A Multicenter, Open-Label, Phase I Study Evaluating the Safety and Tolerability of HMPL-306 in Subjects With Locally Advanced or Metastatic Solid Tumors With IDH Mutations
Phase: PHASE1
Conditions: Isocitrate Dehydrogenase Gene Mutation
Sponsor: Hutchmed

Clinical Study Protocol 2020-306-GLOB2 
HMPL-306  
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Clinical Study Protocol 
A MULTICENTER, OPEN-LABEL PHASE I STUDY EVALUATING 
THE SAFETY AND TOLERABILITY OF HMPL-306 IN SUBJECTS 
WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS 
WITH IDH MUTATIONS 
Short Title 
A Phase 1 Study of HMPL-306 in Locally 
Advanced Solid Tumors with IDH Mutations 
Investigational Product(s): 
HMPL-306 
Protocol Number: 
2020-306-GLOB2 
Clinical Phase: 
1 
Date of Issue: 
17 May 2022 
Amendment: 
2 
Sponsor: 
HUTCHMED Limited 
Building 4, 720 Cailun Road 
China (Shanghai) Pilot Free Trade Zone 
Shanghai, China 201203 
Regulatory Agency Identifier 
Number (s) 
IND: 151196 
EudraCT: 2020-003729-44 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the confidential and proprietary information of 
HUTCHMED Limited, and except as may be required by applicable laws or regulation, may 
not be disclosed to others without prior written permission of HUTCHMED Limited. 
 

Clinical Study Protocol 2020-306-GLOB2 
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STATEMENT OF COMPLIANCE  
The study will be conducted in compliance with this clinical study protocol, Good Clinical Practice 
(GCP) as outlined by International Council for Harmonization (ICH) E6(R2), and all applicable 
local and national regulatory requirements.  Enrollment at any clinical study site may not begin 
prior to that site receiving approval from the ethics committee of record for the protocol and all 
materials provided to potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard to 
the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 

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SPONSOR’S APPROVAL  
Title 
A Multicenter, Open-Label Phase I Study Evaluating the Safety and Tolerability of 
HMPL-306 in Subjects with Locally Advanced or Metastatic Solid Tumors with IDH 
Mutations 
Protocol Number 
2020-306-GLOB2 
Date of Issue 
17 May 2022 
Amendment 
2 
The design of this study as outlined by this protocol has been reviewed and approved by the 
Sponsor’s responsible personnel as indicated in the signature table below. 
Name: 
Title: 
, MD, MBA 
 
  
 
HUTCHMED International Corporation 
Signature: 
See appended signature page 
 
Date: [DD Month YYYY] 
PPD
PPD

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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2020-306-GLOB2 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to participants prior 
to initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those participants 
• To maintain records of each subject’s participation and all data required by the protocol 
 
Name: 
Title:  
Institution:  
 
 
 
Signature:  
Date:   
 
 
 

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DOCUMENT HISTORY  
Amendment 
Version 
Date of Issue 
Original 
1 
18 Sep 2020 
1 
1 
29 October 2020 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................... 6 
1 
PROTOCOL SUMMARY ............................................................................................... 15 
1.1 
Synopsis ........................................................................................................................ 15 
1.2 
Study Schematic............................................................................................................ 18 
1.3 
Schedule of Events ........................................................................................................ 18 
2 
INTRODUCTION ........................................................................................................... 27 
2.1 
Study Rationale ............................................................................................................. 27 
2.2 
Background ................................................................................................................... 28 
2.3 
Benefit/Risk Assessment .............................................................................................. 30 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 33 
4 
STUDY PLAN ................................................................................................................. 35 
4.1 
Study Design ................................................................................................................. 35 
4.2 
Design Rationale ........................................................................................................... 39 
5 
POPULATION ................................................................................................................ 41 
5.1 
Definitions..................................................................................................................... 41 
5.2 
Inclusion Criteria .......................................................................................................... 41 
5.3 
Exclusion Criteria ......................................................................................................... 43 
6 
STUDY CONDUCT ........................................................................................................ 45 
6.1 
Study Procedures .......................................................................................................... 45 
6.2 
Discontinuation or Withdrawal ..................................................................................... 50 
7 
STUDY INTERVENTIONS ........................................................................................... 54 
7.1 
Study Drug Administration ........................................................................................... 54 
7.2 
Description of Products................................................................................................. 54 
7.3 
Assessment and Verification of Compliance ................................................................ 55 
7.4 
Dose Adjustments ......................................................................................................... 55 
7.5 
Special Adverse Events Handling Principles ................................................................ 58 
8 
SAFETY MONITORING ................................................................................................ 59 
8.1 
Definitions..................................................................................................................... 59 
8.2 
Adverse Event Reporting .............................................................................................. 60 
8.3 
Prior and Concomitant Therapies ................................................................................. 61 
8.4 
Eliciting Adverse Events............................................................................................... 62 

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8.5 
Assessment of Severity ................................................................................................. 62 
8.6 
Causality Assessment.................................................................................................... 63 
8.7 
Documenting Adverse Events....................................................................................... 63 
9 
ANALYSIS ...................................................................................................................... 67 
9.1 
Statistics and Analysis Method ..................................................................................... 67 
9.2 
Statistical Analysis ........................................................................................................ 68 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 72 
10.1 
Good Clinical Practice .................................................................................................. 72 
10.2 
Ethics Review ............................................................................................................... 72 
10.3 
Informed Consent.......................................................................................................... 72 
10.4 
Data Privacy .................................................................................................................. 73 
10.5 
Disclosure ..................................................................................................................... 74 
10.6 
Data Quality Assurance ................................................................................................ 74 
10.7 
Biological Specimens and Data .................................................................................... 74 
11 
OVERSIGHT ................................................................................................................... 75 
11.1 
Independent Monitoring................................................................................................ 75 
11.2 
Quality Control and Assurance ..................................................................................... 75 
11.3 
Study Termination or Study Site Closure ..................................................................... 77 
12 
PUBLICATION POLICY ............................................................................................... 79 
13 
FINANCING AND INSURANCE .................................................................................. 80 
14 
REFERENCES ................................................................................................................ 81 
15 
APPENDICES ................................................................................................................. 85 
 
LIST OF TABLES 
Table 1 
Schedule of Events (excluding Cohort C-1) ........................................................ 19 
Table 2 
Schedule of Events – Cohort C-1......................................................................... 23 
Table 3 
Summary of Potential Risks of HMPL-306 ......................................................... 30 
Table 4 
Objectives and Corresponding Endpoints ............................................................ 33 
Table 5 
Subject Dose Grouping (Dose Escalation Plan) .................................................. 36 
Table 6 
mTPI-2 Decision Table for Dose Selection ......................................................... 37 
Table 7 
Dose Adjustment for Hematologic Toxicity ........................................................ 56 
Table 8 
Dose Adjustment for Non-Hematologic Toxicity................................................ 56 

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Table 9 
Dose Adjustment for QT Interval Prolongation................................................... 57 
Table 10 
Hydroxyurea Initial Dose Reference ................................................................... 58 
Table 11 
Determination of Correlation Between Adverse Events and Study Drug ........... 63 
Table 12 
Medications That Can Prolong QT Interval......................................................... 91 
Table 13 
Time Point Response: Patients with Target Lesions (with or without Non-Target 
Lesions) .............................................................................................................. 101 
Table 14 
Time Point Response: Patients with Non-Target Lesions Only ........................ 101 
Table 15 
Best Overall Response When Confirmation of Complete Response and Partial 
Response is Required ......................................................................................... 102 
LIST OF FIGURES 
Figure 1 
Study Schema....................................................................................................... 18 
Figure 2 
Study Schema, Cohort C-1 .................................................................................. 18 
LIST OF APPENDICES 
Appendix 1 
PK, PD, and Biomarker Assessments (Excluding Cohort C-1) ........................... 86 
Appendix 2 
PK, PD, and Biomarker Assessments for Cohort C-1 ......................................... 88 
Appendix 3 
ECOG Performance Status .................................................................................. 90 
Appendix 4 
Prohibited Medications ........................................................................................ 91 
Appendix 5 
New York Heart Association Function Classification ......................................... 92 
Appendix 6 
.............................................................. 93 
Appendix 7 
List of 
 ... 94 
Appendix 8 
Response Evaluation Criteria in Solid Tumors (RECIST version 1.1 ................. 95 
Appendix 9 
Response Assessment in Neuro-Oncology Criteria for Gliomas ....................... 106 
Appendix 10 COVID-19 Risk Assessment ............................................................................. 108 
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AMENDMENT SUMMARY  
This 2020-306-GLOB2 Amendment 2 replaces the 2020-306-GLOB2 Amendment 1 protocol.  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
The primary purpose of Amendment 2 is to explore additional dose levels in Part 1.  The changes 
made in this amendment are described in the table below.  Editorial and formatting changes are 
not included in this summary. 
Details of prior amendments are summarized in Appendix 12. 
Section Number 
Summary of Change 
Rationale for Change 
Title Page, Footers, Signature Page, 
and Globally 
The Sponsor company name, 
address, and logo, where 
appropriate, were updated 
throughout.  
The administrative updates were 
made to appropriately reflect the 
change of Sponsor company name. 
Synopsis and Section 6 – Study 
Conduct 
The approximate duration of the 
study was updated from 36 to 
42 months to reflect the additional 
dose levels added to Dose 
Escalation. 
The updates were made to be 
consistent with the additional dose 
levels added to Part 1.  
Synopsis; Section 1.2 – Study 
Schematic; and Section 4.1.1 – 
Part 1 (Dose Escalation), Table 5 – 
Subject Dose Grouping (Dose 
Escalation Plan) 
The Part 1 dose escalation language 
was updated to reflect the addition 
of dose levels 5, 6, 7, and 8, or 
 
 mg dose levels, 
respectively. 
The updates were made to further 
investigate PK exposure and PD 
effects at higher dose levels. 
Synopsis and Section 3 – 
Objectives and Endpoints 
The “Cohort C-1 Only” language 
was removed from the Part 2 
exploratory objective.  
The indicated language was 
removed as this exploratory 
objective applies to all cohorts. 
Section 1.3 – Schedule of Events, 
Table 1 – Schedule of Events 
(excluding Cohort C-1) and Table 2 
– Schedule of Events - Cohort C-1 
The table was updated to include a 
pregnancy test on D1.  
This test was added to align with 
global regulatory requests. 
Section 1.3 – Schedule of Events, 
Table 1 – Schedule of Events 
(excluding Cohort C-1); and 
Section 6.1.14 – IDH Mutation 
Confirmation 
The language was added to clarify 
that a fresh tissue biopsy is required 
if archival tissue is not available. 
The language updates were made 
for clarity.  
Section 1.3 – Schedule of Events; 
Table 1 – Schedule of Events 
(excluding Cohort C-1), Table 2 – 
Schedule of Events – Cohort C-1 
 
The language was updated to 
clarify that the Ophthalmologic 
examination after the start of study 
drug administration must be 
±1 week of D15 in cycle 2 in Table 
1 and 2. In Table 2 language was 
added to clarify that 
Ophthalmologic examinations must 
be completed -1 week of D28 (day 
prior to surgery).  
The language updates were made 
for clarification.  
Section 1.3 – Schedule of Events, 
Table 2 – Schedule of Events – 
Cohort C-1  
The language was updated to 
indicate that patients enrolled to the 
control arm will not need to 
The language updates were made 
for clarity.  
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undergo pharmacokinetic sampling 
during the pre-surgery period of the 
study.  
The language updates were made to 
clarify that tumor imaging must be 
submitted within 2 weeks after 
surgery for Cohort C-1, and only a 
brain scan is required at the surgery 
time point; other tumor imaging can 
be done if clinically indicated. 
Section 4.1.1 – Part 1 (Dose 
Escalation) 
The language indicating that 
multiple subjects, with an 
additional maximum of 3 subjects, 
in screening when the last subject 
of the cohort starts treatment may 
be enrolled in this cohort with 
evaluation and consent from the 
Sponsor and investigator was 
removed.  
The language that discusses the 
rationale behind the addition of 
dose levels 5 to 8 was added. 
The language was removed as the 
intent is only to enroll the 
predefined number of patient per 
cohort. 
 
The rationale language for dose 
levels 5 to 8 was added for clarity.  
Section 4.1.2 – Part 2 (Dose 
Expansion) 
The word “non-enhancing” was 
removed to indicate that Cohort C-1 
will enroll 15 subjects with 
recurrent low grade glioma. 
The language was removed as it is 
intended to allow Grade 3 gliomas 
to enroll who many have enhancing 
gliomas. 
Section 4.2.2 – Rationale for Study 
Population Selection 
The language referencing the 
updated Appendix 11 was added. 
The language was added to provide 
an expanded discussion on the 
rationale for patient selection, and 
line of therapy for Cohorts A to D. 
Section 4.2.3 – Rationale for 
Biomarker Testing 
The language was updated to 
include 
The language updates were made 
for accuracy. 
Section 5.2 – Inclusion Criteria 
The language for criterion 14a was 
updated to include “non-
enhancing”. 
The language in criterion 8 was 
made to clarify that international 
normalized ratio of ≤1.5 or an 
activated partial thromboplastin 
time of ≤1.5 × ULN. 
The language updates were made 
for accuracy and clarity. 
Section 5.3 – Exclusion Criteria 
The language in criterion 1 was 
updated to indicate that 
radiotherapy received <12 weeks 
for glioma subjects is an exclusion. 
Criterion 18 was added to exclude 
subjects with a known 
hypersensitivity to HMPL-306 or 
any of its excipients.  
The language updates were made 
for clarity, accuracy, and safety 
reasons.  
Section 6.1.10.10 – IDH Mutational 
Status 
The language was updated to 
indicate that IDH mutations should 
be tested locally via a biopsy tissue 
collection at the clinical site.  
The language update was made for 
clarity.  
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Section 6.1.13 – Tumor Assessment 
The language updates were made to 
clarify when the tumor assessments 
will be performed during the study. 
The language updates were made 
for clarity.  
Section 6.2.1.1 – Permanent 
Discontinuation of Treatment 
The language introducing the 
reasons for discontinuation was 
updated from “could” to “must be 
discontinued from treatment…”  
The language in Criterion 3 was 
updated to include adverse events 
that warrant withdrawal of study 
treatment as determined by 
principal investigator or as outlined 
in Section 7.4.2.  
The language update was made to 
comply with regulatory requested 
change.  
The language update to Criterion 3 
was for clarity and guidance. 
Section 7.2.1 – Formulation, 
Storage, Preparation, and Handling 
The language updates were remove 
“white” from the description of the 
high-density polyethylene bottles 
and add clarify that HMPL-306 
should be stored with protection 
from light and moisture. 
The language updates were made 
for clarity.  
Section 9.1.2 – Sample Size 
Rationale and Section 9.1.2.1 – 
Dose Escalation Part 
The number of estimated subjects 
to be recruited subjects was updated 
from 110 to 115 subjects to 122 to 
131 subjects. 
The number of subjects in the dose 
escalation part was updated from 15 
to 20 subjects to 27 to 36 subjects. 
The number of subjects was 
updated to reflect the additional 
cohorts added to dose escalation.  
Appendix 1 – PK, PD, and 
Biomarker Assessments (Excluding 
Cohort C-1) 
The tables in Appendices 1 and 2 
were updated to indicate an ECG is 
required at screening.  
The footnote 2 in Appendices 1 and 
2 was updated to include 
 
testing and to clarify testing 
schedule. 
The language updates were made 
for clarity and accuracy. 
Appendix 6 – 
 
 
Several 
 
 were deleted 
from Appendix 6 list, and 3 
 were added. 
List was revised based on clinical 
relevance. 
Appendix 11 – Expanded 
Population Selection Rationale 
Appendix was added to elaborate 
on the rationale for study patient, 
and line of therapy selection for 
Cohorts A to D.  
The appendix was added to provide 
an expanded rationale for study 
patient selection, and line of 
therapy for Cohorts A to D.  
 
 
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LIST OF ABBREVIATIONS  
Abbreviations 
Definitions 
2-HG 
2-hydroxyglutaric acid 
ADL 
Activity of daily living 
AE 
Adverse event 
α-KG 
α-ketoglutaric acid 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AR 
Accumulation ratio 
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration-time curve 
BCRP 
Breast cancer resistance protein 
CI 
Confidence interval 
CL/F 
Total plasma clearance of drug after extravascular administration 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration within the dosing interval (at steady 
state) 
Ctrough 
Observed plasma concentration at the end of a dosing interval (taken directly 
before the next dose administration) 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRF  
case report form 
CRO 
Contract research organization 
CRR 
Complete response rate 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria of Adverse Events 
ctDNA 
Circulating tumor DNA 
CV% 
Coefficient of variation 
CxDx 
Cycle x Day x 
CYP 
Cytochrome P450 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 

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Abbreviations 
Definitions 
EDC 
Electronic data capture 
EOT 
End-of-treatment 
FDG 
18F-fluorodeoxyglucose 
FIH 
First-in-human 
FLAIR 
Fluid-attenuated inversion recovery 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
HBcAb 
Hepatitis B core antibody 
HBeAb 
Hepatitis B e-antibody 
HBeAg 
Hepatitis B e-antigen 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
hERG 
human Ether-à-go-go-Related Gene 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IDH 
Isocitrate dehydrogenase 
IHC 
Immunohistochemistry 
IMP 
Investigational medical product 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mIDH 
Mutant IDH 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTPI-2 
Modified toxicity probability interval-2 
MUGA 
Multigated acquisition  
NCI 
National Cancer Institute  
NGS 
Next-generation sequencing 
NOAEL 
No observed adverse effect level 
OATP1B3 
Organic anion-transporting polypeptide 1B3 

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Abbreviations 
Definitions 
ORR 
Objective response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PO 
Orally 
PR 
Partial response 
PS 
Performance status  
pT 
Toxicity probability 
QD 
Once a day 
QT 
Interval from the start of the Q wave to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SDV 
Source data verification 
SIV 
Study Initiation Visit 
SRC 
Safety Review Committee 
t1/2 
Elimination half-life 
TLS 
Tumor lysis syndrome 
Tmax 
Time to peak plasma concentration 
TEAE 
Treatment-emergent adverse event 
TTR 
Time-to-response 
UGT 
Uridine diphosphate glucuronosyltransferase 
 

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1 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Title 
A Multicenter, Open-Label Phase I Study Evaluating the Safety and 
Tolerability of HMPL-306 in Subjects with Locally Advanced or Metastatic 
Solid Tumors with IDH Mutations 
Short Title 
A Phase 1 Study of HMPL-306 in Locally Advanced Solid Tumors with IDH 
mutations 
Acronym 
Not applicable 
Phase 
1 
Rationale 
Isocitrate dehydrogenase (IDH) is a rate-limiting enzyme in the tricarboxylic 
acid cycle participating in cellular energy metabolism and catalyzes the 
oxidative decarboxylation of isocitrate to generation of α-ketonyl 
acetylbenzoic acid glutarate (α-KG) and carbon dioxide.  There are 3 isoforms 
of IDH enzymes in the human body, namely IDH1 located in cell cytoplasm, 
IDH2 in the mitochondria, and IDH3 in the mitochondria. 
IDH1 or IDH2 mutations or co-mutations have been associated with various 
tumors, including glioma, chondrosarcoma, and cholangiocarcinoma. 
HMPL-306 is a novel, small-molecule, orally available, highly selective, and 
potent inhibitor of mutant IDH.  It demonstrated a remarkable inhibitory effect 
on 2-hydroxyglutaric acid (2-HG) in tumor cells with IDH mutations, and 
therefore, this phase 1 open-label study is planned to evaluate the safety, 
tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of 
HMPL-306 in subjects with locally advanced or metastatic solid tumors with 
IDH mutations. 
Target Population 
Adult male and female subjects ≥18 years of age with locally advanced or 
metastatic solid tumors with any IDH mutation.  
Part 1: locally advanced or metastatic solid tumors 
Part 2:  
• 
Cohort A: Cholangiocarcinoma 
• 
Cohort B: Skeletal chondrosarcoma 
• 
Cohort C: Low-grade glioma 
o 
Cohort C-1: Perioperative glioma 
• 
Cohort D: Any other solid tumor harboring an IDH mutation 
Intervention 
Part 1 (dose escalation): 
 mg 
HMPL-306 orally (PO) once daily (QD) 
Part 2 (dose expansion): recommended phase 2 dose (RP2D) and/or maximum 
tolerated dose (MTD) from Part 1 PO QD 
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Objectives and Endpoints 
Objectives 
Corresponding Endpoints 
Primary: 
Part 1 – Dose Escalation: To evaluate the safety and 
tolerability of HMPL-306, thereby determining the 
RP2D and/or the MTD of HMPL-306 in subjects with 
locally advanced or metastatic solid tumors with IDH 
mutations 
Primary: 
Safety including dose-limiting toxicities (DLTs), 
treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), electrocardiograms (ECGs), 
and clinical laboratory abnormalities 
MTD and/or RP2D 
Part 2 – Dose Expansion: To characterize the safety 
and tolerability of HMPL-306 in subjects with locally 
advanced or metastatic solid tumors with an IDH 
mutation 
Safety including TEAEs, SAEs, ECGs, and clinical 
laboratory abnormalities 
Part 2 – Cohort C-1 Only: To determine the 2-HG 
concentration in surgically resected tumors following 
pre-surgical treatment with HMPL-306 when 
compared to untreated tumors 
Observed plasma and tumor concentrations of 2-HG  
Secondary: 
Part 1 and Part 2: To assess the preliminary 
antitumor activity of HMPL-306 in subjects with 
locally advanced or metastatic solid tumors with IDH 
mutations 
Secondary: 
Objective response rate, disease control rate, duration 
of response, time to response, and progression-free 
survival 
Part 1 and Part 2: To assess the pharmacokinetics 
(PK) of HMPL-306 in subjects with locally advanced 
or metastatic solid tumors with IDH mutations 
Observed plasma concentrations and PK parameters of 
HMPL-306 
Part 1 and Part 2: To assess the pharmacodynamics 
(PD) of HMPL-306 in subjects with locally advanced 
or metastatic solid tumors with an IDH mutations 
Observed plasma concentrations of 2-HG 
Part 2 – Cohort C-1 Only: To characterize the safety 
and tolerability of HMPL-306 in subjects with locally 
advanced or metastatic solid tumors with IDH 
mutations 
Safety including, TEAEs, SAEs, deaths, ECGs, and 
clinical laboratory abnormalities 
Exploratory: 
Part 1 and Part 2: To explore the relationship 
between HMPL-306 PK exposure and 2-HG levels and 
percent inhibition 
Exploratory 
Changes from baseline in tumor markers, correlation 
with drug exposure, and association with efficacy and 
safety parameters 
Part 1 and Part 2: To explore the influence of gene 
abnormalities other than IDH mutations on safety, 
efficacy, PD, and PK 
Part 1 and Part 2: To assess the potential predictive 
biomarkers or response or progression though 
collection of serial circulating tumor DNA collection 
Part 2: To explore the relationship between the 
changes in the frequency of genetic mutation, efficacy, 
PK, PD, and safety after HMPL-306 treatment in tumor 
and plasma 
Part 2 – To assess the overall survival (OS) in 
subjects enrolled to expansion Cohorts A, B, and D. 
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Brief Summary: This is a phase 1, open-label, multicenter study to evaluate the safety and tolerability of 
HMPL-306 administered orally in the treatment of subjects with locally advanced or metastatic solid tumors with 
IDH mutation. The study consists of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). The dose 
escalation part will determine the MTD/RP2D. The dose expansion part will administer the MTD/RP2D to 
4 cohorts of subjects: 
• 
Cohort A: Cholangiocarcinoma 
• 
Cohort B: Skeletal chondrosarcoma 
• 
Cohort C: Low-grade glioma 
o 
Cohort C-1: Perioperative glioma 
• 
Cohort D: Any other solid tumor harboring an IDH mutation 
Condition/Disease 
Locally advanced solid tumors with IDH mutation 
Study Duration 
Approximately 42 months 
Treatment Duration 
28-day continuous dosing treatment cycle 
Health 
Measurement/Observation 
This study will determine the MTD and/or RP2D, as well as safety 
assessments including DLTs, TEAEs, SAEs, deaths, ECGs, and clinical 
laboratory abnormalities.  During the dose expansion part, subjects will receive 
HMPL-306 at MTD or RP2D for 28 days in each cycle until disease 
progression, death, intolerable toxicity, the subject can no longer benefit from 
the study treatment at the investigator’s discretion, withdrawal of consent, lost 
to follow-up, death, or the end of study, whichever comes first. For Cohort C-
1, all subjects will have the option of receiving HMPL-306 following surgery.  
Subjects with no residual disease following surgery will be allowed to receive 
HMPL-306 for up to 1 year or until disease progression, whichever occurs 
first. If residual disease is evident following surgery, those subjects may 
receive HMPL-306 until disease progression. 
Visit Frequency 
Cycle 1: every week (±1 day, except D1) 
Cycle 2: every 2 weeks (±1 day) 
Cycle 3 and onward: Day 1 (±3 days) 
End of Treatment: within 7 days (±3 days) after the last dose 
For Cohort C-1: 
Pre-surgery: every week (±1 day, except D1) 
Cycles 1 and 2: every 2 weeks (±3 days) 
Cycle 3 and onward: Day 1 (±3 days) 
End of Treatment: within 7 days (±3 days) after the last dose 
Number of Participants 
Part 1: at least 1 subject will be enrolled to dose levels 1, 2, and 3.  At least 3 
subjects will be enrolled to dose levels 4, 5, 6, 7, and 8. 
Part 2: approximately 20 evaluable subjects (15 subjects in Cohort C-1) per 
cohort will be enrolled; for a total of approximately 95 subjects 
Intervention Groups and 
Duration 
Part 1: 
, and 
 mg of HMPL-306 PO QD 
administered to dosing groups for 28 days cycles 
Part 2: MTD/RP2D as determined in Part 1, administered PO QD to 
approximately 95 subjects for 28-day cycles 
Data Monitoring/Other 
Committee 
Yes 
 
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1.2 
Study Schematic  
The study schematic is presented in Figure 1. 
Figure 1 
Study Schema  
 
ECOG = Eastern Cooperative Oncology Group; IDH = isocitrate dehydrogenase; mTPI-2 = modified toxicity 
probability interval-2; PS = performance status; QD = once daily. 
Note: Subjects in dose expansion must have documented mutations. 
The study schematic for Cohort C-1 is presented in Figure 2. 
Figure 2 
Study Schema, Cohort C-1  
 
2-HG = 2-hydroxyglutaric acid; IDH = isocitrate dehydrogenase; MRI = magnetic resonance imaging; 
PK = pharmacokinetics. 
1.3 
Schedule of Events  
The schedule of events (SOE) is presented in Table 1 and Table 2. 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Table 1 
Schedule of Events (excluding Cohort C-1)  
Cycle/Period 
Pre- 
screening 
Screening 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-
up 
Efficacy 
Follow- 
up 
Survival 
Follow-
up 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 Days 
After 
the 
Last 
Dose 
30 Days 
After the 
EOT 
Visit 
Every 
12 
Weeks 
From 
EOT 
Visit 
Every 
12 
Weeks 
From 
EOT 
Visit 
Visit Window (days) 
-- 
-28 to -1 
-- 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
Pre-screening informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Main informed consent2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IDH mutational status3 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
Medical history and demographics4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications and 
concomitant procedures5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs, and 
weight6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG performance status6 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
Ophthalmologic examination7 
 
X 
 
 
 
 
 
X 
(±1 
week)  
Every 
12 weeks 
(±1 week) 
from C4D1 
 
 
 
Laboratory evaluations6 
 
 
Hematology8 
 
X9 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistry10 
 
X9 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood amylase and lipase 
 
X9 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Fasting lipid panel11 
 
X9 
 
 
X 
 
X 
 
X 
X 
 
 
 
Coagulation indicators12 
 
X9 
 
 
X 
 
X 
 
X 
 
 
 
 
Pregnancy test13 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
Urinalysis14 
 
X9 
 
 
 
 
X 
 
X 
X 
 
 
 

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Table 1 
Schedule of Events (excluding Cohort C-1)  
Cycle/Period 
Pre- 
screening 
Screening 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-
up 
Efficacy 
Follow- 
up 
Survival 
Follow-
up 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 Days 
After 
the 
Last 
Dose 
30 Days 
After the 
EOT 
Visit 
Every 
12 
Weeks 
From 
EOT 
Visit 
Every 
12 
Weeks 
From 
EOT 
Visit 
Visit Window (days) 
-- 
-28 to -1 
-- 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
Virological screening15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
 
X9 
 
 
X 
 
X 
 
X 
X 
 
 
 
PK and PD assessments 
Refer to Appendix 1 
 
12-lead ECG6,16 
Refer to Appendix 1 
 
ECHO/MUGA scan 
 
X 
 
 
 
 
X 
 
C3D1 then 
Day 1 of every 
odd cycle (ie, 
C5D1, C7D1, 
etc.) (±1 week) 
 
 
 
Tumor evaluation/imaging17 
 
X 
Every 8 weeks from C1D1 during the first 24 (±1) weeks 
and every 12 (±2) weeks thereafter 
 
X 
 
Tumor tissue for exploratory biomarker 
evaluation.  Applies to Cohorts A, B, 
and D only18 
 
X 
 
 
 
 
X±7 
days 
 
At disease 
progression 
only in dose 
expansion 
 
 
 
Blood for gene mutation analysis19 
 
X 
Only in dose expansion; refer to Appendix 1 
 
 
 
Study drug administration 
 
Dosing will be based on cohort for dose escalation, and will be 
dosed at the RP2D in dose expansion 
 
 
 
 
AEs20 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival follow-up21 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; C = cycle; 
CMV = cytomegalovirus; ctDNA = circulating tumor DNA; D = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic case report form; EOT = end of treatment; FFPE = formalin-fixed paraffin-embedded; HbA1C = glycated hemoglobin; 
HBcAb = hepatitis B core antibody; HBeAb = hepatitis B e-antibody; HBeAg = hepatitis B e-antigen; HBsAb = hepatitis B surface antibody; HBsAb = hepatitis B s-antigen; 

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HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IDH = isocitrate dehydrogenase; INR = international normalized ratio; 
LDH = lactate dehydrogenase; MUGA = multigated acquisition; NGS = next-generation sequencing; PCR = polymerase chain reaction; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); PT = prothrombin time; RNA = ribonucleic acid; RP2D = recommended phase 2 dose; SAE = serious adverse event 
1. 
Pre-screening informed consent must be obtained for subjects who do not have IDH mutational status report.  The pre-screening consent should be signed before any study-
related examinations or procedures are performed.  Subjects who have already tested positive for IDH mutation may enter Screening period directly. 
2. 
Written informed consent must be obtained before any study-related examinations or procedures are performed.  However, before informed consent is obtained, if the 
assessments for standard treatment are performed within 28 days before the planned Day 1 of Cycle 1, they can be used to replace the assessments during the Screening 
Period without repeating the examinations except for assessments that need to be performed 7 days before the start of the study drug administration.  If there is dosing on 
the assessment day, all assessments should be completed before the study drug administration, except 12-lead ECG, ECHO/MUGA scan, ophthalmologic assessments, and 
efficacy assessments. 
3. 
Subjects should have a local report of IDH mutational analysis, confirming mutant IDH.  Further, during Screening, tumor tissue samples will be collected and provided 
to a central laboratory for IDH mutations confirmation.  If archival tissue is not available, a biopsy will be required to collect fresh tissue for central testing. Tissue collection 
for IDH testing at EOT is for patients in dose expansion only. 
4. 
Medical history data include significant clinical disease or symptom, surgical history, history of malignancy (including date of diagnosis; classification and prognosis 
evaluation of the study disease, the treatment performed, and the outcome; and the tumor type and outcomes of any other previous malignancies), smoking history, history 
of alcohol consumption, history of drug abuse, and other medical-related history.  Demographic information includes sex, race, and in some countries, year of birth. 
5. 
Concomitant medications include any prescription and over-the-counter medications.  During the Screening Period, all drugs used by the subject within 28 days prior to 
the start of study drug administration should be recorded in the eCRF.  In subsequent visits, the drugs used by that period and within 30 days after termination of treatment 
should be recorded in the eCRF. Subsequent new antitumor treatment regimens, during the Safety, and Efficacy Follow-up Periods will also be recorded.  
6. 
Physical examination, vital signs, weight, ECOG performance status score, laboratory evaluations, and ECG (unless otherwise stipulated) should be obtained within the 
scheduled visit date.  During Cycle 1 and Cycle 2, all visits should be completed ±1 day of the scheduled date unless otherwise stipulated.  Starting from Cycle 3, unless 
otherwise stipulated, visits during treatment should be completed within ±3 days of the scheduled date. Unscheduled examinations may be performed if clinically indicated. 
7. 
Ophthalmologic assessments, including eye appearance, slit lamp examination, best corrected visual acuity, visual field, eye movement, pupil reflex, optical coherence 
tomography (OCT), and intraocular pressure will be performed during the Screening Period.  If the subject has undergone the relevant examinations 60 days before the 
start of study treatment (C1D1), they need not be repeated.  After the start of study drug administration, OCT will be performed at 6 weeks (±1 week), then OCT, eye 
appearance, and slit lamp examinations will be performed every 12 weeks (±1 week) from C4D1 and at the EOT visit.  Other ophthalmic examinations are to be performed 
when clinically indicated.  If the subject develops an ophthalmic AE related to HMPL-306, the frequency of the examination should be increased to once every cycle until 
the adverse event is relieved or stable. 
8. 
Hematology includes red blood cell count, hemoglobin, hematocrit, white blood cell count with differential and classifications (absolute neutrophil count, neutrophils % 
absolute lymphocyte count, lymphocytes %, absolute eosinophil count, eosinophils %, absolute monocyte count, monocytes %, absolute basophil count and basophils %), 
and platelet count. If abnormal or primitive immature cells are seen, they are also required to be recorded.  Any additional routine blood tests during the study shall be 
arranged by the investigator as needed. 
9. 
These tests should be completed within 7 days before the start of treatment; if completed more than 7 days before the first dose, they must be repeated on C1D1 prior to 
dosing. 
10. 
Blood chemistry includes blood urea nitrogen, creatinine, sodium, potassium, magnesium, chloride, calcium, phosphorus, blood glucose, creatine phosphokinase, total 
bilirubin, direct bilirubin, indirect bilirubin, ALT, AST, ALP, LDH, total protein, and albumin. 
11. 
Fasting lipid panel includes total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. 
12. 
Coagulation indicators include PT, aPTT, and INR. 
13. 
Female subjects of childbearing potential (including those who have undergone tubal ligation) must undergo a serum pregnancy test within 7 days before drug administration 
and record a negative result. After enrollment, serum or urine pregnancy test should be conducted on Day 1 of every treatment cycle starting from Cycle 1, at EOT visit, 
and during Safety Follow-up Period. Unscheduled testing can be performed if there is an indication. 
14. 
Urinalysis includes glucose, protein, ketone body, red blood cells, white blood cells, and urobilinogen. 
15. 
Only required if subject has finding suggestive of active viral infection.  Virological screening includes HIV, HBV (HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb), HCV 
(HCV antibody), and CMV (CMV antibody).  If HBsAg or HBcAb or CMV antibody is positive, CMV DNA or HBV DNA is also required to be assayed by PCR method.  

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If CMV DNA or HBV DNA is negative, subjects may be enrolled and their CMV DNA or HBV DNA should be monitored every cycle). If HCV antibody is positive, 
HCV RNA is required to undergo PCR testing. 
16. 
ECG indicators include PR interval, QRS interval, RR interval, QT/QTcF interval, and heart rate. Evaluation time points are shown in Appendix 1. Unscheduled ECG or 
other cardiac examinations can be performed if clinically indicated. 
17. 
De-identified tumor imaging with study number is to be transmitted to central vendor for image storage. 
18. 
In the expansion part, for subjects participating in the exploratory portion of the study, at the disease progression or EOT, tumor tissues (FFPE block or section, or fresh 
tissue from a biopsy) will be collected to check IDH mutation status and other co-occurring genes alterations to explore the resistance mechanism of HMPL-306. 
19. 
ctDNA samples will be collected in the escalation and expansion part. 
20. 
AEs due to the protocol-required intervention (ex. NGS testing) will be collected in the pre-screening phase. AEs will be collected from signing of the main informed 
consent until 30 days after the last dose or initiation of new antitumor therapy. The relevant AEs will be followed up until they are recovered to the baseline status, already 
in a stable state as assessed by the investigator, start of new antitumor therapy, loss to follow-up, death, withdrawal of informed consent, or it has been confirmed the AEs 
are unrelated to the study drug. SAEs are collected from the signing of the informed consent form until 30 days after the last dose or initiation of new antitumor therapy 
and until resolution regardless of relationship to study treatment. 
21. 
All subjects in dose expansion cohort A, B, and D may be followed for survival status every 12 weeks (±14 days) up to 2 years from EOT visit, until death, lost to follow 
up, or withdrawal of consent. Survival information can be obtained via phone, and information will be documented in the source documents and relevant eCRFs. 
 
 

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Table 2 
Schedule of Events – Cohort C-1  
Cycle/Period 
Pre- 
screening 
Screening 
Pre-Surgery  
Surgery 
C1+1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Visit 
D1 D8 D15 D22 
D28 
(Day 
prior to 
surgery) 
D1 D15 D1 
D15 
D1 
Within 7 Days 
After the Last 
Dose 
30 Days 
After the 
EOT Visit 
Every 
12 Weeks 
From 
EOT Visit 
Visit Window (days) 
-- 
-28 to -1 
-- ±1 ±1 
±1 
-- 
±3 ±3 ±3 
±3 
±3 
±3 
±7 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-screening informed 
consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main Informed consent3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDH mutational status4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Medical history and 
demographics5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications and 
concomitant procedures6 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital 
signs, and weight7 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status7 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Ophthalmologic 
examination8 
 
X 
 
 
 
 
X9 
(-1 
week) 
 
 
 
 
X9 
(±1 week) 
Every 12 weeks (±1 week) from 
C4D1 
 
 
Laboratory evaluations: 
 
Hematology10 
 
X11 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry12 
 
X11 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Blood amylase and 
lipase 
 
X11 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Fasting lipid panel13 
 
X11 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Coagulation indicators14 
 
X11 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 

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Table 2 
Schedule of Events – Cohort C-1  
Cycle/Period 
Pre- 
screening 
Screening 
Pre-Surgery  
Surgery 
C1+1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Visit 
D1 D8 D15 D22 
D28 
(Day 
prior to 
surgery) 
D1 D15 D1 
D15 
D1 
Within 7 Days 
After the Last 
Dose 
30 Days 
After the 
EOT Visit 
Every 
12 Weeks 
From 
EOT Visit 
Visit Window (days) 
-- 
-28 to -1 
-- ±1 ±1 
±1 
-- 
±3 ±3 ±3 
±3 
±3 
±3 
±7 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test15 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Urinalysis15,16 
 
X11 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Virological screening17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
 
X11 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
PK and PD assessments18 
 
 
Refer to Appendix 2 
12-lead ECG7, 19 
 
X 
Refer to Appendix 2 
ECHO/MUGA scan 
 
X 
 
 
 
 
 
 
X 
 
X 
 
C3D1 then Day 
1 of every odd 
cycle (ie, 
C5D1, C7D1, 
etc.) (± 1 week) 
 
 
 
Tumor 
evaluation/imaging20 
 
X 
 
 
 
 
 
X 
within 
2 weeks 
post op 
Every 8 weeks from C1D1 during the first 24 (±1 week) 
weeks and every 12 (±2 weeks) weeks thereafter 
 
X 
Blood for gene mutation 
analysis 
 
X 
 
 
 
 
 
 
Refer to Appendix 2 
 
 
Study drug administration 
 
 
HMPL-306 will be dosed at 
the RP2D 
 
HMPL-306 will be dosed at the RP2D 
 
 
 
AEs21 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; C = cycle; 
CMV = cytomegalovirus; D = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic case report form; EOT = end of treatment; HBcAb = hepatitis B core antibody; HBeAb = hepatitis B e-antibody; HBeAg = hepatitis B e-antigen; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B s-antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IDH = isocitrate dehydrogenase; INR = international normalized ratio; LDH = lactate dehydrogenase; MUGA = multigated acquisition; NGS = next-generation sequencing; 
PCR = polymerase chain reaction; PD = pharmacodynamic(s); PI = principal investigator; PK = pharmacokinetic(s); PT = prothrombin time; RNA = ribonucleic acid; 
RP2D = recommended phase 2 dose; SAE = serious adverse event. 
1. 
If the subject chooses to continue treatment with HMPL-306, C1 will begin 4 to 8 weeks after surgery based on the clinical judgment of the PI. 
2. 
Pre-screening informed consent is signed to obtain IDH mutational status report.  Subjects who have already tested positive for IDH mutation may enter the Screening 
period directly. 
3. 
Written informed consent must be obtained before any study-related assessments or procedures are performed.  However, before informed consent is obtained, if the 
examinations for standard treatment are performed within 28 days before the planned Day 1 of Cycle 1, they can be used to replace the examinations during the Screening 
Period without repeating the examinations, except for examinations that need to be performed 7 days before the start of the study drug administration, as specified in the 
table.  For subjects enrolled in dose escalation, all screening examinations should be completed before study drug administration on Day -7.  If there is dosing on the 
assessment day, all assessment examinations should be completed before the study drug administration, except 12-lead ECG, ECHO/MUGA scan, ophthalmologic 
examination, and efficacy assessments. 
4. 
Subjects who have reports of positive IDH1 and/or IDH2 mutation tests may directly enter the Screening Period. 
5. 
Medical history data include significant clinical disease or symptom, surgical history, history of malignancy (including date of diagnosis; classification and prognosis 
evaluation of the study disease, the treatment performed, and the outcome; and the tumor types and outcomes of any other previous malignancies), smoking history, history 
of alcohol consumption, history of drug abuse, and other medical-related history.  Demographic information includes sex, race, and in some countries, date of birth. 
6. 
Concomitant medications include any prescription and over-the-counter medications.  During the Screening Period, all drugs used for the subject within 28 days prior to 
the start of study drug administration should be recorded in the eCRF.  In subsequent visits, the drugs used by that period and within 30 days after termination of treatment 
should be recorded in the eCRF.  Subsequent new antitumor treatment regimens during the Safety and Efficacy Follow-up Periods will also be recorded. 
7. 
Physical examination, vital signs, weight, ECOG performance status score, weight measurement, laboratory evaluations, and ECG (unless otherwise stipulated) should be 
obtained within the scheduled visit date.  During Cycle 1 and Cycle 2, all visits should be completed ±1 day of the scheduled date unless otherwise stipulated.  Starting 
from Cycle 3, unless otherwise stipulated, visits during treatment should be completed ±3 days of the scheduled date.  Unscheduled examinations may be performed if 
clinically indicated. 
8. 
Ophthalmologic assessments, including eye appearance, slit lamp examination, best corrected visual acuity, visual field, eye movement, pupil reflex, 
optical coherence tomography (OCT), and intraocular pressure will be performed during the Screening Period.  If the subject has undergone the relevant 
examinations 60 days before the start of study treatment (C1D1), they need not be repeated.  After the start of study drug administration, OCT will be 
performed at 6 weeks (±1 week), then OCT, eye appearance, and slit lamp examinations will be performed every 12 weeks (±1 week) from C4D1 and at 
the EOT visit.  Other ophthalmic examinations are to be performed when clinically indicated.  If the subject develops an ophthalmic AE related to HMPL 
306, the frequency of the examination should be increased to once every cycle until the AE is relieved or stable  
9. 
Only for patients receiving HMPL-306. 
10. 
Hematology includes red blood cell count, hemoglobin, hematocrit, white blood cell count with differential (neutrophils absolute neutrophil count and neutrophils %], 
lymphocytes [absolute lymphocyte count and lymphocytes %], eosinophils [absolute eosinophil count and eosinophils %], monocytes [absolute monocyte count and 
monocytes %], and basophils [absolute basophil count and basophils %), and platelet count.  If abnormal or primitive immature cells are seen, they are also required to be 
recorded.  Any additional routine blood tests during the study shall be arranged by the investigator as needed. 
11. 
These tests should be completed within 7 days before the start of treatment; if completed more than 7 days before the first dose, they must be repeated on C1D1 prior to 
dosing. 
12. 
Blood chemistry includes blood urea nitrogen, creatinine, sodium, potassium, magnesium, chloride, calcium, phosphorus, blood glucose, creatine phosphokinase, total 
bilirubin, direct bilirubin, indirect bilirubin, ALT, AST, ALP, LDH, total protein, and albumin. 
13. 
Fasting lipid panel includes total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. 
14. 
Coagulation indicators include PT, aPTT, and INR. 

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15. 
Female subjects of childbearing potential (including those who have undergone tubal ligation) must undergo a serum pregnancy test within 7 days before drug 
administration and record a negative result.  After enrollment, serum or urine pregnancy test should be conducted on, Day 1 of every treatment cycle starting from Cycle 1, 
at EOT visit, and during Safety Follow-up Period. Unscheduled testing can be performed if there is an indication. 
16. 
Urinalysis includes urine glucose, protein, ketone body, red blood cells, white blood cells, and urobilinogen. 
17. 
Only required if subject has finding suggestive of active viral infection.  Virological screening includes HIV, HBV (HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb), HCV 
(HCV antibody), and CMV (CMV antibody).  If HBsAg or HBcAb or CMV antibody is positive, CMV DNA or HBV DNA is also required to be assayed by PCR method. 
If CMV DNA or HBV DNA is negative, subjects may be enrolled and their CMV DNA or HBV DNA should be monitored every cycle.  If HCV antibody is positive, HCV 
RNA is required to undergo PCR testing. 
18. 
Patient enrolled to the control arm will not need to undergo PK sampling during the pre-surgery period of the study. 
19. 
The 12-lead ECG indicators include PR interval, QRS interval, RR interval, QT/QTcF interval, and heart rate. Evaluation time points are shown in Appendix 2.  
Unscheduled ECG or other cardiac examinations can be performed if clinically indicated. 
20. 
De-identified tumor imaging with study number is to be transmitted to central vendor for image storage.  Only the brain scan is required at the surgery time point, but other 
tumor imaging may be done if clinically indicated.  Tumor imaging must be transmitted to the central vendor for image storage within 2 weeks after surgery. 
21. 
AEs due to the protocol-required intervention (NGS testing) will be collected in the pre-screening phase.  AEs will be collected from signing of the informed consent until 
30 days after the last dose or initiation of new antitumor therapy. The relevant AEs will be followed up until they are recovered to the baseline status, already in a stable 
state as assessed by the investigator, start of new antitumor therapy, loss to follow-up, death, withdrawal of informed consent, the end of study, or it has been confirmed 
the AEs are unrelated to the study drug. SAEs are collected from the signing of the informed consent form until 30 days after the last dose or initiation of new antitumor 
therapy, whichever is earlier and until resolution regardless of relationship to study treatment. 

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2 
INTRODUCTION  
2.1 
Study Rationale  
2.1.1 
Investigational Product  
HMPL-306 is an innovative, small-molecule, orally available, highly selective, and very potent 
inhibitor of both isocitrate dehydrogenase (IDH) 1 mutants and IDH2 mutants. 
2.1.2 
Isocitrate Dehydrogenase  
Isocitrate dehydrogenase is a rate-limiting enzyme in the tricarboxylic acid cycle participating in 
cellular energy metabolism and catalyzes the oxidative decarboxylation of isocitrate to generation 
of α-ketonyl acetylbenzoic acidglutarate (α-KG) and carbon dioxide.  There are 3 isoforms of IDH 
enzymes in the human body, namely IDH1 located in cell cytoplasm, IDH2 in mitochondria, and 
IDH3 in mitochondria (Wang 2013, Yoshihara 2001). 
2.1.2.1 
Mutations of IDH  
IDH1 or IDH2 mutations or co-mutations have been associated with various tumors, including 
glioma, 
chondrosarcoma, 
and 
cholangiocarcinoma 
(Kosmider 2010, 
Marcucci 2010, 
Pardanani 2010, Yan 2009).  Mutations or co-mutations involving IDH1 and or IDH2 in tumor 
cells lead to abnormal functions, whereby mutant IDH converts α-KG into carcinogenic metabolite 
(R)-2-hydroxyglutarate (2-HG) (Dang 2009, Fathi 2012).  Accumulation of 2-HG in cells leads to 
series of epigenetic changes, including hypermethylation of deoxyribonucleic acid (DNA) and 
histone proteins, causing blockade of cell differentiation (Chowdhury 2011, Koivunen 2012, 
Xu 2011). 
2.1.2.2 
Mutations and Malignancies  
Glioma is the most common intracranial malignant tumor, accounting for about 40% to 50% of all 
intracranial tumors.  Studies have found that the incidence of IDH1 mutation in secondary glioma 
is more than 75% (Parsons 2008).  At present, the IDH1 mutation inhibitors ivosidenib, BAY-
1436032, and DS-1001 and the IDH1/IDH2 mutation inhibitor vorasidenib (AG-881) are being 
clinically evaluated for their therapeutic effect on gliomas with IDH1 mutation.  In phase 1 clinical 
studies, the disease control rate of ivosidenib and vorasidenib on non-enhancing gliomas was 88% 
(n=35) (Mellinghoff 2017) and 91% (n=23), respectively (Mellinghoff 2018). 
Chondrosarcoma is the most common bone sarcoma in adults and includes several subtypes: 
conventional, dedifferentiated, mesenchymal, and clear cell.  Approximately 85% of all 
chondrosarcoma cases are of conventional subtype, and another 9% to 10% being dedifferentiated.  
For primary chondrosarcomas, surgery remains the primary method of treatment; however, there 
are no standard treatments for advanced disease (Italiano 2013).  Chemotherapy is ineffective in 
conventional chondrosarcoma, and although chemotherapy options exist for dedifferentiated and 
mesenchymal subtypes, they provide minimal benefit.  Recent studies have demonstrated that up 
to 65% of chondrosarcoma cases harbor an IDH1/IDH2 mutation.  In a phase 1 study, ivosidenib, 
an IDH1 inhibitor, demonstrated a median progression-free survival (PFS) of 5.6 months (95% 
confidence interval [CI], 1.9-7.4 months) and a PFS rate at 6 months of 39.5% among 21 patients 
with advanced chondrosarcoma (Tap 2020). 

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Cholangiocarcinoma refers to malignant tumor originating in the bile duct epithelial cells, 
accounting for 10% to 15% of all primary liver cancers and less than 1% of all systemic tumors.  
Prognosis for intrahepatic cholangiocarcinoma is poor, with a 5-year survival rate of only 10%.  It 
is more commonly seen in the 70- to 80-year-old demographics and has a slightly higher incidence 
rate in males (male:female ratio, 1.2-1.5:1.0).  Intrahepatic cholangiocarcinoma arising from the 
intrahepatic biliary tree accounts for 10% to 20% of cholangiocarcinoma (Valle 2016).  About 
25% of patients with intrahepatic cholangiocarcinoma have IDH1 mutation (Lowery 2017).  In the 
randomized, phase 3, ClarIDHy study, ivosidenib, an IDH1 inhibitor, demonstrated a median PFS 
of 2.7 months [95% CI, 1.6-3.6 months] for ivosidenib versus 1.4 months [95% CI, 1.4-
2.5 months] for placebo (hazard ratio [HR], 0.47 [95% CI, 0.33-0.68]; p<0.0001).  The median 
overall survival (OS) was 10.8 months (95% CI, 7.7-17.6 months) for the ivosidenib group versus 
9.7 months (95% CI, 4.8-12.1 months) for the placebo group (HR, 0.69 [95% CI, 0.44-
1.10 months]; p=0.060) (Abou-Alfa 2020). 
HMPL-306 is a novel, small-molecule, orally available, highly selective, and potent inhibitor of 
mIDH.  It demonstrated a remarkable inhibitory effect on 2-HG in tumor cells with any IDH 
mutations, and therefore, this phase 1, open-label study is planned to evaluate the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-
306 in patients with locally advanced or metastatic solid tumors with IDH mutations. 
2.2 
Background  
2.2.1 
Description of HMPL-306  
HMPL-306 is a highly selective, potent inhibitor that targets mutant IDH1/IDH2, which is 
characterized by a high oral bioavailability, a low clearance rate, an extensive tissue distribution, 
a relatively low risk of drug-drug interactions, and satisfactory preclinical safety features.  
HMPL-306 is available in tablet formulation of 2 strengths: 
 mg and 
 mg. 
2.2.2 
Supportive Nonclinical Data  
2.2.2.1 
Pharmacology  
Further details on pharmacology are provided in the Investigator’s Brochure (IB). 
2.2.2.1.1 
In Vitro Pharmacodynamics  
In an in vitro enzyme activity study with IDH1 mutation, HMPL-306 showed intermediate 
inhibitory activity on the IDH1-R132H mutant, which exhibits selectivity compared to its 
inhibitory activity on wild-type IDH1 enzyme.  In the in vitro enzyme activity study of IDH2 
mutations, HMPL-306 had strong inhibitory activity on IDH2-R140Q and IDH2-R172K mutant 
enzymes, similar to the activity of positive control compound AG-221 and had high selectivity 
(~18 times) compared to its inhibitory activity on wild-type IDH2 enzyme.  HMPL-306 also 
significantly inhibits the production of 2-HG in multiple mutant IDH cell lines. 
HMPL-306 has 
 effect on 
 or on 322 kinases in the 
SelectScreenTM platform, showing high kinase selectivity.  On the CEREP platform, 
 
, HMPL-306 did not show 
.  
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2.2.2.1.2 
In Vivo Pharmacodynamics  
Target inhibitory effect of HMPL-306 on 2-HG in U87MG-IDH2R140Q-M31 tumor model 
Following 
 dose administration of HMPL-306, the inhibitory effect against 2-HG increased 
with the dose and drug concentration, showing good PK/PD correlation.  The inhibitory effect on 
2-HG after administration of HMPL-306 at 
 mg/kg 
 
showed that 24 hours after the last dose, HMPL-306’s inhibitory rate on 2-HG was maintained at 
more than 96%, and the inhibitory rate was significantly higher than that after a single dose at the 
same dosage. 
Target Inhibitory effect of HMPL-306 on 2-HG in HT1080-IDH1R132C tumor model 
HMPL-306 was administered at 
 mg/kg, and the target inhibition of 
HMPL-306 on IDH1 mutation was evaluated by measuring changes of 2-HG levels after 2 to 
40 hours.  The results showed that, at 16 and 24 hours after dosing in all dose groups, the inhibitory 
rate of HMPL-306 against 2-HG in tumor tissues reached more than 90%.  After 
 
 mg/kg 
, 2-HG inhibition rate in tumor tissues reached 97%.  
Compared with the results of 
 mg/kg, its inhibitory effect on the target was 
stronger with the increase in drug exposure after 
. 
2.2.2.1.3 
Safety Pharmacology  
The effect of HMPL-306 on hERG potassium channels expressed in transfected human embryonic 
kidney (HEK293) cells: The IC50 of HMPL-306 was 
 μM on hERG potassium channels. 
A study on the effect on cardiovascular system: 
 were observed following 
a single dose of 
, and 
 mg/kg of HMPL-306 in Beagle dogs.  The no observed adverse 
effect level (NOAEL) of was 
 mg/kg. 
A study of the effect on the central nervous system (CNS): 
 following a 
single dose of 
 and 
mg/kg of HMPL-306 in Sprague-Dawley rats.  The NOAEL for the 
CNS was 
 mg/kg. 
A study on the effect on the respiratory system: 
 following a single dose of 
, and 
 mg/kg of HMPL-306 Sprague-Dawley rats.  The NOAEL was 
 mg/kg. 
2.2.2.2 
Toxicology  
The completed toxicological studies of HMPL-306 included: studies on single-dose toxicity in rats 
and dogs, 4-week repeated dose toxicity studies with an 8-week recovery period in rats and dogs, 
and genetic toxicity tests combination study (bacterial response mutation test, chromosome 
aberration test, in vivo micronucleus test). 
The results of toxicology tests showed that after HMPL-306 was given to rats and dogs in a single 
dose, 
, and the maximum tolerated dose was 
 mg/kg and 
 mg/kg, 
respectively.  
In the repeated-dose toxicity study of rats and dogs, 
 
 in the two species.  In rats, 
 
 were observed.  In rats, the NOAEL of HMPL-306 API 
was  mg/kg and the highest non-severely toxic dose (HNSTD) was 
 mg/kg.  
 
 were observed in dogs.  The NOAEL and HNSTD of HMPL-306 
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API in dogs were determined to be 
 mg/kg in female dogs and 
 mg/kg in male dogs 
respectively.  The common target organ of rats and dogs was 
.  The 
changes in the 
 were also observed in the high-dose group of rats at the end of 
the dosing period.  After the 8-week recovery period, except that the 
 
 in the high-dose female rat group, the other changes mentioned above had 
recovered. 
The results of the 
 
 
Further details on toxicology are provided in the IB. 
2.2.2.3 
Pharmacokinetics  
HMPL-306 has 
 in rats and dogs, 
, and 
; it 
is widely distributed in rats, with the 
.  The exposure of HMPL-306 in the 
 
.  The main in vivo 
metabolites in rats were the 
 
.  HMPL-306 was mainly 
.  Drug 
interaction of HMPL-306 may come largely from: 1) 
 by HMPL-306; 
2) 
 by HMPL-306; 3) The impact of other drugs on 
the major metabolic enzymes 
 of HMPL-306. 
Further details on pharmacokinetics are provided in the IB. 
2.3 
Benefit/Risk Assessment  
2.3.1 
Risk Assessment  
HMPL-306 is in the early stage of development, and the clinical safety profile has not yet been 
established, but some potential risks have been observed from nonclinical studies and clinical data 
from drugs in the same class.  Measures for managing these potential risks are as shown in Table 3. 
Table 3 
Summary of Potential Risks of HMPL-306  
Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Gastrointestinal 
disorders 
 was observed in rats with 
doses up to 
 mg/kg of HMPL-306. 
Gastrointestinal diseases such as nausea, 
vomiting, diarrhea, mucositis, constipation, 
abdominal pain, etc. occurred in clinical 
studies of both enasidenib and ivosidenib. 
General guidance to be provided in the 
protocol for dose 
interruption/reduction/discontinuation in 
response to AEs. 
Embryotoxicity 
At the present stage, the study of effect of 
HMPL-306 on embryo development has not 
been implemented. 
Enasidenib and ivosidenib were associated 
with maternal toxicity and adverse 
embryo-fetal effects in pregnant rats. 
Women who are pregnant (pregnancy test is 
positive before drug administration) or 
breastfeeding will be excluded from the study. 
Male with partners of childbearing potential or 
female subjects of childbearing potential will 
be required to use effective contraception 
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Table 3 
Summary of Potential Risks of HMPL-306  
Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
methods.  Female subjects of childbearing 
potential will be tested for pregnancy at every 
cycle.  
Non-infectious 
leukocytosis 
Neutrophil count was seen increased by 
% in animals administered HMPL-306 
(
 mg/kg/day), and no abnormalities were 
observed at the end of the recovery period. 
Non-infectious leukocytosis occurred in 
clinical trials of both enasidenib and 
ivosidenib. 
Peripheral white blood cell count will be 
monitored at baseline and during the study at 
regular intervals, particularly at least once 
weekly in the first 2 cycles (28 days/cycle) of 
the initial drug administration.  Afterward, it 
will be monitored once a cycle. 
Abnormal 
hepatic 
function 
In the HMPL-306 high-dose (
 mg/kg/day) 
group in rats, the 
 showed 
a 
% increase and 
 
showed 
% increase. 
In clinical trials of both enasidenib and 
ivosidenib, AEs of abnormal hepatic function 
occurred, including elevated liver enzymes 
and elevated bilirubin. 
Liver function will be routinely monitored. 
Eye disorders 
A total of 3 rats in the medium-dose 
(
 mg/kg/day) and high-dose 
(
 mg/kg/day) groups were found to have 
 
 
. 
Considering that it is a vital functional organ, 
ophthalmological examination will be added 
to the clinical trials. 
Ophthalmologic examinations will be 
performed during the Screening.  If the subject 
has undergone the relevant examinations 
60 days before treatment, they will not be 
required to repeat the test for Screening.  After 
the start of treatment, ocular appearance, and 
slit lamp examinations will be performed 
every 3 cycles (ie, Day 1 of Cycles 4, 7, and 
10) and during the end of treatment visit.  
Other ophthalmic examinations will be 
performed when clinically indicated. 
Male 
reproductive 
system lesions 
In rats given a medium-dose of HMPL-306 
(
 mg/kg/day), 
 
 
 
 In the high-dose 
(
 mg/kg/day) group, 
 
 
 
Male subjects of childbearing potential will be 
included only if they agree to use effective 
contraception methods during the study and 
within 180 days after the last administration of 
the study drug. 
Pancreatic 
lesions 
 
 was observed in male rats 
administered with a high-dose of HMPL-306 
(
 mg/kg/day) and was not observed during 
the recovery period. 
Serum lipase and amylase will be monitored. 
QTcF Interval 
Prolongation 
The inhibitory rate of the negative reference 
standard and positive reference standard to 
the hERG potassium current of HMPL-306 
QTcF will be monitored throughout the study, 
and dose modification guidelines are presented 
for associated AEs based on CTCAE grading 
criteria. 
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Table 3 
Summary of Potential Risks of HMPL-306  
Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
was within acceptable range (IC50 was as 
high as 
 μM). 
, QTcF interval 
prolongation has been seen as a class effect 
with other approved IDH inhibitors and may 
be seen with HMPL-306. 
AE = adverse event; CTCAE = Common Terminology Criteria of Adverse Events; hERG = human Ether-à-go-
go-Related Gene; IC50 = half-maximal inhibitory concentration; QTcF = interval from start of the Q wave to 
the end of the T wave interval corrected for heart rate using Fridericia's formula. 
2.3.2 
Benefit Assessment  
This study will enroll subjects with solid tumors, including glioma, chondrosarcoma, or 
cholangiocarcinoma.  This study provides an opportunity for subjects with glioma, 
chondrosarcoma, or cholangiocarcinoma to participate in a trial of HMPL-306, a novel agent that 
targets a mutation that is common among these tumors.  
2.3.3 
Overall Benefit/Risk Conclusion  
At present, there are no IDH1 and/or IDH2 inhibitors approved for treatment of the types of cancers 
being studied in this clinical trial. 
HMPL-306 is a dual inhibitor of IDH1 and IDH2, which, in preclinical studies, has demonstrated 
similar efficacy to single-target IDH inhibitors (ivosidenib), and may have similar benefit to other 
IDH1 and/or IDH2 inhibitors in the same class. 
Preclinical studies, including toxicology studies, indicate that HMPL-306 is well tolerated. 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with HMPL-306 are justified by the anticipated benefits that may be 
afforded to participants with solid tumors with IDH mutations as defined in Section 5.2. 
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3 
OBJECTIVES AND ENDPOINTS  
The objectives and corresponding endpoints are summarized in Table 4. 
Table 4 
Objectives and Corresponding Endpoints  
Tier 
Objectives 
Endpoints 
Primary 
Part 1 – Dose Escalation: To evaluate the safety and 
tolerability of HMPL-306, thereby determining the RP2D 
and/or the MTD of HMPL-306 in subjects with locally 
advanced or metastatic solid tumors with IDH mutations 
MTD and/or RP2D 
Safety including DLTs, TEAEs, 
SAEs, ECGs, and clinical 
laboratory abnormalities 
Part 2 – Dose Expansion: To characterize the safety and 
tolerability of HMPL-306 in subjects with locally advanced 
or metastatic solid tumors with IDH mutation 
Safety including TEAEs, SAEs, 
ECGs, and clinical laboratory 
abnormalities 
Part 2 – Cohort C-1 Only: To determine the 2-HG 
concentration in surgically resected tumors following 
pre-surgical treatment with HMPL-306 when compared to 
untreated tumors 
Observed plasma and tumor 
concentrations of 2-HG  
Secondary 
Part 1 and Part 2: To assess the preliminary antitumor 
activity of HMPL-306 in subjects with locally advanced or 
metastatic solid tumors with IDH mutations 
ORR, DCR, DoR, TTR, and PFS 
Part 1 and Part 2: To assess the PK of HMPL-306 in 
subjects with locally advanced or metastatic solid tumors 
with IDH mutation 
Observed plasma concentrations 
and PK parameters of HMPL-306 
Part 1 and Part 2: To assess the PD of HMPL-306 in 
subjects with locally advanced or metastatic solid tumors 
with IDH mutation 
Observed plasma concentrations of 
2-HG 
Part 2 – Cohort C-1 Only: To characterize the safety and 
tolerability of HMPL-306 in subjects with locally advanced 
or metastatic solid tumors with IDH mutations 
Safety including, TEAEs, SAEs, 
deaths, ECGs, and clinical 
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Table 4 
Objectives and Corresponding Endpoints  
Tier 
Objectives 
Endpoints 
Exploratory 
Part 1 and Part 2: To explore the relationship between 
HMPL-306 PK exposure and 2-HG levels and percent 
inhibition 
Changes from baseline in tumor 
markers, correlation with drug 
exposure, and association with 
efficacy and safety parameters 
Part 1 and Part 2: To explore the influence of gene 
abnormalities other than IDH mutations on safety, efficacy, 
PD, and PK 
Part 1 and Part 2: To assess the potential predictive 
biomarkers or response or progression though collection of 
serial ctDNA collection 
Part 2: To explore the relationship between the changes in 
the frequency of genetic mutation, efficacy, PK, PD, and 
safety after HMPL-306 treatment in tumor and plasma 
Part 2 – To assess the OS in subjects enrolled to expansion 
Cohorts A, B, and D. 
OS 
2-HG = 2-hydroxyglutaric acid; ctDNA = circulating tumor DNA; DCR = disease control rate; DLT = dose-limiting toxicity; 
DoR = duration of response; ECG = electrocardiogram; IDH = isocitrate dehydrogenase; MTD = maximum tolerated dose; 
ORR = objective response rate; OS = overall survival; PD = pharmacodynamics; PFS = progression-free survival; 
PK = pharmacokinetics; RP2D = recommended phase 2 dose; SAE = serious adverse event; TEAE = treatment emergent 
adverse event; TTR = time to response. 
 

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4 
STUDY PLAN  
4.1 
Study Design  
This is a phase 1, open-label, multicenter study to evaluate the safety and tolerability of HMPL-306 
administered orally (PO) in treatment of subjects with locally advanced or metastatic solid tumors 
with IDH mutation. 
The study consists of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). 
4.1.1 
Part 1 (Dose Escalation)  
The first part of the study is dose escalation where cohorts of subjects will receive ascending oral 
doses of HMPL-306 to determine maximum tolerated dose (MTD) and/or the recommended phase 
2 dose (RP2D).  The modified toxicity probability interval-2 (mTPI-2) (Yang 2015) design will be 
utilized for dose escalation until determination of MTD/RP2D.  The mTPI-2 method uses a 
Bayesian framework and a hierarchical model to compute the dose escalation based on the interval 
between the toxicity rate of each dose level and target probability (Guo 2017).  This study is 
designed targeting a dose-limiting toxicity (DLT) rate of 25% with an equivalence interval of 20% 
to 30%.  
Like the 3+3 design, the mTPI-2 method incorporates pre-specified escalation rules that can be 
presented in a table (Table 6).  As shown in Table 6, the number of subjects dosed at a given dose 
level is shown in the columns, while the rows indicate the number of DLTs experienced.  The 
escalation/de-escalation rules from the table will be used for each dose level evaluated; the subject 
numbers and DLTs do not carry over from cohort to cohort.  As an example, within a cohort: 
• If none of the 3 subjects experience a DLT → escalate the dose (“E” at column 3 row 0) 
to the next dose level cohort 
• If 1 out of 4 subjects experience a DLT → stay at the same dose level (“S” in column 4 
row 1) 
• If 2 out 3 subjects experience a DLT → de-escalate to a lower dose level (“D” at 
column 3 row 2) 
• If 3 out of 3 subjects experience a DLT → the dose is determined to be unacceptably 
toxic and will not be used again, de-escalate to a lower dose level (“DU” at column 3 row 3) 
The following rules apply during dose escalation: 
• The initial dose will be 
 mg PO, once a day (QD) 
• Although in the mTPI-2 method the cohort size is not fixed, at least 3 subjects will be 
enrolled at each dose level.  When all subjects at a dose level complete DLT assessment, the 
study will escalate to the next dose level and another 3 subjects will be recruited in the order 
of dose escalation plan until RP2D or MTD Table 6.  A minimum of 3 subjects will be 
enrolled in each cohort. 
• The sample size of a dose cohort that has already passed the preliminary DLT assessment 
(1 to 3 subjects) and has shown efficacy can be extended to 12 cases in order to further 
evaluate the safety and efficacy signals of this dose 
• The study stage will prematurely end when any of the following conditions are met: 
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• Excessive toxicity is present in the initial dose 
• Although no excessive toxicity is present in the first dose level cohort, if the dose returns 
to the initial dose according to the rules in Table 6 and excessive toxicity is present at the 
initial dose (for example, 4 or more DLTs are observed in 6 subjects) 
Please see Section 
. 
A cycle of study treatment is defined as 28 days of continuous daily dosing, according to the cohort 
and dose level.  At the starting dose, subjects will be administered HMPL-306 at 
 mg PO, QD, 
and the dose will escalate successively according to the sequence of 
 mg QD, 
 mg QD, 
 mg QD, 
 mg QD, 
 mg QD, 
 mg QD, and 
 mg QD. (see Table 5).  The modified 
Fibonacci design will be used to escalate the dose (see Table 6 for details on the dose escalation 
decision). 
The addition of dose levels 5 to 8 in Protocol Amendment 2 is based on the cumulative safety and 
preliminary PK and PD data review conducted by the Sponsor and the Safety Review Committee 
(SRC) members.  Following completion of enrollment of dose levels 1 to 4, the PD data reviewed 
did not demonstrate the desired level of 2-HG inhibition for the Sponsor and the SRC members to 
declare the RP2D to move to Part 2.  Pharmacokinetic data review showed dose proportional 
increase in PK exposure over the dose range of 
 mg to 
 mg QD.  As there were no DLTs or 
safety concerns noted in dose levels 1 to 4, the Sponsor and SRC members agreed to continue 
escalation at higher dose levels. 
Table 5 
Subject Dose Grouping (Dose Escalation Plan)  
Dose Level 
Dose of HMPL-306 
PO, QDa with water 
1 
mg 
2 
 mg 
3 
 mg 
4 
 mg 
5 
 mg 
6 
 mg 
7 
 mg 
8 
 mg 
PO = orally; QD = once a day. 
 
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Table 6 
mTPI-2 Decision Table for Dose Selection  
Target toxicity probability (pT)=25%; ε1=0.05; ε2=0.05 
 
E=increased to the next higher dose; D=reduced to a previous lower dose; DLT=dose-limiting toxicity; DU=reduced 
to a previous lower dose and the current dose will not be used again in this trial; MTD=maximum tolerated 
dose; mTPI-2=modified toxicity probability interval-2; pT=toxicity probability; S=maintaining the same dose. 
*If 2 out of 2 subjects have DLTs when treated at the lowest dose level, the Sponsor, based on recommendations 
from the Safety Review Committee (SRC), can choose to terminate the study or to enroll 1 more subject. 
Note: The horizontal axis indicates the number of subjects who are treated at the current dose, and the longitudinal 
axis is the number of subjects observed with DLTs. ε1 and ε2 are fractions used to define an equivalence 
interval of the MTD. 
Safety Review Committee 
Safety monitoring and evaluation of dose escalation will be carried out by the SRC, which is 
comprised of the Sponsor and investigators.  The SRC will determine whether it is safe to continue 
to the next predefined dose level, stay at the currently assigned dose level, or whether the dose 
should be de-escalated to a lower dose level and finally determine the RP2D based on the 
risk-benefit evaluation. 
Dose -Limiting Toxicity 
DLT is defined as the occurrence of any of the treatment-emergent adverse events (TEAEs) 
described in Section 8.1.3 during the DLT assessment window, unless the TEAEs are clearly 
unrelated to the study drug or judged by the investigator as not clinically significant. 
DLT Assessment Window: 
For all subjects in dose escalation, DLTs will be assessed during the DLT assessment window of 
28 days (Cycle 1 Day 1 [C1D1] through C1D28). 

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DLT-Evaluable Subject: 
A subject is DLT evaluable if the following criteria are met:  
• Has received at least 75% of the assigned dose of study medication during the DLT 
assessment window 
OR 
• Has not completed the DLT assessment period due to a DLT 
For decisions on dose escalation, each dose cohort shall present protocol-required numbers of 
DLT-evaluable subjects.  Subjects who are not DLT evaluable in a dose cohort will be replaced to 
guarantee the protocol-required numbers of DLT-evaluable subjects for dose escalation 
evaluations. 
Subjects who complete the DLT assessment window and are deemed by the investigator to be 
benefiting from HMPL-306 treatment will be allowed to continue treatment until disease 
progression, intolerable toxicity, at the investigator’s discretion that the subject can no longer 
benefit from the study treatment, withdrawal of consent, lost to follow-up, the end of study, or 
death, whichever comes first. 
Maximum Tolerated Dose 
The MTD determination will be driven by the mTPI-2 method, and as such, the MTD will be any 
doses with true toxicity probability in the equivalence interval.  For this study, the equivalence 
interval is defined as 20% to 30%. 
Recommended Phase 2 Dose  
RP2D determination will take the following criteria under consideration: 
• Determination of MTD achieved during the dose escalation part 
• Assessment of safety, PK, and PD 
4.1.2 
Part 2 (Dose Expansion)  
In the dose expansion part, 4 cohorts of subjects will receive HMPL-306 to further evaluate the 
safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 at MTD or RP2D in 
approximately 95 subjects with locally advanced or metastatic solid tumors with IDH mutations. 
There will be approximately 20 subjects (15 subjects in Cohort C-1) in each of the following 
cohorts:  
• Cohort A: Cholangiocarcinoma 
• Cohort B: Skeletal chondrosarcoma 
• Cohort C: Low-grade glioma 
− Cohort C-1: Perioperative glioma 
• Cohort D: Any other solid tumor harboring an IDH mutation 
Depending on preliminary efficacy, safety signals, or operational feasibility, the Sponsor in 
conjunction with the SRC may decide to reduce or increase enrollment in these cohorts. 

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Study Treatment 
Subjects will receive HMPL-306 at MTD or RP2D for 28 days in each cycle until disease 
progression, death, intolerable toxicity, the investigator’s judgement that the subject can no longer 
benefit from the study treatment, withdrawal of consent, loss to follow-up, death, or the end of the 
study, whichever occurs first. 
Cohort C-1: Perioperative Glioma 
This cohort will serve as an open-label, window of opportunity study to assess the concentration 
of 2-HG in surgically resected tumors following pre-surgical treatment with HMPL-306 when 
compared to untreated tumors.  This cohort will enroll 15 subjects with recurrent low-grade glioma 
with IDH1 or IDH2 mutations who are candidates for surgical resection.  Subjects will be 
randomized in a 2:1 fashion to receive either open-label HMPL-306 at the RP2D for 4 weeks prior 
to surgery or no treatment (control) for 4 weeks prior to surgery. 
All subjects enrolled to this cohort will undergo pre- and post-treatment procedures as outlined in 
Table 2.  All subjects will have the option of receiving HMPL-306 following surgery.  Subjects 
with no residual disease following surgery will be allowed to receive HMPL-306 for up to 1 year 
or until disease progression, whichever occurs first.  If residual disease is evident following 
surgery, those subjects may receive HMPL-306 until disease progression. 
4.2 
Design Rationale  
4.2.1 
Rationale for Starting Dose and Dosing Regimen  
HMPL-306 is intended for use in subjects with advanced solid tumors.  Hence, the starting dose is 
calculated based on the S9 guidelines from International Conference on Harmonization (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use, using the HNSTD 
and no-observed-adverse-effect level dose.  According to the HNSTD of the repeated dose 
toxicology study of rats and dogs, the safe doses obtained based on the equivalent area in human 
are 
 mg/day and 
 mg/day, respectively.  In accordance with ICH S9, the initial dose for 
the first-in-human (FIH) study should be 1/10 of the HNSTD in rats or 1/6 of the HNSTD in dogs.  
Consequently, the starting dose calculated for FIH study should be 
 mg/day.  Further, the 
nude mouse PD test showed that 
 mg/day is the clinical dose that is likely to have an effect in 
humans based on the equivalent skin surface area in human.  Based on the aforementioned study 
results and calculations, the initial dose for this FIH phase 1 clinical trial is 
 mg/day.  Therefore, 
the safety window is more than 14 times and about 78 times as calculated, according to study 
results in rats and dogs, respectively.  It is also inadvisable to intentionally provide an ineffective 
treatment dose for a long time to subjects with cancer with intractable disease. 
Furthermore, according to ICH S9, the dosing interval for the FIH study should be based on the 
dosing interval used in the preclinical toxicity study for continuous dosing and half-life in the test 
species.  The dosing interval of HMPL-306 in the 4-week repeated dose toxicity study in animals 
was once daily.  The half-life was
 hours in rats and 
 hours in dogs.  Therefore, the regimen 
of once daily dosing will be first explored in this phase 1 study.  Nevertheless, if other dosing 
frequency is necessitated, then the investigator and the Sponsor will discuss and make a collective 
decision regarding the dosage regimen going forward in the clinical study.  The decision will be 
based on the evaluation of clinical data available at that time, particularly the pharmacometric/PK 
data. 
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4.2.2 
Rationale for Study Population Selection  
IDH1 or IDH2 mutations have been identified as driver mutations leading to the proliferation and 
metastasis across various tumor types.  Solid tumors such as cholangiocarcinoma, skeletal 
chondrosarcoma, and low-grade glioma have been identified as tumor types with a high prevalence 
of IDH1 and/or IDH2 mutations, making them good clinical candidates for treatment with an IDH1 
and/or IDH2 inhibitor.  Thus, this study plans to enroll the aforementioned population to assess 
the safety, tolerability, and preliminary efficacy of HMPL-306 treatment. 
Additional discussion of rationale for including specific tumor types with a high prevalence of 
IDH1 and/or IDH2 mutations, and line of therapy can be found in Appendix 11. 
4.2.3 
Rationale for Biomarker Testing  
As a highly selective inhibitor of mutant IDH1R132H/C, IDH2R140Q, and IDH2R172K, 
HMPL-306 has the potential to play a crucial role in the treatment of subjects with solid tumors 
with any of these IDH mutations.  Consequently, this study will conduct testing for IDH mutations 
and enroll subjects with any IDH mutations or any combinations thereof. 
Based on available data from development experience of IDH inhibitors on the market, the 
mutation of 
 that coexist with mutant IDH1 may 
affect the efficacy of IDH1 inhibitor ivosidenib.  Clinical studies of IDH2 inhibitor enasidenib also 
found that overall response was worse in subjects with aberration of 
 
  This suggests that testing for other gene co-mutations that coexist with mutant IDH is 
helpful to retrospectively analyze the efficacy of HMPL-306 in these subjects.  Therefore, at 
baseline (before the start of treatment), circulating tumor DNA (ctDNA) blood samples are 
collected to test for full spectrum of possible gene mutations.  This has the potential to reveal gene 
mutations and co-mutations that co-exist in subjects having clinical benefits from antitumor 
activity of HMPL-306. 
 and 
 may be one of the main metabolic enzymes for in vivo metabolism of 
HMPL-306.  The mutation of 
 and 
 may have an impact on PK parameters of 
HMPL-306, which may further affect the efficacy and safety of the investigational product (IP).  
Therefore, there is the necessity for collection of blood samples at baseline for 
 and 
 genetic testing. 
2-HG is a tumor metabolite produced by mutant IDH enzyme-catalyzed substrate α-KG.  The 
changes in the blood levels of 2-HG and that in tumor tissue, if available, are helpful to determine 
the degree of target inhibition provided by the HMPL-306 as an indicator of PD effectiveness.  
This study will monitor the changes in the levels of 2-HG in blood in all cohorts and glioma tissue 
in Cohort C-1.  In this way, the mechanism of action of HMPL-306 can be verified to evaluate its 
correlation with the efficacy of the IP. 
Progressive disease is often associated with new mutations or co-mutations or changes 
(upregulation) in the expression of current mutant gene.  In this study, blood samples containing 
ctDNA will be collected to monitor changes in the levels of full spectrum of possible gene 
mutations or co-mutations associated with all tumor types under study.  This is to explore all 
possible biomarkers and their expression levels in correlation with the efficacy of HMPL-306, as 
well as potential mechanism of drug resistance. 
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5 
POPULATION  
5.1 
Definitions  
Subjects officially enter the Screening Period following the provision of informed consent either 
directly or via a legally authorized representative where it is permitted by local law. 
Pre-screening failure refers to subjects who have signed pre-screening informed consent but are 
tested negative for any IDH mutations or have withdrawn consent.  Subjects who fail pre-screening 
will have the following information recorded: demographic information, disease diagnosis, IDH 
mutations status, and reason for pre-screening failure. 
A screen failure is a consented subject who has been deemed ineligible on the basis of 1 or more 
eligibility criteria or who has withdrawn consent prior to treatment assignment.  Screen failures 
may be rescreened.  However, before informed consent is obtained, if the assessments for standard 
treatment are performed within 28 days before the planned C1D1, they can be used to replace the 
assessments during the Screening Period without repeating the assessments, except for 
assessments that need to be performed 7 days before the start of the study drug administration, as 
specified in Table 1 and Table 2.  If there is dosing on the assessment day, all assessments should 
be completed before the study drug administration, except for 12-lead electrocardiogram (ECG), 
echocardiogram (ECHO)/multigated acquisition (MUGA) scan, ophthalmologic assessments, and 
efficacy assessments. 
An enrolled subject is one who has been deemed eligible and has been assigned to a treatment 
group. 
Inclusion/exclusion waivers will not be granted. 
5.2 
Inclusion Criteria  
Subjects may be enrolled in this study only if they satisfy all the following criteria: 
1. Subjects must be ≥18 years of age. 
2. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) score of 0 or 1. 
3. Subjects must have a measurable or evaluable disease for Part 1 (Dose Escalation) and 
subjects must have a measurable disease according to Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 (or Response Assessment in Neuro-Oncology 
[RANO] criteria for gliomas) for Part 2 (Dose Expansion). 
4. Subjects must have an absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of 
≥75×109/L, and hemoglobin of ≥8 g/dL. 
5. Subjects must have adequate hepatic function as evidenced by the following: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤3× upper limit of normal 
(ULN), except for subjects with liver metastasis who are included if ≤5× ULN and total 
bilirubin ≤1.5× ULN. 
6. Subjects must have serum albumin ≥2.8 g/dL. 
7. Subjects must have creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault 
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8. Subjects must have an international normalized ratio (INR) of ≤1.5 or an activated partial 
thromboplastin time (aPTT) of ≤1.5× ULN. 
9. Subjects must be recovered to ≤Grade 1 from all toxic effects of any prior surgery, 
radiotherapy, or other therapy. 
10. Subjects must have recovered from surgery, at least 2 weeks post-surgery prior to starting 
study drug. 
11. For gliomas (Part 1, and Cohort C), subjects must not show enhancing disease on 
T1-gadolinium-magnetic resonance imaging (Gd MRI). 
12. Female subjects of childbearing potential must have a negative serum pregnancy test 
within 7 days of study drug administration.  NOTE: Postmenopausal is defined as 
≥24 months of amenorrhea and at least 50 years of age. 
13. Female subjects of childbearing potential and male subjects with partners of childbearing 
potential must agree to use a highly effective form(s) of contraception that results in a 
low failure rate (<1% per year) when used consistently and correctly, starting during the 
Screening Period, continuing throughout the entire study period, and for 180 days after 
taking the last dose of study drug.  Such methods include oral hormonal contraception 
(combined estrogen/progestogen or progestogen-only) or highly effective non-oral 
hormonal contraception (eg, Depo-Provera and Implanon) associated with inhibition of 
ovulation together with a barrier method (eg, diaphragm, always containing a 
spermicide), intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
ligation, vasectomized partner, or sexual abstinence in line with the preferred and usual 
lifestyle of the subject. Oral and non-oral hormonal contraception should always be 
combined with an additional contraceptive method (ie, barrier method) because of a 
potential interaction with the study drug.  The same criteria are applicable to male 
subjects involved in this clinical trial if they have a partner of childbirth potential, and 
male subjects must always use a condom. 
Part 1, Dose Escalation: 
14. Subjects must have a documented IDH mutation per immunohistochemistry (IHC), 
polymerase chain reaction (PCR), or next generation sequencing (NGS) testing of tumor 
tissue. 
15. Subjects must have histologically or cytologically documented, locally advanced or 
metastatic solid malignancy of any type that has recurred or progressed on available 
standard treatment and for which no curative therapy exists. 
a. Subjects with Grade 3 non-enhancing glioma are permitted to enroll to Part 1. 
Part 2, Dose Expansion: 
16. Subjects in Cohorts A, B, C, C-1, and D must have documented IDH mutation of any of 
the following subsets: IDH1 (R132), IDH2 (R140), or IDH2 (R172), including any 
co-mutations, per validated NGS testing of tumor tissue 
17. Subjects must have histologically or cytologically documented: 
b. Cohort A: Locally advanced or metastatic cholangiocarcinoma not eligible for 
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≥1 gemcitabine- or 5-fluorouracil-containing regimen. Subjects must have not 
progressed on prior IDH treatment unless isoform switching of the IDH mutation has 
been documented following progression on an IDH inhibitor 
c. Cohort B: Locally advanced or metastatic skeletal chondrosarcoma. Subjects must 
have not progressed on prior IDH treatment unless isoform switching of the IDH 
mutation is documented following progression on an IDH inhibitor 
d. Cohort C: Recurrent Grade 2 gliomas that are not a candidate for clinical resection. 
Progression or recurrence must have occurred ≤12 months prior to study enrollment. 
Subjects must have not progressed on prior IDH treatment unless isoform switching 
of the IDH 
e. Cohort C-1: Subjects with recurrent Grades 2 and 3 gliomas who are candidates for 
clinical resection but for whom surgery is not urgently indicated. Subjects must not 
have received prior treatment with an IDH inhibitor 
f. Cohort D: Any other locally advanced or metastatic solid tumor harboring an IDH 
mutation that has progressed on at least 1 line of prior therapy. Subjects must have 
not progressed on prior IDH treatment unless isoform switching of the IDH mutation 
is documented following progression on an IDH inhibitor 
5.3 
Exclusion Criteria  
Subjects are not eligible for enrollment into this study if they meet any of the following criteria: 
1. Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their 
first day of study drug administration (radiotherapy <12 weeks for glioma subjects) 
2. Subjects who received an investigational agent <14 days prior to their first day of study 
drug administration 
3. Subjects who are pregnant or breastfeeding 
4. Subjects with an active severe infection or with an unexplained fever >38.5°C during 
screening visits or on their first day of study drug administration (at the discretion of the 
investigator, subjects with infection that is controlled with appropriate therapy are 
eligible) 
a. See Appendix 10 for procedures specific to subjects with suspected or confirmed 
coronavirus disease 2019 (COVID-19) 
5. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart 
failure or left ventricular ejection fraction <40% by ECHO or MUGA scan within 
approximately 28 days of C1D1 (Appendix 5) 
6. Subjects with a known history of myocardial infarction within 6 months of the first dose 
7. Subjects with a known unstable or uncontrolled angina pectoris 
8. Subjects with clinically significant or severe gastrointestinal disease or condition that the 
investigators suspect may affect drug absorption, including, but not limited to, active 
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tumor with active bleeding, or other gastrointestinal conditions that may cause bleeding 
or perforation, by investigator’s discretion 
9. Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias 
10. Subjects with interval from the start of the Q wave to the end of the T wave (QT) 
corrected for heart rate using Fridericia's formula (QTcF) interval ≥470 ms or other 
factors that increase the risk of QT prolongation or arrhythmic events 
11. Subjects taking medications that are known to prolong the QT interval (including, but not 
limited to, the list in Appendix 4).  NOTE: Subjects may participate if medications are 
changed to acceptable alternatives 
12. Subjects taking medications that can 
 
(Appendix 6) within 1 week or 5 half-lives (whichever is longer) from the start of study 
treatment 
13. Subjects who receive small-molecule or large-molecule (such as antibody-based drug) 
drugs in previous clinical studies for <2 weeks or <4 weeks, respectively, from the time 
of the start of study treatment to the last use 
14. Subjects with known infection with human immunodeficiency virus (HIV) or active 
hepatitis B virus (HBV) or hepatitis C virus (HCV).  Screening not required unless 
subject has clinical findings suggestive of infection with HIV, or HBV or HCV 
15. Subjects with brain metastases that are untreated or symptomatic or that require therapy 
to control symptoms, or any radiation, surgery, or other therapy (including those used to 
control symptoms) within 4 weeks of the first dose.  Subjects with glioma who are on a 
stable, steroid-dosing regimen at the time of Screening may be permitted to enroll with 
the Sponsor’s approval 
16. Subjects with a clinically significant liver disease or condition such as Gilbert syndrome 
and that, at the discretion of the investigator, may affect drug metabolism 
17. Dose Expansion Only: Progression on a prior IDH inhibitor treatment unless isoform 
switching of the IDH mutation is documented following progression on an IDH inhibitor 
a. Subjects in cohort C-1 must not have received treatment with an IDH inhibitor 
18. Subjects with a known hypersensitivity to HMPL-306 or to any of its excipients 
 
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6 
STUDY CONDUCT  
Recruitment period is estimated to take approximately 18 months.  Estimated duration for the 
entire study from the time the study is open to enrollment until completion of data analyses is 
approximately 42 months.  During the study, assessments at each study visit will be performed as 
listed in Table 1 and Table 2, as described in this section. 
6.1 
Study Procedures  
6.1.1 
Pre-Screening Period  
Pre-screening period is defined from signing of pre-screening informed consent to obtaining IDH 
mutational status report or withdrawal of consent. Subjects who have already tested positive for 
IDH mutation may enter the Screening period directly. 
6.1.2 
Screening Period  
The Screening period is defined as the period from the Screening visit to before the first dose of 
HMPL-306 administration (up to 28 days prior to C1D1). 
6.1.3 
Treatment Period  
The treatment period is defined as the time from HMPL-306 administration on C1D1 to end-of 
treatment (EOT) visit. 
6.1.4 
Medical History and Demographic Information  
Medical history data include significant clinical disease or symptom, surgical history, history of 
malignancy (including date of diagnosis; classification and prognosis evaluation of the study 
disease, the treatment performed, and the outcome; and the tumor type and outcomes of any other 
previous malignancies), smoking history, history of alcohol consumption, history of drug abuse, 
and other medical-related history.  Prognosis evaluation of the study disease will be performed 
according to the RECIST Version 1.1 (Appendix 8) or RANO for gliomas (Appendix 9). 
Demographic information includes sex, race, and in some countries, year of birth should be 
recorded at Screening and in the applicable electronic case report form (eCRF) as permitted by 
local regulations. 
6.1.5 
Prior and Concomitant Medications and Concomitant Procedures  
Concomitant medications include any prescription and over-the-counter medications.  During the 
Screening Period, all drugs used by the subject within 28 days prior to the start of HMPL-306 
administration should be recorded in the eCRF.  In subsequent visits, the drugs used by that period 
and within 30 days after termination of treatment should be recorded in the eCRF.  Subsequent 
new antitumor treatment regimens during the Safety and Efficacy Follow-up Periods will also be 
recorded.  Concomitant medications should be reviewed during the study according to the schedule 
in Table 1 and Table 2. 
6.1.6 
Vital Signs  
Vital signs include blood pressure, body temperature, heart rate, and respiratory rate.  Vital signs 
should be assessed during the study according to the schedule in Table 1 and Table 2. 

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6.1.7 
Physical Examination, Weight, and Height  
Physical examination and weight measurement will be conducted during the study according to 
the schedule in Table 1 and Table 2.  Physical examination includes the examination of the head, 
neck, ears, nose, eyes, throat, skin and mucous membranes, and gastrointestinal tract, as well as 
cardiovascular, renal, skeletal, muscular, respiratory, and nervous systems. 
Height will only be measured during the Screening Period. 
6.1.8 
ECOG Performance Status  
ECOG PS scoring will be performed during the study according to the schedule in Table 1 and 
Table 2.  Performance status will be carefully scored in strict accordance with the criteria 
(Appendix 3), especially to determine eligibility for enrollment. 
6.1.9 
Ophthalmologic Assessments  
Ophthalmologic assessments, including eye appearance, slit lamp examination, best corrected 
visual acuity, visual field, eye movement, pupil reflex, optical coherence tomography, and 
intraocular pressure, will be performed during the study according to the schedule in Table 1 and 
Table 2.  If the subject has undergone the relevant examinations 60 days before the start of IP 
treatment (C1D1), they need not be repeated.  Other ophthalmic examinations are to be performed 
when clinically indicated.  If the subject develops an ophthalmic AE related to HMPL-306, the 
frequency of the examination should be increased to once every cycle until the AE is relieved or 
stable. 
6.1.10 
Laboratory Evaluations  
Assessments will be performed in the laboratories of the respective study site to monitor.  The 
range of normal values of all study sites will be collected prior to the start of the study. 
6.1.10.1 
Hematology  
Hematology, including red blood cell count, hemoglobin, hematocrit, white blood cell count with 
differential and classifications (neutrophils [ANC and neutrophils %], lymphocytes [absolute 
lymphocyte count and lymphocytes %], eosinophils [absolute eosinophil count and eosinophils 
%], monocytes [absolute monocyte count and monocytes %], and basophils [absolute basophil 
count and basophils %]), and platelet count, will be performed during the study according to the 
schedule in Table 1 and Table 2.  If abnormal or primitive immature cells are seen, they will also 
be recorded.  Any additional routine blood tests during the study shall be arranged by the 
investigator as needed. 
6.1.10.2 
Blood Chemistry  
Blood chemistry, including blood urea nitrogen, creatinine, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, blood glucose, creatine phosphokinase, total bilirubin, direct 
bilirubin, indirect bilirubin, ALT, AST, ALP, lactate dehydrogenase, total protein, and albumin, 
will be performed during the study according to the schedule in Table 1 and Table 2. 

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6.1.10.3 
Blood Amylase and Lipase  
Tests for blood amylase and lipase will be performed during the study according to the schedule 
in Table 1 and Table 2. 
6.1.10.4 
Fasting Lipid Panel  
Fasting lipid panel, including total cholesterol, high-density lipoprotein, low-density lipoprotein, 
and triglycerides, will be performed during the study according to the schedule in Table 1 and 
Table 2. 
6.1.10.5 
Coagulation Indicators  
Tests for coagulation indicators, including prothrombin time, aPTT, and INR, will be performed 
during the study according to the schedule in Table 1 and Table 2. 
6.1.10.6 
Glycated Hemoglobin  
Tests for glycated hemoglobin (HbA1C) will be performed as per schedule in Table 1 and Table 2. 
6.1.10.7 
Serum Pregnancy Test  
Female subjects of childbearing potential (including those who have undergone tubal ligation) 
must undergo a serum pregnancy test within 7 days of study drug administration and record a 
negative result.  After enrollment, serum or urine pregnancy test should be conducted according 
to the schedule in Table 1 and Table 2.  Unscheduled testing can be performed if there is an 
indication. 
6.1.10.8 
Urinalysis  
Urinalysis (or dipstick), including glucose, protein, ketone body, red blood cells, white blood cells, 
and urobilinogen, will be performed during the study according to the schedule in Table 1 and 
Table 2. 
6.1.10.9 
Virological Screening  
Virological screening is only required if subject has finding suggestive of active viral infection 
and includes HIV, HBV (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody 
[HBsAb], hepatitis B e-antigen [HBeAg], hepatitis B e-antibody [HBeAb], and hepatitis B core 
antibody [HBcAb]), cytomegalovirus (CMV antibody), and HCV (HCV antibody).  If HBsAg or 
HBcAb or CMV antibody is positive, CMV DNA or HBV DNA is also required to be assayed by 
PCR method.  If CMV DNA or HBV DNA is negative, subjects may be enrolled and their CMV 
DNA or HBV DNA should be monitored every cycle.  If HCV antibody is positive, HCV RNA is 
required to undergo PCR testing.  Virological screening will be performed during the Screening 
Period. 
6.1.10.10 
IDH Mutational Status  
Subjects who have reports of positive IDH mutation status may directly enter the Screening phase 
without pre-screening.  Information regarding test methodology will be collected for subjects in 
Part 1.  Subjects who have not been tested for IDH mutations should be tested locally (via biopsy 
tissue collection) at the clinical trial site to determine IDH mutation status before enrollment. 

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Subjects will be required to provide samples for IDH mutational status confirmation as outlined in 
Section 6.1.14. 
6.1.11 
Electrocardiogram  
The 12-lead ECG indicators include PR interval, QRS interval, RR interval, QT/QTcF interval, 
and heart rate.  Evaluation time points are shown in Appendix 1 and Appendix 2.  Unscheduled 
ECG or other cardiac examinations can be performed if clinically indicated. 
6.1.12 
Echocardiogram/Multigated Acquisition Scan  
To evaluate the ejection fraction of subjects, ECHO (preferred method) or MUGA scan will be 
performed during the study according to the schedule in Table 1 and Table 2.  It is recommended 
to use the same assessment method throughout the study for each subject. 
6.1.13 
Tumor Assessment  
Tumor time point response assessment will be performed by the investigators according to 
RECIST Version 1.1 (Appendix 8) or RANO criteria for glioma subjects (Appendix 9).  The tumor 
assessments will be performed during screening, every 8 weeks (±1 week) beginning on C1D1 for 
the first 24 weeks , and every 12 weeks (±2 weeks) thereafter as specified in Table 1 and Table 2, 
through EOT or end of Efficacy Follow-up (if applicable). 
All measurable and evaluable lesions should be assessed and documented using image-based 
evaluation.  All subjects are to be evaluated utilizing contrast-enhanced computed tomography 
(CT) scan or positron emission tomography (PET) scan or Gd MRI for glioma subjects to identify 
and follow selected lesions throughout the study.  In addition, other radiographic or scintigraphic 
procedures (such as radionuclide bone scans), as deemed appropriate by the investigator, will be 
performed to assess sites of neoplastic involvement. 
Tumor assessments completed as standard of care prior to signing of the informed consent but, 
within 28 days of first dose of study treatment, may be used as baseline scans.  Assessments 
throughout the study should be made using the same modality as used at Screening. 
6.1.14 
IDH Mutation Confirmation  
Samples will be collected for central confirmation of IDH mutation status in order to validate local 
results or reports used by sites to determine eligibility for trial.  Collected samples will follow 
specified procedures as indicated in the laboratory manual.  If archival tissue is not available, a 
fresh tissue biopsy will be required.  This independent confirmation will use NGS, performed at a 
central laboratory at pre-specified intervals as determined by the Sponsor. All samples should be 
prepared, labeled, handled, packaged, stored, and transported in accordance with required 
processes as provided in the study-specific laboratory manual.  
6.1.15 
Pharmacokinetics and Pharmacodynamic Evaluation  
6.1.15.1 
Sample Collection and Handling  
Blood samples will be collected for PK and PD analysis of HMPL-306 and 2-HG levels in plasma, 
respectively.  For Cohort C-1, glioma samples will be collected during surgery for the analysis of 
2-HG and HMPL-306 levels.  The full PK and PD evaluation schedule is presented in Appendix 1 

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and in Appendix 2 for Cohort C-1.  Patients enrolled to the control arm of Cohort C-1 will not 
need to undergo PK sampling in the pre-surgery period of the study. 
The collection, handling, and transportation of biological samples should be carried out in 
accordance with the requirements in the study-specific laboratory manual. 
6.1.15.2 
Analytical Procedures  
Plasma samples will be analyzed to determine concentrations of HMPL-306 and 2-HG using a 
validated, specific, and sensitive liquid chromatography/mass spectrometry/mass spectrometry 
(LC MS/MS) method.  Glioma tissue samples will be analyzed to determine concentrations of 
HMPL-306 and 2-HG using a qualified method. 
Plasma samples may also be analyzed to document the presence of circulating metabolites using a 
qualified research method.  If conducted, metabolite analysis will be reported outside of the clinical 
study report. 
6.1.16 
Exploratory Biomarker Evaluation in Tumor Specimen  
Biomarkers related to HMPL-306 and solid tumors will be explored to analyze the possible 
correlation between biomarkers and clinical results. 
Tumor tissue will be collected according to the schedule in Table 1 and Table 2.  In the expansion 
part, for subjects participating in the exploratory portion of the study, at disease progression during 
HMPL-306 treatment or EOT, tumor tissues (formalin-fixed paraffin-embedded samples; block or 
10 unstained slides, minimum tissue area, 25 mm2) will be collected to check IDH mutation status 
and other co-occurring gene alterations to explore the resistance mechanism of HMPL-306.  For 
Cohort C-1, the tumor samples collected during the surgery will also be used to assess the 
molecular and cellular changes if the remaining sample is available after PK/PD study. 
All tests are completed by the central laboratory, and all samples should be prepared, labeled, and 
transported according to the requirements in the study-specific laboratory manual. 
6.1.17 
Circulating Tumor DNA  
Blood samples including ctDNA will be collected according to the schedule in Appendix 1 and 
Appendix 2.  ctDNA samples will be collected at the escalation and expansion part for tumor 
somatic mutations (eg, 
, etc) detection.  For collection and shipping instructions, 
please refer to the study-specific laboratory manual.  The dates of blood sampling must be recorded 
in the eCRF. 
6.1.18 
Lifestyle Management  
Subjects enrolled in this study are advised to avoid unnecessary exposure to sunlight or any other 
source of ultraviolet light during their participation in the study and until 30 days after their last 
dose of study drug.  Subjects are encouraged to wear sunglasses and apply sunscreen products with 
protective coefficient of at least SPF 15 as necessary.  The safety risks of HMPL-306 under 
sunlight are not yet clear, and further nonclinical studies are planned to assess its photo-toxicity 
effects of HMPL-306. 
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6.1.19 
End of Treatment Visit  
Subjects who have completed the study or have discontinued study treatment will be asked to 
return to the investigational site to receive safety examinations and assessments within 7 (±3) days 
after the last dose of study drug. 
6.1.20 
Follow-up Period  
Safety Follow-up 
Subjects who have completed the study treatment will be evaluated for safety 30 days (±7) days 
following the EOT visit for study drug-related AEs until resolution and SAEs until resolution 
regardless of relationship to study treatment. 
Efficacy Follow-up 
Subjects who discontinue the study drug due to reasons other than disease progression, death, lost 
to follow-up, or withdrawal of consent will remain on study and will be followed every 12 weeks 
(±14 days) from EOT visit for tumor assessment until disease progression, initiation of new 
anticancer therapy, withdrawal of consent, lost to follow-up, death, or the end of the study, 
whichever comes first. 
Survival Follow-up 
All subjects in expansion cohorts A, B, and D may be followed for survival status every 12 weeks 
(±14 days), for a maximum of 2 years from EOT visit until death, lost to follow-up, or withdrawal 
of consent.  Survival information can be obtained via phone, and information will be documented 
in the source documents and relevant eCRFs. 
6.1.21 
End of Study  
The end of the study is defined as the date on which all subjects have their last visit or 1 year after 
the last subject has their first visit, whichever comes first. 
6.2 
Discontinuation or Withdrawal  
6.2.1 
Individual Subjects  
6.2.1.1 
Permanent Discontinuation of Treatment  
The investigator has the right to discontinue a subject from the study for any medical condition 
that the investigator determines is in the best interest of the subject, reasons of non-compliance 
(eg, missed doses, visits), or pregnancy. 
Any subject who discontinues treatment should be encouraged to return to the study site for an 
EOT visit and continue with the remaining study visits outlined in Table 1 and Table 2.  The 
primary reason for discontinuation must be recorded on the appropriate eCRF. 
Subjects must be discontinued from treatment for any of the following reasons: 
1. Disease progression.  If the subject is experiencing a treatment benefit, in the opinion of 
the investigator, the subject may continue study drug beyond radiographic progression 
until clinical progression.  Determination of clinical progression is at the discretion of the 

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investigator and may include both objective and subjective data.  The continuation 
decision should be made by the investigator in consultation with the Sponsor 
2. Withdrawal of consent 
3. Intolerable toxicity or AEs that warrant withdrawal of study treatment as determined by 
the principal investigator or as outlined in Section 7.4.2. 
4. Poor subject compliance 
5. Use of other antitumor treatment during the study 
6. Pregnancy 
7. Subject is lost to follow-up 
8. The investigator or the Sponsor determines it is in the best interest of the subject 
9. Study is terminated by the Sponsor 
10. Death 
11. End of this study 
6.2.1.2 
Withdrawal from Study  
All subjects have the right to withdraw from the study at any time.  During the treatment period 
and follow-up period, a subject who withdraws consent to continue participation in the study will 
not be followed for any reason after consent has been withdrawn.  Every effort should be made to 
obtain information on subjects who discontinue study drug but who do not withdraw consent to 
continue participation in the study.  If a participant withdraws consent for disclosure of future 
information, the Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
All subjects who withdraw from the study may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
6.2.1.3 
Replacement of Subjects  
Subjects who are not DLT evaluable in a dose cohort will be replaced to guarantee the 
protocol-required number of DLT-evaluable subjects for dose escalation evaluations.  Subjects 
who are not eligible for response assessment (defined as those subjects who completed a follow-up 
tumor assessment after Cycle 2) in Part 2 of the study may be replaced.  
6.2.1.4 
Subjects Lost to Follow-up  
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
Before a subject is deemed lost to follow up, the investigator or designee must make every effort 
to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a certified 
letter to the subject’s last known mailing address or local equivalent methods).  These contact 
attempts should be documented in the participant’s medical record. 
Should the subject continue to be unreachable, he/she will be considered withdrawn from the 
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7 
STUDY INTERVENTIONS  
7.1 
Study Drug Administration  
Subjects will receive dosing of HMPL-306 PO, QD, in each 28-day cycle. 
Subjects should take HMPL-306 on an empty stomach (defined as no food ±2 hours of dosing) at 
a relatively fixed time every day, with about 240 mL of water.  The accurate actual time of dosing 
should be recorded in the subject diary each time. 
7.1.1 
Part 1 (Dose Escalation)  
In dose escalation, dosage will be according to dose level (see Table 5). 
Dose escalation will begin at 
 mg QD of HMPL-306 in a 28-day continuous dosing treatment 
cycle.  The dose will escalate successively according to the sequence of 
 mg QD, 
 mg QD, 
 mg QD, 
mg QD, 
 mg QD, 
 mg QD, and 
 mg QD. 
7.1.2 
Part 2 (Dose Expansion)  
In dose expansion, HMPL-306 will be administered PO, QD, in a 28-day continuous dosing 
treatment cycle at MTD and/or RP2D. 
7.2 
Description of Products  
HMPL-306 will be provided as a tablet formulation in 2 strengths: 
 mg and 
 mg. 
7.2.1 
Formulation, Storage, Preparation, and Handling  
HMPL-306 is formulated as tablets, which are packaged in high-density polyethylene bottles, with 
30 tablets per bottle.  The contents of the label will be in accordance with all applicable regulatory 
requirements. 
HMPL-306 should be sealed and stored in a secure, limited access area under appropriate 
conditions.  The storage temperature should be between 
℃ to 
℃ with 
 
.  HMPL-306 should not be used beyond the expiration date provided by the 
manufacturer. 
The temperature-monitoring log should be recorded and filed in the study binder. 
7.2.2 
Drug Accountability  
7.2.2.1 
Assignment/Disposal (Study Site)  
All study drug required for this study will be provided by the Sponsor.  The recipient will 
acknowledge receipt of the drug by returning the appropriate documentation form indicating 
shipment content and that condition supplies will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to, and disposed of by the 
study site should be recorded by using the Drug Inventory Log. 
Study drug will be disposed of at the study site according to the study site’s institutional standard 
operating procedure or will be returned to the Sponsor or designee with appropriate 
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documentation, as determined by the study site.  If the study site chooses to destroy study drug, 
the method of destruction must be documented. 
7.2.2.2 
Drug Return (Subject)  
On Day -2 to Day 1, only drug assignment will be performed.  The first dose of study drug should 
be administered on C1D1.  Subjects will be provided with a pill diary and will be instructed on 
how to account for each day’s dose appropriately.  Subjects should return all unused study drug 
and containers from the previous cycle on Day 1 (date of scheduled visits) of each subsequent 
cycle, and the new study drug will be dispensed on the same day.  Site study staff should review 
subject’s pill diary and provide a new diary if necessary at the Day 1 visit of each cycle. 
If a dose adjustment is required, the subject must return to the investigational site and return all 
unused study drug.  The site must log into the eCRF, adjust the dose, reassign the drug serial 
number, and dispense new study drug dose to the subject.  If the dose is adjusted a second time, 
the site must log into the eCRF and record the second dose adjustment.  On this occasion, it is not 
necessary to reassign a new drug serial number.  If tumor evaluation shows PD during the previous 
cycle and the new drug has been dispensed, the subject must return all unused study drug on the 
30-day safety visit after EOT. 
7.3 
Assessment and Verification of Compliance  
The investigator is responsible for ensuring the subject’s treatment compliance.  The Sponsor will 
provide supervision through on-site monitoring visits made by its representatives.  The 
investigators should maintain complete and accurate records of drug use.  The dosing regimen and 
subject’s actual dosing should be recorded in the original treatment records, as well as eCRF.  At 
each treatment visit, the investigators or study staff should comprehensively assess the subject’s 
treatment compliance according to the drug dispensing and return status at each visit and the actual 
dosing conditions, such as missed doses and overdosing reported by the subject.  The subjects must 
return all drug bottles and remaining capsules at the end of the study.  The investigational sites 
must return all remaining supplies and drugs to the Sponsor or provide evidence of destruction at 
the conclusion of the study. 
7.4 
Dose Adjustments  
7.4.1 
Adjustment of Dose within the DLT Assessment Window  
In the DLT assessment window, subjects without DLT must not undergo dose reduction of 
HMPL-306. 
• If a DLT occurs, HMPL-306 administration will be suspended and appropriate supportive 
treatment will be given 
• If a DLT returns to Grade 1 or lower within 14 days, HMPL-306 may be resumed at the 
previous lower dose if the investigator assesses that the subject may still benefit 
• If a DLT has not returned to Grade 1 (inclusive) or lower within 14 days, or DLT 
reoccurs at the lowered dose, HMPL-306 will be terminated 

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• If the subject has an AE that does not meet the DLT criteria, the subject should continue 
HMPL-306 according to the original planned dose; for Grades 3 and 4 non-DLT AEs, 
HMPL-306 can be suspended as necessary as assessed by the investigator 
7.4.2 
Dose Adjustment Outside the DLT Assessment Window (Including Dose 
Expansion Part)  
Table 7 
Dose Adjustment for Hematologic Toxicity  
CTCAE v5.0 Grade 
Action 
Grade 1 or 2 
None 
Grade 3 or 4 (believed to be related to HMPL-306 and 
NOT underlying disease) 
• Hold drug. 
• If the toxicity improves to Grade ≤2 within 
28 days, then resume at original dose. 
• If the toxicity recurs at original dose, then 
resume at 1 dose lower provided the toxicity 
improves to Grade ≤2 within 28 days. 
• If the toxicity recurs in setting of prior dose 
level reduction, then resume at the next lower dose 
provided the toxicity improves to Grade ≤2 within 
28 days. 
• In the event the toxicity does not improve to 
Grade ≤2 within 28 days or toxicity recurs despite 
2 dose reductions, HMPL-306 treatment is to be 
permanently discontinued. 
AE = adverse event; CTCAE v5.0 = Common Terminology Criteria of Adverse Events version 5.0. 
 
Table 8 
Dose Adjustment for Non-Hematologic Toxicity  
CTCAE v5.0 Grade 
Action 
Grade 1 or 2 
None 
Grade 31 
• 
Hold drug. 
• 
If the toxicity improves to Grade ≤2 within 
28 days then resume at original dose. 
• 
If the toxicity recurs at original dose, then 
resume at 1 dose lower provided the toxicity 
improves to Grade ≤2 within 28 days. 
• 
If the toxicity recurs in setting of prior dose 
level reduction, then resume at the next lower 
dose provided the toxicity improves to 
Grade ≤2 within 28 days. 
• 
In the event the toxicity does not improve to 
Grade ≤2 within 28 days or toxicity recurs 
despite 2 dose reductions, HMPL-306 
treatment is to be permanently discontinued. 
Grade 41 
• 
Permanently discontinue treatment with 
HMPL-306. 
CTCAE v5.0 = Common Terminology Criteria of Adverse Events version 5.0. 
1.  Dose adjustments or modifications for Grade ≥3 nausea, vomiting, diarrhea, constipation, fatigue, and 
electrolyte imbalance are not required if they can be controlled by systemic or local drug administration. 
 

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7.4.3 
Dose Adjustment for QT Interval Prolongation  
Table 9 
Dose Adjustment for QT Interval Prolongation  
Degree of QTcF Prolongation 
Action 
QTcF 480 ms to 500 ms 
• 
Hold drug. 
• 
Monitor and supplement electrolyte levels as 
clinically indicated. 
Review and adjust concomitant medications with 
known QTcF interval-prolonging effects. 
Restart HMPL-306 at original dose if QTcF 
interval returns to ≤480 ms. 
• 
Monitor ECGs at least weekly for 2 weeks 
following resolution of QTcF prolongation. 
QTcF 500 ms 
• 
Hold drug. 
• 
Monitor and supplement electrolyte levels as 
clinically indicated. 
• 
Review and adjust concomitant medications with 
known QTcF interval-prolonging effects. 
• 
Restart HMPL-306 at half of the original dose 
when QTcF interval returns to within 30 ms of 
baseline or ≤480 ms. 
• 
Monitor ECGs at least weekly for 2 weeks 
following resolution of QTcF prolongation.  
Consider re-escalating HMPL-306 to the original 
dose if an alternative etiology for QTcF 
prolongation can be identified. 
QTcF interval prolongation with signs/symptoms of 
life-threatening arrhythmia 
• 
Discontinue HMPL-306 permanently. 
ECG = electrocardiogram; QT = interval from the start of the Q wave to the end of the T wave; QTcF = QT 
interval corrected for heart rate using Fridericia's formula. 
7.4.4 
General Dose Adjustment Note  
The severity of DLTs/AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.  Reasons for dose 
modifications or delays, the supportive measures taken, and the outcome should be documented in 
the subject’s chart and recorded in the eCRF. 
• For any concomitant conditions already apparent at baseline, the dose modifications will 
apply according to the corresponding shift in toxicity grade, if the investigator feels it is 
appropriate.  For example, if a subject has Grade 1 asthenia at baseline that increases to 
Grade 2 during treatment, this will be considered a shift of 1 grade and will be treated as 
Grade 1 toxicity for dose modification purposes 
• For toxicities that are considered by the investigator to be unlikely to develop into serious 
or life-threatening events, treatment can be continued at the same dose 
• To recover from acute toxicity, unless otherwise indicated, the treatment can be delayed 
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discontinued.  Continuation/resumption of treatment after an interruption of more than 
14 days must be discussed with the medical monitor or his or her designee 
• Where several toxicities with different grades or severity occur at the same time, the dose 
modifications should be according to the highest grade observed 
7.5 
Special Adverse Events Handling Principles  
7.5.1 
Handling Principles for Leukocytosis  
Subjects who develop leukocytosis should be graded per NCI CTCAE Version 5.0 and treated by 
the following measures in a timely manner: 
• Hydroxyurea oral therapy is immediately given, and it can be used at up to 2 to 3 g twice 
a day (see Table 10) 
• Leukapheresis is performed if clinically necessary 
When the above treatment measures are unable to effectively control the clinical symptoms, 
HMPL-306 treatment should be suspended.  After the clinical symptoms have been fully relieved, 
the HMPL-306 administration can be resumed.  The dose of the drug resumed should be decided 
after discussion with the Sponsor-appointed medical monitor. 
Table 10 
Hydroxyurea Initial Dose Reference  
Hydroxyurea 
Dose 
Peripheral White Blood Cell Count 
Absolute Value of Increase from Baseline of 
Peripheral White Blood Cell Count 
1000 mg QD 
25×109/L to 50×109/L 
15×109/L to <30×109/L 
2000 mg BID 
>50×109/L to 75×109/L 
30×109/L to <50×109/L 
3000 mg BID 
>75×109/L 
≥50×109/L 
BID = twice daily; QD = once a day. 

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8 
SAFETY MONITORING  
8.1 
Definitions  
8.1.1 
Adverse Event  
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product or other protocol-imposed intervention, whether or 
not considered related to the medicinal product.  
8.1.2 
Serious Adverse Event  
An AE is considered “serious” if, in the view of either the investigator or the Sponsor, it results 
in any of the following outcomes:  
• Death 
• A life-threatening AE. An event is considered “life threatening” if, in the view of the 
investigator, its occurrence places the subject at immediate risk of death.  It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concomitant medication.  Overdose per se will not be reported as an AE/serious adverse 
event (SAE) unless it is an intentional overdose taken with possible suicidal/self-harming 
intent.  Such overdoses should be reported regardless of sequelae 
8.1.3 
Dose-Limiting Toxicity  
DLT is defined as the occurrence of any of the following TEAEs during the DLT assessment 
window, unless the TEAEs are clearly unrelated to the study drug or judged by the investigator as 
not clinically significant. 
1. Non-hematologic toxicities: 
• Any Grade 4 non-hematologic toxicity 
• Grade 3 non-hematologic toxicity, except for the following conditions: 

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− Recovered to Grade ≤1 within 3 days after supportive therapy is administered for 
nausea, vomiting, diarrhea, constipation, fatigue, and electrolyte imbalance 
− Grade 3 hypothyroidism, adrenal gland or pituitary insufficiency, and inflammatory 
reactions at the tumor site 
− Grade 3 hypertension downgraded to Grade ≤1 within 1 week with appropriate 
supportive therapy 
2. Hematologic toxicity: 
• Grade ≥3 febrile neutropenia (neutrophil count <1.0×109/L, accompanied with a single 
body temperature measurement of ≥38.3°C or ≥38°C persisting for 1 hour) 
• Grade 4 neutropenia 
• Grade 4 thrombocytopenia 
• Grade 3 thrombocytopenia accompanied with clinically significant bleeding, in addition 
to that requiring transfusion 
• Grade 4 anemia requiring a dose delay of ≥14 days 
3. Any life-threatening complication or abnormality not covered in the NCI CTCAE 
Version 5.0. 
8.2 
Adverse Event Reporting  
8.2.1 
Adverse Event Reporting Period  
After signing of the pre-screening informed consent, AEs due to the protocol-required intervention 
will be collected in the pre-screening phase. 
After signing of the main study informed consent, all SAEs and AEs regardless of attribution will 
be collected until 30 days after the last dose of study drug or start of a new treatment of antitumor 
therapy, whichever is earlier.  The relevant AEs will be followed up until they are recovered to the 
baseline status, already in a stable state as assessed by the investigator, start of new antitumor 
therapy, loss to follow-up, death, withdrawal of informed consent, the end of study, or it has been 
confirmed that the AEs are unrelated to the study drug.  After this period, the investigators should 
report only SAEs that are considered to be related to the study drug. 
8.2.2 
Expedited Reporting  
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial.  The investigator must report such events (both initial 
and follow-up) to the Sponsor immediately; under no circumstances should reporting take place 
more than 24 hours after the investigator learns of the event.  The following is a list of events that 
the investigator must report to the Sponsor within 24 hours after first learning of the event, 
regardless of relationship to study drug: 
• SAEs 
• Pregnancy 

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8.2.3 
Dose Limiting Toxicity Reporting  
For each DLT event that occurs in the dose escalation part, the investigator must confirm to the 
Sponsor within 2 business days after learning of it and should conduct phone or online meetings 
with the medical monitor and report any DLT events observed in the DLT evaluation window. 
8.3 
Prior and Concomitant Therapies  
8.3.1 
Prohibited Therapies  
Any therapy intended for the treatment of cancer (with exceptions as noted in Section 8.3.2), 
whether currently marketed or experimental, is prohibited.  This includes, but is not limited to, the 
following: chemotherapy, hormonal therapy, biologic therapy, radiotherapy, or herbal therapy. 
Concomitant use of medications that have a known risk of causing QT prolongation and/or 
torsades de pointes (refer to Appendix 5). 
HMPL-306 is a substrate of 
.  The potential effects of medications that can 
affect the PK of HMPL-306 via 
 pathway have not been tested in the clinic.  During the 
study treatment period, medications that can 
 (Appendix 6) 
should be avoided, and such drugs should be discontinued 1 week or 5 half-lives (whichever is 
longer) before the start of the study treatment. 
Prophylactic use of antiemetic drugs or colony-stimulating factors, platelet irritation factor, or 
erythropoietin is not allowed during the DLT assessment window.  Outside the DLT assessment 
window, it may be allowed if the investigator considers it necessary. 
8.3.2 
Permitted Therapies  
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a subject.  All concomitant therapy within 28 days prior to randomization and the Safety 
Follow-up visit should be reported to the investigator and recorded on the appropriate eCRF. 
Subjects who use oral contraceptives, hormone-replacement therapy, or other allowed 
maintenance therapy may continue their use if indicated. 
Prophylactic antiemetic, granulocyte colony-stimulating factors, granulocyte macrophage colony-
stimulating factors, platelet-simulating factors, or erythropoietin are permitted as clinically 
indicated. 
Levetiracetam is the preferred agent for epileptic prophylaxis.  Other agents may be used but 
require prior discussion with the Sponsor before initiation unless medically urgent. 
All supportive measures consistent with optimal subject care will be given throughout the study. 
8.3.3 
Drug-Drug Interactions  
There are currently no data on a drug demonstrating clear interactions with HMPL-306 in the 
human body.  In vitro data indicate that HMPL-306 exhibited an 
 
 
 
 
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During the study treatment period, the use of medications that are 
 
 (Appendix 7) should be avoided.  If the investigator believes 
it is necessary to use it, consent of the Sponsor-appointed medical monitor should be obtained 
before use, and close observation should be performed during use for a possible reduction in 
efficacy or increase in toxicity due to drug interactions. 
8.3.4 
Rescue Therapies  
Not applicable. 
8.3.5 
Duration of Follow-up for Adverse Events  
The investigator will follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the subject is lost to follow-up, subject’s death, or the end of the study.  Resolution of 
AEs and SAEs (with dates) should be documented on the appropriate eCRF and in the subject’s 
medical record to facilitate source data verification (SDV).  For SAEs, if, after follow-up, return 
to baseline status or stabilization cannot be established, an explanation should be recorded in the 
additional case details section of the eCRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate the SAE report 
(eg, hospital discharge summary, consultant report, or autopsy report) may be followed-up by 
telephone, fax, email, and/or a monitoring visit. 
All pregnancies that occur during the study should be followed until pregnancy outcome. 
8.4 
Eliciting Adverse Events  
A consistent methodology of non-directive questioning for eliciting AEs at all subject evaluation 
time points should be adopted.  Examples of non-directive questions include the following: 
• “How have you felt since your last clinic visit?” 
• “Have you had any new or changed health problems since you were last here?” 
8.5 
Assessment of Severity  
Investigators will seek information on AEs and SAEs at each subject contact.  All AEs and SAEs, 
whether reported by the subject or noted by authorized study personnel, will be recorded in the 
subject’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the applicable eCRF, the investigator will make an assessment 
of severity through clinical description by referring to the 5-grade determination standard in the 
NCI CTCAE Version 5.0.  Please use the guideline below for the assessment of severity when the 
observed or reported AE is not listed in the NCI CTCAE Version 5.0: 
• 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 (ADLs). (Note: Instrumental ADLs 
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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 
ADLs (Note: Self-care ADLs 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 
8.6 
Causality Assessment  
Investigators should use their knowledge of the subject, the circumstances surrounding the AE, 
and an evaluation of any potential alternative causes to determine whether an AE is considered to 
be related to the study drug.  To ensure consistency of causality assessments, investigators should 
apply the general guidelines as provided in Table 11 below: 
Table 11 
Determination of Correlation Between Adverse Events and Study Drug  
Correlation 
Criteria for Assessment 
Not related 
If there is no possibility of correlation between the event and the study drug, the adverse event 
will be deemed “unrelated” to the study drug. 
The situations that meet this assessment factor include, but are not limited to, the following: 
Adverse events caused by influence of underlying disease or concurrent disease or other drugs, 
unreasonable or no temporal relationship between the adverse events and the trial drug, and/or 
existence of other factors that may more likely lead to adverse events. 
Related 
If the event has a potential relationship with the study drug, the adverse event will be 
considered as “related” to the study drug. 
The situations that meet this assessment factor include, but are not limited to, the following: 
There is a reasonable temporal relationship between the adverse event and the study drug or the 
adverse event recurs after re-challenge; compared to the potential relationship with the study 
drug, the possibility of other factors that may cause the adverse event are not present, or the 
possibility is lesser or the same. 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal relationship 
unless further evidence becomes available to refute this.  Causal relationship in cases where the 
disease under study has deteriorated due to lack of effect should be classified as no reasonable 
possibility. 
8.7 
Documenting Adverse Events  
When an AE or SAE is recorded, the preferred medical terminology or concept should be used.  
Abbreviations and colloquialisms (eg, jargon or slang) should be avoided. 
All AEs (including SAEs) should be recorded on the AE eCRF, and the check box for “Serious” 
should be ticked for entries that fit the criteria for SAEs.  The investigator should also complete 
an SAE report and submit this to the Sponsor or its designee within 24 hours of knowledge of the 
event.  
Only 1 medical concept should be recorded in the event field on the eCRF. 

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8.7.1 
Diagnosis versus Symptoms and Signs  
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(eg, hepatic failure should be recorded instead of jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded as an AE 
or SAE on the eCRF.  If a diagnosis is subsequently established, it should be reported as follow-
up information. 
8.7.2 
Adverse Event Occurring Secondary to Other Events  
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause with the exception of severe or serious secondary 
events.  For example, if severe diarrhea is known to have resulted in dehydration, it is sufficient to 
record only diarrhea as an AE or SAE on the eCRF if the dehydration is mild. 
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the eCRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the eCRF. 
8.7.3 
Persistent or Recurrent Adverse Events  
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points.  Such events should only be recorded once in the eCRF unless the severity changes.  
If a persistent AE becomes more or less severe, it should be recorded again in a new eCRF entry.  
Please refer to the eCRF Completion Guidelines for information on completing each eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on the eCRF. 
8.7.4 
Abnormal Laboratory Values or Abnormal Vital Signs  
Not every laboratory abnormality/abnormal vital sign qualifies as an AE.  A laboratory test 
result/abnormal vital sign must be reported as an AE if it is a change from baseline and meets any 
of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (eg, dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Clinically significant in the investigator’s judgment 
Investigators are responsible for reviewing all laboratory findings and abnormal vital signs and 
determining whether each abnormality should be reported as an AE. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, ALP and 
bilirubin 5× ULN associated with cholecystitis), only the diagnosis (eg, cholecystitis) needs to be 
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If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF.  If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE.  For example, an elevated serum potassium level of 7.0 mmol/L should be recorded as 
“hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes. 
8.7.5 
Preexisting Medical Condition  
A preexisting medical condition is one that is present at Screening.  Such conditions should be 
recorded on the eCRF as medical history.  A preexisting medical condition should be recorded as 
an AE or SAE only if the frequency, severity, or character of the condition worsens during the 
study (excluding deterioration of the study disease conditions).  When such events are recorded on 
the eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (eg, “more frequent headaches”). 
8.7.6 
Pregnancy  
A female subject must be instructed to stop taking the study drug and immediately inform the 
investigator if she becomes pregnant during the study.  The investigator should report all 
pregnancies within 24 hours of awareness to the Sponsor (the reporting period for pregnancy 
continues up to 30 days after completion of the study drug).  The investigator should counsel the 
subject and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
Monitoring of the subject should continue until outcome of the pregnancy.  Pregnancies occurring 
up to 30 days after the completion of the study drug must also be reported to the investigator. 
Male subjects must also be instructed to inform the investigator immediately if their partner 
becomes pregnant during the study or within 100 days after the last dose of study drug.  If such an 
event occurs, it should be reported as described above. 
Pregnancy loss of any kind should always be classified as serious AE (as the Sponsor considers 
these medically significant), recorded on the eCRF, and expeditiously reported to Sponsor. 
Any congenital anomaly/birth defect in a child born to a female subject or female partner of a male 
subject exposed to the study drug should be recorded and reported as an SAE. 
8.7.7 
Worsening of Malignancy  
Worsening and/or progression of the subject’s malignancy should not be recorded as an AE or 
SAE.  These data will be captured as efficacy assessment data only.  If there is any uncertainty 
about an AE being related only to the disease under study, it should be reported as an AE or SAE. 
8.7.8 
Death  
All deaths that occur during the protocol-specified AE reporting period must have the underlying 
cause reported to the Sponsor as an SAE, with death listed as the outcome.  Deaths due to the 
progression of disease must also be reported to the Sponsor as an SAE.  Death events that occur 
after 30 days following the last dose of study drug must be reported to the Sponsor as an SAE only 

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if it is confirmed as related to study drug.  If the primary cause of death is unknown and cannot be 
ascertained at the time of reporting, please record “Unknown cause death” on the eCRF, and the 
“unexplained/unknown death” should be reported expeditiously as an SAE.  The SAE should be 
reported before the specific cause of death has been determined. 
8.7.9 
Overdose  
For this study, any dose of HMPL-306 greater than the intended dose will be considered an 
overdose.  No specific information is available on the treatment of overdose of HMPL-306.  In the 
event of overdose, further HMPL-306 administration should be held, and the subject should be 
observed closely for signs of toxicities.  Appropriate supportive treatment should also be provided 
if clinically indicated.  In the event of accidental or intentional overdose, the investigator or other 
site personnel should inform the Sponsor study representatives immediately, or no later than 24 
hours. 
• An overdose with associated AEs/SAEs should be recorded as the AE 
diagnosis/symptoms on the relevant AE/SAE modules in the case report form (CRF) and on 
the study drug CRF module 
• An overdose with no associated signs or symptoms should only be reported on the study 
drug CRF module 
• Overdose will not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
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9 
ANALYSIS  
9.1 
Statistics and Analysis Method  
All statistical analyses will be performed under the direction of the Sponsor’s personnel.  Details 
of the statistical analysis and data reporting will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized prior to the database lock.  
The timing of analysis for each cohort may be different depending on completion of each cohort, 
and the final analysis of the study will be conducted at the time of the analysis of the last cohort.  
No interim analysis is planned for the study.  However, the accrued data from any cohort may be 
analyzed for internal decision-making purposes, for example, to provide information for a potential 
phase 3 study design. 
9.1.1 
Statistical Hypothesis  
No formal hypothesis testing is planned for this study.  For efficacy endpoints, the study will 
provide the estimates and the associated 95% CI for precision. 
9.1.2 
Sample Size Rationale  
Approximately 122 to 131 subjects are estimated to be recruited based on the number of study 
cohorts and the number of study subjects included in each cohort.  Subjects not evaluable for DLT 
will be replaced, and this may result in the number of subjects enrolled being more than expected. 
9.1.2.1 
Dose Escalation Part  
The maximum sample size in this phase will be determined jointly by the Sponsor and the 
investigator.  The exact sample size of the mTPI-2 design in the dose escalation part cannot be 
pre-specified because of the dynamic nature of the Bayesian allocation procedure.  Subjects not 
evaluable for DLT will be replaced, and this may result in the number of subjects enrolled being 
more than expected.  It is estimated that approximately 27 to 36 subjects may be enrolled at this 
part. 
9.1.2.2 
Dose Expansion Part  
In order to better describe the safety of the recommended dose of single-dose HMPL-306 in 
future studies, approximately 95 subjects (4 cohorts of approximately 20 subjects and 1 cohort 
[C-1] of approximately 15 subjects) will be treated with HMPL-306 during this part. For a given 
AE with a true rate of 10%, 5%, or 1%, the probability of observing at least 1 AE in 95 subjects 
is 100%, 99%, and 62%, respectively. 
9.1.3 
Analysis Sets  
The following analysis sets are defined for the study: 
• Safety analysis set: All enrolled subjects who received at least 1 dose of study treatment 
will be included in the safety analysis population.  Safety evaluation will be performed based 
on the first dose of study treatment received by a subject.  This is the primary population for 
the safety and efficacy analysis endpoint PFS. 

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• DLT evaluable analysis set: All subjects enrolled in the dose escalation phase of the study 
who are evaluable for DLT assessment. A subject is DLT evaluable if he/she meets the 
following criteria:  
− has received at least 75% of the assigned dose of study medication during the DLT 
assessment window 
OR 
− has not completed the DLT assessment period due to a DLT 
• Response evaluable analysis set: All subjects who received study treatment and have a 
baseline tumor assessment and at least 1 postbaseline assessment will be considered 
evaluable for antitumor efficacy endpoints such as objective response rate (ORR), disease 
control rate (DCR), time to response (TTR), and duration of response (DoR) 
• PK analysis set: All subjects with at least 1 quantifiable plasma concentration of 
HMPL-306 will be included in the PK analysis population 
• PD analysis set: All subjects with at least 1 quantifiable level of 2-HG in the plasma will 
be included in the PD analysis population 
9.2 
Statistical Analysis  
Data will be summarized by dose/disease cohorts.  Continuous variables will be described using 
the observed number, mean, median, standard deviation, minimum, and maximum; categorical 
variables will be described using frequency.  Kaplan-Meier method will be used to summarize the 
time-to-event data. 
9.2.1 
Subject Disposition  
The number and percentage of subjects that were enrolled in the study, treated, and discontinued 
from study treatment will be presented for the Safety Analysis Set.  The primary reason for 
treatment discontinuation will be summarized according to the categories in the eCRF.  Subject 
disposition will be summarized overall and by tumor types. 
Important protocol deviations will be summarized and listed by category. 
9.2.2 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized for the Safety Analysis Set 
using descriptive statistics. 
A summary of baseline subject and disease characteristics, diagnosis, medical history, prior 
therapies will be reported using descriptive statistics. 
Other subject characteristics will be summarized as deemed appropriate. 
9.2.3 
Prior and Concomitant Medications  
Prior medications will be defined as medications that stopped before the day of first dose of study 
treatment.  Concomitant medications will be defined as medications that 1) started before the first 
dose of study treatment and were continuing at the time of the first dose of study treatment, or 2) 
started on or after the date of the first dose of study treatment up to 30 days after the last 

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treatment.  Concomitant medications will be coded using the World Health Organization Drug 
Dictionary drug codes and will be further coded to the appropriate Anatomical Therapeutic 
Chemical code indicating therapeutic classification.  Prior and concomitant medications will be 
summarized and listed by drug and drug class.  Prior and concomitant medication will be 
summarized overall and by tumor types.  A listing of prior and concomitant medications will be 
provided. 
9.2.4 
Safety Analysis  
The summary of exposure to the drug, AEs, AEs leading to drug modification or discontinuation 
including DLTs, changes in laboratory results, and changes in vital signs etc. will be presented.  
The severity of all AEs will be graded according to NCI CTCAE Version 5.0, and all AEs will be 
coded by Medical Dictionary for Drug Regulatory Activities (MedDRA).  
Safety evaluation will include a summary of the following: 
• Incidence of DLTs by grade (Dose Escalation part only) 
• Incidence of TEAEs by grade 
• Incidence of SAEs 
• Incidence of Grades 3 and 4 abnormalities in safety-related laboratory parameters  
• Incidence of TEAEs/TRAEs leading to HMPL-306 dose interruption, reduction, or 
treatment discontinuation 
The number and frequency of subjects experiencing AEs will be summarized according to 
System Organ Class (SOC) and preferred term.  
For drug exposure, the indicators including, but not limited to, the total exposure duration, 
cumulative dose, dose intensity, and relative dose intensity of HMPL-306 will be calculated. 
For laboratory tests that can be graded based on NCI CTCAE Version 5.0, the corresponding 
changes in the test results will be summarized according to the grade.  The changes in vital signs, 
ECG results, and ECOG PS scores from baseline will be summarized. 
9.2.5 
Pharmacokinetics Analysis  
Evaluation on PK will be performed on the PK analysis set.  Concentration data of HMPL-306 in 
plasma and glioma tissue samples will be tabulated and summarized using descriptive statistics 
(number of subjects [n], arithmetic mean with standard deviation, coefficient of variation [CV%], 
and geometric mean, median, minimum, and maximum), as appropriate.  Plasma PK parameters 
will be tabulated and summarized by treatment using descriptive statistics (n, arithmetic mean with 
SD, CV%, geometric mean, median, minimum, and maximum), as appropriate. 
The following plasma PK parameters of HMPL-306 will be determined: 
• 
AUC0-t 
area under the plasma concentration-time curve from time 0 to time of the last measurable 
concentration 
• 
AUCtau 
area under the concentration-time curve during 1 dosing interval 
• 
Cmax 
maximum observed plasma concentration 
• 
Tmax 
time to reach the maximum plasma concentration 

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• 
Cmin 
minimum observed plasma concentration 
• 
Ctrough 
observed plasma concentration at the end of a dosing interval (taken directly before the next 
dose administration) 
• 
CL/F 
total plasma clearance of drug after extravascular administration, uncorrected for absolute 
bioavailability, calculated as dose/AUC0-τ after multiple dose 
• 
AR 
accumulation ratio 
PK analysis will be performed using actual blood collection times relative to dosing times recorded 
in the raw data.  If an actual blood collection time or a dosing time is missing, the nominal time 
may be used. 
Additional PK parameters may be included if deemed appropriate.  Details of the PK analysis, 
including data handling rules and software used to perform the PK analysis, will be provided in 
the SAP. 
9.2.6 
Pharmacodynamic Analysis  
Levels of 2-HG in the plasma and in glioma tissue samples will be tabulated and summarized using 
descriptive statistics (n, arithmetic mean with SD, CV%, geometric mean, median, minimum, and 
maximum), as appropriate.  The correlation between the exposure level of HMPL-306 and 2-HG 
level and percent inhibition will be analyzed using descriptive and graphical means. Details of 
2-HG analysis will be provided in the SAP. 
9.2.7 
Efficacy Analysis  
The investigator shall evaluate efficacy according to the corresponding criteria for all subjects 
according to RECIST Version 1.1 (RANO criteria for glioma subjects). 
Efficacy evaluation indicators include ORR, DCR, DoR, TTR, PFS, and OS. 
• ORR: Defined as the proportion of subjects achieving a best overall response of 
confirmed complete response (CR) or partial response (PR) 
• DCR: Defined as the proportion of subjects achieving a best overall response of 
confirmed CR, PR, or stable disease (SD) 
• DoR: Defined as the time from the first occurrence of PR or CR, whichever comes first 
until disease progression or death 
• TTR: Defined as the time from the start of study treatment to the first occurrence of 
objective response (PR or CR, whichever comes first) 
• PFS: Defined as the time (months) from the start of study treatment until the first 
radiographic documentation of objective progression as assessed by the investigator using 
RECIST Version 1.1 or death from any cause 
• OS: Defined as the time from the start of the study drug until death from any cause 
The estimate of ORR and DCR and the corresponding 95% CI will be presented by tumor type.  
For time-to-event endpoints such as PFS, TTR, DoR, and OS, the medians and rates at various 
time points along with 95% CI will be estimated by Kaplan-Meier methodology. 

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9.2.8 
Exploratory/Biomarker Analysis  
This study will conduct detection and analysis on related biomarkers and will explore the 
biomarker predicting PK/PD correlation and antitumor effects.  Exploratory biomarker evaluations 
may not be included in the clinical study report (CSR), and a separate summary report will be 
prepared. 

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10 
ETHICAL CONSIDERATIONS  
10.1 
Good Clinical Practice  
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct, consensus, and the ethical principles 
derived from international guidelines, including the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
Applicable ICH Good Clinical Practice (GCP) Guidelines that have their origin in the Declaration 
of Helsinki, and applicable regulations and guidelines governing clinical study conduct. 
10.2 
Ethics Review  
The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) must review the 
protocol and amendments, IB, informed consent form (ICF), study-relevant materials (such as 
advertisements for subject recruitment), and any other essential documents.  IEC/IRB approval is 
to be obtained prior to the start of the study at the investigator site. 
All amendments are to be reviewed and approved by the IEC/IRB and applicable regulatory 
authorities (as required) and documented. All SAEs and other significant safety findings should 
be reported to the Sponsor, the IEC/IRB, and applicable regulatory authorities as required. During 
the study, protocol deviations that may increase a subject’s risk should be reported to the IEC/IRB 
in a timely manner. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 2017/745 
for clinical device research (if applicable), and all other applicable local regulations 
10.3 
Informed Consent  
• Investigators or designees must obtain the signed ICF from subjects prior to conducting 
any study-related procedures 
• The investigator or his/her representative will explain the nature of the study to the 
participant or to their legally authorized representative and answer all questions regarding the 
study 

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• Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, where applicable, and the IRB/IEC or study 
center 
• Subjects must be informed that they may withdraw consent to participate in the study 
without any limitations.  If the subject cannot sign the ICF, a legally acceptable 
representative of the subject must sign the ICF 
• If the subject and the legally acceptable representative are not able to read and write, an 
impartial witness should be present throughout the whole process of providing informed 
consent.  Once the subject and the legally acceptable representative give their oral consent, 
the ICF should be signed by the impartial witness to confirm that the subject and the legally 
acceptable representative fully understand the study and their right to withdraw informed 
consent without any limitations 
• Informed consent should be recorded on the eCRF 
• If the risk/benefit assessment changes after the safety analysis, the ICF needs to be 
reviewed and updated, and all updated information should be provided to subjects (including 
subjects who have already received the study drug) 
10.4 
Data Privacy  
All information about the study drug (such as patent application, formulation, manufacturing 
process, and basic study information) is considered confidential as long as it is unpublished. 
All information obtained in the study is considered confidential.  The Sponsor will open the 
information to investigational personnel and any other regulatory authority, when necessary.  To 
ensure the completeness of the study analysis data, investigational personnel are accountable for 
providing all results and data to the Sponsor. 
Investigators must guarantee the privacy of subjects by not disclosing subject-related information 
to third parties without authorization.  eCRFs and other documents submitted to the Sponsor should 
not contain the subject’s name.  
• Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be transferred. 
• Subjects are identified only by the unique identifier. Investigators may retain the 
identification forms, which include subject numbers, names, and addresses. ICFs and other 
documents should be documented properly and should not be given to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be used 
as described in the informed consent.  

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• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the Sponsor, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.5 
Disclosure  
Final study results will be published on a public clinical study website according to applicable 
local guidelines and regulations. 
10.6 
Data Quality Assurance  
• To ensure the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and subject 
medical records in the subject files as original source documents for the study. 
• All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The investigator is responsible 
for verifying that data entries are accurate and correct, electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the eCRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, contract research organizations [CROs]). 
10.7 
Biological Specimens and Data  
For participants who provide informed consent agreeing to participate in future biomedical 
research, any unused samples for study-related research, as well as unused PK samples, may be 
stored for no longer than 15 years, or other period as per local requirements, after the final date of 
the database lock.  After this storage period, any residual samples will be destroyed.  The Sponsor 
will store the samples in a secure storage space with adequate measures to protect confidentiality.  
The unused samples may be utilized for future biomedical research as permitted by local 
regulations.  The results of these future biomedical research analyses will not be shared with 
subjects and will not be presented in the CSR. 
If there are specific site or country requirements involving the pharmacogenomic analyses that the 
Sponsor is unable to comply with, samples will not be collected at those sites. 
All samples will be single/double coded as defined by ICH guideline E15. 

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11 
OVERSIGHT  
11.1 
Independent Monitoring  
No independent data monitoring is planned for this study. The Sponsor will review study safety 
data on an annual basis, or more frequently, if safety concerns arise. 
11.1.1 
Safety Review Committee  
• Participant safety will be continuously monitored by the SRC, which includes safety 
signal detection at any time during the study 
• In addition, an early aggregated safety data review will be performed, the goal of which 
is to allow for a cautious, stepwise approach to HMPL-306 administration.  An initial safety 
review for this study is planned for the first 3 participants who are dosed and have provided 
safety data for 28 days after administration of dose specified in Table 5, depending on the 
assigned cohort 
• All safety data collected will be summarized and reviewed by the SRC for agreement of 
next steps 
• In particular, data will be reviewed by the Sponsor for identification of the following 
events that would potentially contribute to a requirement to re-evaluate the study 
− Any deaths, regardless of causality 
− In addition, safety data will be reviewed on an ongoing basis during study conduct.  
At a minimum of twice a year, study data will be summarized and reviewed with 
investigators to identify potential safety signals.  Additional safety review meetings may 
be scheduled based on concerns of the Sponsor or investigators 
• Enrollment will be paused during the review.  If a stopping rule is met, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to resume. 
11.2 
Quality Control and Assurance  
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements, and applicable standard operating procedures, including quality control of 
documents.  
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site.  The Sponsor and the 
investigator will ensure that any individual or party who performs study-related duties or functions 
on behalf of the Sponsor/investigator is qualified to perform the study-related duties or functions. 
The overall procedures for quality assurance of clinical study data are described in the Sponsor or 
designee’s standard operational procedures.  The planned quality assurance and quality control 
procedures for the study are described in the following sections. 
11.2.1 
Monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, the Sponsor’s 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and their 

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staff.  During the study, the field monitor will visit the site regularly to check the completeness of 
subject records, the accuracy of entries on the eCRFs, the adherence to the protocol to GCP, and 
the progress of enrollment and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications.  Key study personnel, including the investigator, must 
be available to assist the field monitor during these visits. 
The investigator must give the field monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries.  The Sponsor’s monitoring standards require full 
verification of the informed consent, adherence to the inclusion/exclusion criteria, and 
documentation of SAEs.  Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
11.2.2 
Audits  
Authorized representatives of the Sponsor, a regulatory/competent authority, and/or an IRB/IEC 
representative may visit the site to perform audits or inspections, including SDV.  Should this 
occur, the investigator is responsible for the following: 
• Informing the Sponsor of a planned inspection by the authorities as soon as notification is 
received and authorizing the Sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities to 
the Sponsor immediately 
• Taking all appropriate measures requested by the Sponsor to resolve the problems found 
during the audit or inspection 
• Documents subject to audit or inspection include, but are not limited to, all source 
documents, eCRFs, medical records, correspondence, ICFs, IRB/IEC files, documentation of 
certification and quality control of supporting laboratories, and records relevant to the study 
maintained in any supporting pharmacy facilities.  Conditions of study material storage are 
also subject to inspection.  In addition, representatives of the Sponsor may observe the 
conduct of any aspect of the clinical study or its supporting activities both within and outside 
of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
11.2.3 
Records  
11.2.3.1 
Data Capture and Management  
The term eCRF refers to the electronic data capture (EDC) system.  The EDC system is the 
database where pertinent study data are collected.  For all subjects, including screen failures, data 
will be collected on source documents first.  The principal investigator (PI) is responsible for 
assuring that the data entered into eCRFs are complete and accurate and that entry and updates are 
performed in a timely manner.  Data from ECG will be collected at the study sites, and the data 
will be transmitted to a designated CRO for centralized analysis, as well as for further processing 
and data reconciliation.  Imaging data will be collected at the study sites, and a designated CRO 
will perform further processing, data reconciliation, and holding. 

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At all times, the PI has the final responsibility for the accuracy and authenticity of all clinical and 
laboratory data entered into the EDC.  Subject source documents are the investigator’s/physician’s 
subject records maintained at the study site.  In cases where the source documents are the hospital 
or the physician’s chart, the information collected in the EDC must match those charts.  
The completed pages of the EDC system are the sole property of the Sponsor and should not be 
made available in any form to third parties without written permission from the Sponsor, except 
for authorized representatives of the Sponsor or appropriate regulatory authorities. 
11.2.3.2 
Source Documentation  
• The investigator/institution should maintain accurate source documents and study records 
for all subjects that support the information entered into the eCRF.  
• Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete.  Changes to source data should be traceable and not obscure the original entry. 
• All information recorded on eCRFs must be traceable to source documents in the 
subject’s file.  Any changes should be explained if necessary (eg, via an audit trail). 
11.2.3.3 
Records Retention  
Records and documents, including signed ICFs, source documents, study drug documents, 
monitoring visit records, regulatory documents, and all other correspondence and documents 
pertaining to the conduct of this study, must be retained by the investigator for at least 5 years after 
study completion, unless local regulations or institutional policies require a longer retention period. 
If the documents cannot be stored properly at the investigational site, the documents can be 
transferred by the investigator and the Sponsor to an approved storage facility.  The documents 
must be sealed for storage and easily found for review in the case of a regulatory authority audit.  
No records may be transferred to another location or party without written notification to the 
Sponsor. 
No records may be destroyed during the retention period following study completion or 
discontinuation without the written approval of the Sponsor.  Records must be destroyed in a 
manner that ensures confidentiality. 
11.3 
Study Termination or Study Site Closure  
The Sponsor and the investigator have the right to close out a site prematurely. 
Investigator’s Decision 
The investigator must notify the Sponsor of a desire to close out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the Sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The Sponsor will notify the investigator(s) of a decision to close out a study site in writing. Reasons 
may include the following, among others: 
• The investigator has received all items and information necessary to perform the study 
but has not enrolled any subject within a reasonable period of time 

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• The investigator has violated any fundamental obligation in the study agreement, 
including, but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH guidelines 
• The total number of subjects required for the study is enrolled earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate subject therapy and/or 
follow-up. 

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12 
PUBLICATION POLICY  
The study results may be published in scientific journals.  The names of investigators who make 
an important contribution to the study implementation and management and personnel who make 
an important contribution to the study design, analysis, and interpretation (such as the Sponsor’s 
staff or consultants) will be listed in the publication.  The Sponsor will provide the article to 
investigators for review prior to publishing any study results.  Investigators must obtain approval 
from the Sponsor before contributing to any related articles or abstracts. 
The Sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a coordinating 
investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 

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13 
FINANCING AND INSURANCE  
Financing and insurance information will be addressed in a separate agreement. 

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14 
REFERENCES  
Abou-Alfa 2020  
Abou-Alfa G, Macarulla T, Javle M, Kelley R, Lubner S, Adeva J, Cleary J, Catenacci D, et al. 
Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a 
multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 
2020;21(6):796-807. 
Casali 2018  
Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, et al. ESMO guidelines 
committee, paedcan and ern euracan. bone sarcomas: ESMO-PaedCan-EURACAN Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 
4):iv79-iv95. 
Chowdhury 2011  
Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The 
oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 
2011;12(5):463-9. 
Dang 2009  
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated 
IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-44. 
Fathi 2012  
Fathi AT, Sadrzadeh H, Borger DR, Ballen KK, Amrein PC, Attar EC, et al. Prospective serial 
evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, 
to assess disease activity and therapeutic response. Blood. 2012;120(23):4649-52. 
Guo 2017  
Guo W, Wang S-J, Yang S, et al. A Bayesian interval dose-finding design addressing ckham's 
Razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33. 
Italiano 2013  
Italiano A, Mir O, Cioffi A, Palmerini E, Piperno-Neumann S, Perrin C, et al. Advanced 
chondrosarcomas: role of chemotherapy and survival. Annals of Oncology. 2013;24:2916-22. 
Koivunen 2012  
Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, et al. Transformation by the 
(R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484-
8. 
Kosmider 2010  
Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, et al. Mutations 
of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and 
MDS/myeloproliferative neoplasms. Leukemia. 2010;24(5):1094-6. 

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Lowery 2017  
Lowery MA, Abou-Alfa GK, Burris III HA, Janku F, Shroff RT, Cleary JM, et al. Phase 1 study 
of AG-120, an IDH1 mutant enzyme inhibitor: results from the cholangiocarcinoma dose 
escalation and expansion cohorts. American Society of Clinical Oncology Annual Meeting, 
2017; Abstract 4015. 
Marcucci 2010  
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D, et al. IDH1 and 
IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal 
acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 
2010;28(14):2348-55. 
Mellinghoff 2017  
Mellinghoff IK, Touat M, Maher E, De La Fuente MI, Cloughesy TF, Holdhoff M, et al. AG-
120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant 
glioma: updated results from the phase 1 non-enhancing glioma population. Society for Neuro-
Oncology Annual Scientific Meeting, San Francisco, CA, USA; 16-19 November 2017. 
Mellinghoff 2018  
Mellinghoff IK, Penas-Prado M, Peters KB, Cloughesy TF, Burris HA, Maher E, et al. Phase 1 
study of AG-881, an inhibitor of mutant IDH1/IDH2, in patients with advanced IDH mutant 
solid tumors, including glioma. American Society of Clinical Oncology Annual Meeting, 
Chicago, IL, USA; 1-5 June 2018. Abstract 2002. 
Mellinghoff 2020  
Mellinghoff IK, Peters KB, Cloughesy TF, Burris III HA, Maher EA, Janku F. Vorasidenib 
(VOR; AG-881), an inhibitor of mutant IDH1 and IDH2, in patients (PTS) with 
recurrent/progressive glioma: Updated results from the phase I non-enhancing glioma 
population. Journal of Clinical Oncology. 2020;38(15_suppl):2504–.   
NCCN 2020  
Nabors LB, Portnow J, Ahluwalia M, Baehring J, Brem H, Brem S, et al. Central nervous system 
cancers, version 3.2020, nccn clinical practice guidelines in oncology. J Natl Compr Canc Netw. 
2020 Nov 2;18(11):1537-1570. 
NCT02481154  
A phase 1, multicenter, open-label, dose-escalation and expansion, safety, pharmacokinetic, 
pharmacodynamic, and clinical activity study of orally administered ag-881 in patients with 
advanced solid tumors, including gliomas, with an idh1 and/or idh2 mutation. 2015 June 25 [last 
updated 2022 February 11]. In ClinicalTrials.gov [Internet]. Bethesda (MD): US National 
Library of Medicine. Available from https://clinicaltrials.gov/ct2/show/NCT02481154. 

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NCT02989857  
A phase 3, multicenter, randomized, double-blind, placebo-controlled study of ag-120 in 
previously-treated subjects with nonresectable or metastatic cholangiocarcinoma with an idh1 
mutation. 2016 December 12 [last updated 2022 April 13; results first received 13 April 2022; 
cited 2022 May 11]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): US National Library of 
Medicine. Available from https://clinicaltrials.gov/ct2/show/NCT02989857. 
Pardanani 2010  
Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, and Tefferi A. IDH1 and IDH2 
mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia. 
2010;24(6):1146-51. 
Parsons 2008  
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic 
analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807-12. 
Tap 2020  
Tap WD, Villalobos VM, Cote GM, Burris H, et al. Phase I study of the mutant idh1 inhibitor 
ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. Journal of 
clinical oncology,. 2020;38(15):1693-701. 
Valle 2016  
Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D. ESMO Guidelines 
Committee. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2016;27(5):v28-v37 
van den Bent 2011  
van den Bent M, Wefel J, Schiff D, Taphoorn M, Jaeckle K, Junck L, Armstrong T, et al. 
Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome 
in trials of diff use low-grade gliomas. Lancet Oncol. 2011;12:583-93. 
Wang 2013  
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted 
inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 
2013;340(6132):622-6. 
Weller 2021  
Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines 
on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 
Mar;18(3):170-186. 
Xu 2011  
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a 
competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 
2011;19(1):17-30. 

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Yan 2009  
Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 
2009;360(8):765-73. 
Yang 2015  
Yang S, Wang SJ, Ji Y. An integrated dose-finding tool for phase I trials in oncology. Contemp 
Clin Trials. 2015;45(Pt B):426-34. 
Yoshihara 2001  
Yoshihara T, Hamamoto T, Munakata R, Tajiri R, Ohsumi M, Yokota S. Localization of 
cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells: 
biochemical and immunocytochemical studies. J Histochem Cytochem. 2001;49(9):1123-31. 

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15 
APPENDICES  
 

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APPENDIX 1 
PK, PD, AND BIOMARKER ASSESSMENTS (EXCLUDING 
COHORT C-1)  
Study Day 
Time Relative 
to Dosing 
Study 
Drug 
Intake 
Blood 
Samples for 
PK 
Blood 
Samples for 
2-HG 
Blood Samples for 
Gene Mutation 
Analysis 
ECG 
Screening 
 
 
 
X 
X2 
X 
C1D1 
Predose1 
 
X 
X 
 
X4 
0 h 
X 
 
 
 
 
0.5 h (± 2 min) 
 
X 
 
 
 
1 h (± 5 min) 
 
X 
 
 
X4 
2 h (± 10 min) 
 
X 
 
 
X4 
3 h (± 10 min) 
 
X 
 
 
 
4 h (± 15 min) 
 
X 
 
 
X4 
6 h (± 15 min) 
 
X 
 
 
 
8 h (± 15 min) 
 
X 
 
 
 
C1D2 
Predose1 
 
X 
X 
 
 
0h 
X 
 
 
 
 
C1D8 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C1D15 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C1D22 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C2D1 
Predose1 
 
X 
X 
X3 
X4 
0 h 
X 
 
 
 
 
0.5 h (± 2 min) 
 
X 
 
 
 
1 h (± 5 min) 
 
X 
 
 
X4 
2 h (± 10 min) 
 
X 
 
 
X4 
3 h (± 10 min) 
 
X 
 
 
 
4 h (± 15 min) 
 
X 
 
 
X4 
6 h (± 15 min) 
 
X 
 
 
 
8 h (± 15 min) 
 
X 
 
 
 
C2D2 
Predose1 
 
X 
 
 
 
0 h 
X 
 
 
 
 
C2D15 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C3D1 
Predose1 
 
X 
X 
X3 
X 
0 h 
X 
 
 
 
 
C5D1 
Predose1 
 
X 
X 
X3 
X 
0 h 
X 
 
 
 
 

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Study Day 
Time Relative 
to Dosing 
Study 
Drug 
Intake 
Blood 
Samples for 
PK 
Blood 
Samples for 
2-HG 
Blood Samples for 
Gene Mutation 
Analysis 
ECG 
C7D1 
Predose1 
 
X 
X 
X3 
X 
0 h 
X 
 
 
 
 
C10D1 and 
every 
3 cycles 
thereafter 
Predose1 
 
X 
X 
X3 
X 
0 h 
X 
 
 
 
 
EOT 
(Within 
7 days after 
the last dose) 
Anytime 
 
 
X 
X3 
 
Safety 
Follow-up 
period 
(30 days 
after EOT 
Visit) 
Anytime 
 
 
 
 
X 
2-HG = 2-hydroxyglutaric acid; CxDx = Cycle X Day X; ECG = electrocardiogram; EOT = end of treatment; 
PD = pharmacodynamics; PK = pharmacokinetics. 
1 
Should be performed within 30 minutes before the dosing on that day and approximately 24 hours 
(±60 minutes) after dosing on the previous day (ie, Day 1 of Cycle 1 or 2). 
2 
Whole blood will be collected for potential analysis of 
 at baseline in dose 
escalation and dose expansion.  Samples collected in dose expansion will also be used for analysis of gene 
mutation abundance.  
3 
Whole blood will be collected in dose expansion only for analysis of gene mutation abundance, such as 
IDH1, IDH2 (R140 and R172), 
, etc. 
4 
To be performed in triplicate with intervals of approximately 5 minutes. 
 
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APPENDIX 2 
PK, PD, AND BIOMARKER ASSESSMENTS FOR COHORT C-1  
Study Day 
Time Relative 
to Dosing 
Study 
Drug 
Intake 
Blood 
Samples 
for PK 
Blood 
Samples 
for 2-HG 
Blood 
Samples for 
Gene 
Mutation 
Analysis 
Glioma 
Samples 
for 2-HG 
and PK 
ECG 
Screening 
 
 
 
X 
X2 
 
X 
D1 
Predose1 
 
X 
X 
 
 
X3 
0 h 
X 
 
 
 
 
 
0.5 h (±2 min) 
 
X 
 
 
 
 
1 h (±5 min) 
 
X 
 
 
 
X3 
2 h (± 10 min) 
 
X 
 
 
 
X3 
3 h (± 10 min) 
 
X 
 
 
 
 
4 h (± 15 min) 
 
X 
 
 
 
X3 
6 h (± 15 min) 
 
X 
 
 
 
 
8 h (± 15 min) 
 
X 
 
 
 
 
D2 
Predose1 
 
X 
X 
 
 
 
0h 
X 
 
 
 
 
 
D8 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
D15 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
D22 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
D28 
Predose1 
 
X 
X 
X2 
 
X3 
0 h 
X 
 
 
 
 
 
0.5 h (± 2 min) 
 
X 
 
 
 
 
1 h (± 5 min) 
 
X 
 
 
 
X3 
2 h (± 10 min) 
 
X 
 
 
 
X3 
3 h (± 10 min) 
 
X 
 
 
 
 
4 h (± 15 min) 
 
X 
 
 
 
X3 
6 h (± 15 min) 
 
X 
 
 
 
 
8 h (± 15 min) 
 
X 
 
 
 
 
D29 
24 h (± 30 min) 
 
X 
 
 
 
 
Surgery 
Anytime 
 
X 
X 
 
X 
 
C1D1 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
C1D15 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
C2D1 
Predose1 
 
X 
X 
 
 
X 
0 h 
X 
 
 
 
 
 

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Study Day 
Time Relative 
to Dosing 
Study 
Drug 
Intake 
Blood 
Samples 
for PK 
Blood 
Samples 
for 2-HG 
Blood 
Samples for 
Gene 
Mutation 
Analysis 
Glioma 
Samples 
for 2-HG 
and PK 
ECG 
C2D15 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
C3D1 
Predose1 
 
X 
X 
X2 
 
X 
0 h 
X 
 
 
 
 
 
C5D1 
Predose1 
 
X 
X 
X2 
 
X 
0 h 
X 
 
 
 
 
 
C7D1 
Predose1 
 
X 
X 
X2 
 
X 
0 h 
X 
 
 
 
 
 
C10D1 and 
every 
3 cycles 
thereafter 
Predose1 
 
X 
X 
X2 
 
X 
0 h 
X 
 
 
 
 
 
EOT 
(within 
7 days after 
last dose) 
Anytime 
 
 
X 
X2 
 
 
Safety 
Follow-up 
period 
(30 days 
after 
termination 
of treatment) 
Anytime 
 
 
 
 
 
X 
2-HG = 2-hydroxyglutaric acid; CxDx = Cycle X Day X; ECG = electrocardiogram; EOT = end of treatment; 
PD = pharmacodynamics; PK = pharmacokinetics. 
1 
Should be performed within 30 minutes before the dosing on that day and approximately 24 hours 
(±60 minutes) after dosing on the previous day (ie, Day 1 of Cycle 1 or 2). 
2 
Whole blood will be collected for analysis of gene mutation abundance, such as IDH1, IDH2 (R140 and 
R172), 
, etc.  Samples collected at screening will also be used for potential analysis of 
. 
3 
To be performed in triplicate with intervals of approximately 5 minutes. 
 
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APPENDIX 3 
ECOG PERFORMANCE STATUS  
Grade 
Activity Level 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work and office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed or chair 
5 
Death 
ECOG = Eastern Cooperative Oncology Group. 
 

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APPENDIX 4 
PROHIBITED MEDICATIONS  
Medications that can prolong QT interval are listed in Table 12 below: 
Table 12 
Medications That Can Prolong QT Interval  
Aclarubicin 
Ibogaine 
Amiodarone 
Ibutilide 
Anagrelide 
Levofloxacin 
Arsenic trioxide 
Levomepromazine 
Azithromycin 
Levosulpiride 
Chloroquine 
Methadone 
Chlorpromazine 
Moxifloxacin 
Cilostazol 
Ondansetron 
Ciprofloxacin 
Oxaliplatin 
Citalopram 
Papaverine hydrochloride 
Clarithromycin 
Pentamidine 
Cocaine 
Pimozide 
Disopyramide 
Procainamide 
Dofetilide 
Propofol 
Domperidone 
Quinidine 
Donepezil 
Roxithromycin 
Dronedarone 
Sevoflurane 
Droperidol 
Sotalol 
Erythromycin 
Sulpiride 
Escitalopram 
Sultopride 
Flecainide 
Terlipressin 
Fluconazole 
Terodiline 
Halofantrine 
Thioridazine 
Haloperidol 
Vandetanib 
This is not an exhaustive list of drugs that can prolong QT intervals, with the list of the latest drugs that can be 
found in the following link: https://crediblemeds.org/healthcare-providers/ 
 

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APPENDIX 5 
NEW YORK HEART ASSOCIATION FUNCTION CLASSIFICATION  
Grading  
Description 
Level I 
There is no restriction on physical activity: Daily physical activities do not cause asthenia, 
palpitations, dyspnea, or angina. 
Level II 
Mild limitation of physical activity: Feel good during rest, but daily physical activities can cause 
asthenia, palpitations, dyspnea, or angina. 
Level III 
Significantly limited physical activity: There is no subjective symptom when resting, but activities 
that are less than daily physical activities can cause the above symptoms. 
Level IV 
Unable to engage in any physical activities without discomfort: Symptoms occur even when resting. 
There will be increased discomfort when performing any physical activities. 
Source: New York Heart Association. Naming and Diagnostic Criteria for Cardiovascular Disease, Version 9. 
Boston, MA: Little, Brown & Co; 1994: pp. 253-6. 
 

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APPENDIX 6 
  
 
Source: https://www.drugbank.ca 
Note: This is not an exhaustive list containing all 
. The investigator should 
carefully consider the concomitant medication of each subject, assess the risk-benefit ratio, and perform 
appropriate monitoring. 
 
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APPENDIX 7 
LIST OF 
 
  
 
. 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table5-1 
Note: This is not a detailed list containing all 
. 
The investigator should carefully consider the concomitant medication of each subject, assess the risk-benefit 
ratio, and perform appropriate monitoring. 
 
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APPENDIX 8 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1  
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 
are presented below. 
1. Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
described below. 
1.1.1 Measurable Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows: 
• 10 mm by CT or magnetic resonance imaging (MRI) scan (CT/MRI scan slice 
thickness/interval no greater than 5 mm) 
• 10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
− Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and follow-up, only the 
short axis will be measured and followed.  
1.1.2 Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 but  15 mm) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural 
or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone Lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT or MRI 
can be considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 

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Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
1.2 Specifications by Methods of Measurements 
1.2.1 Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
1.2.2 Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study. Imaging-based evaluation should 
always be the preferred option. 
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
and  10 mm in diameter as assessed using calipers (eg, skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the 
study should be guided by the tumor type under investigation and the anatomic location of the 
disease. For patients who develop contraindications to contrast after baseline contrast CT is 
done, the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be 
performed should also be based on the tumor type and the anatomic location of the disease, and 

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should be optimized to allow for comparison with the prior studies if possible. Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. Care must be 
taken in measurement of target lesions on a different modality and interpretation of non-target 
disease or new lesions, since the same lesion may appear to have a different size using a new 
modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of these 
techniques for objective tumor evaluation cannot generally be advised. 
2. Tumor Response Evaluation 
2.1 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
2.2 Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. This means 
that, for instances in which patients have only one or two organ sites involved, a maximum of 
two lesions (one site) and four lesions (two sites), respectively, will be recorded. Other lesions 
(albeit measurable) in those organs will be recorded as non-measurable lesions (even if the size 
is 10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs, but in addition should lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement, in which circumstance the next largest lesion that can be 
measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node that is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but 15 mm) should be considered non-target lesions. Nodes that have a short axis of 10 mm 
are considered non-pathological and should not be recorded or followed. 

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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum. The baseline 
sum of diameters will be used as a reference to characterize further any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the Case Report Form (eCRF) (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
2.3 Response Criteria 
2.3.1 Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
• Complete response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm 
• Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters 
• Progressive disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. The appearance of one or more new lesions is also considered progression 
• Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum on study 
2.3.2 Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to  10 mm on study. This means that when lymph nodes are included 
as target lesions, the sum of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of  10 mm. 
Target Lesions That Become Too Small to Measure. During the study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
too small to measure. When this occurs, it is important that a value be recorded on the eCRF, as 
follows: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned and 

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below measurable limit (BML) should be ticked (BML is equivalent to a “less than” 
sign). (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well, and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximum longest diameter for the coalesced lesion. 
2.3.3 Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
• CR: Disappearance of all non-target lesions and (if applicable) normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) 
• Non-CR/non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
• PD: Unequivocal progression of existing non-target lesions. The appearance of one or 
more new lesions is also considered progression 
2.3.4 Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. 
A modest increase in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in some 
phase 3 trials when it is not a criterion of study entry to have measurable disease.  The same 
general concepts apply here as noted above; however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
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an additional 73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from “trace” to “large” or 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial. 
2.3.5 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (eg, some “new” bone 
lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the patient’s baseline lesions show partial or CR. For example, necrosis of a liver lesion 
may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example, because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm that 
there is definitely a new lesion, then progression should be declared using the date of the initial 
scan. 
18F-Fluorodeoxyglucose Positron Emission Tomography 
While 18F-fluorodeoxyglucose (FDG) PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly, possible “new” disease). New lesions on the basis of 
FDG-PET imaging can be identiﬁed according to the following algorithm: 
A negative FDG-PET scan at baseline with a positive FDG-PET scan during the study is a sign 
of PD based on a new lesion. 
In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during the study: 
• If the positive FDG-PET scan during the study corresponds to a new site of disease 
conﬁrmed by CT, this will be considered PD. 
• If the positive FDG-PET scan during the study is not conﬁrmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine whether there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
• If the positive FDG-PET scan during the study corresponds to a preexisting site of 
disease on CT that is not progressing on the basis of the anatomic images, this will not be 
considered PD. 

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2.4 Evaluation of Response 
2.4.1 Time Point Response (Overall Response) 
It is assumed that, at each protocol-specified time point, a response assessment occurs. Table 13 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 14 is to be used. 
Table 13 
Time Point Response: Patients with Target Lesions (with or without Non-
Target Lesions)  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
 
Table 14 
Time Point Response: Patients with Non-Target Lesions Only  
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a 
“Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is 
increasingly used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised. 
 
2.4.2 Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an assessment, 
usually, the case is also considered not evaluable at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 

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example, if a patient had a baseline sum of 50 mm with 3 measured lesions and, during the study, 
only 2 lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved PD 
status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be Not Evaluable (NE), unless the sum of the diameters of the remaining target 
lesions which were assessed is greater than 20% from nadir, in which case target lesion response 
should be PD. Similarly, if one or more non-target lesions are not assessed, the response for non-
target lesions should be NE, except where there is clear progression for the remaining non-target 
lesions which were assessed. Overall response would be NE if either the target response or the 
non-target response is NE except where this is clear evidence of progression. 
2.4.3 Best Overall Response: All Time points 
The best overall response is determined once all the data for the patient are known. Best response 
determination in trials where confirmation of CR or PR is not required: Best response in these 
trials is defined as the best response across all time points (eg, a patient who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best overall response of 
PR). When SD is believed to be the best response, it must also meet the protocol-specified 
minimum time from baseline. If the minimum time is not met when SD is otherwise the best time 
point response, the patient’s best response depends on the subsequent assessments. For example, 
a patient who has SD at first assessment and PD at second assessment and does not meet 
minimum duration for SD will have a best response of PD. The same patient lost to follow-up 
after the first SD assessment would be considered not evaluable. 
Best response determination in trials where confirmation of CR or PR is required: CRs or PRs 
may be claimed only if the criteria for each are met at a subsequent time point as specified in the 
protocol (generally 4 weeks later). In this circumstance, the best overall response can be 
interpreted as in Table 15. 
Table 15 
Best Overall Response When Confirmation of Complete Response and 
Partial Response is Required  
Overall Response 
First Time point 
Overall Response 
Subsequent Time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met; 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met; 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 

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Table 15 
Best Overall Response When Confirmation of Complete Response and 
Partial Response is Required  
Overall Response 
First Time point 
Overall Response 
Subsequent Time point 
Best Overall Response 
PR 
PD 
SD provided minimum criteria for SD duration met; 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met; 
otherwise NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
a 
If a CR is truly met at the first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether the minimum duration for SD was met. 
However, sometimes “CR” may be claimed when subsequent scans suggest that small lesions were likely 
still present, and in fact, the patient had PR, not CR, at the first time point. Under these circumstances, the 
original CR should be changed to PR, and the best response is PR. 
 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to a “normal” 
size (<0 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be 
based on an increase in size of the nodes. As noted earlier, this means that patients with CR may 
not have a total sum of “zero” on the eCRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease, as shown in 
Table 13 and Table 14. 
For equivocal findings of progression (eg, very small and uncertain new lesions and cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (ie, primary disease still or 
partially present), the primary tumor should also be captured as a target or non-target lesion, as 
appropriate. This is to avoid an incorrect assessment of CR if the primary tumor is still present 
but not evaluated as a target or nontarget lesion. 
2.5 Frequency of Tumor Re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and should be 
adapted to the type and schedule of treatment.  However, in the context of phase 2 studies where 
the beneficial effect of therapy is not known, a follow-up every 6 to 8 weeks (timed to coincide 

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with the end of a cycle) is reasonable.  Smaller or greater time intervals than these could be 
justified in specific regimens or circumstances.  The protocol should specify which organ sites 
are to be evaluated at baseline (usually those most likely to be involved with metastatic disease 
for the tumor type under study) and how often evaluations are repeated.  Normally, all target and 
non-target sites are evaluated at each assessment.  In selected circumstances, certain nontarget 
organs may be evaluated less frequently.  For example, bone scans may need to be repeated only 
when CR is identified in target disease or when progression in the bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the 
trial has as a goal the response rate or the time to an event (progression/death).  If the “time to an 
event” (eg, time to progression, disease-free survival, and progression-free survival) is the main 
endpoint of the study, then routine scheduled re-evaluation of protocol-specified sites of disease 
is warranted.  In randomized comparative trials in particular, the scheduled assessments should 
be performed as identified on a calendar schedule (eg, every 6 to 8 weeks on treatment or every 3 
to 4 months after treatment) and should not be affected by delays in therapy, drug holidays, or 
any other events that might lead to imbalance in a treatment arm in the timing of disease 
assessment. 
2.6 Confirmatory Measurement/Duration of Response 
2.6.1. Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure that responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, for 
example, in randomized trials (phase 2 or 3) or in studies where SD or PD are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results.  However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, particularly in studies that 
are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general, not less than 6 to 8 weeks) that is defined in the study protocol. 
2.6.2. Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
2.6.3. Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of patients achieving SD for a minimum period of time is an endpoint of importance 

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in a particular trial, the protocol should specify the minimal time interval required between 2 
measurements for determination of SD. 
Note: The duration of response and SD, as well as the progression-free survival, is influenced by 
the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to 
define a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and parts, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made. 
 

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APPENDIX 9 
RESPONSE ASSESSMENT IN NEURO-ONCOLOGY CRITERIA FOR 
GLIOMAS  
Patients should be assessed with the same imaging method throughout the trial, with 
pre-specified imaging parameters.  
General minimum imaging protocol of low-grade glioma: 
Basic Magnetic Resonance Imaging Protocol (All Centers) 
• Axial fluid-attenuated inversion recovery (FLAIR) (canthomeatal alignment): 3- to 5-mm 
sections, 1-mm interslice gaps, slice registration preserved as much as possible between 
sequential studies 
• Axial T2: 5-mm sections, 1-mm interslice gap 
• Coronal T1: 5-mm sections, 1-mm interslice gap 
• Post-gadolinium chelate (contrast agent as per local clinical practice): coronal T1 and 
axial T1 
(Alternatively, pre-gadolinium and post-gadolinium volumetric T1 may replace axial and coronal 
T1-weighted sequences) 
Response 
Criteria 
Complete 
response 
Complete response requires all the following criteria compared with the baseline scan: 
• 
complete disappearance of the lesion on T2 or FLAIR imaging (if enhancement 
had been present, it must have resolved completely) 
• 
no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effects, and no new or increased enhancement 
• 
patients must be off corticosteroids or only on physiological replacement doses 
• 
patients should be stable or improved clinically. 
Partial response 
Partial response requires all of the following criteria compared with the baseline scan: 
• 
greater than or equal to 50% decrease in the product of perpendicular diameters of 
the lesion on T2 or FLAIR imaging sustained for at least 4 weeks compared with 
baseline 
• 
no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effects, and no new or increased enhancement 
• 
patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically. 
Minor response 
Minor response requires the following criteria compared with baseline:  
• 
a decrease of the area of non-enhancing lesion on T2 or FLAIR MR imaging 
between 25% and 50% compared with baseline 
• 
no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effect, and no new or increased enhancement 
• 
patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically. 
Stable disease 
Stable disease is present if the changes do not qualify for complete, partial, or minor 
response or progression and requires:  
• 
stable area of non-enhancing abnormalities on T2 or FLAIR imaging 
• 
no new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effect, and no new or increased enhancement 

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Response 
Criteria 
• 
patients should be on a corticosteroid dose that should not be greater than the dose 
at time of baseline scan, and should be stable or improved clinically. 
Progressive 
disease 
(≥12 weeks after 
radiation therapy 
completion) 
Progression is defined by any of the following:  
• 
development of new lesions or increase of enhancement (radiological evidence of 
malignant transformation) 
• 
a 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids compared with baseline scan or best response after 
initiation of therapy, not attributable to radiation effect or to comorbid events 
• 
definite clinical deterioration not attributable to other causes apart from the 
tumour, or decrease in corticosteroid dose 
• 
failure to return for evaluation because of death or deteriorating condition, unless 
caused by documented non-related disorders. 
FLAIR = fluid-attenuated inversion recovery; MR = magnetic resonance. 
Source: Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials 
of diff use low-grade gliomas. Lancet Oncol. 2011;12:583-93 [van den Bent et al 2011]. 
 

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APPENDIX 10 
COVID-19 RISK ASSESSMENT  
HUTCHMED Limited acknowledges that the participants to be enrolled in this study are patients 
with refractory cancer, and therefore, may be at higher risk for complications if they contract 
COVID-19.  Available data indicate that the elderly and people with underlying health conditions 
such as chronic respiratory, cardio-vascular or kidney disease, diabetes, active cancer, and more 
generally severe chronic diseases are more vulnerable to experience complications.  However, 
there is an unmet medical need for new medications that are safe and effective in patients with 
refractory cancer who have limited treatment options. 
During the COVID-19 pandemic, additional risks to subjects may exist either related to going to a 
healthcare facility (eg, being outside of home, possible contact with unsanitized surfaces) or as a 
result of study-related activities (eg, interaction with study staff).  Potential subjects with known 
or suspected COVID-19 infection are ineligible.  Subjects with a known COVID-19 infection may 
be considered for participation following 2 subsequent negative tests are provided.  Patients may 
be screened and enrolled if the site has procedures in place to test and appropriately follow new 
patients on trial and to ensure patient safety and data integrity. It is at the Principal Investigator’s 
discretion to balance the risk/benefit, and patient safety should always be considered. 
Risk management steps being taken by HUTCHMED Limited and its designee: 
4. Subject safety 
• Subjects will be educated by the investigator on COVID-19-related risks (ie, 
using cancer patient guidelines at ESMO web site).  
• Minimize time subjects spends at the clinic  
▪ Blood sampling/visit may be performed at another location (if this can be 
done within local restrictions on social distancing) to reduce site burden and risk 
for infection, eg, local laboratory, home nurse, or opening a satellite site. The 
laboratory results must be reviewed by the investigator, the local laboratory 
included on the 1572, and laboratory normal ranges must be collected. 
▪ Study visits may be conducted with subjects using telemedicine, where the 
investigator and site can videoconference with the patient. In this setting, 
investigators should perform as many assessments as possible, including any AEs, 
concomitant medications, and ECOG performance status.  
• Reduce the risk for COVID-19 infection while travelling to and from the clinic by 
providing an option, where allowed, for car/taxi service to avoid public 
transportation. 
• If a subject enrolled into the study subsequently tests positive for COVID-19, the 
data will be entered into the eCRF as an AE with proper source documentation.   
5. Investigational Medicinal Product handling 
• Investigational Product may be delivered to the subject’s house if permitted under 
the site’s Standard Operating Procedures and patient chain of custody and patient 
privacy is protected. 

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6. Management of protocol deviations due to the COVID-19 pandemic 
HUTCHMED Limited and its designee will adhere to all applicable health authority 
guidelines for documenting and reporting any protocol deviations due to the COVID-19 
pandemic.  The deviations will be reported as instructed to the authorities or institutional 
review boards/independent ethics committees. 
7. Remote monitoring 
HUTCHMED Limited and its designee agree to perform remote monitoring where 
feasible and permitted. For remote source data verification, country legislation will be 
followed and performed only where allowed with written agreement of the Principal 
Investigator. The planned site-level procedures will be described in detail and approvals 
sought as required. If a site cannot support remote monitoring with electronic medical 
records (EMR) access, the site will not be permitted to consent new patients.  Remote 
visits will also be conducted to facilitate site selection and training. 
The risk-benefit ratio for subjects enrolled according to the inclusion and exclusion criteria defined 
in the study protocol and according to the defined COVID-19 risk mitigation measures continues 
to be favorable. 
HUTCHMED Limited and its designee will continue to evaluate the impact of COVID-19 on the 
ability of each site to initiate and execute the trial.  Site-specific positions will be evaluated prior 
to the Site Initiation Visit, with the outcomes and any resultant actions documented and filed in 
the Trial Master File.  
As the COVID-19 situation may be temporary, regulatory guidance will be continuously re-
evaluated and any changes will be communicated as necessary. 
 

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APPENDIX 11 
RATIONALE FOR STUDY POPULATION SELECTION  
Cohort A: Cholangiocarcinoma  
This study plans to enroll subjects with locally advanced or metastatic cholangiocarcinoma not 
eligible for curative resection or transplantation, who previously received ≥1 gemcitabine- or 
5-fluorouracil-containing regimen. 
The current European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for 
Biliary Cancer indicates that the first line setting for locally advanced or metastatic disease is a 
gemcitabine-based combination, or gemcitabine monotherapy based on the patient’s performance 
status. However, there is no standard second-line chemotherapy, or targeted therapy indicated; and 
there is no established second-line systemic therapy following progression after first-line treatment 
(Valle 2016). 
Additionally, a Phase 3 study of AG-120 (IDH1 inhibitor) in patients with cholangiocarcinoma 
harboring mutant IDH1 (mIDH1) conducted in the United States (US) and European Union (EU) 
(NCT02989857), supports the use of an IDH inhibitor in the proposed setting. This study enrolled 
patients with documented disease progression following at least 1 and no more than 2 prior 
systemic regimens for advanced disease and must have received at least 1 gemcitabine- or 
5-fluorouracil (FU) containing regimen. Patients in this study achieved a statistically significant 
improvement in median progression-free survival (PFS) over placebo (2.7 months versus 
1.4 months; hazard ratio [HR] 0.37; 95% confidence interval [CI] 0.25-0.54; p<0.0001). Treatment 
with AG-120 was well tolerated, and no treatment-related deaths occurred (Abou-Alfa 2020). 
Cohort B: Chondrosarcoma 
This study plans to enroll subjects with locally advanced or metastatic skeletal chondrosarcoma.  
The current ESMO Clinical Practice Guidelines for bone sarcomas indicate that primary bone 
tumors are rare, and account for <0.2% of malignant neoplasms registered in the EUROCARE 
database. Given the rarity of the disease and the complexity of management, the accepted standard 
for bone sarcomas is treatment at reference centers and/or within reference networks able to 
provide access to the full spectrum of care and age-specific expertise. In these centers/networks, 
therapy is either clinical studies or locally established treatment protocols. Standard treatment 
practices can vary from center-to-center, and can further vary based on the disease subtype, and 
patient characteristics (Casali 2018). 
Despite the lack of clear treatment options for these patients, there is emerging data for IDH 
inhibitors for the treatment of patients with chondrosarcomas harboring IDH mutations. An 
ongoing Phase 1 study of AG-120 (IDH1 inhibitor) enrolled 21 patients with locally advanced or 
metastatic chondrosarcoma harboring mIDH1. Among the 21 patients enrolled, 11 patients 
(52.4%) received prior systemic therapy. Patients achieved a median PFS of 5.6 months (95% CI, 
1.9 to 7.4 months); the PFS rate at 6 months was 39.5%, and 11 patients (52.4%) experienced 
stable disease. AG 120 also showed minimal toxicity and durable disease control (Tap 2020). 
Cohort C: Glioma 
This study plans to enroll subjects with recurrent Grade 2 gliomas that are not a candidate for 
clinical resection. 
Isocitrate dehydrogenase mutations are highly prevalent in patients with low-grade glioma, 
occurring in up to approximately 80% of all cases. However, given the toxicities associated with 

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chemotherapy and radiation, there remains a significant unmet need to improve treatment options 
for patients living with IDH mutant gliomas. Standard treatment consists of resection, followed by 
radiation and chemotherapy. Treatment is not curative and current therapy is associated with short- 
and long-term toxicity. Upon recurrence, due to heterogeneity of disease, there is no one standard 
treatment regimen. Both EU and US guidelines recommend repeat surgery, alkylating 
chemotherapy re-irradiation, or experimental therapy (Weller 2021; NCCN 2020). 
In accordance with the treatment guidelines, a recent study of AG-881, a dual IDH1/2 inhibitor, 
enrolled patients with gliomas (enhancing or non-enhancing disease) who have recurred or 
progressed following standard therapy OR have previously untreated disease (NCT02481154). 
This study enrolled 22 non-enhancing glioma patients, who had a median of 2 prior lines of 
treatment (range: 1-4). An objective response rate (ORR) of 13.6% was achieved, and 77.3% of 
patients achieved stable disease. At 24 months, 60.5% of patients were still alive, and progression 
free (Mellinghoff 2020). These study results showed encouraging preliminary activity with 
prolonged disease control, and reduced growth of non-enhancing tumors that warrants further 
exploration of IDH1/2 inhibitors in an underserved patient population. 
Cohort D: Other Solid Tumors with an IDH1/2 Mutation 
This study plans to enroll subjects with any other locally advanced or metastatic solid tumor 
harboring an IDH mutation that has progressed on at least 1 line of prior therapy. 
Therapies for patients with locally advanced or metastatic solid tumors are palliative and not 
curative. Therefore, there is an unmet medical need for additional therapies. While IDH1/2 
mutations are most commonly observed in diseases covered by cohorts A to C of the proposed 
clinical study, these mutations are also found less commonly in other solid tumors. In the absence 
of approved therapies targeting IDH mutations, solid tumors harboring IDH mutations are treated 
with standard of care agents according to anatomical site, such as cytotoxic chemotherapy that is 
not tailored to the characteristics of individual patient’s tumor. As a result, patients receive 
therapies that may not be of benefit, while exposed to potential toxicities. Cohort D will provide 
an additional treatment option for patients who have incurable malignancies. The requirement of 
at least one prior therapy should ensure patients do not forego significantly effective palliative 
therapy in lieu of the proposed investigational agent (HMPL-306), but rather have an opportunity 
to explore a new potential treatment tailored to their tumor characteristic. Furthermore, there is no 
limit to the number of prior therapies (with the exception of IDH1/2 inhibitors) for a patient to 
qualify. Lastly, study participants may receive additional approved therapies should they exist after 
participation on the proposed clinical study. 

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APPENDIX 12 
AMENDMENT HISTORY  
Amendment 1 (29 October 2020) Summary 
Section Number 
Summary of Change 
Rationale for Change 
Section 4.1.1 - Part 1 (Dose 
Escalation) 
Table 6 mTPI-2 Decision Table for 
Dose Selection 
• 
Revised DLT rate to 25% 
and subsequent changes to 
DLT/cohort parameters 
• 
Specified minimum of 3 
patients per cohort at each 
dose level 
• 
Updated mTPI-2 table to 
reflect DLT rate of 25% 
Request by FDA 
Section 7.4.3 - Dose Adjustment for 
QT Interval Prolongation 
Deleted provision for allowing 
intra-subject dose escalation 
Request by FDA 
Section 8.1.3 - Dose-Limiting 
Toxicity 
Revised DLTs to: 
• 
Exclude non-hematologic 
AEs that recover to 
Grade ≤1 or lower within 
3 days after supportive 
therapy is administered for 
nausea, vomiting, diarrhea, 
constipation, fatigue, and 
electrolyte imbalance 
• 
Include any Grade 4 
neutropenia 
• 
Include Grade 3 
thrombocytopenia 
accompanied with 
clinically significant 
bleeding, in addition to 
that requiring transfusion. 
Request by FDA 
Section 6.1.9 - Ophthalmologic 
Assessments 
Section 1.3 - Schedule of Events 
• 
Revised ophthalmologic 
assessments to include 
optical coherence 
tomography as part of the 
routing ocular monitoring 
• 
Revised ophthalmologic 
assessments to include an 
OCT assessment at 
6 weeks 
Request by FDA 
Section 5.2 - Inclusion Criteria 
• 
Revised inclusion 
criterion #9 to only allow 
patients to be eligible after 
all toxicities are recovered 
to at least Grade 1 from 
any prior therapy  
• 
Revised inclusion 
criterion #14 to specify 
tumor tissue samples must 
be used for IDH mutation 
determination 
Request by FDA 

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• 
Revised inclusion 
criterion #16 to specify 
that only validated NGS of 
tumor tissue is permitted 
for documentation of IDH 
mutation for Part 2 
eligibility 
Section 7.4.2 - Dose Adjustment 
Outside the DLT Assessment 
Window (Including Dose 
Expansion Part) 
• 
Added Table 7 - Dose 
Adjustment for 
Hematologic Toxicity 
• 
Added Table 8 - Dose 
Adjustment for Non-
hematologic Toxicity 
Request by FDA 
 
Table 3 Summary of Potential 
Risks of HMPL-306 
Added potential Risk of QTc 
interval prolongation 
Request by FDA 
Section 6.1.10.10 - IDH Mutational 
Status 
Added in collection of information 
on IDH mutational test 
methodology for patients in Part 1. 
Request by FDA 
 
Section 7.4.3 - Dose Adjustment for 
QT Interval Prolongation 
Added Table 9 - Dose Adjustment 
for QT Interval Prolongation  
Request by FDA 
Table 5 Subject Dose Grouping 
(Dose Escalation Plan) 
Deleted specification that subjects 
in dose escalation will receive 1 
single dose of HMPL-306, 7 days 
prior to C1D1 
Correct an error 
Section 5.3 - Exclusion Criteria #10 
Lowered the exclusion criteria heart 
rate-corrected QT (QTc) interval 
from >480 ms to ≥470 ms  
Recommendation by FDA 
 

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