data, the status of all patients who discontinue study treatment will 
be followed through 24 months. Patients that have not relapsed, died or withdrawn at 24 
months will be followed until the study ends.
The study will end when all patients have been followed for 24 months post HSCT, unless all 
patients have died or withdrawn from the study prior to this time point. Prior to database lock, 
an additional OS and RFS update will be requested for all living patients.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment 
for expected toxicities, including management of study-drug induced adverse events, i.e., 
nausea and vomiting are provided in Section 6.4.1.1.1. Refer to preclinical toxicity and or 
clinical data found in the Investigator’s Brochure.
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 drug. All medications taken within 28 days prior to 
randomization and all concomitant medications/therapies must be recorded on the 
Concomitant/Non-Drug Therapy eCRF.
Other anticancer agents including chemotherapy, radiation therapy, or biologic response 
modifiers, e.g. FLT3 inhibitors (including sorafenib), are not permitted prior to relapse. Donor 
Lymphocyte Infusion (DLI) is not allowed except for viral specific Cytotoxic T Cells (CTLs)
or low dose CTLs for EBV lymphoproliferative disorders (i.e., DLI for worsening chimerism 
is not allowed prior to relapse). No other investigational drug is allowed during the study.
6.4.1
Permitted concomitant therapy
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.
Based on preclinical investigations demonstrating that midostaurin is an inhibitor of P-gp 
though not a good substrate, the interaction between midostaurin and P-gp subtrate, 
 


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daunorubicin was studied in the clinical study [CPKC412A2106]. The pharmacokinetics of 
daunorubicin did not show any notable modification when coadministered with midostaurin.
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 study drug 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-diarrhetic 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 
suggested. However, the kind and dose of anti-diarrheal should be chosen per investigator 
discretion.
6.4.1.2
Prophylaxis and treatment management of GVHD and systemic 
immunosuppressive medications
As per standard of care, GVHD prophylaxis regimens are recommended (e.g., mycophenolate 
mofetil, cyclosporine, methotrexate, tacrolimus, sirolimus) and should follow standard of care 
at your institution.
If patients develop active GVHD, standard of care per your institution should be followed and 
steroids are permitted. While some of these medications are substrates of CYP3A4, 
midostaurin has minimal impact on CYP3A4 substrates (see Section 1.2.1.1.1 and 
Section 6.4.2 on PK). The recommendation is to avoid the co-administration of a strong 
CYP3A4 inhibitor or a strong and moderate CYP3A4 inducer with midostaurin. Levels of 
cyclosporine, tacrolimus, sirolimus or cyclosporine should be monitored closely, as per 
standard of care.
6.4.1.3
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 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 
3 months post study because of the long half-life of the metabolite, CGP52421.
 


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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 3 months of midostaurin 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) 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). For female subjects on the study 
the vasectomized male partner should be the sole partner for that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Sexually active males unless they use a condom during intercourse while taking drug and for 
5 months after stopping midostaurin medication. They should not father a child in this period. 
A condom is required to be used also by vasectomized men in order to prevent delivery of the 
drug via seminal fluid.
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 [CPKC412A2109]; [CPKC412A2110],. 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 where midostaurin was co-administrated 
with the potent CYP450 3A4 inhibitor ketoconazole, the exposure of midostaurin increased 
by 10-fold (90% confidence interval 7.4-14.5) [CPKC412A2109]. 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. If there are no other treatment options for the patient (i.e life-threatening 
infection), a compensatory reduction in the dose of midostaurin is warranted.
 


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The dose adjustment of midostaurin is aimed to achieve similar exposure to the range 
observed of midostaurin 50mg twice daily without the strong inhibitor. As a result, a dose 
reduction of 7-fold based on the lower bound of the confidence interval of the ratio of [AUC 
midostaurin with ketoconazole/AUC midostaurin without ketoconazole] is recommended 
[CPKC412A2109]. Hence the prescribed dose reduction during the time of a concomitant 
strong CYP3A4 inhibitor (see list below) is midostaurin 25 mg every other day.
If the strong CYP3A4 inhibitor is discontinued, approximately 2 to 3 days should elapse 
before increasing the midostaurin dose back to the dose prior to initiation of the strong 
CYP3A4 inhibitor.
Strong CYP3A4 inhibitors: clarithromycin, telithromycin, troleandomycin, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, itraconazole, ketoconazole, 
posaconazole, voriconazole, boceprevir, telaprevir, cobicistat, conivaptan, nefazodone.
Moderate CYP3A4 inhibitors: Caution should be exercised for patients receiving moderate 
CYP450 3A4 inhibitors. A list of moderate CYP450 3A4 can be found on:
http://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 where midostaurin was co-administrated 
with the potent CYP450 3A4 inducer rifampicin, the Cmax and AUC of midostaurin 
decreased by 73% and 94%, respectively [CPKC412A2110]. To avoid sub-therapeutic 
exposure to midostaurin, moderate or potent CYP450 3A4 inducers should not be 
coadministered.
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:
Midostaurin, administered as a single dose or in multiple doses, did not appear to affect the 
concentrations of midazolam or its metabolite 1’-hydroxymidazolam [CPKC412A2112]. 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 is described below:
Prophylaxis
Fluconazole (moderate CYP3A4 inhibitor)
Micafungin
 


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If a patient requires active treatment for a fungal or mold infection and and the only treatment 
options is an azole that is a strong CYP3A4 inhibitorthen 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, if there are no other treatment options to treat the infection, a dose reduction of 
midostaurin is required.See details in Section 6.4.2. With intra-patient variability with regard 
to CYP3A4 inhibition and midostaurin pharmacokinetics, the suggested approach is to avoid 
strong CYP3A4 inhibitors unless there are no treatment alternatives.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a 9-digit Subject Number (Subject No.), that is 
assigned when the patient is first presented 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 4-digit center number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential 5-digit patient 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 
Interactive Web Response System (IWRS). Once assigned to a patient, a patient number will 
not be reused. If the patient fails to be assigned to treatment for any reason, the reason for not 
being assigned to treatment will be captured through the IWRS system. Patients cannot be re-
randomized.
6.5.2
Treatment assignment or randomization
This is a randomized (1:1) two-arm, open-label study with standard of care with or without
(+/-) midostaurin 50mg twice daily for up to 12 cycles.
The two arms will be: (1) Standard of Care and (2) Standard of Care plus midostaurin.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the 
Interactive Web Response Technology (IWRS) provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms.
After all assessments have been completed, all patients who fulfill all inclusion/exclusion 
criteria will be randomized via IWRS on C1D1 to one of the treatment arms. The investigator 
or his/her delegate will call or log on to the IWRS and confirm that the patient fulfills all the 
inclusion/exclusion criteria. The IWRS will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm. The randomization number will be 
communicated by the IWRS confirmation via email, to the investigator and or delegate for 
patient designation to the trial.
 


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6.5.3
Treatment blinding
Not applicable – Open label treatment
6.6
Study drug preparation and dispensation
Midostaurin will be administered by twice daily oral dosing of 50 mg (i.e. 4 capsules of 
midostaurin 25 mg in two divided doses) beginning on Day 1 and should be administered with 
water following breakfast and dinner. Previous studies have shown midostaurin to be better 
tolerated (with respect to short term nausea and vomiting) if taken following meals. Patients 
should be instructed to swallow capsules whole and not chew capsules. An interval of 
approximately 12 hours between doses is preferred. If vomiting occurs, no re-dosing is 
allowed before the next scheduled dose. If a dose of midostaurin is missed by the patient, the 
dose should not be made up and the patient should only take the next scheduled dose.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
Table 6-3
Preparation and dispensing
Study treatments
Dispensing
Preparation
Midostaurin (PKC412)
Gelatin capsules 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.
Midostaurin is packaged in blister 
packs. Midostaurin should not be 
removed from the blister pack 
until the patient is ready to take 
the scheduled dose. Upon 
opening a blister pack, patients 
may notice a pungent odor but 
will dissipate.
6.6.1
Study drug packaging and labeling
Midostaurin will be supplied by Novartis as soft gelatin capsules to be taken orally. The study 
drug will be provided as open label bulk and packed in child resistant blisters. The drug 
should be stored in the blister pack until use and no further preparation of the study drug is 
needed. Upon opening a blister pack, patients may notice a pungent odor. The odor is due to 
ethyl thioglycolate that forms when ethanol in the capsules interacts with the thermostabilizer 
in the foil. The capsules are not affected, and the odor will dissipate. Each capsule contains 25 
mg of midostaurin. Medication labels will comply with the legal requirements of each country 
and be printed in the local language.
One component of the packaging has a 2-part label. Immediately before dispensing study drug 
to the patient, investigator staff will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) containing that patient’s unique patient 
number.
 


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Table 6-4
Packaging and labeling
Study drug
Packaging
Labeling (and dosing frequency)
Midostaurin (PKC412)
25mg soft gelatin capsules in 
child resistant blisters
Labeled as PKC412 25mg
Study treatment packaging has a 2-part 
label.
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, the study drug should be stored 
according to the instructions specified on the drug labels. Do not store above 25° C.
Table 6-5
Supply and storage of study treatments
Study treatment
Supply
Storage
Midostaurin (PKC412)
Centrally supplied by Novartis
Do not store above 25° C.
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
The data that will be collected on study drug and other therapy use will provide information 
about drug exposure. These data should correspond to the information requested on the eCRFs 
entitled Dosage Administration Record (used for midostaurin administration
only); 
Concomitant Medications; any other eCRFs specific to the project and/or patient diaries.
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.
Compliance will be assured by administrations of the study drug under the supervision of 
investigator or his/her designee, and will be verified by determinations of PKC412 and two 
metabolites in the plasma.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study drug in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study drug and packaging on a regular basis, at the end of the study or at the time 
of study drug discontinuation.
6.6.3.3
Handling of other study treatment
Not applicable.
 


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6.6.4
Disposal and destruction
Patients must return any remaining capsules should to the clinical site for proper disposal. 
Contact of the product with the skin should be avoided.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study drug, 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.
The study drug supply should be destroyed at the designated Novartis facility or third party, as 
appropriate. On site disposal or destruction is permitted upon Novartis review and agreement 
with the local policy/SOP.
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.
No CRF will be used as a source document.
 


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Table 7-1
Visit evaluation schedule
Protocol 
Section 
7.2 (if 
applicable)
Screening
Cycle 1
Day 30 –
Day 100 
Post 
HSCT
Subsequent 
Cycles (2-12)
*Refer to 
Section for 
Frequency
End of 
study 
treatment 
(EoT)
Follow 
up
Survival 
follow up
Study 
Completion 
Evaluation
Visit Number
1
2
3
4
5-15
16 (777)
501, 502 
etc
701,701, 
etc
778
Day of cycle
-14 to -1
1
3
15
1
Last
n/a
n/a
n/a
Obtain Informed Consent
X
IWRS/IRT
X
X
X
X
X
X
X
X
X
Randomization
X
Patient history
X
Demography
X
Inclusion/exclusion criteria
X
X
Relevant medical history/current 
medical conditions
X
Diagnosis and extent of cancer
X
Prior antineoplastic therapy
X
Prior concomitant medications
X
Safety
Serious Adverse Events
X
X
X
X
X
X
X
30 Days 
Post EOT
Adverse events
X
X
X
X
X
X
30 Days 
Post EOT
Concomitant Medications
X
X
X
X
X
X
Physical examination
7.2.2.1.
X
X
X
X
X
X
Vital signs
7.2.2.2.
X
X
X
X
X
X
Height
7.2.2.3.
X
X
Weight
7.2.2.3.
X
X
X
X
X
 


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Protocol 
Section 
7.2 (if 
applicable)
Screening
Cycle 1
Day 30 –
Day 100 
Post 
HSCT
Subsequent 
Cycles (2-12)
*Refer to 
Section for 
Frequency
End of 
study 
treatment 
(EoT)
Follow 
up
Survival 
follow up
Study 
Completion 
Evaluation
Visit Number
1
2
3
4
5-15
16 (777)
501, 502 
etc
701,701, 
etc
778
Day of cycle
-14 to -1
1
3
15
1
Last
n/a
n/a
n/a
Performance status
7.2.2.4.
X
X
X
Laboratory assessments
7.2.2.5.
X
X
X
X
X
Hematology
7.2.2.5.
X
X
X
X
X
X
Chemistry
7.2.2.5.
X
X
X
X
X
Urinalysis
7.2.2.5.
X
Coagulation
7.2.2.5.
X
Thyroid (T4 and TSH)
7.2.2.5.
X
C2D1, C6D1 
and C12D1
X
30 Days 
Post EOT
Pregnancy
7.2.2.5.1.
X
X
Imaging
Chest x-ray/CT Scan
7.2.2.6.
X
ECG
7.2.2.7.1.
X
X
X
X
X
MUGA/ECHO
7.2.2.7.2.
X
C3 and C6
X
Pharmacokinetics
PK Sampling (study maintenance)
7.2.3.1.
X
X
X
Biomarkers
7.2.4.
Central Determination of FLT3-ITD
7.2.4.1.
X
GVHD assessment
X
X
X
X
X
 


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Protocol 
Section 
7.2 (if 
applicable)
Screening
Cycle 1
Day 30 –
Day 100 
Post 
HSCT
Subsequent 
Cycles (2-12)
*Refer to 
Section for 
Frequency
End of 
study 
treatment 
(EoT)
Follow 
up
Survival 
follow up
Study 
Completion 
Evaluation
Visit Number
1
2
3
4
5-15
16 (777)
501, 502 
etc
701,701, 
etc
778
Day of cycle
-14 to -1
1
3
15
1
Last
n/a
n/a
n/a
Study Drug dispensation and review
X
X
X
X
X
SOC Study Drug administration
X
X
X
X
X
Bone marrow
7.2.4.1. 
X
C6D1 and 
C12D1
Archived stored frozen mononuclear 
cells / DNA
X-
historical
 


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7.1.1
Screening
Patients will be eligible to screen for this study 28 days post-HSCT. The trial Informed 
consent, which includes the 
sample Informed 
Consent must be signed prior to any screening procedures begin. Patients should be 
randomized onto the trial within 14 days from date of screening; randomization will occur
after all assessments have been completed on C1D1.
Patients that do not meet eligibility criteria at initial screening, but have met eligibility criteria 
by Day 60 post HSCT may be eligible to enroll onto study. Patients are only required to 
complete failed assessments as long as the patient is re-screened within 14 days of the initial 
screening and have met eligibility by Day 60.
7.1.1.1
Eligibility screening
Following registering in the IWRS for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IWRS 
system. Please refer and comply with detailed guidelines in the IWRS manual.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. All data for screen failures are entered into the IWRS system, 
including the reason for not being started on treatment Screen failure data will not be entered 
into the clinical database unless the patient experienced a Serious Adverse Event during the 
Screening Phase (see Section 8 for SAE reporting details). All screen failure data from the 
IWRS will be exported to a SAS dataset for final data review and archiving.
The reasons for screen failures may include the following:
Unacceptable medical history/concomitant diagnosis
Intercurrent medical event
Unacceptable laboratory value(s)
Unacceptable test procedure result(s)
Did not meet diagnostic/severity criteria
Unacceptable use of excluded medications/therapies
Subject withdrew consent
7.1.1.3
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 to include, but not 
limited to the following information:
Date of birth
Age
Sex
Race
Relevant medical history and if active at start of study
 


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Date of diagnosis
Performance status
FLT3-ITD mutation status
Any additional mutation information, if known
Cytogenetics
Date of first Complete Remission (CR1)
Date of Transplant
A detailed history of all prior antineoplastic therapies, such as medications for treatment of 
leukemia must be recorded on the eCRF including:
Medication name/ Non-drug therapy
Dose
Start/End date
Best response
Additionally all other medications and significant non-drug therapies taken within 28 days 
before first dose is 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 physician 
prescribed, 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
In addition to the general demographic and relevant medical history information, study 
specific information will be collected during the screening period as indicated in the 
assessment schedule (Table 7-1) in order to determine eligibility of the patient.
7.1.2
Treatment and study period
The treatment period for all patients regardless of treatment assignment is defined as Cycles 1 
– 12.
For the treatment period patients will be randomized to SOC +/- midostaurin. Patients 
receiving SOC + midostaurin will receive midostaurin for 12 cycles (max) or until patient 
experiences unacceptable toxicity, relapse, death and/or treatment is discontinued at the 
discretion of the investigator or withdrawal of consent, whichever comes first.
It is likely that patients receiving SOC may have already began this treatment prior to 
randomizing onto the trial as part of his/her post HSCT standard of care treatment regimen. 
Any medications that began prior to the randomization/treatment period will be captured in 
the medical history and subsequently captured on the Concomitant Medication page during 
the treatment period. If the medication is still being taken at the end of the treatment phase, 
the medication should be recorded as ongoing.
Patient visits will occur monthly for one year during the Treatment Period (Cycles 1-12). 
Patients will continue in the Follow-up Phase and have assessments for at least 24 months 
 


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post HSCT. Hematology Lab Panels will be collected on average every two months between 
Follow up assessments to evaluate relapse in addition to survival status.
Patients that have not relapsed, died or withdrawn at 24 months will be asked to provide 
quarterly hematology panels until the study ends.
The study will end when all patients have either been followed for 24 months post HSCT, 
unless all patients have died or have withdrawn from the study. Prior to database lock, an 
additional OS and RFS update will be requested from all living patients.
Table 7-2
Treatment visit frequency and windows
Visits
Frequency
Window
Cycle 1
D1, 3 and 15
+/- 1 day
Cycles 2-12
Monthly, D1
+/- 5 days
End of Treatment (EOT)
SOC:
C12 D28 or at first relapse or 
discontinuation from the study
SOC + Midostaurin:
C12 D28 or at time of midostaurin 
treatment discontinuation
+/- 7 days
7.1.3
End of treatment visit including study completion and premature 
withdrawal
7.1.3.1
End of Treatment (EOT)
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time.

In the SOC arm, the End of Treatment (EOT) is considered as the end of cycle 12, the date 
of first relapse or the date of discontinuation, whichever occurs first.

In the SOC + Midostaurin arm, the EOT is defined as the last study drug (midostaurin) 
intake.
At the time patients discontinue study treatment; a visit should be scheduled as soon as 
possible, an End of Treatment (EOT) Phase eCRF page should be completed, giving the date 
and primary reason for a patient’s premature withdrawal from the study
Patients may be withdrawn from treatment if any of the following occur:

Adverse events

Abnormal laboratory values

Abnormal test procedure result

Subject withdrew consent

Lost to follow up

Administrative problems

Death

Relapse
 


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
Treatment duration competed as per protocol

Protocol deviation
At minimum, patients who discontinue study drug/from the study, including those who refuse 
to return for a final visit will be contacted for safety evaluations during 30 days following the 
end of treatment.
Patients who discontinue study treatment also should return for relapse and follow up 
assessments at visits and should not be considered withdrawn from the study. If patients 
refuse to return for these visits or are unable to do so, every effort should be made to contact 
them or a knowledgeable informant by telephone to determine the patients relapse and/or 
survival status.
7.1.3.2
Study Evaluation Completion (SEC)
If a patient discontinues study treatment, but continues study assessments, the patient remains 
on study until such time as he/she completes protocol criteria for ending study assessments. 
At that time, the reason for study completion should be recorded on the Study Evaluation 
Completion CRF (SEC) page. End of treatment/Premature withdrawal visit is not considered 
as the end of the study.
The reasons for study evaluation completion may include, but not limited to the following:
Subject withdrew consent
Lost to follow-up
Administrative problems
Death
Relapse
Protocol Deviation
Follow up phase completed as per protocol
7.1.4
Follow up for survival and RFS
Patients should be followed up until the end of the study. The study will end when all patients 
have been followed up for at least 24 months, relapsed, died or have withdrawn consent. For 
all living patients, an additional OS and RFS update will be requested prior to database lock.
All patients must have safety evaluations 30 days after the last dose of midostaurin for 
patients in the SOC+ midostaurin arm. For patients in the SOC arm, all patients must have 
safety evaluations 30 days after the end of Cycle 12/first relapse/withdrawal, whichever 
comes first.
During Follow up, patients will be asked to have a hematology panel every 2 months thru 24 
months post HSCT. This date will be calculated from the date of transplant. If a patient 
prematurely discontinues from the treatment phase prior to completing Cycle 12, patients will 
be asked to have a hematology panel every 2 months from the EOT visit until 24 months post 
HSCT as outlined in Table 7-1.
Hematology Lab Panels will be collected every two months between Follow up visits to 
assess relapse in addition to survival status. Patients that have not relapsed, died or withdrawn 
 


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at 24 months will be asked to provide quarterly hematology panels until the study ends. For 
all living patients, an additional OS and RFS update will be requested prior to database lock.
The assessment schedule is outlined in Table 7-3.
Table 7-3
Follow up assessment frequency and windows
Time Point
Assessment
Window
Patients that prematurely discontinue 
from treatment phase prior to 
completion of Cycle 12

Every 2 months from EOT until 24 
months post HSCT

Survival

Hematology Panel

Bone Marrow (BM) at 
investigator’s discretion
+/- 14 days
Patients that complete Cycle 12

Every 2 months from EOT until 24 
months

Survival

Hematology Panel

BM at investigator’s discretion
+/- 14 days
Patients that have not relapsed at 24 
months

Quarterly until the last patient has 
been followed for 24 months

Survival

Hematology Panel
+/- 21 days
Relapse

Hematology Panel

BM
+/- 14 days
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
7.2
Assessment types
7.2.1
Efficacy assessments

Complete Response (CR) is when the following levels are detected in the Peripheral Blood 
(PB); ANC ≥ 1000/uL; Platelet count ≥ 100K and no circulating leukemic myeloblasts in 
peripheral blood and Bone Marrow (BM) has adequate cellularity, BM blast count ≤ 5% 
and no auer rods detected.

Relapse following complete response is defined as reappearance of leukemic blasts in the 
peripheral blood or finding more than 5% blasts in the bone marrow.

Relapse Free Survival (RFS) assesses the clinical benefit of remaining in remission free 
from relapse or death due to the disease. It is defined as the time from transplant to relapse 
or death due to the disease.

Disease Free Survival (DFS) assesses the clinical benefit of remaining in remission free 
from relapse or death from any cause. It is defined as the time from transplant to relapse or 
death from any cause. This is aligned with Novartis AML guidance and FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
2007). If a patient has more than one event (e.g. relapse and death) then the earliest date 
will be taken into account.

Overall Survival (OS) is defined as the time from transplant to death from any cause.
 


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7.2.1.1
Bone marrow aspirate and biopsy
Bone Marrow will be collected at the time points listed in Table 7-4 to assess Efficacy
 
endpoints.
Table 7-4
Bone marrow collection plan
Procedure
Screening/During Treatment Period
During Follow up
Bone Marrow
Results from Initial diagnosis required for 
eligibility
Between D30 – 100 Post HSCT
Cycle 6
Cycle 12
Relapse and/or investigator 
discretion
The BM aspirates are collected in EDTA tubes and are processed at the local laboratory as per 
institutional procedures. If required in case of inspirable bone marrows, core biopsy should be 
performed.
For response assessment it is required that bone marrow assessment and the corresponding 
blood assessment (CBC) is done within a 5 day window.
7.2.2
Safety and tolerability assessments
The assessment of safety will be based mainly on the frequency of Adverse Events (AEs), on 
the number of laboratory values summarized by CTCAE grades and non-relapse mortality
(NRM).
Summary statistics will be provided for data from other tests (e.g. electrocardiogram or vital 
signs) and any other information collected will be listed as appropriate.
All AEs recorded during the study will be summarized by treatment arm. The incidence of 
treatment-emergent AEs (new or worsening from baseline) will be summarized by primary 
system organ class, preferred term, severity (based on CTCAE grades), type of AE and 
relationship to the study drug. Deaths reportable as SAEs and nonfatal SAEs will be listed by 
patient and tabulated by type of AE.
For further details on AE collection and reporting, refer to Section 8.
All assessments must be drawn PRIOR to administration of study treatment (of that day).
Non-relapse mortality assesses the other causes of death not due to disease or relapse (e.g., 
late toxicity due to GVHD). It is calculated from the date of transplant to the date of patient 
death due to reasons other than relapse.
7.2.2.1
Physical examination
A physical examination must be performed at the screening visit, Day 1 and 15 of Cycle 1, 
Day 1 of each subsequent cycle, and on the day of discontinuation/end of treatment (EOT).
Information about the physical examination must be present in the source documentation at 
the study site.
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s eCRF. Significant new findings that
 


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begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s eCRF.
7.2.2.2
Vital signs
Vital signs include temperature, respiratory rate, blood pressure and pulse and will be taken in 
the sitting position. Vitals will be measured at Screening, Cycle 1 Day 1, 3, 15, Day 1 of each 
subsequent cycle and at End of Treatment (EOT)
Information about vital signs must be recorded in the source document at the study site. 
Significant findings present prior to the start of study drug must be in the Relevant Medical 
History/ Current Medical Conditions eCRF. Significant finding made after the start of study 
drug which meet the definition of an adverse event must be recorded on the Adverse Event 
eCRF.
7.2.2.3
Height and weight
Height in centimeters (cm) 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 (EOT). Weight will be measured at Screening, 
Day 1 and 15 of Cycle 1, Day 1 of each subsequent cycle, and on the day of 
discontinuation/end of treatment (EOT).
7.2.2.4
Performance status
ECOG Performance Status will be assessed at Screening, Day 1 of Cycle 1 and at End of 
Treatment (EOT).
Table 7-5
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 selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
7.2.2.5
Laboratory evaluations
Frequency of evaluations must be performed according to the Visit Schedule and Assessment, 
Table 7-1, and parameters outlined in Local Clinical laboratory parameters collection plan
Table 7-6. 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 
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All laboratory values must be drawn PRIOR to randomization / first dose of study drug. 
Every effort should be made to obtain screening laboratory values 14 days prior to study entry 
and these need then not be repeated at study entry if performed within 14 days of the initial 
dose of midostaurin. All other laboratory evaluations must be performed within +/- 48 hours 
of a study visit.
If administration of midostaurin is interrupted due to Grade 3 non-hematologic laboratory 
parameters, refer to Section 6.3, for instructions.
Table 7-6
Local clinical laboratory parameters collection plan
Test 
Category
Test Name
Screening/During 
Treatment
During Follow-
up
Hematology
Total white blood cell count with differential 
(neutrophil count including bands, 
lymphocyte, monocyte, eosinophil, 
basophil/mast cell, % and absolute blast 
count, and early myeloid forms), 
hemoglobin, hematocrit, platelet count and 
reticulocyte count.
Screening
Cycle 1 D1,15
Cycle 2-12; D1
EOT
Refer to Table 7-3
after EOT
Chemistry
Albumin, Alkaline phosphatase, ALT 
(SGPT), AST (SGOT), Bicarbonate, 
Calcium, Chloride, Creatinine, Creatine 
kinase, Sodium, Potassium, phosphorus, 
magnesium, glucose, Direct Bilirubin, 
Indirect Bilirubin, Total Bilirubin, Total 
Cholesterol, LDL, HDL, Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) 
or Urea, Uric Acid, Lipase and Amylase.
Screening
Cycle 1 D1,15
Cycle 2-12; D1 
EOT
Refer to Table 7-3
after EOT
Urinalysis
Macroscopic Panel (Dipstick) (Color, 
Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, 
Specific Gravity)
Any significant findings on dipstick will be 
followed up with a microscopic evaluation 
where bacteria, WBC, RBC sediments will 
also be measured.
Microscopic Panel (Red Blood Cells, White 
Blood Cells, Bacteria, and additional 
findings)
Screening or more 
frequent if 
clinically indicated.
n/a
Coagulation
Prothrombin time (PT), International 
normalized ratio [INR]), Partial 
thromboplastin time (PTT) or Activated 
partial thromboplastin time (APTT)
Screening or more 
frequent if 
clinically indicated
n/a
Thyroid
T4 [free], TSH
Screening, C2D1, 
C6D1, C12D1 or 
more frequent if 
clinically indicated
30 Days after end 
of treatment 
(EOT)
Note: All efforts should be made to collect the labs prior to dosing. Fasting is not required.
 


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7.2.2.5.1 Pregnancy and assessments of fertility
All women of childbearing potential must have a negative serum or urine pregnancy test ≤ 48 
hours prior to administration of midostaurin on Day 1 of Cycle 1.
Women 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).
Note: Barrier contraceptives must be used throughout the study in both sexes.
7.2.2.6
Radiological examinations
A screening chest image; Chest x-ray (CXR) or CT scan must be performed to assess study 
eligibility. If a CXR or CT scan was done within 14 days of screening assessments then it 
does not need to be repeated.
7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed

at screening

at Cycle 1: Day 1 (pre-dose)

at Cycle 1: Day 3

at Cycles 2-12: Day 1

End of Treatment (EOT) or Treatment Discontinuation
Currently the effect of midostaurin on QTc interval prolongation is not fully characterized. 
Therefore, all patients experiencing a post baseline prolonged QTc interval must have 
potassium and magnesium checked and any electrolytes imbalances corrected. Additionally, 
the investigator should consider the risk benefit of any concomitant medications that may 
prolong the QTc interval. For the purpose of this trial, the correction formula according to 
Fredericia, i.e. QTcF is being referred to - wherever QTc is mentioned.
The baseline ECG QTc interval must be less or equal than 450 ms.
 


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Table 7-7
ECG collection plan
QTc Interval
Action
ECG > 450msec
If the ECG shows a QTc interval greater than 450 msecs at 
screening or during the trial, triplicates should be performed, one 
minute apart to confirm the finding (after replacement of any 
electrolyte imbalance). If 2/3 or 3/3 of the ECGs confirm the QT 
prolongation (i.e. QTc interval > 450 msecs) the patient must not 
be included into the trial.
> 450 msecs and ≤ 470 msecs
Check magnesium and potassium levels and correct any 
abnormalities. If possible, stop any medications that may prolong 
the QTc interval. Continue midostaurin at the same dose.
QTc interval > 470 msecs and 
≤500 msecs,
Check magnesium and potassium levels and correct any 
abnormalities. If possible, stop any medications that may prolong 
the QTc interval. Decrease midostaurin to 25 mg twice daily for the 
remainder of the cycle/or for 2 weeks. Resume midostaurin at the 
initial dose in the next cycle provided that QTc interval improves to 
≤ 470 msecs.
> 500 msecs
Check magnesium and potassium levels and correct any 
abnormalities. Hold or interrupt midostaurin for the remainder of 
the cycle, and, if possible, stop any medications that may prolong 
the QTc interval. If QTc improves to ≤ 470 msecs just prior to the 
next cycle, resume midostaurin at the initial dose. If QTc interval is 
not improved in time to start the next cycle do not administer 
midostaurin during that cycle.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF 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 eCRF 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 eCRF page.
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
An echocardiogram or MUGA scan must be performed

at screening prior to Day 1

at Cycle 3, 6

at the EOT visit
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 trial.
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.
 


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Should the investigator consider that there is an EF decrease which is clinically relevant, 
Novartis must be informed. The study drug must be withheld. A discussion will take place 
with the sponsor to determine the necessary steps to be taken to safeguard the patient.
7.2.3
Pharmacokinetics (PK)
Blood samples for pharmacokinetic assessment will be collected only for patients receiving 
midostaurin.
Routine PK blood collection will be completed at each visit; 
 
7.2.3.1
Routine pharmacokinetic (PK) blood collection
Trough blood samples must be taken prior to midostaurin administration, refer to Table 7-8
for collection schedule. A pharmacokinetic collection applies only to patients randomized to 
the midostaurin treatment arm.
Patients are instructed to bring their medication with them during their weekly visits and not 
to eat prior to their visit. After the trough/pre-dose PK samples are collected on the visit day, 
patients will then be instructed to take midostaurin following food intake.
The collection date and time of all samples must be documented on the Routine PK blood 
collection eCRF page in addition to the date and time of dosing.
Refer to the CPKC412AUS23 Laboratory Manual for detailed instructions for the collection, 
handling, and shipment of PK samples.
Table 7-8
Routine pharmacokinetic blood collection log
Treatment 
Period or Cycle
Day
Scheduled Time 
Point
PK Sample No
Sample Volume
1
1
Pre-dose/0h
101
3 mL
1
15
Pre-dose/0h
102
3 mL
2
1
Pre-dose/0h
103
3 mL
3
1
Pre-dose/0h
104
3 mL
4
1
Pre-dose/0h
105
3 mL
5
1
Pre-dose/0h
106
3 mL
6
1
Pre-dose/0h
107
3 mL
7
1
Pre-dose/0h
108
3 mL
8
1
Pre-dose/0h
109
3 mL
9
1
Pre-dose/0h
110
3 mL
10
1
Pre-dose/0h
111
3 mL
11
1
Pre-dose/0h
112
3 mL
12
1
Pre-dose/0h
113
3 mL
 


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7.2.4
Biomarkers
7.2.4.1
Central determination of FLT3 ITD status
In this study, patients are permitted to enroll based on the locally known FLT3-ITD mutation 
status which was determined at diagnosis. In order to establish the concordance of the original 
FLT3 ITD mutation status with that which is determined centrally using a fully characterized 
 


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and analytical validated assay, FLT3-ITD mutation status will be re-assessed using remaining 
historical material, if available, from the original diagnostic specimen. All patients will be 
asked to provide a historical sample of tissue at the time from which they had confirmation of 
their diagnosis. The specimens which may be used for this purpose include stored frozen 
mononuclear cells or DNA if available.
 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Patients whose FLT3-ITD status is known will sign the main study ICF.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Except for screen failures, Adverse events that begin or worsen after informed consent should 
be recorded in the Adverse Events eCRF. Conditions that were already present at the time of 
informed consent should be recorded in the Relevant Medical History/Current Medical 
Conditions page of the patient’s eCRF. Adverse event monitoring should be continued for at 
least 30 days (or 5 half-lives, whichever is longer) following the end of treatment as defined 
in Section 7.1.3. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected on the 
EOT/SEC/Survival Information eCRFs.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start, End or Ongoing )
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
 


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5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
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 eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an 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 eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.2
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
 


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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-ITD 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 SAEs experienced after this 30 days period (or 5 half-lives) whichever is longer) should 
only be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new 
event.
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 send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
 


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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 (new occurrence) and 
is thought to be related to the Novartis study treatment, an oncology Novartis Drug Safety and 
Epidemiology (DS&E) department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that 
this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancy prevention requirements
Refer to Exclusion criteria Section 5.3.
8.5
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
In addition, pregnancy outcomes must 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.
8.6
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.
 


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8.7
Data Monitoring Committee
No Data Monitoring Committee (DMC) will be used in this trial since this is a double-arm, 
open label study. Safety data will be monitored by internal safety personnel in conjunction 
with the independent review committee (IRC).
8.8
Independent Review committee
The Independent review committee (IRC) will consist of 3 to 5 physicians that are transplant 
experts not participating in the trial.
The IRC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The IRC will complete 
a safety review of the initital 10, 20, and 30 patients on SOC or SOC + midostaurin 
completing at least 3 cycles or discontinued. Additional patients may be reviewed up to 
complete trial enrollment at the IRC’s discretion. The IRC will review safety information to 
include (but not limited to) adverse events, serious AEs, lab parameters, bone marrow results 
 in addition to protocol amendments as appropriate. Together with the 
clinical trial team, the IRC will also develop recommendations for publications of study 
results including authorship rules. The details of the role of the Independent Review
Committee will be defined in a Independent Review Committee charter.
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 
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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 eCRFs 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 eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study drug 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 eCRFs 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 
eCRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
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.
Results from FLT3 mutation analysis, 
, PK sampling 
 
 will be centrally analyzed and the data will be transferred to Novartis (or designated 
CRO) upon completion of analysis.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
 


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classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Biomarker and PK samples will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Diary data will be entered onto a paper diary by the patient. Planned and or changes in 
dosingwill be captured into the eCRF.
Screening, randomization and enrollment data changes will be tracked using an Interactive 
Web Response (IWRS). The system will be supplied by a vendor(s), who will also manage 
the database. The data will be sent electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any 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.
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
The primary analysis of RFS will be done when all patients have been followed up to 18 
months post-HSCT.
The final safety and efficacy analyses will be conducted when all living patients have been 
followed up to 24 months post-HSCT.
All data will be analyzed by a designated CRO. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum and maximum will be presented.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all randomized patients. According to the intent to 
treat (ITT) principle, patients will be analyzed according to the treatment arm (SOC +/-
midostaurin) they have been assigned to during the randomization procedure.
10.1.2
Safety Set
Patients are analyzed according to the treatment received. Patients who received at least one 
dose of midostaurin during the study will be allocated to the SOC + midostaurin treatment 
arm. Patients randomized to the SOC + midostaurin arm but who never received midostaurin 
will be allocated to the SOC treatment arm.
10.1.3
Per-Protocol Set
The Per Protocol Set (PPS) consists of all patients from the Full Analysis Set without any 
major protocol deviations. Protocol deviations leading to the exclusion of from the PPS will 
 


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be specified in the study Validation and Planning (VAP) and Report and Analysis Plan (RAP) 
documents prior to database lock.
10.1.4
Pharmacokinetic Analysis Set
The Pharmacokinetic Set (PK Set) comprises all patients that have been administered at 
least one dose of midostaurin and that have provided at least one evaluable PK sample.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized by treatment group using the FAS.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by treatment group for the safety set.
10.3.1
Study medication
The study drug (midostaurin) administration will be summarized. The number of treated 
patients, number of patients who had dose reduction/interruption and the duration of treatment 
will be presented.
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason).
The safety population will be used for all above mentioned tables and listings.
10.3.2
Concomitant therapies
Concomitant medications and non-drug therapies taken concurrently with the study drugs will 
be listed and summarized by ATC class, preferred term and treatment arm by means of 
frequency counts and percentages. These summaries will include medications starting on or 
after the start of study treatment or medications starting prior to the start of study treatment 
and continuing after the start of study treatment.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed.
The safety population will be used for all above mentioned concomitant medication tables and 
listings.
10.4
Primary objective
10.4.1
Relapse free survival
The primary endpoint is relapse free survival (RFS), defined as the time from transplant to 
relapse or death due to the disease 18 months post transplant. If a patient has more than one 
event (e.g. relapse then death) then the earliest date will be taken into account.
 


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10.4.2
Statistical hypothesis, model, and method of analysis
Kaplan-Meier plots will be used to depict RFS over time in each treatment arm. Median 
survival will be obtained along with 95% CI calculated using the method of Brookmeyer & 
Crowley. Kaplan-Meier estimates with 95% CI will be summarized every 6 month using
Greenwood’s formula for the standard error of the Kaplan-Meier estimate. The primary 
objective is related to the Kaplan-Meier estimate at 18 months.
In addition to the Kaplan-Meier estimates, a Cox proportional hazards model will be used to 
provide an estimate of the Hazard Ratio (HRSOC+Midaustorin/SOC) and associated Wald 95% 
Confidence Interval (CI).The primary analysis will be performed on the FAS.
10.4.3
Handling of missing values/censoring/discontinuations
Patients alive in remission at the time of the data cut-off point used for the analysis will have 
RFS censored at the time of last measurement prior to the data cut-off point. The number of 
patients having an event and number of patients censored will be summarized. A summary of 
reasons censoring will be provided by treatment arm.
Novartis AML guidance and the FDA guideline on endpoints (Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, 2007) will not consider a relapse event if observed 
after two or more consecutive missing assessments and will censor the RFS and DFS at the 
last adequate assessment date.
10.4.4
Supportive analyses
The primary analysis will be repeated on the PP Set as a supportive analysis.
In addition to that, a sensitivity analysis will be performed on RFS using the time from 
randomization as reference time-point instead of the time from transplant.
The same statistical analyses as the previous one described Section 10.4.2 will be performed 
on this variable.
This sensitivity analysis will be performed on the FAS.
10.5
Secondary objectives
10.5.1
Key secondary efficacy evaluation
The secondary efficacy variables include:

Disease Free Survival (DFS)

Relapse Free Survival (RFS)

Overall Survival (OS)
DFS is defined as the time from transplant to relapse or death from any cause. RFS is defined 
as the time from transplant to relapse or death due to the disease. OS is defined as the time 
from transplantation to the date of death from any cause. Follow up will continue until all 
patients have been followed for 24 months post HSCT unless all patients have died or have 
withdrawn from the study prior to that time.
 


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Kaplan-Meier plots will be used to depict each secondary endpoint over time in each 
treatment arm. Median survival will be obtained along with 95% CI calculated using the 
method of Brookmeyer & Crowley. Kaplan-Meier estimates with 95% CI will be summarized 
every 6 month using Greenwood’s formula for the standard error of the Kaplan-Meier 
estimate.
In addition to the Kaplan-Meier estimates, Cox proportional hazards models will be used to 
provide estimates of the Hazard Ratio (HRSOC+Midaustorin/SOC) and associated Wald 95% 
Confidence Interval (CI) for each secondary endpoint.
These analyses will be performed on the FAS.
10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the Safety Set (SS) will be used. All listings and tables will be 
presented by treatment group.
The safety summary tables will include only “on-treatment” assessments. On treatment
assessments will be considered as:

SOC arm (whichever comes first):
From randomization until discontinuation, relapse or completion of treatment phase 
(12cycles) + 30 days

SOC + PKC arm:
From first intake of study drug to last intake of study drug + 30 days
Safety will be assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4.0. Incidence of adverse events (AEs), serious adverse events (SAEs), changes from 
baseline in clinically notable changes in vital signs and CTC grading for laboratory results 
(hematology, blood chemistry, ECGs) will be reported.
10.5.2.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.
10.5.2.3 Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using 
Common Toxicity Criteria for Adverse Events (CTCAE).
 


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Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters with CTC grades. In 
addition, shift tables using laboratory normal ranges to compare baseline to the worst post-
baseline value will be produced for other parameters without CTC grades, if any (Ranges: 
Low, Normal, High).
All laboratory values will be listed by laboratory parameter and patient. Separate listings will 
display notable laboratory abnormalities (i.e. newly occurring CTCAE grade 3 or 4 laboratory 
toxicities).
10.5.2.4 Other safety data
Summary statistics for data from other tests will be provided, notable values will be flagged, 
and any other information collected will be listed as appropriate.
Descriptive summary statistics will be provided for data for:
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs and weight
Summary statistics of raw data and change from baseline values (means, medians, standard 
deviations), newly occurring or worsening abnormalities of vital signs and weight.
Listings with flagged notable values and any other information collected will be provided as 
appropriate.
10.5.2.5 Tolerability
To determine whether midostaurin can be administered at a daily dose of 50mg twice daily at 
least 80% of the time to 50% or more of patients during the first 100 days after allogeneic 
HSCT
10.5.2.6 Non-relapse mortality
NRM is defined as the duration between the date of transplant and the date of patient death 
due to reasons other than relapse.
Kaplan-Meier plots will be used to depict non-relapse mortality over time in each treatment 
arm. Median survival will be obtained along with 95% CI calculated using the method of 
Brookmeyer & Crowley. Kaplan-Meier estimates with 95% CI will be summarized every 6 
month using Greenwood’s formula for the standard error of the Kaplan-Meier estimate.
In addition to the Kaplan-Meier estimates, Cox proportional hazards models will be used to 
provide estimates of the Hazard Ratio (HRSOC+Midaustorin/SOC) and associated Wald 95% 
Confidence Interval (CI) for each secondary endpoint.
These analyses will be performed on the FAS.
 


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10.5.3
Pharmacokinetics
Descriptive statistics will be presented for all concentration data of midostaurin and its 
metabolites obtained by Cycle, and/or Day and time-point. These include geometric and 
arithmetic means, standard deviation (SD), and coefficient of variance (CV).
10.5.3.1 FLT3 ITD mutation status
Descriptive statistics of FLT3 ITD mutation status centrally assessed will be provided.
10.5.3.2 Data handling principles
Missing concentration values will be reported as is in data listings. Concentration values 
below Lower Limit of Quantitation (LLOQ, BLLOQ) will be handled as zero in summary 
statistics, and reported as is in data listings. Any missing pharmacokinetic parameter data will 
not be imputed.
10.5.4
Biomarkers
The FLT3 results from the centralized assay using archived material will be compared to the 
local result, and differences will be described.
In addition, the clinical outcome of RFS and DFS based on the FLT3 ITD result from the 
centralized assay compared to the local FLT3 ITD status will also be described.
10.7
Interim analysis
Not applicable
10.8
Sample size calculation
This study is a Phase II exploratory trial and is not powered to detect a statistical difference 
between the two arms. The sample size for the trial was chosen; 30 patients per treatment arm 
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is not feasible considering the rare nature of FLT3-ITD mutant AML receiving a HSCT. With 
a 22-25% FLT3-ITD mutation rate and approximately 25% rate of HSCT, estimated from the 
ongoing Phase III study (2301, CALGB 10603, Ratify), more than 1050 newly diagnosed 
AML patients would need to be evaluated to identify 60 patients undergoing HSCT in CR1. 
The control arm, Standard of Care (SOC), in this study provides the first prospective subjects 
treated at the same centers in the same timeframe which will allow an estimate of treatment 
effect which can be used to design a larger trial. There are no published sets of prospective, 
FLT3-ITD AML outcomes after transplantation
If the two arms were compared, the following gives the power that could be achieved under 2 
scenarios of relapse rate with 30 patients per treatment arm.
Scenario 1: Assuming a 30% relapse rate in the SOC arm
Scenario 2: Assuming a 50% reduction with midostaurin (experimental arm)
i.e., 15% relapse rate in the experimental arm, a sample size of 30 patients in each arm will 
detect the reduction with 71% power. This calculation is based on one-sided type I error rate 
of 20%. The power would be 81% if we assume relapse rate to be even lower at 12% keeping 
everything else the same.
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 or, if incapable of
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
 


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capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.3.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
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 
 


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records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study electronic case report form (eCRF) 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 eCRFs and all other 
required reports. Data reported on the eCRF, that are derived from source documents, should 
be consistent with the source documents or the discrepancies should be explained. All data 
requested on the eCRF must be entered. Any missing data must be explained. For electronic 
eCRFs an audit trail will be maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
 


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12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
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 (2011) Cancer Facts & Figures. Atlanta, GA.
Barry EV, Clark JJ, Cools J, et al (2007) Uniform sensitivity of FLT3 activation loop mutants 
to the tyrosine kinase inhibitor midostaurin. Blood. 110(13):4476- 4479.
Bornhauser M, Illmer T, Schaich M, et al (2007) Improved Outcomes after stem-cell 
transplantation in FLT3-ITD-positive AML. Blood. 109 (5): 2264-65.
Brunet S, Labopin M, Esteve J, et al (2012) Impact of FLT3 Internal Tandem Duplication on 
the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid 
leukemia in first remission: a retrospective analysis. J Clin Oncol. 30(7). 735-741.
Brunet S, Labopin M, Esteve J, et al (2012) Impact of FLT3 Internal Tandem Duplication on 
the Outcome of Related and Unrelated Hematopoietic Transplantation for Adult Acute 
Myeloid Leukemia in First Remission: A Retrospective Analysis. J Clin Oncol. 30: 735-741.
Burnett A (2011) Acute Myeloid Leukemia in Postgraduate Hematology. Sixth Edition. 
Wiley-blackwell publishing. Edited by A Victor Hoffbrand. West Sussex UK.
Burnett A, Wetzler M, Lowenberg B (2011) Therapeutic Advances in Acute Myeloid 
Leukemia. J Clin Oncol. 29:487-494.
 
del Corral A, Dutriex C, Huntsman-Labed A, et al (2012) Midostaurin does not prolong 
cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers 
Cancer Chemotherapy and Pharmacology; 69(5): 1255-1263.
Estey E (2010) Understanding and Managing Ultra High-Risk Hematological Malignancies: 
High Cytogenetic or Molecular Genetic Risk Acute Myeloid Leukemia. Hematology 
2010:474-480.
Fernandez HF, Sun Z, Yao X, et al (2009) Anthracycline Dose INtenstification in Acute 
Myeloid Leukemia. New England Journal of Medicine; 361:1249-1259.
 
Fischer T, Stone R, DeAngelo D, et al (2010) Phase IIB trial of oral midostaurin (PKC412), 
the FMS-like tyrosine kinase 3 receptor (FLT3), and multi-targeted kinase inhibitor, in 
patients with acute myeloid leukemia and high risk myelodysplastic syndrome with either 
wild type or mutated FLT3. J Clin Oncol; 28(28): 4339-4345.
Flockhart DA (2009) Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007) Version 5.0 released on Jan 12, 2009.
http://medicine.iupui.edu/flockhart/table.htm.
Gale R, Hills R, Kottardis P, et al (2005) No evidence that FLT3 status should be considered 
as an indicator for tranplantation in acute myeloid leukemia (AML): an analysis of 1135 
patients excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. 
BLOOD; 106(10), 3658–65.
 


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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.
Gale RE, Hills R, Wheatley K, et al (2007) Still a need for more robust evidence that 
FLT3/ITD status should influence the decision to proceed to transplantation in AML patients 
BLOOD; 109(5), 2265 - 2265.
Gotlib J, Kluin-Nelemans H, George T, et al (2012) KIT Inhibitor Midostaurin in Patients 
with Advanced Systemic Mastocytosis: Results of a Planned Interim Analysis of the Global 
CPKC412D2201 Trial. Blood. 2010;116:[abstract 316].
Hayakawa F, Towatari M, Kiyoi H, et al (2000) Tandem-duplicated Flt3 constitutively 
activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent 
cell lines. Oncogene;19(5):624-631.
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(12):2386-2392.
Kindler T, Lipka D, Fisher T (2010) FLT3 as a therapeutic target in AML: still challenging 
after all these years. Blood;116:5089-5102.
Kiyoi H, Naoe T, Nakano Y, et al (1999) Prognostic implication of FLT3 and N-RAS gene 
mutations in acute myeloid leukemia. Blood;93(9):3074-3080.
Kiyoi H, Towatari M, Yokota S, et al (1998) Internal tandem duplication of the FLT3 gene is 
a novel modality of elongation mutation which causes constitutive activation of the product. 
Leukemia;12(9):1333-1337.
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.
 
 
Manley PW, Boulton C, Caravatti G, et al (2003) Preclinical profile of PKC412 (midostaurin) 
as an FLT3 inhibitor for the therapy of AML. Presented at the American Association for 
Cancer Research Annual Meeting, Washington, DC, July 11-14, 2003 (poster 1004).
Meshinchi S, Alonzo TA, Stirewalt DL, et al (2006) Clinical implications of FLT3 mutations 
in pediatric AML. Blood;108(12):3654-3661.
Meshinchi S, Arceci RJ, Sanders JE, et al (2006) Role of allogeneic stem cell transplantation 
in FLT3/ITD-positive AML. Blood;108:400; author reply 400-401.
 


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Metabolism and Transport (2011) Drug Interaction Database, Version 4.0, University of 
Washington, Department of Pharmaceutics (2008) www.druginteractioninfo.org (Last update: 
Jan, 2011).
Metzelder S, Wang Y, Wollmer E, et al (2009) Compassionate use of sorafenib in FLT3-ITD-
positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell 
transplantation. Blood;113(26):6567-6571.
NCCN Guidelines v1. (2012) National Comprehensive Care Network. NCCN Clinical 
Practice Guidelines in Oncology – Acute Myeloid Leukemia. Version 2.2012.
Pravtz K, Sato T, Murphy K, et al (2010) FLT3-mutant allelic burden and clinical status are 
predictive of response to FLT3 inhibitors in AML. Blood; 115(7):1425-1432.
Ravandi F, Burnett A, Agura E, et al (2007) Progress in the Treatment of Acute Myeloid 
Leukemia. Cancer;110:1900–10.
Roesel J, Fabbro D, Mestan J, et al (2004) Antiproliferative activity of PKC412 in various 
human AML cell lines RD-2004-01878.
 
Schlenk RF, Dohner K, Krauter J, et al (2008) Mutations and treatment outcome in 
cytogenetically normal acute myeloid leukemia. N Engl J Med;358:1909-1918.
Schnittger S, Schoch C, Dugas M, et al (2002) Analysis of FLT3 length mutations in 1003 
patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and 
prognosis in the AMLCG study and usefulness as a marker for the detection of minimal 
residual disease. Blood;100(1):59-66.
Sora F, Chiusolo P, Metafuni E, et al (2011) Sorafenib for refractory FMS-like tyrosine kinase 
receptor-3 (FLT3/ITD+) acute myeloid leukemia after allogenic stem cell 
transplantation. Leuk Res;35(3):422-423.
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; 2005;105:54-60.
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 
wildtype FLT3. ASH 2009 Abstract #634, Blood, Vol 114.
Stone RM, Fischer T, Paquette R, et al (2012) Phase IB study of FLT3 kinase inhibitor 
midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid 
leukemia. Leukemia 26, 2061-2068.
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.
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Van den Brink M, Porter D, Giralt S, et al (2010) Relapse after allogeneic hematopoietic cell 
therapy. Biol Blood Marrow Transplant. 16:S138-S145.
Weisberg E, Boulton C, Kelly LM, et al (2002) Inhibition of mutant FLT3 receptors in 
leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell; 1: 433-
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Whitman SP, Archer KJ, Feng L, et al (2001) Absence of the wild-type allele predicts poor 
prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal 
tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res;61(19):7233-
7239.
Yanada M, Matsuo K, Emi N, et al (2005) Efficacy of allogeneic hematooietic stem cell 
transplant depends on cytogenetic risk for AML is first disease remission: a meta-analysis. 
Cancer; 103: 1652-58.
Yin O, Wang Y, Lanza C, et al (2008) Pharmacokinetics (PK) and pharmacodynamics (PD) 
of midostaurin (PKC412) in patients with acute myeloid leukemia (AML). J Clin Oncol 
26:388s, (abstr 7064).
 

SAP_001.pdf: 
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CPKC412AUS23 
Clinical Development 
PKC412, MIDOSTAURIN 
Protocol CPKC412AUS23 / NCT01883362
A Phase II, randomized trial of standard of care, with or 
without midostaurin to prevent relapse following allogeneic 
hematopoietic stem cell transplantation in patients with 
FLT3-ITD mutated acute myeloid leukemia 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final V 1.0 
Release date: 
07FEB2018 
Number of pages: 
35 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Template Document History – Changes compared to previous version 
 
Date 
Version 
number 
Summary of changes 
25-Aug-2017 0.1 
First version 
11-Dec-2017 
0.2 
Second version 
07-Feb-2018 
1.0 
Final version 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
 
 
 
 
Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Biostatistician 
Print Name: 
, PhD 
 
 
 
Sign Name: 
 
 
 
 
 
Novartis 
Pharmaceuticals 
Corp. 
Representative 
Print Name: 
, Ph.D. 
 
  
Novartis Pharmaceuticals Corporation 
 
Sign Name: 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.1.1 
Subject Population .................................................................................. 7 
1.1.2 
Randomization ........................................................................................ 7 
1.2 
Interim and Final Analysis....................................................................................... 7 
1.3 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets .......................................................................................................... 13 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 14 
2.3.1 
Basic demographic and background data .............................................. 14 
2.3.2 
History of AML Disease ....................................................................... 14 
2.3.3 
Pre-HSCT Treatment for AML ............................................................. 14 
2.3.4 
Pre-HSCT Preparative Regimen, Disease Status .................................. 15 
2.3.5 
FLT3-ITD Positive Mutational Analysis at Diagnosis ......................... 15 
2.3.6 
Medical history ...................................................................................... 15 
2.3.7 
Subject disposition ................................................................................ 15 
2.3.8 
Protocol deviations ................................................................................ 16 
2.3.9 
Analysis sets .......................................................................................... 16 
2.4 
Treatments (study treatment, concomitant therapies, compliance) ....................... 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 18 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 19 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 19 
2.5.4 
Supportive analyses ............................................................................... 20 
2.6 
Analysis of the key secondary objective ............................................................... 20 
2.6.1 
Key secondary endpoint ........................................................................ 20 
2.6.2 
Handling of missing values/censoring/discontinuations ....................... 23 
2.6.3 
Statistical method of analysis ................................................................ 23 
2.7 
Analysis of Secondary Objective........................... Error! Bookmark not defined. 
2.7.1 
Secondary endpoint ............................... Error! Bookmark not defined. 


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2.7.2 
Statistical method of analysis ................ Error! Bookmark not defined. 
2.8 
Safety analyses ....................................................................................................... 23 
2.8.1 
Treatment Emergent Adverse events (AEs) .......................................... 23 
2.8.2 
Laboratory data ..................................................................................... 24 
2.8.3 
Pregnancy and assessments of fertility ................................................. 27 
2.8.4 
Radiological examinations .................................................................... 27 
2.8.5 
Extramedullary Disease Assessment ..................................................... 27 
2.8.6 
ECG ....................................................................................................... 27 
2.8.7 
Vital signs.............................................................................................. 28 
2.8.8 
ECOG Performance Status .................................................................... 29 
2.8.9 
Cardiac imaging - MUGA (multiple gated acquisition) scan or 
Echocardiogram .................................................................................... 29 
2.8.10 
Non-relapse mortality ............................ Error! Bookmark not defined. 
2.9 
Pharmacokinetic Concentrations ........................................................................... 29 
 
 22 
 
 22 
 
 22 
 
 22 
 
. 22 
2.12 
Interim analysis ...................................................................................................... 31 
3 
Sample size calculation ..................................................................................................... 31 
4 
Change to protocol specified analyses .............................................................................. 31 
5 
Appendix ........................................................................................................................... 31 
5.1.1 
Study drug ............................................................................................. 31 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 32 
5.2 
Laboratory parameters derivations ........................................................................ 33 
5.3 
Statistical models ................................................................................................... 34 
6 
Reference ........................................................................................................................... 35 
 
 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
FAS 
Full Analysis Set 
HSTC 
Hematopoietic Stem Cell Transplantation 
eCRF 
Electronic Case Report Form 
IVRS 
Interactive Voice Response Technology 
IWRS 
Interactive Web Response Technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
Relapse-Free Survival 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, Figures 
WHO 
World Health Organization 
 
 
 


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1 
Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the statistical methods for all 
safety and efficacy analyses planned to be included for the clinical study report (CSR) of 
study CPKC412AUS23 (A Phase II, randomized trial of standard of care, with or without 
midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplantation 
(HSCT) in patients with FLT3-ITD mutated acute myeloid leukemia). 
The content of this SAP is based on protocol CPKC412AUS23 Amendment Version 02. All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock of the study data. 
 
The planned analysis identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, conference submissions or future manuscripts. Post-hoc 
 
 not identified in this SAP may be performed to further examine study data. Any post-
hoc, unplanned, 
 performed will be clearly identified as such. 
 
In addition to the study protocol, the following documents were reviewed in preparation of 
this SAP: 
• Electronic case report form (eCRF) for Protocol CPKC412AUS23 
• ICH Guidance on Statistical Principles for Clinical Trials (E9) 
1.1 
Study design 
This is a randomized, open label Phase II study to investigate the efficacy and safety of twice 
daily midostaurin in patients with FLT3 ITD AML after HSCT. 
Subjects will be treated with the Standard of Care (SOC) treatment with or without (+/-) 
midostaurin in a 1:1 randomization. All subjects who have engrafted and recovered counts by 
day 42 after HSCT will be eligible for randomization no later than 60 days after transplant 
(may occur as early as day 28 post transplant), regardless of treatment assignment.  
Midostaurin will be given at a dose of 50mg twice daily continuously in cycles of 4 weeks (28 
days) each for up to 12 cycles or disease relapse or withdrawal due to any cause, whichever 
occurs earlier. 
Subject visits will occur monthly for one year during the Treatment Phase (Cycles 1-12). 
Visits will continue in the Follow-up Phase through 24 months post HSCT. Hematology Lab 
Panels will be collected every two months to assess relapse in addition to survival status. 
Subjects that have not relapsed, died or withdrawn at 24 months will be asked to provide 
quarterly hematology panels until the study ends. 
The study will end when all subjects have been followed for 24 months post HSCT, unless all 
subjects have died or withdrawn from the study prior to this time point. Prior to database lock, 
an additional overall survival (OS) and relapse free survival (RFS) update will be requested 
for all living subjects. 
No formal interim efficacy analysis is planned in this study. Safety will be evaluated by an 
independent review committee after 10, 20, and 30 subjects, regardless of treatment arm, have 
completed at least 3 cycles or discontinued. An independent review committee of 3 to 5 study 


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investigators will review safety information to include (but not limited to) adverse events, 
serious AEs, lab parameters, bone marrow results 
. 
1.1.1 
Subject Population 
Male and Female subjects, aged 18 to ≤ 70 years old, with acute myeloid leukemia (AML) 
must have documented FLT3-ITD mutation and have undergone allogeneic HSCT in first 
complete remission (CR1) to be eligible to enter the study. Sixty (60) subjects will be enrolled 
during the study 
1.1.2 
Randomization 
This is a randomized (1:1) two-arm, open-label study with standard of care with or without 
(+/-) midostaurin 50mg twice daily for up to 12 cycles. 
The two arms will be: (1) Standard of Care and (2) Standard of Care plus midostaurin. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A subject randomization list will be produced by the 
Interactive Web Response Technology (IWRS) provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms. 
After all assessments have been completed, all subjects who fulfill all inclusion/exclusion 
criteria will be randomized via IWRS on C1D1 to one of the treatment arms. The investigator 
or his/her delegate will call or log on to the IWRS and confirm that the subject fulfills all the 
inclusion/exclusion criteria. The IWRS will assign a randomization number to the subject, 
which will be used to link the subject to a treatment arm. The randomization number will be 
communicated by the IWRS confirmation 
1.2 
Interim and Final Analysis 
No formal interim analysis will be performed for this study. However, there will be 2 
snapshots of the data taken per year for the purpose of publication and IRC data review. 
The primary analysis of RFS will be done when all subjects have been followed up to 18 
months post-HSCT. 
The final safety and efficacy analyses will be conducted when all living subjects have been 
followed up to 24 months post-HSCT. 


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1.3 
Study objectives and endpoints 
Objective 
Endpoint 
Primary 
To determine if the addition of midostaurin to 
standard of care (SOC) therapy reduces relapse 
after at least 18 months of follow-up following 
allogeneic HSCT in FLT3-ITD mutant AML 
patients in first complete remission (CR1) 
Relapse Free Survival (RFS) is defined as the time from 
transplant to relapse or death due to the disease 18 
months post transplant 
Key Secondary: 
To evaluate disease free survival (DFS)  
 
To evaluate relapse free survival (RFS) all along 
the study  
To evaluate non-relapse mortality (NRM) 
 
 
To evaluate overall survival (OS)  
 
To evaluate safety and tolerability of midostaurin 
in patients with FLT3 –ITD AML in the post-
transplant setting 
 
 
 
 
To evaluate pharmacokinetics (PK) of 
midostaurin in the post-transplant  
 
To assess FLT3-ITD mutation status centrally in 
archived material from diagnosis, if available 
DFS is defined as the time from transplant to relapse or 
death from any cause 
Relapse Free Survival (RFS) is defined as the time from 
transplant to relapse or death due to the disease 
NRM is calculated from the date of transplant to date of 
patient death due to reasons other than 
relapse/progressive AML. 
 
OS is defined as the time from transplant to the date of 
death from any cause 
 
Safety will be assessed by the Common Toxicity 
Criteria for Adverse Events (CTCAE) version 4.0. 
Incidence of adverse events (AEs), serious adverse 
events (SAEs), changes from baseline in clinically 
notable changes in vital signs and CTC grading for 
laboratory results (hematology, blood chemistry, ECGs) 
will be reported. 
 
PK concentration-steady state levels 
 
FLT3-ITD mutation status, including the mutant: wild 
type ratio 


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2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be performed 
.  No interim analysis will be 
performed for this study.  SAS version 9.3 or later software will be used to perform all data 
analyses and to generated tables, figures, and listings. 
Data included in the analysis 
The analysis cut-off date for the primary analysis of study data will be established after all 
subjects have been followed up to 18 months post-HSCT or have discontinued study. All 
statistical analyses will be performed using all data collected in the database up to the data 
cutoff date. All data with an assessment date or event start date (e.g. vital sign assessment 
date or start date of an adverse event) prior to or on the cut-off date will be included in the 
analysis. Any data collected beyond the cut-off date will not be included in the analysis and 
will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘ongoing. The same rule will be applied to events starting before or on the cut-
off date and not having documented end date. This approach applies, in particular, to adverse 
event and concomitant medication reports. For these events, the end date will not be imputed 
and therefore will not appear in the listings. 
The final safety and efficacy analyses will be conducted when all living subjects have been 
followed up to 24 months post-HSCT. 
All listings will be presented by actual treatment received. 
General analysis conventions 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by treatment group; a missing category will be included as applicable. Percentages will be 
calculated using the number of subjects in the relevant population as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by 
treatment group. 
2.1.1 
General definitions  
Investigational drug and study treatment 
The term investigational treatment will refer to midostaurin. The term study treatment will 
refer to either standard of care (SOC) or SOC+Midostaurin. 


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Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) (e) CRF. The date of first administration of study drug will also be referred as 
start of investigational drug. 
Date of last administration of investigational drug/study treatment 
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug. 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of study treatment was administered as per the Dosage Administration CRF if the subject 
received midostaurin or date of randomization if the subject received Standard of Care. The 
date of first administration of study treatment will also be referred as start of study treatment. 
Date of last administration of study treatment  
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per Dose Administration (e) CRF if the subject 
received midostaurin or date of end of treatment visit, end of cycle 12, date of first relapse or 
date of discontinuation whichever occurs first if the subject received Standard of Care.  
Date of study completion 
The date of study completion is defined as the date the study completion evaluation visit is 
complete. 
Study day 
The study day, describes the day of the event or assessment date, relative to the date of 
randomization 
The study day is defined as: 
 The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the randomization start date; 
 The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the randomization start date. 
The reference start date for safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, pk etc.) is the start of 
study treatment.  
The reference start date for all other, non-safety assessments (i.e., survival time, disease 
relapse) is the date of randomization.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If 
duration is reported in months, duration in days will be divided by 30.4375.  If duration is 
reported in years, duration in days will be divided by 365.25. 
Baseline 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. 
In the context of baseline definition, the efficacy evaluations also include PRO and 
performance status.   
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken or ‘‘baseline” assessment.  
In case time of assessment and time of treatment start is captured (e.g. pre-dose ECG), the last 
available assessment before the treatment start date/time is used for baseline.  
If subjects have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods  
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments:  
1. pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment 
2. on-treatment period:  
a. SOC arm (whichever comes first): From randomization until discontinuation, 
relapse or completion of treatment phase (12 cycles) + 30 days 
b. SOC + Midostaurin arm: From date of first study drug to date of last of study 
drug + 30 days 
3. follow-up period: starting at day 30+1 after last administration of study treatment. 
If dates are incomplete in a way that clear assignment to pre-, on-, follow-up period cannot be 
made, then the respective data will be assigned to the on-treatment period.   
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change 
from baseline summaries). In addition, a separate summary for death including on treatment 
and post treatment deaths will be provided.  In particular, summary tables for adverse events 
(AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (treatment-emergent AEs).   
However, all safety data (including those from the follow-up period) will be listed and those 
collected during the pre-treatment and follow-up period will be flagged. 


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Windows for multiple assessments  
In order to summarize data collected over time (including unscheduled visits), the assessments 
will be time slotted. The following general rule will be applied in creating the assessment 
windows: If more than one assessment is done within the same time window, the assessment 
performed closest to the target date will be used. If 2 assessments within a time window are 
equidistant from the target date, then the earlier of the 2 assessments will be used. If multiple 
assessments on the same date then the average will be used.  Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be listed. 
Table 1 Time windows for assessments  
 
Assessment 
Target day of assessment 
Time Window 
Screening 
-7 
Day -14 to -1 
        Cycle 1 Day 1 
1 
Day  1 to 2 
        Cycle 1 Day 3 
3 
Day  3 to 7 
        Cycle 1 Day 15 
15 
Day 8 to day 21 
Cycle 2 Day 1 
29 
Day 22 to day 42 
Cycle 3 Day 1 
57 
Day 43 to day 70 
Cycle 4 Day 1 
85 
Day 71 to day 98 
Cycle 5 Day 1 
113 
Day 99 to day 126 
Cycle k Day 1 (k≥5) 
d=(k-1)*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the 
end of treatment visit 
Last contact date  
The last contact date will be derived for subjects not known to have died at the analysis cut-
off using the last complete date among the following: 
 
Table 2 
Last contact date data sources  
Source data 
Conditions 
Date of Randomization  
 
No Condition 
Last contact date/last date subject was known to 
be alive from Survival Follow-up page or Study 
Completion Evaluation 
 
- Subject status is reported to be alive, lost to 
follow-up or unknown. 
Start/End* dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
 
No condition. 
Laboratory/PK collection dates 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one non-missing parameter value 
Performance Status date 
Non-missing performance status 


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Source data 
Conditions 
 
GVHD Assessment date 
Non-missing grade or type 
Start/End dates of AE  
Non-missing verbatim term 
The last contact date is defined as the latest complete date from the above list on or before 
the data cut-off date. The cut-off date will not be used for last contact date, unless the subject 
was seen or contacted on that date. No date post cut-off date will be used. Completely 
imputed dates (e.g. the analysis cut-off date programmatically imputed to replace the 
missing end date of a dose administration record) will not be used to derive the last contact 
date. Partial date imputation is allowed for event (death)/censoring if coming from ‘Survival 
information’ eCRF.  
The last contact date will be used for censoring of subjects in the analysis of overall survival. 
2.2 
Analysis sets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all randomized subjects. According to the intent to 
treat (ITT) principle, subjects will be analyzed according to the treatment arm (SOC +/- 
midostaurin) they have been assigned to during the randomization procedure. 
Safety Set 
Subjects who received at least one dose of midostaurin during the study will be allocated to 
the SOC + midostaurin treatment arm. Subjects randomized to the SOC + midostaurin arm but 
who never received midostaurin will be allocated to the SOC treatment arm. Subjects will be 
analyzed according to the study treatment actually received. 
Per-Protocol Set 
The Per Protocol Set (PPS) consists of all subjects from the Full Analysis Set without any 
major protocol deviations.  
Protocol deviations leading to the exclusion from the PPS will be specified in the Statistical 
Analysis Plan (SAP) prior to database lock.  
Pharmacokinetic Analysis Set 
The Pharmacokinetic Set (PK Set) comprises all subjects that have been administered at least 
one dose of midostaurin and that have provided at least one evaluable PK sample. A profile 
is considered evaluable if all of the following conditions are satisfied: 
 Subject receives one of the planned  treatments  
 Subject provides at least one primary PK parameter 


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Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a 
subject withdraws full consent is recorded in the eCRF.   
2.3 
Subject disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment group and for all 
subjects and listings will be reported by treatment group to assess baseline comparability.  No 
inferential statistics will be provided. 
2.3.1 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment group on the FAS. Categorical data (e.g. gender, race) will be summarized by 
frequency counts and percentages; the number and percentage of subjects with missing data 
will be provided. Continuous data (e.g. age, weight, height, body mass index) will be 
summarized by descriptive statistics (N, mean, median, standard deviation, minimum and 
maximum).  
BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at Baseline. Body 
Surface Area (BSA) will be calculated using Gehan and George formula: 
BSA[m2]=234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000 unless otherwise 
specified.   
Additionally, the number of day since transplant to randomization, donor type and product 
type will be summarized by treatment group on the FAS.  
These summaries will be repeated on the safety set. 
2.3.2 
History of AML Disease 
Summary statistics will be tabulated for history of AML Disease at initial diagnosis and post-
diagnosis. This analysis will include the following: AML Status. AML (2016 revision of the 
WHO) subclassification, months since initial diagnosis to randomization, WBC counts (x 
109/L), bone marrow results (%),  
Cytogenetics details (i.e. sample type, number of metaphases examined, abnormalities, 
method and % abnormal) will be summarized for initial post-diagnosis separately. 
2.3.3 
Pre-HSCT Treatment for AML 
All pre-HSCT treatment for AML details will be listed. The purpose of therapy, number of 
cycles, type of therapy and duration (days), if applicable, will be summarized. The best 
response to the line of therapy across all therapies will be summarized using frequency 
counts.  


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2.3.4 
Pre-HSCT Preparative Regimen, Disease Status 
All Pre-HSCT preparative regimen details will be listed. Details regarding the disease status 
assessment prior to preparative regimen will also be listed. 
2.3.5 
FLT3-ITD Positive Mutational Analysis at Diagnosis 
Subjects were permitted to enroll based on the locally known FLT3-ITD mutation status 
which was determined at diagnosis. Specimen type, length of ITD nucleotides, ITD Alleic 
ratio, whether the subject has TKD mutation and whether an archived sample retrieved for 
central lab confirmation of FLT3-ITD mutations was obtained will be summarized for the 
FAS. 
All data will be listed. 
2.3.6 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF will be listed and summarized by treatment group and grade. Separate 
summaries will be presented for active and non-active medical conditions.   
The summaries will be presented by primary system organ class (SOC), preferred term (PT) 
and treatment group. Medical history and current medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. The MedDRA version 
used for reporting will be specified in the CSR and as a footnote in the applicable 
tables/listings. 
2.3.7 
Subject disposition 
The following summaries will be provided (with % based on the total number of FAS 
subjects) and presented overall and by treatment group: 
 Number (%) of subjects who were randomized 
 Number (%) of subjects who were randomized but not treated 
 Number (%) of subjects who completed and discontinued the study treatment 
period (based on the ‘End of Treatment’ page)  
 Primary reason for study treatment period discontinuation (based on the ‘End of 
Treatment’ page) 
 Number (%) of subjects who have entered the post-treatment follow-up (based on 
the ‘End of Treatment’ page); 
 Number (%) of subjects who have completed and discontinued from the post-
treatment follow-up (based on the Study Evaluation Completion page); 
 Reasons for discontinuation from the post-treatment follow-up (based on Study 
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2.3.8 
Protocol deviations 
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category, overall and by treatment group for the FAS. Major protocol deviations 
leading to exclusion from the Per Protocol Set will be tabulated separately overall and by 
treatment group. All protocol deviations identified from both edit check and monitoring will 
be listed. 
2.3.9 
Analysis sets 
The number (%) of subjects in each analysis set (defined in Section 2.2) will be summarized 
by treatment group. Percentages will be based on the FAS 
2.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by treatment group for the safety set. 
2.4.1 
Study treatment / compliance 
Duration of investigational drug exposure, actual cumulative dose, dose intensity (DI) and 
relative dose intensity (RDI) will be summarized by treatment group. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  
Duration of exposure to investigational drug 
Duration of exposure to investigational drug (months) = (last date of exposure to 
investigational drug) – (date of first administration of investigational drug) + 1 divided by 
30.4375.  
Duration of exposure will be summarized as continuous summaries (i.e. mean, standard 
deviation etc.) and categorized into time intervals (< 3 months, 3 to < 6 months, 6 to < 9 
months, 9 months to 12 months greater than 12 months); frequency counts and percentages 
will be presented for the number (%) of subjects in each interval.  
Cumulative dose 
Cumulative dose of investigational drug is defined as the total dose given during the 
investigational drug exposure and will be summarized.  
The planned cumulative dose for investigational drug refers to the total planned dose as per 
the protocol up to the last date of investigational drug administration. The planned dose is as 
follows: 50mg b.i.d for 28 consecutive days of each cycle for 12 cycles. 
The planned cumulative dose will not summarized/listed. It will be used for relative dose 
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The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the investigational drug as documented in the Dose Administration 
eCRF.  
For patients randomized to receive investigational drug and did not take any investigational 
drug the cumulative dose is by definition equal to zero. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period. 
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the subject is assumed to have taken a non-zero dose during dosing periods.  
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (mg /days) = Actual Cumulative dose (mg) / Duration of exposure to study treatment 
(days). 
For patients who did not take any investigational drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg /days) = Planned Cumulative dose (mg) / Duration of exposure (days). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg /days) / PDI (mg /days) 
DI and RDI will be summarized safety subjects who received investigational drug. 
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, permanent discontinuations or 
interruptions along with the reasons will be summarized. Similarly, subjects who are re-
challenged will also be summarized 
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for 
permanent discontinuation’ will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption are entered on consecutive days with different reasons they will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries 
on consecutive days, then it will be counted as one interruption.  


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Reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered/total daily dose is lower than the 
calculated dose amount based on the prescribed dose. Therefore any dose change to correct a 
dosing error will not be considered a dose reduction.  Only dose change is collected in the 
CRF, number of reductions will be derived programmatically based on the change and the 
direction of the change. 
If dose is recorded but regimen is missing or entered as ‘none’, it is assumed that the 
investigational drug was taken as per-protocol. 
2.4.2 
Prior, concomitant and post therapies 
2.4.2.1 
Prior Antineoplastic Therapy - Surgery 
The number and percentage of patients who received any prior anti-neoplastic surgery will be 
summarized. Prior anti-neoplastic surgeries will be summarized by lowest System Organ 
Class and preferred term as coded by MedDRA Version 16.0.  
All prior antineoplastic therapy data will be listed for the FAS. 
The above analyses will be performed using the safety set. 
2.4.2.2 
Prior and Concomitant Medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period.  
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary v13.3 and summarized by ATC class 4 and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term.  
Medications will be classified as prior or concomitant based on the following rules: 
 Prior medications are medications that started before the first dose of study treatment 
regardless of whether the medication ended before or after the first dose of study 
treatment 
 Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study 
treatment and continuing after the start date of study treatment. 
o Medications starting on or after the start of study treatment but no later than 30 
days after start of last dose of study treatment and 
o Medications starting prior to start of study treatment and continuing after the 
start of study treatment 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study 
treatment will be flagged in the listing. A separate summary of subjects who received strong 


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CYP3A4 inhibitors will be provided. In the listing of concomitant medications, these 
inhibitors will be flagged. The safety Analysis Set will be used for all prior and concomitant 
medication tables and listings. 
2.5 
Analysis of the primary objective 
The primary objective of this study is to determine if the addition of midostaurin to standard 
of care (SOC) therapy compared to SOC reduces relapse after at least 18 months of follow-up 
following allogeneic HSCT in FLT3-ITD mutant AML patients in first complete remission 
(CR1). 
2.5.1 
Primary endpoint 
The primary endpoint is relapse free survival (RFS), defined as the time from transplant to 
relapse or death due to the disease 18 months post-transplant. If a patient has more than one 
event (e.g. relapse then death) then the earliest date will be taken into account. The primary 
analysis will be based on FAS.  
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary efficacy variable, RFS will be analyzed based on the data observed in the FAS 
up-to the cut-off date, according to the treatment group assigned at randomization.  The 
survival distribution of RFS will be estimated using the Kaplan-Meier method. Kaplan-Meier 
plots will be used to depict RFS over time in each treatment group. 25th percentile, Median, 
and 75th percentile survival will be obtained along with 95% CI calculated using the method 
of Brookmeyer & Crowley. Kaplan-Meier estimates with 95% CI will be summarized every 6 
month using Greenwood’s formula for the standard error of the Kaplan-Meier estimate.  
2.5.3 
Handling of missing values/censoring/discontinuations 
The final analysis for RFS will be performed after all subjects have reached approximately 18 
months post- transplant. An analysis cut-off date will be established after these subjects have 
reached this milestone. 
Patients alive in remission at the time of the data cut-off point used for the analysis will have 
RFS censored at the time of last measurement prior to the data cut-off point. The number of 
subjects having an event and number of patients censored will be summarized. A summary of 
reasons censoring will be provided by treatment group. 
If no post-baseline assessments are available (before an event or a censoring reason occurred) 
then the date of randomization/start date of treatment will be used. 
Refer to Table 3 for censoring and event date options and outcomes for RFS. 
Table 3     Outcome and event/censor dates for RFS analysis 
 
Situation 
Date 
Outcome 
No baseline assessment 
Date of randomization  
Censored 


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Situation 
Date 
Outcome 
Relapse or death at or before 
next scheduled Assessment 
Date of relapse (or death) 
whichever is earlier 
Relapsed 
 
Relapse or death after exactly 
one missing assessment 
Date of relapse (or death) 
whichever is earlier 
Relapsed 
 
Relapse or death after two or 
more missing assessments 
Date of last adequate 
assessment prior to 
missed assessment  
Censored 
 
No relapse (or death) 
Date of last adequate 
assessment  
Censored 
 
Treatment/Study discontinuation 
due to ‘Relapse’  
Date of Relapse  
Relapsed 
 
Death before first assessment 
Date of death 
Relapsed 
2.5.4 
Supportive analyses 
The primary analysis will be repeated on the PP Set as a supportive analysis. 
In addition, a sensitivity analysis will be performed on RFS using the time from 
randomization as reference time-point instead of the time from transplant. The same statistical 
analyses as the previous one described will be performed on this variable. This sensitivity 
analysis will be performed on both the FAS and PPS.  
2.6 
Analysis of the secondary objective 
2.6.1 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate disease free survival (DFS) 
 To evaluate relapse free survival (RFS) all along the study 
 To evaluate non-relapse mortality (NRM) 
 To evaluate overall survival (OS) 
 To evaluate safety and tolerability of midostaurin in patients FLT3-ITD 
AML in the post-transplant setting 
 To evaluate pharmacokinetics (PK) of midostaurin 
 To assess FLT3-ITD mutation status centrally in archived material from diagnosis (if 
available) including the mutant:wild type ratio 
2.6.2 
Secondary endpoints 
The secondary efficacy variables include: 
 Disease Free Survival (DFS): defined as the date from transplant to date of relapse or 
death from any cause. 


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 Relapse Free Survival (RFS): defined as the date from transplant to date of relapse or 
death due to the disease 24 months post HSCT. 
 Overall Survival (OS): defined as the date from transplant to the date of death from 
any cause. 
 NRM: defined as the date from transplant to date of patient death due to reasons other 
than relapse/progressive AML. 
 PK concentration-steady state levels 
 FLT3-ITD mutation status, including the mutant: wild type ratio. 
 
Kaplan-Meier plots will be used to depict DFS, RFS, OS and NRM over time in each 
treatment group. Median survival will be obtained along with 95% CI calculated using the 
method of Brookmeyer & Crowley.  
Kaplan-Meier estimates with 95% CI will be summarized every 6 month using Greenwood’s 
formula for the standard error of the Kaplan-Meier estimate.   
In addition to the Kaplan-Meier, Cox proportional hazard model will be used to provide 
estimate of the hazard ratio (HRSOC+Midaustorin/SOC) and associated Wald 95% CI for each 
secondary endpoint. These analyses will be performed on the FAS. 
 


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2.10 
Safety analyses 
All safety analyses will be based on the safety set. Safety analyses will be presented overall, 
by treatment group (SOC or SOC + Midostaurin) and visit within treatment group if 
applicable. All safety listings will be presented on the FAS unless otherwise specified. 
2.10.1 
Treatment Emergent Adverse events (AEs) 
Treatment emergent AEs (TEAEs) are defined as AEs that started or worsened during the on-
treatment period. The start day used to define the TEAEs in the entire study is the first day of 
study treatment administration. AEs with a start day before or after on-treatment period will 
not be summarized, they will be listed. 
TEAEs will be summarized by number and percentage of subjects having at least one AE, 
having at least one AE in each primary system organ class (SOC) and for each preferred term 
(PT) using MedDRA Version 16.0 coding. A subject with multiple occurrences of an AE will 
be counted only once in the respective TEAE category. A subject with multiple CTCAE 
grades for the same preferred term will be summarized under the maximum CTCAE grade 
recorded for the event. TEAE with missing CTCAE grade will be included in the ‘All grades’ 
column of the summary tables. 
In TEAE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order 
for the preferred term will be based on their frequency in the treatment group.  
The following TEAE summaries will be produced by treatment group: 
 Overview of TEAEs and deaths (number and % of subjects with any AE, any TEAE,  
died, 
any 
SAE, 
AE 
leading 
to 
treatment 
discontinuation, 
any 
dose 
adjustments/interruptions, TEAE suspected to be related to study treatment) 
 TEAEs by SOC and PT 
 Most common (>=5%) TEAEs 


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 TEAEs by maximum severity 
 TEAEs suspected to be related to study treatment  
 Serious Adverse Events 
 TEAEs leading to treatment discontinuation,  
 TEAEs leading to dose interruption/adjustment  
 TEAEs leading to fatal outcome.  
If partial dates occur, the convention for replacing missing dates for the purposes of 
calculating derived using the same method as described in Section 5.1.2. . 
If an AE has a missing severity, it will be imputed as “Grade 4”; any missing relationship to 
study drug of an AE will be imputed as related.  No other missing data will be imputed unless 
otherwise specified. 
All AEs, SAEs, TEAEs leading to treatment discontinuation, TEAEs suspected to be related 
and TEAEs leading to fatal outcome will be presented in separate listings on the FAS. 
2.10.2 
Laboratory data 
All laboratory values will be converted into SI units and the severity grade calculated using 
Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03.   For laboratory tests 
covered by CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or 
higher. Grade 5 will not be used.  A table of CTCAE grades for the parameters of interest in 
the study is given below (U.S. HHS Dept., 2010). 
Observed and change from baseline for Biochemistry and Hematology parameters will be 
summarized using descriptive statistics included 25th and 75th percentiles by treatment group 
and overall.


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Table 5 Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 
 
Parameter 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (g/L) 
Anemia 
<LLN – 100 
<100 – 80 
<80 
Life-threatening 
consequences; urgent 
intervention indicated 
Hemoglobin (g/L) 
Hemoglobin 
increased 
Increase in >0 – 20  above 
ULN or above BL if BL is 
above ULN 
Increase in >20 – 40  above 
ULN or above BL if BL is 
above ULN 
Increase in >40 above ULN 
or above baseline if 
baseline is above ULN 
N/A 
White blood cells 
(10^9/L) 
White blood cell 
decreased 
<LLN – 3x10^9/L 
<3 – 2x10^9/L 
<2 – 1x10^9/L 
<1x10^9/L 
Lymphocytes 
(10^9/L) 
Lymphocyte count 
decreased 
<LLN – 0.8x10^9/L 
<0.8 – 0.5x10^9/L 
<0.5 – 0.2x10^9/L 
<0.2x10^9/L 
Lymphocytes 
(10^9/L) 
Lymphocyte count 
increased 
N/A 
>4 - 20 
>20 
N/A 
Neutrophils (10^9/L) 
Neutrophil count 
decreased 
<LLN – 1.5x10^9/L 
<1.5 – 1.0x10^9/L 
<1.0 – 0.5x10^9/L 
<0.5x10^9/L 
Platelets (10^9/L) 
Platelet count 
decreased 
<LLN – 75.0x10^9/L 
<75.0 – 50.0x10^9/L 
<50.0 – 25.0x10^9/L 
<25.0x10^9/L 
Albumin (g/L) 
Hypoalbuminemia 
<LLN – 30 
<30 – 20 
<20 
Life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase 
(IU/L) 
Alkaline 
phosphatase 
increased 
>ULN – 2.5xULN 
>2.5 – 5.0xULN 
>5.0 – 20.0xULN 
>20.0xULN 
Alanine 
aminotransferase 
(IU/L) 
Alanine 
aminotransferase 
increased 
>ULN – 3.0xULN 
>3.0 – 5.0xULN 
>5.0 – 20.0xULN 
>20.0xULN 
Aspartate 
aminotransferase 
(IU/L) 
Aspartate 
aminotransferase 
increased 
>ULN – 3.0xULN 
>3.0 – 5.0xULN 
>5.0 – 20.0xULN 
>20.0xULN 
Bilirubin (umol/L) 
Blood bilirubin 
increased 
>ULN – 1.5xULN 
>1.5 – 3.0xULN 
>3.0 – 10.0xULN 
>10.0ULN 
Calcium (mmol/L) 
Hypocalcemia 
Corrected serum calcium 
<LLN – 2.0; Iodized calcium 
Corrected serum calcium 
<2.0 - 1.75; Ionized calcium 
Corrected serum 
calcium<1.75 - 1.5; Ionized 
Corrected serum calcium 
<1.5; Ionized calcium <0.8; 


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Parameter 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
<LLN – 1.0 
<1.0- 0.9 
calcium <0.9-0.8; 
hospitalization indicated 
life-threatening 
consequences 
Calcium (mmol/L) 
Hypercalcemia 
Corrected serum calcium 
of >ULN -2.9; Ionized 
calcium >ULN - 1.5 
Corrected serum calcium 
of >2.9 - 3.1; Ionized 
calcium >1.5- 1.6; 
symptomatic 
Corrected serum calcium 
of >3.1 - 3.4; Ionized 
calcium >1.6-1.8; 
hospitalization indicated 
Corrected serum calcium 
of >3.4; Ionized 
calcium >1.8; life-
threatening consequences 
Cholesterol (mmol/L) 
Cholesterol high 
>ULN – 7.75 
>7.75 – 10.34 
>10.34 – 12.92 
>12.92 
Creatinine 
Creatinine increased 
>1 - 1.5 x baseline; >ULN -
1.5 x ULN 
>1.5 - 3.0 x baseline; >1.5 -
3.0 x ULN 
>3.0 baseline; >3.0 - 6.0 
xULN 
>6.0 x ULN 
Glucose (mmol/L) 
Hypoglycemia 
<LLN – 3.0 
<3.0 – 2.2 
<2.2 – 1.7 
<1.7; life-threatening 
consequences; seizures 
Glucose (mmol/L) 
Hyperglycemia 
>ULN – 8.9 
>8.9 – 13.9 
>13.9 – 27.8; 
hospitalization indicated 
>27.8; life-threatening 
consequences 
Lipase 
Lipase increased 
>ULN – 1.5xULN 
>1.5 – 2.0xULN 
>2.0 – 5.0xULN 
>5.0xULN 
Magnesium (mmol/L) 
Hypomagnesemia 
<LLN – 0.5 
<0.5 – 0.4 
<0.4 – 0.3 
<0.3; life-threatening 
consequences 
Magnesium (mmol/L) 
Hypermagnesemia 
>ULN – 1.23 
N/A 
>1.23 – 3.30 
>3.30; life-threatening 
consequences 
Phosphate (mmol/L) 
Hypophosphatemia 
<LLN – 0.8 
<0.8 – 0.6 
<0.6 – 0.3 
<0.3; life-threatening 
consequences 
Potassium (mmol/L) 
Hypokalemia 
<LLN – 3.0 
<LLN – 3.0; symptomatic; 
intervention indicated 
<3.0 – 2.5; hospitalization 
indicated 
 
<2.5; life-threatening 
consequences 
Potassium (mmol/L) 
Hyperkalemia 
>ULN – 5.5 
>5.5 – 6.0 
>6.0 – 7.0; hospitalization 
indicated 
>7.0; life-threatening 
consequences 
Sodium (mmol/L) 
Hyponatremia 
<LLN - 130 
N/A 
<130 - 120 
<120; life-threatening 
consequences 
Sodium (mmol/L) 
Hypernatremia 
>ULN - 150 
>150 - 155 
>155 – 160; hospitalization 
indicated 
>160; life-threatening 
consequences 
Triglycerides 
(mmol/L) 
Hypertriglyceridemia 
1.71 – 3.42 
>3.42 – 5.7 
>5.7 – 11.4 
>11.4; life-threatening 
consequences 


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Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters with CTC grades.  
In addition, shift tables using laboratory normal ranges to compare baseline to the worst 
postbaseline value will be produced for all parameters, if any (Ranges: 
Low, Normal, High). 
All laboratory values will be listed by laboratory parameter and visit for each subject. 
Separate listings will display notable laboratory abnormalities which will include only newly 
occurring CTCAE grade 3 or 4 laboratory toxicities. 
2.10.3 
Pregnancy and assessments of fertility 
All Pregnancy test data will be listed only. 
2.10.4 
Radiological examinations 
A screening chest image; Chest x-ray (CXR) or CT scan will be performed to assess study 
eligibility. All data collected will be listed only. 
2.10.5 
Extramedullary Disease Assessment 
The extramedullary disease assessment (EMD) will be performed at Screening, Cycle 1: Day 
1 and at End of Treatment. If there is evidence of extra-medullary involvement, the location 
and method will be summarized by treatment group and visit. 
2.10.6 
ECG  
A standard 12 lead ECG will be performed at Screening, Cycle 1: Day 1 (pre-dose), Cycle 1: 
Day 3, Cycles 2-12: Day 1 and End of Treatment (EOT) or Treatment Discontinuation.  
Summary statistics (mean, median, SD, 25th and 75th percentile) for observed values and 
change from baseline of heart rate, PR interval, QRS duration, QT interval, QTcF, and 
frequencies and percentages of presence of clinically significant abnormalities will be 
presented by treatment group and visit. 
In case the study requires ECG replicates at any assessment, the average of the ECG 
parameters at that assessment will be used in the analyses. 
 
A change from baseline to worst on-treatment result for post-baseline assessments will be 
presented by treatment group. 
The number and percentage of subjects with any post-baseline notable ECG value will be 
presented by treatment group.  
 QT or QTcF 
- 
Value > 450 and ≤ 480 ms 
- 
Value > 480 and ≤ 500 ms 
- 
Value > 500 ms 
- 
Increase from Baseline > 30 ms to ≤  60ms 


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- 
Increase from Baseline > 60 ms 
 HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
 PR 
- 
Increase from baseline >25% and  to a value > 200 ms 
- 
Value > 200 ms 
 QRS 
- 
Increase from baseline >25% and  to a value > 120 ms  
- 
Value > 120 ms 
A listing of all ECG assessments will be produced by treatment group. A separate listing with 
notable results will be produced.  separate listing of ECG evaluations for all patients with at 
least one abnormality will be presented including only subjects with an abnormality and the 
visit the abnormality occurred in. 
2.10.7 
Vital signs 
Vital signs include temperature, respiratory rate, blood pressure and pulse and will be taken in 
the sitting position. Vitals will be measured at Screening, Cycle 1 Day 1, 3, 15, Day 1 of each 
subsequent cycle and at End of Treatment (EOT).  
Summary statistics of actual value and change from baseline values (means, medians, 
standard deviations, 25th and 75th percentile) of vital signs and weight collected on treatment 
will be summarized. 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 6 
below. 
Table 6      Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
>= 39.1  
- 


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Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
temperature 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented by treatment group.       
All vital sign data will be listed. A separate listing with notable values will be provided.  
2.10.8 
ECOG Performance Status 
The ECOG PS scale Table 7 will be used to assess physical health of patients, ranging from 0 
(most active) to 5 (least active): 
Table 7 
ECOG Performance Scale 
Score 
Description 
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 
Frequency counts and percentages of patients in each score category will be provided by 
treatment group and visits based on the windows defined in Section 2.1. 
2.10.9 
Cardiac imaging - MUGA (multiple gated acquisition) scan or 
Echocardiogram 
An echocardiogram or MUGA scan will be performed on screening prior to Day 1, at Cycle 3, 
6 and at the EOT visit 
The left ventricular ejection fraction (LVEF) will be summarized and the overall 
interpretation will be summarized using frequency and percentages by treatment group and 
visit. 
2.11 
Pharmacokinetic Concentrations   
Plasma concentrations of midostaurin and its two major metabolites CGP52421 and 
CGP62221will be measured using a validated liquid chromatography/ mass spectrometry 
(LC-MS/MS) assay with a lower 


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Descriptive statistics (n, m (number of non-zero concentrations), mean, CV% mean, SD, 
median, geometric mean, CV% geo-mean, minimum and maximum) for Midostaurin 
concentration will be presented at each scheduled time point for the Pharmacokinetic analysis 
set. 
All concentration values below the lower limit of quantitation (LLOQ) are set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values will be 
treated as zero in any calculations of summary statistics, and treated as missing for the 
calculation of the geometric means and their CV%. The number of non-zero concentrations 
will also be reported in the summary statistics. 
Missing values for any PK data will not be imputed and will be treated as missing. 
The mean (+/- SD) and geometric mean trough concentration-time profiles for Midostaurin 
over time will be displayed graphically for Pharmacokinetic analysis set. 
All individual plasma Midostaurin concentration data will be listed for the PK analysis set. 
General Data Handling and preprocessing 
The Cycle 1 Day 1 assessment (pre-dose) will be used as the baseline value.  
When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.  
Derivation of Change and Percent Change Variables 
Absolute and relative change (percent change) and fold change from baseline will be 
calculated for each subject and/or treatment group. 
Fold change is calculated as the ratio of biomarker value at ((visit i) / (Baseline biomarker 
value)), while percent change is computed as ((visit i – baseline) / baseline) * 100.  
The average percent change from baseline is computed as the average expression level at each 
time point and then the percent change using the average values.  Please note that the number 
of subjects for the average of percent change from baseline might vary due to potential 
missing values at respective time points. 
If both the baseline and post baseline values are below LLOQ, absolute change, percent 
change and fold change from baseline will not be imputed and reported as missing. 
Analysis 
 


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2.12 
Interim analysis 
No formal interim analysis is planned for this study. However, there will be two interim 
snapshots of the data taken per year. 
3 
Sample size calculation 
This study is a Phase II exploratory trial and is not powered to detect a statistical difference 
between the two arms. The sample size for the trial was chosen; 30 patients per treatment arm 
to have separate estimates of the primary endpoint relapse free survival. Powering of the trial 
is not feasible considering the rare nature of FLT3-ITD mutant AML receiving a HSCT. With 
a 22-25% FLT3-ITD mutation rate and approximately 25% rate of HSCT, estimated from the 
ongoing Phase III study (2301, CALGB 10603, Ratify), more than 1050 newly diagnosed 
AML patients would need to be evaluated to identify 60 patients undergoing HSCT in CR1. 
The control arm, Standard of Care (SOC), in this study provides the first prospective subjects 
treated at the same centers in the same timeframe which will allow an estimate of treatment 
effect which can be used to design a larger trial. There are no published sets of prospective, 
FLT3-ITD AML outcomes after transplantation 
If the two arms were compared, the following gives the power that could be achieved under 2 
scenarios of relapse rate with 30 patients per treatment arm. 
Scenario 1: Assuming a 30% relapse rate in the SOC arm 
Scenario 2: Assuming a 50% reduction with midostaurin (experimental arm) 
i.e., 15% relapse rate in the experimental arm, a sample size of 30 patients in each arm will 
detect the reduction with 71% power. This calculation is based on one-sided type I error rate 
of 20%. The power would be 81% if we assume relapse rate to be even lower at 12% keeping 
everything else the same. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 
5 
Appendix 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:  
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date.  
Scenario 1 should not applicable for final analyses. All patients should have EOT page 
complete before the Database lock for Final CSR  


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Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:  
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.   
Case 2: Only Year (yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year (yyyy) of the dose end date is available and yyyy = the year of EOT date:  
            Use EOT date 
Case 4: Both Year (yyyy) and Month (mm) are available for dose end date, and yyyy = the 
year of EOT date and mm < the month of EOT date:  
            Use last day of the Month (mm) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment 
component related calculations and no imputation will be made. If start date is missing then 
end-date should not be imputed. 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 8 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing 
Element 
Rule 
day, month, 
and year 
 No imputation will be done for completely missing dates 
day, month 
 If available year = year of study treatment start date then  
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 


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Missing 
Element 
Rule 
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 9 
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* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data 
listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  
The above imputations are only used for determination of on-treatment assessments/events 
(i.e. concomitant medication, treatment emergent adverse event). 
5.1.2.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan.  
5.2 
Laboratory parameters derivations 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However, this data may not 
be reported as absolute counts but rather as percentage of WBC.  


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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 an xxx differential 
Xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading 
5.3 
Statistical models 
Analysis of time to events Data 
The following endpoints will be analyzed in the same manner:  
 Disease free survival (DFS)  
 Relapse Free Survival (RFS)  
 Non-relapse mortality (NRM)  
 Overall survival (OS) 
Kaplan-Meier estimates 
An estimate of the survival function in each treatment group will be constructed using 
Kaplan-Meier (product-limit) method as implemented in PROC LIFETEST with 
METHOD=KM option. The PROC 
LIFETEST statement will use the option 
CONFTYPE=LOGLOG. 
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence 
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula [Collett 1994]. 
 
Treatment of ties 
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the 
Cox proportional hazards model. 
 


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Checking proportionality of hazard assumption 
Plots (SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS will 
be used to provide visual checks of the proportional hazard assumption.  
 SURVIVAL plots estimated survivor functions.  The shape of the curves should be 
basically the same if hazards are proportional. 
 LOGSURV plots the cumulative hazard functions The larger cumulative hazard 
should be a multiple of smaller if hazards are proportional 
 LOGLOGS plots log (cumulative hazard). The LOGLOG plot will show parallel 
curves if hazards are proportional.  
6 
Reference 
1. Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J and Burger HU. 
Blinded independent central review of progression in cancer clinical trials: results from a 
meta-analysis. European Journal of Cancer 2011; 47: 1772-1778. 
2. Armitage P, McPherson CK and Rowe BC (1969). Repeated significance tests on 
accumulating data. J .R. Statist. Soc. A, 132, 232-244.  
3. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41.    
4. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
5. FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies. 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/on
cologicdrugsadvisorycommittee/ucm311141.pdf  
6. Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time Data (2002). 
Wiley Series in Probability and Statistics.