Clinical trial NCT03451084
Conditions: Acute Myeloid Leukemia
Keywords: AML, ASLAN, DHODH
Sponsor: ASLAN Pharmaceuticals
Start date: 2018-01-05; Completion date: 2019-12-13
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
ASLAN003-003 is a multi-center, Phase IIA study to evalute the efficacy of ASLAN003 in AML patients who are ineligible for standard treatment with an expansion cohort in relapsed/refractory patients, and to determine the appropriate dose of ASLAN003 in combination with azacitidine in older (more than or equal to 60 years) AML patients who have exhausted any approved and available treatment options.

Detailed description:
ASLAN003-003 is a multi-center, Phase IIA study to determine the optimum dose of ASLAN003 based on the safety, efficacy, and tolerability of varying doses of ASLAN003 (100 mg QD, 200 mg QD, 100 mg BID, and possibly 200 mg BID) administered to AML subjects daily for a continuous 28-day treatment cycle until disease relapse, disease progression, unacceptable toxicity, or withdrawal of consent.

The study has 2 parts and plans to enroll a total of 44 to 56 patients with 18 to 24 patients in Part 1 and 26 to 32 patients in Part 2 (comprising Parts 2A and 2B). The Overall Complete Remission Rate will be evaluated in AML patients not eligible for standard treatment (Part 1) and in relapsed and refractory AML patients (Part 2A) using the optimum dose of ASLAN003 established in Part 1 of the study. In Part 2B of the study, the appropriate dose of ASLAN003 in combination with azacitidine in older (more than or equal to 60 years) AML patients who have exhausted any approved and available treatment options will be determined.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: ASLAN003
Intervention descriptions: intervention 1: Patients will be administered with the study drug, ASLAN003. The study drug is to be administered orally, QD or BID. It is recommended to administer the study drug with food or within 30 minutes after food intake.

Protocol documents:
Prot_002.pdf: 
CLINICAL STUDY PROTOCOL 
 
A PHASE IIA DOSE OPTIMISATION STUDY OF ASLAN003 IN ACUTE 
MYELOID LEUKEMIA 
 
Sponsor: 
ASLAN Pharmaceuticals Pte. Ltd. 
83 Clemenceau Avenue 
#12-03 UE Square 
Singapore 239920 
Clinical Research Organization: 
IQVIA 
PAREXEL 
Sponsor Protocol No.: 
ASLAN003-003 
Study Drug Name: 
ASLAN003 
Development Phase: 
Phase IIA 
Date of Protocol: 
31 May 2018 
Version of Protocol: 
Version 3.0 (Final) 
Date of Previous Protocol: 
29 Jan 2018  
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki1, and with other applicable 
regulatory requirements. 
This document contains proprietary and confidential information of ASLAN Pharmaceuticals Pte. Ltd. 
(ASLAN). Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written approval 
of ASLAN with the exception that this document may be disclosed to study personnel under your 
supervision who need to know the contents for conducting the study and appropriate Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs) under the condition that the personnel have agreed 
to keep this information confidential. The foregoing shall not apply to disclosure required by governmental 
regulations or laws; however, ASLAN shall be promptly notified of any such disclosure. Nothing herein 
constitutes an invitation or offer to invest in or deal in the securities of ASLAN. Anyone considering 
investment in ASLAN should refer to the information officially published the Taiwan Stock Exchange 
Market Observation System. 
 
CONFIDENTIAL 


Sponsor: ASLAN Pharmaceuticals Pte. Ltd. 
Clinical Study Protocol 
Protocol Number: ASLAN003-003 
CONFIDENTIAL 
Version 3.0_Final 
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PROTOCOL SYNOPSIS 
Protocol 
Number: 
ASLAN003-003 
Protocol Title 
A PHASE IIA DOSE OPTIMISATION STUDY OF ASLAN003 IN 
ACUTE MYELOID LEUKEMIA 
 
Sponsor: 
ASLAN Pharmaceuticals Pte. Ltd. 
 
Investigational 
Product: 
ASLAN003 
 
Study Centers: 
The study will be conducted at multiple centers in Australia, Singapore 
and other countries.  
 
Phase: 
Phase IIA 
 
Objectives: 
Primary Objective 
 
Part 1: 
• 
To determine the optimum dose of ASLAN003 monotherapy based 
on the efficacy, safety and tolerability profile in Acute Myeloid 
Leukemia (AML) patients who are ineligible for standard therapy. 
 
Part 2: 
• 
To provide a preliminary estimate of the efficacy of ASLAN003 at 
the optimum dose selected from Part 1. 
 
Secondary Objective 
 
Part 1: 
• 
To evaluate the pharmacokinetics (PKs) of ASLAN003 and its 
metabolite LAS186558 in patients with AML. 
 
Part 2: 
• 
To further assess the safety and tolerability data of ASLAN003 at 
the optimum dose selected from Part 1. 
 
Exploratory Objectives:  
• 
To examine the myeloid differentiation effects of ASLAN003 
using assays including but not limited to an ex vivo flow cytometry 
assay. 
• 
To explore possible relationships between molecular abnormalities 
and measures of clinical response in patients with AML. 
 


Sponsor: ASLAN Pharmaceuticals Pte. Ltd. 
Clinical Study Protocol 
Protocol Number: ASLAN003-003 
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Study Design: 
This is a multicenter, single arm, non-randomised Phase IIA Study to 
evaluate ASLAN003 as a monotherapy in patients with AML.  
 
AML patients who are ineligible for standard treatment including, but not 
limited to the following conditions, will be enrolled in the study:  
• 
Newly diagnosed patients who are ineligible for standard therapy 
i.e., standard dose induction chemotherapy and reduced dose 
chemotherapy;  
• 
Patients with relapse from prior remission;  
• 
Patients with failed response to prior therapy including 
chemotherapy, hypomethylating agents, and bone marrow (BM) 
transplantation. 
 
Up to a total of 18-24 patients will be enrolled into this study - 6 patients 
in each dose cohort. The planned sequence of cohort enrollment is 100 mg 
QD - 200 mg QD - 100 mg BID. Furthermore, an additional cohort of 200 
mg BID may also be enrolled, subject to agreement from the steering 
committee (SC) based on a review of safety data from the 100 mg BID 
cohort. A SC meeting will be set up and will meet to review all clinical 
information, including efficacy, safety and PK data obtained from this 
Study. Details of the SC outcome will be specified in the SC charter.  
 
An expansion cohort of 20 patients (Part 2) will be recruited to study the 
optimum dose selected by the SC. The optimum dose will be selected from 
at least one cohort showing tolerable safety profile and clinical benefit in 
disease presentation. Details will be specified in the SC charter. 
 
Patients with especially high blast cell count should be closely monitored 
for a possible differentiation syndrome. Investigators could manage 
suspected patients proactively according to the recommendations in the 
National Comprehensive Cancer Network (NCCN) guidelines acute 
promyelocytic leukemia (APL) differentiation syndrome section. 
 
Bone marrow aspiration samples (BMA) will be collected before the first 
day of treatment, will be cultured in vitro and incubated with ASLAN003 
to examine the efficacy of ASLAN003 ex vivo. Molecular studies will also 
be done to check for any phenotypic and genotypic changes in the 
patients’ BM sample. A BM aspiration smear will be collected and 
processed locally before the first day of treatment. Ex vivo assay and 
molecular assessment will be processed centrally (Please refer to the BMA 
lab manual for details). This will be done in selected sites to be determined 
by the Sponsor. 
 
All patients will continue to receive ASLAN003 until disease relapse, 
treatment failure, unacceptable toxicity, withdrawal of consent or death.  
 


Sponsor: ASLAN Pharmaceuticals Pte. Ltd. 
Clinical Study Protocol 
Protocol Number: ASLAN003-003 
CONFIDENTIAL 
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Abbreviations: AML = acute myeloid leukemia; QD = once daily, BID = twice 
daily. 
 
Number 
of 
patients: 
Up to a total of 18-24 patients are planned to be enrolled in Part 1 of this 
Phase IIA study to be conducted in Australia, Singapore and other 
countries. 
 
Approximately 20 patients are planned to be enrolled in the expansion 
cohort of Part 2 of this Phase IIA study to be conducted in Australia, 
Singapore and other countries. 
 
Study 
Population: 
Inclusion Criteria 
 
Patients who meet all of the following criteria are eligible for enrollment 
in the study: 
 
1. Patients who are of or older than the legal age in the respective 
countries at the time when written informed consent is obtained 
2. Patients who are able to understand and willing to sign the informed 
consent form (ICF) 
3. Patients who are diagnosed with AML according to the 2016 revision 
to the World Health Organization classification of myeloid 
neoplasms and acute leukemia (refer to Appendix 1: WHO 
Classification of Acute Myeloid Leukemia) 
4. Patients who have a sufficient archival or fresh BM aspiration sample 
for the evaluation of relevant exploratory endpoint.  
Note: Patients who do not have sufficient archival BM aspiration 
sample and refuse to repeat the procedure may be enrolled in the 
trial only after written confirmation by ASLAN 
 


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5. Patients who are ineligible for standard treatment of AML including 
but not limited to the following conditions: 
• Newly diagnosed patients who are ineligible for standard therapy 
namely standard dose induction chemotherapy and reduced dose 
chemotherapy;  
• Patients who relapsed from prior remission;  
• Patients who failed to respond to prior therapy including 
chemotherapy, hypomethylating agents, and bone marrow 
transplantation. 
6. Patients who have an ECOG performance status of ≤ 2 
7. Patients with adequate renal and hepatic function, as defined below: 
• Estimated Glomerular Filtration Rate (eGFR) or creatinine 
clearance (CrCl) (CrCl calculated by the Cockroft and Gault 
method) ≥ 40 ml/min/1.73 m2 
• Total bilirubin, AST, and ALT ≤ 1.5 × ULN 
 
Exclusion Criteria: 
 
Patients with any of the following criteria will be excluded from the study: 
 
1. Patients who are diagnosed with de novo myeloid sarcoma without 
BM involvement 
2. Patients 
who 
are 
diagnosed 
with 
acute 
promyelocytic 
leukemia/retinoic acid receptor alpha (PML-RARA) 
3. Patients who received any other standard or investigational treatment 
for their leukemia within the last 7 days before starting the first dose 
of study drug, with the exception of leukapheresis and hydroxyurea 
4. Patients with unresolved serious toxicity (≥ CTCAE 4.03 Grade 2) 
from prior administration of standard or investigational treatment for 
their leukemia 
5. Patients who have a positive test for human immunodeficiency virus 
(HIV), viral hepatitis C infection (patients with sustained viral 
response are not excluded), active viral hepatitis B infection (positive 
hepatitis B surface antigen [HBsAg]) with hepatitis B virus 
deoxyribonucleic acid (DNA) exceeding 2000 IU/ml 
6. Patients who have a known history of liver cirrhosis Child-Pugh score 
B or C 
7. Patients who have any history of other malignancy unless in remission 
for more than 1 year (skin carcinoma and carcinoma-in-situ of uterine 
cervix treated with curative intent is not exclusionary) 
8. Female patients who are pregnant or breast-feeding 
9. Patients with a known history of alcohol or drug addiction on the basis 
that there could be a higher risk of non-compliance to study treatment 
per Investigator’s discretion 
 


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10. Patients with a history or presence of a clinically significant condition 
which in the opinion of the Investigator could jeopardize the safety of 
the patient or the validity of the study results 
11. Patients who have been previously treated with ASLAN003 
 
Study 
Endpoints: 
Primary Endpoints:  
 
Part 1: 
• 
The primary objective of determining the optimum monotherapy 
dose of ASLAN003 in AML patients is based on the following 
endpoints: 
o 
Overall Complete Remission Rate (OCRR): Defined as the 
proportion of patients with a best response of complete 
remission (CR) or complete remission with incomplete 
hematologic recovery (CRi), defined in accordance with the 
International Working Group (IWG) Response Criteria in 
AML. 
o 
Safety and tolerability: Based on AEs, safety assessments 
(including vital signs, electrocardiogram [ECG] parameters, 
clinical laboratory tests) and treatment exposure/dose 
intensity. 
Part 2: 
• 
Overall Complete Remission Rate (OCRR) 
 
Secondary Endpoints:  
• 
Efficacy (Parts 1 and 2): 
o Relapse Free Survival (RFS): Defined as the time the criteria for 
remission (CR or CRi) are first met until there is evidence of 
patient relapse, regardless of whether the patient is still taking 
study drug. Relapse is defined as: 
 The reappearance of leukemic blasts in the peripheral 
blood or > 5% blasts in the BM not attributable to any 
other cause; 
 The appearance of new dysplastic changes; 
 The reappearance of or development of cytologically 
proven extramedullary disease; 
 The reappearance of a cytogenetic or molecular 
abnormality. 
o Clinical Benefit Rate (CBR): defined as the proportion of 
patients with an AML IWG best response of CR, CRi or PR.  
o % change from baseline in BM blasts at Day 29. 
 
• 
Safety and tolerability (Part 2 ONLY): 
o Based on AEs, safety assessments (including vital signs, 
electrocardiogram [ECG] parameters and clinical laboratory 
tests) and treatment exposure/dose intensity. 


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• 
Pharmacokinetics (Part 1 ONLY): 
If estimable, the following parameters will be calculated on Days 1 
and 8, Cycle 1: 
o PK parameters for ASLAN003: maximum observed plasma 
concentration (Cmax), Cmax at steady state (Cmax ss), trough plasma 
concentration (Ctrough), time corresponding to occurrence of 
Cmax (tmax), and Cmax ss (tmax ss), AUC over the dosing interval 
(AUCtau), AUCtau at steady state (AUCtau ss), terminal 
elimination half-life (t1/2), effective elimination half-life at 
steady state (t1/2 eff), apparent total clearance of the drug from 
plasma after oral administration (CL/F), apparent volume of 
distribution at steady state after oral administration (Vss/F), 
accumulation ratio for AUC (RacAUC) and accumulation ratio 
for Cmax (RacCmax). 
o PK parameters for LAS186558: Cmax, Ctrough, tmax, AUCtau, t1/2, 
t1/2 eff, RacAUC, RacCmax, metabolic ratio (MR) for Cmax 
(MRCmax) and AUC (MRAUC). 
 
Exploratory Endpoint (Parts 1 and 2):  
• 
Assessment of the degree of blast cell differentiation by 
ASLAN003 using assays including but not limited to ex vivo flow 
cytometry assay using selected myeloid cell markers (such as 
CD11b).  
• 
Assessment of the molecular abnormalities of AML blast cells at 
baseline. 
 
Study 
Treatment: 
Part 1: 
Patients will be administered with the study drug, ASLAN003. The 
starting dose of ASLAN003 is 100 mg QD given orally (PO). The 
maximum dose for optimum dose determination is 200 mg BID. It is 
recommended to administer ASLAN003 with food or within 30 minutes 
after food intake. 
 
Part 2: 
An optimum dose selected by the SC from Part 1 is given orally (PO). It 
is recommended to administer ASLAN003 with food or within 30 minutes 
after food intake. 
 
Visit Schedule: 
In order to address the primary objectives of the study, if treatment is 
interrupted for any reason, it is important that all planned safety and 
efficacy assessments are performed at the scheduled time, regardless of 
whether the patient is receiving study treatment, or not, at the time. 
Study 
Duration: 
Screening Period: 28 days 
 


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Treatment Period: All patients will receive a continuous 28-day 
treatment cycle of ASLAN003 until disease relapse, treatment failure 
(defined as failure to achieve a PR or higher within 4 cycles), development 
of unacceptable toxicity, withdrawal of consent or death. 
 
Follow-up Period: All patients will be required to complete a safety 
follow-up visit within 28 days after the last dose of study treatment. All 
patients achieving CR or CRi will be followed for survival every 12 weeks 
post end of treatment (EOT) until disease relapse or death (in the absence 
of disease relapse) to find out the RFS. 
 
The planned duration of entire study (treatment and follow-up) is 
approximately 2 years. 
 
Study 
Assessments: 
The schedule of the assessment for the study is provided in Table 1.  
 
Safety Assessments: 
Patient safety will be evaluated based on the incidence of AEs and serious 
AEs (SAEs), physical examination, vital signs (blood pressure [systolic 
and diastolic], heart rate, respiratory rate, weight, and body temperature), 
ECG parameters, and clinical laboratory tests (hematology, clinical 
chemistry, coagulation and urinalysis).  
 
All AEs will be evaluated according to NCI-CTCAE 4.03 and will be 
captured from the time of informed consent and continued until the safety 
follow-up assessment (28 days after last administration of study 
treatment). For the purpose of this study, fluctuations of pre-existing 
conditions that do not represent a clinically significant exacerbation or 
worsening are not to be considered AEs. 
 
Pharmacokinetic Assessments (Part 1 ONLY): 
The blood samples for determination of plasma concentration of study 
drug will be collected on Day 1 and Day 8 at the following timepoints of 
Cycle 1 for QD regime: pre-dose, 1, 2, 4, 5, 6, 8, and 24 hours post dose.  
 
In BID regime i.e 100mg BID and 200mg BID the PK sampling will be 
done at following timepoints: pre-dose, 1,2, 4, 5, 6, 8, and 12 hours (or 
evening pre-dose). 
 
The plasma concentration-time data will be used to calculate the PK 
parameters for ASLAN003 and metabolite.” 
Part 2: will be determined by SC if needed. 
 


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Efficacy Assessments: 
For patients who do not have a sufficient archival of BM aspiration 
sample, a BM aspiration will be performed during Screening. 
 
Efficacy will be evaluated with BM aspiration and peripheral blood based 
on the IWG Criteria for AML (Cheson, 2003) every 4 weeks, on Day 1 of 
every cycle from Cycle 2 to Cycle 5 and every 12 weeks thereafter. 
Patients who have already achieved CR can omit the BM aspiration at 
subsequent assessments if there is a normal complete blood count with 
differential of the peripheral blood. Investigator may perform additional 
efficacy assessment if required based on clinical judgment. Bone marrow 
aspiration smears will be processed locally.  
 
Note: If treatment is interrupted for any reason, the scheduled efficacy 
assessments should be performed at the intended time point, regardless of 
whether the patient is currently receiving study treatment. Repeat 
assessments at the resume of treatment may be performed at the 
investigator’s discretion. 
 
Other Assessments: 
Assays including but not limited to ex vivo flow cytometry assay using 
selected myeloid cell markers (such as CD11b) will be performed to assess 
the degree of blast cell differentiation upon treatment with ASLAN003. 
The percentage of CD11b positive cells will be determined before and 
after ex vivo treatment with ASLAN003. Molecular abnormalities of AML 
patients will also be assessed using polymerase chain reaction (PCR) or 
next-generation sequencing (NGS) The ex vivo assay and molecular 
assessment will be processed centrally (Please refer to the BMA lab 
manual for details). 
 
Prohibited 
Medications 
Any approved or investigational treatment given for the purpose to treat 
the leukemia, including but not limited to chemotherapy, hypomethylating 
agents, herbal medicine, Chinese medicine, leukapheresis, etc. will be 
prohibited during the study. 
 
For the management of leukocytosis, hydroxyurea use per site practice is 
allowed for patients with peripheral blast count more than 20,000 cells/uL 
in the first two weeks of study treatment. Once the peripheral blast count 
drops to less than 20,000 cells/uL, site is required to discontinue with 
hydroxyurea to ensure no impact on efficacy readout. Hydroxyurea use is 
allowed for suspected or confirmed differentiation syndrome. 
 
Statistical 
Analysis: 
Part 1: 
The proposed design has been selected to provide an assessment of the 
efficacy, safety and tolerability of different doses of ASLAN003 in 


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patients with AML, whilst limiting the number of patients exposed to 
experimental treatments and procedures. Up to a total of 18-24 patients 
will be recruited in the study. 
 
Part 2: 
The study is not formally powered. The sample size of 20 patients has 
been selected to provide further efficacy and tolerability data at the 
selected dose level, prior to conducting larger randomized trials. 
 
Methods of Analysis: 
There are no formal statistical analyses planned. All primary and 
secondary endpoints will be listed and summarized using appropriate 
descriptive statistics and graphical displays. Safety will be assessed in the 
safety population and efficacy will be assessed in the evaluable for 
response (EFR) population. 
 
Furthermore, waterfall plots of the % change from baseline in BM blasts 
at Day 28, and the best % change from baseline in BM blasts will be 
presented. 
 
Pharmacokinetics: 
Concentrations and PK parameters will be listed and summarized using 
descriptive statistics in tables and graphs, as appropriate.  
 
 
 


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Table 1: Schedule of Study Assessments  
 
Study Visit 
Screening 
StudyTreatment Period 
End of 
Treatment 
Safety 
Follow-up 
Survival 
Follow-
Up 
Treatment Cycles  
(28 days per cycle) 
Day -28 to 
0 
Cycle 1 
Cycle 
2 
Subsequent 
Cycles 
EOT 
28 days 
after last 
administra
tion of 
study 
medication 
Every 12 
weeks 
post 
EOT for 
RFS 
Study Days 
Day 
1 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 1 
Day 1 
Study Allowed 
Window 
NA 
NA 
±1 
+1 
±2 
±2 
±2 
±2 
Within 7 
days of last 
dose of 
study 
treatment  
±7 
±7 
General and Safety Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs (blood 
pressure, heart rate, 
respiratory rate, 
temperature) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
12-Lead 
Electrocardiogram 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Eastern Cooperative 
Oncology Group 
Performance Status 
(ECOG) 
X 
X 
 
 
 
 
 
 
X 
 
 
Body weight 
X 
X 
 
 
 
 
X 
X 
X 
 
 


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Study Visit 
Screening 
StudyTreatment Period 
End of 
Treatment 
Safety 
Follow-up 
Survival 
Follow-
Up 
Treatment Cycles  
(28 days per cycle) 
Day -28 to 
0 
Cycle 1 
Cycle 
2 
Subsequent 
Cycles 
EOT 
28 days 
after last 
administra
tion of 
study 
medication 
Every 12 
weeks 
post 
EOT for 
RFS 
Study Days 
Day 
1 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 1 
Day 1 
Study Allowed 
Window 
NA 
NA 
±1 
+1 
±2 
±2 
±2 
±2 
Within 7 
days of last 
dose of 
study 
treatment  
±7 
±7 
Adverse 
Events/Serious 
Adverse Eventsa 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant 
Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Laboratory Assessments 
Serum / urine β-human 
Chorionic 
Gonadotropinᵇ 
X 
 
 
 
 
 
 
 
X 
 
 
Hematology 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Clinical Chemistry, 
Urinalysisc 
X 
X 
X 
Xd 
X 
X 
X 
X 
X 
 
 
Serologye 
X 
 
 
 
 
 
 
 
 
 
 
Coagulationf 
X 
 
 
 
X 
 
 
 
X 
 
 
Blood 
Pharmacokinetics 
Samplingg 
 
X 
X 
 
 
 
 
 
 
 
 
Bone Marrow 
Aspirationh 
X 
 
 
 
 
 
X 
X 
 
 
 


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Study Visit 
Screening 
StudyTreatment Period 
End of 
Treatment 
Safety 
Follow-up 
Survival 
Follow-
Up 
Treatment Cycles  
(28 days per cycle) 
Day -28 to 
0 
Cycle 1 
Cycle 
2 
Subsequent 
Cycles 
EOT 
28 days 
after last 
administra
tion of 
study 
medication 
Every 12 
weeks 
post 
EOT for 
RFS 
Study Days 
Day 
1 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 1 
Day 1 
Study Allowed 
Window 
NA 
NA 
±1 
+1 
±2 
±2 
±2 
±2 
Within 7 
days of last 
dose of 
study 
treatment  
±7 
±7 
Other Assessment 
Survival status contact 
by phonei 
 
 
 
 
 
 
 
 
 
 
X 
Study Drug Administration 
ASLAN003 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations: ALT = alanine aminotransferase; AST = Aspartate aminotransferase; CR = complete remission; CRi = complete remission with incomplete 
hematologic recovery; DNA = deoxyribonucleic acid; eCRF = electronic case report form; EOT = end of treatment; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; NA = not applicable; PK=pharmacokinetics; RFS = relapse free survival. 
Footnotes: 
a. 
Adverse event collection starts at the time of informed consent and continues until 28 days after the last administration of study drug If a patient never 
receives study drug, but experience AE after informed consent form is signed, ONLY events the Investigator assessed as may have been caused by a study 
specific protocol procedure will be reported in eCRF. 
b. Serum or urine pregnancy test to be performed at the Screening visit for all females except those surgically sterile or 2 years postmenopausal. Serum or 
urine pregnancy tests will be performed at EOT. Unscheduled serum or urine pregnancy tests are allowed at the Investigator’s discretion. 
c. 
Screening clinical laboratory tests (clinical chemistry, urinalysis and coagulation) must be completed from Day -28 to 0. Screening clinical laboratory 
tests may be used in lieu of pre-treatment, Cycle 1 Day 1 tests, if performed within 1 week prior to the first administration of study drug.  
d. ONLY AST, ALT and total bilirubin to be performed on Cycle 1 Day 10. 
e. 
Serology tests must be completed from Day -28 to 0. If HBsAg result indicate active infection then test HBV DNA. 
f. 
Coagulation laboratory test will be performed at Screening, Cycle 1 Day 15 and EOT visit, however the Investigator may perform coagulation tests at 
other visits if required based on clinical judgment. 


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g. Blood samples for PK analysis of ASLAN003 and LAS186558 for QD regime include: Day 1 and Day 8: pre-dose, 1, 2, 4, 5, 6, 8, and 24 hours post dose. 
In BID regime i.e 100mg BID and 200mg BID the PK sampling will be done at following timepoints: pre-dose, 1, 2, 4, 5, 6, 8, and 12 hours (or evening 
pre-dose). For Part 2- Steering Committee will decide whether PK analysis is required or not and ASLAN pharmaceuticals will be updated accordingly. 
h. Bone marrow aspiration is mandatory to be performed every 4 weeks on Day 1 of every cycle from Cycle 2 to Cycle 5 and every 12 weeks thereafter. 
Patients who have already achieved CR could omit the bone marrow aspiration at subsequent assessments if there is a normal complete blood count with 
differential of the peripheral blood. The Investigator may perform additional monthly bone marrow aspirate if required based on clinical judgment. Bone 
marrow aspiration smear will be processed locally. ONLY BMA collected during screening visit will be used to perform ex vivo assay and molecular 
assessment centrally (Please refer to the lab manual for details). 
i. 
Survival follow-up by either telephone or clinic visit will be performed in patients achieving CR or CRi every 12 weeks post EOT until disease relapse or 
death (in the absence of disease relapse) to enable the assessments of RFS. 
j. 
Cycle 2 Day 1 corresponds to day 29 of the study treatment. 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................ 2 
TABLE OF CONTENTS .......................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................ 19 
1 
INTRODUCTION .............................................................................................. 22 
1.1 
Disease Background .................................................................................. 22 
1.2 
Currently Available Treatments for Acute Myeloid Leukemia ........... 23 
1.3 
ASLAN003 (The Investigational Drug) ................................................... 24 
1.3.1 Pre-clinical Pharmacology of ASLAN003 ..................................... 24 
1.3.2 Safety Pharmacology of ASLAN003 .............................................. 25 
1.3.3 Pre-clinical Pharmacokinetics and Toxicokinetics of ASLAN003 . 26 
1.3.4 Toxicology of ASLAN003 .............................................................. 27 
1.4 
Clinical Experience with ASLAN003 ...................................................... 28 
1.5 
Known or Potential Risks Associated with ASLAN003 ........................ 30 
1.6 
Rationale for the Study ............................................................................. 30 
2 
STUDY OBJECTIVES ...................................................................................... 32 
2.1 
Primary Objective ..................................................................................... 32 
2.2 
Secondary Objective ................................................................................. 32 
2.3 
Exploratory Objectives ............................................................................. 32 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ...................................... 33 
3.1 
Study Design Overview ............................................................................. 33 
3.2 
Steering Committee ................................................................................... 35 
3.3 
Criteria for Evaluation of the Study ....................................................... 35 
3.3.1 Primary Endpoints ........................................................................... 35 
3.3.2 Secondary Endpoints:...................................................................... 35 
3.3.3 Exploratory Endpoint (Parts 1 and 2): ............................................ 36 
3.4 
Duration of the study participation ......................................................... 36 
4 
STUDY POPULATION ..................................................................................... 38 
4.1 
Inclusion Criteria ...................................................................................... 38 
4.2 
Exclusion Criteria ..................................................................................... 38 
4.3 
Patient Withdrawal and Replacement .................................................... 39 
4.4 
Planned Sample Size and Number of Study Centers ............................. 41 
4.5 
Patient Identification and Allocation of Treatment ............................... 41 
5 
INVESTIGATIONAL PRODUCT ................................................................... 43 
5.1 
Identity of Investigational Product .......................................................... 43 
5.2 
Study Drug Administration ...................................................................... 43 
5.3 
Permitted Dose Interruptions of Study Drug ......................................... 43 
5.4 
Intra-patient dose escalation .................................................................... 44 
5.5 
Packaging, Labeling and Storage ............................................................ 44 
5.6 
Blinding ...................................................................................................... 44 
5.7 
Study Drug Accountability ....................................................................... 44 


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5.8 
Study Drug Compliance ........................................................................... 45 
5.9 
Previous and Concomitant Medications/Non-drug therapies ............... 45 
5.9.1 Permitted Concomitant Therapy ..................................................... 45 
5.9.2 Prohibited Concomitant Therapy .................................................... 45 
6 
STUDY VARIABLES AND METHODS OF ASSESSMENT ....................... 46 
6.1 
Determination of Optimum Dose ............................................................. 46 
6.2 
Efficacy Variables ..................................................................................... 46 
6.3 
Safety Variables ......................................................................................... 48 
6.3.1 Adverse Events................................................................................ 48 
6.3.1.1 Collection of Adverse Events ................................................... 48 
6.3.1.2 Definitions ................................................................................ 48 
6.3.1.3 Assessment of Adverse Events .................................................. 49 
6.3.1.4 Seriousness ............................................................................... 49 
6.3.1.5 Intensity .................................................................................... 50 
6.3.1.6 Causality .................................................................................. 50 
6.3.1.7 Recording Adverse Events ....................................................... 51 
6.3.1.8 Reporting Serious Adverse Events ........................................... 52 
6.3.1.9 Follow-up of Adverse Events ................................................... 52 
6.3.1.10 Suspected Unexpected Serious Adverse Reactions ............. 53 
6.3.1.11 Pregnancy............................................................................ 53 
6.3.1.12 Laboratory Variables .......................................................... 55 
6.3.2 Physical Examinations .................................................................... 57 
6.3.3 Vital Signs ....................................................................................... 57 
6.3.4 Electrocardiograms ......................................................................... 57 
6.3.5 ECOG Performance Status .............................................................. 57 
6.3.6 Additional Safety Assessments ....................................................... 57 
6.4 
Pharmacokinetics Assessment (Part 1 ONLY) ....................................... 58 
6.4.1 Collection of Blood Samples .......................................................... 58 
6.4.2 Determination of Drug Concentrations in Blood Samples ............. 59 
6.5 
Other Exploratory Assessment ................................................................ 59 
6.6 
Demographics and Baseline Characteristics .......................................... 59 
6.6.1 Patient Demography ........................................................................ 59 
6.6.2 Disease History ............................................................................... 59 
6.6.3 Medical History ............................................................................... 60 
6.6.4 Previous and Concomitant Medications.......................................... 60 
6.7 
Other Variables ......................................................................................... 60 
7 
STUDY CONDUCT ............................................................................................ 61 
7.1 
Schedule of Procedures ............................................................................. 61 
7.2 
Procedures by Visit ................................................................................... 61 
7.2.1 Screening (Days -28 to 0) ............................................................... 61 
7.2.2 Treatment Visits .............................................................................. 62 
7.2.2.1 Cycle 1, Day 1 .......................................................................... 62 
7.2.2.2 Cycle 1, Day 8 (±1 day) ........................................................... 62 
7.2.2.3 Cycle 1, Day 10 (+1 day) ......................................................... 63 
7.2.2.4 Cycle 1, Day 15 (±2 days) ........................................................ 63 


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7.2.2.5 Cycle 1, Day 22 (±2 days) ........................................................ 63 
7.2.2.6 Cycle 2 and Subsequent Cycles - Day 1 (±2 days) .................. 63 
7.2.3 End of Treatment (EOT) Visit ........................................................ 64 
7.2.4 Safety Follow-up (±7 days) ............................................................. 64 
7.2.5 Survival Follow-up (±7 days) ......................................................... 64 
8 
STATISTICAL METHODS .............................................................................. 65 
8.1 
General Statistical Considerations .......................................................... 65 
8.2 
Sample size determination ........................................................................ 65 
8.3 
Analysis population ................................................................................... 65 
8.3.1 Safety Population ............................................................................ 65 
8.3.2 Full Analysis Set ............................................................................. 65 
8.3.3 Evaluable for Response Set ............................................................. 65 
8.3.4 Pharmacokinetic analysis set........................................................... 66 
8.4 
Methods of Statistical Analysis ................................................................ 66 
8.4.1 Assessment of Efficacy ................................................................... 66 
8.4.2 Optimum Dose determination ......................................................... 67 
8.4.3 Safety Analyses ............................................................................... 67 
8.4.3.1 Adverse Events ......................................................................... 67 
8.4.3.2 Clinical Laboratory Evaluations ............................................. 69 
8.4.3.3 Vital Signs and ECG measurements ........................................ 69 
8.4.4 Pharmacokinetic Analysis ............................................................... 69 
8.4.5 Exploratory Analysis ....................................................................... 69 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ......................... 70 
9.1 
Data Quality Assurance ............................................................................ 70 
9.1.1 Database Management and Quality Control ................................... 70 
9.1.2 Monitoring ...................................................................................... 70 
9.1.3 Audit and Inspections:..................................................................... 71 
9.2 
Case Report Forms and Source Documentation .................................... 71 
9.2.1 Data collection ................................................................................ 72 
9.3 
Access to Source Data ............................................................................... 72 
9.4 
Data Processing ......................................................................................... 73 
9.5 
Archiving Study Records .......................................................................... 73 
9.6 
Good Clinical Practice .............................................................................. 73 
9.7 
Informed Consent ..................................................................................... 73 
9.8 
Protocol Approval and Amendment ....................................................... 74 
9.9 
Name of Committee................................................................................... 74 
9.10 Duration of the Study ............................................................................... 74 
9.11 Premature Termination of the Study ...................................................... 74 
9.12 Confidentiality ........................................................................................... 75 
9.13 Other Ethical and Regulatory Issues ...................................................... 75 
9.14 Liability and Insurance ............................................................................ 75 
9.15 Publication Policy ...................................................................................... 75 
10 REFERENCES ................................................................................................... 76 
11 APPENDICES ..................................................................................................... 78 


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11.1 Appendix 1: WHO Classification of Acute Myeloid Leukemia ............ 78 
11.2 Appendix 2: ECOG Performance Status ................................................ 79 
11.3 Appendix 3: Child-Pugh Score ................................................................ 80 
12 SIGNATURE PAGE .......................................................................................... 81 
13 LIST OF STUDY PERSONNEL ....................................................................... 83 
 
IN-TEXT TABLES 
Table 1: Schedule of Study Assessments.................................................................... 11 
Table 2: Grade 3/4 AST/ALT/CCT ............................................................................ 43 
Table 3: Laboratory Assessment ................................................................................. 56 
Table 4: ASLAN003 Pharmacokinetic Assessment Schedule.................................... 58 
 
IN-TEXT FIGURES 
Figure 1: Study Design Description .......................................................................... 344 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ADL 
Activities of Daily Living 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
aPTT 
activated partial thromboplastin time 
APL 
Acute promyelocytic leukemia 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the plasma concentration curve 
AUCtau 
AUC over the dosing interval 
AUCtau ss 
AUCtau at steady state 
AUC0-24 
area under the curve during 24 hours 
AUC0-inf 
area under the curve from time 0 extrapolated to infinite time 
BM 
BMA 
Bone marrow 
Bone Marrow Aspiration 
°C 
degrees Celsius 
CART 
Chimeric antigen receptor-T 
CBR 
Cell/uL 
clinical benefit rate 
cells per micro liter 
CI 
Confidence interval 
CL/F 
Apparent total clearance of the drug from plasma after oral 
administration  
Cmax 
maximum observed plasma concentration 
Cmax ss 
Cmax at steady state 
CNS 
central nervous system 
CSR 
clinical study report 
CR 
complete remission 
CRi 
complete remission with incomplete hematologic recovery 
CRF 
case report form 
CRO 
clinical research organization 
CrCl 
creatinine clearance  
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough plasma concentration 
CYP 
cytochrome P450 
DHODH 
dihydroorotate dehydrogenase 
DLT 
dose-limiting toxicity 
DNA 
deoxyribose nucleic acid 
eCRF 
electronic case report form 
ECG 
electrocardiogram 


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EDC 
electronic data capture 
ED90 
concentration producing 90% effect 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
EPO 
erythropoietin 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FLT3 
fms-related tyrosine kinase 3 gene 
FOB 
Functional Observational Battery 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GO 
Gemtuzumab ozogamicin 
GSH 
glutathione 
h 
hour 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HgbA1c 
hemoglobin A1c 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
ICF 
informed consent form 
IDH 
Isocitrate dehydrogenase 
IEC 
Independent Ethics Committee 
IFN 
interferon 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITD 
tandem duplication mutation 
i.p. 
intraperitoneal 
i.v. 
intravenous 
IWG 
International Working Group 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNPCE 
micronucleated polychromatic erythrocytes 
MR 
metabolic ratio 
MRCmax 
MRAUC 
metabolic ratio for Cmax 
metabolic ratio for AUC  


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NADPH 
nicotinamide adenine dinucleotide phosphate 
NCCN 
National Comprehensive Cancer Network 
NGS 
next-generation sequencing 
NOEL 
no observed effect level 
OCRR 
overall complete remission rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic(s) 
PML-RARA 
promyelocytic leukemia/retinoic acid receptor alpha 
PO 
per os (by mouth/orally) 
PR 
partial remission 
QD 
once daily 
RacAUC 
accumulation ratio for AUC 
RacCmax 
accumulation ratio for Cmax  
RBC 
red blood cell (count) 
RFS 
relapse free survival 
SAD 
single ascending dose 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SC 
Steering Committee 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
t1/2 eff 
effective elimination half-life at the steady state  
TEAE 
treatment-emergent adverse event 
TK 
tyrosine kinase 
TKD 
tyrosine kinase domain 
TLF 
Tables, listings and figures 
tmax 
time corresponding to occurrence of Cmax 
tmax ss 
tmax at steady state 
ULN 
Vss/F 
upper limit of normal 
apparent volume of distribution at steady state after oral administration 
WBC 
white blood cell (count) 


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1 
INTRODUCTION 
ASLAN003 (LAS186323) is a novel inhibitor of the enzyme dihydroorotate 
dehydrogenase (DHODH); it was initially discovered and patented by Almirall, S.A. In 
May 2012, global rights to the compound LAS186323 were granted to ASLAN 
Pharmaceuticals and the compound was then re-named as ASLAN003. The molecule was 
initially evaluated for the treatment of rheumatoid arthritis; and is currently being 
investigated for the treatment of acute myeloid leukemia (AML). ASLAN003 is a potent, 
small molecule, reversible, selective inhibitor of dihydroorotate dedrogenase (DHODH), 
with a pharmacokinetic (PK) profile allowing once daily (QD) administration. 
 
1.1 
Disease Background 
AML, a heterogeneous hematologic malignancy, is the most common acute leukemia 
among adults and characterized by abnormal proliferation and differentiation of a clonal 
population of myeloid blasts in the bone marrow (BM) and peripheral blood. AML 
accounts for 25% of all leukemia of adults in the Western world, with the highest incidence 
rates occurring in the United States, Australia and Europe.2 In 2016 in the United States, 
about 19,950 people were diagnosed with AML and 10,430 patients died from this disease. 
The median age of diagnosis is at 67 years and the incidence increases with age, with 54% 
of patients diagnosed at ≥ 65 years and approximately a third diagnosed at ≥ 75 years of 
age.3 In Australia, AML accounts for about 1.1% of all cancer cases annually;4 an 
age-standardized incidence rate of 3.8 per 100,000 persons: 4.7 per 100,000 persons in 
males and 3.0 per 100,000 persons in females is reported as per 2014 overview.5 The 
incidence of AML in the white population (3.8 per 100,000 person) is higher than that of 
the Asian population (3.2 per 100,000 person).6 According to the Singapore Cancer 
Registry 2015, myeloid neoplasms were the 10th most common cancer amongst males in 
Singapore in 2008-2012; and AML was the most common myeloid neoplasm accounting 
for 35.9% of 1,434 cases.7 In the majority of cases, AML develops as a de novo malignancy 
in previously healthy individuals. Many environmental factors, underlying hematological 
diseases (e.g. myelodysplasia) and prior chemotherapy for solid tumors or hematologic 
malignancies increase the risk of developing AML.3,8 
 
Based on their cytogenetic and molecular abnormalities, AML can be categorized into 
favorable-, 
intermediate- 
and 
poor-risk 
groups.3 Patients 
with 
chromosomal 
rearrangements t(8;21), t(15;17), t(16;16) or inv(16) are associated with favorable 
prognosis with longer remission and survival, whereas patients with monosomy 5 or 7, 
t(6;9), t(9;22), inv(3), t(3;3), 11q23 abnormalities, monosomal karyotype or complex 
karyotype (>3 clonal chromosomal abnormalities) are associated with poor prognosis with 
higher risk of treatment failure and death. In contrast, patients with normal karyotype AML 
(NK-AML), +8 alone or t(9;11) are regarded as intermediate-risk group with an 
intermediate risk of relapse. Differences in molecular abnormalities are associated with 
varied clinical outcomes.3,8 In general, TP53 mutations are associated with a poor 
prognosis. On the contrary, bi-allelic mutation of CCAAT Enhancer Binding Protein 
(CEBPα) and mutation of nucleophosmin 1 in the absence of fms-related tyrosine kinase 
3 gene (FLT3)-ITD are associated with favorable overall survival (OS) or a higher 
complete response (CR).3,8-10 


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1.2 
Currently Available Treatments for Acute Myeloid Leukemia  
The current standard treatment of AML includes induction therapy and consolidation 
therapy. For patients younger than age 60 years, the continuous infusion of the 
standard-dose cytarabine for 7 days with 3 days of anthracycline is commonly used for 
induction therapy to remove excess blasts and achieve CR.3 Elderly patients usually 
present with poor performance profile and are often unable to tolerate the toxicity of 
chemotherapy. Studies show hypomethylating agents (e.g. decitabine and azacitidine), 
which are used for the treatment of myelodysplastic syndrome, improved survival in 
elderly patients when compared to supportive care or low dose cytarabine.3,8 Although 
established chemotherapy regimens achieve 60% to 80% CR in de novo AML patients 
after induction therapy, approximately 50% to 55% of patients in the high risk group will 
relapse after consolidation therapy or transplantation.8,11 
 
Inhibition of tyrosine kinase (TK) receptors have been used successfully in various solid 
and hematological malignancies. Mutations in the FLT3 are found in 30% of adults with 
newly diagnosed AML.12 Approximately three quarters of these patients have a FLT3 
internal tandem duplication mutation (ITD), while 8% of patients with newly diagnosed 
AML have a FLT3 point mutation in the tyrosine kinase domain (TKD). Furthermore, 
FLT3-ITD mutations have been associated with increased risk of relapse, while the 
prognostic relevance of FLT3-TKD mutations is controversial. Due to poor prognosis in 
patients with FLT3-ITD mutation, targeting this tyrosine kinase has been considered as a 
potential therapeutic strategy in AML. Several anti-FLT3 agents are being developed, 
including the first-generation inhibitors such as sorafenib and midostaurin, and 
second-generation agents such as quizartinib and crenolanib. However, with exception to 
crenolanib which is currently being studied in clinical trials, the effects of other FLT-3 
inhibitors are limited due to relapse or the rapid development of resistance.8,9 
 
The gain of function mutations in Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) 
enzymes are found in approximately 20% of AML cases. Recent attempts have been made 
to target these mutant enzymes as a potential treatment for AML. Preliminary results in 
the clinical study of an IDH1 inhibitor, AG120, showed response in 7 out of 14 IDH-1 
positive patients. An IDH2 inhibitor, AG221, demonstrated an improvement on survival 
in an AML xenograft model. A Phase I trial of AG221 in IDH2 mutated leukemia patients 
is currently ongoing.8 
 
In addition to small molecular inhibitors, antibody therapies in AML are also currently 
under development. Gemtuzumab ozogamicin (GO) is a humanized recombinant antibody 
against CD33; the latter is a transmembrane protein expressed on cells of myeloid lineage. 
GO is conjugated to calicheamicin, a deoxyribonucleic acid (DNA)-cleaving cytotoxic 
agent, and able to be internalized in CD33-positive cells.8 GO was approved by Food and 
Drug Administration (FDA) in 2000 to treat AML in the patients 60 years or older with 
AML recurrence. However, it was withdrawn in 2009 since the post approval clinical trial 
was stopped early with no improvement in clinical benefit but with an increased number 
of deaths in the patients treated with GO plus chemotherapy compared to chemotherapy 
alone.13 Chimeric antigen receptor-T (CART) cells against AML is also a therapeutic 
strategy under development. Both CD33-directed and β member of the folate receptor 


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family (FRβ) -directed CART cell therapy showed efficacy in AML in vitro models, as 
well as, in an AML xenograft model. However, the investigations are still at an early 
stage.8,9 
 
Despite several novel agents being investigated for the treatment of AML, the backbone 
of the induction regimen has remained the same for decades as no convincing 
improvements in overall survival (OS) has been demonstrated for the new agents. While 
AML comprises many disparate genetic subtypes, one shared hallmark is the arrest of 
leukemic myeloblasts at an immature and self-renewing stage of development. Thus, 
therapies that overcome differentiation arrest may represent a powerful treatment strategy. 
 
Recent data from the Harvard School of Medicine, pointed to a very specific effect on blast 
maturation and a screen of 330,000 compounds revealed that this effect was uniquely 
linked to DHODH inhibition.14 Using a conditional myeloid differentiation arrest system 
with HoxA9, a high-throughput phenotypic screen and identification of small compounds 
able to remove the differentiation block was carried out. DHODH enzyme inhibitors were 
found to be the most active compounds enabling myeloid differentiation in human and 
mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased 
levels of leukemia-initiating cells, and improved survival.13 These data demonstrate the 
role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a 
strategy for overcoming differentiation blockade in AML. 
 
1.3 
ASLAN003 (The Investigational Drug) 
ASLAN003 is small molecule inhibitor that targets the enzyme DHODH. It was initially 
investigated in the treatment of rheumatoid arthritis with the aim of improving several 
features of leflunomide (ARAVA®)/teriflunomide, namely increasing its potency against 
the human DHODH enzyme, extending its terminal elimination half-life, and improving 
its side effect profile. ASLAN003 has a higher in vitro potency than teriflunomide for 
both inhibiting the human DHODH enzymatic activity and human T-cell proliferation.  
 
The investigational product consists of an orange-colored hard gelatin capsule 
containing 10 mg or 50 mg of ASLAN003 for oral administration. Each capsule contains 
ASLAN003, lactose monohydrate, colloidal silicon dioxide and sodium stearyl 
fumarate. 
 
The pre-clinical pharmacology and toxicology findings for ASLAN003 are summarized 
below. Clinical experience with ASLAN003 has also been included in the sections 
below. For more details, please refer to the Investigator’s Brochure for ASLAN003.15 
1.3.1 Pre-clinical Pharmacology of ASLAN003 
The effectiveness of ASLAN003 has been extensively investigated using in vitro and in 
vivo experimental models. ASLAN003 is a potent human DHODH inhibitor showing a 
31-fold increase in potency compared to teriflunomide, the active metabolite of 
leflunomide (half maximal inhibitory concentration [IC50] of 35 nM vs. 1083 nM, 
respectively). The metabolites of ASLAN003, the O-demethylated metabolite 
(LAS186558) and its hydroxylated metabolite (LAS186876) were less active than the 


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parent compound (IC50 of 247 nM and 157 nM, respectively) against human DHODH. 
ASLAN003 is a selective inhibitor of DHODH with no significant inhibition (>50% at 
10 μM) against a large panel of enzymes, receptors and ion channels except for ML2, a 
melatonin receptor involved in sleep disorders. Although the relevance of this finding is 
unknown, it should be noted that ASLAN003 does not cross the blood-brain barrier. 
 
ASLAN003 has demonstrated efficient inhibition of human lymphocyte proliferation 
from human peripheral blood mononuclear cells (PBMC), with an IC50 of 1.4 µM, which 
was about 30-fold more potent than teriflunomide (46 µM). Similarly, ASLAN003 
efficiently inhibited the proliferation of immortalized human epidermal keratinocytes 
with an IC50 of 0.58 µM, while the IC50 for teriflunomide is 15 µM in the same assay. In 
agreement with results obtained in both the enzymatic and PBMC proliferation assays, 
ASLAN003 was found to be more potent than teriflunomide (100-fold) in inhibiting 
interferon-gamma (IFNγ) secretion by stimulated lymphocytes from whole blood 
samples (IC50 of 2.5 µM vs. 259 µM, respectively). ASLAN003 was not cytotoxic to 
Chinese Hamster Ovary cells at concentrations up to 100 μM, while a 63% reduction in 
adenosine triphosphate (ATP) was observed at 200 μM. ASLAN003 was not toxic to 
cultured human hepatocytes in vitro despite its potency as human DHODH inhibitor. 
The in vitro therapeutic index, defined as the ratio IC50 cytotoxicity/IC50 PBMC 
proliferation, is 67 for ASLAN003 compared with 1.9 for teriflunomide. These data 
indicate that the inhibition of DHODH by ASLAN003 is not related to a direct toxicity 
in hepatocytes. 
 
ASLAN003 has also been studied in selected AML cell lines of various morphology 
subtypes – HL-60, MOLM-14, THP-1, KG-1 and NB4. ASLAN003 induced 
differentiation of AML cell lines: KG-1, MOLM-14 and THP-1, at nanomolar 
concentrations with minimal cell toxicity effects, as shown by up-regulation of CD11b 
on the surface of the treated AML cells. In contrast, acute promyelocytic leukemia cell 
lines, NB-4 and HL-60, showed limited differentiation response upon treatment with 
ASLAN003 even at micromolar concentrations. Supplementation with 50 µM uridine 
abrogated the differentiation effect of ASLAN003, demonstrating that differentiation 
resulted from the inhibition of DHODH, since uridine is a product of the de novo 
pyrimidine synthesis pathway. The differentiation effects of ASLAN003 were also 
observed in ex vivo assays conducted with primary blast cell samples obtained from 
AML patients’ bone marrow. Please refer to the Investigator’s Brochure for more 
details.15 
 
1.3.2 Safety Pharmacology of ASLAN003 
The effects of ASLAN003 were investigated on vital functions such as cardiovascular, 
respiratory, central nervous system (CNS), and liver function in various pre-clinical 
models. The cardiovascular safety profile was studied in both in vitro and in vivo studies. 
ASLAN003 up to 10 μM concentrations had no effects on the hERG current (IKr) 
expressed in HEK-293 cells in in vitro studies. At 30 and 100 uM concentrations, 
ASLAN003 showed a weak block of hERG with a maximum reduction of 17% in 
current amplitude. Assessment of the action potential in piglet Purkinje fibers in the 


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presence of ASLAN003 showed no changes at a concentration of 3 μM but showed a 
progressive lengthening of the action potential duration at 40% and 90% repolarization 
(APD40 and APD90), at concentrations of 10 or 30 µM that probably reflected a 
potassium channel blocking effect. At 100 µM, ASLAN003 reduced the resting 
membrane potential, the maximum rate of depolarization, and the APD40 and APD90 
in a manner consistent with a sodium/calcium channel blocking effect. ASLAN003 
given at 10 mg/kg i.v. to anaesthetized guinea pigs were devoid of effects including any 
effects upon QTc. In anesthetized Beagle dogs, ASLAN003, at doses as high as 
200 mg/kg intraduodenally, did not produce clinically relevant changes in 
electrocardiogram intervals. 
 
Vertebral blood flow was decreased at the highest dose (200 mg/kg) by 45% although 
when dosed at 10 mg/kg intravenous (i.v.) to pithed rats, ASLAN003 did not produce a 
change in the blood pressure. In contrast, leflunomide produced a significant increases 
in diastolic blood pressure. When dosed to rats at 100 mg/kg, ASLAN003 had no effects 
upon respiratory function measured by tidal volume, respiratory rate or specific 
pulmonary resistance. 
 
Following oral doses of 1, 10 and 100 mg/kg ASLAN003 in a Functional Observational 
Battery (FOB) test in rats, only a slight increase in spontaneous activity and mild 
exophthalmia was observed. Furthermore, in a specific test to assess motor activity, 
ASLAN003 did not modify the distance traveled by each animal at any of the doses 
tested. 
 
An acute model of hepatotoxicity in rats and mice was developed to investigate the 
effects of ASLAN003 upon liver enzymes and bilirubin levels in plasma. The study 
design allowed comparison with teriflunomide. A dose of 100 mg/kg of teriflunomide 
significantly increased liver enzymes in both species. In contrast, ASLAN003 showed 
no effect at doses up to 300 mg/kg intraperitoneal (i.p.) suggesting a lower hepatotoxic 
potential for ASLAN003 than teriflunomide. 
 
1.3.3 Pre-clinical Pharmacokinetics and Toxicokinetics of ASLAN003 
The PK of ASLAN003 after the single i.v. administration was studied in Wistar rats, 
Beagle dogs and Cynomolgus monkeys. Following administration, ASLAN003 showed 
a low clearance in all animal species (< 0.1 l/h/kg) and a low value for distribution 
volume (apparent volume of distribution at steady state: 0.1-0.2 l/kg). The longest 
elimination half-life (t1/2) was observed in rats (12-14 hour [h]), followed by monkeys 
(7 h) and dogs (4 h). Following a single oral dose of 1 and 10 mg/kg of ASLAN003 in 
Wistar rats and Beagle dogs, the tmax mean value found was between 1.5 and 3h. A 
longer tmax value (6 h) was found in the rats at the higher dose administered. The peak 
concentration (Cmax) found for ASLAN003 was between 3 to 5 times lower in dogs than 
in rats. Changes in Cmax and area under the curve during 24 hours (AUC(0-24)) were 
dose-proportional at the oral dose range studied in rats, whereas the values increased 
less proportionally with the oral dose in dogs. Comparison of the oral dose AUC values 
with the results obtained after intravenous administration suggested moderate (59% to 


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65%) to low (21% to 35%) oral bioavailability in rats and dogs, respectively. In dogs, 
the t1/2 was independent of the administration route, whereas in rats the t1/2 after oral 
administration (23h) was somewhat longer than that obtained after i.v. dosing (14h) at 
the same dose, suggesting that the absorption constant could be much slower than the 
elimination rate constant.  
 
Toxicokinetic studies carried out in rats and dogs confirmed the systemic exposure of 
the animals to ASLAN003, and to its metabolites LAS186558 and LAS186876. Plasma 
levels for both metabolites were always significantly lower than those of the unchanged 
parent compound. The main oxidative metabolites found in vivo were the same as those 
formed by human liver microsomes. In liver microsomes, ASLAN003 was extensively 
metabolized (NADPH-dependent) mainly via CYP1A2 and CYP2C9. Two main 
oxidative metabolites have been identified in all toxicological species and humans: 
LAS186558 (O-demethylated metabolite) and LAS186876 (hydroxylated metabolite). 
Phase II metabolism was also demonstrated in all species by the formation of a 
glucuronide derivative of ASLAN003 (LAS186323) in all the species studied. 
Exploratory studies performed to assess the potential of ASLAN003 to inhibit different 
human CYP450 enzymes suggested that ASLAN003 has some inhibitory effects on 
CYP2C9 (IC50 5-25 µM), but it is unlikely to modify its own metabolic clearance and/or 
the metabolic clearance of concomitant medication. The formation of reactive 
metabolites (glutathione [GSH]-adducts) was studied in rats and human liver 
microsomes. The potential of ASLAN003 to form reactive intermediates was 
considered to be low. 
 
1.3.4 Toxicology of ASLAN003 
The preclinical safety of ASLAN003 was assessed following single (rats and mice) and 
repeated oral dose administration (rats and dogs).  
 
ASLAN003 was acutely toxic at high doses above 500 mg/kg. Following high doses, 
generalized clinical signs including hypothermia, piloerection and decreased activity 
were observed. Necropsy observations in mice included the presence of blackish content 
in the stomach and duodenum and blackish punctiform areas in the glandular mucosa.  
 
In rats in a 4-week repeated dose toxicity study, showed ASLAN003 was severely toxic 
when dosed at 15 mg/kg necessitating dose reduction to 10 mg/kg and subsequently 
discontinuation of dosing in females. The main histopathological changes were 
decreased cellularity in organs of the immune system, hematopoietic system and 
presence of cytotoxic enteropathy in the GI. Decrease in red blood cell (RBC) parameters 
together with an increase in platelets and reticulocytes were seen in male animals that 
received 7.5 mg/kg or 10 mg/kg but not in females, probably due to the severe bone 
marrow toxicity was seen in female animals. Following a 2-week recovery period, all of 
the hematological and histopathological changes had completely resolved. The no 
observed effect level (NOEL) in rats was established at 2.5 mg/kg/day.  
 


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In dogs, the main clinical finding was diarrhea and the main histopathological change 
was cytotoxic enteropathy. These adverse effects were probably related to the 
anti-proliferative activity of DHODH inhibition and were fully reversible. Following 
dosing at 20 mg/kg/day, the effects on clinical condition were sufficiently severe to 
justify dose reduction to 17.5 mg/kg/day and discontinuation in 2 dogs at 
17.5 mg/kg/day/dose and 1 dog at 15 mg/kg/day dose. In addition to the cytotoxic 
enteropathy, decreased cellularity of the bone marrow and lymphoid atrophy were 
observed following 15 to 20 mg/kg/day. The NOEL in dogs were established at 
7.5 mg/kg/day.  
 
ASLAN003 was non irritating to the rabbit skin or eyes. ASLAN003 did not exhibit 
phototoxic potential in guinea pigs.  
 
ASLAN003 showed no evidence of mutagenic activity in a bacterial reverse mutation 
assay (Ames Test) or in an in vitro chromosomal aberration test in human peripheral 
lymphocytes. In an in vivo mouse micronucleus test, produced a small but statistically 
significant (p<0.05) increase in the micronucleated polychromatic erythrocytes 
(MNPCE) in male mice, at a dose of 2000 mg/kg of ASLAN003. A second study in male 
mice confirmed this weak response at dose levels above 1000 mg/kg and established 
500 mg/kg to be the no effect dose for induction of MNPCE. The increased frequencies 
of MNPCE produced by ASLAN003 were associated with preceding increase in plasma 
concentrations of erythropoietin (EPO). Since increased erythropoiesis is an accepted 
physiological mechanism by which MNPCE frequencies increase, the effect of 
ASLAN003 on MNPCE frequency is considered secondary to its effect on EPO rather 
than the intrinsic genotoxicity of the molecule.  
 
In vitro analysis of liver safety biomarkers in elderly human patients who experienced 
elevations in liver enzymes in the Phase I study (ASLAN003-001), as well as 
mechanistic studies of cytotoxicity of ASLAN003 in human hepatocytes were 
performed. It demonstrated that DHODH inhibition by high doses of ASLAN003 caused 
reversible hepatocyte apoptosis via the induction of p53. The transient elevation in liver 
enzymes is accompanied by a delayed increase in circulating biomarker of liver 
regeneration. 
 
1.4 
Clinical Experience with ASLAN003 
ASLAN003 has been administered to healthy subjects in 3 Phase I studies.  
 
The safety, tolerability and PKs of ASLAN003 and its metabolites have been evaluated in 
healthy male subjects following oral administration of single ascending doses of 1, 2, 5, 
10, 25, 50 and 100 mg (7 dose levels) of ASLAN003 in healthy male Caucasian subjects 
in a Phase I study (Study M/186323/01). Although t1/2 was consistent across the different 
dose levels, Cmax and AUC increased less proportionally with increasing dose. The main 
metabolite circulating in plasma was LAS186558 with mean AUC values across all 
administered doses between 3.4% and 9.8% of the mean AUC values of the parent drug; 
metabolite. LAS186876 was a minor metabolite and was formed at less than 2% of parent 
drug AUC. ASLAN003 was well-tolerated at all doses studied.  


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In another Phase I, randomized, double-blind, placebo-controlled, 2-part study (Study 
ASLAN003-001), the safety, tolerability and PKs of single ascending doses (SAD) and 
multiple ascending doses (MAD) of ASLAN003 were evaluated in healthy Asian subjects. 
ASLAN003 administered as single and multiple doses of 100 mg, 200 mg, and 400 mg 
under fed and fasted conditions safe and well-tolerated in healthy subjects. For ASLAN003 
and its 2 oxidative plasma metabolites, there was no evidence of departures from dose 
proportionality following a single dose under fasted conditions in terms of area under the 
curve from time 0 extrapolated to infinite time (AUC(0-inf)), whereas the analyses revealed 
less dose proportional increase in Cmax.  
 
Following a single oral dose of 200 mg ASLAN003 with a high-fat meal (fed state), the 
median tmax was delayed by 1.5 hours as compared to the 200 mg dose in the fasted state. 
The Cmax and AUC of ASLAN003 were increased by 29% and 18% respectively and 
inter-subject variability was reduced. Mean t1/2 was similar under both fed and fasted 
dosing conditions for both parent drug and the 2 metabolites.  
 
In the MAD part of the study (100 mg, 200 mg, and 400 mg, QD for 7 days), the plasma 
AUCtau and Cmax for ASLAN003 and LAS186876 revealed no evidence of departures from 
dose proportionality with increasing doses of ASLAN003 when taken after a meal. 
However, the AUCtau and Cmax for LAS186558 increased in a less dose-proportional 
manner.  
 
The tmax and t1/2 for ASLAN003 were dose-independent following QD doses across the 
selected dose range; 5 and 16 hours, respectively. Steady-state concentrations of 
ASLAN003, LAS186558, and LAS186876 were achieved by Day 4 across the selected 
dose range. Following daily repeated dosing, exposure to ASLAN003 and LAS186558 
(AUC) appeared to accumulate slightly (less than 30% increase). The exposure was higher 
in elderly subjects (AUCtau) of ASLAN003 was increased by 53% and Cmax by 41%), 
which may be explained by their lower body weight. Renal elimination of free 
(unconjugated) ASLAN003, LAS186558, and LAS186876 were negligible (<0.8% of the 
administered dose). Phase II metabolism appeared to be an important route of elimination. 
Conjugation was most prevalent for ASLAN003 and LAS186558. 
 
Most frequently reported adverse events (AEs) across this ASLAN003-001 study were 
abnormality in laboratory investigations and included  elevated alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), gamma glutamyltransferase, blood cholesterol 
increased, blood creatine phosphokinase increased, electrocardiogram (ECG) PR, and 
blood glucose increased. The safety assessment results reported in patients aged ≥ 55 years 
were mostly comparable with those of younger subjects other than for greater changes in 
the laboratory assessments in the elderly subjects compared to the younger subjects, 
notably the liver function tests. 
 
Another Phase IB study (Study ASLAN003-002) evaluated the safety, tolerability and PKs 
of multiple doses of 100 mg of ASLAN003 QD for 14 days in healthy elderly Asian 
subjects (age > 55 years old). The study was conducted at a single center in Singapore 
where 7 of the planned 8 elderly subjects were enrolled into Stage 1 of the study, of which 


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5 subjects received ASLAN 100 mg QD on Day 1; and 4 of these subjects received ASLAN 
100 mg QD on Day 8. Only 1 subject completed 14 days of QD dosing. Stage 2 of the 
study was not conducted. Following daily repeated dosing, mean plasma exposure to 
ASLAN003 expressed as AUC(0-24) increased 1.2-fold after multiple dosing on Day 8 
compared to a single dose on Day 1. Following repeat QD dosing, the relative systemic 
exposures to the metabolites LAS186558 and LAS186876 were around 10% and 1%, 
respectively. 
 
Elevations in liver function tests in ASLAN003-002 study was similar to the observation 
in the previous study (ASLAN003-001). This is likely to be a class effect of DHODH 
inhibitors. Monitoring of liver function in patients is recommended. It is possible that 
elderly subjects could be more susceptible to these effects. 
 
1.5 
Known or Potential Risks Associated with ASLAN003 
ASLAN003 has demonstrated an acceptable safety profile in nonclinical toxicology 
studies and completed Phase I studies in humans. However, as with any new 
investigational drug, unexpected AEs may occur with the use of ASLAN003. The 
following is a summary of potential risks; additional details are presented in the IB: 
• ASLAN003 must not be administered to pregnant or nursing women. 
• ALT, AST, and total bilirubin along with signs or symptoms of liver toxicity should 
be monitored during ASLAN003 treatment. 
 
1.6 
Rationale for the Study 
A recent publication by Sykes et al. (2016)14 summarized 5 years of primary science and 
identified DHODH as a critical enzyme in the differentiation of human AML blast cells to 
granulocytes. In vitro studies with ASLAN003 have demonstrated that the compound 
induces the differentiation of AML cell lines: KG-1, MOLM-14 and THP-1, through 
inhibition of DHODH. Ex vivo analyses with ASLAN003 have also demonstrated myeloid 
differentiation of primary AML blast cells obtained from patients. 
 
In Phase I studies, ASLAN003 was generally well-tolerated. No clinically significant 
changes in liver transaminase enzymes were noted in healthy male volunteers (except for 
elderly subjects who had greater liver function alterations) when ASLAN003 was dosed at 
clinically relevant exposures. ASLAN003 may offer an important addition to induction 
therapies, or in combination with other therapies such as azacytidine, or as a monotherapy. 
 
We now intend to study the effects of ASLAN003 over a dose range, with the purpose to 
a) study efficacy in AML patients, and b) determine the dose optimum dose based on the 
combined efficacy and safety data. 
 
ASLAN003 is very potent in inducing differentiation of AML cells lines (ED90 < 50 nM 
for THP-1). From these predictions, a starting dose of 100 mg QD would be most 
appropriate to obtain a good coverage of ED90 values. Since ASLAN003 is an acidic 
compound, the protein binding effect in human plasma should be considered. A starting 


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dose of ASLAN003 100 mg should obtain full 24-hour coverage of the effect. The fact that 
blast cell counts vary drastically among AML patients, suggests that a higher treatment 
dose might be necessary to show the optimum efficacy in some patients. Considering that 
AML patients are generally older in age and often carry comorbidities, it may be prudent 
to use doses lower than the maximum dose (400 mg) employed in healthy subjects. 
Therefore, the study will use 3-4 dose groups: 100 mg QD, 200 mg QD, 100 mg BID and 
potentially an additional cohort of 200 mg BID, which may only commence, subject to 
agreement from the steering committee based on a review of safety data from the 100 mg 
BID cohort. . 
 
According to the pharmacokinetic data from the patients who had been treated with 
ASLAN003 100mg once daily in this study, the trough plasma concentration is below the 
IC50 of enzymatic hDHODH. A simulation model shows increasing the frequency of 
ASLAN003 administration keeps the plasma concentration of ASLAN003 above the IC50. 
Therefore, the dose and dosing frequency in two cohort (ASLAN003 100 mg BID and 
ASLAN003 200 mg BID) are changed and one additional cohorts with dosing ASLAN003 
twice daily is added to the study design. The daily total dose of ASLAN003 is still within 
the maximum dose, tested safe in prior trials. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Part 1: 
• 
To determine the optimum dose of ASLAN003 monotherapy based on the efficacy, 
safety and tolerability profile in AML patients who are ineligible for standard 
therapy. 
 
Part 2: 
• 
To provide a preliminary estimate of the efficacy of ASLAN003 at the optimum 
dose selected from Part 1. 
 
2.2 
Secondary Objective 
Part 1: 
• 
To evaluate the PKs of ASLAN003 and its metabolite LAS186558 in patients with 
AML. 
 
Part 2: 
• 
To further assess the safety and tolerability data of ASLAN003 at the optimum dose 
selected from Part 1.  
 
2.3 
Exploratory Objectives 
• 
To examine the myeloid differentiation effects of ASLAN003 using assays 
including but not limited to an ex vivo flow cytometry assay. 
• 
To explore possible relationships between molecular abnormalities and measures 
of clinical response in patients with AML.  


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Study Design Overview 
This is a multicenter, single arm, non-randomized, Phase IIA Study to evaluate 
ASLAN003 as a monotherapy in patients with AML.  
 
AML patients who are ineligible for standard treatment including, but not limited to the 
following conditions, will be enrolled in the study:  
• Newly diagnosed patients who are ineligible for standard therapy i.e., standard dose 
induction chemotherapy and reduced dose chemotherapy;  
• Patients with relapse from prior remission;  
• Patients with failed response to prior therapy including chemotherapy, 
hypomethylating agents, and bone marrow transplantation.  
 
Rationale for dose selection: ASLAN003 is very potent at inducing differentiation in 
AML cells lines (ED90< 50 nM for THP-1). From these predictions, a starting dose of 
100 mg QD would be the most appropriate to obtain a good coverage of ED90 values. Since 
ASLAN003 is an acidic compound, the protein binding effect in human plasma will be 
high leading to lower levels of free drug, a starting dose of 100 mg QD is recommended 
to provide full 24-hour coverage. 
 
Blast cell counts vary widely among AML patients, which may indicate that a higher 
treatment dose of ASLAN003 might be necessary to obtain the optimum efficacy. 
However, it is also important to consider the age and fitness of the AML patients who 
might have multiple comorbidities, and the maximum experienced dose (400 mg QD) 
established in healthy subjects might not be tolerated. Considering that AML patients are 
generally older in age and often carry comorbidities, it may be prudent to use doses lower 
than the maximum dose (400 mg) determined in healthy subjects.  
 
Up to a total of 18-24 patients will be enrolled in Part 1 of this study - 6 patients in each 
dose cohort. The planned sequence of cohort enrollment is ASLAN003 100 mg QD, 200 
mg QD, 100 mg BID and potentially an additional cohort of 200 mg BID (this additional 
cohort of 6 patients may commence, subject to agreement by the steering committee (SC) 
based on a review of safety data in 100 mg BID cohort). 
A SC meeting will be set up to review all the clinical information including efficacy, safety, 
and PK data.  Details of the SC outcome will be specified in the SC charter. 
 
An expansion cohort of 20 patients (Part 2) will be recruited to study the optimum dose 
selected by the SC. The optimum dose will be selected from at least one cohort showing 
tolerable safety profile and clinical benefit in disease presentation. Details will be specified 
in the SC charter. 
 
Patients with especially high blast cell count should be closely monitored for a possible 
differentiation syndrome. Investigators could manage suspected patients proactively 


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according to the recommendation in the National Comprehensive Cancer Network (NCCN) 
guidelines APL differentiation syndrome section. 
 
Bone marrow aspiration samples will be collected before the first day of treatment, will be 
cultured in vitro and incubated with ASLAN003 to examine the myeloid differentiation 
efficacy of ASLAN003 ex vivo. Molecular studies will also be done to check for any 
phenotypic and genotypic changes in the patients’ bone marrow sample. A bone marrow 
aspiration smear will be processed locally. Ex vivo assay and molecular assessment will be 
processed centrally (Please refer to the lab manual for details). 
 
All patients will continue to receive ASLAN003 until disease relapse, treatment failure, 
unacceptable toxicity, withdrawal of consent or death. 
 
For the PK evaluations, blood samples will be collected at the following timepoints on 
Day 1 and Day 8 of the QD, 28-day treatment cycle: pre-dose, 1, 2, 4, 5, 6, 8, and 24 hours 
post dose. In BID regime i.e 100mg BID and 200mg BID the PK sampling will be done at 
following timepoints: pre-dose, 1, 2, 4, 5, 6, 8, and 12 hours (or evening pre-dose). 
 
For Part 2 PK evaluations- Steering Committee will decide whether PK analysis is required 
or not and ASLAN pharmaceuticals will be updated accordingly 
 
The schedule of the assessments are presented in Table 1.  
 
Figure 1: Study Design Description 
 
 
 
Abbreviations: AML = acute myeloid leukemia; QD = once daily, BID = twice daily. 
 


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3.2 
Steering Committee 
A Steering Committee (SC) will be established for the purpose of assessing the efficacy, 
safety, tolerability, and PK data for the duration of the study. 
 
The SC will evaluate the progress of the study on an ongoing basis and will make key 
decisions on the study in the best interest of the patients. Examples include continuation 
or discontinuation of the study, investigation of a lower dose level not stated in the protocol 
if efficacy is observed at a higher dose level. Details of the steering committee outcome 
will be specified in the SC charter.  
 
An expansion cohort of 20 patients (Part 2) will be recruited to study the optimum dose 
selected by the SC. The optimum dose will be selected from at least one cohort showing 
tolerable safety profile and clinical benefit in disease presentation. Details will be specified 
in the SC charter. 
 
3.3 
Criteria for Evaluation of the Study 
3.3.1 Primary Endpoints 
Part 1: 
The primary objective of determining the optimum monotherapy dose of ASLAN003 in 
AML patients is based on the following endpoints: 
• 
Overall Complete Remission Rate (OCRR): Defined as the proportion of patients 
with a best response of complete remission (CR) or complete remission with 
incomplete hematologic recovery (CRi), defined in accordance with the 
International Working Group (IWG) Response Criteria in AML. 
• 
Safety and tolerability: Based on AEs, safety assessments (including vital signs, 
ECG parameters, clinical laboratory tests) and treatment exposure/dose intensity.  
Part 2: 
• 
OCRR: defined as described above for Part 1. 
3.3.2 Secondary Endpoints:  
• 
Efficacy (Parts 1 and 2): 
o Relapse Free Survival (RFS): Defined as the time the criteria for remission (CR 
or CRi) are first met until there is evidence of patient relapse, regardless of 
whether the patient is still taking study drug. Relapse is defined as: 
 The reappearance of leukemic blasts in the peripheral blood or > 5% 
blasts in the bone marrow not attributable to any other cause; 
 The appearance of new dysplastic changes; 
 The reappearance of or development of cytologically proven 
extrameduallary disease; 
 The reappearance of a cytogenetic or molecular abnormality. 


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o Clinical Benefit Rate (CBR): defined as the proportion of patients with an AML 
IWG best response of CR, CRi or partial remission (PR). 
o % change from baseline in BM blasts at Day 29. 
 
• 
Safety and tolerability (Part 2 ONLY): 
o Based on AEs, safety assessments (including vital signs, electrocardiogram 
[ECG] parameters, clinical laboratory tests) and treatment exposure/dose 
intensity. 
• 
Pharmacokinetics (Part 1 ONLY): 
If estimable, the following parameters will be calculated on Days 1 and 8, Cycle 1: 
o PK parameters for ASLAN003: maximum observed plasma concentration 
(Cmax), Cmax at steady state (Cmax ss), trough plasma concentration (Ctrough), time 
corresponding to occurrence of Cmax (tmax), and Cmax ss (tmax ss), AUC over the 
dosing interval (AUCtau), AUCtau at steady state (AUCtau ss), terminal elimination 
half-life at steady state (t1/2), effective elimination half-life at steady state 
(t1/2 eff), apparent total clearance of the drug from plasma after oral 
administration (CL/F), apparent volume of distribution at steady state after oral 
administration (Vss/F), accumulation ratio for AUC (RacAUC), and 
accumulation ratio for Cmax (RacCmax). 
o PK parameters for LAS186558: Cmax, Ctrough, tmax, AUCtau, t1/2 eff, RacAUC, 
RacCmax, metabolic ratio (MR) for Cmax (MRCmax) and AUC (MRAUC). 
3.3.3 Exploratory Endpoint (Parts 1 and 2):  
• Assessment of the degree of blast cell differentiation by ASLAN003 using assays 
including but not limited to ex vivo flow cytometry assay using selected myeloid 
cell markers (such as CD11b).  
• Assessment of the molecular abnormalities of AML blast cells at baseline. 
 
3.4 
Duration of the study participation 
The study duration consists of the following periods: 
 
Screening Period:  
28 days 
 
Treatment Period:  
All patients will receive a continuous 28-day treatment cycle of 
ASLAN003 until disease relapse, treatment failure (defined as 
failure to achieve a PR or higher within 4 cycles) unacceptable 
toxicity, withdrawal of consent or death. 
 
Follow-up Period:  
All patients will be required to complete a safety follow-up visit 
within 28 days after the last dose of study treatment. All patients 
achieving CR or CRi will be followed for survival every 12 weeks 
post end of treatment (EOT) until disease relapse or death (in the 
absence of disease relapse) to find out the RFS. 


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Visit Schedule:         In order to address the primary objectives of the study, if treatment 
is interrupted for any reason, it is important that all planned safety 
and efficacy assessments are performed at the scheduled time, 
regardless of whether the patient is receiving study treatment, or not, 
at the time. 
 
The planned duration of entire study (treatment and follow-up) is approximately 2 years. 


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4 
STUDY POPULATION 
The study population consists of AML patients who are ineligible for standard treatment 
including but not limited to the following conditions:  
• Newly diagnosed patients who are ineligible for standard therapy namely standard 
dose induction chemotherapy and reduced dose chemotherapy;  
• Patients who relapsed from prior remission;  
• Patients who failed to respond to prior therapy including chemotherapy, 
hypomethylating agents, and bone marrow transplantation. 
Patients must be able to provide written consent; meet all the inclusion criteria and none 
of the exclusion criteria, stated below. 
 
4.1 
Inclusion Criteria 
Patients will be enrolled into the study only if they meet all of the following criteria: 
1. Patients who are of or older than the legal age in the respective countries at the time 
when written informed consent is obtained 
2. Patients who are able to understand and willing to sign the informed consent form 
(ICF) 
3. Patients who are diagnosed with AML according to the 2016 revision to the World 
Health Organization classification of myeloid neoplasms and acute leukemia (refer to 
Appendix 1: WHO Classification of Acute Myeloid Leukemia) 
4. Patients who have a sufficient archival or fresh BM aspiration sample for the 
evaluation of relevant exploratory endpoint.  
Note: Patients who do not have sufficient archival BM aspiration sample and refuse 
to repeat the procedure may be enrolled in the trial only after written confirmation 
by ASLAN 
5. Patients who are ineligible for standard treatment of AML including but not limited 
to the following conditions: 
• Newly diagnosed patients who are ineligible for standard therapy namely 
standard dose induction chemotherapy and reduced dose chemotherapy;  
• Patients who relapsed from prior remission;  
• Patients who failed to respond to prior therapy including chemotherapy, 
hypomethylating agents, and bone marrow transplantation. 
6. Patients who have an Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤ 2 
7. Patients with adequate renal and hepatic function, as defined below: 
• Estimated Glomerular Filtration Rate (eGFR) or creatinine clearance (CrCl) 
(CrCL calculated by the Cockroft and Gault method) ≥ 40 ml/min/1.73 m2 
• Total bilirubin, AST, and ALT ≤ 1.5 x ULN 
 
4.2 
Exclusion Criteria  
Patients will be not be enrolled in the study if they meet any of the following criteria: 
1. Patients who are diagnosed with de novo myeloid sarcoma without bone marrow 
involvement 


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2. Patients who are diagnosed with acute promyelocytic leukemia/retinoic acid receptor 
alpha (PML-RARA) 
3. Patients who received any other standard or investigational treatment for their 
leukemia within the last 7 days before starting the first dose of study drug, with the 
exception of leukapheresis and hydroxyurea 
4. Patients with unresolved serious toxicity (≥ CTCAE 4.03 Grade 2) from prior 
administration of standard or investigational treatment for their leukemia 
5. Patients who have a positive test for human immunodeficiency virus (HIV), viral 
hepatitis C infection (patients with sustained viral response are not excluded), active 
viral hepatitis B infection (positive hepatitis B surface antigen [HBsAg]) with 
hepatitis B virus DNA exceeding 2000 IU/ml 
6. Patients who have a known history of liver cirrhosis Child-Pugh score B or C 
7. Patients who have any history of other malignancy unless in remission for more than 
1 year (skin carcinoma and carcinoma-in-situ of uterine cervix treated with curative 
intent is not exclusionary) 
8. Female patients who are pregnant or breast-feeding 
9. Patients with a known history of alcohol or drug addiction on the basis that there could 
be a higher risk of non-compliance to study treatment per Investigator’s discretion 
10. Patients with a history or presence of a clinically significant condition which in the 
opinion of the Investigator could jeopardize the safety of the patient or the validity of 
the study results 
11. Patients who have been previously treated with ASLAN003 
 
4.3 
Patient Withdrawal and Replacement 
Patients may withdraw from any part of the study at any time without penalty and for any 
reason without prejudice to his or her future medical care. The Investigator will advise the 
Sponsor of the withdrawal of any patient. 
 
Patients must be withdrawn from study drug under the following circumstances: 
• Patient voluntarily withdraws from study participation; 
• Disease recurrence; 
• Ineffective treatment; 
• Unacceptable toxicity; 
• Patient’s withdrawal of consent; 
• Death; 
• Pregnancy (refer to section 6.3.1.11) 
• Significant protocol deviation; 
• Lost to follow-up; 
• If deemed by the Investigator that it is not in the patient’s interest to continue 
withthe study. 
Withdraws from study participation (follow-up permitted):  
Patients withdrawing from the study drug will be encouraged where possible to return to 
the site for a study follow-up visit, in particular for safety evaluations, study assessments 
and survival follow-up. 


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Disease recurrence:  
Sites should continue to perform efficacy assessments for patients achieving CR or CRi 
until disease recurrence (or death in the absence of recurrence) in accordance with IWG 
criteria for AML. Patients will be withdrawn from the treatment if there is evidence of 
disease recurrence as defined by IWG Criteria16 (Cheson, 2003). 
 
Ineffective treatment:  
The study drug may be discontinued in the event of: 
• Treatment failure (in patients who do not achieve a PR or above after 4 cycles of 
treatment) 
• Relapse, as defined by the IWG Response criteria (for patients with a CR or CRi) 
• No longer meeting the criteria for a PR (in patients who were previously 
determined to have a PR) 
Once ineffective treatment has been established, as described above, no further efficacy 
assessments are required. 
 
Unacceptable toxicity:  
If the symptoms are not controlled with standard treatments and are considered to be 
clinically significant, study drug will be stopped and the patient will be withdrawn from 
the study drug. Patients removed from study drug for unacceptable toxicity will be 
followed until resolution or stabilization of the AE. 
Patients with a response (CR or CRi) withdrawn from the treatment prior to disease relapse 
should continue to be followed until the relapse in accordance with the study plan. 
 
Consent Withdrawal:  
Patients may withdraw from the study at any time at their own request. The withdrawal of 
consent should be explained in detail in the medical records by the Investigator and entered 
in the appropriate electronic case report form (eCRF) page. Details of withdrawal should 
indicate whether the withdrawal is from further treatment with the study drug only or also 
from the study procedures and/or post treatment study follow-up. CR or CRi patients who 
request to withdraw from further treatment and study procedures may be followed up for 
survival status (if consented by the patients). Similarly, CR or CRi patients who withdraw 
from treatment only should continue to be followed until disease relapse. 
 
Lost to follow-up: 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient to reschedule the visit, by phone, e-mail, text message, and if necessary, by letter 
and/or certified mail, in instances where the patient is not responsive to contact attempts. 
On a case-by-case basis, a patient visit should be arranged. All efforts should be 
documented in the patient’s medical source record. A patient is considered lost to 
follow-up if the patient cannot be reached after 3 months from the scheduled visit or before 
the date of data cut-off date, whichever is earlier. However, if the patient re-initiates 


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contact beyond 3 months, or the site is informed of the patient’s survival status or date of 
death, the available data may still be collected on the eCRF, assuming that patient consent 
has not been withdrawn. 
 
All patients who are withdrawn or discontinued from the study are required to complete a 
safety follow-up visit within 28 days after the last administration of study drug, where 
possible. If the Investigator is unable to complete the safety follow-up visit assessments, 
the reason(s) must be recorded in the eCRF. All AEs/SAEs will be collected until 28 days 
after the last administration of study drug. 
 
If a patient discontinues study drug and is withdrawn from the study for any reason, the 
study center must immediately notify the medical monitor. The Investigator should also 
ensure the return of unused study drug. 
 
Patient Replacement: 
As a general principle, patients will not be replaced if they withdraw following the 
completion of Cycle 1.  
 
4.4 
Planned Sample Size and Number of Study Centers 
Part 1: 
It is planned to recruit up to a total of 18-24 patients across multiple centers in Australia, 
Singapore and other countries.  
 
Part 2: 
It is planned to recruit a total of 20 patients across multiple centers in Australia, Singapore 
and other countries.  
 
4.5 
Patient Identification and Allocation of Treatment  
At Screening, each patient will receive a unique Screening number from electronic data 
capture system (EDC). The number will start with “S” and be followed by 4 digits starting 
with S0001 for Part 1 and S2001 for Part 2. 
 
Part 1:  
Following confirmation of eligibility, all patients will be sequentially assigned to the dose 
cohorts after being screened for eligibility and providing consent. At administration of the 
first dose of study drug, patients will be assigned with a 4-digit patient number in the order 
in which they are enrolled in the study starting from 0001.  
Enrolled patients who drop out of the study before receiving the study drug will retain their 
Screening number. 
 
 
 


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Part 2: 
Following confirmation of eligibility and providing consent, all patients will be 
sequentially assigned to the dose level selected from Part 1. At administration of the first 
dose of study drug, patients will be assigned with a 4-digit patient number in the order in 
which they are enrolled in the study starting from 2001.  
Enrolled patients who drop out of the study before receiving the study drug will retain their 
Screening number. 
 


S p o ns or: A S L A N P har mace uticals  Pte. Lt d.  
Cli nical St u d y  Pr ot oc ol  
Pr ot oc ol N u m ber: A S L A N 0 0 3 -0 0 3  
C O N FI D E N TI A L  
 
Versi o n 3. 0 _ Fi nal  
4 3  of 8 3  
3 1 -Ma y -2 0 1 8  
C o nfi de ntial © 2 0 1 8 A S L A N P har mace uticals, all ri g hts res er ve d  
5  
I N V E S TI G A TI O N A L P R O D U C T 
5. 1  
I de ntit y of I n vesti g ati o n al Pr o d uct  
T he i n vesti gati o nal pr o d uct f or t his st u d y is A S L A N 0 0 3.  
 
A S L A N 0 0 3 is s u p plie d as a f or m ulate d ora n ge-c ol ore d har d gelati n  ca ps ul e ( Size N o. 2). 
Eac h ca ps ule c o ntai ns A S L A N 0 0 3 dr u g s u bsta nce 5 0  m g, lact ose m o n o h y drate, c oll oi dal 
silic o n di o xi de a n d s o di u m stear yl f u marate. 
 
5. 2  
St u d y Dr u g A d mi nistr ati o n   
A S L A N 0 0 3 will be s u p plie d b y A S L A N P har mace uticals  Pte. Lt d . T he st u d y dr u g  is t o be 
a d mi nistere d or all y, Q D  or BI D . It is rec o m me n d e d t o a d mi nister t he st u d y dr u g wit h f o o d 
or wit hi n 3 0 mi n utes after f o o d i nta ke. 
 
5. 3  
Per mitte d D ose I nterr u pti o ns of St u d y Dr u g  
If  patie nts  e x perie nce  a  C T C A E  Gra d e ≥ 3  t o xicit y  attri b ute d  t o  A S L A N 0 0 3  b y  t he 
i n vesti gat or, t h e st u d y dr u g s h o ul d b e i nterr u pt e d. Patie nts wit h Gra d e ≥ 3 A Es w hic h are 
ass ociate d  wit h  u n derl yi n g  disease  s uc h  as  a n e mia,  b o ne  marr o w  h y p o ce ll ular,  fe bril e 
ne utr o pe nia, a n d decreas e d l y m p h o c yt e c o u nt, ne utr o p hil c o u nt, a n d platelet c o u nt ma y  
kee p recei vi n g A S L A N 0 0 3 treat me nt at i n vesti gat or’s discreti o n . T he st u d y dr u g sh o ul d 
be  res u me d  o nce  t he  A E  rec o vers  t o Gra de  1  or  less . If  st u d y  dr u g  is  i nterr u pte d  f or 
c o nti n u o us 2 8 da ys d ue t o A E, t he p atie nt m ust be wit h dra w n fr o m t h e st u d y dr u g  a n d 
rec or d e d as u nacce pta bl e t o xicit y. If u p o n re-i ntr o d ucti o n of A S L A N 0 0 3, a Gra de 2 A E of 
t he sa me e ve nt r e-occ urs, a d ose re d ucti o n o n a case -b y -case basis  ca n be i m ple me nte d 
u p o n a gree me nt wit h t he C R O/ S p o ns or. F or Gra de ≥ 3 A S T, A L T, or G G T ele v ati o ns, 
i nterr u pti o n of st u d y dr u g is base d o n t he ass ess me nt of C hil d– P u g h sc ore ( Class A, B or 
C, refer t o A p p e n di x 3) a n d is de m o nstrate d i n Ta ble 2. 
 
T a ble 2  
If Gr a de 3 A S T/ A L T/ G G T  
Class A:  
Re d uce  d ose  b y  5 0  m g  f or  1 
wee k  t he n r eassess 
≥G 4: Refer t o “If Gra de ≥ 4 A S T/ A L T/ G G T ”  
* Class A, still G 3: Re d uce d ose b y 5 0 m g  
* Class A, G 2: M ai ntai n c urre nt d ose  
* Class A, ≤ G 1: Res u me last hi g her d os e  
Class ≥B wit h  Gra d e 1 t o 3: Refer t o t h e acti o n of  “ If 
Gra de 3 A S T/ A L T/ G G T, Class ≤ B”  
Class  ≥ B:  
I nterr u pt u ntil ≤G 1, t he n res u me ori gi nal or re d uce d d ose per i n v esti gat or’s discreti o n 
If Gr a de 4 A S T/ A L T/ G G T 
D ose interr u pti o n, a n d f oll o w 
u p wee kl y u ntil ≤G 1 
Class A :  Re d uce  d ose  b y  5 0  m g  or  mai ntai n  ori gi nal 
d os e per i n vesti gat or’s discreti o n # 


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Class ≥ B 
Reduce dose by 50 mg# 
*Monitor dose every week until back to original dose 
# Withdrawal if a secondary G4 event is observed 
5.4 
Intra-patient dose escalation 
Intra-patient dose escalation  is allowed when the patient has no ongoing study drug-related 
AE ,and all patients in the cohort of targeted dose have completed at least one cycle of 
treatment without unexpected safety issue identified. Prior agreement with ASLAN 
Pharmaceuticals would need to be obtained for the dose escalation. 
 
5.5 
Packaging, Labeling and Storage 
Study drug will be packaged and labelled by the Sponsor according to all local regulatory 
requirements. Study drugs are packaged in aluminum foil blisters in 2 × 3 format. Blisters 
are further packaged using either fibreboard cartons or wallets to facilitate clinical use. 
Study centers and pharmacies are to store ASLAN003 under controlled conditions 
15°C -25°C. Upon dispensing to patients, study drug may be stored up to 30°C or in a 
fridge 2-8°C. The storage area of the study center, must be a secure, temperature 
controlled, locked environment with restricted access. Study centers will be required to 
keep a temperature log to establish a record of compliance with these storage conditions. 
Accurate records must be kept regarding dispensing and return of the study drug for each 
individual patient in the study. Reasons for deviating from the expected dispensing or 
return of the study drug must be recorded. 
No special procedures for the safe handling of ASLAN003 are required. The Sponsor will 
be permitted upon request to audit the supplies, storage, dispensing procedures and records. 
 
5.6 
Blinding  
Part 1 is a single-arm, dose optimizing, non-randomized study. Hence, blinding is not 
applicable. 
Part 2 is an open label, single arm design. All patients in Part 2 will receive the same 
treatment and dose, thus blinding is not applicable for Part 2. 
 
5.7 
Study Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. 
Each dispensing of the study drug will be documented in the eCRF. 
The Investigator is responsible for returning all unused or partially used study drug to the 
Sponsor and must verify that all the unused or partially used drug supplies have been 
returned by the patient and that no remaining supplies are in the Investigator’s possession. 
 


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5.8 
Study Drug Compliance 
The administration of all study drugs should be recorded in the appropriate sections of the 
eCRF. Patients will report any self-administered medication for the periods when they are 
not at the study center. 
Patients will be issued a patient Diary Card to record drug compliance, which is to be 
returned to the study center at the next visit. 
Treatment compliance will be assessed by regular capsule counts and comparing the 
entries in the patient Diary Card and the information will be recorded in the appropriate 
section of the eCRF. 
Patients must bring all the wallets of study drug and any remaining tablets as well as the 
patient Diary Card with them at each scheduled visit. Patients will be instructed to notify 
the study center personnel of missed doses. Dates of missed or held doses will be recorded 
in the eCRF. 
 
5.9 
Previous and Concomitant Medications/Non-drug therapies 
Any medication taken by a patient, other than the study drug, will be considered a 
concomitant medication. This includes herbal and other non-traditional remedies. 
Concomitant medication may also include those drugs which were medically indicated for 
any condition. All patients will be asked to provide a complete list of concomitant 
medications that have been taken within 4 weeks before the first treatment visit, including 
prescription, over-the-counter, complementary, and alternative medications. They must 
also inform the Investigator about any new medication that was started while on the trial. 
All concomitant medications must be recorded in the eCRF. Details (including indication, 
doses, frequency, and start/stop dates) of concomitant medication taken, as well as 
concomitant therapy (including indication, start and stop dates) administered within 
4 weeks before the first treatment visit, during the trial, until the completion of the safety 
follow-up visit, must be documented in the medical record and the appropriate eCRF. 
5.9.1 Permitted Concomitant Therapy 
Therapies required to treat AEs, relieve disease symptoms, concurrent diseases and 
supportive care agents, such as antipyretics, antibiotics, blood transfusion, 
colony-stimulating factor, etc. will be permitted during the study. 
5.9.2 Prohibited Concomitant Therapy 
Any approved or investigational treatment given for the purpose to treat the leukemia, 
including but not limited to chemotherapy, hypomethylating agents, herbal medicine, 
Chinese medicine, leukapheresis, etc. will be prohibited during the study. 
For the management of leukocytosis, hydroxyurea use per site practice is allowed for 
patients with peripheral blast count more than 20,000 cells/uL in the first two weeks of 
study treatment. Once the peripheral blast count drops to less than 20,000 cells/uL, site is 
require to discontinue with hydroxyurea to ensure not impacting efficacy readout. 
Hydroxyurea use is allowed for suspected or confirmed differentiation syndrome. 
 


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6 
STUDY VARIABLES AND METHODS OF ASSESSMENT 
6.1 
Determination of Optimum Dose 
Part 1 of the study is designed with co-primary endpoints of efficacy and tolerability, in 
order to facilitate dose selection for further investigation. Data from Part 1 of this Phase 
IIA study will be reviewed in its totality to provide and understanding of the dose-response 
relationship, both in terms of efficacy and tolerability, in order to determine an optimum 
dose for further development in Part 2. 
6.2 
Efficacy Variables 
Efficacy will be evaluated with BM aspiration and peripheral blood results based on the 
IWG Criteria16 for AML (Cheson, 2003). For patients without sufficient archival BM 
sample, BM aspiration will be performed during Screening. All patients will receive bone 
marrow aspiration for efficacy assessment on Day 1 of Cycle 2, 3, 4, 5 and will be repeated 
every 12 weeks after Cycle 5. Patients who’ve already achieved CR could omit the bone 
marrow aspiration at subsequent visits if there is a normal complete blood count with 
differential of the peripheral blood. Investigator may perform more frequent exam if 
required based on clinical judgment. In order to address the primary objectives of the study, 
if treatment is interrupted for any reason, it is important that all planned safety and efficacy 
assessments are performed at the scheduled time, regardless of whether the patient is 
receiving study treatment, or not, at the time 
 
BM aspiration smears will be processed locally.  
 
Following treatment discontinuation, patients who have achieved a CR or CRi, will 
continue to be followed up for every 12 weeks to assess the relapse free survival. For 
patients who have not achieved a CR or CRi during treatment, no further follow-up is 
required following treatment discontinuation. 
 
These criteria categorize the visit response into the following response classifications: 
• CR with incomplete recovery of neutrophils and platelets (CRi): 
Achievement of CRi requires patients to satisfy all of the following: 
- 
A disappearance of blasts in the peripheral blood. 
- 
A decrease in BM blasts to <5% total BM nucleated cells demonstrated in 
BM aspirate. 
- 
Absence of Auer rods 
- 
No persistent extramedullary leukaemia 
 
• Complete Remission: 
Patient satisfies all of the criteria above and in addition has: 
- 
Recovery of Neutrophils to ≥1.0 x 109/L and Platelets to ≥ 100 x 109/L 
- 
Transfusion-independence 
 
• Partial Remission: 
A PR is defined as recovery of neutrophils to to ≥1.0 x 109/L and Platelets to 
≥ 100 x 109/L and either: 


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- 
If the pre-treatment bone marrow blast percentage was 50% to 100%, the 
percentage of blast must decrease to a value between 5% and 25% 
- 
If the pre-treatment BM blast percentage was 20% to less than 49%, they 
must decrease by at least half to a value of more than 5% 
- 
A reduction in BM blast cells to <5% but with persistence of Auer rods. 
 
• Treatment failure: 
Failure to meet the criteria for CR, CRi or PR after 4 cycles of treatment will result in 
a best response of treatment failure. 
 
For the evaluation of OCRR, a binary variable will be created to indicate complete 
response status of each patient (complete responder or non-responder) defined as 
follows: 
 
A patient will be classified as a complete responder if either of the following are 
achieved during the study: 
- 
Achievement of CR 
- 
Achievement of CRi 
 
Patients who do not satisfy the CR criteria outlined above (including patients with 
PR, treatment failure and any patients without evaluable post-treatment assessments) 
will be classified as non-responders for the assessment of OCRR. 
 
Best response status will also be assessed. A patient’s best response is defined as the 
best AML visit response observed, ranked in the following order:  
 
CR > CRi > PR > Treatment failure. 
 
Based on the above definitions, the following efficacy endpoints will be evaluated: 
 
Overall Complete Remission Rate: Defined as the proportion of patients with a best 
response of CR or CRi, defined in accordance with the IWG Response Criteria in 
AML , and described above. 
 
Relapse Free Survival: Defined as the time the criteria for remission (CR or CRi) are 
first met until there is evidence of patient relapse or death from any cause (whichever 
happens first), regardless of whether the patient is still taking study drug.  
 
Relapse is defined as: 
- 
The reappearance of leukemic blasts in the peripheral blood or > 5% blasts 
in the BM not attributable to any other cause 
- 
The appearance of new dysplastic changes 
- 
The 
reappearance 
of 
or 
development 
of 
cytologically 
proven 
extrameduallary disease 
- 
The reappearance of a cytogenetic or molecular abnormality 
 


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Clinical Benefit Rate: Defined as the proportion of patients with an AML IWG best 
response of CR, CRi or PR. 
 
The percentage change from baseline in BM blasts and peripheral blood blasts at Day 
29 will also be evaluated.  
 
6.3 
Safety Variables 
During the study, patients will visit the study site at Screening and at scheduled visits in 
accordance with the schedule of assessment (Table 1). Safety assessments, physical 
examination, vital signs (blood pressure [systolic and diastolic], resting pulse, respiratory 
rate, weight and body temperature), ECG parameters, clinical laboratory tests 
(hematology, clinical chemistry, coagulation and urinalysis) and AEs will be completed at 
study visits as defined in the schedule of assessments. 
6.3.1 Adverse Events 
6.3.1.1 Collection of Adverse Events 
It is responsibility of the Investigator to collect all AEs (both serious and non-serious) 
derived by spontaneous, unsolicited reports of patients, by observation and by routine open 
questionings e.g. "How have you felt since I last saw you?”. Coding of AEs will be done 
as described in Section 9.4. 
6.3.1.2 Definitions 
An AE is any untoward medical occurrence that occurs in a patient or clinical investigation 
patient administered a pharmaceutical product, and which does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to 
the product. 
 
Fluctuations in the pre-existing conditions that do not represent a clinically significant 
exacerbation or worsening will not be considered AEs. Surgical procedures, planned 
before enrolment of the patient in the study, will not be considered AEs if the condition(s) 
was (were) known before study inclusion. In the latter case, the medical condition should 
be reported in the patient’s medical history. 
 
Progression of the malignancy or target disease under the study is generally not considered 
as an AE. 
 
All AEs, including inter-current illnesses, occurring during the study will be documented 
in the eCRF. Concomitant illnesses, which existed before entry into the study, will not be 
considered AEs unless they worsen during the treatment period. All AEs, regardless of the 
source of identification (e.g., physical examination, laboratory assessment, ECG, reported 
by patient), must be documented. 
 


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Pre-existing conditions will be recorded in the eCRF system on the Medical History or 
appropriate page. 
 
A treatment-emergent AE (TEAE) will be defined as an AE that begins or that worsens in 
severity after at least 1 dose of study drug has been administered. 
 
When recording an AE, the Investigator should use the overall diagnosis or syndrome 
using standard medical terminology, rather than recording individual symptoms or signs. 
The eCRF and source documents should be consistent. Any discrepancies between the 
patient’s own words on his/her own records (e.g., diary card) and the corresponding 
medical terminology should be clarified in the source documentation. 
 
Details for completion of the AE case report form (CRF) (including judgment of 
relationship to study drug) are described in the CRF completion guidelines. 
 
6.3.1.3 Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the following categories. 
6.3.1.4 Seriousness 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose: 
• Results in death; 
• Is life-threatening (This means that the patient is at risk of death at the time of the event; 
it does not mean that the event hypothetically might have caused death if it were more 
severe); 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; 
• Is an important medical event(s) that may not be immediately life-threatening or result 
in death or hospitalization but that may jeopardize the patient or require intervention to 
prevent one of the above outcomes. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependenc or 
drug abuse. 
Medical and scientific judgment should be exercised in deciding whether a case is serious 
and whether expedited reporting is appropriate. 
 
Events related to disease progression will not be reported as SAEs unless the events lead 
to death and the death will be reported as an SAE. 
 
Hospitalization due to the following reasons should not be reported as an SAE: 
• Reasons described in the protocol i.e. drug administration, protocol required 
procedures; 


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• Surgery or procedure planned prior to entry into the study; 
• Surgery or procedure planned for pre-existing conditions that do not worsen after 
entry into the study; 
• Social/administrative reasons i.e. due to distance between home and hospital, 
hospice placement for terminal care due to progressive disease etc. 
6.3.1.5 Intensity 
Investigators should assess the severity of AEs according to CTCAE v4.03. In general, 
CTCAE v4.03 Severity Grades are: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL) (Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.); 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (Self-care ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.); 
Grade 4: 
Life-threatening consequences; urgent intervention indicated; 
Grade 5: 
Death related to AE. 
All changes in severity must be recorded in the eCRF. 
6.3.1.6 Causality 
Causal relationship assessments to study drugs are required for purposes of reporting AEs. 
To promote consistency, the following guidelines should be taken into consideration along 
with good clinical and scientific judgment when determining the relationship of drug 
treatments to an AE: 
 
The descriptions provided below will help guide the Investigator in making the assessment 
of causality: 
Definitely Related: A clinical event, including clinical laboratory test abnormality, 
occurring in a plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug should be clinically plausible. 
Probably related: A clinical event, including clinical laboratory test abnormality, 
occurring in a plausible time relationship to the medication administration, which are 
unlikely to be explained by concurrent disease or other drugs or chemicals. The response 
to withdrawal of the drug should be clinically reasonable. Re-challenge not required. 
Possibly Related: A clinical event, including clinical laboratory test abnormality, with a 
reasonable time sequence to the medication administration, which could also be explained 
by concurrent disease or other drugs or chemicals. Information on the drug withdrawal 
may be lacking or unclear. 


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Unlikely Related: A clinical event, including clinical laboratory test abnormality, with 
little or no temporal relationship to medication administration, and to which other drugs, 
chemicals or underlying disease provide plausible explanations. 
Not Related: A clinical event, including clinical laboratory test abnormality that has no 
temporal relationship to the medication or has more likely alternative etiology. 
The study conduct relatedness for SAEs will also be assessed and documented. 
 
Note¹: For the purpose of clinical study report (CSR) reporting, AEs listed as “possibly, 
probably, or definitely” related to the investigational product are considered to have a 
“reasonable causal relationship” to the investigational product. Adverse events listed as 
“unlikely” or “not unrelated” are considered to have a suspected “unrelated” causal 
relationship to the investigational agent. 
 
Note²: The above convention for determining whether AEs have a reasonable causal 
relationship to study treatment applies to AE reporting in the tables, listings and figures 
(TLFs) for the CSR only. As described in Sections 3.1 and 3.2, a SC will oversee patient 
safety during the study, and will have the ability to halt recruitment if 2 or more clinically 
significant adverse drug reactions are observed during the first cycle for any dose cohorts. 
In order to be classified as a clinically significant adverse drug reaction, the Investigator 
must believe that the event is likely to have been related to the investigational agent, rather 
than possibly related. For this purpose, an AE must be classified as either “probably” or 
“definitely” related to the investigational agent. 
6.3.1.7 Recording Adverse Events 
All AEs will be evaluated according to CTCAE version 4.03 and will be captured from the 
time of informed consent and continue until the safety follow-up assessment (28 days 
post-last dose of study drug). For the purpose of this study, fluctuations in the pre-existing 
conditions that do not represent a clinically significant exacerbation or worsening are not 
to be considered as AEs. 
 
Prior to receiving study drug, only AEs that were assessed as related to study procedures 
will be recorded and reported. If a patient begins a new anti-leukemia therapy within 28 
days after the last administration of study drug, the AE reporting period for non-serious 
AEs ends at the time the new therapy is started. 
 
All AEs, as per the definition stated in the protocol regardless of the relationship to study 
drug, will be recorded in the eCRF. 
 
All AE reports should contain a brief description of the event, date and time of onset, date 
and time of resolution, intensity, treatment required, relationship to study drug, action 
taken with the study drug (e.g. dose not changed, dose reduced, drug interrupt,, not 
applicable, and whether or not the AE led to the drug withdrawal), outcome (e.g. not 
recovered/resolved, recovering/resolving, recovered/resolved, recovered/resolved with 
sequelae, fatal, or unknown), and whether the event is classified as serious. 


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6.3.1.8 Reporting Serious Adverse Events 
All SAEs will be recorded from signing of informed consent until 28 days after the last 
dose of the study drug. Prior to receiving investigational product, only SAEs that were 
assessed as related to study procedures will be reported. 
If a patient begins a new anti-leukemia therapy within 28 days after the last administration 
of study drug, the SAE reporting period for SAEs ends at the time the new therapy is 
started. 
The Investigator must report any SAEs, as per the definition stated in the protocol on the 
SAE page of the eCRF within 24 hours of becoming aware of the event. During eCRF 
inaccessibility, a paper SAE Form should be sent to the Sponsor’s assigned safety 
representative (PAREXEL) by email within 24 hours of becoming aware of the event. 
Email: ASLANSafety@parexel.com 
The Investigator and the Sponsor/PAREXEL will review each SAE report and the 
Sponsor/PAREXEL will evaluate the seriousness and the causal relationship of the event 
to the study drug. In addition, the Sponsor/PAREXEL will evaluate the expectedness 
according to the reference document Investigators Brochure (IB). Based on the 
Investigator and Sponsor’s assessment of the event, a decision will be made concerning 
the need for further action. 
Details for the reporting of SUSARs can be found in Section 6.3.1.10. 
 
The minimum information required for an initial report is: 
• Name of the person sending the report (i.e. name, address of Investigator); 
• Patient identification (Screening/randomization number, initials, NOT patient name); 
• Protocol number; 
• Description of SAE; 
• Causality assessment, if possible. 
 
After receipt of the initial report, PAREXEL will review the information and, if necessary, 
contact the Investigator, to obtain further information for assessment of the event. 
PAREXEL will be responsible for all information processing and will expedite the 
reporting to all concerned Investigators, to the IECs/IRBs, where required, and to the 
Regulatory Authorities of all adverse reactions that meet expedited reporting criteria 
according to local requirements. 
6.3.1.9 Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the AE has resolved, any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Investigator and Medical Monitor, until there is a 
satisfactory explanation for the changes observed, until the patient is lost to follow-up, or 
until the patient has died. 


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6.3.1.10 Suspected Unexpected Serious Adverse Reactions 
Any adverse event that is serious, associated with the use of the study drug, and unexpected 
suspected unexpected serious adverse reaction (SUSAR) has additional reporting 
requirements, as described below.  
• 
If the SUSAR is fatal or life-threatening, associated with the use of the study drug, 
and 
unexpected, 
Regulatory 
Authorities 
and 
Independent 
Ethics 
Committees/Institutional Review Boards IECs/IRB will be notified within 7 calendar 
days after the Sponsor learns of the event. Additional follow-up (cause of death, 
autopsy report, and hospital report) information should be reported within an 
additional 8 days (15 days total); 
• 
If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
the use of the study drug, and unexpected, Regulatory Authorities and IECs will be 
notified within 15 calendar days after the Sponsor learns of the event. 
 
The Sponsor will notify the Investigators in a timely fashion of relevant information about 
SUSARs that could adversely affect the safety of patients. Follow-up information will be 
submitted if necessary.  
 
The Sponsor will also provide annual safety updates to the Regulatory Authorities and 
IECs/IRBs responsible for the study. These updates will include information on SUSARs 
and other relevant safety findings. 
6.3.1.11 Pregnancy 
There is no information regarding the effects ASLAN003 could have on the development 
of a human fetus. Therefore, it is important that females and the partners of male patients 
do not become pregnant during the study and for at least 3 months after the patient has 
taken their last dose of ASLAN003. 
 
Female patients of childbearing potential and men enrolled in this study, in addition to 
partners of male patients must agree to use adequate contraception prior to study entry, for 
the duration of study participation, and for 3 months following completion of therapy.  
A female of childbearing potential is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the following 
criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy; or  
• Has not been naturally postmenopausal for at least 2 years (i.e., has had menses at any 
time in the preceding 2 years). 
 
Acceptable forms of contraception 
A highly effective method of birth control is defined as those which result in a low failure 
rate (i.e. less than 1% per year) when used consistently and correctly.  
Individually hormonal, barrier or intrauterine device methods alone are not acceptable. 
Examples of acceptable forms of highly effective contraception for women include: 


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• Established use of oral, injected or implanted hormonal methods of contraception in 
combination with a barrier method (included; diaphragm, cervical cap, condom); 
• Placement of an intrauterine device or intrauterine system in combination with a barrier 
method; 
• Sterilized male partner (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) in combination with a barrier method; 
• Total abstinence: When this is in line with the patients preferred and usual lifestyle. 
Examples of non-acceptable methods of contraception include: 
• Barrier method alone; 
• Periodic abstinence (e.g. calendar, ovulation, sympthothermal, post ovulation); 
• Withdrawal; 
• Spermicide. 
For men it is recommended that a condom be worn for all sexual intercourse (in addition 
to another effective means of contraception) as it is not known if study drug may affect 
sperm risking the potential for congenital abnormalities. 
 
Time Period for the Collection of Pregnancy Information: 
All pregnancies in female patients and in female partners of male patients receiving study 
drug will be recorded from enrollment until 3 months after the last study visit. 
 
Follow-up in the Event of a Pregnancy: 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, or should a male patient’s partner become pregnant or suspect she is pregnant while 
the male is participating in this study, the treating Investigator should be informed 
immediately. Female patients will be withdrawn from study drug, and all pregnancies will 
be reported along the same timelines as a SAE. 
 
If a female patient or the female partner of a male patient who has received study drug 
becomes pregnant the pregnancy will be recorded. The IEC/IRB and the Sponsor will be 
informed. In all cases of pregnancy, the patient will be asked to provide information on the 
outcome of the pregnancy, including premature termination should the case arise. 
 
Spontaneous miscarriage and congenital abnormalities will be reported as a SAE. 
 
The follow-up period will be deemed to have ended when the health status of the child has 
been determined at its birth and followed up for 8 weeks following the birthof any potential 
abnormalities. 
 
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has 
been maternal exposure to the study drug. 
 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication. 


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Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy 
newborn should not be considered a SAE. 
 
All pregnancies must be reported by the Investigator to PAREXEL/Sponsor on the initial 
pregnancy report form within 24 hours after becoming aware of the pregnancy. The 
Investigator must follow-up and document the course and the outcome of all pregnancies 
even if the patient was discontinued from the study or if the study has finished. 
All outcomes of pregnancy must be reported by the Investigator to PAREXEL/Sponsor on 
the pregnancy outcome report form within 24 hours after he or she has gained knowledge 
of the normal delivery or elective abortion. 
 
Any SAE that occurs during pregnancy (including SAEs occurring after last administration 
of study drug) must be recorded on the SAE report form (e.g. maternal serious 
complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, neonatal 
death, congenital anomaly, or birth defect) and reported within 24 hours in accordance 
with the procedure for reporting SAEs. 
 
If a female partner of a male study patient who has been exposed to the study drug becomes 
pregnant, the pregnancy and outcome of pregnancy should be monitored. 
6.3.1.12 Laboratory Variables 
Laboratory assessments will be performed locally at each center’s laboratory by means of 
their established methods. Before starting the study, the Investigator will supply 
IQVIA/Sponsor with a list of the normal ranges and units of measurement. 
 
The laboratory variables that will be assessed in accordance with the schedule of 
procedures described in Table 1 are summarized in Table 3. 
 
The Investigator must review Screening laboratory results for patient eligibility prior to 
enrolling. 
 
Laboratory tests can be repeated earlier than the next scheduled consecutive study visit at 
the Investigator’s discretion and any associated safety issue should be followed up as per 
the Investigator’s clinical judgment until resolution/stabilization. 
 
In the event that the laboratory parameters show a significant shift from baseline values, 
patients will then be scheduled for an interim visit within 2 weeks to repeat the laboratory 
measurements. 
 


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Table 3: Laboratory Assessment 
Hematology: 
RBC count 
MCV 
MCH 
Leucocyte differential count 
Blasts 
Promyelocytes 
Myelocytes 
Metamyelocytes 
Band Neutrophils 
Segmented Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Platelets 
WBC count 
Hemoglobin 
Hematocrit 
Urinalysis: 
pH 
Protein 
Glucose 
Ketone 
Bilirubin 
Blood  
Leukocyte esterace 
Nitrite 
Coagulation 
INR 
aPTT 
 
 
Clinical 
Chemistry: 
Albumin 
Creatinine 
Calcium 
Glucose 
Triglycerides 
Urea 
Uric acid 
Cholesterol 
HgbA1c 
Potassium 
Sodium 
Alkaline phosphatase 
GGT 
AST 
ALT 
Total bilirubin 
Bone 
Marrow 
Aspiration 
Aspiration site 
Cellularity 
Blasts 
Promyelocytes 
Myelocytes + 
Metamyelocytes 
Band + Segment 
Erythroid series 
Mono-histiocytes 
Eosinophils 
Plasma cells 
Lymphoid cells 
Miscellaneous 
Auer rods 
Dysplastic change 
Cytochemical 
Serology*: 
HIV 
HBsAg 
HBV DNA if positive HBsAg 
HCV antibody 
 
 
Pregnancy Test: Serum or urine pregnancy test will be performed at the Screening and end of 
treatment visits for all females except those surgically sterile or 2 years 
postmenopausal. Subsequent serum or urine pregnancy tests are allowed at the 
Investigator’s discretion. 


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Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; aPTT= activated partial; 
thromboplastin; DNA = deoxyribonucleic acid; GGT = Gamma glutamyl transferase; HCV = Hepatitis C 
virus; Hemoglobin A1c = HgbA1c; HBsAg = Hepatitis B surface antigen; HBV= hepatitis B virus; 
HIV = Human immunodeficiency virus; INR = international normalized ration; MCH = Mean corpuscular 
hemoglobin; MCV = Mean corpuscular volume, time; WBC = white blood cells; RBC = red blood cells. 
* If HBsAg result indicate active infection then test HBV DNA. 
6.3.2 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Assessments 
(Table 1).  
 
The Investigator will conduct a complete physical examination in all patients at the 
Screening Visit and partial physical examination in all patients during subsequent visits. 
The physical examinations will cover the following general appearance, head, ears, eyes, 
nose, throat, hair, skin, respiratory, cardiovascular, gastro intestinal, musculoskeletal, 
hepatic, neurological, and mental status. Clinically relevant physically examination 
findings during the study will be recorded as AEs. Findings will be recorded in the eCRF. 
6.3.3 Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Procedures 
(Table 1) 
• Blood pressure (systolic and diastolic; mmHg); 
• Heart rate (beats per minute); 
• Body temperature (degree Celsius[°C]); 
• Respiration rate (breaths per minute). 
Any abnormal findings that are clinically significant, in the opinion of the Investigator, 
will be recorded as an AE. Vital sign measurements will be recorded in the eCRF. 
6.3.4 Electrocardiograms 
Standard 12-lead ECGs will be performed in accordance with the Schedule of Procedures 
(Table 1) 
 
A 12-lead ECG will be performed at screening, the end of investigational therapy, and 
when clinically indicated by the Investigator. The Investigator or qualified designee is 
responsible for determining if any change in patient management is needed and must 
document his/her review of the ECG printed at the time of evaluation. 
6.3.5 ECOG Performance Status 
ECOG will be evaluated for all patients at Screening, and during all study visits until 
follow-up. The detailed description of ECOG Status is provided in Appendix 2: ECOG 
Performance Status.  
6.3.6 Additional Safety Assessments 
There are no additional safety assessments planned for this study. 


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6.4 
Pharmacokinetics Assessment (Part 1 ONLY) 
The blood samples for determination of ASLAN003 and metabolite concentrations will be 
collected on Day 1 and Day 8 Cycle 1 in Table 4 at the following timepoints:  
 
Table 4: ASLAN003 Pharmacokinetic Assessment Schedule 
 
Scheduled Visit 
Time Points (h) 
PK Parameters 
Day 1  
Pre-dose 
 
Cmax, 
Cmax ss, 
Ctrough, 
tmax, 
AUCtau, t1/2, t1/2 eff, Cl/F* & 
Vss/F* 
Post dose: at 1, 2, 4, 5, 6, 
8, 12#, and 24 hours  
Day 8 
Pre-dose 
 
 
Cmax ss, Ctrough, tmax ss, AUCtau ss, 
CL/F*, t1/2, t1/2 eff, MRAUC** 
MRCmax**, 
RacAUC, 
and 
RacCmax 
Post dose: at 1, 2, 4, 5, 6, 
8, 12#, and 24 hours  
Note: Only ASLAN003 and its metabolite’s (LAS186558) concentrations and PK parameters will be 
determined in this study. 
* Parameter calculated only for ASLAN003 
** Parameter calculated only for LAS186558 
# Sample collected for BID regime only. 
Abbreviations: AUC = area under the plasma concentration curve; AUCtau = AUC over the dosing interval; 
AUCtau ss = AUCtau at steady state; CL/F = apparent total clearance of the drug from plasma after oral 
administration at steady state; Cmax = maximum observed plasma concentration; Cmax ss = Cmax at steady state; 
Ctrough = Trough plasma concentration; RacAUC = accumulation ratio for AUC; RacCmax = accumulation 
ratio for Cmax; tmax = time corresponding to occurrence of Cmax; tmax ss = time corresponding to occurrence of 
Cmax ss; MR = metabolic ratio; MRAUC = metabolic ratio for AUC; MRCmax = metabolic ratio for Cmax; t1/2 
= effective elimination half-life; t1/2 eff = effective elimination half-life at the steady state; Vss/F = apparent 
volume of distribution at steady state after oral administration 
 
In BID regime i.e 100mg BID and 200mg BID the PK sampling will be done at following 
timepoints: pre-dose, 1, 2, 4 ,5 ,6 ,8, and 12 hours (or evening pre-dose).For Part 2- Steering 
Committee will decide whether PK analysis is required or not and ASLAN 
pharmaceuticals will be updated accordingly 
 
6.4.1 Collection of Blood Samples 
Blood samples for determination of plasma concentrations of ASLAN003 and LAS186558 
will be collected from patients according to the PK sampling schedule described in 
Table 1: Schedule of Study Assessments. Detailed sample collection, label, storage, and 
shipment processes will be described in the Laboratory Manual. The exact date/time of the 
blood sample collection will be recorded in the patient’s eCRF. 


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6.4.2 Determination of Drug Concentrations in Blood Samples 
Determination of ASLAN003 and LAS186558 plasma concentrations by using a validated 
liquid chromatography/mass spectrometry methodology will be performed by a sponsor 
designated bioanalytical laboratory.  
The analytical methods used to measure plasma concentrations of study drug will be 
described in a separate bioanalytical report. 
The following information will be captured for blood sample collections in each patient’s 
eCRF: 
1. Patient’s number and initial. 
2. Date/time of the drug administration. 
3. Time and date of each blood sample collected for PK analysis 
6.5 
Other Exploratory Assessment 
Assays including but not limited to ex vivo flow cytometry assay using selected myeloid 
cell markers (such as CD11b) will be performed to assess the degree of blast cell 
differentiation upon treatment with ASLAN003. The percentage of CD11b positive cells 
will be determined before and after ex vivo treatment with ASLAN003. Molecular 
abnormalities of AML patients will be assessed using polymerase chain reaction (PCR) or 
next-generation sequencing (NGS). The ex vivo assay and molecular assessment will be 
processed centrally (Please refer to the lab manual for details). 
6.6 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics consist of those variables that are assessed only 
at Screening. 
6.6.1 Patient Demography 
Patient demography consists of: 
• Date of birth; 
• Height; 
• Weight; 
• Vital signs; 
• Race and ethnicity; 
• Gender. 
Demographic information will be recorded in the eCRF 
6.6.2 Disease History 
For disease history the following information related to AML will be documented: 
• Date of first diagnosis  
• Diagnosis as per World Health Organization 2016 revised classification; 
• Prior treatment, response and date; 


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• Date of relapse / failed response to previous therapy; 
6.6.3 Medical History 
For the documentation of the medical history, any relevant previous and concurrent 
diseases will be documented. 
The medical history will be obtained by interviewing the patient or by inspecting his/her 
medical records. Findings will be recorded in the eCRF. 
For coding of medical history, see Section 9.4 
6.6.4 Previous and Concomitant Medications 
Previous and concomitant medication will be documented as described in Section 5.8. 
6.7 
Other Variables 
Not applicable. 


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7 
STUDY CONDUCT 
7.1 
Schedule of Procedures 
The timing and details of study procedures to be conducted, by visit, is described in 
Table 1. 
 
7.2 
Procedures by Visit 
7.2.1 Screening (Days -28 to 0) 
Prior to any study activities, patients will be asked to read and sign an ICF that has been 
approved by an IEC/IRB and the Sponsor and which complies with regulatory 
requirements. 
 
Patients will undergo Screening during a visit that can occur up to 4 weeks prior to the 
Cycle 1 Day 1 Visit. This Screening period will be used to assess eligibility of patients and 
to allow for the washout of prohibited medications. 
 
The following Screening and baseline assessments will be performed: 
• Obtain written informed consent; 
• Verify conformance with entry criteria; 
• Assignment of a Screening number; 
• Demographic data; 
• Other medical history/prior medications; 
• Complete physical examination; 
• Height; 
• Body weight; 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature); 
• 12-lead ECGs; 
• Patients’ ECOG performance status; 
• Prior and Concomitant Medications; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Serum / urine β-human Chorionic Gonadotropin 
• Serology; 
• Coagulation laboratory test; 
• Bone Marrow Aspiration (BMA) [BMA smears will be processed locally. Remaining 
Bone Marrow Aspiration Sample will be processed as per BMA lab manual for ex vivo 
assay and molecular assessment]. 


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7.2.2 Treatment Visits  
Patients will receive study drug ASLAN003 from Day 1 in 28-day treatment cycles until 
disease relapse, treatment failure, unacceptable toxicity, and withdrawal of consent or 
death.  
 
Treatment visits are scheduled as below: 
Visit 1: Cycle 1, Day 1 
Visit 2: Cycle 1, Day 8 
Visit 3: Cycle 1 Day 10 
Visit 4: Cycle 1, Day 15 
Visit 5: Cycle 1, Day 22 
Visit 6 & onwards: Cycle 2, Day 1 and onwards at Day 1 of every subsequent cycle.  
7.2.2.1  Cycle 1, Day 1 
The following procedures will be conducted at this visit: 
• Complete physical examination; 
• Body weight; 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• Patients’ ECOG performance status; 
• All AEs since the last visit will be recorded; 
• Concomitant medications will be recorded; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Study drug (ASLAN003) will be dispensed and administered. 
• Blood sample will be collected for  PK analysis at Day 1, QD regime: pre-dose, 1, 2, 
4, 5, 6, 8, and 24 hours post dose In BID regime i.e 100mg BID and 200mg BID the 
PK sampling will be done at following timepoints: pre-dose, 1, 2, 4, 5, 6, 8, and 12 
hours (or evening pre-dose). For Part 2- Steering Committee will decide whether PK 
analysis is required or not and ASLAN pharmaceuticals will be updated accordingly. 
7.2.2.2 Cycle 1, Day 8 (±1 day) 
The following procedures will be conducted at this visit: 
• Complete physical examination; 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• All AEs since the last visit will be recorded; 
• Concomitant medications will be recorded; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Study drug (ASLAN003) will be dispensed and administered. 


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• Blood sample will be collected for PK analysis at Day 8, QD regime: pre-dose, 1, 2, 4, 
5, 6, 8, and 24 hours post dose. In BID regime i.e 100mg BID and 200mg BID the PK 
sampling will be done at following timepoints: pre-dose, 1, 2, 4, 5, 6, 8, and 12 hours 
(or evening pre-dose). For Part 2- Steering Committee will decide whether PK analysis 
is required or not and ASLAN pharmaceuticals will be updated accordingly. 
7.2.2.3 Cycle 1, Day 10 (+1 day) 
The following procedures will be conducted at this visit: 
• AST, ALT and total bilirubin to be performed; 
• Study drug (ASLAN003) will be dispensed and administered. 
7.2.2.4 Cycle 1, Day 15 (±2 days) 
The following procedures will be conducted at this visit: 
• Complete physical examination; 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• 12-lead ECG 
• All AEs since the last visit will be recorded; 
• Concomitant medications will be recorded; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Coagulation laboratory test; 
• Study drug (ASLAN003) will be dispensed and administered. 
7.2.2.5 Cycle 1, Day 22 (±2 days) 
The following procedures will be conducted at this visit: 
• Complete physical examination; 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• All AEs since the last visit will be recorded; 
• Concomitant medications will be recorded; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Study drug (ASLAN003) will be dispensed and administered. 
7.2.2.6 Cycle 2 and Subsequent Cycles - Day 1 (±2 days) 
On Day 1 of Cycle 2 and all subsequent cycles, the following procedures will be conducted: 
• Complete physical examination; 
• Body weight; 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• 12-lead ECG (only on Cycle 2 Day 1); 
• All AEs since the last visit will be recorded; 


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• Concomitant medications will be recorded; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Study drug (ASLAN003) will be dispensed and administered. 
• BM aspiration is mandatory to be performed on Day 1 of every cycle from Cycle 2 to 
Cycle 5 and every 3 months thereafter. Patients achieving CR could omit the bone 
marrow aspiration at a subsequent assessment if there is a normal complete blood count 
with differential of peripheral blood. Investigator may perform additional BM aspirate 
if required based on clinical judgment. BM aspiration smear will be processed locally.  
7.2.3 End of Treatment (EOT) Visit 
Patients who discontinue from the study drug should have an EOT visit. This visit should 
take place as soon as possible within 7 days of last dose of study treatment after the patient 
stops taking study drug. At this visit, the following procedures will be conducted: 
• Complete physical examination; 
• Body weight; 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• 12-lead ECG 
• Patients’ ECOG performance status; 
• All AEs since the last visit will be recorded; 
• Concomitant medications will be recorded; 
• Routine laboratory evaluations (chemistry, hematology, liver function test and 
urinalysis); 
• Serum / urine β-human Chorionic Gonadotropin; 
• Coagulation laboratory test. 
7.2.4 Safety Follow-up (±7 days) 
Patient will complete a safety follow-up visit 28 days after the last dose of ASLAN003. 
The following procedures will be performed:  
• Complete physical examination; 
• 12-lead ECG 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature); 
• All AEs since the last visit will be recorded; 
• Concomitant medications will be recorded.  
7.2.5 Survival Follow-up (±7 days) 
Survival follow-up by either telephone or clinic visit will be performed in patients 
achieving CR or CRi every 12 weeks post EOT until disease relapse or death (in the 
absence of disease relapse) to enable the assessment of RFS. 


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8 
STATISTICAL METHODS 
All statistical analyses will be performed by or under the direct auspices of ASLAN 
Pharmaceuticals, using SAS® version 9.3 or higher. Further details will be provided in the 
Statistical Analysis Plan (SAP).  
8.1 
General Statistical Considerations 
There are no formal statistical analyses planned. All primary and secondary endpoints will 
be listed and summarized using appropriate descriptive statistics. 
8.2 
Sample size determination 
This Phase IIA study is not formally powered. For Part 1, the proposed design of up to 6 
patients per dose cohort has been selected to provide an assessment of the safety, 
tolerability and efficacy of up to 4 dose cohorts of ASLAN003, in order to select the most 
appropriate dose for further exploration in Part 2.  
 
Part 2 is not formally powered. The sample size of 20 patients has been selected to provide 
further efficacy and tolerability data at the selected dose level from Part 1, prior to 
conducting larger randomized trials in AML. 
8.3 
Analysis population 
8.3.1  Safety Population 
The safety population will include all patients who received at least 1 dose drug in the 
study. Patients will be included in the safety population according to the dose initially 
received, regardless of any subsequent dose modifications.  
 
The safety set will be the primary analysis set used for the assessment of safety and 
tolerability in the study 
8.3.2 Full Analysis Set 
The full analysis set (FAS) is defined as the set of patients who received at least 1 dose of 
study drug, regardless of any protocol deviations or dosing errors. Patients will be included 
in the FAS according to the intended initial dose cohort, regardless of any subsequent dose 
reductions, increases or interruptions. 
 
The FAS will be used to assess the sensitivity of the primary efficacy analyses (based on 
the evaluable for response [EFR]) to exclusions from the EFR. 
8.3.3 Evaluable for Response Set 
The evaluable for response (EFR) set is defined as a subset of the FAS, excluding any 
patients with major protocol deviations. Deviations that would lead to exclusion from the 
FAS are: 
• Patients who do not have AML as defined by the 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia (failure of 
inclusion criteria 3 in Section 4.1. 


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• Patients eligible for induction therapy (failure of inclusion criteria 5 in Section 4.1) 
• Patients who are diagnosed with de novo myeloid sarcoma without bone marrow 
involvement (exclusion criteria 1 in Section 4.2) 
• Patients who are diagnosed with acute promyelocytic leukemia with the PML-
RARA (exclusion criteria 2 in Section 4.2) 
• Patients who received any other standard or investigational treatment for their 
leukemia within 7 days before starting the first dose of study drug, with the 
exception of leukapheresis and hydroxyurea (exclusion criteria 3 in Section 4.2) 
 
The EFR will be the primary analysis set used for the evaluation of all efficacy objectives. 
8.3.4 Pharmacokinetic analysis set 
The PK population contains all patients who receive one complete dose of ASLAN003 and 
have at least 1 measured concentration at a scheduled postdose time point without any 
major protocol deviations or events that affect the PK concentrations. Patients in this 
population will be used for all PK analyses. 
 
This population will comprise of all patients who received study treatment as per protocol 
(e.g. 100 mg QD, 200 mg QD, 100 mg BID or 200 mg BID) and did not violate or deviate 
from the protocol and planned dosing regimen in ways that would significantly affect the 
PK analyses (for example skipping doses, or taking reduced doses or taking concomitant 
medications with the potential to cause a drug-drug interaction) during the PK sampling 
period. Patients who deviated from the planned dosing regimen may still provide some 
data for inclusion in the PK set if they have at least one usable PK profile. The population, 
and decisions regarding which profiles are usable, will be defined by the Study Team 
Physician, Pharmacokineticist, and Statistician prior to any analyses being performed. 
 
8.4 
Methods of Statistical Analysis 
There are no formal statistical analyses planned. All primary and secondary endpoints will 
be listed and summarized using appropriate descriptive statistics. 
 
Unless otherwise stated, data for Part 1 and Part 2 will be processed separately. 
8.4.1  Assessment of Efficacy 
The primary outcome variable is defined in Section 6.2. A binary variable will be created 
to indicate complete response status for each patient (complete responder or 
non-responder). 
 
For Part 1, AML response data will be listed, and summarized showing frequency and 
proportion of the best response (CR, CRi, PR or treatment failure), OCRR (complete 
responder or non-responder) and Clinical Benefit Rate (CBR) by dose cohort and overall. 
 
For Part 2, AML response data will be listed, and summarized showing frequency and 
proportion of the best response, OCRR and Clinical Benefit Rate (CBR), along with 


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corresponding two-sided 80% CIs based on the Clopper-Pearson exact method. 
 
Waterfall plots of the % change from baseline in BM blasts at Day 29, and the best % 
change from baseline in BM blasts will be presented. For Part 1, all dose cohorts will be 
included on the same plot, but different bar types will be used to distinguish the different 
dose cohorts. 
 
Relapse-free survival will be listed. For Part 2 only, if there are sufficient events, RFS  will 
be summarized by using the Kaplan-Meier estimates to present 25th, 50th (median), and 
75th percentiles , as well as the number and percentage of events and censored 
observations. 
8.4.2 Optimum Dose determination 
The study is designed with co-primary endpoints of efficacy and tolerability, in order to 
facilitate dose selection for further investigation. Data from this Phase IIA study will be 
reviewed in its totality to provide and understanding of the dose-response relationship, 
both in terms of efficacy and tolerability, in order to determine an optimum dose for further 
development. 
8.4.3 Safety Analyses 
Safety data will be listed and summarized as described below. Further details will be 
provided in the SAP. 
8.4.3.1 Adverse Events 
All AE data will be listed along with information regarding patient’s original dosecohort, 
the dose at onset of the AE, onset time (study day), duration, severity, and relationship to 
study treatment. 
 
Treatment emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of study treatment. The following summaries will be produced for all TEAEs. 
 
• An overview table of the incidence of TEAEs, Grade 3+ TEAEs, SAEs, TEAEs 
leading to treatment discontinuation and TEAEs leading to death, by dose cohort 
(Part 1 ONLY) and overall. For each summary category, the results will be shown 
overall (regardless of causality), and for the incidence of causally-related TEAEs. 
For example, the overall incidence of TEAEs will be presented, as well as the 
incidence of TEAEs classified as at least “possibly related” to ASLAN003 by the 
Investigator; 
• Summary of TEAEs by system organ class (SOC) and preferred term: Both the 
number and percentage of patients in each category (patient-level summary) and 
the number of episodes (episode-level summary). This summary table will be 
repeated for TEAEs attributed as causally related to study treatment; 


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• Summary of TEAEs occurring in patients, sorted in descending order of frequency 
(i.e., most frequent event shown first) presented by dose cohort (Part 1 ONLY) and 
overall. The order of frequency will be determined by the most frequent preferred 
term overall. For each event, the results will be presented for all CTCAE grades, 
and also split by Grade 1-2, and Grade 3+; 
• Summary of TEAEs attributed as causally related to study treatment, and occurring 
in patients, sorted in descending order of frequency (i.e., most frequent event 
shown first) overall. Results will be presented by dose cohort (Part 1 ONLY) and 
overall. For each event, the results will be presented for all CTCAE grades, and 
also split by Grade 1 to Grade 2, and Grade 3+; 
• Summary of CTCAE Grade 3 and above TEAEs sorted in descending order of 
frequency (i.e., most frequent event shown first). The order of frequency will be 
determined by the most frequent preferred term overall. Results will be presented 
by dose cohort (Part 1 ONLY) and overall; 
• A summary of CTCAE Grade 3 and above TEAEs attributed as causally related1 
to study treatment sorted in descending order of frequency (i.e., most frequent event 
shown first). The order of frequency will be determined by the most frequent 
preferred term overall. Results will be presented by dose cohort (Part 1 ONLY) and 
overall; 
• Summary of SAEs by preferred term  
• Summary of SAEs attributed as causally related to study treatment, sorted by 
descending frequency. 
Additionally, the following will be listed: 
• AEs with outcome of death along with the date of onset, study day, initial study 
dose, dose at onset, treatment status at onset (pre-treatment, ongoing or 
post-treatment) and Investigator’s assessment of severity and relationship to study 
drug; 
• All SAEs along with the date of onset, study day, initial study dose, dose at onset, 
treatment status at onset (pre-treatment, ongoing or post-treatment), date of 
resolution (if AE is resolved), Investigator’s assessment of severity and 
relationship to study drug; 
• AEs leading to discontinuation of study drug, listed along with the date of onset, 
study day, initial study dose, dose at onset, treatment status at onset (pre-treatment, 
ongoing or post-treatment), and investigator’s assessment of severity and 
relationship to study drug. Dependent on the number of AEs leading to treatment 
discontinuation, this data may also be summarized. 


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For the above summaries and listings, an AE will be considered to have a possible causal 
relationship if a causality assessment of “possibly related”, “probably related” or 
“definitely related” is assigned by the Investigator. 
 
If an AE is reported more than once during the study period, the greatest severity and the 
worst-case attribution will be presented in summary tables. Any AEs commencing 
> 28 days after discontinuation of study treatment will not be included in the tabulations 
of AE data.  
 
To further assess the tolerability of ASLAN003, exposure and dose intensity will be listed 
and summarized by dose cohort (Part 1 ONLY) and overall. Further details will be 
provided in the study SAP. 
8.4.3.2 Clinical Laboratory Evaluations 
All clinical laboratory data (clinical chemistry, hematology and urinalysis data) will be 
listed and summarized by visit. In addition, all data measured on a continuous scale will 
be displayed graphically as described below: 
 
- 
Patient profile plots to show both absolute values, and the % change from baseline 
over time. For Pat 1, separate plots will be produced for each dose cohort. 
- 
Box plots of the change from baseline over time, by dose cohort (Part 1 ONLY), 
including a horizontal reference line at zero. 
8.4.3.3 Vital Signs and ECG measurements 
Vitals signs and ECG data will be listed. In addition, all data measured on a continuous 
scale (except respiration rate and pulse) will be displayed graphically as described below: 
 
- 
Patient profile plots to show both absolute values, and the % change from baseline 
over time. For Part 1, separate plots will be produced for each dose cohort. 
- 
Box plots of the change from baseline over time, by dose cohort (Part 1 ONLY), 
including a horizontal reference line at zero. 
8.4.4 Pharmacokinetic Analysis 
Concentration data and all derived PK parameters will be listed and summarized using 
appropriate descriptive statistics. 
 
 
8.4.5 Exploratory Analysis 
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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of 
each Investigator, inspect the site facilities, and inform the Investigator of responsibilities 
and the procedures for ensuring adequate and correct documentation. 
 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded in the eCRF system for this study must be consistent 
with the patients’ source documentation (i.e., medical records). The Investigator must 
permit study-related monitoring, audits, IRB/IEC review, and national or foreign 
regulatory inspections and provide direct access to source data documents. 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
in the CRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study center 
using eCRFs. Data from external sources (such as laboratory data) will be imported into 
the database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the 
time and date will be logged to provide an audit trail. 
 
If additional corrections are needed, the responsible monitor or data manger will raise a 
query in the EDC application. The appropriate staff at the study site will answer queries 
sent to the Investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification 
is complete and all queries are closed, the monitor will freeze the eCRF page. 
 
The specific procedures to be used for data entry and query resolution using the eCRF will 
be provided to study sites in a training manual. In addition, site personnel will receive 
training on the EDC system/eCRF. 
9.1.2 Monitoring 
The Sponsor has engaged the services of IQVIA, to perform all monitoring functions 
within this clinical study. IQVIA monitors will work in accordance with IQVIA Standard 
operating procedures (SOPs) and have the same rights and responsibilities as monitors 
from the Sponsor organization. Monitors will establish and maintain regular contact 
between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study site, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, 


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monitors will check that written informed consent has been obtained from all subjects 
correctly and that data are recorded correctly and completely. Monitors are also entitled to 
compare entries in eCRFs with corresponding source data and to inform the Investigator 
of any errors or omissions. Monitors will also control adherence to the protocol at the study 
site. They will arrange for the supply of study drugs and ensure appropriate storage 
conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements 
and standards. Regular monitoring visits will be made to each site while subjects are 
enrolled in the study. The monitor will make written reports to the Sponsor on each 
occasion contact with the Investigator is made, regardless of whether it is by phone or in 
person. 
During monitoring visits, all the checks will be 100% including the following items:  
• Subject identification number; 
• Subject consent obtained;  
• Subject eligibility criteria (inclusion and exclusion criteria); 
• Efficacy variables; 
• Medical record of AE. 
9.1.3 Audit and Inspections: 
Study sites, the study database, and study documentation may be subject to Quality 
Assurance audit during the course of the study by the Sponsor or IQVIA on behalf of the 
Sponsor. In addition, inspections may be conducted by regulatory bodies at their 
discretion.  
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of 
each Investigator, inspect the site facilities, and inform the Investigator of responsibilities 
and the procedures for ensuring adequate and correct documentation.  
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded in the eCRFs system for this study must be consistent 
with the subjects’ source documentation (i.e., medical records). 
 
9.2 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the eCRFs promptly. All source 
documents from which eCRF entries are derived should be placed in the patient’s medical 
records. Measurements for which source documents are usually available to include 
laboratory assessments, ECG recordings, BM aspiration records. 
 
The original eCRF entries for each patient may be checked against source documents at 
the study site by the IQVIA site monitor. 
 
After review by the site monitor, completed eCRF entries will be uploaded and forwarded 
to IQVIA. Instances of missing or uninterpretable data will be discussed with the 
Investigator for resolution. The specific procedures to be used for data entry and query 


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resolution using the eCRF will be provided to study sites in a training manual. In addition, 
site personnel will receive training on the EDC system/eCRF. 
9.2.1 Data collection 
The Investigators (and appropriately authorized staff) will be given access to an online 
web-based EDC) system which is 21 Code of Federal Regulations Part 11 compliant. This 
system is specifically designed for the collection of the clinical data in electronic format. 
Access and right to the EDC system will be carefully controlled and configured according 
to each individual’s role throughout the study. In general, only the Investigator and 
authorized staff will be able to enter data and make corrections in the eCRFs. 
 
The eCRF should be completed for each patient included in the study and should reflect 
the latest observations of the patients participating in the study. Therefore, the eCRFs are 
to be completed as soon as possible during or immediately after the patient’s visit or 
assessment. The Investigator must verify that all data entries in the eCRF are accurate and 
correct. If some assessments cannot be done, or if certain information is unavailable, not 
applicable or unknown, the Investigator should indicate this in the eCRF. 
 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the 
site will be informed about new issues to be resolved on-line. All discrepancies will be 
solved on-line directly by the Investigator or by authorized staff. Off-line edit checks will 
be done to examine relationships over time and across panels to facilitate quality data. 
 
After completion, the Investigator will be required to electronically sign off the clinical 
data. Data about all study drug dispensed to the patient and any dosage changes will be 
tracked on the eCRF. 
 
9.3 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
eCRF entries and individual patient’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. 
 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, Regulatory 
Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality 
Assurance Group may wish to carry out such source data checks and/or on-site audit 
inspections. Direct access to source data will be required for these inspections and audits; 
they will be carried out giving due consideration to data protection and medical 
confidentiality.  
 


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9.4 
Data Processing 
All data will be entered by IQVIA using an independent double data entry system (as 
detailed in Section 9.2.1). 
 
The data-review and data-handling document, to be developed during the initiation phase 
of the study, will include specifications for consistency and plausibility checks on data and 
will also include data-handling rules for obvious data errors. Query/correction sheets for 
unresolved queries will be sent to the study monitors for resolution with the Investigator. 
The database will be updated on the basis of signed corrections.  
 
Previous and concomitant medications will be coded using the World Health Organization 
Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
 
Previous and concomitant diseases as well as AEs will be coded using MedDRA. 
 
The versions of the coding dictionaries will be provided in the CSR. 
 
9.5 
Archiving Study Records 
According to International Council for Harmonisation (ICH) guidelines, essential 
documents should be retained for a minimum of 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 elapsed since the formal 
discontinuation of clinical development of the investigational product. However, these 
documents should be retained for a longer period if required by the applicable legal 
requirements or as advised by the Sponsor. 
 
9.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the Good Clinical Practice guidelines of the ICH, 
and of the Declaration of Helsinki1 (2013). The study also will be carried out in keeping 
with local legal and/or regulatory requirements. 
 
9.7 
Informed Consent 
Before each patient is enrolled to the study, informed consent will be obtained from the 
patient (or his/her legally authorized representative) according to the regulatory and legal 
requirements of the participating country. This consent form must be dated and retained 
by the Investigator as part of the study records. The Investigator will not undertake any 
investigation specifically required only for the clinical study until valid consent has been 
obtained. The terms of the consent and when it was obtained must also be documented in 
the eCRF system. 
 


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If a protocol amendment is required, the informed consent form may need to be revised to 
reflect the changes according to the amendment. If the consent form is revised, it must be 
reviewed and approved by the appropriate IEC/IRB, and signed by all patients 
subsequently enrolled in the study as well as those currently enrolled in the study. 
 
A specific written informed consent for the Screening of protein expression levels and gene 
mutational status of the proteins and genes will also be prepared, submitted and approved 
by the IRBs/IECs, and has to be signed by the patients before the blood samples are drawn. 
 
9.8 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal 
requirements. The Investigator must ensure that all ethical and legal requirements have 
been met before the first patient is enrolled in the study. 
 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent 
Authority approval prior to implementation (if appropriate). Following approval, the 
protocol amendment(s) will be submitted to the Investigational New Drug application 
under which the study is being conducted.  
 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without 
the need for a formal amendment. All amendments will be distributed to all protocol 
recipients, with appropriate instructions. 
 
9.9 
Name of Committee 
Not applicable. 
 
9.10 Duration of the Study 
Patients will be treated with study drug in the study until disease progression, unacceptable 
toxicity, death, or discontinuation from the study drug due to any other reason i.e. lost to 
follow-up or withdrawal of consent. 
 
9.11 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to patients if the study continues, the study may be 
terminated after appropriate consultation between the relevant parties. The study may also 
be terminated early at the Sponsor’s discretion in the absence of such a finding. 
 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study; 
• Failure to enroll patients at an acceptable rate; 


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• A decision on the part of the Sponsor to suspend or discontinue development of the 
drug. 
 
9.12 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor. 
 
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRF system and other documents submitted to IQVIA by their patient number, initials 
and/or birth date, not by name. Documents not to be submitted to IQVIA that identify the 
patient (e.g. the signed informed consent) must be maintained in confidence by the 
Investigator. 
 
9.13 Other Ethical and Regulatory Issues 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators, and IECs/IRB. 
 
A significant safety issue is one that has a significant impact on the course of the clinical 
study or program (including the potential for suspension of the development program or 
amendments to protocols) or warrants immediate update of informed consent. 
 
9.14 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance coverage in accordance 
with all local legal requirements. The civil liability of the Investigator, the persons 
instructed by him or her and the hospital, practice, or institute in which they are employed 
and the liability of the Sponsor with respect to financial loss due to personal injury and 
other damage that may arise as a result of the carrying out of this study are governed by 
the applicable law. 
 
The Sponsor will arrange for patients participating in this study to be insured against 
financial loss due to personal injury caused by the study drug being tested or by medical 
steps taken in the course of the study. 
 
9.15 Publication Policy 
By signing the study protocol, the Investigator agrees with to the use of results of the study 
for the purpose of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, Regulatory Authorities will be 
notified of the Investigator's name, address, qualifications and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. Details are provided in a separate document. 
 
 


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10  REFERENCES 
1. World Medical Association Declaration of Helsinki. Recommendations guiding 
physicians in biomedical research involving human patients. Adopted by the 18th 
WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th 
WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 1996. 
2.  Deschler B, Lubbert M. Acute Myeloid Leukemia: Epidemiology and Etiology. 
Cancer. 2006. 2009-2107. 
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology. Acute Myeloid Leukemia. 2017; version 1 
4.  Acute Myeloid Leukaemia. Cancer Council NSW. [Online], [Accessed on 04 July 
2017]; 
Available 
from: 
https://www.cancercouncil.com.au/acute-myeloid-
leukaemia/ 
5. Australian Institute of Health and Welfare 2014. Cancer in Australia: an overview 
2014. Cancer series No 90. Cat. no. CAN 88. Canberra: AIHW. 
6.  Howlader N, Noone AM, Krapcho M, Neyman N, et al. SEER Cancer Statistics 
Review, 1975–2009 (Vintage 2009 Populations), National Cancer Institute, Bethesda, 
MD, http://seeer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 
SEER data submission, posted on SEER web site 2012. 
7. Cancer incidence and mortality 2003-2012 and selected Trends 1973-2012 in 
Singapore. Singapore Cancer Registry Report No. 8. Singapore Cancer Registry 
Annual Registry Report 2015. National Registry of Diseases Office. [Online], 
[Accessed on 04 July 2017]; Available from: https://www.nrdo.gov.sg/publications  
8. De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive 
review and 2016 update'. Blood Cancer J. 2016;6(7):e441 
9. Saultz JN, Garzon R. Acute Myeloid Leukemia: A Concise Review. J Clin Med. 
2016;5(3). pii: E33 
10. Dohner H, Estey E, Grimwade D, et. al. (2016) Diagnosis and management of AML 
in adults: 2017 ELN recommendations from an international expert panel. Blood 
129:424.  
11. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid 
leukemia. J Clin Oncol. 2011 Feb 10;29(5):487-94. 
12. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still 
challenging after all these years. Blood. 2010 Dec 9;116(24):5089-102. 
13. Food and Drug Administration. FDA news release. FDA: Pfizer Voluntarily 
Withdraws Cancer Treatment Mylotarg from U.S. Market. 2010 
14. Sykes DB, Kfoury YS, Mercier FE, et. al. Inhibition of Dihydroorotate 
Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. 
Cell. 2016;167(1):171-186.  
15. ASLAN003. Investigator’s Brochure. Edition No. R. 186323. 6.MI dated 16 Aug 
2017. 
16. Cheson BD, Bennett JM, Kopecky KJ, et al; International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised 


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recommendations of the International Working Group for Diagnosis, Standardization 
of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic 
Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. 


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11 APPENDICES 
11.1 Appendix 1: WHO Classification of Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) and related neoplasms 
AML with recurrent genetic abnormalities 
AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 
AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A 
AML with t(6;9)(p23;q34.1);DEK-NUP214 
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM 
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 
Provisional entity: AML with BCR-ABL1 
AML with mutated NPM1 
AML with biallelic mutations of CEBPA 
Provisional entity: AML with mutated RUNX1 
AML with myelodysplasia-related changes 
Therapy-related myeloid neoplasms 
AML, NOS 
AML with minimal differentiation 
AML without maturation 
AML with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic/monocytic leukemia 
Pure erythroid leukemia 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis 
Myeloid proliferations related to Down syndrome 
Transient abnormal myelopoiesis (TAM) 
Myeloid leukemia associated with Down syndrome 
 
 
 


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11.2 Appendix 2: ECOG Performance Status 
Grade  
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g. light housework, office work) 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
In bed > 50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair 
5 
Dead 
 
 


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11.3 Appendix 3: Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, mg/dL 
<2 
2–3 
>3 
Serum albumin, g/dL 
>3.5 
2.8–3.5 
<2.8 
Prothrombin time, INR 
<1.7 
1.7–2.3 
>2.3 
Ascites 
Absent 
Slight 
Moderate  
Hepatic encephalopathy 
None 
Grade I–II 
Grade III–IV 
Child-Turcotte-Pugh (CTP) Class obtained by adding score for each parameter (total 
points) 
Class A: 5-6 points 
Class B: 7-9 points 
Class C: 10-15 points 
Kasper, Dennis L.,, etal. Harrison’s Principles of Internal Medicine. 19th edition. New 
York: McGraw Hill Education, 2015. 
 




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Declaration of the Investigator 
 
Title: A PHASE IIA DOSE OPTIMISATION STUDY OF ASLAN003 IN ACUTE 
MYELOID LEUKEMIA  
 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, IB, eCRF, and other scientific data. 
The study will not be commenced without the prior written approval of a properly 
constituted IRB/IEC. No changes will be made to the study protocol without the prior 
written approval of the Sponsor and the IRB or IEC, except where necessary to eliminate 
an immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
Responsible Investigator of the local study center 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 
 
 


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13 LIST OF STUDY PERSONNEL 
Sponsor 
ASLAN Pharmaceuticals Pte. Ltd. 
83 Clemenceau Avenue 
#12-03 UE Square 
Singapore 239920 
 
Contract Research 
Organization 
 
IQVIA 
 
Adverse Event Reporting 
 
PAREXEL 
 

SAP_003.pdf: