Clinical trial NCT03552029
Conditions: Acute Myeloid Leukemia
Keywords: Relapsed/Refractory Newly Diagnosed Unfit for Chemotherapy Positive for FLT3-ITD Mutation
Sponsor: Daiichi Sankyo
Start date: 2018-12-12; Completion date: 2021-04-01
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Participants with AML that have gone into remission and come back (relapsed) or gone into remission with a number of leukemia cells still in their system (refractory) will be recruited for this study. They will also be positive for FLT3-ITD mutation.

Participants will receive a combined dose of quizartinib and milademetan that have not been approved by the US Food and Drug Administration yet (m).

The combination of these drugs will be provided in different amounts on defined days (dosing schedules).

It is expected that the combination of milademetan and quizartinib will be safe and well tolerated. It is expected that the combination may fight the leukemia better than a single drug.

The study will run for approximately 3 years. There may be up to 156 participants.

The study has 2 parts:

* Part 1 will test 24-36 participants in approximately 15 study centers globally. Participants will receive two study drugs (milademetan and quizartinib) in different amounts on specific days. Information will be gathered to see what dosing schedule of the drug combination is best (maximum tolerated/recommended dose).
* Part 2 of the study will confirm the recommended dosing schedule identified in Part 1 is effective. A larger number of participants will receive the recommended dose in approximately 15 additional sites worldwide as necessary, based on the enrollment rate, the population, and the standard of care available to them at the time of enrollment.

Detailed description:

Arms: arm 1: Participants with relapsed/refractory FLT3-ITD Mutant AML receive quizartinib + milademetan at increasing and/or decreasing doses and schedules arm 2: Participants with relapsed/refractory FLT3-ITD Mutant AML receive the recommended dose of quizartinib + milademetan determined by Part 1 arm 3: Participants with newly diagnosed FLT3-ITD Mutant AML unfit for chemotherapy receive the recommended dose of quizartinib + milademetan determined by Part 1
Interventions: intervention 1: Quizartinib intervention 2: Milademetan intervention 3: Milademetan
Intervention descriptions: intervention 1: 20 or 30 mg tablets for oral administration intervention 2: 5, 20, 80 or 200 mg capsules for oral administration intervention 3: 5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized

Protocol documents:
Prot_SAP_000.pdf: 
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Page 1 
CLINICAL STUDY PROTOCOL 
 
A PHASE 1 STUDY OF MILADEMETAN IN 
COMBINATION WITH QUIZARTINIB IN SUBJECTS 
WITH FLT3-ITD MUTANT ACUTE MYELOID 
LEUKEMIA THAT ARE RELAPSED/REFRACTORY, OR 
NEWLY DIAGNOSED AND UNFIT FOR INTENSIVE 
CHEMOTHERAPY 
 
DS3032-A-U105 
IND NUMBER:  135361 
EudraCT NUMBER:  2019-001344-22 
 
VERSION 5.0, 27 AUG 2019 
VERSION 4.0, 01 APR 2019 
VERSION 3.0, 11 OCT 2018 
VERSION 2.0 (For Agency Assessment), 12 MAR 2018 
VERSION 1.0, 31 JAN 2018 
 
DAIICHI SANKYO, INC. 
211 MOUNT AIRY ROAD 
BASKING RIDGE, NJ 07920 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc (DSI).  The 
information is provided to you in confidence which is requested under an agreed upon and 
signed Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it 
or reveal any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
DSI. 




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SUMMARY OF CHANGES 
Amendment Rationale: 
The main purposes of this amendment are to allow concomitant administration of strong CYP3A 
inhibitors with milademetan, to update dosing recommendations of milademetan and quizartinib 
when concomitantly administered with strong CYP3A inhibitors, to remove the fasting 
restriction for milademetan outside of the drug-drug interaction (DDI) substudy, and to clarify 
the efficacy endpoints. 
Changes to the Protocol: 
Please refer to the comparison document for protocol Version 5.0 (dated 27 Aug 2019) vs. 
protocol Version 4.0 (dated 01 Apr 2019) for actual changes in-text.  The summary of changes 
below is a top-line summary of major changes in the DS3032-A-U105 clinical study protocol 
(Version 5.0) by section. 
DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
1 
Updated objectives and efficacy outcome measure definitions. 
The following sections were updated: 
 Protocol Synopsis (Study Objectives) 
 Section 2 (Study Objectives and Hypothesis) 
 Section 7 (Efficacy Assessments) 
 Section 11.4 (Efficacy Analyses) 
 Section 17.4 (Response Criteria for AML) 
 Section 17.5 (Additional Definitions/Response Criteria) 
 Figure 17.1 (Hematologic Recovery Requirements for CR and CRi) 
 Figure 17.2 (Hematologic Recovery Requirements for CR and CRh) 
2 
Clarified that study is a first-in-human with 2 investigational agents and that study will 
be conducted globally. 
The following sections were updated: 
 Protocol Synopsis (Study Design) 
 Section 1.3 (Potential Risks for Study Subjects) 
 Section 3.1 (Overall Design) 


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DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
3 
Updated study sites for dose escalation to include sites in Japan, Asia, and Europe in 
addition to the United States.  The number of study sites was also updated from 
approximately 10 to approximately 15 for dose escalation, with approximately 15 
additional sites to be added as necessary for the dose expansion part. 
The following sections were updated: 
 Protocol Synopsis (Study Sites and Location) 
 Section 3.1 (Overall Design) 
4 
Added duration of subject participation and of study to align with Synopsis and included 
a study design table. 
The following sections were updated: 
 Section 3.1 (Overall Design) 
5 
Updated proposed dose cohorts and schedules in dose escalation. 
The following sections were updated: 
 Protocol Synopsis (Study Design) 
 Section 3.1.2 (Part 1 [Dose Escalation]) 
 Table 3.2 (Proposed Cohorts and Dose Levels of Quizartinib and 
Milademetan for Dose Escalation) 
6 
Clarified cohort stopping criteria, updated definition of dose-limiting toxicities (DLTs) 
and dose interruptions/reductions, and updated expected adverse reactions and risks for 
quizartinib and milademetan. 
The following sections were updated: 
 Protocol Synopsis (Study Design) 
 Section 1.3 (Potential Risks for Study Subjects) 
 Section 3.1.1 (Dose Limiting Toxicity Definition) 
 Section 3.1.2.1 (Stopping Rules [Dose Escalation]) 
 Section 5.4 (Dose Interruptions and Reductions) 


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DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
7 
Updated dose modification schedule during concomitant use of strong CYP3A 
inhibitors and due to drug-related myelosuppression. 
The following sections were updated: 
 Protocol Synopsis (Study Design) 
 Section 3.1.2 (Part 1 [Dose Escalation]) 
 Section 3.1.2.2 (Dose Modification of Milademetan due to 
Thrombocytopenia and/or Neutropenia [Cycle 2 and Later]) 
8 
Updated inclusion criteria to clarify permitted diagnoses and prior therapies for study 
parts/cohorts, updated Eastern Cooperative Oncology Group (ECOG) Performance 
Status ranges, unified renal function criteria and total bilirubin criterion across study 
parts/cohorts, updated the definition of childbearing potential and pregnancy testing 
requirements, and added required compliance for pharmacogenomics testing. 
The following sections were updated: 
 Protocol Synopsis (Subject Eligibility Criteria) 
 Section 4.1 (Inclusion Criteria) 
 Section 6 (Study Procedures) 
 Section 9.6 (Exposure In Utero During Clinical Studies) 
9 
Updated exclusion criteria regarding New York Heart Association (NYHA) Class III or 
IV congestive heart failure, left ventricular ejection fraction, diffusing capacity of the 
lung for carbon monoxide and forced expiratory volume, and prior hematopoietic cell 
transplantation. 
The following sections were updated: 
 Protocol Synopsis (Subject Eligibility Criteria) 
 Section 4.2 (Exclusion Criteria) 
10 
Clarified the sample size determination, removed modified continual reassessment 
method (mCRM) as a model during dose escalation, and added clarifying details for 
dosing and model design in dose expansion. 
The following sections were updated: 
 Protocol Synopsis (Planned Sample Size) 
 Section 3.1.2 (Part 1 [Dose Escalation]) 
 Section 3.1.3 (Part 2 [Dose Expansion]) 
 Section 11.10 (Sample Size Determination) 


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DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
11 
Added an allowance to use LVEF value from prior ECHO/MUGA scan. 
The following sections were updated: 
 Section 5.7.1 (Subject Re-screening Procedures) 
 Section 17.3 (Schedule of Events) 
12 
Updated study procedures to require FSH testing for confirmation of menarche, define 
length of transfusion history, to clarify on-site administration of study drugs, to require 
documentation of transfusions, to update required bone marrow sampling for disease 
and biomarker assessments, to add an additional informed consent for PGx sample 
storing, to update schedule for banking plasma samples, and to define diagnostic tool for 
FLT3-ITD mutation assessment. 
The following sections were updated: 
 Section 6.1 (Screening) 
 Section 6.3 (Treatment Period) 
 Section 17.3 Schedule of Events 
 Section 17.7 (Highly Effective Methods of Birth Control) 
 Section 17.8 (FLT3-ITD Mutation Assay) 
13 
Removed urinalysis from required clinical laboratory test panel. 
The following sections were updated: 
 Protocol Synopsis (Study Endpoints) 
 Section 2.4.1 (Safety Endpoints) 
 Section 6 (Study Procedures) 
 Section 9.7 (Clinical Laboratory Evaluations) 
 Section 11.6 (Safety Analyses) 
 Section 17.3 (Schedule of Events) 
14 
Replaced previous “Subject Withdrawal/Discontinuation” section with 
“Discontinuation” section and added subsections for “Study Drug Discontinuation” and 
“Study Discontinuation”. 
The following section was updated: 
 Section 5.7 (Discontinuation) 


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DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
15 
Clarified subject re-screening procedures. 
The following section was updated: 
 Section 5.7.4 (Subject Re-screening Procedures) 
16 
Updated language for ECG measurements and ECHO/MUGA scans. 
The following sections were updated: 
 Section 6 (Study Procedures) 
 Section 17.3 (Schedule of Events) 
17 
Updated and clarified bone marrow testing requirements and frequency for disease 
assessment and biomarker testing. 
The following sections were updated: 
 Section 6 (Study Procedures) 
 Section 7.1.1 (Bone Marrow Biopsies/Aspirates) 
 Section 7.1.1.1 (Bone Marrow Samples for Translational Research) 
 Section 17.3 (Schedule of Events) 
 Figure 7.1 (Schedule for Bone Marrow Biopsies/Aspirates) 
18 
Clarified follow-up phase procedures and added reminder to obtain confirmation of 
consent to follow-up. 
The following sections were updated: 
 Section 6.4 (End-of-Treatment - Part 1 and Part 2 [Post-cycle]) 
 Section 6.5 (Follow-up Phase – Part 1 and Part 2) 
 Section 17.3 (Schedule of Events) 
19 
Updated address list. 
The following sections were updated: 
 Section 15.10 (Address List) 


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DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
20 
Removed references to pyoderma gangrenosum. 
The following sections were updated: 
 Section 1.3 (Potential Risks for Study Subjects) 
 Section 16 (References) 
 Section 17.3 (Pyoderma Gangrenosum) 
21 
Added reference tables for ECOG Performance Status Scale and NYHA Functional 
Classifications. 
The following sections were updated: 
 Section 17.9 (Eastern Cooperative Oncology Group [ECOG] Performance 
Status) 
 Section 17.10 (New York Heart Association [NYHA] Functional 
Classification) 
22 
Minor editorial and formatting changes were made throughout the document. 
 


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PROTOCOL SYNOPSIS 
EudraCT Number: 
2019-001344-22 
IND Number: 
135361 
Protocol Number: 
DS3032-A-U105 
Investigational Product(s): 
milademetan; quizartinib (in combination) 
Active Ingredient(s)/INN: 
milademetan; quizartinib 
Study Title: 
A Phase 1 study of milademetan in combination with quizartinib 
in subjects with FLT3-ITD mutant acute myeloid leukemia that 
are relapsed/refractory, or newly diagnosed and unfit for intensive 
chemotherapy 
Study Phase: 
Phase 1 
Indication Under 
Investigation: 
FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-
ITD) mutant acute myeloid leukemia (AML) 
Study Objectives: 
Primary Objectives: 
Part 1 (Dose Escalation): 
 To determine the safety and tolerability of the drug 
combination, identification of the optimum dosing 
schedule, maximum tolerated dose (MTD), and the 
recommended dose for expansion cohort (RDE). 
Part 2 (Dose Expansion): 
 To confirm safety and tolerability of the combination 
therapy at RDE and to identify the recommended Phase 2 
dose. 
 Assessment of efficacy. 
Secondary Objectives: 
Part 1 only: 
 Preliminary assessment of efficacy. 
Part 1 and Part 2: 
 To evaluate the pharmacokinetics (PK) of milademetan, 
quizartinib, and the active metabolite of quizartinib, 
AC886. 
Outcome Measures 


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Primary Outcome Measures 
Part 1 only: 
 Number of subjects with dose limiting toxicities (DLTs). 
[Time Frame:  Approximately 18 months from start of the study] 
Part 1 and Part 2: 
 Number of subjects who experienced an adverse event 
(AE) during the study. 
[Time Frame:  Approximately 3 years from start of study] 
Part 2 only: 
 Number of subjects with response to treatment. 
Response to treatment will be assessed using 2017 
European LeukemiaNet (ELN) recommendations.  These 
include the rates of complete remission (CR); CR with 
incomplete blood count recovery (CRi); composite 
complete remission (CRc); duration of composite 
complete remission (DOR); morphologic leukemia-free 
state (MLFS); partial remission (PR); overall response rate 
(ORR); and stable disease (SD).  CR with partial 
hematological recovery (CRh) will be evaluated separately 
from the other response criteria. 
[Time Frame:  Approximately 3 years from start of study] 
Secondary Outcome Measures 
Part 1 only: 
 Number of subjects with response to treatment. 
Response to treatment will be assessed using 2017 ELN 
recommendations.  These include the rates of CR, CRi, 
CRc, DOR, MLFS, PR, ORR, and SD.  CRh will be 
evaluated separately from the other response criteria. 
[Time Frame:  Approximately 18 months from start of study] 
Part 1 and Part 2: 
 Plasma concentrations and PK parameters of milademetan, 
quizartinib, and AC886. 
[Time Frame:  Approximately 3 years from start of study] 


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Study Design: 
DS3032-A-U105 is a first-in-human co-development study of 2 
investigational agents:  milademetan and quizartinib.  This will be 
an open-label, Phase 1 study of milademetan in combination with 
quizartinib in subjects with FLT3-ITD mutant AML, with a dose 
escalation part (Part 1) and a dose expansion part (Part 2).  
Quizartinib will be administered once daily (qd) in 28-day cycles, 
and milademetan will be administered qd on Days 1 to 14 of each 
28-day cycle (qd 14/28) or in alternative dosing schedules. 
Part 1 (Dose Escalation): 
Dose escalation will assess the safety, tolerability, PK, and 
preliminary efficacy of increasing doses of milademetan and 
quizartinib in subjects with FLT3-ITD mutant relapsed/refractory 
(R/R) AML.  The evaluation period for DLTs will be 28 days 
(Cycle 1) from the start of study drug administration.  The dose 
escalation will be guided by a Bayesian logistic regression model 
(BLRM) for dual agent combination and governed by the 
escalation with overdose control (EWOC) principle.  The 
determination of MTD(s) will be guided by the BLRM using 
accumulated DLT data as well as other safety and PK data.  The 
RDE will be decided based on considerations of the respective 
MTD(s) guided by the BLRM and on an overall assessment of 
safety data from all cycles, PK data, and preliminary efficacy 
data. 
Cohorts of 3 to 6 subjects will be enrolled and assessed for DLT 
before escalation to a new higher dose.  For a subject to be 
considered evaluable for DLT, the subject must have received at 
least 75% of the prescribed Cycle 1 doses and completed safety 
assessments of the DLT evaluation period, or experienced a DLT 
in this period.  Subjects who started treatment but who do not 
meet the criteria to be DLT-evaluable will not be included in the 
BLRM update.  In some cases, a subject in the previous cohort 
may experience a DLT after the enrollment of subjects to a new 
cohort has begun.  In this event, the dose level assignment of the 
next subject(s) in the new cohort will be based on an updated 
BLRM using DLT outcome data from all assessed dose cohorts 
up to that point. 
A delay of at least 7 days will occur between the first subject 
dosed and the second subject dosed in the first cohort.  If 2 
evaluable subjects in any cohort experience DLT before the 
enrollment of the next subject, the model will be re-evaluated and 
discussion between the Investigators and Sponsor will occur 
before enrollment of any additional subjects in the cohort. 


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Enrollment of subjects to a new cohort requires completion of 
DLT evaluation of at least 3 subjects treated in the current cohort 
at the intended dose levels.  The Investigator and Sponsor will 
also assess safety and tolerability on an ongoing basis and will 
continue dosing if there are no safety or risk/benefit concerns and 
if the subject is deriving clinical benefit.  Additional subjects for 
the characterization of safety, PK, or PD may be added at any 
dose escalation cohort below the MTD dose level or at the MTD 
in parallel with ongoing escalation up to a maximum of 12 
subjects in each cohort.  Further details can be found in the Cohort 
Management Plan. 
Milademetan Dose Levels 
The proposed starting dose of milademetan will be 90 mg, which 
will be escalated through 120 mg and 160 mg; all 3 doses will 
follow the qd 14/28 dosing schedule unless the safety data suggest 
the use of a less frequent dose schedule.  Based on emerging 
safety and efficacy data during dose escalation, the dose levels of 
milademetan may be evaluated up to 200 mg or 260 mg in 
alternative dosing schedules with less frequent doses (eg, Days 1 
to 7 of each 28-day cycle [qd 7/28] and Days 1 to 3 of each 14 
days administered twice in a 28-day cycle [qd 3/14 × 2]).  The 
maximum dose for milademetan will be up to 260 mg in the qd 
3/14 × 2 schedule as determined in the DS3032-A-U101 study. 
Quizartinib Dose Levels 
There are 3 proposed dose levels of quizartinib:  30 mg, 40 mg, 
and 60 mg.  Quizartinib monotherapy from 30 mg to 60 mg doses 
was demonstrated to be safe and clinically active in the Phase 2 
(2689-CL-2004) study.  However, the optimal dose/schedule of 
quizartinib is unknown when it is combined with milademetan.  
Therefore, 30 mg qd quizartinib will be used as the starting dose, 
as this dose demonstrated a similar CRc rate as 60 mg qd 
quizartinib. 
If quizartinib is increased to the 60-mg dose level, subjects will be 
dosed at 30 mg for the first 14 days to evaluate the QT 
prolongation risk in each subject. 
 QTc by Fridericia’s method (QTcF) ≤450 ms 
o escalate dose to 60 mg quizartinib on Day 15 of 
Cycle 1 and continue at same dose in subsequent 
cycles 
 QTcF >450 ms but ≤480 ms 


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o continue at 30 mg quizartinib in combination with 
assigned dose of milademetan, in the absence of 
other risk factors 
 QTcF >480 ms but ≤500 ms 
o continue with quizartinib dose reduction of 1 level 
in combination with assigned dose of milademetan, 
in the absence of other risk factors 
o multiple stepwise dose reductions allowed to 
mitigate QTcF prolongation risks 
 QTcF >500 ms, recurring despite dose reductions and 
correction/elimination of other risk factors 
o permanently discontinue from quizartinib 
In cohorts with quizartinib 60 mg, it is possible that not all 
subjects may be assignable to quizartinib 60 mg on Day 15 after 
the 30 mg lead-in for the first 14 days, and therefore additional 
subjects may be enrolled for evaluation of the cohorts. 
Dose Escalation Plan 
The proposed dose levels shown in the following table were 
chosen based on the safety and preliminary efficacy data from the 
single agent studies.  The dose and schedule of milademetan will 
be first optimized during dose escalation in combination with 
30 mg qd quizartinib.  When a decision is made to escalate the 
dose, the milademetan dose can be escalated to the next dose level 
at the existing dosing schedule suggested by BLRM (eg, qd 
14/28), at a less frequent dosing schedule (ie, qd 7/28 or qd 3/14 × 
2), or in separate cohorts of 2 schedules in parallel; the MTD(s) in 
those schedules may be separately assessed.  While the BLRM 
will provide the dose recommendation, the decision to use a less 
frequent dose schedule will be taken after discussion between the 
Investigators and Sponsor based on the overall safety data thus 
far.  However, dose escalation from any dose level in a less 
frequent dose schedule to a more frequent dose schedule is not 
allowed. 
Once the most optimal dose and schedule of milademetan is 
identified, the quizartinib qd dose will be escalated from 30 mg to 
40 mg, and then from 40 mg to 60 mg, in combination with the 
optimal dose of milademetan.  During dose escalation, 
simultaneous dose escalation of both agents will not be not 
allowed.  Additional dose combinations not shown in the table 
may be tested based on emerging safety data during dose 
escalation. 


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Proposed Cohorts and Dose Levels of Quizartinib and 
Milademetan for Dose Escalation 
Quizartinib Dose 
Milademetan Dose 
30 mg qd 
90 mg qd 14/28a 
30 mg qd 
120 mg qd 14/28a 
30 mg qd 
160 mg qd 14/28a 
30 mg qd 
200 mg qd 7/28a 
30 mg qd 
260 mg qd 3/14 × 2 
40 mg qd 
Most optimal dose and schedule 
identified in combination with 
30 mg qd quizartinib 
60 mg qd following 30-
mg lead-in (14 days)  
Most optimal dose and schedule 
identified in combination with 
30 mg qd quizartinib 
qd = once daily 
a At any milademetan dose level, if the evaluated dosing schedule is not 
tolerated, alternative dosing schedules of less frequent doses (eg, qd 7/28 or 
qd 3/14 × 2) may be evaluated.  However, dose escalation from any dose 
level in a less frequent dose schedule to a more frequent dose schedule is not 
allowed. 
Note:  Some of the cohorts shown in the table may be dropped based on the 
emerging safety data during dose escalation. 
For subjects receiving concomitant therapy with a strong 
CYP3A inhibitor: 
Special considerations are required for subjects receiving 
concomitant therapy with a strong CYP3A inhibitor. 
The following dose reductions will be performed with the 
concomitant administration of a strong CYP3A inhibitor. 
 Quizartinib: 
o 60 mg dose will be reduced to 30 mg 
o 30 mg and 40 mg doses will be reduced to 20 mg 
 Consequently, quizartinib 30-mg lead-in to 60 mg 
will be reduced to a 20-mg lead-in to 30 mg 
 Milademetan: 
o Dose will be reduced to half of the prescribed dose (ie, 
90-mg, 120-mg, and 160-mg doses of milademetan 
will be reduced to 45 mg, 60 mg, and 80 mg, 
respectively) 


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Resumption of regularly scheduled doses of quizartinib and 
milademetan after discontinuation of the strong CYP3A inhibitor 
should be as follows: 
 Quizartinib: 
o Resume regularly scheduled dose the day following 
discontinuation 
 Milademetan: 
o Resume regularly scheduled dose after a 3-day 
washout period following discontinuation 
Dose Limiting Toxicity Definition 
A DLT is defined as any non-hematological treatment-emergent 
adverse event (TEAE) unless incontrovertibly related to disease 
progression, intercurrent illness, or concomitant medication, that 
occurs during the DLT evaluation period (28 days) in each dose-
level cohort, and is Grade 3 or higher according to the National 
Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 5.0, with the exceptions as defined 
below: 
For elevations in hepatic function tests, a DLT is defined as 
follows: 
 Grade 3 or higher aspartate aminotransferase 
(AST)/alanine aminotransferase (ALT) levels, OR 
 Elevation in total bilirubin ≥3.0 × ULN that does not 
return to ≤Grade 2 elevation within 7 days. 
Myelosuppression and associated complications are expected 
events during leukemia therapy, however, the following 
prolonged myelosuppression is considered a DLT: 
 Absolute neutrophil count (ANC) <0.5 × 109/L, platelets 
<20 × 109/L, and marrow cellularity <5% at 6 weeks or 
later from start of therapy without any evidence of 
leukemia. 
However, completion of the 28-day safety evaluation is sufficient 
for the subject to be evaluable.  If a DLT based on 
myelosuppression occurs after the cohort review and dose 
escalation decisions, dose level assignment of the next subject in 
the new cohort will be based on an updated BLRM using DLT 
outcome data from all assessed dose cohorts. 
Subjects who are unable to complete at least 75% of the 
prescribed dose of milademetan or at least 75% of the prescribed 


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dose of quizartinib in Cycle 1 (28 days) as a result of nondisease-
related ≥Grade 2 events will be considered to have a DLT. 
The following AEs are not considered DLTs: 
 Grade 3 fatigue lasting <3 days. 
 Grade 3 nausea or vomiting that has resolved to Grade ≤2 
within 48 hours following administration of preventive, as 
well as additional, antiemetic therapies for managing 
established nausea or vomiting. 
 Grade 3 diarrhea that has resolved to Grade ≤2 within 48 
hours after standard antidiarrheal therapies. 
 Alopecia. 
 Grade ≥3 electrolyte abnormalities that are corrected to 
≤Grade 1 within 24 hours. 
Part 2 (Dose Expansion): 
The dose expansion part will begin after the completion of the 
dose escalation part and will enroll in 2 parallel cohorts of 
approximately 40 subjects each; dose expansion subjects will be 
treated at the RDE to confirm safety and tolerability, and to assess 
the preliminary efficacy of the combination therapy at the RDE.  
Cohort 1 will enroll subjects with FLT3-ITD mutant AML who 
were refractory to or had relapsed after prior AML therapy (R/R 
AML).  Cohort 2 will enroll AML therapy-naive subjects with 
FLT3-ITD mutant AML who are unfit to receive intensive 
induction chemotherapy. 
In a subgroup of the first 12 subjects in Part 2 Cohort 1 (R/R 
AML), subjects will additionally be dosed with milademetan 
alone at the RDE dose on Day 1 of Cycle 1 to evaluate the drug-
drug interaction (DDI) between milademetan and quizartinib; the 
rest of the treatment schedule will be identical to the other 
subjects in Part 2, except that the drugs are administered in unfed 
conditions in the substudy.  Subjects in the DDI substudy are not 
allowed to receive strong CYP3A inhibitors within 7 days prior to 
the first dose OR 5 terminal half-lives, whichever is longer.  
Strong CYP3A inhibitors will only be allowed in the DDI 
substudy subjects after completion of the first 2 cycles with the 
recommended dose reductions of milademetan and quizartinib. 
Study Duration: 
The duration of subject participation is not fixed in this study.  
Participation in the study begins when the subject signs the 
informed consent and ends after the 30 (± 5) days follow-up after 
the last dose of study treatment (30-day Follow-up) followed by 


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site visits or phone calls every 3 months (Long-term Survival 
Follow-up).  Subjects who continue to derive clinical benefit from 
treatment in the absence of withdrawal of subject consent, disease 
progression, or unacceptable toxicity may continue treatment.  
When all the subjects enrolled in the study have either completed 
the Long-term Survival Follow-up, have discontinued, or have 
completed at least 6 months of treatment, primary analysis will 
begin.  The study is expected to last approximately 4 to 5 years 
from the time the first subject is enrolled in Part 1 of the study. 
Study Sites and Location: 
Dose Escalation:  Approximately 15 sites in the United States, 
Japan, Asia, and Europe.  Additional sites and countries may be 
added as needed. 
Dose Expansion:  Along with the 15 sites for dose escalation, 
approximately 15 additional sites worldwide may be added as 
necessary for the dose expansion part, which will commence after 
the completion of the dose escalation part, based on the 
enrollment rate, the prevalence of the subject population, and the 
standard of care available to the subjects at the time. 
Subject Eligibility Criteria: 
Inclusion Criteria (Part 1 and Part 2) 
1. Subjects with histological confirmation of primary, secondary, 
or therapy-related AML according to the 2016 World Health 
Organization criteria classification with FLT3-ITD mutation 
(≥3% FLT3-ITD/total FLT3). 
 Part 1 – R/R AML 
o Subjects who have treatment failure to prior AML 
therapy (defined as failure to achieve at least CRi) or 
have relapsed after prior AML therapy, and 
o Subjects ≥18 years old 
 Part 2 
o Cohort 1 – R/R AML (same as Part 1) 
o Cohort 2 –Subjects with newly diagnosed AML who 
are ineligible for intensive induction chemotherapy.  
Subjects must have had no prior AML treatment, with 
the exceptions of therapy for antecedent hematologic 
malignancies (eg, azacitidine for myelodysplastic 
syndrome) or hydroxyurea. 
a. Subjects ≥75 years old, OR 
b. Subjects between 18 and 74 years old (inclusive) 
with at least one of the following comorbidities: 


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 Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 3; 
 Cardiac history of congestive heart failure 
(CHF) requiring treatment, left ventricular 
ejection fraction (LVEF) ≤50%, or chronic 
stable angina; 
 Diffusing capacity of the lung for carbon 
monoxide (DLCO) ≤65% or forced expiratory 
volume in 1 second (FEV1) ≤65%; 
 Any other comorbidity that the Investigator 
judges to be incompatible with intensive 
chemotherapy must be reviewed by the 
Sponsor Medical Monitor during screening and 
before study enrollment. 
Note:  In both Part 1 and Part 2, subjects with a known record of 
FLT3-ITD mutant AML within the last 30 days from informed 
consent based on local testing can enroll in the study.  FLT3-ITD 
status will be tested in a central laboratory for confirmation of 
eligibility, and any results indicating absence of FLT3-ITD will 
be communicated to the Investigator for possible discontinuation 
of the subject from study participation if ongoing clinical benefit 
is not observed.  Subjects in Part 2 who do not show confirmation 
of FLT3-ITD mutation by central laboratory testing will be 
replaced.  However, those who are deriving clinically benefit may 
be allowed to continue treatment. 
2. Has an ECOG Performance Status: 
 In Part 1 and Part 2 Cohort 1 (subjects with R/R AML): 
o 0 to 2 for subjects ≥18 years old 
 In Part 2 Cohort 2 (subjects with newly diagnosed AML): 
o 0 to 2 for subjects ≥75 years old 
o 0 to 3 for subjects between 18 and 74 years old 
(inclusive) 
3. Has adequate renal function, defined as creatinine 
clearance 60 mL/min, as calculated using the modified 
Cockcroft-Gault equation ([{140 – age in years} × {actual 
weight in kg}] divided by [{72 × serum creatinine in mg/dL}] 
multiply by 0.85 if female), OR if creatinine clearance 50-60 
mL/min AND has serum creatinine ≤1.5 × upper limit of 
normal (ULN) (in obese subjects, the lean body weight can be 
used in the equation instead of actual body weight). 


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4. Has electrolyte levels (including those for potassium, calcium, 
and magnesium) within normal limits. 
5. Serum AST and ALT ≤2.5 × ULN (≤5 × ULN if deemed 
elevated due to leukemia). 
6. Serum total bilirubin ≤1.5 × ULN (≤3 × ULN if deemed 
elevated due to leukemia or in subjects with documented 
Gilbert’s Syndrome). 
7. Discontinuation of prior AML treatment before the start of 
study treatment (except hydroxyurea to control leukocytosis) 
for at least 2 weeks for cytotoxic agents, or for at least 5 half-
lives for non-cytotoxic agents.  Hydroxyurea is allowed until 
48 hours prior to start of the study treatment. 
8. Subject, if female of childbearing potential, must have a 
negative serum pregnancy test upon entry into this study and 
must be willing to use highly effective birth control during the 
period of therapy and for 6 months following the last 
investigational drug dose.  A female is considered of 
childbearing potential following menarche and until becoming 
postmenopausal (no menstrual period for a minimum of 12 
months), unless permanently sterile (undergone a 
hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) or confirmed by follicle stimulating hormone 
(FSH) test.  If male, must be surgically sterile or be willing to 
use 1 form of highly effective contraception method upon 
enrollment, during the course of the study, and for 6 months 
following the last investigational drug dose. 
9. Willingness to abstain from grapefruit/grapefruit juice and 
Seville oranges from 7 days before the first dose of study drug 
on Day 1 until the end of the study. 
10. Able and willing to provide bone marrow biopsies/aspirates 
and buccal swab/saliva for PGx testing as requested by the 
protocol. 
Exclusion Criteria 
1. Presence of central nervous system (CNS) involvement of 
leukemia.  Patients with a history of CNS leukemia may be 
eligible if the CNS leukemia is adequately controlled (defined 
as no active clinical symptoms of CNS disease and at least 2 
consecutive lumbar punctures with no evidence of disease 
prior to study enrollment) after discussion with the Sponsor 
Medical Monitor. 
2. Acute promyelocytic leukemia (AML subtype M3). 


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3. Has other concurrent malignancy that required systemic 
antineoplastic treatment within the previous 2 years, except 
for localized cancers that have apparently been cured (eg, non-
melanoma skin cancer, superficial bladder cancer, or 
carcinoma in situ of the cervix or breast). 
4. Uncontrolled or significant cardiovascular disease, including: 
a. QTcF interval >450 ms (average of triplicate 
determinations). 
b. Bradycardia of less than 50 bpm unless the subject has a 
pacemaker. 
c. Diagnosed or suspected long QT syndrome, or known 
family history of long QT syndrome. 
d. History of clinically relevant ventricular arrhythmias, such 
as ventricular tachycardia, ventricular fibrillation, or 
torsade de pointes. 
e. History of second or third degree heart block.  Subjects 
with a history of heart block may be eligible if they 
currently have pacemakers and have no history of fainting 
or clinically relevant arrhythmia with pacemakers. 
f. Myocardial infarction within 6 months prior to Screening. 
g. Uncontrolled angina pectoris within 6 months prior to 
Screening. 
h. New York Heart Association (NYHA) Class III or IV 
congestive heart failure. 
i. Known LVEF ≤50% or institutional lower limit of normal. 
 As an exception, subjects with newly diagnosed AML 
between 18 and 74 years old (inclusive) in Part 2 
Cohort 2 with LVEF ≤50% or institutional lower limit 
of normal will be eligible. 
j. Known DLCO ≤65% or FEV1 ≤65%. 
 As an exception, subjects with newly diagnosed AML 
between 18 and 74 years old (inclusive) in Part 2 
Cohort 2 with DLCO ≤65% or FEV1 ≤65% will be 
eligible. 
k. Uncontrolled hypertension. 
l. Left bundle branch block. 
5. Has an uncontrolled infection requiring intravenous 
antibiotics, antivirals, or antifungals. 


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6. Has known human immunodeficiency virus infection that is 
uncontrolled (increasing plasma HIV RNA viral load) with 
medication, or active hepatitis B or C infection based on 
positive tests during Screening. 
7. Persistent, clinically significant >Grade 1 non-hematologic 
toxicity from prior AML therapies. 
8. Pregnant or breast feeding. 
9. Receiving drugs that are strong inducers of CYP3A or 
consumption of St John’s Wort (hypericin) within 14 days 
prior to the first dose and during treatment. 
10. Received anti-AML therapy (except for hydroxyurea) within 
the following washout periods before starting study 
medication: 
 Seven days OR 5 half-lives, whichever is longer, for small 
molecule drugs. 
 Twenty-one days OR 5 half-lives, whichever is shorter, for 
antibody-based, immune-based, biologic, or cellular 
therapies. 
11. Has received allogenic hematopoietic cell transplantation 
(HCT) within 60 days of the first dose of study drugs. 
12. Clinically significant graft versus host disease (GVHD) or 
GVHD requiring initiation of systemic treatment or systemic 
treatment escalation within 21 days prior to Screening and/or 
>Grade 1 persistent or clinically significant GVHD or other 
non-hematologic toxicity related to HCT. 
13. Medical condition, serious intercurrent illness, or other 
circumstance that, in the Investigator’s judgment, could 
jeopardize the candidate’s safety as a study subject, or that 
could interfere with study objectives. 
14. Prior treatment with mouse double minute homolog 2 
(MDM2) inhibitors. 
Additional exclusion criterion for the Part 2 Cohort 1 subgroup of 
12 subjects for the DDI substudy 
15. Receiving drugs that are strong CYP3A inhibitors within 7 
days OR 5 terminal half-lives, whichever is longer, prior to 
the first dose and until completion of 2 cycles of treatment. 
Dosage Form, Dose and Route 
of Administration: 
Quizartinib is a small molecule inhibitor of FLT3.  The drug is 
supplied as tablets in strengths of 20 mg quizartinib hydrochloride 


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(17.7 mg free base) and 30 mg quizartinib hydrochloride (26.5 mg 
free base) for oral administration. 
Milademetan is a small molecule inhibitor of MDM2-p53 
interaction that activates p53 pathway.  The drug is supplied as 
capsules in strengths of 5 mg, 20 mg, 30 mg, 45 mg, 80 mg, 
100 mg, and 200 mg for oral administration.  The indicated 
capsule strengths are equivalent to the amount of free base 
(DS-3032a). 
Milademetan (DS-3032a) is the free base and the active moiety of 
the salt form (DS-3032b).  The salt form (DS-3032b) is the active 
pharmaceutical ingredient of the oral capsule formulation.  
Throughout the remainder of this document, DS-3032a and DS-
3032b will be referred to as “milademetan” unless indicated 
otherwise. 
The 2 investigational drugs will be administered in combination 
as indicated in the dose escalation and dose expansion parts of the 
study.  Quizartinib and milademetan may be administered without 
regard to the timing of food, except as noted for the DDI 
substudy. 
Study Endpoints: 
Primary Endpoint: 
The primary endpoints for safety will include serious adverse 
events (SAEs), TEAEs, DLTs, physical examination findings 
(including ECOG Performance Status), vital sign measurements, 
clinical laboratory parameters (serum chemistry and hematology), 
and electrocardiogram (ECG) parameters, particularly the QTcF.  
Adverse events will be categorized using the Medical Dictionary 
for Regulatory Activities (MedDRA) version 22.0.  Adverse 
events and laboratory test results will be graded using the NCI-
CTCAE version 5.0. 
Secondary Endpoints 
The secondary endpoints for PK will include maximum plasma 
concentration (Cmax) and area under the plasma concentration-
time curve up to time 24 hours (AUC24h) for milademetan, 
quizartinib, and AC886 estimated by non-compartmental analysis, 
as well as their plasma concentrations at different timepoints 
relative to dosing. 
Efficacy endpoints in both Part 1 and Part 2 include the following: 
 CR rate 
 CRi rate 
 CRc rate (CR+CRi) 


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 DOR:  Time from the first objective evidence of CRc to 
the first objective evidence of relapse or death 
 MLFS rate 
 PR rate 
 ORR (CRc+MLFS+PR) 
 SD rate 
 CRh rate 
o CRh will be evaluated separately from the other 
response criteria 
Planned Sample Size: 
The dose escalation part of this study will be guided by a BLRM 
for dual agent combination and governed by the EWOC principle. 
Because of the adaptive nature of the dose escalation part of the 
trial, the exact sample size is unknown.  Based on prior 
assumptions and simulations, the sample size is expected to have 
a median of 21 subjects.  Approximately 24 to 36 DLT-evaluable 
subjects are needed to determine the MTDs and RDE. 
The dose expansion part will commence after the completion of 
the dose escalation part and will enroll in 2 parallel cohorts of 
approximately 40 subjects each (total of approximately 
80 subjects); dose expansion subjects will be treated at the RDE to 
confirm the safety and tolerability and to assess the preliminary 
efficacy of the combination therapy at RDE.  Cohort 1 will enroll 
subjects with FLT3-ITD mutant R/R AML.  Cohort 2 will enroll 
approximately 40 treatment-naive subjects with FLT3-ITD mutant 
AML who are unfit to receive intensive induction chemotherapy. 
Statistical Analyses: 
The primary objective of this study is to assess the safety, 
tolerability of milademetan in combination with quizartinib and 
establish RDE in subjects with FLT3-ITD mutant AML.  
Statistical analysis as described below will occur after all subjects 
from both dose escalation and dose expansion have either 
completed the study or discontinued from the study or have 
received at least 6 months of therapy.  However, the ongoing 
subjects deriving clinical benefit may continue to receive the 
treatment. 
The primary endpoint of safety (including TEAEs, SAEs, ECGs, 
etc) will be descriptive and will be presented in tabular format 
with the appropriate summary statistics.  In the dose escalation 
part, the number of DLTs will be listed for each dose cohort of 
milademetan in combination with quizartinib. 


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The secondary endpoint of efficacy will include the rates of CR, 
CRi, CRc, DOR, MLFS, PR, ORR, SD, and CRh.  The efficacy 
endpoints will be listed and summarized using descriptive 
statistics.  For response rates (CRc, ORR, etc), point estimates and 
95% exact binomial confidence intervals will be provided.  Time 
to event endpoint (DOR) will be summarized descriptively using 
the Kaplan Meier method. 
For the secondary endpoint of PK, plasma concentrations of 
milademetan, quizartinib, and AC886 will be listed and 
summarized using descriptive statistics by dose cohort at each 
timepoint.  A non-compartmental analysis will be performed to 
estimate the PK parameters Cmax, time to reach maximum 
plasma concentration (Tmax), AUC24h, and time to reach 
maximum plasma concentration (Ctrough) for the 3 analytes. 
Drug-drug interaction assessment between milademetan and 
quizartinib will be performed in a substudy of 12 subjects in Part 
2 Cohort 1 by comparing the PK parameters (Cmax and 
AUC24h).  In this substudy, concomitant administration of strong 
CYP3A inhibitors will be prohibited for the first 2 cycles of 
treatment.  Effects of quizartinib after repeated doses on single 
dose milademetan PK (Cmax and AUC24h) will be assessed by 
analysis of variance (ANOVA) model where reference and test 
treatments for milademetan PK will be Cycle 1/Day −1 and Cycle 
2/Day 1, respectively.  The effect of milademetan after repeated 
doses on steady-state quizartinib and AC886 PK (Cmax and 
AUC24h) will also be evaluated using an ANOVA model where 
the reference and test treatments for quizartinib and AC886 PK 
will be Cycle 1/ Day 28 and Cycle 2/Day 14, respectively.  The 
PK parameters will be transformed prior to analysis using a 
natural logarithm-transformation.  The 90% confidence intervals 
for the ratios of the geometric means for the PK parameters 
(Cmax and AUC24h) will be calculated. 
Lastly an exposure-response analysis may also be performed to 
assess the relationship between plasma exposure of milademetan, 
quizartinib and AC886 and ECG, particularly QTcF.  The 
population PK and efficacy response analyses may be reported 
separately from the clinical study report. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
SUMMARY OF CHANGES ...........................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................9 
TABLE OF CONTENTS ...............................................................................................................25 
LIST OF TABLES .........................................................................................................................32 
LIST OF FIGURES .......................................................................................................................33 
LIST OF ABBREVIATIONS ........................................................................................................34 
1. 
INTRODUCTION ........................................................................................................37 
1.1. 
Background ...................................................................................................................37 
1.2. 
Study Rationale .............................................................................................................39 
1.3. 
Potential Risks for Study Subjects ................................................................................40 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ..............................................................41 
2.1. 
Study Objectives ...........................................................................................................41 
2.1.1. 
Primary Objectives ........................................................................................................41 
2.1.2. 
Secondary Objectives ....................................................................................................41 
2.1.3. 
Exploratory Objectives..................................................................................................41 
2.2. 
Outcome Measures ........................................................................................................41 
2.2.1. 
Primary Outcome Measures ..........................................................................................41 
2.2.2. 
Secondary Outcome Measures ......................................................................................42 
2.2.3. 
Exploratory Outcome Measures ....................................................................................42 
2.3. 
Study Hypothesis ..........................................................................................................42 
2.4. 
Study Endpoints ............................................................................................................42 
2.4.1. 
Safety Endpoint .............................................................................................................42 
2.4.2. 
Pharmacokinetic/Pharmacodynamic/Biomarker Endpoint(s) .......................................43 
2.4.3. 
Efficacy Endpoint(s) .....................................................................................................43 
2.4.3.1. 
Exploratory Efficacy Endpoints ....................................................................................44 
2.4.4. 
Other Endpoints ............................................................................................................44 
3. 
STUDY DESIGN ..........................................................................................................45 
3.1. 
Overall Design ..............................................................................................................45 
3.1.1. 
Dose Limiting Toxicity Definition................................................................................45 
3.1.2. 
Part 1 (Dose Escalation) ................................................................................................46 


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3.1.2.1. 
Stopping Rules (Dose Escalation) .................................................................................50 
3.1.2.2. 
Dose Modification of Milademetan due to Thrombocytopenia and/or 
Neutropenia (Cycle 2 and Later) ...................................................................................50 
3.1.3. 
Part 2 (Dose Expansion)................................................................................................50 
3.2. 
Discussion of Study Design ..........................................................................................51 
4. 
STUDY POPULATION ...............................................................................................52 
4.1. 
Inclusion Criteria ...........................................................................................................52 
4.2. 
Exclusion Criteria..........................................................................................................53 
5. 
STUDY TREATMENT(S) ...........................................................................................56 
5.1. 
Assigning Subjects to Treatments and Blinding ...........................................................56 
5.2. 
Study Drug(s) ................................................................................................................56 
5.2.1. 
Description ....................................................................................................................56 
5.2.2. 
Labeling and Packaging ................................................................................................56 
5.2.3. 
Preparation ....................................................................................................................56 
5.2.4. 
Administration ..............................................................................................................56 
5.2.5. 
Storage...........................................................................................................................57 
5.2.6. 
Drug Accountability ......................................................................................................57 
5.3. 
Control Treatment .........................................................................................................57 
5.4. 
Dose Interruptions and Reductions ...............................................................................57 
5.4.1. 
Dose Interruptions and Reductions For QTcF Prolongation.........................................57 
5.4.1.1. 
Managing QTc Prolongation .........................................................................................58 
5.4.1.2. 
Managing Electrolyte Abnormalities ............................................................................58 
5.4.1.3. 
Managing Nausea and Vomiting ...................................................................................59 
5.4.2. 
Dose Interruptions and Reductions For Non-hematologic Toxicities...........................59 
5.4.3. 
Dose Interruptions and Reductions for Hematologic Toxicities ...................................59 
5.4.4. 
Dose Reductions With Concomitant Administration of a Strong CYP3A 
Inhibitor .........................................................................................................................60 
5.5. 
Method of Assessing Treatment Compliance ...............................................................60 
5.6. 
Prior and Concomitant Medications..............................................................................61 
5.6.1. 
Prior Medication............................................................................................................61 
5.6.2. 
Concomitant Medication (Drugs and Therapies) ..........................................................61 
5.7. 
Discontinuation .............................................................................................................61 
5.7.1. 
Study Drug Discontinuation ..........................................................................................61 


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5.7.2. 
Study Discontinuation ...................................................................................................62 
5.7.3. 
Subject Replacement .....................................................................................................63 
5.7.4. 
Subject Re-screening Procedures ..................................................................................63 
6. 
STUDY PROCEDURES ..............................................................................................64 
6.1. 
Screening .......................................................................................................................64 
6.1.1. 
Part 1 (Dose Escalation) and Part 2 (Dose Expansion), Screening (Pre-cycle) ............64 
6.2. 
Randomization ..............................................................................................................65 
6.3. 
Treatment Period ...........................................................................................................65 
6.3.1. 
Part 1 (Dose Escalation) ................................................................................................65 
6.3.1.1. 
Part 1 (Dose Escalation), Cycle 1/Day 1 .......................................................................65 
6.3.1.2. 
Part 1 (Dose Escalation), Cycle 1/Day 2 .......................................................................66 
6.3.1.3. 
Part 1 (Dose Escalation), Cycle 1/Day 8 .......................................................................67 
6.3.1.4. 
Part 1 (Dose Escalation), Cycle 1/Day 14 .....................................................................67 
6.3.1.5. 
Part 1 (Dose Escalation), Cycle 1/Day 15 .....................................................................68 
6.3.1.6. 
Part 1 (Dose Escalation), Cycle 1/Day 22 .....................................................................69 
6.3.1.7. 
Part 1 (Dose Escalation), Cycle 2/Day 1 .......................................................................69 
6.3.1.8. 
Part 1 (Dose Escalation), Cycle 2/Day 8 .......................................................................70 
6.3.1.9. 
Part 1 (Dose Escalation), Cycle 2/Day 15 .....................................................................71 
6.3.1.10. Part 1 (Dose Escalation), Cycle 2/Day 22 .....................................................................71 
6.3.1.11. Part 1 (Dose Escalation), Cycle 3/Day 1 .......................................................................72 
6.3.1.12. Part 1 (Dose Escalation), Cycle 3/Days 8, 15, and 22 ..................................................73 
6.3.1.13. Part 1 (Dose Escalation), Day 1 of Cycle 4 and All Subsequent Cycles ......................73 
6.3.2. 
Treatment Period, Part 2 (Dose Expansion), Except Subjects in the DDI 
Substudy ........................................................................................................................75 
6.3.2.1. 
Part 2 (Dose Expansion), Cycle 1/Day 1 ......................................................................75 
6.3.2.2. 
Part 2 (Dose Expansion), Cycle 1/Day 2 ......................................................................76 
6.3.2.3. 
Part 2 (Dose Expansion), Cycle 1/Day 8 ......................................................................77 
6.3.2.4. 
Part 2 (Dose Expansion), Cycle 1/Day 14 ....................................................................78 
6.3.2.5. 
Part 2 (Dose Expansion), Cycle 1/Day 15 ....................................................................78 
6.3.2.6. 
Part 2 (Dose Expansion), Cycle 1/Day 22 ....................................................................79 
6.3.2.7. 
Part 2 (Dose Expansion), Cycle 2/Day 1 ......................................................................80 
6.3.2.8. 
Part 2 (Dose Expansion), Cycle 2/Days 8, 15, and 22 ..................................................81 
6.3.2.9. 
Part 2 (Dose Expansion), Cycle 3/Day 1 ......................................................................81 


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6.3.2.10. Part 2 (Dose Expansion), Cycle 3/Days 8, 15, and 22 ..................................................82 
6.3.2.11. Part 2 (Dose Expansion), Day 1 of Cycle 4 and All Subsequent Cycles ......................83 
6.3.3. 
Treatment Period, Part 2 (Dose Expansion), Subjects in the DDI Substudy ................85 
6.3.3.1. 
Part 2 (Dose Expansion DDI Substudy), Pre-cycle/Day −2 .........................................85 
6.3.3.2. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day −1 ............................................85 
6.3.3.3. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 1 ..............................................86 
6.3.3.4. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 2 ..............................................87 
6.3.3.5. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 8 ..............................................87 
6.3.3.6. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 14 ............................................88 
6.3.3.7. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 15 ............................................89 
6.3.3.8. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 22 ............................................89 
6.3.3.9. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 28 ............................................90 
6.3.3.10. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 1 ..............................................91 
6.3.3.11. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 2 ..............................................92 
6.3.3.12. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 8 ..............................................92 
6.3.3.13. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 14 ............................................93 
6.3.3.14. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 15 ............................................93 
6.3.3.15. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 22 ............................................94 
6.3.3.16. Part 2 (Dose Expansion DDI Substudy), Cycle 3/Day 1 ..............................................94 
6.3.3.17. Part 2 (Dose Expansion DDI Substudy), Cycle 3/Days 8, 15, and 22 ..........................95 
6.3.3.18. Part 2 (Dose Expansion DDI Substudy), Day 1 of Cycle 4 and All Subsequent 
Cycles ............................................................................................................................96 
6.4. 
End-of-Treatment - Part 1 and Part 2 (Post-cycle)........................................................98 
6.4.1. 
End-of-Treatment Bone Marrow Re-biopsy/Aspirate (Part 1 and Part 2) ....................98 
6.5. 
Follow-up Phase – Part 1 and Part 2 .............................................................................99 
6.5.1. 
Follow-up 30 Days After End-of-treatment ..................................................................99 
6.5.2. 
Long-term Survival Follow-up .....................................................................................99 
7. 
EFFICACY ASSESSMENTS .....................................................................................100 
7.1. 
Assessments for Efficacy Endpoint(s) ........................................................................100 
7.1.1. 
Bone Marrow Biopsies/Aspirates ...............................................................................100 
7.1.1.1. 
Bone Marrow Samples for Translational Research ....................................................101 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ......................102 
8.1. 
Pharmacokinetic (PK) Assessment(s) .........................................................................102 


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8.2. 
Biomarkers ..................................................................................................................104 
8.2.1. 
Pharmacodynamic Assessment(s) ...............................................................................104 
8.2.2. 
Biomarkers for Subject Selection ...............................................................................104 
8.2.3. 
Additional Biomarker Assessments ............................................................................104 
8.3. 
Immunogenicity ..........................................................................................................105 
8.4. 
Pharmacogenomic Analysis ........................................................................................105 
9. 
SAFETY EVALUATION AND REPORTING .........................................................106 
9.1. 
Adverse Event Collection and Reporting ....................................................................106 
9.2. 
Adverse Event .............................................................................................................107 
9.2.1. 
Definition of Adverse Event .......................................................................................107 
9.2.2. 
Serious Adverse Event ................................................................................................107 
9.2.3. 
Severity Assessment ...................................................................................................108 
9.2.4. 
Causality Assessment ..................................................................................................108 
9.2.5. 
Action Taken Regarding Study Drug(s) .....................................................................108 
9.2.6. 
Other Action Taken for Event .....................................................................................109 
9.2.7. 
Adverse Event Outcome .............................................................................................109 
9.3. 
Adverse Events of Special Interest .............................................................................109 
9.3.1. 
QTc Prolongation, Torsades de Pointes, and Other Ventricular Arrhythmias ............109 
9.3.2. 
Concurrent Elevations of Aminotransferases and Bilirubin .......................................110 
9.4. 
Safety Reporting Procedure For Investigators ............................................................110 
9.5. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee .............................................................................................110 
9.6. 
Exposure In Utero During Clinical Studies ................................................................111 
9.7. 
Clinical Laboratory Evaluations .................................................................................111 
9.8. 
Vital Signs ...................................................................................................................112 
9.9. 
Electrocardiograms .....................................................................................................112 
9.10. 
Physical Examinations ................................................................................................112 
9.11. 
Other Examinations .....................................................................................................112 
10. 
OTHER ASSESSMENTS ...........................................................................................113 
11. 
STATISTICAL METHODS .......................................................................................114 
11.1. 
General Statistical Considerations ..............................................................................114 
11.2. 
Analysis Sets ...............................................................................................................114 
11.3. 
Study Population Data ................................................................................................115 


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11.4. 
Efficacy Analyses........................................................................................................115 
11.5. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses .........................................115 
11.5.1. 
Pharmacokinetic Analyses ..........................................................................................115 
11.5.2. 
Pharmacodynamic/Biomarker/Pharmacogenomic Analyses ......................................116 
11.6. 
Safety Analyses ...........................................................................................................116 
11.6.1. 
Adverse Event Analyses .............................................................................................116 
11.6.2. 
Clinical Laboratory Evaluation Analyses ...................................................................116 
11.6.3. 
Vital Sign Analyses .....................................................................................................117 
11.6.4. 
Electrocardiogram Analyses .......................................................................................117 
11.6.5. 
Other Safety Analyses .................................................................................................117 
11.7. 
Other Endpoint Analyses ............................................................................................117 
11.8. 
Interim Analyses .........................................................................................................117 
11.9. 
Data Monitoring Committee .......................................................................................117 
11.10. 
Sample Size Determination .........................................................................................117 
11.11. 
Statistical Analysis Process .........................................................................................118 
11.12. 
Specification of Bayesian Logistic Regression Model With Escalation With 
Overdose Control ........................................................................................................118 
11.12.1. Bayesian Logistic Regression Model With Escalation With Overdose Control.........118 
11.12.2. Prior Specification for Bayesian Logistic Regression Model Parameters ..................119 
11.12.3. Escalation With Overdose Control Principle ..............................................................119 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ..............................................121 
12.1. 
Monitoring and Inspections ........................................................................................121 
12.2. 
Data Collection............................................................................................................121 
12.3. 
Data Management .......................................................................................................122 
12.4. 
Study Documentation and Storage ..............................................................................122 
12.5. 
Record Keeping ...........................................................................................................123 
13. 
FINANCING AND INSURANCE .............................................................................124 
13.1. 
Finances.......................................................................................................................124 
13.2. 
Reimbursement, Indemnity, and Insurance .................................................................124 
14. 
PUBLICATION POLICY ...........................................................................................125 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ..............................126 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance......................................126 
15.2. 
Subject Confidentiality................................................................................................126 


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15.3. 
Informed Consent ........................................................................................................126 
15.4. 
Regulatory Compliance ...............................................................................................127 
15.5. 
Protocol Deviations .....................................................................................................128 
15.6. 
Supply of New Information Affecting the Conduct of the Study ...............................128 
15.7. 
Protocol Amendments .................................................................................................129 
15.8. 
Study Termination .......................................................................................................129 
15.9. 
Data and Safety Monitoring Board .............................................................................129 
15.10. 
Address List ................................................................................................................130 
15.10.1. Sponsor ........................................................................................................................130 
15.10.1.1. Sponsor’s Responsible Medical Officer......................................................................130 
15.10.1.2. Sponsor’s Clinical Scientist ........................................................................................130 
15.10.1.3. Sponsor’s Clinical Study Manager /Delivery Lead ....................................................130 
15.10.1.4. Sponsor’s Safety Contacts ..........................................................................................130 
15.10.1.5. Sponsor’s Biostatistician .............................................................................................130 
15.10.2. CRO ............................................................................................................................131 
15.10.3. EDC Vendor ................................................................................................................131 
15.10.4. IXRS Vendor ...............................................................................................................131 
15.10.5. Central Laboratory ......................................................................................................131 
16. 
REFERENCES ............................................................................................................132 
17. 
APPENDICES ............................................................................................................135 
17.1. 
Hepatic Events and Liver Enzyme Elevation..............................................................135 
17.1.1. 
Liver Safety Monitoring and Evaluations ...................................................................135 
17.2. 
Sweet’s Syndrome (Acute Febrile Neutrophilic Dermatosis) .....................................136 
17.3. 
Schedule of Events ......................................................................................................137 
17.4. 
Response Criteria for AML19 ......................................................................................157 
17.5. 
Additional Definitions/Response Criteria ...................................................................159 
17.6. 
Prohibited Concomitant Medications ..........................................................................160 
17.7. 
Highly Effective Methods of Birth Control ................................................................163 
17.8. 
FLT3-ITD Mutation Assay .........................................................................................164 
17.9. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .........................165 
17.10. 
New York Heart Association (NYHA) Functional Classification ..............................166 
 


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LIST OF TABLES 
Table 3.1: Study Design ...............................................................................................................45 
Table 3.2: Proposed Cohorts and Dose Levels of Quizartinib and Milademetan for Dose 
Escalation ....................................................................................................................49 
Table 8.1: Intensive PK Sampling (Part 1) ................................................................................102 
Table 8.2: Sparse PK Sampling (Part 2) ....................................................................................102 
Table 8.3: PK Substudy Timepoints ..........................................................................................103 
Table 17.1: Schedule of Events (for Part 1) – Milademetan QD 14/28 Regimen .......................137 
Table 17.2: Schedule of Events (for Part 1) - Alternative Milademetan QD 7/28 Regimen .......141 
Table 17.3: Schedule of Events (for Part 1) - Alternative Milademetan QD 3/14 × 2 
Regimen ....................................................................................................................145 
Table 17.4: Schedule of Events (for Part 2, Except Subjects in DDI Substudy) – 
Milademetan QD 14/28 Regimen§ ............................................................................149 
Table 17.5: Schedule of Events (for the Part 2 Subgroup of 12 Subjects for DDI 
Substudy) – Milademetan QD 14/28 Regimen§ .......................................................153 
 


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LIST OF FIGURES 
Figure 1.1: Effects of Milademetan and Quizartinib on Estimated Tumor Volume in 
MOLM-13-bearing NOD SCID Mice ........................................................................38 
Figure 3.1: Proposed Dosing Schedule of Quizartinib – Milademetan Combination ...................48 
Figure 7.1: Schedule for Bone Marrow Biopsies/Aspirates ........................................................101 
Figure 8.1: PK Substudy Design (Part 2) with Milademetan QD 14/28 Schedule .....................103 
Figure 17.1: Hematologic Recovery Requirements for CR and CRi ........................................158 
Figure 17.2: Hematologic Recovery Requirements for CR and CRh .......................................159 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC24h 
Area Under the Plasma Concentration-time Curve up to Time 24 Hours 
AUCinf 
Area Under the Plasma Concentration-time Curve up to Infinity 
BLRM 
Bayesian Logistic Regression Model 
Cmax 
Maximum Plasma Concentration 
CR 
Complete Remission 
CRc 
Composite Complete Remission 
CRh 
Complete Remission with Partial Hematological Recovery 
CRi 
Complete Remission with Incomplete Blood Count Recovery 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
Ctrough 
Trough Plasma Concentration 
DDI 
Drug-drug Interaction 
DISS 
Drug-induced Sweet’s Syndrome 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Composite Complete Remission 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EFS 
Event-free Survival 
EIU 
Exposure In Utero 
ELN 
European LeukemiaNet 


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ABBREVIATION 
DEFINITION 
EWOC 
Escalation with Overdose Control 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 Second 
FLT3 
FMS-like Tyrosine Kinase 3 
FLT3-ITD 
FMS-like Tyrosine Kinase 3 Internal Tandem Duplication 
GCP 
Good Clinical Practice  
GI 
Gastrointestinal 
GVHD 
Graft Versus Host Disease 
Hgb 
Hemoglobin 
HCT 
Hematopoietic Cell Transplant 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITD 
Internal Tandem Duplication 
IXRS 
Interactive Web/Voice Response System 
LSC 
Leukemic Stem Cells 
LVEF 
Left Ventricular Ejection Fraction 
MDM2 
Mouse Double Minute 2 Homolog 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
MLFS 
Morphologic Leukemia-free State 
MRD 
Minimal Residual Disease 
MUGA 
Multigated Acquisition 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PGx 
Pharmacogenomics 


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ABBREVIATION 
DEFINITION 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PR 
Partial Remission 
qd 
Once Daily 
QTcF 
QTc by Fridericia’s method 
RDE 
Recommended Dose for Expansion 
R/R 
Relapsed/Refractory 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
Tmax 
Time to Reach Maximum Plasma Concentration 
TR 
Transplantation Rate 
ULN 
Upper Limit of Normal 
US 
United States 


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1. 
INTRODUCTION 
1.1. 
Background 
FMS-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells, and signaling 
through FLT3 promotes proliferation and survival in these cells.  FLT3 internal tandem 
duplication (FLT3-ITD) occurs in approximately 25% of subjects with acute myeloid leukemia 
(AML).1,2  The FLT3-ITD mutation is associated with a shorter duration of response, a greater 
cumulative incidence of relapse, and shorter survival after relapse.  There is an unmet medical 
need for effective treatment for patients with relapsed/refractory (R/R) AML with the FLT3-ITD 
mutation.  In FLT3-ITD mutant AML, constitutive FLT3 signaling results in activation of 
STAT5 leading to transcriptional upregulation of Mcl-1, Bcl2, c-Myc, and other proteins that 
support survival and proliferation of the leukemic cells and survival of the leukemic stem cells 
(LSCs).3,4,5  Duration of response is still short with the currently studied FLT3 inhibitors, and an 
effective therapy for durable responses in FLT3-ITD mutant AML should target the FLT3 
signaling and survival mechanisms of the LSC. 
Quizartinib (AC220) is a potent and selective inhibitor of FLT3 that is currently in Phase 3 trials, 
and previous Phase 1 and Phase 2 studies of quizartinib monotherapy have shown high response 
rates in patients with R/R FLT3-ITD mutant AML. 
A Phase 2 study of quizartinib monotherapy (2689-CL-2004) randomized 76 subjects with 
FLT3-ITD mutant AML who were refractory to or had relapsed after second-line AML therapy 
with or without consolidating hematopoietic cell transplant (HCT) to a starting dose of 30 mg or 
60 mg once daily (qd) with intra-subject dose escalation allowed to 60 mg or 90 mg daily, 
respectively, after 1 cycle. The rates of composite complete remission (CRc) through the End-of-
treatment were the same (47%) in both groups and were consistent with the rate observed at 
higher doses (90 mg, 135 mg, and 200 mg daily) in subjects with R/R FLT3-ITD mutant AML in 
an earlier Phase 2 study (49%).  In the 30 mg and 60 mg dose groups, the dose was escalated in 
63% and 19% of subjects, respectively.  The duration of CRc was 4.2 and 9.1 weeks, and median 
overall survival was 20.9 and 27.3 weeks in the 30 mg and 60 mg dose groups, respectively. 
The tumor suppressor protein p53 (encoded by TP53 gene) plays an essential role in preventing 
neoplasia by inducing cell cycle arrest or apoptosis in cells undergoing various types of 
physiological stress. Inactivation of TP53 by mutation occurs in approximately half of human 
tumors, resulting in loss of tumor suppressor activity, and thereby removing a pivotal barrier to 
neoplastic development. More than 90% of AML patients retain wild type TP53 in the malignant 
cells, but the p53 protein activity is frequently inhibited by binding of overexpressed mouse 
double minute 2 homolog (MDM2) in these cells, resulting in ubiquitination and proteasomal 
degradation of p53.6  Pharmacologic inhibition of the interaction between MDM2 and wild type 
p53 in tumor cells could restore p53 activity with subsequent antitumor effects from the 
p53-downstream genes.7 
DS-3032b (International Nonproprietary Name:  milademetan), a novel, specific, small molecule 
inhibitor of MDM2, disrupts interactions between MDM2 and the tumor suppressor protein p53 
in tumor cells, and is currently being developed as an oral drug for the treatment of solid tumors 
and hematological malignancies.  MDM2 inhibition and antileukemic effect were demonstrated 
in a Phase 1 open-label study (DS3032-A-U102) in subjects with advanced hematological 


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malignancies.  As of 08 Jan 2018, the dose escalation part has enrolled and treated 52 subjects 
with AML or high risk myelodysplastic syndrome (MDS).  Thirty-seven subjects were treated at 
a dosing schedule of qd for 21 out of a 28 days cycle (qd 21/28) at doses starting from 60 mg and 
then at increasing doses of 90 mg, 120 mg, 160 mg, and 210 mg.  Maximum tolerated dose 
(MTD) was determined to be 160 mg in the qd 21/28 schedule.  An additional 15 subjects were 
treated under alternative, dosing schedules currently under investigation (7 subjects at 160 mg qd 
7/28, 3 subjects at 160 mg 3/14 twice in a 28 day cycle, 4 subjects at 160 mg qd 14/28, and 1 
subject at 220 mg qd 14/28).  Ten of the 15 subjects treated in the alternative dosing schedules 
were evaluable for dose limiting toxicities (DLTs), and no DLTs have been observed in these 
subjects.  The remaining 5 subjects were not evaluable due to discontinuation before completing 
the Cycle 1 evaluation.  Among the subjects treated under the qd 21/28 dosing schedule, bone 
marrow blast reduction was noted in 14/26 (54%) evaluable subjects with at least 1 post-dose 
assessment.  Eight subjects achieved ≥50% blast reduction and 2 subjects achieved complete 
remission (CR).  Three additional subjects achieved blast reduction to <5% without peripheral 
blood count recovery that correspond to morphologic leukemia-free state.  Best response in all 
subjects was achieved after the first cycle of therapy. 
To evaluate the potential benefit of combining a FLT3 inhibitor and MDM2 inhibitor for the 
treatment of patients with FLT3-ITD mutant AML, an in vivo nonclinical pharmacology study 
was conducted in male NOD SCID mice bearing MOLM-13 (FLT3-ITD mutant; p53 wild type) 
human AML xenografts by treatment with both milademetan and quizartinib orally qd for 11 
days after establishing the tumors (Figure 1.1). 
Figure 1.1: 
Effects of Milademetan and Quizartinib on Estimated Tumor Volume in 
MOLM-13-bearing NOD SCID Mice 
 


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Quizartinib was dosed daily at 0.5 mg/kg and 1 mg/kg and milademetan was dosed daily at 25 
mg/kg and 50 mg/kg.  Antitumor effects were assessed based on estimated tumor volume on Day 
11.  In all cases, synergistic activity was seen for all doses of the 2 drugs in combined treatment, 
showing superior tumor inhibition by these combinations compared to either agent alone.  The 
synergistic effect between quizartinib and milademetan was also observed in other preliminary 
experiments using AML FLT3-ITD mutant/TP53WT cell lines. 
Quizartinib is a substrate for CYP3A and P-glycoprotein (P-gp).  The clinical data suggest that 
P-gp plays a minimal role in the absorption or clearance of quizartinib.  Therefore, no dose 
adjustment is required when quizartinib is co-administered with a P-gp inhibitor or a P-gp 
inducer.  However, a dose adjustment for quizartinib is required if administered concomitantly 
with a strong CYP3A inhibitor, but not with moderate or weak inhibitors of CYP3A.  Quizartinib 
is neither an inhibitor nor an inducer of CYP3A, and is thus unlikely to inhibit milademetan 
metabolism.  Quizartinib may have the potential to inhibit P-gp in vivo. 
Milademetan is a substrate for CYP3A and P-gp.  A Phase I study in healthy subjects was 
conducted to evaluate the effect of co-administration of strong CYP3A inhibitors (itraconazole 
and posaconazole) on milademetan PK (DS3032-A-U107).  Co-administration of milademetan 
100 mg with itraconazole 200 mg at steady state increased milademetan mean maximum plasma 
concentration (Cmax) and area under the plasma concentration-time curve up to infinity 
(AUCinf) by 8% and 115%, respectively.  Similarly, posaconazole 200 mg at steady state 
increased milademetan mean Cmax by approximately 19% and AUCinf by approximately 149%.  
Therefore, it is recommended that the milademetan dose be reduced by half when it is 
concomitantly administered with a strong CYP3A inhibitor. 
Milademetan is likely a moderate or weak inhibitor of both CYP3A and P-gp.  Milademetan is 
expected to result in minimal change in quizartinib pharmacokinetics (PK) based on the in vitro 
and in vivo assessment of drug-drug interaction (DDI) potential.  However, the in vivo DDI 
potential between quizartinib and milademetan through P-gp inhibition needs to be evaluated in a 
clinical study. 
1.2. 
Study Rationale 
Combined treatment of quizartinib and milademetan has the potential to show synergistic 
antileukemic activity by targeting 2 distinct cellular pathways:  FLT3-ITD signaling pathway and 
p53 activation pathway.  Quizartinib suppresses the induction of Bcl2 family survival proteins 
(Mcl-1, Bcl2) by inhibiting FLT3-ITD signaling and preventing STAT5 activation.  MDM2 
inhibition increases p53 levels and the p53-induced proteins (eg, PUMA and NOXA) that 
inactivate the anti-apoptotic Bcl2 family proteins by direct binding, thereby suppressing the anti-
apoptotic mechanisms in the FLT3-ITD mutant AML and LSCs.8,9  While several cytotoxic 
agents can also induce p53 in proliferating cells, MDM2 inhibitors will increase p53 levels 
irrespective of cell proliferation in the relatively quiescent LSCs.  Each of these treatments also 
exerts other antileukemic effects contributing to their overall synergy.  FLT3-ITD constitutive 
signaling leads to the induction of oncogenic proteins (eg, c-MYC and pim-2) that will be 
suppressed by quizartinib,10 while increased levels of p53 resulting from MDM2 inhibition also 
induces pro-apoptotic Bcl2 family proteins including BAX.11  In addition, p53 activation has 
been reported to block the stroma cell-mediated resistance to FLT3 inhibition by downregulating 
the production of CXCL12 by bone marrow stromal cells.12  Therefore, a combination of these 2 


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agents aimed at inhibiting FLT3 and re-activating p53 function by MDM2 inhibition could 
potentially be effective in FLT3-ITD mutant AML by a stronger induction of the mitochondrial 
initiated apoptosis on the bone marrow blasts and the LSCs, and by suppressing the stromal cell-
mediated survival signals. 
The scientific rationale and the nonclinical and available clinical data support the clinical 
investigation of the combined treatment of quizartinib and milademetan in subjects with FLT3-
ITD mutant AML. 
1.3. 
Potential Risks for Study Subjects 
DS3032-A-U105 is a first-in-human co-development study of 2 investigational agents:  
milademetan and quizartinib.  The safety, tolerability, and PK of quizartinib have been 
extensively evaluated in humans.  Adverse reactions with quizartinib from studies to date include 
general disorders (eg, pyrexia and fatigue), gastrointestinal disorders (eg, nausea, diarrhea, and 
vomiting), hematologic disorders (eg, anemia, neutropenia, and thrombocytopenia), QTc 
prolongation, torsades de pointes, neutrophilic dermatosis/differentiation syndrome, DDIs with 
strong CYP3A inhibitors, DDIs with strong or moderate CYP3A inducers, and the consequences 
of cytopenias including increased risk of infection and bleeding. 
Based on early clinical studies that have been conducted with milademetan, the adverse events 
(AEs) anticipated with milademetan are primarily related to the gastrointestinal tract (eg, nausea, 
vomiting, diarrhea, and poor appetite), marrow suppression (primarily thrombocytopenia), 
electrolyte disturbances, and DDIs with strong CYP3A inhibitors. 
For the combination studies of quizartinib with milademetan, while there is some overlap 
between the AE profiles of the 2 drugs (especially with respect to myelosuppression, infection, 
and gastrointestinal AEs) and the background disease pathology, all of these events can be 
monitored and are manageable.  Investigators specializing in treating AML subjects are very 
familiar with the identification and management of these types of AEs and the protocol is 
designed to facilitate their detection.  Milademetan does not bind human ether-a-go-go-related 
gene (hERG) channels and had no effects in dog telemetry studies, making it unlikely that 
combining milademetan with quizartinib would affect quizartinib-associated alterations in QT 
interval. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
Part 1 (Dose Escalation): 
 To determine the safety and tolerability of the drug combination, identification of the 
optimum dosing schedule, MTD, and the recommended dose for expansion cohort 
(RDE). 
Part 2 (Dose Expansion): 
 To confirm safety and tolerability of the combination therapy at RDE and to identify the 
recommended Phase 2 dose. 
 Assessment of efficacy. 
2.1.2. 
Secondary Objectives 
Part 1 only: 
 Preliminary assessment of efficacy. 
Part 1 and Part 2: 
 To evaluate the PK of milademetan, quizartinib, and the active metabolite of quizartinib, 
AC886. 
2.1.3. 
Exploratory Objectives 
Part 1 and Part 2: 
 To evaluate the pharmacodynamic effects of the combination treatment at each dose 
level. 
Part 2 only: 
 Additional assessments of efficacy. 
2.2. 
Outcome Measures 
2.2.1. 
Primary Outcome Measures 
Part 1 only: 
 Number of subjects with DLTs. 
[Time Frame:  Approximately 18 months from start of the study] 
Part 1 and Part 2: 
 Number of subjects who experienced an AE during the study. 
[Time Frame:  Approximately 3 years from start of study] 
Part 2 only: 
 Number of subjects with response to treatment. 


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Response to treatment will be assessed using 2017 European LeukemiaNet (ELN) 
recommendations.  These include the rates of CR; CR with incomplete blood count 
recovery (CRi); CRc; duration of composite complete remission (DOR); morphologic 
leukemia-free state (MLFS); partial remission (PR); overall response rate (ORR); and 
stable disease (SD).  CR with partial hematological recovery (CRh) will be evaluated 
separately from the other response criteria. 
[Time Frame:  Approximately 3 years from start of study] 
2.2.2. 
Secondary Outcome Measures 
Part 1 only: 
 Number of subjects with response to treatment. 
Response to treatment will be assessed using 2017 ELN recommendations.  These 
include the rates of CR, CRi, CRc, DOR, MLFS, PR, ORR, and SD.  CRh will be 
evaluated separately from the other response criteria.  The efficacy measurements are 
listed in Section 2.4.3. 
[Time Frame:  Approximately 18 months from start of study] 
Part 1 and Part 2: 
 Plasma concentrations and PK parameters of milademetan, quizartinib, and AC886. 
[Time Frame:  Approximately 3 years from start of study] 
2.2.3. 
Exploratory Outcome Measures 
Part 1 and Part 2: 
 Pharmacodynamic and biomarker measurements. 
Part 2 only: 
 Additional measurements to assess number of subjects with response to treatment. 
2.3. 
Study Hypothesis 
Combined treatment of subjects with FLT3-ITD mutant AML with quizartinib and milademetan 
will be safe and well tolerated and will show enhanced anti-leukemic activity over that observed 
in the previous single agent studies. 
2.4. 
Study Endpoints 
2.4.1. 
Safety Endpoint 
The primary safety endpoints will include serious adverse events (SAEs), treatment-emergent 
adverse events (TEAEs), DLTs, physical examination findings (including Eastern Cooperative 
Oncology Group [ECOG] Performance Status), vital sign measurements, clinical laboratory 
parameters (serum chemistry and hematology), and electrocardiogram (ECG) parameters, 
particularly the QTc by Fridericia’s method (QTcF).  Adverse events (AEs) will be categorized 
using the Medical Dictionary for Regulatory Activities (MedDRA) version 22.0.  Adverse events 


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and laboratory test results will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. 
2.4.2. 
Pharmacokinetic/Pharmacodynamic/Biomarker Endpoint(s) 
Pharmacokinetics 
 Plasma concentrations relative to dosing for milademetan, quizartinib, and AC886. 
 PK parameters (Cmax and area under the plasma concentration-time curve up to time 
24 hours [AUC24h]) for milademetan, quizartinib, and AC886 estimated by non-
compartmental analysis. 
 Effect of quizartinib on milademetan PK and effect of milademetan on quizartinib PK 
in the DDI substudy in the dose expansion part. 
Pharmacodynamics 
Pharmacodynamic assessments are exploratory endpoints and may include, but are not limited to, 
the following: 
 Changes in LSC numbers. 
 Changes in FLT3 signaled STAT5 downstream gene expression (eg, Mcl-1, Bcl2, c-
Myc), and p53 downstream targets (eg, MDM2, MIC-1, PUMA, NOXA, Bax, CXCL12) 
in bone marrow AML or peripheral blood blasts and/or non-leukemic cells. 
 Changes in circulating proteins such as MIC-1 and/or cell surface or cellular proteins. 
 Minimal residual disease (MRD) may be tested in the bone marrow or peripheral blood 
samples obtained from subjects who achieve a reduction of blasts in bone marrow to 
<5%. 
 Baseline and post-baseline mutation status of genes involved in AML pathogenesis. 
Other biomarkers 
 FLT3-ITD status of the leukemic cells will be tested in a central laboratory. 
 Prior confirmation of TP53 wild type status is not required for starting treatment, but 
TP53 mutant or wild type status will be retrospectively tested at the end of the study. 
2.4.3. 
Efficacy Endpoint(s) 
The secondary endpoints of efficacy include the following assessments.  The response rate will 
be summarized based on the Investigator-assessed best response after the first dose of study 
treatment and before the last disease assessment during the study (Section 7.1).  The response 
criteria are according to the 2017 ELN recommendations in Section 17.4 and Section 17.5: 
 CR rate 
 CRi rate 
 CRc rate (CR+CRi) 


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 DOR:  Time from the first objective evidence of CRc to the first objective evidence of 
relapse or death 
 MLFS rate 
 PR rate 
 ORR (CRc+MLFS+PR) 
 SD rate 
 CRh rate 
o CRh will be evaluated separately from the other response criteria 
2.4.3.1. 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints may include the following assessments: 
 Transplantation rate:  Percent of subjects undergoing allogeneic HCT directly following 
protocol-specified treatment with no intervening AML therapy 
 Event-free survival (EFS):  Time from first dose date until relapse after CR or CRi, 
refractory disease, or death from any cause, whichever is observed first 
 Overall survival (OS):  Time from first dose date until death from any cause 
 Transfusion independence 
2.4.4. 
Other Endpoints 
Not applicable. 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This will be an open-label, Phase 1 study of milademetan in combination with quizartinib in 
subjects with FLT3-ITD mutant AML, with a dose escalation part (Part 1) and a dose expansion 
part (Part 2).  Quizartinib will be administered qd in 28-day cycles, and milademetan will be 
administered qd on Days 1 to 14 of each 28-day cycle (qd 14/28 schedule) or in alternative 
dosing schedules. 
The dose escalation part of the study is planned to be conducted in approximately 15 sites in the 
United States (US), Japan, Asia, and Europe.  Additional sites and countries may be added as 
needed. 
Along with the 15 sites for dose escalation, approximately 15 additional sites worldwide may be 
added as necessary for the dose expansion part, which will commence after the completion of the 
dose escalation part, based on the enrollment rate, the prevalence of the subject population, and 
the standard of care available to the subjects at the time.  The duration of subject participation is 
not fixed in this study.  The study is expected to last approximately 4 to 5 years from the time the 
first subject is enrolled in Part 1 of the study. 
An overview of the study design is provided in Table 3.1. 
Table 3.1: 
Study Design 
Part 
Cohort 
Target Disease 
Target Population 
Estimated 
Enrollment (n) 
Part 1 
Dose Escalation 
Multiple escalating 
dosage/schedule 
cohorts 
Relapsed/Refractory 
AML 
Subjects ≥18 years old 
Approximately 
24 to 36 
Part 2 
Dose Expansion 
Cohort 1a 
Relapsed/Refractory 
AML 
Subjects ≥18 years old 
Approximately 
40 
Cohort 2 
Newly diagnosed 
AML 
Subjects unfit for 
intensive chemotherapy 
who are: 
 
≥75 years old, OR 
 
Between 18 and 74 
years old with at least 
1 comorbidity 
Approximately 
40 
AML = acute myeloid leukemia 
a The first 12 subjects in Part 2 Cohort 1 will be enrolled as a drug-drug interaction (DDI) substudy cohort to 
evaluate the DDI between milademetan and quizartinib. 
3.1.1. 
Dose Limiting Toxicity Definition 
A DLT is defined as any non-hematological TEAE unless incontrovertibly related to disease 
progression, intercurrent illness, or concomitant medication, that occurs during the DLT 
evaluation period (28 days) in each dose-level cohort, and is Grade 3 or higher according to the 
NCI-CTCAE version 5.0, with the exceptions as defined below: 


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For elevations in hepatic function tests, a DLT is defined as follows: 
 Grade 3 or higher aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 
levels, OR 
 Elevation in total bilirubin ≥3.0 × ULN that does not return to ≤Grade 2 elevation 
within 7 days. 
Myelosuppression and associated complications are expected events during leukemia therapy, 
however, the following prolonged myelosuppression is considered a DLT: 
 ANC <0.5 × 109/L, platelets <20 × 109/L, and marrow cellularity <5% at 6 weeks or 
later from start of therapy without any evidence of leukemia. 
However, completion of the 28-day safety evaluation is sufficient for the subject to be evaluable.  
If a DLT based on myelosuppression occurs after the cohort review and dose escalation 
decisions, dose level assignment of the next subject in the new cohort will be based on an 
updated Bayesian logistic regression model (BLRM) using DLT outcome data from all assessed 
dose cohorts. 
Subjects who are unable to complete at least 75% of the prescribed dose of milademetan or at 
least 75% of the prescribed dose of quizartinib in Cycle 1 (28 days) as a result of nondisease-
related ≥Grade 2 events will be considered to have a DLT. 
The following AEs are not considered DLTs: 
 Grade 3 fatigue lasting <3 days. 
 Grade 3 nausea or vomiting that has resolved to ≤Grade 2 within 48 hours following 
administration of preventive, as well as additional, antiemetic therapies for managing 
established nausea or vomiting. 
 Grade 3 diarrhea that has resolved to ≤Grade 2 within 48 hours after standard 
antidiarrheal therapies. 
 Alopecia. 
 Grade ≥3 electrolyte abnormalities that are corrected to ≤Grade 1 within 24 hours. 
3.1.2. 
Part 1 (Dose Escalation) 
Dose escalation will assess the safety, tolerability, PK, and preliminary efficacy of increasing 
doses of milademetan and quizartinib in subjects with FLT3-ITD mutant R/R AML.  The 
evaluation period for DLTs will be 28 days (Cycle 1) from the start of study drug administration.  
The dose escalation will be guided by a BLRM for dual agent combination and governed by the 
escalation with overdose control (EWOC) principle13,14 (Section 11.12).  The determination of 
MTD(s) will be guided by the BLRM using accumulated DLT data as well as other safety and 
PK data.  The RDE will be decided based on considerations of the respective MTD(s) guided by 
the BLRM and on an overall assessment of safety data from all cycles, PK data, and preliminary 
efficacy data. 
Cohorts of 3 to 6 subjects will be enrolled and assessed for DLT before escalation to a new 
higher dose.  For a subject to be considered evaluable for DLT, the subject must have received at 
least 75% of the prescribed Cycle 1 doses and completed safety assessments of the DLT 


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evaluation period, or experienced a DLT in this period.  Subjects who started treatment but who 
do not meet the criteria to be DLT-evaluable will not be included in the BLRM update.  In some 
cases, a subject in the previous cohort may experience a DLT after the enrollment of subjects to a 
new cohort has begun.  In this event, the dose level assignment of the next subject(s) in the new 
cohort will be based on an updated BLRM using DLT outcome data from all assessed dose 
cohorts up to that point. 
A delay of at least 7 days will occur between the first subject dosed and the second subject dosed 
in the first cohort.  If 2 evaluable subjects in any cohort experience DLT before the enrollment of 
the next subject, the model will be re-evaluated and discussion between the Investigators and 
Sponsor will occur before enrollment of any additional subjects in the cohort. 
Enrollment of subjects to a new cohort requires completion of DLT evaluation of at least 3 
subjects treated in the current cohort at the intended dose levels.  The Investigator and Sponsor 
will also assess safety and tolerability on an ongoing basis and will continue dosing if there are 
no safety or risk/benefit concerns and if the subject is deriving clinical benefit.  Additional 
subjects for the characterization of safety, PK, or PD may be added at any dose escalation cohort 
below the MTD dose level or at the MTD in parallel with ongoing escalation up to a maximum 
of 12 subjects in each cohort.  Further details can be found in the Cohort Management Plan. 
Milademetan Dose Levels 
The proposed starting dose of milademetan will be 90 mg, which will be escalated through 
120 mg and 160 mg; all 3 doses will follow the qd 14/28 dosing schedule unless the safety data 
suggest the use of a less frequent dose schedule.  Based on emerging safety and efficacy data 
during dose escalation, the dose levels of milademetan may be evaluated up to 200 mg or 260 mg 
in alternative dosing schedules with less frequent doses (eg, Days 1 to 7 of each 28-day cycle [qd 
7/28] and Days 1 to 3 of each 14 days administered twice in a 28-day cycle [qd 3/14 × 2]) 
(Figure 3.1).  The maximum dose for milademetan will be up to 260 mg in the qd 3/14 × 2 
schedule as determined in the DS3032-A-U101 study.


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Figure 3.1: 
Proposed Dosing Schedule of Quizartinib – Milademetan Combination 
 
* The proposed doses under these schedules include all the possible doses including those previously planned to be 
evaluated in a more frequent dose schedule but switched to the less frequent schedule based on emerging safety 
data. 
As a conservative approach, the starting dose of milademetan will be 90 mg in a qd 14/28 
schedule.  This dose is 2 dose levels below the single agent MTD (ie, 160 mg) for AML/MDS in 
the DS3032-A-U102 study, and 1 dose level below the single agent MTD (ie, 120 mg) for solid 
tumors in the DS3032-A-U101 study, both following the qd 21 of 28-day schedule (qd 21/28).  
The maximum dose for milademetan will be up to 260 mg in the qd 3/14 × 2 schedule as 
determined in the DS3032-A-U101 study.15 
Quizartinib Dose Levels 
There are 3 proposed dose levels of quizartinib:  30 mg, 40 mg, and 60 mg.  Quizartinib 
monotherapy from 30 mg to 60 mg doses was demonstrated to be safe and clinically active in the 
Phase 2 (2689-CL-2004) study.  However, the optimal dose/schedule of quizartinib is unknown 
when it is combined with milademetan.  Therefore, 30 mg qd quizartinib will be used as the 
starting dose, as this dose demonstrated a similar CRc rate as 60 mg qd quizartinib.16 
If quizartinib is increased to the 60-mg dose level, subjects will be dosed at 30 mg for the first 14 
days to evaluate the QT prolongation risk in each subject.  If the QTc by Fridericia’s method 
(QTcF) remains ≤450 ms, the dose will be escalated to the intended dose of the cohort (ie, 60 mg 
quizartinib) on Day 15 of Cycle 1 and continued at the same dose in subsequent cycles.  If the 
QTcF is >450 ms but ≤480 ms, the subject can continue at 30 mg quizartinib in combination with 
the assigned dose of milademetan, in the absence of other risk factors.  If the QTcF is >480 ms 
but ≤500 ms, the subject can continue with a quizartinib dose reduction of 1 level in combination 
with the assigned dose of milademetan, in the absence of other risk factors.  Multiple stepwise 
dose reductions from 60 mg to 40 mg, 40 mg to 30 mg, and 30 mg to 20 mg are allowed to 
mitigate the QTcF prolongation risks of the subjects.  If the QTcF is >500 ms and recurs despite 


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appropriate dose reductions and correction/elimination of other risk factors (eg, serum electrolyte 
abnormalities, concomitant QT-prolonging medication), the subject will be permanently 
discontinued from quizartinib. 
In cohorts with quizartinib 60 mg, it is possible that not all subjects may be assignable to 
quizartinib 60 mg on Day 15 after the 30 mg lead-in for the first 14 days, and therefore 
additional subjects may be enrolled for evaluation of the cohorts. 
Dose Escalation Plan 
The proposed dose levels shown in Table 3.2 were chosen based on the safety and preliminary 
efficacy data from the single agent studies.  The dose and schedule of milademetan will be first 
optimized during dose escalation in combination with 30 mg qd quizartinib.  When a decision is 
made to escalate the dose, the milademetan dose can be escalated to the next dose level at the 
existing dosing schedule suggested by BLRM (eg, qd 14/28), at a less frequent dosing schedule 
(ie, qd 7/28 or qd 3/14 × 2), or in separate cohorts of 2 schedules in parallel; the MTD(s) in those 
schedules may be separately assessed.  While the BLRM will provide the dose recommendation, 
the decision to use a less frequent dose schedule will be taken after discussion between the 
Investigators and Sponsor based on the overall safety data thus far.  However, dose escalation 
from any dose level in a less frequent dose schedule to a more frequent dose schedule is not 
allowed. 
Once the most optimal dose and schedule of milademetan is identified, the quizartinib qd dose 
will be escalated from 30 mg to 40 mg, and then from 40 mg to 60 mg, in combination with the 
optimal dose of milademetan.  During dose escalation, simultaneous dose escalation of both 
agents will not be not allowed.  Additional dose combinations not shown in the table may be 
tested based on emerging safety data during dose escalation. 
Table 3.2: 
Proposed Cohorts and Dose Levels of Quizartinib and Milademetan for Dose 
Escalation 
Quizartinib Dose 
Milademetan Dose 
30 mg qd 
90 mg qd 14/28a 
30 mg qd 
120 mg qd 14/28a 
30 mg qd 
160 mg qd 14/28a 
30 mg qd 
200 mg qd 7/28a 
30 mg qd 
260 mg qd 3/14 × 2 
40 mg qd 
Most optimal dose and schedule identified in combination 
with 30 mg qd quizartinib 
60 mg qd following 30-mg 
lead-in (14 days) 
Most optimal dose and schedule identified in combination 
with 30 mg qd quizartinib 
qd = once daily 
a At any milademetan dose level, if the evaluated dosing schedule is not tolerated, alternative dosing schedules of 
less frequent doses (eg, qd 7/28 or qd 3/14 × 2) may be evaluated.  However, dose escalation from any dose level 
in a less frequent dose schedule to a more frequent dose schedule is not allowed. 
Note:  Some of the cohorts shown in the table may be dropped based on the emerging safety data during dose 
escalation. 


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3.1.2.1. 
Stopping Rules (Dose Escalation) 
The following stopping rule will be implemented for the dose escalation part: 
 At least 6 evaluable subjects have been enrolled at the MTD level with at least 21 
evaluable subjects in total enrolled in the dose escalation part. 
The RDE will be decided based on considerations of the respective MTD(s) guided by the 
BLRM and on an overall assessment of safety data from all cycles, PK data, and preliminary 
efficacy data. 
3.1.2.2. 
Dose Modification of Milademetan due to Thrombocytopenia and/or 
Neutropenia (Cycle 2 and Later) 
If a subject experiences prolonged thrombocytopenia (platelets <50 × 109/L) and/or neutropenia 
(ANC <0.5 × 109/L) that is drug-related in the Investigator’s clinical judgement before starting 
the subsequent milademetan cycle, then the Investigator after consultation with the Sponsor 
Medical Monitor may reduce the dose frequency of milademetan (eg, 10/28 days, 7/28 days, or 
3/14 days × 2) in subsequent cycles while maintaining the same daily dose of milademetan.  
Efforts will be made to preferentially adjust the milademetan dose frequency while maintaining 
quizartinib at a stable dose without interruption for as long as possible. 
3.1.3. 
Part 2 (Dose Expansion) 
The dose expansion part will commence after the completion of the dose escalation part and will 
enroll in 2 parallel cohorts of approximately 40 subjects each (total of approximately 80 
subjects); dose expansion subjects will be treated at the RDE to confirm safety and tolerability, 
and to assess the preliminary efficacy of the combination therapy at the RDE.  Cohort 1 will 
enroll subjects with FLT3-ITD mutant AML who were refractory to or had relapsed after prior 
AML therapy (R/R AML).  Cohort 2 will enroll AML therapy-naive subjects with FLT3-ITD 
mutant AML who are unfit to receive intensive induction chemotherapy (see eligibility criteria in 
Section 4.1). 
In a subgroup of the first 12 subjects in Part 2 Cohort 1 (R/R AML), subjects will additionally be 
dosed with milademetan alone at the RDE dose on Day 1 of Cycle 1 to evaluate the DDI between 
milademetan and quizartinib; the rest of the treatment schedule will be identical to the other 
subjects in Part 2, except that the drugs are administered in unfed conditions in the substudy 
(Section 5.2.4).  Subjects in the DDI substudy are not allowed to receive strong CYP3A 
inhibitors within 7 days prior to the first dose OR 5 terminal half-lives, whichever is longer.  
Strong CYP3A inhibitors will be allowed in the DDI substudy subjects only after completion of 
the first 2 cycles with the recommended dose reductions of milademetan and quizartinib 
(Section 3.1.2). 
For Part 2 of the study, the Simon 2-stage optimal design will be utilized.  In stage 1, a futility 
analysis will be conducted when Investigator-assessed best response from the first 2 cycles of 
study treatment are available in 19 evaluable subjects (Section 11.10). 
Additionally, after 19 subjects are enrolled in each cohort, if the cumulative incidence of 
clinically relevant AEs that meet the definition of DLT exceeds 30%, further enrollment in that 
cohort will be discontinued at the current RDE and a lower dose of milademetan and/or 
quizartinib will be considered as RDE for re-evaluating the safety of the cohort. 


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3.2. 
Discussion of Study Design 
This will be an open-label, Phase 1 study of milademetan in combination with quizartinib in 
subjects with FLT3-ITD mutant AML with a dose escalation part followed by dose expansion.  
The proposed dose levels for dose escalation in Table 3.2 were chosen based on the safety and 
preliminary efficacy data in the single agent studies described in Section 1.1.  Quizartinib is 
expected to be the primary mediator of efficacy in this population of FLT3-ITD mutant AML 
patients with constitutive activation of STAT5 and upregulation of STAT5 target genes including 
the anti-apoptotic Mcl-1 as a predominant survival factor for the leukemic blasts and LSCs.  
Therefore, the 30 mg and 60 mg doses of quizartinib that were demonstrated to be safe and 
clinically active in the Phase 2 (2689-CL-2004) study were chosen, along with an intermediate 
dose of 40 mg, for the combination with milademetan.  Milademetan in combination with any of 
the above doses of quizartinib in escalating doses from 90 mg may achieve maximal suppression 
of anti-apoptotic mechanisms by induction of p53 downstream genes. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Subjects with histological confirmation of primary, secondary, or therapy-related AML 
according to the 2016 World Health Organization criteria classification17 with FLT3-ITD 
mutation (≥3% FLT3-ITD/total FLT3). 
 Part 1 – R/R AML 
o Subjects who have treatment failure to prior AML therapy (defined as 
failure to achieve at least CRi) or have relapsed after prior AML therapy, 
and 
o Subjects ≥18 years old 
 Part 2 
o Cohort 1 – R/R AML (same as Part 1) 
o Cohort 2 – Subjects with newly diagnosed AML who are ineligible for 
intensive induction chemotherapy.  Subjects must have had no prior AML 
treatment, with the exceptions of therapy for antecedent hematologic 
malignancies (eg, azacitidine for MDS) or hydroxyurea. 
a. Subjects ≥75 years old, OR 
b. Subjects between 18 and 74 years old (inclusive) with at least one 
of the following comorbidities: 
 ECOG Performance Status of 3; 
 Cardiac history of congestive heart failure (CHF) requiring 
treatment, left ventricular ejection fraction (LVEF) ≤50%, or 
chronic stable angina; 
 Diffusing capacity of the lung for carbon monoxide (DLCO) 
≤65% or forced expiratory volume in 1 second (FEV1) ≤65%; 
 Any other comorbidity that the Investigator judges to be 
incompatible with intensive chemotherapy must be reviewed 
by the Sponsor Medical Monitor during screening and before 
study enrollment. 
Note:  In both Part 1 and Part 2, subjects with a known record of FLT3-ITD mutant AML 
within the last 30 days from informed consent based on local testing can enroll in the 
study.  FLT3-ITD status will be tested in a central laboratory for confirmation of 
eligibility, and any results indicating absence of FLT3-ITD will be communicated to the 
Investigator for possible discontinuation of the subject from study participation if 
ongoing clinical benefit is not observed.  Subjects in Part 2 who do not show 
confirmation of FLT3-ITD mutation by central laboratory testing will be replaced.  
However, those who are deriving clinical benefit may be allowed to continue treatment. 


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2. Has an ECOG Performance Status (Section 17.9): 
 In Part 1 and Part 2 Cohort 1 (subjects with R/R AML): 
o 0 to 2 for subjects ≥18 years old 
 In Part 2 Cohort 2 (subjects with newly diagnosed AML): 
o 0 to 2 for subjects ≥75 years old 
o 0 to 3 for subjects between 18 and 74 years old (inclusive) 
3. Has adequate renal function, defined as creatinine clearance 60 mL/min, as calculated 
using the modified Cockcroft-Gault equation ([{140 – age in years} × {actual weight in 
kg}] divided by [{72 × serum creatinine in mg/dL}] multiply by 0.85 if female), OR if 
creatinine clearance 50-60 mL/min AND has serum creatinine ≤1.5 × upper limit of 
normal (ULN) (in obese subjects, the lean body weight can be used in the equation 
instead of actual body weight). 
4. Has electrolyte levels (including those for potassium, calcium, and magnesium) within 
normal limits. 
5. Serum AST and ALT ≤2.5 × ULN (≤5 × ULN if deemed elevated due to leukemia). 
6. Serum total bilirubin ≤1.5 × ULN (≤3 × ULN if deemed elevated due to leukemia or in 
subjects with documented Gilbert’s Syndrome). 
7. Discontinuation of prior AML treatment before the start of study treatment (except 
hydroxyurea to control leukocytosis) for at least 2 weeks for cytotoxic agents, or for at 
least 5 half-lives for non-cytotoxic agents.  Hydroxyurea is allowed until 48 hours prior 
to start of the study treatment. 
8. Subject, if female of childbearing potential, must have a negative serum pregnancy test 
upon entry into this study and must be willing to use highly effective birth control (as 
defined in Section 17.7) during the period of therapy and for 6 months following the last 
investigational drug dose.  A female is considered of childbearing potential following 
menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 
months), unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy) or confirmed by follicle stimulating hormone (FSH) test.  If 
male, must be surgically sterile or be willing to use 1 form of highly effective 
contraception method upon enrollment, during the course of the study, and for 6 months 
following the last investigational drug dose. 
9. Willingness to abstain from grapefruit/grapefruit juice and Seville oranges from 7 days 
before the first dose of study drug on Day 1 until the end of the study. 
10. Able and willing to provide bone marrow biopsies/aspirates and buccal swab/saliva for 
PGx testing as requested by the protocol. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 


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1. Presence of central nervous system (CNS) involvement of leukemia.  Patients with a 
history of CNS leukemia may be eligible if the CNS leukemia is adequately controlled 
(defined as no active clinical symptoms of CNS disease and at least 2 consecutive lumbar 
punctures with no evidence of disease prior to study enrollment) after discussion with the 
Sponsor Medical Monitor. 
2. Acute promyelocytic leukemia (AML subtype M3). 
3. Has other concurrent malignancy that required systemic antineoplastic treatment within 
the previous 2 years, except for localized cancers that have apparently been cured (eg, 
non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix 
or breast). 
4. Uncontrolled or significant cardiovascular disease, including: 
a. QTcF interval >450 ms (average of triplicate determinations). 
b. Bradycardia of less than 50 bpm unless the subject has a pacemaker. 
c. Diagnosed or suspected long QT syndrome, or known family history of long QT 
syndrome. 
d. History of clinically relevant ventricular arrhythmias, such as ventricular 
tachycardia, ventricular fibrillation, or torsade de pointes. 
e. History of second or third degree heart block.  Subjects with a history of heart 
block may be eligible if they currently have pacemakers and have no history of 
fainting or clinically relevant arrhythmia with pacemakers. 
f. Myocardial infarction within 6 months prior to Screening. 
g. Uncontrolled angina pectoris within 6 months prior to Screening. 
h. New York Heart Association (NYHA) Class III or IV congestive heart failure 
(Section 17.10). 
i. Known LVEF ≤50% or institutional lower limit of normal. 
 As an exception, subjects with newly diagnosed AML between 18 and 74 
years old (inclusive) in Part 2 Cohort 2 with LVEF ≤50% or institutional 
lower limit of normal will be eligible. 
j. Known DLCO ≤65% or FEV1 ≤65%. 
 As an exception, subjects with newly diagnosed AML between 18 and 74 
years old (inclusive) in Part 2 Cohort 2 with DLCO ≤65% or FEV1 ≤65% 
will be eligible. 
k. Uncontrolled hypertension. 
l. Left bundle branch block. 
5. Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals. 


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6. Has known human immunodeficiency virus infection that is uncontrolled (increasing 
plasma HIV RNA viral load) with medication, or active hepatitis B or C infection based 
on positive tests during Screening. 
7. Persistent, clinically significant >Grade 1 non-hematologic toxicity from prior AML 
therapies. 
8. Pregnant or breast feeding. 
9. Receiving drugs that are strong inducers of CYP3A or consumption of St John’s Wort 
(hypericin) within 14 days prior to the first dose and during treatment. 
10. Received anti-AML therapy (except for hydroxyurea) within the following washout 
periods before starting study medication: 
 Seven days OR 5 half-lives, whichever is longer, for small molecule drugs. 
 Twenty-one days OR 5 half-lives, whichever is shorter, for antibody-based, 
immune-based, biologic, or cellular therapies. 
11. Has received allogeneic hematopoietic cell transplantation (HCT) within 60 days of the 
first dose of study drugs. 
12. Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation of 
systemic treatment or systemic treatment escalation within 21 days prior to Screening 
and/or >Grade 1 persistent or clinically significant non-hematologic toxicity related to 
HCT. 
13. Medical condition, serious intercurrent illness, or other circumstance that, in the 
Investigator’s judgment, could jeopardize the candidate’s safety as a study subject, or that 
could interfere with study objectives. 
14. Prior treatment with MDM2 inhibitors. 
Additional exclusion criterion for the Part 2 Cohort 1 subgroup of 12 subjects for the DDI 
substudy 
15. Receiving drugs that are strong CYP3A inhibitors within 7 days OR 5 terminal half-lives, 
whichever is longer, prior to the first dose and until completion of 2 cycles of treatment. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
Both parts of the study are open-label and no blinding will be performed. 
5.2. 
Study Drug(s) 
5.2.1. 
Description 
Quizartinib is a small molecule inhibitor of FLT3.  The drug is supplied as tablets in strengths of 
20 mg quizartinib hydrochloride (17.7 mg free base) and 30 mg quizartinib hydrochloride (26.5 
mg free base) for oral administration. 
Milademetan is a small molecule inhibitor of MDM2-p53 interaction that activates p53 pathway.  
The drug is supplied as capsules in strengths of 5 mg, 20 mg, 30 mg, 45 mg, 80 mg, 100 mg, and 
200 mg for oral administration.  The indicated capsule strengths are equivalent to the amount of 
free base (DS-3032a). 
Milademetan (DS-3032a) is the free base and the active moiety of the salt form (DS-3032b).  
The salt form (DS-3032b) is the active pharmaceutical ingredient of the oral capsule formulation.  
Throughout the remainder of this document, DS-3032a and DS-3032b will be referred to as 
“milademetan” unless indicated otherwise. 
The 2 investigational drugs will be administered in combination as indicated in the dose 
escalation and dose expansion parts of the study.  Quizartinib and milademetan may be 
administered without regard to the timing of food, except as noted for the DDI substudy. 
5.2.2. 
Labeling and Packaging 
Milademetan 5 mg, 20 mg, 80 mg, and 200 mg capsules will be supplied in labeled blister cards 
(wallets), each containing 7 capsules; milademetan 30 mg and 100 mg capsules will be supplied 
in labeled high-density polyethylene (HDPE) bottles with a child-resistant cap, and each bottle 
will contain 35 capsules.  Quizartinib will be supplied in labeled HDPE bottles with a child-
resistant cap and each bottle will contain 30 tablets.  The blister label and the bottle label will 
include all information required by national and local regulations. 
5.2.3. 
Preparation 
Study drug will be provided to sites as fully prepared blister cards (wallets) and bottles.  Blister 
cards (wallets) and bottles will be individually numbered.  Assignment of blister cards (wallets) 
and bottles to subjects will be done via the Interactive Web/Voice Response System (IXRS). 
5.2.4. 
Administration 
Quizartinib will be administered orally qd. 
Milademetan will be administered on Days 1 to 14 of every 28 day cycle.  Alternative dosing 
schedules in 28 day cycles may be used for milademetan (eg, qd 7/28 and qd 3/14 × 2) based on 
emerging safety and efficacy data. 
Quizartinib and milademetan may be administered without regard to the timing of food, except 
in the DDI substudy, where quizartinib and milademetan will be dosed on an empty stomach (no 
food for at least 2 hours pre-dose and 1 hour post-dose) on Cycle 1/Day –1, Cycle 1/Day 28, 


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Cycle 2/Day 1, and Cycle 2/Day 14.  In the DDI substudy, subjects will also be required to fast 
for 2 additional hours post-dose. 
Milademetan and quizartinib administration that occurs at clinic visits will be supervised by a 
member of the site staff. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area under the recommended 
storage conditions.  The required storage conditions are clearly depicted on the drug label. 
If storage conditions are not maintained per specified requirements, Covance or Daiichi Sankyo, 
Inc. (hereinafter referred to as Daiichi Sankyo) should be contacted. 
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, and drug expiration date. 
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment. 
A Drug Accountability Record will be provided for the study drugs milademetan and quizartinib.  
The record must be kept current and should contain the dates and quantities of study drug 
received, subject’s identification number and/or initials or supply number (as applicable) for 
whom the study drug was dispensed, the date and quantity of study drug dispensed and 
remaining, as well as the initials of the dispenser. 
Study drugs will be returned or destroyed locally only after the study monitor has completed a 
final inventory to verify the quantity to be returned.  The return of study drug must be 
documented and the documentation included in the shipment.  At the end of the study, a final 
study drug reconciliation statement for milademetan and quizartinib must be completed by the 
Investigator or designee and provided to the Sponsor.  Unused drug supplies may be destroyed 
by the Investigator when approved in writing by the Sponsor and Sponsor has received copies of 
the study site’s drug handling and disposition standard operating procedures (SOPs) and it is 
assured that the Sponsor will receive copies of the certificate of destruction which is traceable to 
the study drugs.  Destruction of the study drugs at the site is preferred. 
5.3. 
Control Treatment 
This is a single arm study and there is no control treatment. 
5.4. 
Dose Interruptions and Reductions 
Dose interruptions and/or dose reductions are allowed based on safety and clinical benefit.  
QTcF prolongation and non-hematologic toxicities may result in the dose reduction or dose 
interruption of quizartinib and/or milademetan. 
5.4.1. 
Dose Interruptions and Reductions For QTcF Prolongation 
The following dose interruptions and/or reductions will be made for QTcF prolongation: 
 QTcF average of triplicate readings >480 ms to ≤500 ms 


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- Quizartinib dose will be reduced by 1 level without interruption, eg, from 60 mg 
to 40 mg, from 40 mg to 30 mg, and from 30 mg to 20 mg, depending on the dose 
at which the QT prolongation occurred.  If the QTcF prolongation occurs at 20 
mg, then quizartinib will be discontinued. 
 QTcF average of triplicate readings >500 ms 
- Quizartinib dosing will be interrupted for up to 14 days.  If QTcF returns to within 
30 ms of baseline or ≤450 ms within 14 days, treatment may be resumed at a 
reduced dose (eg, from 60 mg to 40 mg, from 40 mg to 30 mg, and from 30 mg to 
20 mg), depending on the dose at which the QT prolongation occurred. 
- If QTcF prolongation is >500 ms and recurs despite appropriate dose reductions 
and correction/elimination of other risk factors (eg, serum electrolyte 
abnormalities, concomitant QT prolonging medication), the subject will be 
permanently discontinued from quizartinib. 
 QTcF >500 ms or >60 ms change from baseline, and signs/symptoms of serious 
arrhythmia, eg, torsade de pointes or monomorphic ventricular tachycardia 
- Quizartinib will be discontinued. 
5.4.1.1. 
Managing QTc Prolongation 
Electrolytes (potassium, calcium, and magnesium) should be checked and supplementation given 
to correct any values outside the normal range. 
Concomitant medications should be reviewed to identify and, if appropriate, discontinue any 
medication with known QT prolonging effects. 
Subjects who experience >480 ms QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved. 
5.4.1.2. 
Managing Electrolyte Abnormalities 
Electrolytes, including potassium, calcium and magnesium, must be within normal limits prior to 
the commencement of each cycle. 
Hypokalemia should be managed with oral or IV potassium supplementation, as clinically 
indicated, and serial potassium level monitoring should be performed until potassium levels 
normalize.  Serum potassium should be maintained between 3.5 mEq/L to 5.0 mEq/L (3.5 
mmol/L to 5.0 mmol/L). 
Appropriate management should include reduction of serum electrolyte losses, replacement of 
electrolyte stores, and evaluation and treatment of associated toxicities.  If possible, the 
underlying cause of hypokalemia should be investigated to prevent further episodes.  
Electrocardiograms should be monitored and magnesium should be replaced if there is 
concomitant hypomagnesemia.  Serum magnesium should be maintained between 1.5 mEq/L to 
2.5 mEq/L (0.75 mmol/L to 1.25 mmol/L) and total serum calcium should be maintained 
between 8.5 mg/dL to 10.2 mg/dL (2.18 mmol/L to 2.58 mmol/L). 


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If Grade 3 hypokalemia occurs (potassium <3.0 mmol/L to 2.5 mmol/L), IV potassium 
replacement, close subject follow-up, continuous ECG monitoring, and serial potassium levels 
every 2 to 4 hours until recovery to Grade 1 (<lower limit of normal to 3.0 mmol/L) should be 
considered. 
5.4.1.3. 
Managing Nausea and Vomiting 
Established nausea and vomiting should be managed to the fullest extent possible.  Acceptable 
non-QT-prolonging agents such as aprepitant, metoclopramide, fosaprepitant, and droperidol can 
be administered.18 
5.4.2. 
Dose Interruptions and Reductions For Non-hematologic Toxicities 
The following guidelines should be followed for subjects who develop a Grade 3 or 4 non-
hematologic toxicity that is at least possibly related to study drug(s) and persisting >48 hours 
without improvement to ≤Grade 2 or without waiting 48 hours if in the Investigators judgment 
the AE poses a serious risk to the subject: 
 Dosing will be interrupted for up to 28 days. 
- If toxicity improves to ≤Grade 1 within 28 days, treatment may be resumed at the 
previous dose. 
- If toxicity improves to Grade 2 within 28 days, treatment may be resumed at a 
reduced dose (1 level below) for milademetan and/or quizartinib only after the 
toxicity has resolved to <Grade 2 (Grade 1 or less).  Optionally for milademetan, 
the Investigator after consultation with the Sponsor Medical Monitor may reduce 
the dose frequency (eg, 10/28 days, or 7/28 days, or 3/14 days × 2) in Cycle 2 or 
subsequent cycles while maintaining the same daily dose of milademetan. 
- If toxicity does not improve/resolve within 28 days, then treatment may be 
discontinued after discussion between the Investigator and Sponsor Medical 
Monitor. 
5.4.3. 
Dose Interruptions and Reductions for Hematologic Toxicities 
Active monitoring and appropriate treatment should be employed for neutropenia and 
thrombocytopenia.  For myelosuppression not related to underlying AML (ANC <0.5 × 109/L 
and/or platelet count <50 × 109/L): 
 If toxicities persist, the Investigator should discuss with the Sponsor prior to any 
additional dose reductions of either quizartinib or milademetan. 
 Reduce the dose of milademetan by 1 level. 
 For milademetan, the Investigator should consult with the Sponsor Medical Monitor: 
 Reduce the dose frequency (eg, 10/28 days, or 7/28 days, or 3/14 days × 2) while 
keeping the same dose level, OR 
 Reduce the dose of milademetan by 1 dose level while keeping the same dosing 
schedule 


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When the subject is no longer myelosuppressed, both study drugs may be resumed at the 
previous dose and/or dosing schedule. 
5.4.4. 
Dose Reductions With Concomitant Administration of a Strong CYP3A 
Inhibitor 
The following dose reductions will be performed with the concomitant administration of a strong 
CYP3A inhibitor: 
 Quizartinib: 
- 60 mg dose will be reduced to 30 mg 
- 30 mg and 40 mg doses will be reduced to 20 mg 
 Consequently, quizartinib 30 mg lead-in to 60 mg will be reduced to a 20 
mg lead-in to 30 mg 
 Milademetan: 
- Dose will be reduced to half of the prescribed dose (ie, 90-mg, 120-mg, and 160-
mg doses of milademetan will be reduced to 45 mg, 60 mg, and 80 mg, 
respectively) 
Resumption of regularly scheduled doses of quizartinib and milademetan after discontinuation of 
strong CYP3A inhibitor should be as follows: 
 Quizartinib:  Resume regularly scheduled dose the day following discontinuation 
 Milademetan:  Resume regularly scheduled dose after a 3-day washout period following 
discontinuation 
5.5. 
Method of Assessing Treatment Compliance 
The following measures will be employed to ensure treatment compliance during dosing at the 
clinical site: 
 Milademetan and quizartinib dispensed only to subjects participating in the study and 
complying with the instructions from the clinical study personnel. 
 In regions where at-home dosing of study drugs is required, milademetan and 
quizartinib may be dispensed in amounts exceeding the minimum amount required 
for the period of time until the next visit.  Subjects will be instructed to bring back to 
the site all unused milademetan and quizartinib at the next visit.  Alternatively, to 
ensure compliance, the site personnel may choose to dispense only the adequate 
amount of study drug required until the next scheduled visit.  Compliance with the 
study drug regimen will be determined by counting unused capsules returned and 
reviewing the pill diary provided to the subjects to fill in. 
 Milademetan and quizartinib administration that occurs at clinic visits will be 
supervised by a member of the site staff. 


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5.6. 
Prior and Concomitant Medications 
5.6.1. 
Prior Medication 
All non-cancer medications received by subjects within 30 days prior to Screening will be 
recorded as prior medications. 
All anti-cancer medications that the subject received at any point, irrespective of the time relative 
to screening, will be recorded from the medical history. 
5.6.2. 
Concomitant Medication (Drugs and Therapies) 
Concomitant medications and therapies include all prescription, over-the-counter, and herbal 
remedies. 
Information on concomitant medications will be collected from the time of informed consent 
through 30 days after the last dose of study treatment (does not apply to the allogeneic HCT 
period until the subject is able to return to the site).  Data collected will include medication 
name, indication, dose, start date, and stop date. 
Concomitant use of non-anticancer medications that are not inducers of CYP3A are allowed 
(refer to Section 17.6). 
Concomitant use of anticancer medications, and drugs, herbs or fruits that are strong inducers of 
CYP3A are prohibited.  Grapefruit/grapefruit juice and Seville oranges are prohibited 7 days 
before the first dose of study drug and during treatment.  St John’s Wort (hypericin) will not be 
permitted for 14 days prior to the first dose and during treatment. 
Concomitant medications that prolong the QT/QTc interval are prohibited (refer to Section 17.6).  
Exceptions are made for antibiotics and antifungals that are used as standard of care for the 
prevention or treatment of infections or if the Investigator believes that beginning therapy with a 
potentially QTc-prolonging medication is vital to an individual subject’s care while on study. 
Proton pump inhibitors and other gastric pH modifiers should be avoided, except locally acting 
antacids that can be administered in the window of 2 hours before or after quizartinib and 
milademetan administration. 
Hydroxyurea is permitted for control of leukocytosis during Screening, but should be 
discontinued 48 hours prior to start of study treatment.  However, hydroxyurea can be re-started 
in Cycle 1 as clinically necessary up to a maximum of 8 days and up to a maximum dose of 5 
g/day. If there is a clinical need to administer hydroxyurea for longer than 8 days or beyond 
Cycle 1 that should be discussed between the Investigator and Sponsor Medical Monitor. 
5.7. 
Discontinuation 
A subject may discontinue from study drug treatment, but may agree to receive long-term 
follow-up phone calls. 
5.7.1. 
Study Drug Discontinuation 
The following reasons are considered sufficient to discontinue a subject from study drug 
treatment: 
 AE 


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 Death 
 PD or relapse which meets protocol-defined response criteria (Section 17.4) 
 Clinical PD or relapse based on Investigator’s judgement 
 Allogeneic HCT 
 Pregnancy 
 Protocol deviation 
 Lost to follow-up 
 Withdrawal by subject’s decision 
 Other (the reason should be discussed between the Investigator and Sponsor Medical 
Monitor, and should be recorded on the case report form [CRF]) 
All subjects discontinued from study treatment due to any reason other than withdrawal of 
consent for follow-up will undergo assessment at follow-up visits. 
If the subject discontinues study treatment due to an AE, the Investigator will follow the subject 
until the AE has resolved or stabilized, or until the subject is available for follow-up. 
Response criteria-met or clinical PD/relapse is considered a sufficient reason to discontinue 
study drug treatment; however, the Investigator may continue the subject on study drug treatment 
until the Investigator has determined alternative AML therapies and considers the study drug 
treatment to be no longer beneficial to the subject.  The decision to discontinue a subject from 
study drug treatment remains the responsibility of the Investigator and should not be delayed or 
refused by the Sponsor. 
When one of the study drugs is discontinued due to toxicities, Investigators may continue the 
other study drug if this is considered to be safe and in the best interest of the subject after 
consultation with the Sponsor Medical Monitor. 
5.7.2. 
Study Discontinuation 
If a subject is withdrawn from the study (eg, has completed the 30-day safety window and 
withdrawn consent for receiving long-term follow-up, or has proceeded to next treatment 
regimen), the Investigator will complete and report the observations as thoroughly as possible up 
to the date of withdrawal, including the date of last treatment and the reason for withdrawal. 
All subjects who are withdrawn from the study should complete protocol-specified withdrawal 
procedures. 
Subjects may be withdrawn from the study at any time after signing the Informed Consent Form 
(ICF) for the following reasons: 
 Withdrawal by subject’s decision 
 Death 
 PD or relapse 
 Lost to follow-up 


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 Other (the reason should be specified on the CRF) 
5.7.3. 
Subject Replacement 
For a subject to be considered evaluable for DLT, the subject must have received at least 75% of 
the prescribed Cycle 1 doses and completed safety assessments of the DLT evaluation period or 
experienced a DLT in this period.  Subjects who are unable to complete at least 75% of 
prescribed Cycle 1 doses of milademetan and quizartinib or unable to be evaluated for safety 
during the DLT evaluation period as a result of unequivocal progression of disease or non-
compliance may be replaced. 
In both Part 1 and Part 2, subjects with a known record of FLT3-ITD mutant AML within the 
last 30 days from informed consent based on local testing can enroll in the study.  However, 
FLT3-ITD status will be tested in a central laboratory for confirmation of eligibility and any 
results indicating absence of FLT3-ITD will be communicated to the Investigator for possible 
discontinuation of the subject from study participation if ongoing clinical benefit is not observed.  
Subjects in Part 2 who do not show confirmation of FLT3-ITD mutation by central laboratory 
testing will be replaced.  However, those who are deriving clinical benefit may be allowed to 
continue treatment. 
5.7.4. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet eligibility criteria upon initial 
screening.  The subject identification number must remain the same at the time of re-screening.  
The initial screening information and the reason why the subject is ineligible for the initial 
evaluation will be recorded on the Screening Log.  If the subject successfully repeats the failed 
initial screening assessment(s) within the 14-day Screening period, the subject may be enrolled.  
No other data from the initial screening will be entered into the clinical database for a subject 
who is re-screened.  If performing an echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan is not possible during screening, an LVEF value from an ECHO/MUGA 
performed within 60 days before the first dose of study drugs can be used for eligibility 
determination if no changes in cardiac conditions were observed based on the Investigator’s 
clinical assessment. 


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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in the Schedule of Events tables (Section 
17.3).  Throughout the treatment period, serum pregnancy tests are to be done as indicated for 
women of childbearing potential.  Depending on the study site’s region (eg, US), study drugs and 
a pill diary may be dispensed for at-home study drug dosing, as noted in the study procedures 
and in the Schedule of Events tables. 
6.1. 
Screening 
6.1.1. 
Part 1 (Dose Escalation) and Part 2 (Dose Expansion), Screening (Pre-cycle) 
The screening (Pre-cycle) period occurs within 14 days prior to starting study therapy for Part 1 
and Part 2 (except subjects in the DDI substudy) and within 15 days prior to starting study 
therapy for Part 2 (DDI substudy).  The following procedures will be performed during the Part 1 
and Part 2 screening periods: 
 Obtain written (ie, signed and dated) informed consent. 
 Assign a subject identifier number. 
 Record demographic, medical history information including AML and antecedent 
hematologic disorder, and prior AML therapy history (ie, best response, relapse date). 
 Perform a complete physical examination and record weight and height. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratories (hematology and serum chemistry). 
 Obtain blood sample for testing active hepatitis B or C infection. 
 Obtain blood sample for testing FLT3 mutation. 
 Obtain a serum sample for pregnancy testing in women of childbearing potential. 
 Obtain an FSH test in women of childbearing potential to confirm menarche. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Measure LVEF by either ECHO or MUGA. 
 Record prior (within 30 days of consent) and current medications. 
 Transfusion history (type, date of transfusion, number of units) for the 56 days prior 
to first dose date of study drugs (first day exclusive). 
 Assess subjects for AEs. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 
 Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual). 


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 Complete the Inclusion/Exclusion Criteria Form for subject registration. 
- The Sponsor (and/or Contract Research Organization [CRO]) will perform 
registration after verifying that the subject meets the inclusion/exclusion criteria 
(Sections 4.1 and 4.2) provided by the Investigator.  If the Sponsor has any 
questions regarding the information sent by the Investigator, he or she will 
immediately contact the Investigator to check the details.  Directly after 
registration, the Sponsor will forward the results of registration to the 
Investigator. 
- The Investigator must not prescribe or administer the study drug until the subject 
has completed registration.  If the Sponsor disqualifies a subject from 
participation in the clinical study, the Investigator will be notified.  The 
Investigator will then explain this outcome to the relevant subject. 
6.2. 
Randomization 
Not applicable. 
6.3. 
Treatment Period 
6.3.1. 
Part 1 (Dose Escalation) 
Unless otherwise stated, an activity occurs before study drug administration. 
6.3.1.1. 
Part 1 (Dose Escalation), Cycle 1/Day 1 
The following procedures will be completed pre-dose during the Part 1, Cycle 1/Day 1 visit.  If 
the Screening visit for Part 1 is completed within 24 hours of Cycle 1/Day 1, the assessments 
need not be repeated, with the exception of ECOG Performance Status Scale, vital signs, and 12-
lead ECG.  Blood samples for safety laboratory tests need not be collected if previously collected 
within 72 hours of Cycle 1/Day 1. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 


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 Assess subjects for AEs. 
 Obtain a buccal swab or saliva for pharmacogenomics (PGx). 
 Informed consent specifically allowing PGx testing sample storage must be 
obtained before collecting sample. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
The following procedures will be completed post-dose during the Part 1, Cycle 1/Day 1 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature) at 3 hours (± 10 minutes) post-dose. 
 Perform a 12-lead ECG in triplicate at 1, 2, 4, and 6 hours post-dose as indicated in 
ECG manual.  Subject should be in supine position for 5 minutes prior to each 
reading. 
 Obtain a blood sample for PK measurements at the following timepoints:  0.5, 1, 2, 3, 
4, and 6-8 hours post-dose as indicated in Section 8. 
6.3.1.2. 
Part 1 (Dose Escalation), Cycle 1/Day 2 
The following procedures will be performed pre-dose during the Part 1, Cycle 1/Day 2 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Obtain a blood sample for PK measurements. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense a pill diary with dose administration instructions (for at-home dosing, if 
regionally required). 


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6.3.1.3. 
Part 1 (Dose Escalation), Cycle 1/Day 8 
The following procedures will be performed pre-dose during the Part 1, Cycle 1/Day 8 visit (± 2 
days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Obtain a blood sample for PK measurements. 
 Obtain a blood sample for banking plasma. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol.  (Not administered if subject is in the qd 7/28 
or qd 3/14 × 2 schedule). 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required).  (Not 
dispensed if subject is in the qd 7/28 or qd 3/14 × 2 schedule). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.1.4. 
Part 1 (Dose Escalation), Cycle 1/Day 14 
The following procedures will be completed pre-dose during the Part 1, Cycle 1/Day 14 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for serum MIC-1 analysis. 


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 Obtain a blood sample for PK measurements. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol.  (Not administered if subject is in the qd 7/28 
or qd 3/14 × 2 schedule). 
 Administer quizartinib per protocol. 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 1, Cycle 1/Day 14 visit: 
 Perform a 12-lead ECG in triplicate at 1, 2, 4, and 6 hours post-dose as indicated in 
ECG manual.  Subject should be in supine position for 5 minutes prior to each 
reading. 
 Obtain a blood sample for PK measurements at the following timepoints:  0.5, 1, 2, 3, 
4, and 6-8 hours post-dose as indicated in Section 8. 
 For 60 mg quizartinib cohorts, determine whether the QTcF allows for escalating the 
quizartinib dose to 60 mg for Day 15 onwards. 
6.3.1.5. 
Part 1 (Dose Escalation), Cycle 1/Day 15 
The following procedures will be completed pre-dose during the Part 1, Cycle 1/Day 15 visit: 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Administer milademetan per protocol if subject is in the qd 3/14 × 2 dosing schedule. 
The following procedures will be completed post-dose during the Part 1, Cycle 1/Day 15 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 


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 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense milademetan per protocol if subject is in the qd 3/14 × 2 dosing schedule. 
6.3.1.6. 
Part 1 (Dose Escalation), Cycle 1/Day 22 
The following procedures will be completed pre-dose during the Part 1, Cycle 1/Day 22 visit (± 
2 days): 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for serum MIC-1 analysis. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 1, Cycle 1/Day 22 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.1.7. 
Part 1 (Dose Escalation), Cycle 2/Day 1 
The following procedures will be completed pre-dose during the Part 1, Cycle 2/Day 1 visit (± 2 
days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 


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 Obtain a blood sample for PK measurements. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 
 Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual).  
Additionally, submission of bone marrow samples for MRD analysis is required if 
<5% blasts in bone marrow is observed. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 1, Cycle 2/Day 1 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.1.8. 
Part 1 (Dose Escalation), Cycle 2/Day 8 
The following procedures will be completed pre-dose during the Part 1, Cycle 2/Day 8 visit (± 2 
days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 


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 Assess subjects for AEs. 
 Administer milademetan per protocol if subject is in the qd 14/28 dosing schedule. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required) if subject is 
in the qd 14/28 dosing schedule. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.1.9. 
Part 1 (Dose Escalation), Cycle 2/Day 15 
The following procedures will be completed pre-dose during the Part 1, Cycle 2/Day 15 visit (± 
2 days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Administer milademetan per protocol if subject is in the qd 3/14 × 2 dosing schedule. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense milademetan per protocol if subject is in the qd 3/14 × 2 dosing schedule. 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.1.10. Part 1 (Dose Escalation), Cycle 2/Day 22 
The following procedures will be completed pre-dose during the Part 1, Cycle 2/Day 22 visit (± 
2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 


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 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.1.11. Part 1 (Dose Escalation), Cycle 3/Day 1 
The following procedures will be completed pre-dose during the Part 1, Cycle 3/Day 1 visit (± 4 
days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a serum sample for pregnancy testing in women of childbearing potential. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 
 Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual).  
Additionally, submission of bone marrow samples for MRD analysis is required if 
<5% blasts in bone marrow is observed. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 


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 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 1, Cycle 3/Day 1 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.1.12. Part 1 (Dose Escalation), Cycle 3/Days 8, 15, and 22 
The following procedures will be completed pre-dose during the Part 1, Cycle 3/Days 8, 15, and 
22 visits (± 4 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol only on Part 1, Cycle 3/Day 8 visit if subject is 
in the qd 14/28 dosing schedule and only on Part 1, Cycle 3/Day 15 visit if subject is 
in qd 3/14 × 2 dosing schedule (no administration of milademetan for subjects in the 
qd 7/28 dosing schedule). 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required) only on Part 
1, Cycle 3/Day 8 visit if subject is in the qd 14/28 dosing schedule and only on Part 1, 
Cycle 3/Day 15 visit if subject is in the qd 3/14 × 2 dosing schedule (no dispensing of 
milademetan for subjects in the qd 7/28 dosing schedule). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.1.13. Part 1 (Dose Escalation), Day 1 of Cycle 4 and All Subsequent Cycles 
The following procedures will be performed pre-dose during the Part 1, Cycle 4/Day 1 (± 4 
days), and all subsequent cycles on Day 1 (± 4 days): 


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 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry).  
In subjects who develop gastrointestinal (GI) AEs, such as vomiting and diarrhea of 
Grade ≥2, blood chemistry and 12-lead ECGs will be assessed weekly or more 
frequently as clinically needed until the GI AEs and electrolyte abnormalities are 
resolved to Grade ≤1.  In subjects with potassium, calcium, and magnesium Grade 
≥1, blood chemistry and 12-lead ECGs will be assessed twice a week. 
 Obtain a serum sample for pregnancy testing in women of childbearing potential on 
Day 1 of every 3 cycles from Cycle 3 (ie, Cycles 6, 9, 12, etc). 
 Perform a 12-lead ECG in triplicate up to Part 1, Cycle 6/Day 1 after subject has been 
in supine position for 5 minutes prior. 
 Obtain blood samples for PK measurements up to Part 1, Cycle 6/Day 1. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests 
(see details in Section 7.1.1 and instructions in the Laboratory Manual): 
 If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1 (eg, CR on Cycle 
3/Day 1), then bone marrow biopsies/aspirates will be not required on Cycle 
4/Day 1. 
o Perform bone marrow biopsies/aspirates on Day 1 of Cycles 6, 9, and 12 if 
subject remains in CR, CRi, or MLFS. 
o If subject remains in CR, CRi, or MLFS on Cycle 12/Day 1, bone marrow 
biopsies/aspirates will be required at Day 1 of Cycles 18, 24, and every 6 
cycles thereafter. 
 If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1(eg, PR on 
Cycle 3/Day 1), then bone marrow biopsies/aspirates will be required on 
Cycle 4/Day 1 and on Day 1 of every cycle thereafter until subject achieves CR, 
CRi, or MLFS. 
 Unscheduled bone marrow biopsies/aspirates can be performed whenever 
clinically indicated. 
Note:  Submission of bone marrow specimens beyond Cycle 3/Day 1 is required at the 
following visits (see details in Section 7.1.1.1 and instructions in the Laboratory Manual): 
 Bone marrow samples on Day 1 of Cycles 6, 9, 12, 18, 24, and every 6 cycles 
thereafter. 
 Bone marrow sample from unscheduled bone marrow biopsies/aspirates when 
disease progression (relapse or progressive disease) is suspected. 


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 Additionally, submission of bone marrow samples for MRD analysis (eg, flow 
cytometry and/or next generation sequencing) is required on the day when <5% 
blasts in bone marrow is observed and/or at the subsequent timepoints for bone 
marrow sample collection. 
 Bone marrow samples from other timepoints are not required to be submitted (eg, 
Cycle 4/Day1). 
 Obtain blood samples for plasma and exploratory biomarkers analyses (every 3 cycles 
after Cycle 3). 
 Obtain a blood sample for banking plasma (every 3 cycles after Cycle 2). 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 1, Cycles 4 to 6 on Day 1: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose up to Part 1, Cycle 6/Day 1 
as indicated in ECG manual.  Subject should be in supine position for 5 minutes prior 
to each reading. 
 Obtain blood samples for PK measurements at 3 hours post-dose up to Part 1, Cycle 
6/Day 1 as indicated in Section 8. 
6.3.2. 
Treatment Period, Part 2 (Dose Expansion), Except Subjects in the DDI 
Substudy 
Unless otherwise stated, an activity occurs before study drug administration. 
Note:  Electrolytes, including potassium, calcium, and magnesium, must be within normal limits 
prior to the commencement of each cycle. 
6.3.2.1. 
Part 2 (Dose Expansion), Cycle 1/Day 1 
The following procedures will be completed pre-dose during the Part 2, Cycle 1/Day 1 visit.  If 
the Screening visit for Part 2 is completed within 24 hours of Cycle 1/Day 1, the assessments 
need not be repeated, with the exception of ECOG Performance Status Scale, vital signs, and 12-
lead ECG.  Blood samples for safety laboratory tests need not be collected if previously collected 
within 72 hours of Cycle 1/Day 1. 
 Perform a complete physical examination and record weight. 


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 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Obtain a buccal swab or saliva for PGx. 
 Informed consent specifically allowing PGx testing sample storage must be 
obtained before collecting sample. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 1 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature) at 3 hours (± 10 minutes) post-dose. 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain blood samples for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.2.2. 
Part 2 (Dose Expansion), Cycle 1/Day 2 
The following procedures will be performed pre-dose during the Part 2, Cycle 1/Day 2 visits. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for serum MIC-1 analysis. 


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 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense a pill diary with dose administration instructions (for at-home dosing, if 
regionally required). 
6.3.2.3. 
Part 2 (Dose Expansion), Cycle 1/Day 8 
The following procedures will be performed pre-dose during the Part 2, Cycle 1/Day 8 visits (± 2 
days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 8 visits: 


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 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.2.4. 
Part 2 (Dose Expansion), Cycle 1/Day 14 
The following procedures will be completed pre-dose during the Part 2, Cycle 1/Day 14 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 14 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.2.5. 
Part 2 (Dose Expansion), Cycle 1/Day 15 
The following procedures will be completed pre-dose during the Part 2, Cycle 1/Day 15 visit: 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 


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 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Administer milademetan per protocol if subject is in the qd 3/14 × 2 dosing schedule. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 15 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense milademetan per protocol if subject is in the qd 3/14 × 2 dosing schedule. 
6.3.2.6. 
Part 2 (Dose Expansion), Cycle 1/Day 22 
The following procedures will be completed pre-dose during the Part 2, Cycle 1/Day 22 visit (± 
2 days): 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 22 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 


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6.3.2.7. 
Part 2 (Dose Expansion), Cycle 2/Day 1 
The following procedures will be completed pre-dose during the Part 2, Cycle 2/Day 1 visit (± 2 
days): 
 Perform a complete physical examination and record weight. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 
o Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual).  
Additionally, submission of bone marrow samples for MRD analysis is required if 
<5% blasts in bone marrow is observed. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 2/Day 1 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 


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6.3.2.8. 
Part 2 (Dose Expansion), Cycle 2/Days 8, 15, and 22 
The following procedures will be completed pre-dose during the Part 2, Cycle 2/Days 8, 15, and 
22 visits (± 2 days): 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol on only Part 2, Cycle 2/Day 8 visit, or (if 
subject is in the qd 3/14 × 2 dosing schedule) on Part 2, Cycle 2/Day 15 visit. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required) on only Part 
2, Cycle 2/Day 8 visit, or (if subject is in the qd 3/14 × 2 dosing schedule) on Part 2, 
Cycle 2/Day 15 visit. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 2/Days 8, 15, and 
22 visits: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.2.9. 
Part 2 (Dose Expansion), Cycle 3/Day 1 
The following procedures will be completed pre-dose during the Part 2, Cycle 3/Day 1 visit (± 4 
days): 
 Perform a complete physical examination and record weight. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 


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 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a serum sample for pregnancy testing in women of childbearing potential. 
 Obtain a blood sample for PK measurements. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 
o Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual).  
Additionally, submission of bone marrow samples for MRD analysis is required if 
<5% blasts in bone marrow is observed. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 3/Day 1 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.2.10. Part 2 (Dose Expansion), Cycle 3/Days 8, 15, and 22 
The following procedures will be completed pre-dose during the Part 2, Cycle 3/Days 8, 15, and 
22 visits (± 4 days): 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 


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 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol on only Part 2, Cycle 3/Day 8 visit, or (if 
subject is in the qd 3/14 × 2 dosing schedule) on Part 2, Cycle 3/Day 15 visit. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required) on only Part 
2, Cycle 3/Day 8 visit, or (if subject is in the qd 3/14 × 2 dosing schedule) on Part 2, 
Cycle 3/Day 15 visit. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 3/Days 8, 15, and 
22 visits: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.2.11. Part 2 (Dose Expansion), Day 1 of Cycle 4 and All Subsequent Cycles 
The following procedures will be performed pre-dose during the Part 2, Cycle 4/Day 1 visit (± 4 
days), and all subsequent cycles on Day 1 visits (± 4 days): 
 Perform a complete physical examination and record weight. 
 Perform a 12-lead ECG in triplicate up to Part 2, Cycle 6/Day 1 after subject has been 
in supine position for 5 minutes prior. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry).  
In subjects who develop GI AEs, such as vomiting and diarrhea of Grade ≥2, blood 
chemistry and 12-lead ECGs will be assessed weekly or more frequently as clinically 
needed until the GI AEs and electrolyte abnormalities are resolved to Grade ≤1.  In 
subjects with potassium, calcium, and magnesium Grade ≥1, blood chemistry and 12-
lead ECGs will be assessed twice a week. 
 Obtain a serum sample for pregnancy testing in women of childbearing potential on 
Day 1 of every 3 cycles from Cycle 3 (ie, Cycles 6, 9, 12, etc). 
 Obtain a blood sample for PK measurements up to Part 2, Cycle 6/Day 1. 


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 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests 
(see details in Section 7.1.1 and instructions in the Laboratory Manual): 
 If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1 (eg, CR on Cycle 
3/Day 1), then bone marrow biopsies/aspirates will be not required on Cycle 
4/Day 1. 
o Perform bone marrow biopsies/aspirates on Day 1 of Cycles 6, 9, and 12 if 
subject remains in CR, CRi, or MLFS. 
o If subject remains in CR, CRi, or MLFS on Cycle 12/Day 1, bone marrow 
biopsies/aspirates will be required at Day 1 of Cycles 18, 24, and every 6 
cycles thereafter. 
 If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1(eg, PR on 
Cycle 3/Day 1), then bone marrow biopsies/aspirates will be required on 
Cycle 4/Day 1 and on Day 1 of every cycle thereafter until subject achieves CR, 
CRi, or MLFS. 
 Unscheduled bone marrow biopsies/aspirates can be performed whenever 
clinically indicated. 
Note:  Submission of bone marrow specimens beyond Cycle 3/Day 1 is required at the 
following visits (see details in Section 7.1.1.1 and instructions in the Laboratory Manual): 
 Bone marrow samples on Day 1 of Cycles 6, 9, 12, 18, 24, and every 6 cycles 
thereafter. 
 Bone marrow sample from unscheduled bone marrow biopsies/aspirates when 
disease progression (relapse or progressive disease) is suspected. 
 Additionally, submission of bone marrow samples for MRD analysis (eg, flow 
cytometry and/or next generation sequencing) is required on the day when <5% 
blasts in bone marrow is observed and/or at the subsequent timepoints for bone 
marrow sample collection. 
 Bone marrow samples from other timepoints are not required to be submitted (eg, 
Cycle 4/Day1). 
 Obtain blood samples for exploratory biomarkers.  Sample for biomarker assessment 
is every 3 cycles after Cycle 3. 
 Obtain a blood sample for banking plasma (every 3 cycles after Cycle 2). 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 


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 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycles 4 to 6 on Day 1: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose up to Part 2, Cycle 6/Day 1 
as indicated in ECG manual.  Subject should be in supine position for 5 minutes prior 
to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose up to Part 2, Cycle 
6/Day 1 as indicated in Section 8. 
6.3.3. 
Treatment Period, Part 2 (Dose Expansion), Subjects in the DDI Substudy 
Unless otherwise stated, an activity occurs before study drug administration. 
6.3.3.1. 
Part 2 (Dose Expansion DDI Substudy), Pre-cycle/Day −2 
The following procedures will be completed during the Part 2 DDI substudy, Pre-cycle/Day −2 
visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Perform a 12-lead ECG in triplicate at 0, 1, 2, 4, and 6 hours approximately time-
matched with Day –1 measurements as indicated in ECG manual.  Subject should be 
in supine position for 5 minutes prior to each reading. 
6.3.3.2. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day −1 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day −1 visit.  If the Screening visit for Part 2 is completed within 72 hours of Cycle 1/Day −1, 
blood samples for safety laboratory tests need not be collected.  Study medication will be 
administered on an empty stomach (no food for at least 2 hours pre-dose): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 


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 Obtain a blood sample for serum MIC-1 analysis. 
 Obtain a blood sample for banking plasma. 
 Obtain blood samples for exploratory biomarkers. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Obtain a buccal swab or saliva for PGx. 
 Informed consent specifically allowing PGx testing sample storage must be 
obtained before collecting sample. 
 Administer milademetan per protocol. 
 Subjects must fast for 2 hours post-dose. 
The following procedures will be completed post-dose during the Part 2 DDI substudy, Cycle 
1/Day −1 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature) at 3 hours (± 10 minutes) post-dose. 
 Perform a 12-lead ECG in triplicate at 1, 2, 4, and 6 hours post-dose as indicated in 
ECG manual.  Subject should be in supine position for 5 minutes prior to each 
reading. 
 Obtain blood samples for PK measurements at the following timepoints:  0.5, 1, 2, 3, 
4, 6, and 8 hours post-dose as indicated in Section 8.  Blood samples should be 
collected within 10 minutes after corresponding ECG measurements. 
6.3.3.3. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 1 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day 1 visit.  If the safety assessments were completed on Cycle 1/Day −1, they need not be 
repeated for Cycle 1/Day 1, except for PK and ECGs and vital signs. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 


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The following procedures will be completed post-dose during the Part 2 DDI substudy, Cycle 
1/Day 1 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature) at 3 hours (± 10 minutes) post-dose. 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.3.4. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 2 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day 2 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense a pill diary with dose administration instructions (for at-home dosing, if 
regionally required). 
6.3.3.5. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 8 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day 8 visit (± 2 days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 


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 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Obtain a blood sample for banking plasma. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.3.6. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 14 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day 14 visit (± 2 days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 


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 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 14 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.3.7. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 15 
The following procedures will be completed pre-dose during the Part 2, Cycle 1/Day 15 visit: 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 15 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
6.3.3.8. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 22 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day 22 visit (± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 


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 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 1/Day 22 visit: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose. 
6.3.3.9. 
Part 2 (Dose Expansion DDI Substudy), Cycle 1/Day 28 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
1/Day 28 visit.  Study medication will be administered on an empty stomach (no food for at least 
2 hours pre-dose): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Subjects must fast for 2 hours post-dose. 
 Dispense and review pill diary and assess treatment compliance. 
The following procedures will be completed post-dose during the Part 2 DDI substudy, Cycle 
1/Day 28 visit: 
 Perform a 12-lead ECG in triplicate at 1, 2, 4, and 6 hours post-dose as indicated in 
ECG manual.  Subject should be in supine position for 5 minutes prior to each 
reading. 
 Obtain a blood sample for PK measurements at the following timepoints:  0.5, 1, 2, 3, 
4, 6, and 8 hours post-dose as indicated in Section 8. 


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6.3.3.10. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 1 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
2/Day 1 visit.  Study medication will be administered on an empty stomach (no food for at least 
2 hours pre-dose): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 
 Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual).  
Additionally, submission of bone marrow samples for MRD analysis is required if 
<5% blasts in bone marrow is observed. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for serum MIC-1 analysis. 
 Obtain a blood sample for banking plasma. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Subjects must fast for 2 hours post-dose of both study drugs. 
The following procedures will be completed post-dose during the Part 2 DDI substudy, Cycle 
2/Day 1 visit: 
 Perform a 12-lead ECG in triplicate at 1, 2, 4, and 6 hours post-dose as indicated in 
ECG manual.  Subject should be in supine position for 5 minutes prior to each 
reading. 
 Obtain a blood sample for PK measurements at the following timepoints:  0.5, 1, 2, 3, 
4, 6, and 8 hours post-dose as indicated in Section 8. 


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6.3.3.11. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 2 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
2/Day 2 visits: 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain blood samples for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other).  
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense/review pill diary (for at-home dosing, if regionally required). 
6.3.3.12. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 8 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
2/Day 8 visits (± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain blood samples for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Review pill diary and assess treatment compliance (for at-home dosing, if regionally 
required). 


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6.3.3.13. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 14 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
2/Day 14 visit.  Study medication will be administered on an empty stomach (no food for at least 
2 hours pre-dose): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Subjects must fast for 2 hours post-dose of both study drugs. 
 Review and dispense pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2 DDI substudy, Cycle 
2/Day 14 visit: 
 Perform a 12-lead ECG in triplicate at 1, 2, 4, and 6 hours post-dose as indicated in 
ECG manual.  Subject should be in supine position for 5 minutes prior to each 
reading. 
 Obtain a blood sample for PK measurements at the following timepoints:  0.5, 1, 2, 3, 
4, 6, and 8 hours post-dose as indicated in Section 8. 
6.3.3.14. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 15 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, 
Cycle 2/Day 15 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 


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 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense pill diary and assess treatment compliance (for at-home dosing, if regionally 
required). 
6.3.3.15. Part 2 (Dose Expansion DDI Substudy), Cycle 2/Day 22 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, 
Cycle 2/Day 22 visit (± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer quizartinib per protocol. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense pill diary and assess treatment compliance (for at-home dosing, if regionally 
required). 
6.3.3.16. Part 2 (Dose Expansion DDI Substudy), Cycle 3/Day 1 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
3/Day 1 visit (± 4 days): 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a serum sample for pregnancy testing in women of childbearing potential. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests. 


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 Note:  Submission of bone marrow specimens is required for biomarker tests (see 
details in Section 7.1.1.1 and instructions in the Laboratory Manual).  
Additionally, submission of bone marrow samples for MRD analysis is required if 
<5% blasts in bone marrow is observed. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 3/Day 1: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 
6.3.3.17. Part 2 (Dose Expansion DDI Substudy), Cycle 3/Days 8, 15, and 22 
The following procedures will be completed pre-dose during the Part 2 DDI substudy, Cycle 
3/Days 8, 15, and 22 visits: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol on only Part 2, Cycle 3/Day 8 visit. 
 Administer quizartinib per protocol. 


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 Dispense milademetan per protocol (to take home, if regionally required) on only Part 
2, Cycle 3/Day 8 visit. 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Review and dispense pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
6.3.3.18. Part 2 (Dose Expansion DDI Substudy), Day 1 of Cycle 4 and All Subsequent 
Cycles 
The following procedures will be completed pre-dose during the Part 2 DDI substudy on Cycle 
4/Day 1 (± 4 days) and all subsequent Cycles/Day 1 (± 4 days) visits: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry).  
In subjects who develop GI AEs, such as vomiting and diarrhea of Grade ≥2, blood 
chemistry and 12-lead ECGs will be assessed weekly or more frequently as clinically 
needed until the GI AEs and electrolyte abnormalities are resolved to Grade ≤1.  In 
subjects with potassium, calcium, and magnesium Grade ≥1, blood chemistry and 12-
lead ECGs will be assessed twice a week. 
 Obtain a serum sample for pregnancy testing in women of childbearing potential on 
Day 1 of every 3 cycles from Cycle 3 (ie, Cycles 6, 9, 12, etc). 
 Perform a 12-lead ECG in triplicate (up to Cycle 6/Day 1) after subject has been in 
supine position for 5 minutes prior. 
 Obtain blood samples for exploratory biomarkers.  Sample for biomarker assessment 
is every 2 cycles after Cycle 2. 
 Obtain a blood sample for banking plasma (every 2 cycles after Cycle 4). 
 Obtain bone marrow biopsies/aspirates for disease assessment and biomarker tests 
(see details in Section 7.1.1 and instructions in the Laboratory Manual): 
 If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1 (eg, CR on Cycle 
3/Day 1), then bone marrow biopsies/aspirates will be not required on Cycle 
4/Day 1. 
o Perform bone marrow biopsies/aspirates on Day 1 of Cycles 6, 9, and 12 if 
subject remains in CR, CRi, or MLFS. 
o If subject remains in CR, CRi, or MLFS on Cycle 12/Day 1, bone marrow 
biopsies/aspirates will be required at Day 1 of Cycles 18, 24, and every 6 
cycles thereafter. 


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 If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1(eg, PR on 
Cycle 3/Day 1), then bone marrow biopsies/aspirates will be required on 
Cycle 4/Day 1 and on Day 1 of every cycle thereafter until subject achieves CR, 
CRi, or MLFS. 
 Unscheduled bone marrow biopsies/aspirates can be performed whenever 
clinically indicated. 
Note:  Submission of bone marrow specimens beyond Cycle 3/Day 1 is required at the 
following visits (see details in Section 7.1.1.1 and instructions in the Laboratory Manual): 
 Bone marrow samples on Day 1 of Cycles 6, 9, 12, 18, 24, and every 6 cycles 
thereafter. 
 Bone marrow sample from unscheduled bone marrow biopsies/aspirates when 
disease progression (relapse or progressive disease) is suspected. 
 Additionally, submission of bone marrow samples for MRD analysis (eg, flow 
cytometry and/or next generation sequencing) is required on the day when <5% 
blasts in bone marrow is observed and/or at the subsequent timepoints for bone 
marrow sample collection. 
 Bone marrow samples from other timepoints are not required to be submitted (eg, 
Cycle 4/Day1). 
 Obtain a blood sample for PK measurements (up to Cycle 6/Day 1). 
 Record concomitant medications. 
 Record transfusion (RBC, platelet, other). 
 Assess subjects for AEs. 
 Administer milademetan per protocol. 
 Administer quizartinib per protocol. 
 Dispense milademetan per protocol (to take home, if regionally required). 
 Dispense quizartinib per protocol (to take home, if regionally required). 
 Dispense and review pill diary (for at-home dosing, if regionally required) and assess 
treatment compliance. 
The following procedures will be completed post-dose during the Part 2, Cycle 4/Day 1, and up 
to Part 2, Cycle 6 on Day 1 visits: 
 Perform a 12-lead ECG in triplicate at 3 hours post-dose as indicated in ECG manual.  
Subject should be in supine position for 5 minutes prior to each reading. 
 Obtain a blood sample for PK measurements at 3 hours post-dose as indicated in 
Section 8. 


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6.4. 
End-of-Treatment - Part 1 and Part 2 (Post-cycle) 
The End-of-treatment visit should occur at the earliest day possible within 30 days after the last 
administration of study drug(s), but before beginning any other form of anticancer therapy. 
The following assessments will be performed at this visit: 
 Obtain confirmation of subject’s consent to being contacted for follow-up phase 
(Section 6.5). 
 Perform a complete physical examination and record weight and height. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature). 
 Assess functional status using the ECOG Performance Status Scale. 
 Obtain blood samples for safety laboratory tests (hematology and serum chemistry). 
 Obtain a serum sample for pregnancy testing in women of childbearing potential. 
 Perform a 12-lead ECG in triplicate after subject has been in supine position for 5 
minutes prior. 
 Obtain a blood sample for PK measurements. 
 Obtain blood samples for exploratory biomarkers. 
 Obtain a blood sample for banking plasma. 
 Obtain blood for biomarkers from subjects who achieved an initial CR, CRi, MLFS, 
or PR but later relapsed (after CR or CRi) or developed PD (after MLFS or PR) while 
on therapy. 
 Record concomitant medications. 
 Assess subjects for AEs. 
 Review pill diary and assess treatment compliance. 
 Record reason for treatment discontinuation. 
 Bone marrow re-biopsy and/or aspirate for subjects who achieved an initial CR, CRi, 
MLFS, or PR but later relapsed (after CR or CRi) or developed PD (after MLFS or 
PR) while on therapy (See Section 6.4.1). 
6.4.1. 
End-of-Treatment Bone Marrow Re-biopsy/Aspirate (Part 1 and Part 2) 
To search for possible mechanisms of acquired resistance to milademetan and quizartinib 
combination, a bone marrow re-biopsy or aspirate will be performed in subjects who have 
achieved an initial CR, CRi, MLFS, or PR but later relapse (after CR or CRi) or develop PD 
(after MLFS or PR) while on therapy.  Bone marrow re-biopsy or aspirate would be performed 
within 30 days following the last dose of study drugs, prior to initiating subsequent AML 
therapy. 


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6.5. 
Follow-up Phase – Part 1 and Part 2 
All subjects who discontinued study treatment will enter the Follow-up Phase and will undergo 
the following assessments.  Subjects discontinued from study treatment because of withdrawal of 
consent for follow-up are exempted. 
6.5.1. 
Follow-up 30 Days After End-of-treatment 
The 30-day Follow-up visit should occur 30 (± 5) days after the last administration of study 
drug(s).  Follow-up information will be collected via a phone call or site visit.  The Investigator 
should follow subjects with AEs until the event has resolved or the condition has stabilized.  In 
case of unresolved AEs, including significant abnormal laboratory values at the End-of-treatment 
assessment, these events will be followed up until resolution or until they become clinically not 
relevant. 
The following information will be collected at the 30-day Follow-up visit: 
 
Assessment of AEs. 
 Current medications. 
 Subject survival status. 
 Date and cause of death, if applicable 
 Subsequent AML therapy. 
 HCT and HCT-relevant information, if performed. 
6.5.2. 
Long-term Survival Follow-up 
The Long-term Survival Follow-ups should occur every 3 months (± 2 weeks) after the first 30-
day Follow-up visit until subject death or until the Sponsor terminates the study.  Additionally, 
the most updated survival follow-up status may be collected when the Sponsor performs survival 
analysis (for example, asking for survival status again when a subject had survival follow-up 2 
months prior). 
The following information will be collected, if feasible: 
 Subject survival status. 
 Date and cause of death, if applicable. 
 Subsequent AML therapy. 
 HCT and HCT-relevant information, if performed. 
If direct contacts are not possible or if Long-term Survival Follow-up is not performed due to 
withdrawal of consent, subject refusal to participate in long-term follow-up, or loss to follow-up, 
the site must make every effort to collect survival status from public records (eg, death 
certificates) in accordance with local laws and document as best possible the specific reason for 
inability to collect long-term follow-up data. 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoint(s) 
Efficacy assessments will be based on Investigators’ evaluations of bone marrow, peripheral and 
physical examination or pathological diagnosis of extramedullary disease at Screening and at 
protocol-defined timepoints (eg, Cycle 2/Day 1, etc) while the subject remains on study drug.  
The clinical activity of the treatment will be assessed using 2017 ELN recommendations. 19  The 
percentage of subjects undergoing allogeneic HCT directly following protocol-specified 
treatment with no intervening AML therapy and transfusion independence is based on 
Investigators’ reports.  The response criteria are defined in Section 17.4 and Section 17.5.  The 
efficacy endpoints are listed in Section 2.4.3. 
7.1.1. 
Bone Marrow Biopsies/Aspirates 
An overview of the schedule for bone marrow biopsies/aspirates is presented in Figure 7.1. 
During the first 12 cycles (first year): 
 Bone marrow biopsies/aspirates are mandated on Day 1 of Cycles 2 and 3 for all subjects. 
 If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1 (eg, CR on Cycle 3/Day 1), 
then bone marrow biopsies/aspirates will not be required on Cycle 4/Day 1. 
o Perform bone marrow biopsies/aspirates on Day 1 of Cycles 6, 9, and 12 if subject 
remains in CR, CRi, or MLFS. 
 If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1 (eg, PR on Cycle 
3/Day 1), then bone marrow biopsies/aspirates will be required on Cycle 4/Day 1 and on 
Day 1 of every cycle thereafter until subject achieves CR, CRi, or MLFS. 
 Beyond Cycle 4/Day 1, for subjects who achieve first CR, CRi, or MLFS, perform bone 
marrow biopsies/aspirates on Day 1 of Cycles 6, 9, and 12.  For example: 
o If subject achieves first CRi (without prior MLFS) on Cycle 5/Day 1, perform next 
bone marrow biopsies/aspirates on Cycle 6/Day 1. 
o If subject achieves first CR (without prior CRi or MLFS) on Cycle 7/Day 1, perform 
next bone marrow biopsies/aspirates on Cycle 9/Day 1. 
Beyond 12 cycle (second year or later): 
 If subject remains in CR, CRi, or MLFS on Cycle 12/Day 1, bone marrow 
biopsies/aspirates will be required on Day 1 of Cycles 18, 24, and every 6 cycles 
thereafter. 
Unscheduled bone marrow biopsies/aspirates can be performed whenever clinically indicated.  
All unscheduled bone marrow assessments performed on non-visit days must be reported as 
unscheduled visits. 


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Figure 7.1: 
Schedule for Bone Marrow Biopsies/Aspirates 
 
BM = bone marrow; BMA = bone marrow aspirate; BMB = bone marrow biopsy; CR = complete remission; CRi = 
CR with incomplete blood count recovery; EOT = end of treatment; MLFS = morphologic leukemia-free state; PR = 
partial remission 
7.1.1.1. 
Bone Marrow Samples for Translational Research 
 Bone marrow samples for translational research must be submitted at the following visits: 
o Bone marrow samples at Screening and on Day 1 of Cycles 2, 3, 6, 9, 12, 18, 24, and 
every 6 cycles thereafter. 
o Bone marrow sample from unscheduled bone marrow biopsies/aspirates when disease 
progression (relapse or progressive disease) is suspected. 
o Additionally, submission of bone marrow samples for MRD analysis (eg, flow 
cytometry and/or next generation sequencing) is required on the day when <5% blasts 
in bone marrow is observed and/or at the subsequent timepoints for bone marrow 
sample collection. 
 Bone marrow samples from other timepoints are not required to be submitted (eg, Cycle 
4/Day1). 
Please refer to the Laboratory Manual for additional details and instructions. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
In Part 1, blood samples will be collected for the measurement of plasma concentrations of 
milademetan, quizartinib and AC886 as shown in Table 8.1.  The PK parameters (Cmax and 
AUC24h) will be estimated by non-compartmental analysis.  In addition, blood concentrations of 
quizartinib and AC886 may also be evaluated. 
Table 8.1: 
Intensive PK Sampling (Part 1) 
Cycle 1 
  
Day 1 
Hour Post-dose 
Pre-dosea 
0.5b 
1b 
2b 
3b 
4c 
6-8d 
24c,e 
  
Day 14 
Hour Post-dose 
Pre-dosea 
0.5b 
1b 
2b 
3b 
4c 
6-8d 
24c,e 
a Within 1 hour prior to drug administration. 
b ± 10 min 
c ± 15 min 
d PK sample will be collected between time window of 6 to 8 hours post-dose.  Actual time of sample collection 
must be recorded. 
e The 24-hour timepoint will be collected as pre-dose of the visit on the following day. 
Note:  For PK samples corresponding to ECG measurements, blood samples should be collected within 10 minutes 
after ECG measurements. 
In Part 2 (except subjects in the DDI substudy), sparse PK samples for plasma concentrations of 
milademetan, quizartinib, and AC886 will be collected as shown in Table 8.2.  Please see 
Section 9.9 for details of PK time-matched ECG collection. Blood should be collected within 10 
minutes after ECG measurement. 
Table 8.2: 
Sparse PK Sampling (Part 2) 
Cycle 1/Days 1, 8, 14, 15,c and 22c 
Hour Post-dose 
Pre-dose a,b 
3b 
Cycles 2 to 3/Days 1, 8, 15,c and 22c 
Hour Post-dose 
Pre-dosea,b 
3b 
Cycles 4 to 6/Day 1 
Hour Post-dose 
Pre-dosea,b 
3b 
a Within 1 hour prior to drug administration. 
b ± 10 min. 
c Measurement of quizartinib and AC886 only. 
Note:  For PK samples corresponding to ECG measurements, blood samples should be collected within 10 minutes 
after ECG measurements. 
The effect of quizartinib on milademetan PK and the effect of milademetan on quizartinib PK 
will be studied in a subset of 12 subjects in the dose expansion cohorts.  In this substudy, 
concomitant administration of strong CYP3A inhibitors will be prohibited for the first 2 cycles of 


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treatment.  The substudy will include administration of milademetan alone on Cycle 1/Day −1 
only, quizartinib administered alone (Days 15 to 28) of each cycle and concomitant 
administration of quizartinib and milademetan (Days 1 to 14) of each cycle as shown in 
Figure 8.1.  Pharmacokinetic samples will be collected as shown in Table 8.3.  The PK 
parameters (Cmax and AUC24h) for milademetan, quizartinib, and AC886 will be assessed to 
evaluate the effects of (1) steady-state quizartinib on single dose milademetan PK and (2) 
repeated doses of milademetan on steady-state PK of quizartinib and AC886.  The effect of 
quizartinib on milademetan will be assessed by the comparison of Treatment A:  milademetan 
single dose (C1D−1) to Treatment C:  milademetan single dose + quizartinib multiple dose 
(C2D1).  The effect of milademetan on quizartinib will be assessed by the comparison of 
Treatment B:  quizartinib multiple dose (C1D28) to Treatment D:  quizartinib multiple dose + 
milademetan multiple dose (C2D14).  ECGs will be measured at approximately the same time 
each day starting at Day −2 to capture the circadian rhythm in ECG for an estimate of time-
matched change from baseline in QTcF (ΔΔQTcF).  The timepoints for ECG measurements are 
at pre-dose (or Hour 0), 1, 2, 4 and 6 hours post-dose. 
Figure 8.1: 
PK Substudy Design (Part 2) with Milademetan QD 14/28 Schedule 
 
PK= pharmacokinetics, QD = once daily. 
Table 8.3: 
PK Substudy Timepoints 
Cycle 1 
  
Day −1 (milademetan only) 
Hour Post-dose 
Pre-dosea 
0.5b 
1b 
2b 
3b 
4c 
6c 
8c 
24c 
  
Day 28 (quizartinib, AC886) 
Hour Post-dose 
Pre-dosea 
0.5b 
1b 
2b 
3b 
4c 
6c 
8c 
24c 
Cycle 2 
  
Day 1 (milademetan, quizartinib, AC886) 
Hour Post-dose 
Pre-dosea 
0.5b 
1b 
2b 
3b 
4c 
6c 
8c 
24c 
 
Day 14 (milademetan, quizartinib, AC886) 
Hour Post-dose 
Pre-dosea 
0.5b 
1b 
2b 
3b 
4c 
6c 
8c 
24c 
a Within 1 hour prior to drug administration. 
b  ± 5 min. 
c ± 10 min. 
For PK samples corresponding to ECG measurements, blood samples should be collected within 10 min after ECG 
measurement. 
Cycle 2
Day -2
Day -1
Day 1
Day 14
Day 28
Day 1
Day 14
DS-3032 PK
DS-3032 PK
DS-3032 PK
Quizartinib PK
Quizartinib PK Quizartinib PK
ECG
ECG
ECG
ECG
ECG
DS-3032b dose: QD x 14d
DS-3032b dose: QD x 14 d
Quizartinib dose: QD x 28d 
Quizartinib dose: QD x 28d 
Cycle 1


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See Section 9.9 for details of PK time-matched ECG collection.  Blood should be collected 
within 10 minutes after ECG measurement. 
8.2. 
Biomarkers 
In this study, exploratory biomarker analyses will be used to investigate the effect of the 
quizartinib and milademetan at the molecular and cellular level to determine how changes in the 
markers may relate to exposure and clinical outcomes.  Detailed instructions for the collection, 
handling, shipping and storage of biomarker samples are outlined in the Laboratory Manual. 
8.2.1. 
Pharmacodynamic Assessment(s) 
Pharmacodynamic assessments may include but are not limited to exploratory analysis of 
changes in LSC numbers, FLT3 signaled STAT5 downstream gene expression (eg, Mcl-1, Bcl2, 
c-Myc), and p53 downstream targets (eg, MDM2, MIC-1, PUMA, NOXA, Bax, CXCL12) in 
bone marrow AML or peripheral blood blasts and/or non-leukemic cells by analyzing RNA 
and/or proteins.  Blood samples will be collected to monitor the changes in expression of 
pharmacodynamic biomarkers such as MIC-1 (and others).  In subjects experiencing reduction of 
blasts in bone marrow to <5%, MRD may be monitored.  In addition, mutations in TP53, FLT3, 
or other genes that may be present at baseline and occur during the course of treatment and/or at 
remission may be analyzed in bone marrow, peripheral blood, or circulating tumor DNA as 
exploratory evaluations. 
8.2.2. 
Biomarkers for Subject Selection 
Subjects with a known record of FLT3-ITD mutant AML based on local testing can enroll in the 
study and start to receive the treatment.  However, the FLT3 status will be tested again in a 
central laboratory for confirmation of FLT3-ITD mutation.  If the FLT3-ITD mutation is not 
detected in the centralized testing, the Investigator will discuss the results with the subject and 
the subject can decide to continue the study if deriving clinical benefit, or choose to discontinue 
the study participation. 
Several publications reported the mutual exclusivity between TP53 mutations and FLT3/ITD 
mutations in AML,20,21,22 and thus most of FLT3-ITD mutant AML may be TP53 wild type.  
Therefore, confirmation of TP53 wild type status is not required prior to starting the study 
treatment. 
TP53 genotypes will be analyzed retrospectively at the end of the study, to confirm the TP53 
mutation status.  In addition, the mutation status of other genes that are involved in disease and 
disease progression may be monitored.  DNA isolated from non-malignant cells (including 
buccal swab or saliva samples) will be used as a control for these mutation analyses. 
8.2.3. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, exploratory research may be 
conducted on the AML samples.  These studies would extend the search for other potential 
biomarkers related to the effects of quizartinib and milademetan on AML and/or the resistance to 
the treatment.  This may include the development of ways to detect, monitor or treat AML.  
These additional investigations would be dependent upon clinical outcome, reagent, and sample 
availability.  These biomarkers may be analyzed from various samples, including bone marrow 
or peripheral blood cells, and plasma or serum samples. 


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8.3. 
Immunogenicity 
No specific immunogenicity testing has been planned for the study drugs. 
8.4. 
Pharmacogenomic Analysis 
As part of this study, a buccal swab or saliva sample will be banked for possible future PGx 
analysis in germline DNA.  In addition, this DNA may be used as a control to understand the 
differences between germline and tumor DNA. 
In all parts of the study, on Day 1 of Cycle 1 prior to study drug administration (Day −1 for the 
DDI substudy subjects), a buccal swab or saliva sample must be collected from subjects.  This 
sample will be processed to isolate genomic DNA and analyzed only for genes suspected to 
contribute to the safety and efficacy of the study drugs (milademetan and quizartinib) or as 
control samples for the molecular analysis of the leukemic cells. 
Results will provide information on how individuals metabolize and/or react to the study drug or 
help to identify subjects who are more likely or less likely to benefit from the study drug.  The 
information may be useful in increasing the knowledge of differences among individuals in the 
way they metabolize the study drug, as well as helping in the development of new drugs or 
improvement of existing drugs. 
Because emerging information regarding the safety and efficacy of milademetan and quizartinib 
may become available in the future, samples will be retained for possible future analysis.  
Samples will be retained until the DNA has been exhausted or until the Sponsor instructs the 
genotyping contractor to destroy the sample (in accordance with laboratory procedures).  During 
the period of storage, the DNA sample will not be immortalized or sold to anyone.  Subjects will 
have the right to withdraw consent to their participation in the clinical study and may request to 
have their unused PGx sample destroyed at any time. 
To ensure subject confidentiality, sample tubes will be identified only by a barcode label.  This 
barcode will be linked to the subject’s identifier number. 
Please refer to the Laboratory Manual for instructions for sample collection, preparation, 
handling, storage, and shipment. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 9.2.1 for definitions) occurring after the subject signs the ICF and 
up to 30 (± 5) days after the last dose of study medication (ie, the follow-up period), whether 
observed by the Investigator or reported by the subject, will be recorded on the Adverse Event 
Case Report Form page.  Medical conditions (including laboratory values/vital signs that are out 
of range) that were diagnosed or known to exist prior to informed consent will be recorded as 
part of medical history. 
All AEs, SAEs, and AEs of special interest (AESIs) are to be reported according to the 
procedures in Section 9.4. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study drug discontinuation, dose reduction, require corrective 
treatment, or constitute an AE in the Investigator’s clinical judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by evaluating the 
subject.  Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit.  Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms.  The Investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.2.  The Investigator’s assessment must be clearly documented in the site’s source 
documentation. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for pre-existing conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.2.2 for definitions). 
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Disease progression is a study endpoint and, consequently, should not be reported as an 
AE/SAE.  However, when a subject dies from disease progression with no other immediate 
causes, “disease progression” should be reported as an SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an SAE. 


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9.2. 
Adverse Event 
9.2.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (International Conference on 
Harmonisation [ICH] E2A Guideline.  Clinical Safety Data Management:  Definitions and 
Standards for Expedited Reporting, October 1994).23 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 
9.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note:  The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting, October 1994).23 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  Examples include 
allergic bronchospasm, convulsions, and blood dyscrasias or development of drug dependency or 
drug abuse. 
Note: 
 Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE. 
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 


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9.2.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE.24 
 Grade 1 Mild AE 
 Grade 2 Moderate AE 
 Grade 3 Severe AE 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to AE 
Severity vs. Seriousness:  Severity is used to describe the intensity of a specific event while the 
event itself, however, may be of relatively minor medical significance (such as severe headache).  
This is not the same as "seriousness," which is based on subject/event outcome at the time of the 
event.  For example, the NCI-CTCAE Grade 4 (life-threatening consequences; urgent 
intervention indicated) is assessed based on unique clinical descriptions of severity for each AE, 
and these criteria may be different from those used for the assessment of AE seriousness. An AE 
assessed as Grade 4 based on the NCI-CTCAE grades may or may not be assessed as serious 
based on the seriousness criteria. 
9.2.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drugs on the 
basis of his/her clinical judgment and the following definitions.  The causality assessment must 
be made based on the available information and can be updated as new information becomes 
available. 
 Related: 
- The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
- The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
 Not Related: 
- The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications). 
9.2.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed:  No change in study drug dosage was made. 
 Drug Withdrawn:  The study drug was permanently stopped. 
 Dose Reduced:  The dosage of study drug was reduced. 


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 Drug Interrupted:  The study drug was temporarily stopped. 
 Not Applicable:  Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
9.2.6. 
Other Action Taken for Event 
 None. 
- No treatment was required. 
 Medication required. 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 Other. 
9.2.7. 
Adverse Event Outcome 
 Recovered/Resolved 
- The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
- The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved 
- The AE itself is still present and observable. 
 Recovered/Resolved with Sequelae 
- The residual effects of the AE are still present and observable. 
- Include sequelae/residual effects. 
 Fatal 
- Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
9.3. 
Adverse Events of Special Interest 
9.3.1. 
QTc Prolongation, Torsades de Pointes, and Other Ventricular Arrhythmias 
Subjects who experience >480 ms QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved, as 
described in Section 5.4.1. 
QTcF prolongation ≥Grade 3, either serious or non-serious and whether or not causally related, 
must be recorded as AE or SAE in the Electronic Data Capture (EDC) system within 24 hours of 
awareness of the central ECG laboratory reading, with the Investigator’s assessment of 
seriousness, causality, and a detailed narrative.24 


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9.3.2. 
Concurrent Elevations of Aminotransferases and Bilirubin 
Concurrent elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of ALT or AST ≥3 × ULN with 
simultaneous total bilirubin ≥2 × ULN should always be recorded as an AE or SAE within 24 
hours of awareness, with the Investigator’s assessment of seriousness, causality, and a detailed 
narrative.24 
Subjects will be monitored as described in Section 17.1. 
9.4. 
Safety Reporting Procedure For Investigators 
All AEs, including SAEs, and Events of Special Interest will be reported in EDC. 
The following types of events should be reported by the Investigator in EDC within 24 hours of 
awareness: 
 SAEs (see Section 9.2.2 for definition) 
 QTcF prolongation ≥Grade 3, either serious or non-serious and whether or not 
causally related (see Section 5.4.1 for additional monitoring details) 
 Hepatic events meeting combination abnormalities [ALT or AST ≥3 × ULN with 
simultaneous total bilirubin ≥2 × ULN], both serious and non-serious and whether or 
not causally related (see Section 5.4.2 for additional monitoring details) 
All events (serious and non-serious) must be reported with Investigator’s assessment of the 
event’s seriousness, severity, and causality to the study drug.  A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided.  
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative.  For fatal events, the narrative should state 
whether an autopsy was or will be performed, and include the results if available.  Source 
documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
See Section 15.10.1.4 for contact information for SAE reporting.  Please call the local SAE 
Hotline (see Study Manual) or your study monitor for any questions on SAE reporting. 
9.5. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators, Institutional Review Boards/Ethics 
Committees (IRBs/ECs), and regulatory authorities of any Suspected Unexpected Serious 
Adverse Reactions (SUSARs) occurring in other study sites or other studies of the 
investigational drug, as appropriate per local reporting requirements.  Daiichi Sankyo and/or 
CRO will comply with any additional local safety reporting requirements. 


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In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to inform the IRB per 
Sponsor’s instruction. 
9.6. 
Exposure In Utero During Clinical Studies 
Women of childbearing potential must have negative serum pregnancy test results at times 
specified in the Schedule of Events (Section 17.3).  If required by local regulations, additional 
pregnancy tests will be performed.  Serum pregnancy tests will be performed at the local 
laboratory. 
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or within 
6 months of discontinuing the study drug. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  This information is important for both drug safety and public health 
concerns.  It is the responsibility of the Investigator, or designee, to report any pregnancy in a 
female subject using the Exposure In Utero (EIU) Reporting form.  Please contact your study 
monitor to receive the EIU Reporting Form upon learning of a pregnancy.  The Investigator 
should make every effort to follow the subject until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  The adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as a SAE (ie, post-partum complications, spontaneous or 
induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted 
fetus), the Investigator should follow the procedures for reporting SAEs outlined in Section 9.4. 
9.7. 
Clinical Laboratory Evaluations 
The following items will be measured.  For clinical laboratory parameters, the reference range of 
the institution that performs the measurements will be used. 
Information will be entered in the CRF on whether measured, date of measurement, and 
measurement results for the following items: 
1. Hematology tests 
Red blood cell count, Hgb, hematocrit, white blood cell count, differential white blood 
cell count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelet 
count. 
2. Serum chemistry tests 
Total protein, albumin, albumin/globulin ratio, total bilirubin, direct bilirubin, AST, 
ALT, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, 
creatine kinase, blood urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, 
calcium, phosphorus, magnesium, total cholesterol, triglycerides, glucose, and C-
reactive protein. 


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9.8. 
Vital Signs 
Blood pressure and pulse rate will be measured after the subject has rested in a recumbent 
position for 5 minutes or more. 
Information will be entered in the CRF on whether or not measured, date of measurement, and 
measurement results for the following items: 
Systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, body temperature, 
height, and body weight.  Height needs to be collected only at Screening and End-of-treatment. 
9.9. 
Electrocardiograms 
Triplicate 12-lead ECGs (3 separate ECGs) will be obtained at the times specified in the study 
schedule (Section 17.3).  This will be performed after the subject has rested in a recumbent 
position for at least 5 minutes.  Additional ECGs may be taken at the Investigator’s discretion.  
The triplicate ECGs will be read in a central ECG laboratory, but the ECGs will also be reviewed 
by a suitably qualified physician at the study site to allow immediate decisions about subject 
safety.  The clinical significance of any ECG change must be assessed by the Investigator in the 
context of the subject’s medical history, physical examination, and concomitant medications.  
Whether or not measurement was performed, date performed, results, and findings will be 
recorded in the CRF. 
In Part 1 and Part 2 (excluding DDI substudy) pharmacokinetic time-matched ECG will be 
collected at pre-dose and 3 hours post-dose on Cycle 1/Days 1, 15, and 22, and then on Day 1 of 
Cycles to 2 to 6. 
In Part 2 (DDI substudy) pharmacokinetic time-matched ECG will be at 0, 1, 2, 4, and 6 hours on 
Cycle 1/Day −2 for baseline; pre-dose and 1, 2, 4, and 6 hours post-dose on Cycle 1/Days −1 and 
28, Cycle 2/Days 1 and 14).  Pharmacokinetic time-matched ECGs will be collected at pre-dose 
and 3 hours post-dose on Days 14, 15, and 22 of Cycle 1 and Day 1 of Cycles 3 to 6. 
9.10. 
Physical Examinations 
A complete physical examination (including ECOG performance status) will be performed at 
Screening to establish a baseline for study entry, and at additional times specified in the study 
schedule (Section 17.3). Whenever possible, the same individual will perform subsequent 
examinations to identify changes from baseline.  Symptom-directed physical examinations 
performed during the treatment period will be based on the subject’s medical history and AEs, 
and will include weight determination and a review of body systems. 
9.11. 
Other Examinations 
Not applicable. 


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10. 
OTHER ASSESSMENTS 
Not applicable. 


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11. 
STATISTICAL METHODS 
11.1. 
General Statistical Considerations 
The primary objective of this study is to assess the safety and tolerability of milademetan in 
combination with quizartinib and establish RDE in subjects with FLT3-ITD mutant AML. 
Final data analysis for the clinical study report will occur at the end of the study when all 
subjects have either completed the End-of-study Follow-up or discontinued from the study or 
have received at least 6 months of therapy.  However, the ongoing subjects deriving clinical 
benefit may continue to receive the treatment. 
Descriptive statistics will be provided for selected demographic, safety, efficacy, PK, and 
available exploratory pharmacodynamic data from both dose escalation and dose expansion by 
dose cohort and visit as appropriate.  Descriptive statistics on continuous data will include 
means, medians, standard deviations, minimum and maximum (as well as geometric means and 
geometric coefficient of variation for Cmax and AUC24h), while categorical data will be 
summarized using frequency counts and percentages.  Graphical summaries of the data may be 
presented. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
non-missing value of a variable taken before the first dose of study drug will be used as the 
baseline value, unless otherwise specified.  In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified. 
Safety analyses will be performed based on the Safety Analysis Set.  Analysis of PK parameters 
will be based on the PK Analysis Set.  Efficacy endpoints will be analyzed based on the Full 
Analysis Set.  Data will be summarized overall (combining subjects treated at the RDE in the 
dose escalation and dose expansion). 
A detailed Statistical Analysis Plan (SAP) describing the methodology to be used in the final 
analysis will be prepared and finalized before database lock.  Statistical methods described 
within this document may be changed based on advances in research. 
11.2. 
Analysis Sets 
The following analysis sets will be defined in this study. 
 Enrolled Analysis Set will include all subjects who sign the ICF. 
 Safety Analysis Set (and Full Analysis Set) will include all subjects who received at 
least 1 dose of milademetan or quizartinib. 
 DLT Evaluable Set will include all subjects enrolled in the dose escalation who had a 
DLT within Cycle 1 (28 days) on the study, or without DLT but received at least 75% 
scheduled dose of milademetan and quizartinib and completed the Cycle 1 evaluation. 
 PK Analysis Set will include all subjects in the Safety Analysis Set who have 
sufficient plasma concentration data to characterize PK profile. 


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11.3. 
Study Population Data 
Disposition and reasons for ending the treatment and discontinuing from the study will be 
summarized and listed for subjects in the Full Analysis Set. 
Demographic and baseline characteristics such as age, sex, race, baseline ECOG performance 
status, histology, cancer stage, best response to prior chemotherapy, lines of prior regimens, and 
prior treatment type will be summarized for the Enrolled Analysis Set, Full Analysis Set, and 
Safety Analysis Set.  If 2 analysis sets within a part of the study are identical to each other, the 
table will be presented only once. 
Study drug exposure, treatment duration, and compliance with study therapy will be summarized 
using descriptive statistics for the Safety Analysis Set. 
11.4. 
Efficacy Analyses 
The secondary endpoints of efficacy will include the rates of CR, CRi, CRc, MLFS, PR, SD, 
ORR, and DOR, according to Investigator’s assessment (Section 2.4.3, Section 17.4, and 
Section 17.5).  Transplantation rate and transfusion independence will be based on data reported 
by study sites.  Stable disease rate will be summarized when SD has persisted for at least 3 
months.  Additionally, CRh rate will be evaluated separately from the other response criteria.  
The efficacy endpoints will be listed and summarized using descriptive statistics based on the 
FAS by dose cohort for dose escalation and dose expansion. 
For response rates (CRc, ORR, etc), point estimates and 2-sided 95% exact binomial confidence 
intervals will be provided.  Time to event endpoint (DOR) will be summarized descriptively 
using the Kaplan Meier method. 
11.5. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
11.5.1. 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be performed on the PK Analysis Set.  Plasma concentration-time 
data for milademetan, quizartinib, and AC886 will be listed, plotted, and summarized using 
descriptive statistics by dose cohort at each timepoint. Pharmacokinetic parameters (Cmax, 
AUC24h, time to reach maximum plasma concentration [Tmax], trough plasma concentration 
[Ctrough]) will be calculated for each subject as possible.  The PK parameters will be listed and 
summarized using descriptive statistics by dose cohort and study day. 
In the DDI substudy of 12 subjects in the dose expansion part, Cmax and AUC24h for 
milademetan, quizartinib, and AC886 will be calculated and summarized on Cycle 1/Day −1 
(milademetan only), Cycle 1/Day 28 (quizartinib, and AC886 only), Cycle 2/Day 1, and Cycle 
2/Day 14. 
Effects of quizartinib after repeated doses on single dose milademetan PK (Cmax and AUC24h) 
will be assessed by analysis of variance (ANOVA) model where reference and test treatments for 
milademetan PK will be Cycle 1/Day −1 and Cycle 2/Day 1, respectively.  The effect of 
milademetan after repeated doses on steady-state quizartinib and AC886 PK (Cmax and 
AUC24h) will also be evaluated using an ANOVA model where the reference and test treatments 
for quizartinib and AC886 PK will be Cycle 1/Day 28 and Cycle 2/Day 14, respectively.  The 
PK parameters will be transformed prior to analysis using a natural logarithm-transformation.  


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The 90% confidence intervals for the ratios of the geometric means for the PK parameters (Cmax 
and AUC24h) will be calculated. 
A population PK model may be developed to assess the PK of milademetan and 
quizartinib/AC886.  The relationship between PK and clinical response defined as the key 
primary and secondary endpoints may be assessed.  The population PK and efficacy response 
analyses may be reported separately from the clinical study report. 
11.5.2. 
Pharmacodynamic/Biomarker/Pharmacogenomic Analyses 
AML blasts from bone marrow and peripheral blood for expression of p53 downstream genes 
(eg, MDM2, MIC-1, PUMA, NOXA, Bax, CXCL12), and downstream genes of FLT3 
constitutive signaling (eg, Mcl-1, Bcl2 c-MYC) will be presented descriptively by dose cohort in 
the Safety Analysis Set.  In addition, changes in LSCs and circulating proteins such as MIC-1 
may be presented by dose cohort. 
11.6. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set and subjects will be analyzed 
according to their actual treatment received. Safety endpoints will include TEAEs, SAEs, DLTs, 
physical examination findings (including ECOG performance status), vital sign measurements, 
standard clinical laboratory parameters (serum chemistry and hematology), and ECG parameters 
(including QTcF).  Adverse events and laboratory test results will be graded according to the 
NCI-CTCAE version 5.0. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  In the dose escalation part, the number of DLTs identified in the 
DLT Evaluable Set will be listed by dose cohort. 
11.6.1. 
Adverse Event Analyses 
A TEAE is defined as an AE that emerges during the treatment period (from first dose date until 
30 [± 5] days after the last dosing date), having been absent at pre-treatment; or re-emerges 
during treatment, having been present at baseline but stopped prior to treatment; or worsens in 
severity after starting treatment relative to the pre-treatment state, when the AE is continuous. 
The number and percentage of subjects reporting TEAEs will be tabulated by the worst NCI-
CTCAE grade, system organ class (SOC), and preferred term.  Similarly, the number and 
percentage of subjects reporting treatment-emergent SAEs will be tabulated, as well as 
TEAEs/SAEs considered related to milademetan and/or quizartinib. 
A by-subject AE (including TEAE) data listing will be provided including, but not limited to, 
verbatim term, preferred term, SOC, NCI-CTCAE grade, and relationship to study drug. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from milademetan and/or quizartinib, will be listed. 
11.6.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results and changes from 
baseline by scheduled time of evaluation, including the End-of-treatment visit, maximum post-
treatment value, and minimum post-treatment value. 


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Abnormal laboratory results will be graded according to NCI-CTCAE version 5.0, if applicable, 
and the grade will be presented in a by-subject data listing.  A shift table, presenting by treatment 
cohort the 2-way frequency tabulation for baseline and the worst post-treatment value according 
to the CTCAE grade, will be provided for clinical laboratory tests.  Abnormal clinical laboratory 
test results deemed of clinical significance or of Grade 3 or 4 will be listed. 
11.6.3. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation, including the End-of-treatment visit and the maximum 
and minimum post-treatment values. 
11.6.4. 
Electrocardiogram Analyses 
Electrocardiogram parameters (PR, RR, QRS, QT, and QTcF) will be summarized using 
descriptive statistics for actual values and for changes from baseline by scheduled time of 
evaluation, including the End-of-treatment visit and the maximum post-treatment value.  The 
corrected QT intervals using Fridericia’s formula will be calculated as follows:  QTcF = 
QT/(RR)1/3. 
The incidence of notable ECG changes in maximum absolute QT and QTcF intervals (>450 ms, 
>480 ms, and >500 ms) over all post-treatment evaluations, as well as in QT and QTcF 
maximum changes from baseline (>30 ms and >60 ms) over all post-treatment evaluations will 
be summarized.  A listing of ECG data will be provided. 
11.6.5. 
Other Safety Analyses 
Physical examination findings (including ECOG performance status) will be listed for the Safety 
Analysis Set.  The ECOG performance status will be summarized for the Safety Analysis Set.  A 
shift table, presenting the 2-way frequency tabulation for baseline and post-baseline visits will be 
provided for ECOG performance status. 
11.7. 
Other Endpoint Analyses 
Not applicable. 
11.8. 
Interim Analyses 
No formal interim analysis is planned, except for the assessment of the MTD/RDE after each 
escalation cohort in the dose escalation part. 
11.9. 
Data Monitoring Committee 
Not applicable. 
11.10. 
Sample Size Determination 
The dose escalation part of this study will be guided by a BLRM for dual agent combination and 
governed by the EWOC principle.  Because of the adaptive nature of the dose escalation part of 
the trial, the exact sample size is unknown.  Based on prior assumptions and simulations, the 
sample size is expected to have a median of 21 subjects.  Approximately 24 to 36 DLT-evaluable 
subjects are needed to determine the MTDs and RDE. 


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In the dose expansion part, there are 2 planned cohorts.  Simon 2-stage optimal design will be 
used to implement a futility stop.  Hypotheses regarding the rates (CR/CRi plus MLFS) for the 
combination to be tested are H0:  p <15% and H1:  p >30% with 1-sided alpha = 0.10 and 80% 
power.  At stage 1, a futility analysis will be conducted when Investigator-assessed best response 
from the first 2 cycles of study treatment are available in 19 evaluable subjects.  If CR/CRi plus 
MLFS has been achieved as the best response prior to Cycle 3/Day 1 in less than 4 out of 19 
evaluable subjects, enrollment will be stopped.  Otherwise, the enrollment for stage 2 will be 
completed with an addition of approximately 20 subjects (for a total of 39 subjects evaluable for 
best response in both stage 1 and stage 2).  This futility analysis will be conducted for cohort 1 
(R/R AML) and cohort 2 (newly diagnosed AML), separately.  The sample size for the DDI 
substudy was selected based on practical considerations. 
11.11. 
Statistical Analysis Process 
The clinical study will be analyzed by the Sponsor or its agent/CRO. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, study drug 
exposure, and prior and concomitant medications.  The SAP will also include a description of 
how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, 
Cary, NC 27513). 
11.12. 
Specification of Bayesian Logistic Regression Model With Escalation 
With Overdose Control 
11.12.1. 
Bayesian Logistic Regression Model With Escalation With Overdose Control 
The dose-toxicity relationship using the EWOC principle for single agent will be described by a 
2-parameter BLRM.14 
logit(π(d)) = log(α) + β log(d/d*), α >0, β >0 
where  
 
and π(d) is the probability of a DLT or the DLT rate at dose d.  Doses are rescaled as d/d* with 
the reference dose (d* = 160 mg for milademetan and 60 mg for quizartinib).  As a consequence, 
log(α) is equal to logit(π(d*)) at dose d*.  Note that for a dose equal to zero, the probability of 
toxicity is zero. 
For dual agents, the dual-combination model is defined by 2 logistic single agent models with an 
interaction between 2 agents and the model contains 5 parameters.14  In the 5-parameter model, 2 
parameters (log(α1), log(β1)) characterize 2-parameter BLRM for milademetan, 2 parameters 


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(log(α2), log(β2)) are used for quizartinib BLRM, and the fifth parameter (log-odds-multiplier, η) 
will fit the interaction between milademetan and quizartinib. 
11.12.2. 
Prior Specification for Bayesian Logistic Regression Model Parameters 
The Bayesian approach requires the specification of a prior distribution for the BLRM 
parameters.  A bivariate normal prior for the model parameters (log(α), log(β)) is elicited based 
on prior assumptions about the medians from existing clinical data and confidence intervals for 
the probabilities of a DLT at each dose. 
Prior specification of BLRM parameters (log(α1), log(β1)) for milademetan will based on existing 
DLT data (qd 21/28 dosing schedule) from Study DS3032-A-U102.  The median prior 
probabilities of DLT are computed to be approximately 1% and 19% for 90 mg (starting dose) 
and 160 mg (reference dose), respectively.  Prior credible intervals (obtained from informative 
beta distributions using Study DS3032-A-U102 data) will be used for prior tuning. 
For prior specification of (log(α2), log(β2)) for quizartinib, the median prior probabilities of DLT 
from existing quizartinib studies are estimated to be approximately 5% and 17% for 30 mg 
(starting dose) and 60 mg (reference dose), respectively.  Wide prior credible intervals (obtained 
from minimally informative beta distributions) will be used for prior tuning. 
For the remaining doses, the medians of probability of DLT are assumed to be linear in log-dose 
on the logit-scale.  There was no a priori evidence for interaction between the 2 compounds, but 
considerable uncertainty remained.  The uncertainty was incorporated as follows:  the upper 
97.5% quantile for the odds-multiplier was set to 9 at the combination dose (d1*, d2*) = (160 
mg, 60 mg). From these specifications, the prior for ηallows for synergistic and antagonistic 
interaction between 2 agents. 
Based on the above assumptions, the optimal parameters of the dual-combination BLRM model 
can be estimated using EAST software (version 6.4, Cytel Inc.) with ESCALATE module as 
follows: 
Parameters 
Means 
Standard deviations 
Correlation 
log(α1), log(β1) 
−1.450, 0.954 
0.740, 0.381 
0 
log(α2), log(β2) 
−1.586, 0.673 
0.964, 0.947 
0 
η 
0 
1.121 
 
The parameters may be adjusted based on data from ongoing studies with the same study 
medication. 
11.12.3. 
Escalation With Overdose Control Principle 
Dose recommendation for the next cohort will be based on summaries of the posterior 
probability of the DLT rate for possible combination doses of milademetan (90 mg, 120 mg, 
160  mg qd 14/28) and quizartinib (30 mg, 40 mg, and 60 mg qd 28/28).  After each cohort of 
subjects completes the DLT evaluation during Cycle 1, the posterior distributions of the DLT 
rate are derived for all provisional dose levels based on the BLRM using the DLT outcome data 
from all assessed doses and a prespecified prior distribution for the model parameters.  The 


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posterior probability of the DLT rate in the following 3 intervals at each dose level will be 
calculated and used for dose recommendation for the next cohort according to the EWOC 
principle: 
 [0%, 16%) as the underdosing DLT rate interval 
 [16%, 33%) as the target DLT rate interval 
 [33%, 100%] as the overdosing DLT rate interval 
It is therefore conceivable that the posterior probability of DLT rate for dose recommendation 
may be generated using alternative provisional doses as long as the predicted exposure 
increments are between 30% and 100%. 
The EWOC principle requires that the recommended dose for the next cohort of subjects is the 
one with the highest posterior probability of the DLT rate in the target DLT rate interval of 
[16%, 33%) among all doses fulfilling the overdose control constraint:  there is <25% of 
probability for the overdosing (<25% of probability of DLT rate falling in overdosing DLT rate 
interval [33%, 100%]).  In addition, the mean of the posterior distribution of DLT target rate at 
this dose is ≤25%. 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
12.1. 
Monitoring and Inspections 
The Sponsor or CRO monitor and Regulatory Authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (eg, CRFs, source data, and other pertinent 
documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH Good Clinical Practice (GCP) and local regulations on the conduct of 
clinical research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely.  The frequency of the monitoring visit will vary based on the 
activity at each study site.  The monitor is responsible for inspecting the CRFs and ensuring 
completeness of the study essential documents.  The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the CRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action(s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be selected for 
audit by representatives from the Sponsor.  Audit of study site facilities (eg, pharmacy, drug 
storage areas, laboratories) and review of study-related records will occur in order to evaluate the 
study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  The Investigator should respond to audit findings.  In the event that a Regulatory 
Authority informs the Investigator that it intends to conduct an inspection, the Sponsor shall be 
notified immediately. 
12.2. 
Data Collection 
Daiichi Sankyo or a designee will supply electronic CRFs (eCRFs).  An eCRF must be 
completed for each subject who signs an ICF and undergoes any screening procedure.  If a 
subject is not treated, the reason must be recorded on the eCRF.  All data collected during the 
study will be recorded in this individual, subject-specific eCRF.  Instructions will be provided for 
the completion of the eCRF and any corrections made will be automatically documented via the 
EDC software’s “audit trail.” 
Completion of the eCRF should be kept current to enable the monitor to review the subject’s 
status throughout the course of the study.  All information and other material to be used by 
subjects and investigative staff must use vocabulary and language that are clearly understood.  
The eCRF will be completed, reviewed and signed off or e-signed by the Investigator.  The 
Investigator will sign and date the indicated places on the eCRF via the EDC system’s electronic 
signature.  These signatures will indicate that the Investigator inspected or reviewed the data on 
the eCRF, the data queries, and the site notifications, and agrees with the content. 


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12.3. 
Data Management 
This is an open-label study. 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to the 
CRO.  Data will be vetted both electronically and manually for CRFs and the data will be 
electronically vetted by programmed data rules within the application.  Queries generated by 
rules and raised by reviewers will be generated within the EDC application.  During this review, 
subject data will be checked for consistency, completeness and any apparent discrepancies. To 
resolve any questions arising from the Clinical Data Management review process, eCRFs queries 
will be raised and resolved within the EDC application. 
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA.  All prior cancer therapy and prior or concomitant 
medications entered into the database will be coded by using the World Health Organization 
Drug Dictionary. 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
CRFs will be included on the Signature List. 
Investigators will maintain a confidential Screening Log of all potential study candidates that 
includes limited information of the subjects, date and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, CRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (Trial Master File).  Source 
documents include all recordings and observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study.  These 
records will be retained in a secure file for the period required by the institution or study site 


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policy.  Prior to transfer or destruction of these records, the Sponsor must be notified in writing 
and be given the opportunity to further store such records. 
12.5. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents contained in the Trial Master File include: 
 Subject files containing completed CRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the EC/IRB and the Sponsor. 
 Records related to the study drugs including acknowledgment of receipt at study site, 
accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
All study-related essential documentation will be retained by the Investigator until at least 
2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have lapsed 
since the formal discontinuation of clinical development of the investigational drug.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor.  It is the responsibility of the 
Sponsor to inform the Investigator/institution as to when these documents no longer need to be 
retained. 
Subject's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
No study document should be destroyed without prior written agreement between Sponsor and 
the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify Sponsor in writing of the new responsible 
person and/or the new location. 


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical study 
agreement with Daiichi Sankyo.  This agreement will include the financial information agreed 
upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 


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14. 
PUBLICATION POLICY 
CCI


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
applicable regulatory requirement(s) including the following: 
 European Commission Directive (2001/20/EC Apr 2001) and/or; 
 European Commission Directive (2005/28/EC Apr 2005) and/or; 
 US Food and Drug Administration (FDA) GCP Regulations:  Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March, 1997 
and/or; 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 of 25 November, 2014; 
 Other applicable local regulations. 
15.2. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The Investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
15.3. 
Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive satisfactory answers to their inquiries, and should have adequate time to 
decide whether or not to participate in the study.  The written ICF should be prepared in the local 
language(s) of the potential subject population. 


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In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The consent form and any revision(s) should be 
approved by the EC or IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICF should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject.  The date and time (if applicable) that informed consent was 
given should be recorded on the CRF. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, etc) 
are provided in the Sponsor’s ICF template for the Investigator to prepare the documents to be 
used at his or her study site.  Updates to applicable forms will be communicated via letter from 
the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act.  Also, a separate special consent will be required for Pharmacogenomic 
testing for this protocol. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator’s Brochure, any 
written instructions to be given to the subject, available safety information, subject recruitment 
procedures (eg, advertisements), information about payments and compensation available to the 
subjects, and documentation evidencing the Investigator’s qualifications should be submitted to 
the EC or IRB for ethical review and approval according to local regulations, prior to the study 
start.  The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for reviewing and approving the final clinical study 
report and testifying to the accuracy of the description of the study conduct.  Because the 
Coordinating Investigator should have personal knowledge of the conduct of the study, he or she 
will normally be chosen from among those Investigators who have enrolled and treated at least 1 
subject.  However, where an Investigator has special knowledge of the field or of the trial, the 
Coordinating Investigator can be chosen prior to enrolment of the first subject.  In all cases, the 
Coordinating Investigator must be chosen prior to locking the database. 
The Investigator and/or Sponsor must submit and, where necessary, obtain approval from the EC 
or IRB for all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study site and 
other AE reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation.  If changes to 


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the initial protocol and other relevant study documents are made, this representative will also 
ensure that any revised documents required for submission are submitted to regulatory 
authorities and implementation of these changes happen only after approval by the relevant 
regulatory bodies, as required. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately. 
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the Investigator becomes aware of. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the Regulatory Authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject.  Sponsor must be 
notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion criteria, 
dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at least 1 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB/EC of deviations from the protocol in 
accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 
ECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IEC/IRB.  The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 


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15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the Investigator by Daiichi Sankyo or the CRO.  Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol. 
A local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country.  Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities (please note that this is not applicable in the EU; non-substantial protocol 
amendments may be implemented without IRB/EC and regulatory approval) where appropriate, 
unless immediate implementation of the change is necessary for subject safety. 
15.8. 
Study Termination 
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. Reasons for study termination may 
include, but are not limited to: 
 AEs unknown to date (ie, not previously reported in any similar investigational drug 
study with respect to their nature, severity, and/or duration). 
 Increased frequency and/or severity and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at Check-in as baseline signs and 
symptoms). 
 Medical or ethical reasons affecting the continued performance of the study. 
 Difficulties in the recruitment of subjects. 
 Cancellation of drug development. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.  Reasons for the early 
closure of a study site by the Sponsor or Investigator may include, but are not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/EC 
or local health authorities, the Sponsor's procedures, or GCP guidelines. 
 Inadequate recruitment of subjects by the Investigator. 
15.9. 
Data and Safety Monitoring Board 
Not applicable. 


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15.10. 
Address List 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
regularly updated as necessary. 
15.10.1. 
Sponsor 
Daiichi Sankyo, Inc. 
211 Mount Airy Rd. 
Basking Ridge, NJ 07920, US 
15.10.1.1. # 
 
Senior Director, Global Oncology Research and Development 
15.10.1.2. #Scientist 
 
Senior Director, Global Oncology Research and Development 
15.10.1.3. #!!
 
 
Sr. Clinical Study Manager, Clinical Development Operations 
15.10.1.4. #Safety Contacts 
 
Senior Director, Clinical Safety and Pharmacovigilance 
15.10.1.5. Sponsor#s Biostatistician 
 
Director, Biostatistics and Data Management 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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15.10.2. 
CRO 
Covance 
206 Carnegie Center 
Princeton, NJ 08540-6233, US 
15.10.3. 
EDC Vendor 
Chiltern International Inc 
3147 S. 17th St., Suite 300 
Wilmington, NC 28412, US 
15.10.4. 
IXRS Vendor 
Almac 
25 Fretz Rd 
Souderton, PA 18964, US 
 
15.10.5. 
Central Laboratory 
Covance Laboratory Services 
8211 SciCor Drive 
Indianapolis, IN 46214-2985, US 
PPD
PPD
PPD
PPD


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16. 
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dermatosis.  Orphanet J Rare Dis. 2007; 2:34 
26. Fathi AT, Le L, Hasserjian RP et al.  FLT3 inhibitor-induced neutrophilic dermatosis.  
Blood. 2013; 122(2):239-42. doi: 10.1182/blood-2013-01-478172. Epub 2013 May 17. 
27. Varadarajan N, Boni A, Elder DE et al.  FLT3 inhibitor-associated neutrophilic 
dermatoses. JAMA Dermatol. 2016; 152(4):480-2. doi: 
10.1001/jamadermatol.2015.6121. 
28. Norsworthy KJ, Luo L, Hsu V, et al. FDA Approval Summary: Ivosidenib for Relapsed 
or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation. 
Clin Cancer Res. 2019 Jun 1;25(11):3205-3209. doi: 10.1158/1078-0432.CCR-18-3749. 
Epub 2019 Jan 28. 
29. Clinical Trial Facilitation Group (CTFG) of the European Heads of Medicines Agencies 
(HMA) – Recommendations related to contraception and pregnancy testing (15 Sep 


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2014). Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
30. ECOG-ACRIN Cancer Research Group. Available from: https://ecog-
acrin.org/resources/ecog-performance-status. 
31. American Heart Association. Classes of Heart Failure. Available from: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes
ofHeartFailure_UCM_306328_Article.jsp?appName=MobileApp. 


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17. 
APPENDICES 
17.1. 
Hepatic Events and Liver Enzyme Elevation 
Elevation of liver enzymes that meet the criteria below should be investigated and the cause 
identified when possible: 
 ALT >8 × ULN; or 
 AST or ALT >5 × ULN for more than 2 weeks; or 
 ALT or AST >3 × ULN, but not reaching the limits in the above criteria, in 
combination with clinical symptoms suggestive of hepatitis; or 
 ALT or AST ≥3 × ULN with total bilirubin ≥2 × ULN. 
Once the cause of liver enzyme elevation is identified, remove or treat the contributing cause.  If 
the above criteria are met and the elevation is considered to be related or possibly related to the 
study treatment, then the dosing should be interrupted. 
Liver enzyme level testing will be repeated at least weekly, or more frequently, based on degree 
of hepatic laboratory abnormality.  If the liver enzyme levels return to baseline levels, study drug 
may be resumed at the full dose.  If toxicity does not improve/resolve within 28 days, then the 
study treatment will be discontinued. 
Upon resumption of study drug, if liver enzyme elevations recur, treatment may be resumed at a 
reduced dose of milademetan and/or quizartinib following return enzymes to baseline levels. 
17.1.1. 
Liver Safety Monitoring and Evaluations 
Any subject who temporarily interrupts or permanently discontinues study drug due to confirmed 
liver enzyme abnormalities and/or jaundice in the absence of a known cause, must have an 
evaluation to determine the cause of the event. 
Evaluation may include the following depending on the clinical situation: 
 Medical history and physical exam, including focus on medications and 
substances used:  alcohol, acetaminophen, azole antifungals, change in medication 
dosages, new medications added, over-the-counter medication use, and 
recreational drug use.  Check for change in diet or use of dietary supplements; 
 Abdominal ultrasound; 
 Hepatitis A, B, C, and E screening (anti-hepatitis A virus immunoglobulin M, 
hepatitis B surface antigen, anti-hepatitis C virus plus viral titer, and evaluation 
for Hepatitis E), antinuclear antibody and anti-Smith antibody, cytomegalovirus, 
Epstein Barr virus; 
 Additional evaluations as deemed appropriate by the Investigator to exclude other 
causes of liver enzyme and bilirubin elevations; 
 All laboratory results, including local laboratory reference ranges are to be 
recorded. 


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17.2. 
Sweet’s Syndrome (Acute Febrile Neutrophilic Dermatosis) 
Sweet's syndrome can be idiopathic, malignancy-associated, or drug-induced.25  The incidence of 
drug-induced Sweet’s Syndrome (DISS) following FLT3 inhibitor monotherapy is 
approximately 10% during the treatment period in the setting of R/R AML.26  DISS is unlikely to 
occur in the setting of concurrent cytoreduction with traditional chemotherapy due to suppression 
of terminal differentiation of FLT3-ITD myeloblasts and associated clinical manifestations. 
Diagnostic criteria for DISS include abrupt onset of painful erythematous plaques or nodules, 
pyrexia >38°C, temporal relationship between drug ingestion and clinical presentation, 
temporally-related resolution of lesions after drug withdrawal or treatment with systemic 
corticosteroids, and histopathologic evidence of a dense neutrophilic infiltrate without evidence 
of leukocytoclastic vasculitis.  Cardiac, pulmonary and upper airway neutrophil infiltration can 
present as life-threatening emergencies.25 
The symptoms of neutrophilic dermatosis can generally be managed with systemic corticosteroid 
administration. Other first-line systemic treatments for Sweet's syndrome include potassium 
iodide and colchicine.25  The interruption or discontinuation of quizartinib is usually not 
required26,27 and discussion with the Sponsor Medical Monitor is optional.  However, for 
advanced Grade 3 or 4 toxicities the decision to continue, interrupt or discontinue quizartinib 
therapy must be made by the Investigator based on the individual subject’s condition, taking into 
account the risks and benefits of continuing quizartinib therapy, and in consultation with the 
Sponsor Medical Monitor. 






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f Obtain an FSH test in women of childbearing potential to confirm menarche. 
g At SCR, collect transfusion history for the 56 days prior to first dose of study drugs. 
h Physical examinations, including weight, will be performed on the indicated visit days.  Physical examinations on Cycle 1/Day 1 need not be repeated if 
previously performed within 24 hours before the first dose. 
i Vital sign measurements will include systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, and body temperature.  They will be 
collected on the indicated visits, as well as at 3 hours (± 10 minutes) post-dose on Cycle 1/Day 1. 
j Blood samples for safety laboratories (hematology and serum chemistry) will be collected on indicated visits.  Creatinine clearance will be calculated at the 
SCR visit.  The sample for safety laboratories on Cycle 1/Day 1 need not be collected if previously collected within 72 hours prior to first dose. 
k Electrocardiograms will be performed in triplicate at pre-dose and at 1, 2, 4, and 6 hours post-dose on Cycle 1/Days 1 and 14, and at pre-dose on other 
indicated visit days.  On Days 15 and 22 of Cycle 1 and Day 1 of Cycles 2 to 6, ECGs will also be collected  at 3 hours post-dose.  The ECG should be 
performed within 10 minutes prior to PK sample collection.  Subject should be in supine position for 5 minutes prior to each reading.  Other unscheduled ECGs 
may be performed as clinically indicated. 
l An ECHO/MUGA scan that was performed within 60 days before the first dose of study drugs may be used. 
m BM samples for disease assessment and exploratory biomarkers analysis are required at SCR and pre-dose on Day 1 of Cycles 2 and 3. 
n If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1, then BMBs/BMAs will not be required on Cycle 4/Day 1.  Perform BMBs/BMAs on Day 1 of 
Cycles 6, 9, and 12 if subject remains in CR, CRi, or MLFS.  If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1 (eg, PR on Cycle 3/Day 1), 
BMBs/BMAs will be required on Cycle 4/Day 1, and on Day 1 of every cycle thereafter until subject achieves CR, CRi, or MLFS.  Beyond Cycle 12/Day 1, 
subjects who remain in CR, CRi, or MLFS on Cycle 12/Day 1 will need to undergo BMBs/BMAs on Day 1 of Cycles 18, 24, and every 6 cycles thereafter. All 
unscheduled BM assessments performed on non-visit days must be reported as unscheduled visits. 
o BM samples at Screening and on Day 1 of Cycles 2, 3, 6, 9, 12, 18, 24, and every 6 cycles thereafter will be submitted for translational research.  BM samples 
from unscheduled BMBs/BMAs should be also submitted for translational research when disease progression (relapse or progressive disease) is suspected.  
Additionally, submit BM samples for minimal residual disease analysis (eg, flow cytometry and/or next generation sequencing) on the day when <5% blasts in 
BM is observed and/or at the subsequent timepoints for BM sample collection.  BM samples from other timepoints are not required to be submitted (eg, Cycle 
4/Day1).  Blood for exploratory biomarker analysis will be collected at the indicated timepoints in Cycle 1, and at the same timepoints as BMBs/BMAs in 
subsequent cycles.  Refer to the Laboratory Manual for additional details and instructions. 
p Peripheral blood collected for exploratory analysis of blasts and other pharmacodynamic circulating biomarkers at the indicated timepoints in Cycle 1, Cycle 2, 
and Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) 
and at EOT. 
q Peripheral blood collected for banking plasma for future exploratory molecular analysis of biomarkers at the indicated timepoints in Cycle 1, Cycle 2, and 
Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) and 
at EOT. 
r Serum will be collected from the blood obtained at the indicated timepoints for MIC-1 analysis. 
s Informed consent specifically allowing PGx testing sample storage must be obtained before collecting sample. 
t Quizartinib and milademetan are administered per protocol at the clinical site at the indicated visits without regard to the timing of food.  Quizartinib will be 
dispensed for continuous qd dosing for each 28 day cycle and milademetan will be dispensed for qd dosing for 14 days of each 28-day cycle. 
u PK samples for milademetan, quizartinib, and AC886 are collected at pre-dose and at 0.5, 1, 2, 3, 4, and 6-8 hours post-dose on Cycle 1/Days 1 and 14, and at 
pre-dose on all other indicated visit days.  Please refer to Table 8.1 for collection schedule and other information.  PK samples at pre-dose and 3 hours post-


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dose will be collected on Cycle 1/Days 15 and 22, and on Day 1 of Cycles 2 to 6 with time-matched ECGs (within 10 minutes before the PK sample 
collection). 
v Study drugs and pill diary may be dispensed for at-home dosage, if regionally required. 
w A BM re-biopsy or aspirate must be performed within 30 (± 5) days of the last dose of study drug in subjects who have achieved an initial CR, CRi, MLFS, or 
PR to the treatment but later relapsed/developed PD while on therapy. 
x If feasible, collect subject survival status, date and cause of death (if applicable), subsequent AML therapy, and HCT and HCT-relevant information (if 
performed). 
 






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h Physical examinations, including weight, will be performed on the indicated visit days.  Physical examinations on Cycle 1/Day 1 need not be repeated if 
previously performed within 24 hours before the first dose. 
i Vital sign measurements will include systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, and body temperature.  They will be 
collected on the indicated visits, as well as at 3 hours (± 10 minutes) post-dose on Cycle 1/Day 1. 
j Blood samples for safety laboratories (hematology and serum chemistry) will be collected on indicated visits.  Creatinine clearance will be calculated at the 
SCR visit.  The sample for safety laboratories on Cycle 1/Day 1 need not be collected if previously collected within 72 hours prior to first dose. 
k Electrocardiograms will be performed in triplicate at pre-dose and at 1, 2, 4, and 6 hours post-dose on Cycle 1/Days 1 and 14, and at pre-dose on other 
indicated visit days.  On Days 15 and 22 of Cycle 1 and Day 1 of Cycles 2 to 6, ECGs will also be collected at 3 hours post-dose.  The ECG should be 
performed within 10 minutes prior to PK sample collection.  Subject should be in supine position for 5 minutes prior to each reading.  Other unscheduled ECGs 
may be performed as clinically indicated. 
l An ECHO/MUGA scan that was performed within 60 days before the first dose of study drugs may be used. 
m BM samples for disease assessment and exploratory biomarkers analysis are required at SCR and pre-dose on Day 1 of Cycles 2 and 3. 
n If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1, then BMBs/BMAs will not be required on Cycle 4/Day 1.  Perform BMBs/BMAs on Day 1 of 
Cycles 6, 9, and 12 if subject remains in CR, CRi, or MLFS.  If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1 (eg, PR on Cycle 3/Day 1), 
BMBs/BMAs will be required on Cycle 4/Day 1, and on Day 1 of every cycle thereafter until subject achieves CR, CRi, or MLFS.  Beyond Cycle 12/Day 1, 
subjects who remain in CR, CRi, or MLFS on Cycle 12/Day 1 will need to undergo BMBs/BMAs on Day 1 of Cycles 18, 24, and every 6 cycles thereafter. All 
unscheduled BM assessments performed on non-visit days must be reported as unscheduled visits. 
o BM samples at Screening and on Day 1 of Cycles 2, 3, 6, 9, 12, 18, 24, and every 6 cycles thereafter will be submitted for translational research.  BM samples 
from unscheduled BMBs/BMAs should be also submitted for translational research when disease progression (relapse or progressive disease) is suspected.  
Additionally, submit BM samples for minimal residual disease analysis (eg, flow cytometry and/or next generation sequencing) on the day when <5% blasts in 
BM is observed and/or at the subsequent timepoints for BM sample collection.  BM samples from other timepoints are not required to be submitted (eg, Cycle 
4/Day1).  Blood for exploratory biomarker analysis will be collected at the indicated timepoints in Cycle 1, and at the same timepoints as BMBs/BMAs in 
subsequent cycles.  Refer to the Laboratory Manual for additional details and instructions. 
p Peripheral blood collected for exploratory analysis of blasts and other pharmacodynamic circulating biomarkers at the indicated timepoints in Cycle 1, Cycle 2, 
and Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) 
and at EOT. 
q Peripheral blood collected for banking plasma for future exploratory molecular analysis of biomarkers at the indicated timepoints in Cycle 1, Cycle 2, and 
Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) and 
at EOT. 
r Serum will be collected from the blood obtained at the indicated timepoints for MIC-1 analysis. 
s Informed consent specifically allowing PGx testing sample storage must be obtained before collecting sample. 
t Quizartinib and milademetan are administered per protocol at the clinical site at the indicated visits without regard to the timing of food.  Quizartinib will be 
dispensed for continuous qd dosing for each 28-day cycle and milademetan will be dispensed for qd dosing for 7 days of each 28 day cycle. 
u PK samples for milademetan, quizartinib, and AC886 are collected at pre-dose and at 0.5, 1, 2, 3, 4, and 6-8 hours post-dose on Cycle 1/Days 1 and 14, and at 
pre-dose on all other indicated visit days.  Please refer to Table 8.1 for collection schedule and other information.  PK samples at pre-dose and 3 hours post-
dose will be collected on Cycle 1/Days 15 and 22, and on Day 1 of Cycles 2 to 6 with time-matched ECGs (within 10 minutes before the PK sample 
collection). 
v Study drugs and pill diary may be dispensed for at-home dosage, if regionally required. 


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w A BM re-biopsy or aspirate must be performed within 30 (± 5) days of the last dose of study drug in subjects who have achieved an initial CR, CRi, MLFS, or 
PR to the treatment but later relapsed/developed PD while on therapy. 
x If feasible, collect subject survival status, date and cause of death (if applicable), subsequent AML therapy, and HCT and HCT-relevant information (if 
performed). 
 






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g At SCR, collect transfusion history for the 56 days prior to first dose of study drugs. 
h Physical examinations, including weight, will be performed on the indicated visit days.  Physical examinations on Cycle 1/Day 1 need not be repeated if 
previously performed within 24 hours before the first dose. 
i Vital sign measurements will include systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, and body temperature.  They will be 
collected on the indicated visits, as well as at 3 hours (± 10 minutes) post-dose on Cycle 1/Day 1. 
j Blood samples for safety laboratories (hematology and serum chemistry) will be collected on indicated visits.  Creatinine clearance will be calculated at the 
SCR visit.  The sample for safety laboratories on Cycle 1/Day 1 need not be collected if previously collected within 72 hours prior to first dose. 
k Electrocardiograms will be performed in triplicate at pre-dose and at 1, 2, 4, and 6 hours post-dose on Cycle 1/Days 1 and 14, and at pre-dose on other 
indicated visit days.  On Days 15 and 22 of Cycle 1 and Day 1 of Cycles 2 to 6, ECGs will also be collected at 3 hours post-dose.  The ECG should be 
performed within 10 minutes prior to PK sample collection.  Subject should be in supine position for 5 minutes prior to each reading.  Other unscheduled ECGs 
may be performed as clinically indicated. 
l An ECHO/MUGA scan that was performed within 60 days before the first dose of study drugs may be used. 
m Bone marrow samples for disease assessment and exploratory biomarkers analysis are required at SCR and pre-dose on Day 1 of Cycles 2 and 3. 
n If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1, then BMBs/BMAs will not be required on Cycle 4/Day 1.  Perform BMBs/BMAs on Day 1 of 
Cycles 6, 9, and 12 if subject remains in CR, CRi, or MLFS.  If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1 (eg, PR on Cycle 3/Day 1), 
BMBs/BMAs will be required on Cycle 4/Day 1, and on Day 1 of every cycle thereafter until subject achieves CR, CRi, or MLFS.  Beyond Cycle 12/Day 1, 
subjects who remain in CR, CRi, or MLFS on Cycle 12/Day 1 will need to undergo BMBs/BMAs on Day 1 of Cycles 18, 24, and every 6 cycles thereafter. All 
unscheduled BM assessments performed on non-visit days must be reported as unscheduled visits. 
o BM samples at Screening and on Day 1 of Cycles 2, 3, 6, 9, 12, 18, 24, and every 6 cycles thereafter will be submitted for translational research.  BM samples 
from unscheduled BMBs/BMAs should be also submitted for translational research when disease progression (relapse or progressive disease) is suspected.  
Additionally, submit BM samples for minimal residual disease analysis (eg, flow cytometry and/or next generation sequencing) on the day when <5% blasts in 
BM is observed and/or at the subsequent timepoints for BM sample collection.  BM samples from other timepoints are not required to be submitted (eg, Cycle 
4/Day1).  Blood for exploratory biomarker analysis will be collected at the indicated timepoints in Cycle 1, and at the same timepoints as BMBs/BMAs in 
subsequent cycles.  Refer to the Laboratory Manual for additional details and instructions. 
p Peripheral blood collected for exploratory analysis of blasts and other pharmacodynamic circulating biomarkers at the indicated timepoints in Cycle 1, Cycle 2, 
and Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) 
and at EOT. 
q Peripheral blood collected for banking plasma for future exploratory molecular analysis of biomarkers at the indicated timepoints in Cycle 1, Cycle 2, and 
Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) and 
at EOT. 
r Serum will be collected from the blood obtained at the indicated timepoints for MIC-1 analysis. 
s Informed consent specifically allowing PGx testing sample storage must be obtained before collecting sample. 
t Quizartinib and milademetan are administered per protocol at the clinical site at the indicated visits without regard to the timing of food.  Quizartinib will be 
dispensed for continuous qd dosing for each 28 day cycle and milademetan will be dispensed for qd dosing at home for Days 2 to 3 and Days 16 to 17 of each 
28 day cycle. 
u PK samples for milademetan, quizartinib, and AC886 are collected at pre-dose and at 0.5, 1, 2, 3, 4, and 6-8 hours post-dose on Cycle 1/Days 1 and 14, and at 
pre-dose on all other indicated visit days.  Please refer to Table 8.1 for collection schedule and other information.  PK samples at pre-dose and 3 hours post-


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dose will be collected on Cycle 1/Days 15 and 22, and on Day 1 of Cycles 2 to 6 with time-matched ECGs (within 10 minutes before the PK sample 
collection). 
v Study drugs and pill diary may be dispensed for at-home dosage, if regionally required. 
w A BM re-biopsy or aspirate may be performed within 30 (± 5) days of the last dose of study drug in subjects who have achieved an initial CR, CRi, MLFS, or 
PR to the treatment but later relapsed/developed PD while on therapy. 
x If feasible, collect subject survival status, date and cause of death (if applicable), subsequent AML therapy, and HCT and HCT-relevant information (if 
performed). 
 






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b End-of-treatment visit will occur within 30 days after the last administration of study drug(s).  If a subject begins another anticancer therapy before the end of 
the 30 day period, every effort will be made to complete all of the EOT assessments prior to commencing the new therapy.  If there is an abnormality in need of 
monitoring beyond the EOT visit, subjects will be followed until resolution or confirmed stability of the abnormality, provided the subject is available for 
follow-up. 
c Follow-up will occur first at 30 (± 5) days after the last dose of the study drug (this can be accomplished by a site visit or phone call if the subject cannot return 
to the site) and then every 3 months (± 2 weeks) until death or until Sponsor terminates study. 
d A serum pregnancy test will be required for all female subjects of childbearing potential. 
e Cycle 4 and beyond, a serum pregnancy test in women of childbearing potential will be required on Day 1 of every 3 cycles from Cycle 3 (ie, Cycles 6, 9, 12, 
etc). 
f Obtain an FSH test in women of childbearing potential to confirm menarche. 
g At SCR, collect transfusion history for the 56 days prior to first dose of study drugs. 
h Physical examinations, including weight, will be performed on the indicated visit days.  Physical examinations on Cycle 1/Day 1 need not be repeated if 
previously performed within 24 hours before the first dose. 
i Vital sign measurements will include systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, and body temperature.  They will be 
collected on the indicated visits, as well as at 3 hours (± 10 minutes) post-dose on Cycle 1/Day 1. 
j Blood samples for safety laboratories (hematology and serum chemistry) will be collected on indicated visits.  Creatinine clearance will be calculated at the 
SCR visit.  The sample for safety laboratories on Cycle 1/Day 1 need not be collected if previously collected within 72 hours prior to first dose. 
k Electrocardiograms will be performed in triplicate at pre-dose and 3 hours post-dose at the indicated visit days up to 6 cycles.  The ECG should be performed 
within 10 minutes prior to PK sample collection.  Subject should be in supine position for 5 minutes prior to each reading.  Other unscheduled ECGs may be 
performed as clinically indicated. 
l An ECHO/MUGA scan that was performed within 60 days before the first dose of study drugs may be used. 
m BM samples for disease assessment and exploratory biomarkers analysis are required at SCR and pre-dose on Day 1 of Cycles 2 and 3. 
n If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1, then BMBs/BMAs will not be required on Cycle 4/Day 1.  Perform BMBs/BMAs on Day 1 of 
Cycles 6, 9, and 12 if subject remains in CR, CRi, or MLFS.  If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1 (eg, PR on Cycle 3/Day 1), 
BMBs/BMAs will be required on Cycle 4/Day 1, and on Day 1 of every cycle thereafter until subject achieves CR, CRi, or MLFS.  Beyond Cycle 12/Day 1, 
subjects who remain in CR, CRi, or MLFS on Cycle 12/Day 1 will need to undergo BMBs/BMAs on Day 1 of Cycles 18, 24, and every 6 cycles thereafter. All 
unscheduled BM assessments performed on non-visit days must be reported as unscheduled visits. 
o BM samples at Screening and on Day 1 of Cycles 2, 3, 6, 9, 12, 18, 24, and every 6 cycles thereafter will be submitted for translational research.  BM samples 
from unscheduled BMBs/BMAs should be also submitted for translational research when disease progression (relapse or progressive disease) is suspected.  
Additionally, submit BM samples for minimal residual disease analysis (eg, flow cytometry and/or next generation sequencing) on the day when <5% blasts in 
BM is observed and/or at the subsequent timepoints for BM sample collection.  BM samples from other timepoints are not required to be submitted (eg, Cycle 
4/Day1).  Blood for exploratory biomarker analysis will be collected at the indicated timepoints in Cycle 1, and at the same timepoints as BMBs/BMAs in 
subsequent cycles.  Refer to the Laboratory Manual for additional details and instructions. 
p Peripheral blood collected for exploratory analysis of blasts and other pharmacodynamic circulating biomarkers at the indicated timepoints in Cycle 1, Cycle 2, 
and Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) 
and at EOT. 


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q Peripheral blood collected for banking plasma for future exploratory molecular analysis of biomarkers at the indicated timepoints in Cycle 1, Cycle 2, and 
Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) and 
at EOT. 
r Serum will be collected from the blood obtained at the indicated timepoints for MIC-1 analysis. 
s Informed consent specifically allowing PGx testing sample storage must be obtained before collecting sample. 
t Quizartinib and milademetan are administered per protocol at the clinical site at the indicated visits without regard to the timing of food.  Quizartinib will be 
dispensed for continuous qd dosing for each 28 day cycle and milademetan will be dispensed for qd dosing for 14 days of each 28 day cycle. 
u Sparse PK samples for plasma concentrations of milademetan, quizartinib and AC886 will be collected and analyzed at pre-dose and 3 hours post-dose on the 
indicated visit days up to 6 cycles with time-matched ECGs. Please refer to Table 8.2 for collection schedule and other information. 
v Study drugs and pill diary may be dispensed for at-home dosage, if regionally required. 
w A BM re-biopsy or aspirate must be performed within 30 (± 5) days of the last dose of study drug study drug in subjects who have achieved an initial CR, CRi, 
MLFS, or PR to the treatment but later relapsed/developed PD while on therapy. 
x If feasible, collect subject survival status, date and cause of death (if applicable), subsequent AML therapy, and HCT and HCT-relevant information (if 
performed). 
 






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b End-of-treatment visit will occur within 30 days after the last administration of study drug(s).  If a subject begins another anticancer therapy before the end of 
the 30 day period, every effort will be made to complete all of the EOT assessments prior to commencing the new therapy.  If there is an abnormality in need of 
monitoring beyond the EOT visit, subjects will be followed until resolution or confirmed stability of the abnormality. 
c Follow-up will occur first at 30 (± 5) days after the last dose of the study drug (this can be accomplished by a site visit or phone call if the subject cannot return 
to the site) and then every 3 months (± 2 weeks) until death or until Sponsor terminates study. 
d A serum pregnancy test will be required for all female subjects of childbearing potential. 
e Cycle 4 and beyond, a serum pregnancy test in women of childbearing potential will be required on Day 1 of every 3 cycles from Cycle 3 (ie, Cycles 6, 9, 12, 
etc). 
f Obtain an FSH test in women of childbearing potential to confirm menarche. 
g  At SCR, collect transfusion history for the 56 days prior to first dose of study drugs. 
h Physical examinations, including weight, will be performed on the indicated visit days.  Physical examinations on Pre-cycle/Day −2 need not be repeated if 
previously performed within 24 hours before the first dose. 
i Vital sign measurements will include systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, and body temperature.  On Day −1 and Day 
1, vital signs will be measured pre-dose and 3 hours (± 10 minutes) post-dose. 
j Blood samples for safety laboratories (hematology and serum chemistry) will be collected on indicated visits.  Creatinine clearance will be calculated at the 
SCR visit.  The sample for safety laboratories on Cycle 1/Day −1 need not be collected if previously collected within 72 hours prior to first dose. 
k Electrocardiograms will be performed in triplicate at hours 0, 1, 2, 4, and 6 on Pre-cycle/Day −2 for baseline (approximately time-matched to the timepoints on 
Cycle 1/Day −1), at pre-dose, and at hours 1, 2, 4, and 6 post-dose on Cycle 1/Days −1 and 28 and on Cycle 2/Days 1 and 14.  The ECG should be performed 
within 10 minutes prior to the PK sample collection.  ECGs will also be collected at pre-dose and 3 hours post-dose on Days 1, 14, 15, and 22 of Cycle 1 and 
Day 1 of Cycles 3 to 6.  Subject should be in supine position for 5 minutes prior to each reading.  Other unscheduled ECGs may be performed as clinically 
indicated. 
l An ECHO/MUGA scan that was performed within 60 days before the first dose of study drugs may be used. 
m BM samples for disease assessment and exploratory biomarkers analysis are required at SCR and pre-dose on Day 1 of Cycles 2 and 3. 
n If subject achieves CR, CRi, or MLFS before Cycle 4/Day 1, then BMBs/BMAs will not be required on Cycle 4/Day 1.  Perform BMBs/BMAs on Day 1 of 
Cycles 6, 9, and 12 if subject remains in CR, CRi, or MLFS.  If subject does not achieve CR, CRi, or MLFS before Cycle 4/Day 1 (eg, PR on Cycle 3/Day 1), 
BMBs/BMAs will be required on Cycle 4/Day 1, and on Day 1 of every cycle thereafter until subject achieves CR, CRi, or MLFS.  Beyond Cycle 12/Day 1, 
subjects who remain in CR, CRi, or MLFS on Cycle 12/Day 1 will need to undergo BMBs/BMAs on Day 1 of Cycles 18, 24, and every 6 cycles thereafter. All 
unscheduled BM assessments performed on non-visit days must be reported as unscheduled visits. 
o BM samples at Screening and on Day 1 of Cycles 2, 3, 6, 9, 12, 18, 24, and every 6 cycles thereafter will be submitted for translational research.  BM samples 
from unscheduled BMBs/BMAs should be also submitted for translational research when disease progression (relapse or progressive disease) is suspected.  
Additionally, submit BM samples for minimal residual disease analysis (eg, flow cytometry and/or next generation sequencing) on the day when <5% blasts in 
BM is observed and/or at the subsequent timepoints for BM sample collection.  BM samples from other timepoints are not required to be submitted (eg, Cycle 
4/Day1).  Blood for exploratory biomarker analysis will be collected at the indicated timepoints in Cycle 1, and at the same timepoints as BMBs/BMAs in 
subsequent cycles.  Refer to the Laboratory Manual for additional details and instructions. 
p Peripheral blood collected for exploratory analysis of blasts and other pharmacodynamic circulating biomarkers at the indicated timepoints in Cycle 1, Cycle 2, 
and Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) 
and at EOT. 


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q Peripheral blood collected for banking plasma for future exploratory molecular analysis of biomarkers at the indicated timepoints in Cycle 1, Cycle 2, and 
Cycle 3, and then on Day 1 of every 3-6 cycles corresponding to the timepoints for BMBs/BMAs (ie, Cycles 6, 9, 12, 18, 24, and every 6 cycles thereafter) and 
at EOT. 
r Serum will be collected from the blood obtained at the indicated timepoints for MIC-1 analysis. 
s Informed consent specifically allowing PGx testing sample storage must be obtained before collecting sample. 
t Quizartinib and milademetan are administered per protocol at the clinical site at the indicated time without regard to the timing of food, except where noted. 
u Quizartinib and milademetan will be dosed on an empty stomach (no food for at least 2 hours pre-dose) on Cycle 1/Day −1, Cycle 1/Day 28, Cycle 2/Day 1, 
and Cycle 2/Day 14.  Subjects will also be required to fast for 2 additional hours post-dose. 
v PK samples for milademetan, quizartinib and AC886 are collected on the indicated timepoints.  PK samples will be collected at pre-dose and at 0.5, 1, 2, 3, 4, 
6, and 8 hours post-dose on Days −1 and 28 of Cycle 1 and on Days 1 and 14 of Cycle 2, at pre-dose and 3 hour post-dose on Days 1, 14, 15, and 22 of Cycle 1 
and on Day 1 of Cycles 3 to 6, and at pre-dose at all other indicated visit days.  Please also refer to Table 8.3 for collection schedule and other information. 
w Indicates that milademetan and/or quizartinib and AC886 PK samples at pre-dose and 3 hours post-dose will be collected on Days 14, 15 and 22 of Cycle 1 and 
Day 1 of Cycles 3 to 6. 
x Study drugs and pill diary may be dispensed for at-home dosage, if regionally required. 
y A BM re-biopsy or aspirate must be performed within 30 (± 5) days of the last dose of study drug in subjects who have achieved an initial CR, CRi, MLFS, or 
PR to the treatment but later relapsed/developed PD while on therapy. 
z If feasible, collect subject survival status, date and cause of death (if applicable), subsequent AML therapy, and HCT and HCT-relevant information (if 
performed). 


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17.4. 
Response Criteria for AML19 
Category 
Definition 
Complete Remission (CR) 
 
Bone marrow blasts <5% 
 
Absence of circulating blasts and blasts with Auer rods 
 
Absence of extra-medullary disease 
 
Absolute neutrophil count (ANC) ≥1.0 × 109/L 
 
Platelet count ≥100 × 109/L 
CR with Incomplete Blood 
Count Recovery (CRi) 
(Figure 17.1) 
All CR criteria except for residual neutropenia (ANC <1.0 × 109/L) or 
thrombocytopenia (platelet count <100 × 109/L) 
Morphologic Leukemia-free 
State (MLFS) 
 
Bone marrow blasts <5% 
 
Absence of blasts with Auer rods 
 
Absence of extramedullary disease 
 
No hematologic recovery required 
o Note:  Marrow should not merely be “aplastic”; at least 
200 cells should be enumerated or cellularity should be at 
least 10% 
Partial Remission (PR) 
 
Decrease of bone marrow blast percentage by at least 50% to a 
value of 5% to 25% 
 
All hematologic criteria of CR: 
o ANC ≥1.0 × 109/L 
o platelet count ≥100 × 109/L 
Stable Disease (SD) 
Absence of CR, CRi, MLFS, or PR, and criteria for PD not met 
o Note:  SD can be reported as each assessment not persisting 
for 3 months, whereas SD which persists for at least 3 
months will be summarized for the efficacy analysis. 
Relapse (after CR or CRi) 
 
Bone marrow blasts ≥5%, or 
 
Reappearance of leukemic blasts in the peripheral blood, or 
 
Development of extramedullary disease 


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Category 
Definition 
Progressive Disease (PD) 
Evidence for an increase in bone marrow blast percentage and/or 
increase of absolute blast counts in the blood: 
 >50% increase in marrow blasts over baseline (a minimum 15% 
point increase is required in cases with <30% blasts at baseline; or 
persistent marrow blast percentage of >70% over at least 3 months; 
without at least a 100% improvement in ANC to an absolute level of 
>0.5 × 109/L, and/or platelet count to >50 × 109/L (non-transfused); 
or 
 >50% increase in peripheral blasts (WBC × % blasts) to >25 × 109/L 
(in the absence of differentiation syndrome); or 
 New extra-medullary disease 
ANC = absolute neutrophil count; WBC = white blood cells 
 
Figure 17.1: Hematologic Recovery Requirements for CR and CRi 
 
ANC = absolute neutrophil count; CR = complete remission; CRi = CR with incomplete blood count recovery; 
MLFS = morphologic leukemia-free state 


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17.5. 
Additional Definitions/Response Criteria 
CRh evaluation will be conducted separately from those in Section 17.4. 
Category 
Definition 
CR with Partial 
Hematological Recovery 
(CRh)28 
(Figure 17.2) 
All CR criteria except for hematologic recovery – BUT partial 
hematological recovery (ANC >0.5 × 109/L and platelet count >50 × 
109/L) were observed. 
 
Figure 17.2: Hematologic Recovery Requirements for CR and CRh 
 
ANC = absolute neutrophil count; CR = complete remission; CRi = CR with incomplete blood count recovery 
 


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17.6. 
Prohibited Concomitant Medications 
Potential QT/QTc Prolonging Drugs 
The following list describes medications which prolong QTc interval and are prohibited during 
treatment with quizartinib and milademetan combination. 
This list should not be considered all-inclusive.  Consult individual drug labels for specific 
information on a drug’s propensity to prolong QTc interval. 
Note:  Exceptions are made for antibiotics and antifungals that are used as standard of care for 
the prevention or treatment of infections or if the Investigator believes that beginning therapy 
with a potentially QTc-prolonging medication is vital to an individual subject’s care while on 
study (Section 5.6.2). 
Known QT/QTc-Prolonging Drugs 
Generic Drug Name 
Macrolide antibiotics 
azithromycin 
erythromycin 
clarithromycin 
roxithromycin 
Fluoroquinolone antibacterials 
moxifloxacin 
ciprofloxacin 
gatifloxacin 
grepafloxacin 
levofloxacin 
sparfloxacin 
Azole antifungals 
fluconazole 
Antimalarials 
chloroquine 
halofantrine 
quinidine 
Antiprotozoals 
pentamidine 
Antiemetics, gastrokinetics 
droperidol 
ondansetron 
cisapride 
domperidone 
Anticancer 
aclarubicin 
arsenic trioxide 
oxaliplatin 
vandetanib 


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Known QT/QTc-Prolonging Drugs 
Generic Drug Name 
Antipsychotics, antidepressants, anesthetics, and 
other CNS agents 
chlorpromazine 
cocaine 
citalopram 
donepezil 
escitalopram 
haloperidol 
ibogaine 
levomepromazine 
levomethadyl acetate 
levosulpiride 
methadone 
mesoridazine 
pimozide 
propofol 
sevoflurane 
sulpiride 
sultopride 
thioridazine 
Antiplatelet agents 
anagrelide 
cilostazol 
Antihistamines 
astemizole 
terfenadine 
Antiarrhythmics, antihypertensives, 
antihyperlipidemics 
amiodarone 
bepridil 
disopyramide 
dofetilide 
dronedarone 
flecainide 
ibutilide 
papaverine HCl 
probucol 
procainamide 
sotalol 
terlipressin 
terodiline 
Adapted from:  https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf (site list last revised 17 Feb 2019). 


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The following list describes non-QT-prolonging medications that may be administered to 
manage nausea and vomiting.  This list should not be considered all-inclusive. 
Antiemetics (Non-QT-prolonging)15 
aprepitant 
droperidol 
fosaprepitant 
metoclopramide 
The following list describes medications which are strong inducers of CYP3A and are prohibited 
during treatment with quizartinib and milademetan combination.  This list should not be 
considered all-inclusive. 
Strong CYP3A Inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s Wort 
enzalutamide 
mitotane 
Adapted from:  https://www.druginteractioninfo.org 
 


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17.7. 
Highly Effective Methods of Birth Control 
Per the guidance from the Clinical Trial Facilitation Group (CTFG) of the European Heads of 
Medicines Agencies (HMA),29 66 methods that can achieve a failure rate of less 1% per year 
when used consistently and correctly are considered as highly effective birth control methods.  
Per the guidance, such methods include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation including oral, intravaginal and transdermal formulations 
 Progestogen-only hormonal contraception associated with inhibition of ovulation, 
including oral, injectable and implantable formulations 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner (provided that the partner is the sole sexual partner of the woman 
of childbearing potential trial participant and that the vasectomized partner has received 
medical assessment of the surgical success) 
 Complete sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.) 
Prior to starting quizartinib/placebo, the Investigator will discuss highly effective methods of 
birth control as defined above with women of childbearing potential (as defined in Section 4.1) 
and men who are not surgically sterile. 
 


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17.8. 
FLT3-ITD Mutation Assay 
Of note, a companion diagnostic is being developed by Navigate for the US and European Union 
that will allow determination of FLT3-ITD mutation status from blood and/or bone marrow 
samples.  The FLT3-ITD Mutation Assay is a polymerase chain reaction (PCR)-based molecular 
assay for detecting FLT3-ITD mutations utilizing genomic DNA isolated from blood or bone 
marrow.  The internal tandem duplication (ITD) mutation always occurs in exons 14 and 15 of 
the FLT3 gene, which includes the juxtamembrane domain and the N-terminal part of the kinase 
domain.  This region, when amplified by PCR using a single set of DNA primers that flank the 
region, yields ITD mutant reaction products that are greater in size than the 330-base pair non-
mutant (ITD wild type) product.  The FLT3-ITD Mutation Assay uses a fragment size analysis 
method to resolve and detect the different-sized PCR products by capillary electrophoresis. 
This test is approved by the FDA for investigational use and is Conformité Européenne 
(CE)-marked.  It is not approved by the FDA or other regulatory agencies for commercial use.  
The results of the test will be used to support the development of a commercial companion 
diagnostic test.  The FDA has reviewed the methodology and assay development and validation 
of the companion diagnostic test, as documented by Investigational Device Exemption number 
G140012.


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17.9. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The following table summarizes the ECOG Performance Status Scale.30 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature (eg, 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 


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17.10. 
New York Heart Association (NYHA) Functional Classification 
The following table lists the NYHA Classes of Heart Failure.31 
Class 
Patient Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart failure at 
rest.  If any physical activity is undertaken, discomfort increases.