A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HMPL-523 in Patients With Relapsed or Refractory Lymphoma
Phase: PHASE1
Conditions: Non Hodgkin Lymphoma
Sponsor: Hutchmed

Clinical Study Protocol 2018-523-00US1 
HMPL-523 
Amendment 5 
HUTCHMED Limited 
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A Phase I, Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Preliminary 
Efficacy of HMPL-523 in Patients with Relapsed or 
Refractory Lymphoma 
Investigational Product(s) 
HMPL-523 
 Tablets 
Protocol Number 
2018-523-00US1 
Clinical Phase 
Phase I 
Amendment 
5 
Sponsor 
HUTCHMED Limited 
Building 4, 720 Cailun Road 
China (Shanghai) Pilot Free Trade Zone 
Shanghai, China, 201203 
Clinical Trial Registry Identifiers 
ClinicalTrials.gov Identifier: NCT03779113 
EudraCT Identifier: 2018-004807-38  
EU (CTIS) Study Number: 2024-515123-11-00 
IND Number: 129706 
Issue Date 
14 June 2024 
Confidentiality Statement 
The information contained in this document is confidential and is provided to you as a potential 
investigator or consultant for review by you or your designee(s) and affiliated Institutional 
Review Board (IRB) or Institutional Ethics Committee (IEC). Upon acceptance of this 
document, you agree that the information contained herein will not be disclosed to others without 
written consent from HUTCHMED Limited, except to the extent necessary in order to obtain 
approval of this protocol by an IRB or IEC. 
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STATEMENT OF COMPLIANCE  
This study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices as outlined by International Council for Harmonisation (ICH) E6(R2), and all 
applicable local and national regulatory requirements. At the final release of ICH E6(R3), this 
study shall immediately comply with the new regulation. 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 subject’s protection 
and Good Clinical Practice training as outlined by their governing institution. 
 

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SPONSOR’S APPROVAL  
Title 
A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Preliminary Efficacy of HMPL-523 in Patients with Relapsed or Refractory 
Lymphoma 
Protocol Number 
2018-523-00US1 
Amendment 
5 
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: [last name, first name] 
Title: 
  
Executive Vice President, Head of Research and 
Development, and Chief Medical Officer 
HUTCHMED International Corp. 
Signature: 
See appended signature page. 
 
Date: [DD Month YYYY] 
 
PPD

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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2018-523-00US1 
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 of 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 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 patient’s participation and all data required by the protocol 
Name [Last name, first name] 
Title [Title at institution] 
Institution [Address] 
 
 
 
Signature 
Date [DD Month YYYY] 
 
 
 

Clinical Study Protocol 2018-523-00US1 
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Amendment 5 
 
 
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DOCUMENT HISTORY  
Amendment 
Date 
Original Protocol 
11 October 2018 
1 
09 April 2020 
2 
07 August 2021 
3 
23 July 2022 
4 
12 December 2022 
5 
14 June 2024 
 

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AMENDMENT SUMMARY  
Protocol 2018-523-00US1 Amendment 5 replaces Protocol 2018-523-00US1 Amendment 4. 
Protocol Amendment 5 is considered a substantial modification based on the criteria set forth in 
Article 2, 2 (13) of Regulation (EU 536/2014) of the European Parliament and the Council of the 
European Union.  
This amendment now incorporates additional detail to facilitate transition of this study to the new 
EU Clinical Trial Regulation (EU 526/2014) and upcoming ICH E6(R3) release.  
The primary purpose of Amendment 5 is to update the “end of study” definition from 1 year after 
the last patient’s first visit to 2 years after the last patient’s first visit. This is intended to provide 
additional duration on treatment for patients who are deriving clinical benefit on HMPL-523 
treatment. The new end of study definition will be the “date on which all patients have their last 
visit or 2 years after the last patient has his/her first visit, whichever comes first.” 
This study is closed to new enrollment; the last patient was enrolled on 
 
Currently enrolled patients who are deriving clinical benefit from treatment with HMPL-523 
may continue to participate in the study as per the protocol. 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 18. 
Section Number 
Summary of Change 
Rationale for Change  
Cover Page, Sponsor’s Approval, 
Document History, Header, and 
Footer 
Administrative updates made to reflect 
Amendment 5 
The administrative updates were 
made to reflect Amendment 5.  
Section 4.1 Description of Study 
Added the following statement: “The 
start of the clinical study is defined as 
the date the study is open for 
recruitment at any site. This date was 
21-Feb-2019. The start of the clinical 
study in Europe is defined as the date 
the clinical study is open for 
recruitment at the first clinical study 
site within an EU Member State. This 
date was 05-Sep-2019.” 
To comply with necessary 
requirements for studies 
conducted in European Union 
(EU) Member States. 
 
 
Synopsis, Section 4.5 Dose 
Expansion Stage (Stage 2), Table 2 
Dose Expansion Cohorts; 
Section 7.1 Determination of 
Sample Size 
 
Language was added to indicate that as 
of Amendment 5, the study will be 
closed to new enrollment and to update 
the numbers in Table 2 to reflect the 
number of patients enrolled as of 
Amendment 4 and number continuing 
in the study as of Amendment 5. 
The sponsor has discontinued 
development of the study drug 
for lymphoma in the specific 
region and has closed the study 
for further enrollment. 
Synopsis, Section 4.6 End of Study 
Language was updated to change the 
end of study definition from 1 year to 
2 years after the last patient’s first visit. 
Patient-centric decision to 
extend the study to allow for 
additional duration of therapy. 
Section 5.1.1 Inclusion Criteria, 
Criterion #4 
Updated to include that the study is 
now closed to enrollment 
Updated to include that the 
study is now closed to 
enrollment. 
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Section Number 
Summary of Change 
Rationale for Change  
Section 5.3.5 Post-Trial Access to 
HMPL-523 
Added language to reflect the sponsor 
has discontinued development of the 
study drug for lymphoma in the 
specific region     
Updated language to reflect that 
sponsor has discontinued 
development of study drug for 
lymphoma in the specific 
region.  
Section 5.4.3 Recommendations for 
Management of Toxicity Including 
Dose Modification 
Added the following statement: 
“Approved prescribing information for 
other drugs used to treat relapsed or 
refractory lymphoma should be utilized 
to guide management of toxicities 
associated with these drugs.” 
To comply with necessary 
requirements for studies 
conducted in EU Member 
States.   
Section 5.6.2 Informed Consent 
Forms and Screening Log 
Added the following statement: “If the 
subject cannot sign the ICF (eg, due to 
an inability to read or write), 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.” 
To comply with necessary 
requirements for studies 
conducted in EU Member 
States.   
Section 5.6.9 Laboratory 
Assessments, Appendix 1 Schedule 
of Activities 
Updated language to reflect that 
leukocyte immunophenotyping will not 
be performed from Cycle 3 onwards 
To reduce patient burden. 
Section 5.6.10 Electrocardiogram, 
Appendix 1 Schedule of Activities 
Updated language to reflect that 
electrocardiograms will not be 
performed from Cycle 3 onwards 
unless clinically indicated 
To reduce patient burden. 
Section 5.6.12 Tumor and 
Response Evaluation 
Updated language reflecting that tumor 
assessment will be performed quarterly 
for those who discontinue the drug due 
to reasons other than disease 
progression. 
Amended to provide clarity on 
imaging assessment for these  
subject 
Section 5.8 Study/Site 
Discontinuation and Closure 
Added bullet “Sponsor decision to 
discontinue clinical development of the 
drug in the specific indication or in the 
specific region.” 
To expand on Sponsor decision 
regarding clinical development 
of study drug.  
Section 5.9.1 Collection Schedule, 
Appendix 3 Pharmacokinetics and 
Pharmacodynamics Sampling Time 
Points (Dose Expansion Stage) 
Pharmacokinetic 
(PK)/pharmacodynamic collection 
schedule updated to reflect that as of 
Amendment 5, PK samples for 
measurement of plasma concentrations 
To reduce patient burden. 

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Section Number 
Summary of Change 
Rationale for Change  
of HMPL-523 and 
 will not 
be collected on Cycle 5 Day 1 and 
beyond in the dose expansion stage. 
Also, dose modification language was 
removed. 
Section 6.2.2 Serious Adverse 
Events 
Added paragraph “All SAEs will be 
followed until resolution, stabilization, 
event is otherwise explained, or 
participant is lost to follow-up. 
Depending on the event, follow-up 
may require additional tests or medical 
procedures as indicated and/or referral 
to a general physician or a medical 
specialist. All pregnancies that occur 
during participation in the study should 
be followed to determine the outcome 
of the pregnancy.”  
To comply with necessary 
requirements for clinical studies 
conducted in EU Member 
States.   
Section 8.2 Ethical Conduct of the 
Study 
Added EU regulation number 
536/2014 
To comply with necessary 
requirements for studies 
conducted in EU Member 
States. 
Section 9.3 Retention of Records, 
Appendix 17 (new) 
Changed required storage time of 
records from “2 years after the study is 
completed” to “25 years after the study 
is completed or longer if mandated by 
local regulatory requirements.” 
 
Added language to clarify accurate 
recording of source data and 
documents, investigator responsibility 
in recording the study, and storage at 
study site or approved storage facility.  
 
Added the following statement: 
“Subject medical files will be archived 
in accordance with national law.” 
 
Modified the following statement: 
“The Sponsor will store the study 
documentation for at least 2 years after 
the last approval of a marketing 
application in an ICH region and until 
there are no pending or contemplated 
marketing applications in an ICH 
region; at least 2 years have elapsed 
since the formal discontinuation of 
clinical development of HMPL-523; or 
at least 25 years after the end of the 
study, whichever is longer.” 
 
Added statement “It is the 
responsibility of the Sponsor to inform 
To comply with necessary 
requirements for clinical studies 
conducted in EU Member 
States.   
 
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Section Number 
Summary of Change 
Rationale for Change  
the investigator as to when these 
documents no longer need to be 
retained.” 
Section 12.2 Publication 
 
Added paragraphs:  
“Irrespective of the outcome of the 
study, the Sponsor will submit a 
summary of the results of the clinical 
study to any relevant database within 1 
year from the end of the global clinical 
study. It will be accompanied by a 
summary written in a manner that is 
understandable to laypersons. 
 
For studies conducted under 
Regulation EU 536/2014 where the 
study has ended in all Member States 
Concerned in the EU/European 
Economic Area (EEA) but is still 
ongoing in other regions and data from 
those regions are not available (making 
the statistical analysis not relevant), the 
summary of results must be submitted 
to the EU database as soon as it is 
available but no later than 1 year after 
the end of the study globally.” 
 
Added in language to document 
compliance with the legal 
requirement to report clinical 
study results. 
 
Added to represent necessary 
requirements for clinical studies 
conducted in EU Member 
States. 
 
Appendix 17 EU GDPR- and CTR-
Compliant Data Protection (New) 
Added appendix regarding the 
measures that HUTCHMED Limited 
has put into place to meet the 
requirements of the Data Protection 
Laws for EU Member States. 
Added detail regarding 
necessary requirements for 
clinical studies conducted in EU 
Member States.   

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EMERGENCY CONTACT  
Under urgent circumstances, please contact the sponsor’s medical monitor or the designee.  

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
DOCUMENT HISTORY............................................................................................................... 5 
AMENDMENT SUMMARY ........................................................................................................ 6 
EMERGENCY CONTACT ......................................................................................................... 10 
TABLE OF CONTENTS ............................................................................................................. 11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 17 
1 
PROTOCOL SYNOPSIS ................................................................................................ 21 
2 
BACKGROUND ............................................................................................................. 30 
2.1 
Current Therapies and Unmet Medical Need ............................................................... 30 
2.2 
Background on HMPL-523........................................................................................... 31 
2.2.1 
Nonclinical Pharmacology ......................................................................................... 31 
2.2.2 
Nonclinical Pharmacokinetics ................................................................................... 32 
2.2.3 
Nonclinical Toxicology ............................................................................................. 32 
2.2.4 
Clinical Experience .................................................................................................... 34 
2.3 
Study Rationale and Benefit-Risk Assessment ............................................................. 44 
2.3.1 
Study Rationale .......................................................................................................... 44 
2.3.2 
Benefit-Risk Assessment ........................................................................................... 45 
3 
OBJECTIVES .................................................................................................................. 47 
3.1 
Primary Objectives........................................................................................................ 47 
3.2 
Secondary Objectives.................................................................................................... 47 
3.3 
Exploratory Objectives ................................................................................................. 47 
4 
STUDY DESIGN............................................................................................................. 48 
4.1 
Description of Study ..................................................................................................... 48 
4.2 
Dose Escalation Stage (Stage 1) ................................................................................... 48 
4.3 
Intrapatient Dose Escalation ......................................................................................... 49 
4.4 
Definition of a Dose-Limiting Toxicity ........................................................................ 49 
4.4.1 
Dose-Limiting Toxicity Assessment Window ........................................................... 50 
4.4.2 
Definition of Dose-Limiting Toxicity Evaluable Patient ........................................... 50 
4.4.3 
Dosing Beyond Cycle 1 ............................................................................................. 50 

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4.4.4 
Definition of Maximum Tolerated Dose.................................................................... 50 
4.4.5 
Definition of Recommended Phase II Dose............................................................... 50 
4.5 
Dose Expansion Stage (Stage 2) ................................................................................... 51 
4.6 
End of Study ................................................................................................................. 51 
4.7 
Rationale for Study Design ........................................................................................... 52 
4.7.1 
Rationale for the Starting Dose and the Dose Schedule ............................................ 52 
4.7.2 
Rationale for Selection of Patient Population ............................................................ 53 
4.8 
Outcome Measures........................................................................................................ 53 
4.8.1 
Primary Safety Outcome Measure ............................................................................. 53 
4.8.2 
Secondary Safety Outcome Measures ....................................................................... 53 
4.8.3 
Pharmacokinetic Outcome Measures ......................................................................... 54 
4.8.4 
Efficacy Outcome Measures ...................................................................................... 54 
5 
MATERIALS AND METHODS ..................................................................................... 55 
5.1 
Patients .......................................................................................................................... 55 
5.1.1 
Inclusion Criteria ....................................................................................................... 55 
5.1.2 
Exclusion Criteria ...................................................................................................... 56 
5.2 
Method of Treatment Assignment ................................................................................ 58 
5.3 
Study Treatment ............................................................................................................ 58 
5.3.1 
Formulation, Packaging, and Handling ..................................................................... 58 
5.3.2 
Drug Labeling ............................................................................................................ 58 
5.3.3 
Drug Accountability................................................................................................... 59 
5.3.4 
Dosage, Administration, and Compliance ................................................................. 59 
5.3.5 
Post-Trial Access to HMPL-523 ................................................................................ 59 
5.4 
Dose Delays and Modification ...................................................................................... 60 
5.4.1 
During Dose-Limiting Toxicity Assessment Window .............................................. 60 
5.4.2 
After Dose-Limiting Toxicity Assessment Window in Stage 1 or in Stage 2 ........... 60 
5.4.3 
Recommendations for Management of Toxicity Including Dose Modification ........ 61 
5.5 
Concomitant Therapy and Food.................................................................................... 61 
5.5.1 
Permitted Therapy ...................................................................................................... 61 
5.5.2 
Prohibited Therapy and Food..................................................................................... 61 
5.6 
Study Assessments ........................................................................................................ 63 
5.6.1 
Definitions of Study Assessments ............................................................................. 63 

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5.6.2 
Informed Consent Forms and Screening Log ............................................................ 63 
5.6.3 
Medical History and Demographic Data ................................................................... 64 
5.6.4 
Concomitant Medication/Concomitant Procedure ..................................................... 64 
5.6.5 
Eastern Cooperative Oncology Group Performance Status ....................................... 64 
5.6.6 
Rai/Binet Staging, Ann Arbor Staging, and International Prognostic Index ............. 64 
5.6.7 
Vital Signs .................................................................................................................. 64 
5.6.8 
Physical Examination................................................................................................. 65 
5.6.9 
Laboratory Assessments ............................................................................................ 65 
5.6.10 
Electrocardiogram ...................................................................................................... 66 
5.6.11 
Echocardiogram/Multigated Acquisition Scan .......................................................... 67 
5.6.12 
Tumor and Response Evaluation ............................................................................... 67 
5.6.13 
Bone Marrow Aspirate and/or Biopsy ....................................................................... 67 
5.7 
Participant Completion/Discontinuation ....................................................................... 67 
5.7.1 
Study Completion/Early Termination Visit ............................................................... 67 
5.7.2 
Participant Discontinuation ........................................................................................ 68 
5.7.3 
Study Treatment Discontinuation .............................................................................. 68 
5.8 
Study/Site Discontinuation and Closure ....................................................................... 68 
5.9 
Pharmacokinetic and Pharmacodynamic Assessments ................................................. 69 
5.9.1 
Collection Schedule ................................................................................................... 69 
5.9.2 
Samples Handling and Shipment ............................................................................... 69 
5.9.3 
Analytical Procedures ................................................................................................ 69 
6 
ASSESSMENT OF SAFETY .......................................................................................... 70 
6.1 
Safety Plan .................................................................................................................... 70 
6.2 
Safety Parameters and Definitions ................................................................................ 70 
6.2.1 
Adverse Event ............................................................................................................ 70 
6.2.2 
Serious Adverse Events ............................................................................................. 70 
6.2.3 
Protocol-Defined Events of Special Interest Expedited Adverse Events .................. 71 
6.2.4 
Reporting of Dose-Limiting Toxicity ........................................................................ 71 
6.3 
Methods and Timing for Capturing and Assessing Safety Parameters ......................... 72 
6.3.1 
Adverse Event Reporting Period ............................................................................... 72 
6.3.2 
Eliciting Adverse Events............................................................................................ 72 
6.3.3 
Assessment of Severity and Causality of Adverse Events ......................................... 72 

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6.4 
Procedures for Recording Adverse Events ................................................................... 74 
6.4.1 
Diagnosis Versus Signs and Symptoms ..................................................................... 74 
6.4.2 
Adverse Events Occurring Secondary to Other Events ............................................. 74 
6.4.3 
Persistent or Recurrent Adverse Events ..................................................................... 74 
6.4.4 
Abnormal Laboratory Values .................................................................................... 74 
6.4.5 
Abnormal Liver Function Test Results ...................................................................... 75 
6.4.6 
Deaths ........................................................................................................................ 75 
6.4.7 
Preexisting Medical Conditions ................................................................................. 75 
6.4.8 
Worsening of Hematologic Malignancy .................................................................... 76 
6.4.9 
Hospitalization, Prolonged Hospitalization, or Surgery ............................................ 76 
6.4.10 
Pregnancy ................................................................................................................... 76 
6.5 
Expedited Reporting From Investigator to Sponsor ..................................................... 77 
6.5.1 
Reporting Requirements for All Serious Adverse Events and Protocol-Defined 
Events of Special Interest........................................................................................... 77 
6.5.2 
Regulatory Reporting Requirements for Serious Adverse Events ............................. 77 
6.6 
Type and Duration of Follow-up of Patients After Adverse Events ............................. 78 
6.7 
Post-Study Adverse Events ........................................................................................... 78 
7 
STATISTICAL ANALYSIS ........................................................................................... 79 
7.1 
Determination of Sample Size ...................................................................................... 79 
7.1.1 
Stage 1: Dose Escalation ............................................................................................ 79 
7.1.2 
Stage 2: Dose Expansion ........................................................................................... 79 
7.2 
Analysis Population ...................................................................................................... 79 
7.3 
Analysis Planned ........................................................................................................... 80 
7.3.1 
Demographic and Baseline Characteristics ............................................................... 80 
7.3.2 
Disposition of Patients Enrolled in the Study ............................................................ 80 
7.3.3 
Safety Analysis .......................................................................................................... 80 
7.3.4 
Pharmacokinetic Analysis .......................................................................................... 81 
7.3.5 
Efficacy Analysis ....................................................................................................... 82 
7.3.6 
Biomarker Analysis ................................................................................................... 82 
7.4 
Interim Analysis (Not Applicable)................................................................................ 82 
8 
ETHICS............................................................................................................................ 83 
8.1 
Institutional Review Board/Independent Ethics Committee......................................... 83 
8.2 
Ethical Conduct of the Study ........................................................................................ 83 

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8.3 
Patient Information and Consent .................................................................................. 83 
8.4 
Data Privacy and Confidentiality .................................................................................. 84 
9 
STUDY DOCUMENTATION, CASE REPORT FORM, AND RECORDS ................. 85 
9.1 
Source Data Documentation ......................................................................................... 85 
9.2 
Use of Computerized System........................................................................................ 85 
9.3 
Retention of Records..................................................................................................... 85 
10 
MONITORING ................................................................................................................ 87 
11 
DATA MANAGEMENT................................................................................................. 88 
11.1 
Data Quality Assurance ................................................................................................ 88 
11.2 
Electronic Case Report Forms ...................................................................................... 88 
11.3 
Coding ........................................................................................................................... 89 
12 
USE OF INFORMATION AND PUBLICATION ......................................................... 90 
12.1 
Use of Information ........................................................................................................ 90 
12.2 
Publication .................................................................................................................... 90 
13 
REFERENCES ................................................................................................................ 92 
14 
APPENDICES ................................................................................................................. 95 
LIST OF TABLES 
Table 1 
Proposed Dose Escalation Scheme ...................................................................... 49 
Table 2 
Dose Expansion Cohorts ...................................................................................... 51 
Table 3  
HMPL-523 PK and Toxicokinetic Summary ...................................................... 52 
Table 4 
AEs Grading (Severity) Scale .............................................................................. 73 
Table 5 
Causality Attribution Guidance ........................................................................... 73 
Table 6 
Dose Modification/Toxicity Management Recommendations for 
Pulmonary Toxicities (Including Pneumonia/Pneumonitis) .............................. 123 
Table 7 
Dose Modification/Toxicity Management Recommendations for GI 
Toxicities............................................................................................................ 126 
Table 8 
Dose Modification/Toxicity Management Recommendations for Hepatic 
Adverse Events .................................................................................................. 128 
Table 9 
Dose Modification/Toxicity Management Recommendations for Infection ..... 129 
Table 10 
Dose Modification/Toxicity Management Recommendations for 
Neutropenia ........................................................................................................ 131 
Table 11 
Dose Modification/Toxicity Management Recommendations for 
Thrombocytopenia ............................................................................................. 132 
Table 12 
Dose Modification/Toxicity Management Recommendations for Anemia ....... 133 

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Table 13 
Dose Modification/Toxicity Management Recommendations for Rash and 
Cutaneous Skin Reactions.................................................................................. 134 
Table 14 
Dose Modification/Toxicity Management Recommendations for 
Nausea/Vomiting ............................................................................................... 135 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities .......................................................................................... 96 
Appendix 2 
PK Sampling Time Points (Once Daily) (Dose Escalation Stage)d ................... 100 
Appendix 3 
PK and Pharmacodynamics Sampling Time Points (Dose Expansion 
Stage)e ................................................................................................................ 101 
Appendix 4 
International Workshop on Chronic Lymphocytic Leukemia Update of the 
National Cancer Institute-Working Group Guidelines: Response Criteria ........ 102 
Appendix 5 
Consensus-Based Uniform Response Criteria for Waldenström’s 
Macroglobulinemia ............................................................................................ 105 
Appendix 6 
Lugano Response Criteria for Hodgkin and Non-Hodgkin’s Lymphoma ......... 106 
Appendix 7 
Lists of Prohibited Drugs and Those That Should Be Used with Caution ........ 109 
Appendix 8 
Eastern Cooperative Oncology Group Performance Status ............................... 112 
Appendix 9 
Rai Staging System for Chronic Lymphoid Leukemia ...................................... 113 
Appendix 10 Binet Staging System for Chronic Lymphocytic Leukemia .............................. 114 
Appendix 11 Ann Arbor Classification ................................................................................... 115 
Appendix 12 International Prognostic Index ........................................................................... 116 
Appendix 13 Clinical Evaluation of Possible Drug-Induced Liver Injury .............................. 118 
Appendix 14 
 ............................................................................................................ 120 
Appendix 15 Recommendations for Management of Toxicity Including Dose 
Modification ....................................................................................................... 122 
Appendix 16 Prohibited Concomitant Medications That Have A Known Risk Of Qt 
Prolongation And/Or Torsades De Pointes (Tdp) .............................................. 136 
Appendix 17 European Union General Data Protection Regulation- and Clinical Trial 
Regulation-Compliant Data Protection .............................................................. 139 
Appendix 18 Amendment History ........................................................................................... 142 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
β-HCG 
beta human chorionic gonadotropin 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AR 
accumulation ratio 
ARH-77 
cell type derived from the peripheral blood of a patient with IgG 
plasma cell leukemia 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve  
AUC0-t 
area under the concentration-time curve in a selected time interval 
AUCtau 
area under the drug concentration-time curve over the dose interval 
AUCtau,ss 
area under the drug concentration-time curve over the dose interval at 
steady state  
BCL-2 
B-cell lymphoma-2 
BCR 
B-cell receptor 
BCRP 
breast cancer resistance protein 
BID 
twice daily (or 2 times a day) 
BLNK 
B-cell linker protein 
BOR 
best overall response 
B-NHL 
B-cell non-Hodgkin’s lymphoma 
BTK 
Bruton’s tyrosine kinase 
CBCL 
cutaneous B-cell lymphoma 
CCL 
chemokine (C-C motif) ligand 
CL 
clearance 
CL/F 
apparent clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum plasma concentration 
Cmax,ss 
maximum plasma concentration at steady state 
Cmin 
minimum plasma concentration 
CMV 
cytomegalovirus 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRi 
complete response incomplete marrow recovery 
CrCl 
creatinine clearance (estimated per Cockcroft-Gault) 
CRF 
Case Report Form 

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Abbreviation 
Definition 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 enzyme 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EEAS 
efficacy evaluable analysis set 
EU 
European Union 
EUA 
Emergency Use Authorized 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FL 
follicular lymphoma 
GLP 
Good Laboratory Practice 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HL 
Hodgkin’s lymphoma 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
the concentration of a drug that is required for 50% inhibition in vitro 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgM 
immunoglobulin M 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
IRC 
independent review committee 
ITP 
immune thrombocytopenia 
IPI 
International Prognostic Index 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 

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Abbreviation 
Definition 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LPL 
lymphoplasmacytic lymphoma 
MATE 
multidrug and toxin extrusion 
MCL 
mantle cell lymphoma 
mDoR 
median duration of response 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MRP2 
multidrug resistance protein 
MTD 
maximum tolerated dose  
MUGA 
multigated acquisition scan 
MZL 
marginal zone lymphoma 
NC 
not calculable 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
NOAEL 
No-Observed-Adverse-Effect Level 
nPR 
nodular partial response 
OATP 
organic anion transporter protein 
ORR 
objective response rate 
PCR 
polymerase chain reaction  
PD 
progressive disease 
PD1 
programmed cell death protein 1 
PFS 
progression free survival 
PKAS 
pharmacokinetics analysis set 
PI3K 
phosphoinositide3’-kinase 
PI3K 
phosphoinositide 3’-kinase  
P-gp  
p-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
partial response 
PR-L 
partial response with lymphocytosis 
PT 
preferred term 
PTCL 
peripheral T-cell lymphoma 
QD 
once a day (from the Latin quaque die) 
QTcF 
corrected QT interval with Fridericia 
REC-1 
cell type derived from the mantle cell lymphoma 
RES 
response evaluable set 
RNA 
ribonucleic acid 
CCI

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Abbreviation 
Definition 
RP2D 
recommended Phase II dose 
SAE 
serious adverse event 
SD 
stable disease 
SDV 
source data verification 
SLL 
small lymphocytic lymphoma 
SRC 
Safety Review Committee 
SYK or Syk 
spleen tyrosine kinase 
t1/2 
terminal half-life time 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum plasma concentration 
TTP 
time to tumor progression 
TTR 
time to response  
ULN 
upper limit of normal 
US 
United States  
Vss 
volume of distribution at steady state 
WM 
Waldenström’s macroglobulinemia 
 

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1 
PROTOCOL SYNOPSIS  
Protocol Number 
2018-523-00US1 
Title 
A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of HMPL-523 in Patients with 
Relapsed or Refractory Lymphoma 
Study Phase 
Phase I 
Sponsor 
HUTCHMED Limited 
Study Drug 
HMPL-523 
 Tablets (from herein referred to as “HMPL-523”) 
Planned Enrollment 
Approximately 131-155 patients were planned to be enrolled.  
As of Amendment 5, 48 patients have been enrolled, with 3 patients currently 
receiving treatment in the study.  
Study Duration 
Approximately 58 months 
Estimated duration for the entire study from screening period, through treatment 
period, and until the last subject completes treatment. 
Study Status as of 
Protocol Amendment 5  
The study is closed to new enrollment; the last patient was enrolled on 
 As of Amendment 5, 3 patients are receiving treatment in the 
study. 
Study Objectives 
Primary objectives: 
• 
To evaluate the safety and tolerability of HMPL-523 in patients with 
relapsed or refractory lymphoma in the dose escalation stage 
• 
To determine the maximum tolerated dose (MTD)/recommended Phase 
II dose (RP2D) and characterize the dose-limiting toxicities (DLTs) 
associated with HMPL-523 in patients with relapsed or refractory 
lymphoma in the dose escalation stage 
• 
To evaluate the preliminary efficacy of HMPL-523 in patients with 
relapsed or refractory lymphoma in the dose expansion stage 
Secondary objectives: 
• 
To characterize the pharmacokinetics (PK) properties of HMPL-523 in 
patients with relapsed or refractory lymphoma in the dose escalation 
stage and the dose expansion stage 
• 
To evaluate the safety and tolerability of HMPL-523 at the MTD/RP2D 
in patients with relapsed or refractory lymphoma in the dose expansion 
stage 
• 
To evaluate the preliminary efficacy of HMPL-523 in patients with 
relapsed or refractory lymphoma in the dose escalation stage 
Exploratory objectives: 
• 
To evaluate the PK properties of 
 HMPL-523 in 
patients with relapsed or refractory lymphoma in the dose escalation and 
dose expansion stages 
• 
To explore biomarkers for progressive disease, predictive, and others 
(not exhaustive), including antitumor activities of HMPL-523 
Study Design 
This is a Phase I, open-label, multicenter study of HMPL-523 administered orally 
to patients with relapsed or refractory lymphoma who have exhausted approved 
therapy options as described in Section 4.1. 
This study consists of a dose escalation stage (Stage 1) and a dose expansion stage 
(Stage 2). 
 
CCI
CCI
CCI

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Dose Escalation Stage (Stage 1) 
Dosing will begin at 100 mg orally, once daily (QD). A cycle of study treatment 
will be defined as 28 days of continuous dosing. 
The modified 3+3 design will be applied for dose escalation and MTD 
determination to limit the number of patients being exposed to potentially 
ineffective or unsafe doses. The study will enroll 1 patient, and the patient will be 
treated for a 28-day cycle in the initial dose cohort. If there is no DLT and no 
more than 2 treatment-emergent adverse events (TEAEs) of Common 
Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 in the first 
treatment cycle, the study will be escalated to the next dose cohort and continue 
with the standard 3+3 design. Otherwise, the trial will revert to a standard 3+3 
design from the initial dose cohort.  
A minimum of 3 patients will be enrolled in each cohort dose level and observed 
for toxicity in each successive dose cohort after the initial dose cohort. If the 
3 patients initially enrolled in a given dose cohort complete the DLT assessment 
window (Cycle 1, Days 1-28, = C1D1-C1D28) without experiencing a DLT, 
3 patients will be enrolled at the next higher dose level. If 2 or more of the initial 
3 patients enrolled at any dose level experience a DLT during the DLT assessment 
window, the dose escalation will be halted. If 1 of the initial 3 patients enrolled at 
any dose level experiences a DLT during the DLT assessment window, additional 
patients will be enrolled at that dose level for a minimum of 6 evaluable patients 
for DLT. If a DLT is observed in 1 of the 6 evaluable patients at this dose level, 
dose escalation will proceed to the next pre-defined dose level. If DLTs are 
observed in 2 or more of the 6 evaluable patients at a given dose level, the dose 
escalation will be halted. If the dose escalation is completed due to 2 or more 
DLTs at a dose level and that dose level is ≥ 50% higher than the previous dose 
level, then an intermediate dose level may be evaluated for toxicity in the same 
manner as described above. If the dose level is < 50% higher than the previous 
dose level, in which only 3 DLT evaluable patients were enrolled, 3 additional 
patients will be enrolled at that dose level to comprise 6 DLT evaluable patients.  
The proposed dose escalation scheme comprises Cohorts 1 to 5 with oral dosing 
levels of 100 mg QD, 200 mg QD, 400 mg QD, 600 mg QD, and 800 mg QD, 
respectively. 
The need for dose escalation to a specific dose beyond 800 mg QD, or 
de-escalation to 700 mg QD will be evaluated jointly by the investigators and the 
sponsor based on the cumulative clinical safety, pharmacokinetic, and preliminary 
efficacy data.  
Safety monitoring and evaluation of dose escalation will be carried out by the 
Safety Review Committee (SRC), which will be comprised of the sponsor’s study 
team members (including medical monitor, safety monitor and others as may be 
deemed necessary), and the sites’ principal investigators. The SRC will determine 
whether it is safe to continue the assigned HMPL-523 dose for dose escalation or 
whether the dose should be de-escalated to the lower dose level. 
 
Definition of Dose-Limiting Toxicity  
DLT is defined as the occurrence of any of the following TEAEs during the DLT 
assessment window (C1D1-C1D28), unless clearly unrelated to the study drug:  
a. 
Nonhematologic toxicity: All nonhematologic TEAEs of Grade 3 or 
greater with the exception of:  
• 
Grade 3 nausea, vomiting controlled by supportive therapy  
b. Hematologic toxicity: 
• 
Grade 4 neutropenia lasting more than 5 days 

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• 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or 
any requirement for platelets transfusion 
• 
Grade 3 or greater febrile neutropenia (defined as absolute neutrophil count 
(ANC) < 1000/mm3 with a single temperature of > 38.3℃ (101℉) or a 
sustained temperature of ≥ 38℃ (100.4℉) for more than one hour 
• 
Grade 4 anemia unexplained by underlying disease  
c. 
Any TEAE requiring a dose delay of ≥ 15 days 
d. Any case of Hy’s Law 
 
Dose-Limiting Toxicity Assessment Window 
For all patients in Stage 1, dose escalation, DLTs will be assessed during the DLT 
assessment window of 28 days (ie, from Cycle 1 Day 1 [the day of first 
administration of treatment] through to Cycle 1 Day 28). 
 
Definition of DLT Evaluable Patient 
For decisions on dose escalation, each dose cohort shall present protocol-required 
number of DLT-evaluable patients. A patient 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 
Patients who are not DLT evaluable in a dose cohort will be replaced to guarantee 
the protocol required number of DLT evaluable patients for dose escalation 
evaluations. 
 
Dosing Beyond Cycle 1 
Patients who complete the DLT assessment window (Cycle 1 Days 1-28) and are 
deemed by the investigator to be benefiting from HMPL-523 treatment may 
continue with HMPL-523 treatment until disease progression, intolerable toxicity, 
at the investigator’s discretion that the patient can no longer benefit from the study 
treatment, patient withdrawal from the study, the end of study, or death, 
whichever comes first. 
 
Definition of MTD 
The MTD is defined as the maximum dose at which no more than 16.7% of 
patients in a single cohort experiences a DLT in the first cycle (Cycle 1 
Days 1-28).  
 
Definition of RP2D 
The decision regarding the RP2D took the following into consideration: 
• 
Maximum tolerated dose if reached 
• 
Pharmacokinetics with or without associated safety and preliminary 
efficacy findings 
These criteria constituted the basis for RP2D determination. Both the sponsor and 
the investigators agreed upon the RP2D. 
Based on evaluation of data collected during the dose escalation phase, the RP2D 
has been determined to be 700 mg once daily. 
 

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Dose Expansion Stage (Stage 2) 
The safety, tolerability, PK, and preliminary efficacy of HMPL-523 at 
MTD/RP2D, which has been determined to be 700 mg once daily, will be further 
evaluated in patients with relapsed or refractory non-Hodgkin’s and Hodgkin’s 
lymphomas.  
 
Amendment 5 
As of 
 no new patients were enrolled in the study. The study is 
now closed to enrollment. A total of 48 patients were enrolled in the dose-
expansion portion at the time of enrollment closure. At the time of Amendment 5, 
approximately 3 patients are continuing study treatment.  
 
Safety Monitoring 
In addition to periodic safety review by the SRC for dose escalation decisions, 
routine safety monitoring for all enrolled patients will be carried out by the 
investigators and the sponsor after informed consent has been obtained until 
30 days following the last treatment dose or study discontinuation/termination, 
whichever is later. After this period, investigators should report only serious 
adverse events (SAEs) that are related to prior HMPL-523 treatment. All adverse 
events (AEs) will be graded in accordance with the National Cancer Institute 
(NCI) CTCAE version 5.0.  
 
Tumor Assessment 
Tumor response will be assessed by investigators according to the response 
criteria for the respective diseases every 8 weeks (±7 days), for the first 24 weeks, 
and every 12 weeks (±7 days) thereafter. 
Tumor assessment will also be conducted at study completion or at early 
termination visit (for reasons other than disease progression). 
 
Follow-up (Extended Monitoring) 
Patients who discontinue the study drug due to reasons other than disease 
progression will remain on the study and will be followed quarterly for tumor 
assessment until the patient has the first progression, starts new anticancer 
therapy, or dies or until 12 months after the initial dose of the study drug, 
whichever comes first. 
 
End of Study 
The end of the study is defined as the date on which all patients have their last 
visit or 2 years after the last patient has his/her first visit, whichever comes first.  
Study Treatment 
HMPL-523 is in tablet formulation, orally administered daily by patients. 
Inclusion Criteria  
Patients must meet the following criteria to be eligible for study entry: 
1. Signed informed consent form 
2. Age ≥ 18 years 
3. Eastern Cooperative Oncology Group performance status of 0 or 1 
4. Histologically confirmed lymphoma, including Hodgkin’s lymphoma and 
non-Hodgkin’s lymphoma. 
In the dose expansion stage, the tumor types may be restricted to any or all 
of the following tumor types. There may be approximately 10 patients in 
each cohort depending on response signals suggesting efficacy, except for 
HL cohort with 25 patients and 2 identified cohorts with approximately 
20 patients per cohort: relapsed or refractory chronic lymphocytic leukemia 
CCI

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(CLL)/ small lymphocytic lymphoma (SLL) (n = 10), and CLL/SLL 
post-Bruton’s tyrosine kinase (BTK) exposure (n = 20), mantel cell 
lymphoma (MCL), follicular lymphoma (FL) (Grade 1-3a) (n = 20), 
marginal zone lymphoma (MZL), Waldenström’s macroglobulinemia/ 
lymphoplasmacytic lymphoma (WM/LPL), peripheral T-cell lymphoma 
(PTCL), and cutaneous B-cell lymphoma (CBCL). 
As of Amendment 5, the study is closed to new enrollment. 
5. Patients with relapsed or refractory lymphoma who have exhausted all 
approved therapy options as defined below: 
a. 
Refractory to any prior regimen, defined as no response (complete 
response [CR] or partial response [PR]) to previous therapies, or 
progression within 6 months of completion of the last dose of prior 
therapy 
b. Those who can no longer tolerate/withstand cytotoxic chemotherapy 
and/or available standard of treatment/care. Where safety profile and 
risks of toxicity of other treatment options far outweigh any possible 
clinical benefit 
c. 
Those with no curative standard of treatment or where available 
treatments are not reasonable or do not make sense. In particular, those 
who, in the opinion of the attending principal investigator, will benefit 
from a new class of compound with a different mechanism of action 
d. Patients enrolled in the post-BTK CLL cohort should have either disease 
progression or intolerance to prior BTK inhibitor therapy to enroll. 
Approximately 10 out of the 20 patients in this cohort should also have 
either disease progression or intolerance to prior B-cell lymphoma-2 
(BCL-2) (venetoclax or BCL-2 inhibitor on clinical trial) exposure. 
6. In the dose expansion stage, patients must have measurable disease for an 
objective response assessment, except for patients with CLL and WM/LPL  
NOTE: measurable disease with FL, MCL, MZL, PTCL, CBCL, HL, or 
SLL defined as at least 1 bi-dimensionally measurable lesion (nodal disease 
> 1.5 cm, non-nodal disease > 1 cm in its longest dimension by computed 
tomography scan) 
7. Availability of tumor sample for patients in dose expansion cohorts: This 
may be an archival tissue sample obtained after most recent therapy or a 
fresh biopsy; if tumor sample is not available, the sponsor may waive the 
requirement after discussion 
8. Expected survival of more than 24 weeks as determined by the investigator 
9. Patients with prior treatment with any spleen tyrosine kinase (SYK) 
inhibitors (eg, fostamatinib) are eligible for escalation stage 1. However, 
during expansion stage 2, only patients who discontinue SYK inhibitors for 
reasons other than disease progression are eligible 
10. Male patients must agree to use a condom and female patients of 
child-bearing potential must agree to use highly effective contraceptive 
measures for 30 days after the last dose of study drug. These highly effective 
contraceptive measures, as defined by the Clinical Trials Facilitation Group, 
include as combined hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, and transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, and 
implantable), intrauterine contraceptive device, intrauterine hormone release 
system, bilateral tubal occlusion, or a vasectomized partner, provided that 
male partner is the sole sexual partner of the female patient. Postmenopausal 
females (women who have not had menses for at least 1 year without an 
alternative medical cause) are exempt from this criterion. 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 

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1. 
Patients with primary central nervous system lymphoma 
2. 
Any of the following laboratory abnormalities: 
a. 
Absolute neutrophil count < 1.0 × 109/L  
b. 
Hemoglobin < 80 g/L 
c. 
Platelets < 50 × 109/L  
NOTE: In the dose expansion stage, patients with cell counts below the 
thresholds listed above may be considered eligible if, in the investigator’s 
opinion, the reason is believed to be splenic involvement or bone marrow 
infiltration. The investigator will discuss the eligibility of such patients with 
the sponsor, and only upon approval (confirmed in writing) by the sponsor 
will a patient with cell counts below the thresholds be enrolled in the study. 
In the dose expansion stage, patients with Grade ≤ 2 neutropenia per CTCAE 
v5.0 and/or thrombocytopenia and with confirmed splenic involvement or 
bone marrow infiltration are eligible. 
3. 
Inadequate organ function, defined by the following: 
a. 
Total bilirubin  1.5 times the upper limit of normal (× ULN) with the 
following exception: 
• 
Patients with known Gilbert’s disease who have serum bilirubin 
level ≤ 3  ULN and normal aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) may be enrolled. 
b. 
AST and/or ALT  2.5  ULN with the following exception: 
• 
In the dose expansion stage, patients with documented disease 
infiltration of the liver may have AST and ALT levels ≤ 5  ULN. 
c. 
Estimated creatinine clearance (CrCl) per Cockcroft-Gault 
• 
Dose escalation portion of trial (Stage 1) CrCl < 40 mL/min 
• 
Dose expansion portion of trial (Stage 2) CrCl < 30 mL/min 
d. 
Serum amylase or lipase > ULN 
e. 
International normalized ratio 1.5  ULN or activated partial 
thromboplastin time  1.5  ULN 
NOTE: Patients may be considered for the study if kidney function is 
impaired, but this impairment is believed to be a result of the patient’s 
underlying disease. The investigator will discuss the eligibility of such 
patients with the sponsor, and only upon approval (confirmed in 
writing) by the sponsor will a patient with impaired kidney function 
due to underlying disease be enrolled in the study. 
4. 
Patients with clinically detectable second primary malignant tumors at 
enrollment or other malignant tumors within the last 2 years (with the 
exception of radically treated basal cell or squamous cell carcinoma of the 
skin, in situ cervix, or in situ breast cancer) 
5. 
Any anticancer therapy, including chemotherapy, hormonal therapy, biologic 
therapy, vaccine, or radiotherapy, within 3 weeks prior to initiation of study 
treatment  
6. 
Herbal therapy within 1 week prior to the initiation of study treatment 
(3 weeks for St. John’s wort) 
7. 
Prior administration of radioimmunotherapy within 3 months before the 
initiation of study treatment 
8. 
Use of strong cytochrome P450 enzyme (CYP)3A4 inhibitors or inducers 
and substrates of CYP3A4, CYP2B6, or CYP1A2, which are identified as 
narrow therapeutic drugs, within 14 days prior to the initiation of study 
treatment  

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9. 
Adverse events from prior anticancer therapy that have not resolved to Grade 
≤1, except for alopecia 
10. Prior autologous stem cell transplant within 6 months prior to the initiation 
of study treatment  
11. Prior allogeneic stem cell transplant within 6 months prior to the initiation of 
study treatment or with any evidence of active graft versus host disease or 
requirement for immunosuppressants within 28 days prior to the initiation of 
study treatment 
12. Clinically significant active infection (eg, pneumonia) and interstitial lung 
diseases 
13. Major surgical procedure within 4 weeks prior to the initiation of study 
treatment 
14. Clinically significant history of liver disease, including cirrhosis, current 
alcohol abuse, or current known active infection with human 
immunodeficiency virus, hepatitis B virus (HBV), hepatitis C virus (HCV), 
or cytomegalovirus (CMV) 
– 
Active infection is defined as one requiring treatment with antiviral 
therapy or presence of positive test results for hepatitis B (hepatitis 
B surface antigen and/or total hepatitis B core antibody [HBcAb]) 
or HCV antibody. 
– 
Patients who are positive for HBcAb are eligible only if test results 
are also positive for hepatitis B surface antibody and polymerase 
chain reaction is negative for HBV deoxyribonucleic acid. 
– 
Patients who are positive for HCV serology are only eligible if test 
result for HCV ribonucleic acid is negative. 
– 
CMV antibody will be tested at screening, and if positive, viral load 
will be determined. Patients who are positive for CMV antibody are 
only eligible if the test result for CMV DNA is negative.  
15. Pregnant (positive serum beta human chorionic gonadotropin [β-HCG] or 
urine test) or lactating women 
16. New York Heart Association Class II or greater congestive heart failure 
17. Congenital long QT syndrome or corrected QT interval with Fridericia 
> 480 msec 
18. Current use of medication known to cause QT prolongation or Torsades de 
Pointes  
19. History of myocardial infarction or unstable angina within 6 months prior to 
the initiation of the study treatment 
20. History of stroke or transient ischemic attack within 6 months prior to the 
initiation of the study treatment 
21. Inability to take oral medication, prior surgical procedures affecting 
absorption, or active peptic ulcer disease 
22. Treatment in a clinical study within 30 days prior to the initiation of study 
treatment 
23. Ongoing psychiatric disorder, in particular, patients with depression and/or 
suicidal tendencies 
24. Patients with pathological or organic fractures, in particular, those of 
unknown etiology 
25. Any other diseases, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that, in the investigator’s opinion, gives 
reasonable suspicion of a disease or condition that contraindicates the use of 
an investigational drug, may affect the interpretation of the results, or 
renders the patient at high risk from treatment complications 

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Outcome Measures 
Safety Assessment 
Parameter  
Primary safety outcome measure:  
• 
Incidence of DLTs by NCI CTCAE v5.0 grade and associated dose of 
HMPL-523  
Secondary safety outcome measures:  
• 
Incidence of TEAEs by NCI CTCAE v5.0 grade and associated dose of 
HMPL-523  
• 
Incidence of Grade 3 and 4 abnormalities in safety related-laboratory 
parameters and associated dose of HMPL-523  
• 
Incidence of TEAEs leading to HMPL-523 dose interruption, reduction, 
or treatment discontinuation 
Pharmacokinetic 
Assessment Parameter  
Pharmacokinetic outcome measures: 
• 
Maximum plasma concentration 
• 
Time to reach maximum plasma concentration  
• 
Area under the concentration-time curve in a selected time interval 
• 
Area under the concentration-time curve during one dosing interval  
• 
Apparent clearance  
• 
Minimum plasma concentration  
• 
 drug ratio 
• 
Accumulation ratio  
Efficacy Assessment 
Parameter 
Efficacy outcome measures: 
• 
Objective response rate (ORR) is defined as the proportion of patients 
who have a best overall response (BOR) of CR or PR. The BOR in an 
individual patient is the best response recorded from the start of 
treatment until progression or the date of any further anticancer therapy, 
whichever comes first.  
• 
Duration of response (DoR) is defined as the time from when the first 
response (CR or PR) was achieved until the first documentation of 
definitive disease progression or death from any cause, whichever occurs 
first. 
• 
Time to response (TTR) is defined as the time from the date of the first 
dose of the study drug to first response (CR or PR). 
• 
Progression free survival (PFS) is defined as time from the date of the 
first dose of the study drug until the date of disease progression or death 
due to any cause. 
Efficacy in different subgroups will be evaluated according to specified 
guidelines/criteria: 
• 
Chronic lymphocytic leukemia: the modified International Workshop on 
CLL guideline (modified International Workshop on Chronic 
Lymphocytic Leukemia [IWCLL] 2008) 
• 
WM/LPL: consensus of international workshops on WM (IWWM-7 
Consensus) 
• 
Lymphomas other than CLL or WM/LPL: Lugano Response Criteria for 
Hodgkin and Non-Hodgkin’s Lymphoma. 
Statistical Methods 
Determination of Sample Size 
The study is closed to new enrollment; the last patient was enrolled on 
 The total number of patients enrolled in the dose-expansion 
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phase of the study at the time of enrollment closure is 48, with 3 patients 
continuing on treatment. 
The sample size rationale for the study prior to closing for further enrollment is 
described below. 
Stage 1: Dose Escalation 
The sample size for Stage 1 is based on the dose-escalation rules of the 3 + 3 
design. For a given AE with a true rate of 10%, 5%, or 1%, the probability of 
observing at least 1 such AE in a given cohort of 6 patients is 46.9%, 26.5%, and 
5.8%, respectively. 
Stage 2: Dose Expansion 
The planned enrollment for Stage 2 was approximately 70 patients. A total of 70 
patients will provide more robust safety data in the patient populations studied. 
For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at 
least 1 such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. 
Safety Analysis 
Data will be summarized by dose level, subtype of malignancy, and overall, as 
appropriate. The DLTs will be listed. The incidence of TEAEs, SAEs, AEs of 
special interest, and AEs leading to dose interruption, reduction, or treatment 
discontinuation will be presented by Medical Dictionary for Regulatory Activities 
System Organ Class and preferred term, by relationship to study drug, by toxicity 
grade, and by severity for each dose level, and by type of malignancy. For 
laboratory tests that are graded by NCI CTCAE v5.0 or higher, results will be 
summarized by grade. Descriptive statistics for vital signs and 12-lead 
electrocardiogram parameters will be presented by dose level and visit and also by 
type of malignancy and visit. Physical examinations findings will be listed. 
Pharmacokinetic Analysis 
A noncompartmental model analysis will be performed for plasma concentration 
data by a central laboratory using Phoenix WinNonlin. Individual and mean 
plasma concentration of HMPL-523 and 
 versus time data will be 
tabulated and presented. Descriptive statistics (n, mean, standard deviation, 
minimum, median, maximum, geometric mean, and coefficient of variation) for 
all of the relevant PK parameters of HMPL-523 and
 will be 
presented. 
Efficacy Analysis 
Data will be summarized by dose level, subtype of malignancy (when feasible), 
and overall, as appropriate. The estimated ORR and 95% confidence interval will 
be presented for each type of malignancy. Where data allows, median PFS, TTR, 
and DoR will be estimated, and the Kaplan-Meier curve will be plotted for each 
type of malignancy.  
 
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BACKGROUND  
Lymphoma is the most common hematologic malignancy caused by neoplastic proliferation of 
the normal lymphocyte and is divided into 2 types: Hodgkin’s lymphoma (HL) and 
non-Hodgkin’s lymphoma (NHL). B-cell NHL (B-NHL) are a heterogeneous group of 
lymphoproliferative disorders originating in B-lymphocytes and range from slow-growing 
indolent and incurable diseases (eg, follicular lymphoma [FL] or chronic lymphocytic leukemia 
[CLL]) with a median survival of 810 years to more aggressive lymphomas (eg, diffuse large B-
cell lymphoma [DLBCL]) with a median survival of 6 months if left untreated or long-term 
remission in more than 50% of patients with appropriate treatment. Mantle cell lymphoma 
(MCL) shares characteristics of both types, being incurable with a short remission. DLBCL is the 
most common type of NHL and accounts for approximately 30---40% of all new cases, whereas 
FL and MCL account for approximately 20-25% and 6-10% of all new cases, respectively, of 
other lymphomas.  
B-cell CLL is the most common chronic leukemia in adults in Western countries and has been 
classified as a mature B-cell malignancy according to the 2016 revision of the World Health 
Organization classification of lymphoid neoplasms (Swerdlow et al 2017). Waldenström’s 
macroglobulinemia (WM, also known as lymphoplasmacytic lymphoma [LPL]) is another 
indolent B-cell lymphoma that occurs in less than 2% of patients with NHL. A unique 
characteristic of the disease is that the B-cells produce excess amounts of immunoglobulin 
(IgM), thickening the blood, and infiltrate the bone marrow with lymphoplasmacytic cells. 
Currently, median survival is 6.5 years. First-line therapy should consist of the monoclonal 
anti-CD20 antibody. Relapse is almost inevitable and may occur years after initial therapy. 
In 2017, there were an estimated 72240 new incident cases of NHL and 8260 new incident cases 
of HL in the United States (US). These 2 types of malignancy resulted in approximately 
20140 and 1070 deaths, respectively. NHL ranked 7th for cancer incidence and 8th for cancer 
death in the US. The estimated 5-year overall survival of patients with NHL or HL was 71.0% 
and 86.4%, respectively (National Cancer Institute 2018). NHL alone caused 6.3 million 
disability-adjusted life years in 2015 (Global Burden of Disease Cancer Collaboration et al 
2017). 
2.1 
Current Therapies and Unmet Medical Need  
Despite improvements in clinical outcomes of patients with NHL due to advances in treatments 
(including the CD20-specific monoclonal antibody rituximab; ofatumumab and obinutuzumab; 
idelalisib and ibrutinib, which target the B-cell receptor [BCR] pathway; lenalidomide; the B-cell 
lymphoma-2 (BCL-2) inhibitor venetoclax; and inhibitors of programmed cell death protein 1 
[PD1] or PD1 ligand 1 [PDL1]), some indolent B-cell malignancies remain incurable, as do 
approximately half of the aggressive NHLs.  
The BCR signaling pathway plays a crucial role in the survival, proliferation, and trafficking of 
NHL cells. Inhibitors of the key kinases in this pathway, including phosphoinositide 3’-kinase 
(PI3K), Bruton’s tyrosine kinase (BTK), and spleen tyrosine kinase (SYK) have been found to 
decrease NHL cell viability in nonclinical models and clinical studies. In fact, several PI3K 
inhibitors (idelalisib, copanlisib) and BTK inhibitors (ibrutinib, acalabrutinib) have been 
approved recently by the Food and Drug Administration (FDA) for the treatment of CLL/small 

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lymphocytic lymphoma (SLL), FL, marginal zone lymphoma (MZL), MCL, and WM. However, 
not all NHLs will respond to newly approved PI3K or BTK inhibitors.  
Another pathway that has been a successful strategy for targeted therapy in CLL is the 
overexpression of BCL-2, which confers resistance to apoptosis. Venetoclax, an oral inhibitor of 
BCL-2, induces apoptosis in CLL cells and has been shown to be another effective 
chemotherapy-free strategy in both relapsed/refractory and treatment-naïve CLL patients 
(Wierda and Tambaro 2020). Venetoclax is FDA approved for use in both upfront and 
relapsed/refractory CLL. Many, if not most, CLL patients are managed with BTK inhibitors and 
venetoclax as their first two lines of therapy. An emerging unmet need in the clinic is the 
management of patients who have developed resistance to both targeted therapies, so called 
“double refractory” patients (Aronson et al 2022).  
Syk expression by immunohistochemistry in patients with HL was found to be significantly 
associated with shorter failure-free survival (Martin et al 2011). Targeting Syk may be a novel 
strategy for the treatment of HL.  
Therefore, more effective and safer therapies are required for patients with relapsed or refractory 
lymphoma, especially for patients that have progressed or are intolerant to BCR inhibitors. 
2.2 
Background on HMPL-523  
2.2.1 
Nonclinical Pharmacology  
HMPL-523 is a selective small-molecule SYK inhibitor. HMPL-523 has shown good selectivity 
in a kinase selectivity panel and a broad pharmacological panel of 79 targets including receptors 
and ion channels. At the molecular level, HMPL-523 inhibited SYK kinase with the 
concentration of a drug that is required for 50% inhibition in vitro (IC50) of 
 μM. At 
the cellular level, HMPL-523 effectively inhibited SYK activity and activation of B-cell linker 
protein (BLNK), a downstream signal molecule of SYK, in the cell type derived from the mantle 
cell lymphoma (REC-1) MCL cell line and the cell type derived from the peripheral blood of a 
patient with IgG plasma cell leukemia (ARH-77) human plasma cell leukemia cell line with an 
IC50 of 
 μM and 
 μM, respectively. By inhibiting activation of the SYK signaling 
pathway, HMPL-523 significantly inhibited REC-1 and ARH-77 cell survival and induced 
apoptosis of REC-1. HMPL-523 inhibited the survival of multiple B-NHL cell lines. In primary 
B-cells obtained from 2 patients with CLL, HMPL-523 potently inhibited anti-IgM-stimulated 
survival and significantly inhibited the production of chemokine ligands chemokine (C-C motif) 
ligand CCL3 and CCL4, which are important for cancer cell homing, implying these 2 cytokines 
may be candidates for predictive biomarkers for instance. Knowledge of this may be valuable for 
patient stratification purposes. 
HMPL-523 also exerted a significant antitumor effect in B-NHL malignant xenograft models by 
 oral dosing. HMPL-523 inhibited tumor growth in a subcutaneous 
xenograft of MCL REC-1 with tumor growth inhibition of 
% at the dose of 
 mg/kg. In a 
Ba/F3TEL-SYK bearing mice model, HMPL-523 inhibited phosphorylation of SYK and its 
downstream signaling pathway and prolonged the lifespans of Ba/F3TEL-SYK bearing mice with 
increases in lifespan of 
, and 
% at the dose of 
, and 
 mg/kg, respectively, in a dose-dependent manner. 
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HMPL-523 was also evaluated in an acute myeloid leukemia (AML) cell line with aberrant Flt3 
activation. HMPL-523 inhibited proliferation of the MV-4-11 AML cell line (Flt3-ITD+) with an 
IC50 of 
μM. In line with its Flt3 kinase and cellular activity in vitro, HMPL-523 showed 
potent antitumor efficacy in the MV-4-11 tumor model with tumor growth inhibitions of 
, 
 and 
% at 
 mg/kg, respectively. 
Results of safety pharmacology studies showed that HMPL-523 had a low risk on the 
cardiovascular, central nervous, and respiratory systems. 
2.2.2 
Nonclinical Pharmacokinetics  
The pharmacokinetic (PK) properties and metabolic profile of HMPL-523 were evaluated both in 
vitro and in vivo in different nonclinical species. HMPL-523 was found to have moderate to high 
intrinsic membrane permeability and good oral absorption in mice, rats, and dogs. HMPL-523 
showed low clearance (CL) and moderate volume of distribution at steady state (Vss) in mice and 
rats but high CL and Vss in 
 dogs, and monkeys. In rats, HMPL-523 was extensively 
distributed into organs with abundant blood perfusion such as lung, spleen, liver, kidney, and 
pancreas as well as some gastrointestinal organs such as colon and stomach. HMPL-523 crossed 
the blood-brain barrier with difficulty, as indicated by 
 lower concentrations in the brain 
and spinal cord than in the plasma. 
A total of 8 metabolites were identified after HMPL-523 was incubated with liver microsomes 
and S9 fractions from different species. After oral administration in rats, HMPL-523 was 
extensively metabolized into 
 M3 was the predominant metabolite in both in vitro and in vivo 
circulatory systems in rats and dogs. 
 The 
metabolic profiles in rats and dogs appeared to cover all types of metabolites formed in in vitro 
metabolism assays using human liver microsomes and S9 fractions 
. Fecal 
excretion was the major excretion route of [14C]HMPL-523 after oral administration, with an 
excretion rate of approximately 90% of the dose, in which 20% of radioactivity was recovered in 
bile. Only a small amount of radioactivity was excreted via kidney. HMPL-523 was a 
P-glycoprotein (P-gp) substrate but not a substrate of breast cancer resistance protein (BCRP), 
organic anion transporter protein (OATP)1B1, and OATP1B3. HMPL-523 or its 
 
 showed limited inhibitory effects on most cytochrome P450 
enzyme (CYP) 450 isoforms in either a reversible or time-dependent manner. HMPL-523 was a 
possible weak inducer of CYP3A, 1A2, and 2B6 based on in vitro data. Although HMPL-523 
and 
 showed in vitro inhibitory effects on P-gp, BCRP, organic anion transporter 1 (OAT1), 
organic anion transporter 3 (OAT3), OATP1B1, OATP1B3, OCT2, MRP2, multidrug and toxin 
extrusion protein (MATE) 1, and MATE2-K, clinical drug-drug interactions (DDI) is only 
expected with P-gp, BCRP, MATE1, and MATE2-K substrates when human exposure was taken 
into account.  
2.2.3 
Nonclinical Toxicology  
The safety profile of HMPL-523 was evaluated in multiple studies under Good Laboratory 
Practice (GLP) guidelines. In summary, the maximum tolerated dose (MTD) was 
 mg/kg in 
single dose toxicity studies with rats and dogs. In GLP repeat-dose toxicity studies in rats and 
dogs, the main toxicity target organs included the 
, 
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 in both 
species, and 
 (rats only). In addition, 
and 
were increased in both rats and 
dogs with 
 in rats, but without any 
observations in dogs. The histopathology findings of 
 in rats might be species specific. 
The major findings in repeat-dose toxicity studies were reversible after withdrawal of the drug. 
In the 9-month toxicity study in dogs, presence of
 in 
 
 were noted at the end of the dosing and 
recovery phases. This finding can be observed in 
 However, the relationship to HMPL-523 was uncertain. 
HMPL-523 was not genotoxic based on the battery of in vitro and in vivo genotoxicity studies. 
In the rat fertility and early embryo-fetal development study, 
 were noted 
, but no effects were observed on female fertility and early embryo-fetal development 
up to 
 mg/kg/day, the highest dose evaluated. The No-Observed-Adverse-Effect Level 
(NOAEL) for female fertility and early embryo-fetal development was 
 mg/kg/day. At a dose 
of 
mg/kg/day, changes in 
 were found in male rats; as a result, the NOAEL for male fertility was 
 mg/kg/day. In the embryo-fetal development toxicity study in rats, at the dose of 
 mg/kg/day, 
 on the fetus was 
noted as well as maternal 
 As a result, the NOAEL for maternal and embryo-fetal 
developmental toxicity in rats was 
 mg/kg/day. In the embryo-fetal development toxicity study 
in rabbits, a dose of 
mg/kg/day was 
 by the dams, but no effect on 
embryo fetal development was noted. The NOAEL for maternal toxicity was 
 mg/kg/day, and 
the NOAEL for embryo/fetal development was 
 mg/kg/day. 
HMPL-523 was not phototoxic based on the results of the in vivo phototoxicity study in Sprague 
Dawley rats with single doses up to 
 mg/kg, the highest dose employed. HMPL-523 and the 
 were also evaluated in the in vitro neutral red uptake assay with BALB/c 
3T3 mouse fibroblast cells. Both HMPL-523 
 were not phototoxic in this in vitro assay. 
Thus, HMPL-523 is considered not to present a phototoxic hazard to patients. 
, and its toxicity was evaluated in a 
13-week repeat-dose toxicity study in rats by the subcutaneous route with doses up to 
 mg/kg/day. 
 
. Based on the totality of the results of a 
standard battery of genotoxicity evaluations, 
 (negative results in 
bacterial mutation tests and in vivo micronucleus and liver comet assays despite being positive in 
in vitro chromosome aberration tests). In the embryo-fetal developmental toxicity study in rats, 
 changes included 
 at the high 
dose of 
mg/kg/day. No effects on reproductive function and embryo-fetal development 
toxicity were observed at all doses. The NOAEL was  mg/kg/day for parental pregnant rats; the 
NOAEL was 
 mg/kg/day for reproductive function and embryo-fetal development.  
More detailed safety evaluation results with HMPL-523 
 in 
genotoxicity, safety pharmacology, fertility and early embryonic developmental toxicity, and 
embryo-fetal developmental toxicity are provided in the investigator’s brochure (IB). 
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2.2.4 
Clinical Experience  
As of 10 May 2022, 7 clinical studies of HMPL-523 were developed by HUTCHMED Limited 
(4 completed, 3 ongoing). Completed studies are 1 Phase I mono-therapy study in healthy 
volunteers (Study 2014-523-00AU1, conducted in Australia, 
https://clinicaltrials.gov/ct2/show/NCT02105129), 1 Phase I mono-therapy study in patients with 
relapsed or refractory mature B-cell neoplasms (Study 2015-523-00CH1, conducted in China, 
https://clinicaltrials.gov/ct2/show/NCT02857998), 1 Phase Ib double-blind study in patients with 
primary immune thrombocytopenia (ITP) (Study 2018-523-00CH1, conducted in China, 
https://clinicaltrials.gov/ct2/show/NCT03951623), and 1 Phase I combo-therapy study in patients 
with AML (Study 2017-523-00CH3, conducted in China, 
https://clinicaltrials.gov/ct2/show/NCT03483948). Ongoing studies are 2 Phase I mono-therapy 
studies in patients with hematologic malignancies (Study 2015-523-00AU1, conducted in 
Australia, https://clinicaltrials.gov/ct2/show/NCT02503033; and 2018-523-00US1, study 
described in this protocol, conducted in the US and the European Union [EU], 
https://clinicaltrials.gov/ct2/show/NCT03779113), and 1 Phase III double-blind study in patients 
with primary ITP (Study 2020-523-00CH1, conducted in China, 
https://clinicaltrials.gov/ct2/show/NCT05029635). 
Summary results for ongoing studies below are as of 10 May 2022. 
Refer to the IB for further information. 
2.2.4.1 
Study 2014-523-00AU1 in Healthy Volunteers  
This design of this completed study included 3 parts. Part A was a randomized, double-blind, 
placebo-controlled, single ascending dose stage, in which HMPL-523 5 mg, 20 mg, 50 mg, 
100 mg, 200 mg, and 300 mg were administered under fasted conditions, followed by 
HMPL-523 300 mg, 400 mg, 600 mg, and 800 mg under fed conditions with a standard meal. 
Part B was a randomized, double-blind, placebo-controlled, multiple ascending dose stage, in 
which HMPL-523 200 mg, 300 mg, and 400 mg was administered QD for 14 days with a 
standard meal. Part C was an open-label, single dose, cross-over study designed to investigate 
the effect of food on the PK of HMPL-523, in which subjects received a single dose of 
HMPL-523 100 mg under fasted conditions (Period 1) followed by a 7-day washout period and 
then a single dose of HMPL-523 100 mg with a high-fat meal (Period 2). 
Safety 
Part A 
A total of 80 subjects (10 cohorts of 8 subjects) were enrolled in Part A, 60 subjects were dosed 
with HMPL-523, and 20 subjects were dosed with placebo. All subjects completed the study as 
planned. 
Fifteen treatment-emergent adverse events (TEAEs) were reported during the study period by 
12 subjects (20.0%) who received HMPL-523, and 3 TEAEs were reported by 3 subjects 
(15.0%) who received placebo. No dose-limiting toxicities (DLTs) and serious adverse events 
(SAEs) were observed. No TEAEs were considered probably or definitely related to HMPL-523 
and 9 TEAEs were considered possibly related to HMPL-523 by the investigators. TEAEs 
occurring in more than 1 subject included headache (n = 5), upper respiratory tract infections 
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Part B 
A total of 32 subjects (4 cohorts of 8 subjects) were enrolled in Part B and dosed with 
HMPL-523 (n = 24) or placebo (n = 8). Four subjects did not complete the study as planned due 
to TEAEs, which included 1 elevated lipase and 1 seborrheic dermatitis in the 200-mg dose 
cohort, and 1 pyrexia and 1 malaise in the 400-mg dose cohort. 
A total of 51 TEAEs were reported during the study by 19 subjects (79.2%) who received 
HMPL-523, and 10 TEAEs were reported by 6 subjects (75.0%) who received placebo. Two 
DLTs were observed and reported as SAEs. These were 1 elevated lipase (200-mg cohort) and 
1 pyrexia (400-mg cohort). The majority of TEAEs reported in the HMPL-523 treatment groups 
were mild in intensity. A total of 12 events reported by 8 subjects were moderate in intensity, 
and SAEs that were determined to be DLTs were considered severe in intensity. Three TEAEs 
(elevated lipase, pyrexia, and elevated alanine aminotransferase [ALT]) reported by 3 subjects 
were considered probably related to HMPL-523; 29 TEAEs reported by 15 subjects were 
considered possibly related to HMPL-523. TEAEs reported by more than 1 subject who received 
HMPL-523 included headaches (n = 11), increased ALT (n = 5), dizziness (n = 3), malaise 
(n = 3), upper respiratory tract infections (n = 3), increased lipase (n = 2), somnolence (n = 2), 
lethargy (n = 2), constipation (n = 2), and back pain (n = 2). 
Part C 
A total of 6 subjects (1 cohort) were enrolled in Part C and received a single dose of HMPL-523 
100 mg under fasted conditions (Period 1). Following a washout period of 7 days, each subject 
received a single dose of HMPL-523 100 mg with a high-fat meal (Period 2). All subjects 
completed the study as planned. 
A total of 4 subjects (66.7%) reported TEAEs after receiving a single dose of HMPL-523 under 
fasted conditions. No DLTs or SAEs were observed. TEAEs reported by at least one subject 
include pain in extremity (n = 2), plantar fasciitis (n = 1), and cough (n = 1). Three TEAEs (2 
pains in extremity and 1 plantar fasciitis) were mild in intensity, and 1 TEAE (cough) was 
moderate in intensity. All TEAEs were considered to be not related to HMPL-523.  
Pharmacokinetics 
Exposures to HMPL-523 as measured by maximum plasma concentration (Cmax) and area under 
the concentration-time curve (AUC) after administration of single doses of 300 to 800 mg to fed 
subjects were approximately dose-proportional, as were exposures after administration of 
multiple doses of 200 to 400 mg, with low to moderate variability. Administration with a 
high-fat meal increased HMPL-523 Cmax and AUC by approximately 1.6- and 1.5-fold, 
respectively, compared with administration of HMPL-523 after an overnight fast. The binding of 
HMPL-523 to human plasma protein in vitro was 82.9% and was not concentration-dependent in 
the range of 0.5 to 5 µM. The apparent oral clearance ranged from 236 to 376 L/h, and the 
apparent body volume ranged from 3340 to 6480 L, respectively, across all single dose levels 
from 100 to 800 mg. 
Metabolism is the main route of elimination for HMPL-523. 
 The elimination half-life ranged between 9.8 hours and 13.5 hours across HMPL-523 
doses of 100 to 800 mg and was not prolonged at steady state after multiple doses. 
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Pharmacodynamics 
The inhibitory potency of HMPL-523 on anti-IgE-induced basophil activation (CD63+ 
expression) was evaluated in Part B.
 
 
2.2.4.2 
Study 2017-523-00CH3 Phase I Study in Patients with AML  
This study was completed on 16 March 2020. Overall, 7 patients were enrolled including 
3 patients in 400 mg QD cohort and 4 patients in 600 mg QD cohort. The patients received 
400 mg QD or 600 mg QD of HMPL-523 in 28-day cycles together with subcutaneous injection 
of 75 mg/m2 azacitidine on Day 1 to Day 7 of each cycle. 
Safety 
Based on the full analysis set (N = 7) in this study, all patients reported at least one TEAE, 
HMPL-523-related TEAE, and azacitidine-related TEAE.  
Six (85.7%) patients reported HMPL-523-related TEAE of Grade ≥ 3, which included (≥ 30% of 
patients reported) platelet count decreased (71.4%), white blood cell count decreased (57.1%), 
neutrophil count decreased (42.9%), and pneumonia (42.9%).  
Six (85.7%) patients reported azacitidine-related TEAE of Grade ≥ 3, which included (≥ 30% of 
patients reported) platelet count decreased (71.4%), white blood cell count decreased (57.1%), 
neutrophil count decreased (42.9%), and pneumonia (42.9%).  
One patient (03001, 600 mg QD) experienced a DLT event, aspartate aminotransferase (AST) 
increased (Grade 3).  
Four SAEs were reported in 4 patients (57.1%) out of a total of 7 patients who received the 
combo-treatment. 
Pharmacokinetics 
According to the data, when co-administered with azacitidine, the PK profile of HMPL-523 was 
not affected significantly with similar exposures on Day 7 and Day 28 (400 mg QD: geomean 
AUCtau: 2250 h·ng/mL on Day 7 and 2940 h·ng/mL on Day 28; 600 mg QD: geomean AUCtau: 
4090 h·ng/mL on Day 7 and 4410 h·ng/mL on Day 28). For azacitidine, the geomean AUCtau 
was 1480 and 1120 h·ng/mL on Day 7, respectively, when co-administered with 400 mg and 
600 mg QD of HMPL-523. 
Efficacy 
Based on the efficacy evaluable set (N = 6), one patient had best of response (BOR) as complete 
response (CR) with incomplete hematologic recovery (CRi); one had partial response (PR). All 
tumor assessments from the other 4 patients were evaluated as stable disease (SD). 
2.2.4.3 
Study 2015-523-00AU1 Phase I Study in Patients with Relapsed or Refractory 
Hematologic Malignancies  
This is an ongoing Phase I, open-label, study of the safety and PK of HMPL-523 in patients with 
relapsed or refractory hematologic malignancies in Australia. This study includes 2 stages: a 
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dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). In the dose escalation stage, 
the conventional 3+3 design was applied for dose escalation and determination of the MTD. A 
total of approximately 18 to 27 DLT evaluable patients will be enrolled into the QD or the twice 
a day (BID) regimen cohort in the dose escalation stage. The starting dose of HMPL-523 was 
100 mg QD or 300 mg BID, respectively, administered orally in continuous 28-day cycles. In the 
dose expansion stage, approximately 40 patients with relapsed or refractory B-cell NHL or CLL 
will be enrolled at the recommended Phase 2 dose (RP2D) to further evaluate the safety, PK, and 
efficacy of HMPL-523. 
Safety 
 
Pharmacokinetics 
The preliminary PK data of HMPL-523 on Day 1, Day 15, and Day 28 for multiple 100 to 
1000 mg QD and 300 mg and 400 mg BID doses in the dose escalation stage, and on Day 1 and 
Day 28 for the 600 mg and 800 mg QD cohorts in the dose expansion stage were available. In 
this study, all patients were instructed to take HMPL-523 at approximately 30 minutes after a 
meal.  
Median time to reach maximum plasma concentration (Tmax) values for HMPL-523 ranged from 
2.00 to 6.05 hours following multiple 100 to 1000 mg QD doses, and from 1.89 to 4.08 hours 
following multiple 300 mg and 400 mg BID doses. The oral apparent clearance (CL/F) at steady 
state ranged from 164 to 369 L/h. The mean accumulation ratio (AR) for AUCtau ranged from 
1.31 to 2.13 following multiple QD doses, and from 1.93 to 3.70 following multiple BID doses. 
In general, lower Cmax, higher minimum plasma concentration (Cmin) and higher AR for AUCtau 
were observed with BID dosing compared to QD dosing at the same total daily dose. 
Systemic exposures of HMPL-523 increased with dose up to 1000 mg QD on Day 1 and up to 
800 mg QD on Day 15 and Day 28. The exposures at steady state appeared to drop off when 
dose increased from 800 mg QD to 1000 mg QD. The reason is unclear but may be related to the 
large between-subject PK variability (around 60% to 80%) in comparison to the small dose 
increment (25% increase in dose from 800 to 1000 mg). In the dose escalation stage, the highest 
geometric mean exposure was achieved following the 800 mg QD dose on Day 15 with AUCtau 
of approximately 4890 h·ng/mL and Cmax of approximately 385 ng/mL. In the dose expansion 
stage, the geometric mean AUCtau and Cmax on Day 28 were 3330 h·ng/mL and 246 ng/mL, 
respectively, at 800 mg QD, and 2710 h·ng/mL and 191 ng/mL, respectively, at 600 mg QD. The 
preliminary PK results showed that systemic exposure of HMPL-523 in Australian subjects was 
lower than that in Chinese subjects, but other PK characteristics in Chinese and Australian 
subjects were similar. 
The plasma concentration of 
 were monitored in this study (data on 
file). The mean ARs of area under the drug concentration-time curve over the dose interval at 
steady state (AUCtau,ss)
 were 3.16 and 1.75, respectively, following multiple 
100 to 1000 mg QD or 300 and 400 mg BID doses. The mean 
 ratios of 
AUCtau,ss were approximately 
respectively. The mean 
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 respectively.  
Efficacy 
As of 10 May 2020, in study 2015-523-00AU1, 61 patients had at least 1 post-baseline tumor 
assessment, and the objective response rate (ORR) in all enrolled patients was 
%, with 
 patients achieved CR, 
 patients achieved PR/partial response with lymphocytosis (PR-L), 
 patients achieved SD, 
 patients experienced progressive disease (PD), and 4 patients not 
evaluable for best overall response (BOR). 
 patients with FL (  at 600 mg QD,  at 800 mg 
QD, and  at 400 mg BID) achieved CR,  patients with CLL/SLL 
 at 800 mg QD,  at 400 mg 
BID, and  escalated from 100 mg QD to 400 mg QD) achieved PR/PR-L,  patients with FL 
(  at 600 mg QD,  at 800 mg QD, and  at 300 mg BID),  patients with MZL (  at 600 mg QD, 
 at 800 mg QD), and 1 patient with low grade NHL (600 mg QD) achieved PR. 
2.2.4.4 
Study 2015-523-00CH1 Phase I Study in Patients with Relapsed/Refractory 
Lymphoma  
This study was completed on 30 September 2021. Overall, 134 patients were enrolled in the 
study. Twenty-seven patients were treated in the dose escalation phase, including 7 patients in 
the 200-mg QD cohort, 3 patients in the 400-mg QD cohort, 6 patients in the 600-mg QD cohort, 
3 patients in the 800-mg QD cohort, and 8 patients in the 200-mg BID cohort. One hundred 
seven patients were treated in the dose expansion phase, including 32 patients in the 400-mg QD 
cohort and 75 patients in the 600-mg QD cohort. During the dose expansion phase, RP2D was 
600 mg QD for patients whose weight was > 65 kg and 400 mg QD for patients whose weight 
was ≤65 kg.  
Safety 
 
Pharmacokinetics 
 on Day 1, Day 15, 
and Day 28 following multiple 200 to 800 mg QD and 200 mg BID HMPL-523 in the dose 
escalation phase, and 400 mg QD and 600 mg QD doses in the dose expansion phase, in Chinese 
patients with relapsed or refractory mature B-cell tumor. In this study, all patients were 
instructed to take HMPL-523 at approximately 30 minutes after a meal.  
Median Tmax values for HMPL-523 ranged from 3.00 to 5.97 hours following 200 to 800 mg QD 
doses, and from 1.98 to 3.88 hours following multiple 200 mg BID doses. The mean ARs for 
AUCtau on Days 15 and 28 ranged from 1.27 to 2.65 following multiple 200 to 600 mg QD 
doses, and from 1.97 to 2.52 following multiple 200 mg BID doses. In general, lower Cmax, 
similar Cmin, and higher AR for AUCtau were observed with 200 mg BID dosing compared to 
400 mg QD dosing. 
 with the increased HMPL-523 
doses from 200 to 800 mg QD and 200 mg BID. Median Tmax values were similar between QD 
and BID dosing regimen, generally 4.00 hours post-dose 
 and ranging from 1.93 to 
4.08 hours post-dose 
 The mean AR for AUCtau on Days 15 and 28 ranged from 1.22 to 
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3.25 
, and 0.426 to 1.52 
, following multiple 200 to 600 mg QD doses, and from 
2.40 to 3.34 
, and 1.79 to 1.88 
 following multiple 200 mg BID doses. In general, 
lower Cmax, similar Cmin and higher AR for AUCtau were observed with 200 mg BID dosing 
compared to 400 mg QD dosing. 
 
 
following multiple 200 to 600 mg QD or 200 mg BID doses. 
The relationship between dose levels and exposure (for Day 1: Cmax and AUC0-t; for Day 15 or 
Day 28: Cmax, AUCtau, and Cmin) of HMPL-523 
 in dose escalation 
phase was evaluated by Power Model. Following QD oral administration of HMPL-523, on 
Days 1, 15 and 28, the 95% CI of the slope for HMPL-523, 
was not completely 
included in the reference interval 0.839-1.16 [1+ln (0.8)/ln (800/200) - 1+ln (1.25)/ln (800/200)]. 
The linear relationship between dose level and the exposure of HMPL-523 and 
 
 was inconclusive over the dose range of 200 to 800 mg. 
Efficacy 
A total of 114 patients had at least 1 post-baseline tumor assessment (defined as 
efficacy-evaluable analysis set, EEAS), including 23 patients in the dose escalation stage and 
91 patients in the dose expansion stage. 
In the dose escalation stage, tumor responses were observed at the dose levels of 400 to 600 mg 
QD or 200 mg BID. Four patients with FL and 1 patient with SLL achieved PR, and the 
investigator-assessed ORR was 21.7% (95% CI: 7.5%, 43.7%) based on the EEAS (N = 23). Of 
the 5 patients with PRs, median time to response (TTR) was 3.6 months (95% CI: 1.9, -) and 
median duration of response (DoR) was 11.0 months (95% CI: 4.7, -). Based on the safety set 
(included patients who had at least 1 dose of study drug, N = 27), median time to tumor 
progression (TTP) was 8.3 months (95% CI: 1.8, 16.5) and median progression free survival 
(PFS) was 8.3 months (95% CI: 1.8, 16.5). 
In the dose expansion stage, based on the EEAS (N = 91), 5 patients achieved CRs and 33/4 
patients achieved PR/PR-Ls, and the investigator-assessed ORR was 46.2% (95% CI: 35.6, 
56.9). Of the responders, the median DoR was 13.1 months (95% CI: 6.5, -), and median TTR 
was 1.9 months (95% CI: 1.9, 2.0). Based on safety set (N = 107), the median PFS was 
8.2 months (95% CI: 5.5, 12.0), and median TTP was 8.3 months (95% CI: 5.6-13.8).  
Cohort A (CLL/SLL) 
Based on the EEAS (N = 16), 1 patient had CR, and 4/4 patients had PR/PR-L, and the 
investigator-assessed ORR was 56.3% (95% CI: 29.9%, 80.2%). Of the responders, median DoR 
was 13.1 months (95% CI: 1.8, -) and median TTR was 1.9 months (95% CI: 1.8, 1.9). Based on 
the safety set (N = 19), median TTP was 14.9 months (95% CI: 3.7, -) and median PFS was 14.9 
months (95% CI: 3.7, -). 
Among the 12 efficacy-evaluable CLL patients, the ORR was 50.0% (95% CI: 21.1%, 78.9%); 
among the 4 efficacy-evaluable SLL patients, the ORR was 75.0% (95% CI: 19.4%, 99.4%), and 
both were assessed by investigator. 
Cohort B (DLBCL, FL Grade 3b) 
Based on the EEAS (N = 9), 1 and 2 patients achieved CR and PRs, respectively, obtaining an 
ORR of 33.3% (95% CI: 7.5%, 70.1%), as assessed by the investigator. Among the responders, 
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median TTR was 1.9 months (95% CI: 1.8, -) and median DoR was 5.3 months (95% CI: 3.7, -). 
Based on the safety set (N = 14), median TTP was 1.9 months (95% CI: 0.8, 9.1) and median 
PFS was 1.9 months (95% CI: 0.8, 9.1). 
Of the 7 efficacy-evaluable DLBCL patients, the ORR was 28.6% (95% CI: 3.7%, 71.0%). Two 
FL (Grade 3b) patients had evaluable tumor response, and 1 of them had PR. 
Cohort C (MCL) 
Based on the EEAS (N = 7), 2 patients had PRs, and the investigator-assessed ORR was 28.6% 
(95% CI: 3.7%, 71.0%). Among patients with an objective response, median TTR was 
1.9 months (95% CI: 1.9, -) and median DoR was 4.6 months (95% CI: 1.9, -). Based on the 
safety set (N = 10), median TTP was 3.7 months (95% CI: 1.1, -) and median PFS was 3.7 
months (95% CI: 0.9, -). 
Cohort D [MZL, LPL/WM, and FL (Grades 1, 2, and 3a)] 
Based on the EEAS (N = 59), per independent review committee (IRC) assessment, 8 patients 
had CRs, 22 patients had PRs, and the overall ORR was 50.8% (95% CI: 37.5%, 64.1%). Among 
patients with an objective response, median TTR was 2.7 months (95% CI: 1.8, 3.7) and median 
DoR was 15.7 months (95% CI: 7.4, -). Based on the safety set (N = 64), median TTP was 
12.0 months (95% CI: 8.2, -) and median PFS was 12.0 months (95% CI: 6.3, -). The 
investigator-assessed ORR was 47.5% (95% CI: 34.3%, 60.9%), median TTR, DoR, TTP and 
PFS were 2.0 months (95% CI: 1.9, 3.6), 13.9 months (95% CI: 6.4, -), 11.0 months (95% CI: 
6.3, 19.3), and 8.3 months (95% CI: 5.5, 16.6), respectively. 
Of the 43 efficacy-evaluable FL (Grades 1, 2, and 3a) patients, per IRC assessment, 7 patients 
had CRs, and 19 patients had PRs, obtaining an overall ORR of 60.5% (95% CI: 44.4%, 75.0%). 
Of the responders, the median TTR was 3.6 months (95% CI: 1.8, 3.7) and median DoR was not 
reached (95% CI: 6.5, -). Of the 47 FL patients in the safety set, median TTP was 12.0 months 
(95% CI: 8.2, -) and median PFS was 11.0 months (95% CI: 6.3, -). The investigator-assessed 
results were: ORR, 60.5% (95% CI: 44.4%, 75.0%); median TTR, 1.9 months (95% CI: 1.9, 
3.6); median DoR, 14.8 months (95% CI: 6.5, -); median TTP, 12.0 months (95% CI: 6.8, -); and 
median PFS, 11.0 months (95% CI: 6.3, 16.6). 
2.2.4.5 
Study 2018-523-00US1 Phase I Study in Patients with Relapsed/Refractory 
Lymphoma  
This ongoing Phase I, open-label study to evaluate the safety, tolerability, PK, and preliminary 
efficacy of HMPL-523 in patients with relapsed or refractory lymphoma is described in this 
protocol. The expansion cohorts include HL, CLL/SLL, CLL/SLL (post-BTK), MCL, FL, MZL, 
WM/LPL, peripheral T-cell lymphomas (PTCL), and cutaneous B-cell lymphoma (CBCL).  
A post-BTK exposure cohort in CLL/SLL is being evaluated based on recent experience from 
the Phase I study of HMPL-523 in China (2015-523-00CH1) indicating efficacy in this patient 
population. In the dose expansion phase of this study, 19 CLL patients were enrolled with 
16 evaluable for response. The ORR in CLL/SLL patients was 56.3%, including 1 CR (6.3%) 
and 8 PR/PR-L (50%), with a median duration of response (mDoR) of 13.1 months (range: 
1.8 - not calculable [NC]) months). In the 8 CLL/SLL patients with prior BTK exposure, the 
ORR was 50% with median DoR of 14.7 months (95% CI: 1.9, NC) and median PFS of 
16.5 months (95% CI: 1.6, NC). Based on this preliminary efficacy and the need for therapies in 

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CLL/SLL patients who are intolerant of or resistant to BTK inhibitors, the sponsor proposes a 
larger cohort to evaluate efficacy in CLL/SLL patients who have failed or are intolerant to BTK 
inhibitors.  
Early efficacy in FL was also demonstrated in the 2015-523-00CH1 study. This study enrolled 
47 patients with FL, of which 43 were evaluable for response. The ORR was 60.5% (95% CI: 
44.4, 75.0) with mDoR of 14.8 months (95% CI: 6.5, -) and median PFS of 11.0 months (95% 
CI: 6.3, 16.6). As this cohort had the best efficacy in the CH1 lymphoma study, the sponsor 
proposes a larger cohort to evaluate FL patients.  
As discussed in Section 2.1, targeting Syk may be a novel strategy for the treatment of HL.  
Safety 
 
Pharmacokinetics 
As of 10 May 2022, preliminary PK data for HMPL-523 and 
following 
multiple QD doses from 100 to 800 mg in the dose escalation phase were available. All patients 
were instructed to take HMPL-523 at approximately 30 minutes after a meal.  
There were limited calculable PK parameters at steady state at 800 mg QD; therefore, the data 
are excluded from the summary described below. Following multiple oral doses of HMPL-523 
from 100 to 700 mg QD, the median Tmax values for HMPL-523 ranged from 3.0 to 6.0 hours 
post-dose. The exposure of HMPL-523 (maximum plasma concentration at steady state [Cmax,ss] 
and area under the drug concentration-time curve over the dose interval at steady state 
[AUCtau,ss]) increased in approximately dose-proportional manner over the dose range of 100 to 
700 QD. The apparent oral clearance at steady state ranged from 189 to 304 L/h for doses from 
100 to 700 mg QD. HMPL-523 reached PK steady state by Day 15. The mean AR was 
approximately 1.60 (ranging from 1.21 to 2.01) following multiple 100 to 700 mg QD doses. 
The exposure of the 
with increased HMPL-523 doses. 
Median Tmax values for 
 ranged from 4.0 to 8.0 hours, and 2.0 to 4.0 hours 
post-dose, respectively, following multiple doses of 100 to 800 mg QD. The mean ARs of 
AUCtau,ss
 were approximately 1.86 and 1.55, respectively. The mean 
 ratios of AUCtau,ss were approximately 
respectively. The mean 
 ratios of AUCtau,ss 
were approximately 
 respectively. 
Efficacy 
As of the data cut-off date (10 May 2022), this study was still ongoing. No efficacy data was 
available. 
2.2.4.6 
Study 2018-523-00CH1 Phase I Study in Patients with Primary Immune 
Thrombocytopenia  
This study was completed on 18 April 2022. Overall, 45 patients were enrolled in the study. 
During 0 to 8 weeks double-blind phase, 34 patients received HMPL-523 and 11 patients 
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received placebo. During the 16-week open-label phase, 25 patients received study drug and 
7 patients received placebo.  
Safety 
Within 28 days after the first dose in the double-blind period (N = 34 in HMPL-523 cohorts, 
N = 11 in Placebo cohort), the Grade ≥ 2 treatment-related TEAEs were reported in 2 (8.3%) 
patients at all dose cohorts of HMPL-523, including hypertriglyceridemia (4.2%) and anemia 
(4.2%); and in 1 (12.5%) patient of placebo cohort (aspartate aminotransferase increased). 
In the 0- to 8-week double-blind period, 34 (100.0%) versus 9 (81.8%) patients reported TEAEs 
in HMPL-523 versus placebo cohorts, of whom 22 (64.7%) versus 3 (27.3%) patients reported 
treatment-related TEAEs, and the top 3 preferred terms (PTs) were blood lactate dehydrogenase 
increased (20.6% versus 9.1%), alanine aminotransferase increased (14.7% versus 9.1%), and 
amylase increased (14.7% versus 0).  
Seven (20.6%) versus 2 (18.2%) patients reported TEAEs of Grade ≥ 3, of whom 3 (8.8%) 
patients versus none patients reported treatment-related TEAEs of Grade ≥ 3. The 
treatment-related TEAEs of Grade ≥ 3 in HMPL-523 cohorts were all singly reported, including 
gamma-glutamyltransferase increased (2.9%), white blood cell count decreased (2.9%), 
hypertriglyceridemia (2.9%), and hypertension (2.9%). 
None versus one (9.1%) patient in HMPL-523 versus placebo cohorts reported TEAEs leading to 
permanent treatment discontinuation, which included haemorrhage subcutaneous and gingival 
bleeding in placebo cohort and were not treatment related; none versus one (9.1%) patient 
reported TEAEs leading to study drug dose reduction or dose interruption, which included 
alanine aminotransferase increased and aspartate aminotransferase increased in the placebo 
cohort; both were treatment-related. 
Two (33.3%) and 2 (18.2%) patients in the HMPL-523 cohorts (only in 100 mg cohort) and in 
the placebo cohort, respectively, reported SAEs, none of which were treatment-related. No 
TEAEs leading to death occurred.  
In the 0- to 24-week period for all patients treated with HMPL-523, all 41 patients reported 
TEAEs, of whom 31 (75.6%) patients reported treatment-related TEAEs, and the top 3 
treatment-related TEAEs included aspartate aminotransferase increased (29.3%), alanine 
aminotransferase increased (26.8%), and blood lactate dehydrogenase increased (22.0%). 
Nine (22.0%) patients reported TEAEs of Grade ≥ 3 in HMPL-523 cohorts, and of them, 
3 (7.3%) patients reported treatment-related TEAEs of Grade ≥ 3, which were all singly reported, 
including gamma-glutamyltransferase increased (2.4%), white blood cell count decreased 
(2.4%), hypertriglyceridemia (2.4%), and hypertension (2.4%). 
No patients treated with HMPL-523 reported TEAEs that led to permanent discontinuation of 
study drug. Three (7.3%) patients reported TEAEs leading to dose reduction or interruption of 
study drug, which were singly reported and not related to treatment. 
Five (12.2%) patients reported SAEs, which were not related to treatment. No deaths were 
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Pharmacokinetics 
The PK of HMPL-523 in this Phase I Study 2018-523-00CH1 has been characterized on Day 15 
following multiple 100 to 400 mg QD doses in the dose escalation phase and 300 mg QD doses 
in the dose expansion phase in Chinese patients with ITP. All patients were instructed to take 
HMPL-523 at approximately 30 minutes after a meal.  
Following multiple oral doses of HMPL-523 from 100 to 400 mg QD, the median Tmax value for 
HMPL-523 was 4.0 hours post-dose. The systemic exposure (Cmax,ss and AUCtau,ss) increased in a 
dose proportional manner across the dose range of 100 to 400 mg QD. The geometric mean 
Cmax,ss, maximum plasma concentration at steady state, and AUCtau,ss of HMPL-523 following 
the RP2D 300 mg QD were 163 ng/mL, 41.3 ng/mL, and 2070 h·ng/mL, respectively. The 
apparent oral clearance (CLss/F) at steady state on Day 15 ranged from 130 to 173 L/h.  
 Median Tmax values 
 ranged from 3.0 to 
4.0 hours, and 1.5 to 2.0 hours post-dose, respectively, following multiple doses of 100 to 
400 mg QD HMPL-523. The mean 
 ratio of 
AUCtau,ss 
 and 
 respectively.  
Efficacy 
HMPL-523 300 mg QD showed a preliminary efficacy in patients with ITP, with a high response 
rate (patients with platelet count ≥ 50 × 109/L at least once) and durable response rate (patients 
with platelet count ≥ 50 × 109/L in at least 4 of the last 6 scheduled visits) of 80.0% and 40.0%, 
respectively, in all patients treated with HMPL-523. For patients who have received prior 
thrombopoietin or thrombopoietin receptor agonists, the response rate and durable response rate 
were also 80.0% and 40.0%, respectively.  
2.2.4.7 
Study 2020-523-00CH1 Phase III Study in Patients with Primary Immune 
Thrombocytopenia  
This is an ongoing Phase III, randomized, double-blind, placebo-controlled study of safety and 
efficacy of HMPL-523 in patients with ITP. This study includes 2 stages: a double-blind 
treatment stage (Stage 1) and an open-label treatment stage (Stage 2). As of 10 May 2022, the 
study was still ongoing and blind. Nine (9) patients have completed the double-blind treatment 
and entered open-label treatment.  
Safety 
Four (44.4%) patients reported TEAEs, of them 3 (33.3%) patients reported treatment-related 
TEAEs, which included alanine aminotransferase increased (22.2%) and aspartate 
aminotransferase increased (22.2%) which were reported in ≥ 2 patients. No TEAEs of 
Grade ≥ 3 reported.  
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Efficacy  
As of 10 May 2022, this study is still ongoing and blinded; no efficacy data were available.  
2.2.4.8 
  
  
 patients reported at least 1 TEAE, of whom, 
patients reported at least 1 treatment-related TEAE. The top 3 treatment-related TEAEs included 
AST increased 
, ALT increased 
, and neutrophil count decreased
 
 patients reported TEAE of Grade ≥ 3, of whom, 
 
patients reported at least 1 treatment-related TEAE of Grade ≥ 3. The top 3 treatment-related 
TEAEs of Grade ≥ 3 included neutrophil count decreased
 pneumonia
, and white 
blood cell count decreased 
 
 patients out of a total of 233 patients, who received HMPL-523 
mono-therapy treatment in studies 2015-523-00AU1, 2015-523-00CH1, and 2018-523-00US1 
reported SAEs.
 patients reported treatment-related SAEs, and the top 3 PTs 
with highest incidence included pneumonia (
 patients), interstitial lung disease (  patients), 
and febrile neutropenia (  patients).  
As of 10 May 2022,  fatal SAEs were reported in Study 2015-523-00AU1, 5 fatal SAEs were 
reported in Study 2015-523-00CH1, and 1 fatal SAE was reported in Study 2018-523-00US1.  
2.3 
Study Rationale and Benefit-Risk Assessment  
2.3.1 
Study Rationale  
SYK is a member of the SYK/zeta-associated protein 70 family and is a nonreceptor intracellular 
tyrosine kinase. In hematopoietic cells, SYK is recruited to the intracellular membrane by 
activated membrane receptors like the BCR or Fc receptor and then binds to the intracellular 
domain of the receptors. SYK is activated after phosphorylation by Src family kinases and then 
further induces downstream intracellular signals including BLNK, phosphoinositide 3’-kinase  
(PI3K), BTK and phospholipase C 2 (PLCγ2) to regulate B-cell proliferation, growth, 
differentiation, homing, survival, maturation, and immune responses. 
In vitro experiments have also demonstrated that the SYK molecule plays a major role in 
B-NHLs. For example, down-regulation of SYK reduced the proliferating signal as well as the 
expansion of DLBCL cells and spontaneous lymphoma cells from transgenic mice (Cheng et al 
2011). These experiments indicate that over-activated SYK plays an important role in promoting 
the activation of B-NHLs. Therefore, inhibition of SYK activation in B-NHLs may block signal 
transduction, resulting in inhibition of B-cell lymphoma proliferation or induction of tumor cell 
apoptosis. 
Clinical data have shown that SYK is abnormally activated in B-cell lymphomas. SYK 
downstream of the BCR was highly expressed and phosphorylated in CLL cells isolated from the 
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peripheral blood of patients (Hoellenriegel et al 2012). Phosphorylated SYK was positive in 
approximately 44% of patients with DLBCL patients (Cheng et al 2011).  
Some SYK inhibitors, such as fostamatinib (prodrug of R406) and entospletinib (GS-9973), have 
shown encouraging activity in clinical trials against NHLs with tolerable toxicity (Friedberg et al 
2010, Sharman et al 2017).  
The repertoire of cells in which SYK functions as a pro-survival factor extends to hematological 
malignancies not of B-cell origin (a variety of T cell lymphomas) in which it is likely that 
immunoreceptor tyrosine-based activation motif-containing receptors other than the BCR are 
coupled to the activation of SYK (Hahn et al 2009). The expression of SYK can be detected in 
94% of PTCLs, and immunoblotting experiments indicate that the kinase is constitutively 
phosphorylated in these cells. These data indicate that exploring SYK inhibitors in these tumor 
types is reasonable. 
A total of 68 patients with relapsed and refractory lymphomas were enrolled and treated with 
fostamatinib as a single agent in a Phase I/II study. The ORRs were reported at 22% (5 of 23) for 
DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL (Friedberg 
et al 2010).  
A total of 61 patients with relapsed and refractory CLL were treated with fostamatinib as a single 
agent in a Phase II study. The median PFS was 16.6 months, 16.8 months, and 16.4 months for 
the 100-, 200-, and 400-mg groups, respectively. The ORR was 28%, 43%, and 61% for the 
100-, 200-, and 400-mg groups, respectively (Sharman et al 2017).  
The most common adverse effects observed in clinical studies of fostamatinib and entospletinib 
were diarrhea, hypertension, fatigue, and bone marrow toxicities. These TEAEs are manageable 
and reversible. These results suggest that the SYK inhibitor may represent a class of safe and 
effective drugs to treat B-cell lymphomas.  
2.3.2 
Benefit-Risk Assessment  
2.3.2.1 
Risk Assessment  
Important Identified Risks 
Hepatotoxicity 
Increases in hepatic enzymes (ALT, AST, bilirubin, alkaline phosphatase [ALP], and 
gamma-glutamyl transferase) have been observed in animals and humans treated with 
HMPL-523, and are known adverse reactions of other SYK inhibitors (Sharman et al 2015) 
(TavalisseTM Prescribing Information 2018). Patients with a history of liver disease, including 
cirrhosis, current alcohol abuse, or current known active infection with hepatitis B or C virus 
should be excluded from clinical trials.  
Additionally, patients should be excluded if screening AST and/or ALT are > 2.5 × upper limit 
of normal (ULN), or if screening total blood bilirubin > 1.5 × ULN. Liver function tests should 
be performed with each site visit. HMPL-523 should be withheld in the event of any ≥ Grade 3 
adverse event (AE) indicative of hepatic injury.  

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Respiratory Tract Infections 
Respiratory tract infections, including pneumonia have been reported in patients treated with 
HMPL-523, some of which have been life-threatening or fatal. Patients should be excluded from 
clinical trials with HMPL-523 if screening absolute neutrophil count (ANC) < 1.5 × 109/L. 
Complete blood cell count (CBC) should be performed at the beginning of each cycle. 
Prophylactic antibiotics, symptomatic, and supportive treatments should be administered per 
standard practice.  
2.3.2.2 
Benefit Assessment  
HMPL-523 is a highly selective SYK inhibitor with a different structure compared with 
fostamatinib and entospletinib. In most in vitro nonclinical studies, HMPL-523 inhibited SYK 
kinase with inhibitory activity comparable to that of fostamatinib and entospletinib and has 
superior selectivity against the kinase insert domain receptor to fostamatinib. In Phase I studies 
of HMPL-523 in patients with hematologic malignancies in both Australia and China, 
HMPL-523 was well tolerated at doses of up to 600 mg QD. HMPL-523 also demonstrated 
efficacy in patients with hematologic malignancies in these studies. Refer to Section 2.2.4 for 
details of safety and efficacy results in completed and ongoing HMPL-523 clinical studies. 
2.3.2.3 
Overall Benefit-Risk Conclusion  
Overall, the nonclinical data and early clinical data suggest that HMPL-523 is a selective SYK 
inhibitor with a good nonclinical PK and toxicological profile. The nonclinical and preliminary 
clinical data suggest that HMPL-523 should be evaluated as a potential therapeutic agent for 
patients with lymphoma in the US.  

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3 
OBJECTIVES  
3.1 
Primary Objectives  
• To evaluate the safety and tolerability of HMPL-523 in patients with relapsed or 
refractory lymphoma in the dose escalation stage 
• To determine the MTD/RP2D and characterize the DLTs associated with HMPL-523 in 
patients with relapsed or refractory lymphoma in the dose escalation stage 
• To evaluate the preliminary efficacy of HMPL-523 in patients with relapsed or refractory 
lymphoma in the dose expansion stage 
3.2 
Secondary Objectives  
• To characterize the PK properties of HMPL-523 in patients with relapsed or refractory 
lymphoma in the dose escalation stage and the dose expansion stage 
• To evaluate the safety and tolerability of HMPL-523 at the MTD/RP2D in patients with 
relapsed or refractory lymphoma in the dose expansion stage 
• To evaluate the preliminary efficacy of HMPL-523 in patients with relapsed or refractory 
lymphoma in the dose escalation stage 
3.3 
Exploratory Objectives  
• To evaluate the PK properties of 
HMPL-523 in patients with 
relapsed or refractory lymphoma in the dose escalation and dose expansion stages 
• To explore biomarkers for PD, predictive, and others (not exhaustive), including 
antitumor activities of HMPL-523 
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4 
STUDY DESIGN  
4.1 
Description of Study  
This is a Phase I, open-label, multicenter study of HMPL-523 administered orally to patients 
with relapsed or refractory lymphoma who have exhausted approved therapy options. 
The study consists of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). 
Both stages include a screening period, a treatment period, and a follow-up period. The screening 
period starts when the patient has provided written informed consent and ends immediately prior 
to initiation of study drug administration on Day 1 of Cycle 1. The treatment period begins on 
Day 1 of Cycle 1 and concludes on the final day of study drug administration. The follow-up 
period begins at the end of treatment and continues until the patient experiences disease 
progression, starts a new anticancer therapy, or dies, or the sponsor has concluded the study. 
The start of the clinical study is defined as the date the study is open for recruitment at any site. 
This date was 21 February 2019. The start of the clinical study in EU is defined as the date the 
clinical study is open for recruitment at the first clinical study site within an EU Member State. 
This date was 05 September 2019. 
4.2 
Dose Escalation Stage (Stage 1)  
Starting Dose and Rules for Dose Escalation 
Dosing will begin at 100 mg QD. A cycle of study treatment will be defined as 28 days of 
continuous dosing. The modified 3 + 3 design will be applied for dose escalation and MTD 
determination to limit the number of patients being exposed to potentially ineffective or unsafe 
doses. The study will enroll 1 patient, and the patient will be treated for a 28-day cycle in the 
initial dose cohort. If there is no DLT and no more than 2 TEAEs of Common Terminology 
Criteria for Adverse Events (CTCAE) Grade ≥ 2 in the first treatment cycle, the study will be 
escalated to the next dose cohort and continue with the standard 3+3 design. Otherwise, the trial 
will revert to a standard 3+3 design from the initial dose cohort.  
A minimum of 3 patients will be enrolled and observed for toxicity in each successive dose 
cohort after the initial dose cohort. If the 3 patients initially enrolled in a given dose cohort 
complete the DLT assessment window (Cycle 1, Days 1-28) without experiencing a DLT, 
3 patients will be enrolled at the next higher dose level. If 2 or more of the initial 3 patients 
enrolled at any dose level experience a DLT during the DLT assessment window, the dose 
escalation will be halted. If 1 of the initial 3 patients enrolled at any dose level experiences a 
DLT during the DLT assessment window, additional patients will be enrolled at that dose level 
for a minimum of 6 evaluable patients for DLT. If a DLT is observed in 1 of the 6 evaluable 
patients at this dose level, dose escalation will proceed to the next pre-defined dose level. If 
DLTs are observed in 2 or more of the 6 evaluable patients at a given dose level, the dose 
escalation will be halted. If the dose escalation is completed due to 2 or more DLTs at a dose 
level and that dose level is ≥ 50% higher than the previous dose level, then an intermediate dose 
level may be evaluated for toxicity in the same manner as described above. If the dose level is 
50% higher than the previous dose level, in which only 3 DLT evaluable patients were enrolled, 
3 additional patients will be enrolled at that dose level to comprise 6 DLT evaluable patients.  
See Table 1 below for the proposed dose escalation scheme. 

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Table 1 
Proposed Dose Escalation Scheme  
Cohort 
Dose 
Route of Administration 
1 
100 mg QD 
Orally, with water, after meal 
2 
200 mg QD 
Orally, with water, after meal 
3 
400 mg QD 
Orally, with water, after meal 
4 
600 mg QD 
Orally, with water, after meal 
5 
800 mg QD 
Orally, with water, after meal 
Abbreviation: QD = once daily. 
The need for dose escalation to a specific dose beyond 800 mg QD, or de-escalation specifically 
to 700 mg QD, will be evaluated jointly by the investigators and the sponsor based on the 
cumulative clinical safety, PK, and preliminary efficacy data. 
Safety monitoring and evaluation of dose escalation will be carried out by the Safety Review 
Committee (SRC), which will comprise the sponsor’s study team members (including the 
medical monitor, the safety monitor, and others as deemed necessary) and the principal 
investigators of the study sites. Safety data will be evaluated and reviewed by the SRC to 
determine if the assigned HMPL-523 dose is safe to continue for dose escalation or to 
de-escalate to the lower dose level. 
4.3 
Intrapatient Dose Escalation  
Intrapatient dose escalation to a higher dose level may be permitted by the sponsor, provided that 
the current dose level the patient is on has been cleared of DLT (safe and tolerable), and the 
higher dose level cohort being considered also has been cleared of DLT (safe and tolerable), 
prior to the start of that intrapatient dose escalation.  
4.4 
Definition of a Dose-Limiting Toxicity  
DLTs are defined as the occurrence in the DLT assessment window (see Section 4.4.1) of any of 
the following TEAEs, unless they are clearly unrelated to the study drug:  
a. Nonhematologic toxicity: All nonhematologic TEAEs of Grade 3 or greater with the 
exception of:  
i. 
Grade 3 nausea, vomiting controlled by supportive therapy  
b. Hematologic toxicity: 
i. 
Grade 4 neutropenia lasting more than 5 days. 
ii. 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or any 
requirement for platelets transfusion. 
iii. 
Grade 3 or greater febrile neutropenia (defined as ANC < 1000/mm3 with a 
single temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C 
(100.4°F) for more than 1 hour. 
iv. 
Grade 4 anemia unexplained by underlying disease.  

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c. Any TEAE requiring a dose delay of ≥ 15 days.  
d. Any case of Hy’s Law. 
4.4.1 
Dose-Limiting Toxicity Assessment Window  
For all patients participating in Stage 1, DLTs will be assessed during the DLT assessment 
window of 28 days (ie, from Cycle 1 Day 1 [the day of first administration of treatment] through 
Cycle 1 Day 28). 
4.4.2 
Definition of Dose-Limiting Toxicity Evaluable Patient  
For decisions on dose escalation, each dose cohort shall present protocol-required number of 
DLT evaluable patients. A patient 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 DLT assessment period due to a DLT  
Patients who are not DLT evaluable in a dose cohort will be replaced to guarantee the protocol 
required number of DLT evaluable patients for dose escalation evaluations. 
4.4.3 
Dosing Beyond Cycle 1  
Patients who complete the DLT assessment window (Cycle 1 Days 1-28) and are deemed by the 
investigator to be benefiting from treatment with HMPL-523 may continue treatment with 
HMPL-523 until disease progression, intolerable toxicity, at investigator’s assessment that the 
patient is no longer benefiting from the study treatment, patient withdrawal from the study, the 
end of the study, or death. Conversely, if in the opinion of the attending principal investigator the 
patient may have clinical benefit from a higher dose, then, at the request of the principal 
investigator and with the approval of the sponsor, the patient may be able to participate in 
intrapatient dose escalation (Section 4.3). If the study is terminated or ends before a patient 
reaches any of these endpoints, refer to Section 5.3.5. 
4.4.4 
Definition of Maximum Tolerated Dose  
The MTD is defined as the maximum dose at which no more than 16.7% patients in a single 
cohort experiences a DLT in the first cycle (Cycle 1 Days 1-28).  
4.4.5 
Definition of Recommended Phase II Dose  
The decision regarding the RP2D was based on the following considerations:  
• MTD if reached 
• PK with or without associated safety and preliminary efficacy findings  
These criteria constituted the basis for RP2D determination that was agreed by both the sponsor 
and the investigators. 
Based on evaluation of data collected during the dose escalation phase, the RP2D has been 
determined to be 700 mg once daily. 

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4.5 
Dose Expansion Stage (Stage 2)  
The safety, tolerability, PK, and preliminary efficacy of HMPL-523 at the MTD/RP2D, which 
has been determined to be 700 mg once daily, will be further evaluated in patients with relapsed 
or refractory non-Hodgkin’s and Hodgkin’s lymphomas. 
Amendment 4:  
As described in Amendment 4, based on strategic evaluation of the development of HMPL-523, 
the selected lymphoma cohorts were closed as of 30 November 2022: MCL, FL, MZL, 
WM/LPL, PTCL, and CBCL. Enrollment was continued in the CLL and HL cohorts. 
The number of patients enrolled in each cohort as of Amendment 5 is shown in Table 2.   
Amendment 5 
The last patient was enrolled on
. Upon implementation of Protocol 
Amendment 5, a total of 48 patients were enrolled in the dose-expansion portion at the time of 
enrollment closure, and approximately 3 patients total were on  study treatment (Table 2).  
Table 2 
Dose Expansion Cohorts  
Disease Cohort 
Enrollment as of 
Amendment 4 
(Approximate) 
Enrollment as of 
Amendment 5 
(Approximate) 
HL 
25 
25 
CLL 
1 
1 
CLL post BTK** 
6 
7 
Follicular lymphoma 
2 
2 
Mantle cell lymphoma 
2 
2 
Marginal zone lymphoma 
1 
1 
Waldenström’s 
macroglobulinemia/lymphoplasmacytic 
lymphoma 
1 
1 
PTCL 
9 
9 
CBCL 
0 
0 
Abbreviations: BCL-2 = B-cell lymphoma-2; BTK = Bruton tyrosine kinase; CBCL = cutaneous B-cell lymphoma; 
CLL =chronic lymphocytic leukemia; HL = Hodgkin’s lymphoma; PTCL = peripheral T-cell lymphoma. 
**Approximately 10 patients in the CLL post-BTK cohort will have prior BCL-2 inhibitor therapy. 
Patients will receive HMPL-523 at the MTD/RP2D, which has been determined to be 700 mg 
once daily, in every 28-day treatment cycle until disease progression, death, intolerable toxicity, 
at investigator’s discretion that the patient can no longer benefit from the study treatment, patient 
withdrawal from the study, or the end of the study, whichever comes first. 
4.6 
End of Study  
The end of the study is defined as the date on which all patients have their last visit or 2 years 
after the last patient has his/her first visit, whichever comes first.  
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4.7 
Rationale for Study Design  
4.7.1 
Rationale for the Starting Dose and the Dose Schedule  
As of the data cutoff date of 10 May 2022, HMPL-523 has completed a Phase I dose escalation 
study in healthy volunteers in Australia (https://clinicaltrials.gov/ct2/show/NCT02105129), 
a Phase Ib double-blind study in patients with primary ITP in China 
(https://clinicaltrials.gov/ct2/show/NCT03951623), a Phase I combo-therapy study in patients 
with AML in China (https://clinicaltrials.gov/ct2/show/NCT03483948), and a dose escalation 
and expansion Phase I trial in patients with relapsed/refractory lymphoma in China 
(https://clinicaltrials.gov/ct2/show/NCT02857998).  
In the US and EU, HMPL-523 has successfully completed dose escalation at various centers 
(https://clinicaltrials.gov/ct2/show/NCT03779113). 
Safety data from completed dose escalation cohorts of ongoing Phase I clinical trials in both 
China and Australia show that HMPL-523 is tolerable. 
The exposures (AUC and Cmax) of HMPL-523 at steady state in both the Australian and Chinese 
studies increased with the dose increase from 100 to 800 mg.  
The minimum effective dose in patients with hematologic malignancies was expected to be 
approximately 600 mg QD. 
Table 3 summarized the human PK data of HMPL-523 at steady state at 200 and 400 mg QD in 
2 clinical trials as well as the animal toxicokinetic data at the 
 in the 4-week and 13-
week toxicity studies. In addition, the free exposures (AUCtau,u and Cmax,u) were also calculated 
with the free fraction values in human, rat, and dog plasma. Overall, the exposures of HMPL-523 
were lower in Australia than in China. For 100 mg QD, based on the free exposures (AUC), the 
safety window is approximately  fold and 
 fold when based on the 
 of the 13-week 
toxicity studies in dogs and rats, respectively. 
Table 3  
HMPL-523 PK and Toxicokinetic Summary  
Study 
Dose 
Parameters 
fup 
AUCtau 
(h•ng/mL) 
AUCtau,u 
(h•ng/mL) 
Cmax 
(ng/mL) 
Cmax,u 
(ng/mL) 
2015-523-00AU1 
100 mg QD 
0.17 
372 
63.2 
27.1 
4.61 
200 mg QD 
0.17 
536 
91.1 
44.4 
7.55 
400 mg QD 
0.17 
1430 
243 
101 
17.2 
2015-523-00CH1 
200 mg QD 
0.17 
1065 
181 
88.1 
15.0 
400 mg QD 
0.17 
3101 
527 
224 
38.1 
4-week toxicity in rats 
 mg/kg 
 
13-week toxicity in 
rats 
 mg/kg 
 
4-week toxicity in dogs 
 mg/kg 
 
13-week toxicity in 
dogs 
 mg/kg 
 
CCI
C
C
C
CCI
CCI
CCI
CCI
C
CCI

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Abbreviations: AUC = area under the concentration-time curve; Cmax = maximum plasma concentration; fup = free 
fraction values; PK = pharmacokinetic; QD = once daily. 
Note: All PK and toxicokinetic data shown here were gender-combined. 
In summary, nonclinical toxicity studies and 3 Phase I dose escalation trial data provided 
sufficient rational to set 100 mg/day as the initial dose in this Phase I clinical trial. 
4.7.2 
Rationale for Selection of Patient Population  
The clinical data have indicated that SYK is abnormally activated in B-cell lymphomas. In vitro 
experiments have also demonstrated that the SYK molecule plays a major role in the activation 
and proliferation of B-NHLs as abovementioned in Section 2.3. For example, down-regulation of 
SYK was able to reduce proliferating signal as well as expansion of DLBCL cells and 
spontaneous lymphoma cells from transgenic mice (Cheng et al 2011). These experiments 
indicate that over-activated SYK plays an important role in promoting the activation of B-NHLs. 
Therefore, inhibition of SYK activation in B-NHLs may block signal transduction, resulting in 
inhibition of B lymphoma cell proliferation or induction of tumor cell apoptosis. This approach 
may provide a powerful tool for the treatment of B-cell lymphomas. 
The patient population of Stage 1, ie, patients with relapsed or refractory lymphoma who have 
exhausted approved therapy options (as defined in Section 5.1.1), is selected because these 
patients have exhausted all options offered by the standard of care. Based on the previous clinical 
data of HMPL-523 in a similar population, HMPL-523 might be offered as an alternative to these 
patients. The inclusion criterion of the Eastern Cooperative Oncology Group (ECOG) 
performance status score of 0-1 has been selected to make it easy to attribute toxicities to disease 
or the introduction of this agent. 
Patients with relapsed or refractory CLL/SLL, MCL, FL, MZL, PTCL, CBCL, WM/LPL, HL, 
and CLL post-BTK exposure are selected for Stage 2 because the nonclinical and clinical data, 
which is mentioned in Sections 2.2 and 2.3, suggest that patients with these types of lymphoma 
are more likely to be benefit from the treatment of the SYK inhibitor.  
Due to strategic evaluation of HMPL-523 development in the US and EU, Protocol Amendment 
4 will close enrollment to all NHL expansion cohorts (MCL, FL, MZL, WM/LPL, PTCL, and 
CBCL). This decision was not due to any patient safety or efficacy concerns related to HMPL-
523 therapy. Expansion cohorts for CLL and HL will continue to enroll.  
4.8 
Outcome Measures  
4.8.1 
Primary Safety Outcome Measure  
• Incidence of DLTs by National Cancer Institute (NCI) CTCAE v5.0 grade and associated 
dose of HMPL-523  
4.8.2 
Secondary Safety Outcome Measures  
• Incidence of TEAEs by NCI CTCAE v5.0 grade and associated dose of HMPL-523  
• Incidence of Grade 3 and 4 abnormalities in safety-related laboratory parameters and 
associated dose of HMPL-523 
• Incidence of TEAEs leading to HMPL-523 dose interruption, reduction, or treatment 
discontinuation 

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4.8.3 
Pharmacokinetic Outcome Measures  
• 
Cmax 
• 
Tmax 
• Area under the concentration-time curve in a selected time interval (AUC0-t) 
• Area under the concentration-time curve during 1 dosing interval (AUCtau) 
• Apparent clearance (CL/F) 
• Minimum plasma concentration (Cmin) 
• 
 
• AR 
4.8.4 
Efficacy Outcome Measures  
• ORR is defined as the proportion of patients who have a BOR of CR or PR. The BOR in 
an individual patient is the best response recorded from the start of treatment until 
progression or the date of any further anticancer therapy, whichever comes first.  
• DoR is defined as the time from when the first response (CR or PR) was achieved until the 
first documentation of definitive disease progression or death from any cause, whichever 
occurs first. 
• TTR is defined as the time from the date of the first dose of the study drug to first 
response (CR or PR). 
• PFS is defined as the time from the date of the first dose of the study drug until the date of 
disease progression or death due to any cause. 
Efficacy in different subgroups will be evaluated according to specified guidelines/criteria: 
• Chronic lymphocytic leukemia: the modified International Workshop on CLL guideline 
(modified International Workshop on Chronic Lymphocytic Leukemia [IWCLL] 2008, 
see Appendix 4)  
• WM/LPL: consensus of international workshops on WM (IWWM-7 Consensus, see 
Appendix 5) 
• Lymphomas other than CLL or WM/LPL: Lugano Response Criteria for Hodgkin and 
NHL (Cheson et al 2014, see Appendix 6) 
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5 
MATERIALS AND METHODS  
5.1 
Patients  
5.1.1 
Inclusion Criteria  
Patients must meet the following criteria to be eligible for study entry: 
1. Signed informed consent form (ICF). 
2. Age ≥ 18 years. 
3. ECOG performance status of 0 or 1. 
4. Histologically confirmed lymphoma, including HL and NHL. 
In the dose expansion stage, the tumor types may be restricted to any or all of the 
following tumor types. There may be approximately 10 patients in each cohort depending 
on response signals suggesting efficacy, except for HL cohort with 25 patients and 
2 identified cohorts with approximately 20 patients per cohort: relapsed or refractory 
CLL/SLL (n = 10), and CLL/SLL post‑BTK exposure (n = 20), MCL, FL (Grade 1-3a) 
(n = 20), MZL, WM/LPL, PTCL, and CBCL. As of Amendment 5, the study was closed 
to new enrollment.    
5. Patients with relapsed or refractory lymphoma who have exhausted all approved therapy 
options as defined below: 
a. Refractory to any prior regimen, defined as no response (CR or PR) to previous 
therapies, or progression within 6 months of completion of the last dose of prior 
therapy. 
b. Those who can no longer tolerate/withstand cytotoxic chemotherapy and/or available 
standard of treatment/care. Where safety profile and risks of toxicity of other 
treatment options far outweigh any possible clinical benefit. 
c. Those with no curative standard of treatment or where available treatments are not 
reasonable or do not make sense. In particular, in the opinion of the attending primary 
investigator, those who will benefit from a new class of compound with a different 
mechanism of action. 
d. Patients enrolled in the post-BTK CLL cohort should have either disease progression 
or intolerance to prior BTK inhibitor therapy to enroll. Approximately 10 out of the 
20 patients in this cohort should also have disease progression or intolerance to prior 
BCL-2 (venetoclax or BCL-2 inhibitor on clinical trial) exposure. 
6. In the dose expansion stage, patients must have measurable disease for an objective 
response assessment, except for patients with CLL and WM/LPL. 
NOTE: Measurable disease with FL, MCL, MZL, PTCL, CBCL, HL, or SLL is defined 
as at least 1 bi-dimensionally measurable lesion (nodal disease > 1.5 cm, non-nodal 
disease > 1 cm in its longest dimension by computed tomography [CT] scan), as defined 
in Appendix 6. 
7. Availability of tumor sample for patients in dose expansion cohorts: This may be an 
archival tissue sample obtained after most recent therapy or a fresh biopsy; if tumor 
sample is not available, the sponsor may waive the requirement after discussion 
8. Expected survival of more than 24 weeks as determined by the investigator. 

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9. Patients with prior treatment with any SYK inhibitors (eg, fostamatinib) are eligible for 
escalation stage 1. However, during expansion stage 2, only patients who discontinue 
SYK inhibitors for reasons other than disease progression are eligible. 
10. Male patients must agree to use a condom and female patients of child-bearing potential 
must agree to use highly effective contraceptive measures for 30 days after the last dose 
of study drug. These highly effective contraceptive measures, as defined by the Clinical 
Trials Facilitation Group, include combined hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, and transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, and implantable), 
intrauterine contraceptive device, intrauterine hormone release system, bilateral tubal 
occlusion, or a vasectomized partner, provided that male partner is the sole sexual partner 
of the female patient. Postmenopausal females (women who have not had menses for 
at least 1 year without an alternative medical cause) are exempt from this criterion. 
5.1.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
1. Patients with primary central nervous system lymphoma. 
2. Any of the following laboratory abnormalities: 
a. Absolute neutrophil count 1.0×109/L  
b. Hemoglobin 80 g/L 
c. Platelets < 50 × 109/L 
NOTE: In the dose expansion stage, patients with cell counts below the thresholds listed 
above may be considered eligible if, in the investigator’s opinion, the reason is believed 
to be splenic involvement or bone marrow infiltration. The investigator will discuss the 
eligibility of such patients with the sponsor, and only upon approval (confirmed in 
writing) by the sponsor will a patient with cell counts below the thresholds be enrolled in 
the study. 
In the dose expansion stage, patients with Grade ≤2 neutropenia per CTCAE 5.0 and/or 
thrombocytopenia and with confirmed splenic involvement or bone marrow infiltration 
are eligible. 
3. Inadequate organ function, defined by the following: 
d. Total bilirubin 1.5  ULN with the following exception: 
o Patients with known Gilbert’s disease who have serum bilirubin level ≤ 3  ULN 
and normal AST and ALT may be enrolled. 
e. AST and/or ALT 2.5  ULN with the following exception: 
o In the dose expansion stage, patients with documented disease infiltration of the 
liver may have AST and ALT levels ≤ 5  ULN. 
f. Estimated creatinine clearance (CrCl) per Cockcroft-Gault: 
o Dose escalation stage of trial (Stage 1) – CrCl < 40 mL/min 
o Dose expansion stage of trial (Stage 2) – CrCl < 30 mL/min 

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g. Serum amylase or lipase > ULN 
h. International normalized ratio (INR)1.5  ULN or activated partial thromboplastin 
time (aPTT) 1.5  ULN 
NOTE: Patients may be considered for the study if kidney function is impaired, but 
this impairment is believed to be a result of the patient’s underlying disease. The 
investigator will discuss the eligibility of such patients with the sponsor, and only 
upon approval (confirmed in writing) by the sponsor will a patient with impaired 
kidney function due to underlying disease be enrolled in the study. 
4. Patients with clinically detectable second primary malignant tumors at enrollment or 
other malignant tumors within the last 2 years (with the exception of radically treated 
basal cell or squamous cell carcinoma of the skin, in situ cervix, or in situ breast cancer). 
5. Any anticancer therapy, including chemotherapy, hormonal therapy, biologic therapy, 
vaccine, or radiotherapy, within 3 weeks prior to the initiation of study treatment.  
6. Herbal therapy within 1 week prior to the initiation of study treatment (3 weeks for 
St. John’s wort). 
7. Prior administration of radioimmunotherapy within 3 months before the initiation of 
study treatment.  
8. Use of strong CYP3A4 inhibitors or inducers and substrates of CYP3A4, CYP2B6, or 
CYP1A2, which are identified as narrow therapeutic drugs, within 14 days prior to the 
initiation of study treatment (refer to Appendix 7). 
9. AEs from prior anticancer therapy that have not resolved to Grade ≤1, except for 
alopecia. 
10. Prior autologous stem cell transplant within 6 months prior to the initiation of study 
treatment.  
11. Prior allogeneic stem cell transplant within 6 months prior to the initiation of study 
treatment or with any evidence of active graft versus host disease or requirement for 
immunosuppressants within 28 days prior to the initiation of study treatment. 
12. Clinically significant active infection (eg, pneumonia) and interstitial lung diseases: see 
Appendix 14 for coronavirus disease 2019 (COVID-19) risk assessment and vaccine 
guidance. 
13. Major surgical procedure within 4 weeks prior to the initiation of study treatment. 
14. Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
or current known active infection with human immunodeficiency virus (HIV), hepatitis B 
virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV). 
− Active infection is defined as one requiring treatment with antiviral therapy or 
presence of positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] 
and/or total hepatitis B core antibody [HBcAb]) or HCV antibody. 
− Patients who test positive for HBcAb are eligible only if test results are also positive 
for hepatitis B surface antibody and polymerase chain reaction (PCR) is negative for 
HBV DNA. 
− Patients who are positive for HCV serology are only eligible if test result for HCV 
ribonucleic acid (RNA) is negative. 
− CMV antibody will be tested at screening, and if positive, viral load will be 
determined. Patients who are positive for CMV antibody are only eligible if the test result 
for CMV DNA is negative.  

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15. Pregnant (positive serum beta human chorionic gonadotropin [β-HCG] or urine test) or 
lactating women. 
16. New York Heart Association Class II or greater congestive heart failure. 
17. Congenital long QT syndrome or corrected QT interval with Fridericia (QTcF) 
> 480 msec. 
18. Current use of medication known to cause QT prolongation or Torsades de Pointes (see 
full list in Appendix 16). 
19. History of myocardial infarction or unstable angina within 6 months prior to the initiation 
of study treatment.  
20. History of stroke or transient ischemic attack within 6 months prior to the initiation of 
study treatment. 
21. Inability to take oral medication, prior surgical procedures affecting absorption, or active 
peptic ulcer disease. 
22. Treatment in a clinical study within 30 days prior to the initiation of study treatment. 
23. Ongoing psychiatric disorders, in particular, patients with depression and/or suicidal 
tendencies. 
24. Patients with pathological or organic fractures, in particular, those of unknown etiology.  
25. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or renders the patient at high risk from treatment 
complications. 
5.2 
Method of Treatment Assignment  
This is a multicenter, open-label study to evaluate the safety, tolerability, PK, and preliminary 
efficacy of HMPL-523 in patients with relapsed or refractory lymphoma. Patients will be 
assigned to dose levels sequentially in the dose escalation stage. In the dose expansion stage, 
patients will be assigned by the sponsor. Upon completion of all screening evaluations and 
verification that the patient has met all eligibility criteria, the sites will contact the sponsor to 
confirm patient eligibility.  
5.3 Study Treatment  
5.3.1 
Formulation, Packaging, and Handling  
Three strengths of HMPL-523 tablets (100, 150, and 200 mg based on the free base) will be used 
for clinical studies. The drug products are tablets that are packaged in white high-density 
polyethylene bottles. The tablets are composed of widely used pharmaceutical excipients (United 
States Pharmacopeia grade or equivalent) and HMPL-523 
drug substance. The tablets 
should be stored below 25°C. 
For further details, see the HMPL-523 IB. 
5.3.2 
Drug Labeling  
The investigational drug will be labeled as required by local regulations. 
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5.3.3 
Drug Accountability  
All study drugs required for this study will be provided by HUTCHMED Limited or the 
authorized contract research organization (CRO). The recipient will acknowledge receipt of the 
drug by completing and keeping the appropriate documentation form indicating shipment content 
and condition. Damaged supplies will be replaced. 
Accurate records of all study drugs received by, dispensed from, and returned to the study site 
will be recorded in the source documentation. 
The study drug will be disposed of at the study site according to the study site’s institutional 
standard operation procedure and local regulations with the appropriate documentation upon 
approval of sponsor. 
5.3.4 
Dosage, Administration, and Compliance  
Dose levels to be potentially tested in this study include 100, 200, 400, 600, and 800 mg/day 
orally. 
The proposed dose of HMPL-523 is as specified in HMPL-523 should be taken with 
approximately 8 ounces (240 mL) of water under fed conditions, ideally within 30 minutes after 
meal but not later than 90 minutes after a meal (Table 1 ). Patients are advised to take QD dosage 
as required in cohorts/groups. All efforts should be made to ensure that the patient takes 
HMPL-523 at approximately the same time every day during their participation in the study and 
ideally within a ±4-hour window.  
HMPL-523 should be taken with approximately 8 ounces (240 mL) of water under fed 
conditions, ideally within 30 minutes after meal but not later than 90 minutes after a meal 
(Table 1). The administration time should be accurately recorded in the patient diary.  
In the study, patients will not be allowed to make up missed doses during any calendar day; 
patients will resume dosing at their next scheduled dose. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Sections 5.4 and 5.7. 
Any overdose or incorrect administration of the study drug should be noted on the patient’s 
source documentations and case report form (CRF). AEs associated with an overdose or 
incorrect administration of the study drug should be recorded on the patient’s source documents 
and the AE page of the CRF. 
5.3.5 
Post-Trial Access to HMPL-523  
The sponsor does not have any scheduled plans to provide HMPL-523 or any other study 
interventions for patients after the end of the study or for any patient who discontinues or 
withdraws from the study.  
The sponsor will evaluate whether to continue providing HMPL-523 after the study is complete. 
In the event that the sponsor deems post-trial access to HMPL-523 to be appropriate, the sponsor 
may offer post-trial access to the HMPL-523 free of charge to eligible patients as outlined below. 
A patient will be eligible to receive the study drug after the end of the study if all of the 
following conditions are met: 

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• The patient has relapsed/refractory lymphoma that requires continued study drug 
treatment for his or her wellbeing. 
• The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
A patient will not be eligible to receive the study drug after the end of the study if any of the 
following conditions are met: 
• The study drug is commercially marketed in the patient’s country and is reasonably 
accessible to the patient (ie, it is covered by the patient’s insurance or would not otherwise 
create a financial hardship for the patient). 
• The sponsor has discontinued development of the study drug for lymphoma in the specific 
region or data suggest that the study drug is not effective for lymphoma. 
• The sponsor has reasonable safety concerns regarding the study drug as treatment for 
lymphoma. 
• Provision of the study drug is not permitted under the laws and regulations of the patient’s 
country. 
5.4 
Dose Delays and Modification  
5.4.1 
During Dose-Limiting Toxicity Assessment Window  
If a patient experiences a TEAE of Grade 3 or Grade 4 and/or unacceptable toxicity including a 
DLT not attributable to the disease or disease-related processes under investigation, dosing will 
be interrupted and supportive therapy will be administered as required in accordance with local 
practices/guidelines.  
Patients who experience a DLT may resume dosing at the same or the previous lower dose level 
at the discretion of the investigator if the toxicity is resolved or improved to baseline level. If a 
patient experiences an unacceptable toxicity at the reduced dose level, he/she will be 
discontinued from treatment. No patient will have his/her dose reduced by more than 2 dose 
levels. Once dose is reduced, it cannot be re-escalated. 
If a clinically significant TEAE or unacceptable toxicity that does not meet the definition of a 
DLT is observed, the patient may receive subsequent doses to complete the dosing schedule, 
provided that the TEAE is improved to CTCAE Grade ≤2 within 2 weeks.  
Dose reduction in patients without DLT is not permitted in the DLT assessment window without 
the sponsor’s approval.  
5.4.2 
After Dose-Limiting Toxicity Assessment Window in Stage 1 or in Stage 2  
After the DLT assessment window in Stage 1 or in Stage 2, the dose of HMPL-523 may be 
interrupted and/or reduced to the next lower dose level (600 mg) if any of the following are 
observed: 
• Grade 3 or 4 hematologic toxicity 
• Grade 3 or 4 nonhematologic toxicity (except for alopecia and skin eruption, nausea, 
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Treatment with HMPL-523 should be withheld until the toxicity resolves to CTCAE Grade ≤2. 
Dosing may then be resumed at either the same dose level or the previous lower dose level if the 
toxicity is improved to CTCAE Grade ≤2 within 2 weeks at the investigator’s discretion. Consult 
with the sponsor if a treatment hold longer than 2 weeks is required for recovery from toxicity. If 
treatment is resumed at the same dose and the patient experiences the same toxicity over 
Grade 2, the dose should be reduced (600 mg) after resolution of the event. If the dose is reduced 
in Stage 2, additional PK sampling will be required at steady state (please refer to Appendix 3 
and Section 5.9.1). If the patient continues to experience unacceptable toxicity, a second dose 
reduction (400 mg) is permitted. Every patient is allowed to reduce dosing levels of HMPL-523 
only twice. If a patient continues to experience unacceptable toxicity after 2 dose reductions, or 
if HMPL-523 dosing is interrupted for > 14 consecutive days due to toxicity, treatment should be 
discontinued, unless otherwise agreed between the investigator and the sponsor. 
5.4.3 
Recommendations for Management of Toxicity Including Dose Modification  
Recommendations for management of identified toxicities (pulmonary toxicities [including 
pneumonia/pneumonitis], gastrointestinal toxicities, hepatic toxicity, infection, neutropenia, 
thrombocytopenia, anemia, rash/cutaneous skin reactions, and nausea/vomiting), including dose 
modification, are provided in Appendix 15. Approved prescribing information for other drugs 
used to treat relapsed or refractory lymphoma should be utilized to guide management of 
toxicities associated with these drugs.   
5.5 
Concomitant Therapy and Food  
5.5.1 
Permitted Therapy  
Concomitant therapy includes any medication (eg, prescription drugs, over the counter drugs, 
homeopathic remedies, or nutritional supplements) used by a patient from 7 days prior to the 
screening visit to 30 days after the end of treatment or early termination. All such medications 
should be reported to the investigator and recorded on the Concomitant Medications page of the 
electronic case report form (eCRF). 
5.5.2 
Prohibited Therapy and Food  
CYP3A is one of the CYP enzymes involved in the metabolism of HMPL-523, but the extent of 
its involvement is unclear. There is no clinical data on the effect of CYP3A inhibitor or inducer 
on HMPL-523 PK at this time. Therefore, strong inhibitors or inducers of CYP3A are prohibited 
throughout the study. 
In vitro data suggested that HMPL-523 has the potential to induce CYP3A, CYP1A2, and 
CYP2B6. Substrates of CYP3A4, CYP2B6, or CYP1A2 that are identified as narrow therapeutic 
drugs are prohibited during the study; CYP3A4/5, CYP2B6, and CYP1A2 sensitive substrates 
should be used with caution. 
In vitro data suggested that HMPL-523 
 has the potential to inhibit P-gp, BCRP, and 
MATE1/2-K, but the clinical relevance is unknown at this moment. Based on these findings, 
concomitant medications that are sensitive substrates of P-gp, BCRP, or MATE1/2-K identified 
as narrow therapeutic window drugs should be avoided during the study as far as possible unless 
considered essential by the investigator, in which case patients must be monitored closely for 
potentially reduced efficacy or increased toxicity due to DDIs.  
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Lists of prohibited drugs and those that should be used with caution are provided in Appendix 7. 
These lists are not intended to be exhaustive; please refer to the full prescribing information for 
all drugs prior to concomitant use with HMPL-523. 
Concomitant medications that are known to prolong the QT interval should be avoided 
(Appendix 16). If the use of any of these drugs is necessary, the risks and benefits should be 
discussed with the medical monitor prior to its concomitant use with HMPL-523. 
The patients shall not receive other antitumor therapies or procedures concomitantly throughout 
the study, including chemotherapy, radiotherapy, biologic therapy, stem cell transplantation, or 
other investigational drug therapies for study disease.  
Herbal medicines with antitumor effects shall not be used during the study. Patients who take 
any of these products will be considered to have experienced treatment failure, and treatment 
with HMPL-523 will be discontinued. 
If a patient needs to undergo palliative local radiotherapy to relieve disease-related symptoms 
(such as local radiotherapy to relieve cancer bone pain), the patient may resume administration 
of the study investigational drug 7 days after the local radiotherapy is over but should meet the 
following conditions:  
• The patient’s radiotherapy-related toxicity has recovered to Grade < 2. 
• The tumor has not progressed. 
If a patient requires localized surgery for palliative purposes to relieve disease -related symptoms 
or to treat second primary tumors, the following may be considered after discussion with the 
sponsor to ensure that the surgical procedure does not involve target lesions. This would also 
require planning for a sufficient hold of investigational drug before and after the surgery to 
ensure adequate wound healing:  
• 
Stopping HMPL-523 at least 1 week prior to surgery. 
• 
In the case of a major surgery, holding HMPL-523 at least 2 weeks post-surgery to ensure 
proper wound healing and no other surgery-related AEs are ongoing. 
• 
Evaluating primary lymphoma/CLL to ensure there is no disease progression during the 
treatment hold. 
• 
Ensuring no other prohibited concomitant therapy is planned.  
No grapefruit or grapefruit juice (except small amounts as described in Appendix 7), excessive 
alcohol, or any recreational drugs will be allowed during the study. 
HMPL-523 shows pH-dependent solubility (ie, solubility at pH 6.8 < solubility at pH 1 to 2) and 
may be less well absorbed as the gastrointestinal pH increases. Subjects should avoid 
concomitant use of acid-reducing agents during treatment with HMPL-523. If concomitant use of 
an acid-reducing agent is unavoidable, H2-antagonist (eg, famotidine, ranitidine, and nizatidine) 
may be used but should be administered approximately 10 hours before or 2 hours after 
HMPL-523 dosing. Antacid may be used, but the antacid dose should be administered at least 
2 hours before or 2 hours after HMPL-523 dosing. Proton pump inhibitors (eg, esomeprazole, 
lansoprazole, and pantoprazole) should be avoided during the study. If the investigator believes it 
is necessary for the patient to use proton pump inhibitor, consent of the sponsor-appointed 
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during use for a possible reduction in efficacy due to drug interactions. The dose regimen start 
date and end date of proton pump inhibitor should be recorded. 
5.6 
Study Assessments  
5.6.1 
Definitions of Study Assessments  
All patients will be closely monitored for safety and tolerability throughout the study. 
Continuous dosing with HMPL-523 will be offered to patients until disease progression, death, 
intolerable toxicity, at investigator’s discretion that the patient can no longer benefit from the 
study treatment, patient withdrawal from the study, or the end of study.  
The schedule of assessments is provided in Appendix 1, and the schedule of PK sample 
collection is provided in Appendix 2 and Appendix 3. Unless otherwise indicated, the visit 
window during the treatment period is ± 3 days (± 1 day during the DLT observation window). 
Except for the electrocardiogram (ECG), echocardiogram/multigated acquisition scan (MUGA), 
bone marrow biopsy, and/or aspirate and tumor assessment, all the assessments should be 
performed before dosing if the study drug is to be taken on the visit day. Unscheduled 
assessments can be performed if there is a clinical indication. 
5.6.2 
Informed Consent Forms and Screening Log  
Written informed consent for participation in the study must be obtained from the study 
participant before any study specific screening tests or evaluations using an ICF approved by the 
local Institutional Review Board/Independent Ethics Committee (IRB/IEC) that contains all 
elements required by ICH E6(R2) and in compliance with country specific regulation and 
guidelines before any study-specific screening tests or evaluations are performed. The original 
signed ICFs for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site within the subject source documentation. 
If a subject cannot sign the ICF (eg, due to an inability to read or write), a legally acceptable 
representative of the subject must sign the ICF. If both 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. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before Cycle 1 Day 1. Screening tests will be performed within 21 days 
preceding the day of the first dose of the study drug, unless otherwise specified. Results of 
standard of care tests performed before the patient has provided written informed consent and 
within 21 days preceding the day of the first dose of the study drug may be used; such tests do 
not need to be repeated for screening. The investigator will maintain a screening log to record 
details of all patients screened and the reasons for screening failures. Eligibility verification 
forms will be maintained by investigator and confirmed with sponsor before Cycle 1 Day 1. 

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5.6.3 
Medical History and Demographic Data  
Medical history and demographic data will be collected at screening. Medical history includes 
clinically significant diseases or symptoms; surgeries; cancer history (including constitutional 
symptom/B symptoms [unexplained weight loss ≥ 10% over previous 6 months, fever 
> 38°C/100.5°F for 2 or more weeks without other evidence of infection, and night sweats for 
more than 1 month without evidence of infection]); prior cancer diagnosis (including tumor type, 
initial diagnosis date, immunohistochemistry [IHC], flow cytometry, other pathological 
findings); prior anticancer therapies, procedures, and related outcomes; and use of tobacco, 
alcohol, and drugs of abuse prior to the screening visit.  
Demographic data will include date of birth, gender, and self-reported race and ethnicity. 
5.6.4 
Concomitant Medication/Concomitant Procedure  
Any concomitant medication/procedure from within 7 days prior to the screening visit to 30 days 
after the end of treatment or early termination will be recorded. 
5.6.5 
Eastern Cooperative Oncology Group Performance Status  
ECOG performance status (Appendix 8) should be assessed by the same study personnel at 
screening, Days 1 and 15 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of every cycle from 
Cycle 3 onwards, and at study completion or early termination, if possible. Care will be taken to 
accurately score performance status, especially during screening for study eligibility purposes.  
5.6.6 
Rai/Binet Staging, Ann Arbor Staging, and International Prognostic Index  
Appendix 9 and Appendix 10 provide a description of Rai and Binet staging, respectively, for 
patients with CLL. 
Appendix 11 provides a description of Ann Arbor staging for patients with lymphoma other than 
CLL. 
Appendix 12 provides information on the different International Prognostic Index (IPI) for 
patients with FL, MCL, WM/LPL, and other lymphomas. 
Rai/Binet staging, Ann Arbor staging, and IPI score will be collected at screening.  
Prognostic factors of CLL, including cytogenetic testing result (eg, chromosome 17p del) and 
immunoglobulin heavy-chain variable (IGHV) mutation status, should be collected at screening 
if available.  
5.6.7 
Vital Signs  
Vital signs will be collected at screening; Days 1, 8, 15, and 22 of Cycle 1; Days 1 and 15 of 
Cycle 2; Day 1 of every cycle from Cycle 3 onwards; and at study completion or early 
termination. Vital signs include measurements of body temperature (axillary, oral, or tympanic), 
heart rate, respiratory rate, and systolic and diastolic blood pressures while the patient is in a 
seated position. The patient should be seated for 5 minutes before the measurement of blood 
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5.6.8 
Physical Examination  
Physical examination refers to the examination of all body systems, including assessment of 
head, eyes, ears, nose, larynx, neck, heart, chest, abdomen, limbs, skin, lymph nodes, nervous 
system, general condition, height, and weight. Physical examination should be performed at 
screening; Days 1, 8, 15, and 22 of Cycle 1; Days 1 and 15 of Cycle 2; Day 1 of every cycle 
from Cycle 3 onwards; and at study completion or early termination. Height will be assessed 
only at screening. After screening, a change of physical signs from baseline and newly presented 
or patient-reported physical signs should be evaluated. As part of tumor assessment, limited 
physical examinations should also include the evaluation of the presence and degree of enlarged 
lymph nodes, skin lesions, hepatomegaly, and splenomegaly. 
5.6.9 
Laboratory Assessments  
Samples for hematology, chemistry panel, fasting lipid profile, serum amylase and lipase, 
coagulation, viral serology, urinalysis, pregnancy testing, and leukocyte immunophenotyping 
will be analyzed at the study site’s local laboratory. Laboratory assessments will include the 
following: 
• Hematology consists of complete blood count, including red blood cell count, 
hemoglobin, hematocrit, white blood cell count with differential (neutrophils, 
lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet count. 
Hematology should be tested at screening (preferably within 7 days prior to the first dose 
of the investigational medicine); Days 8, 15, and 22 of Cycle 1; Days 1 and 15 of Cycle 2; 
Day 1 of every cycle from Cycle 3 onwards; and at study completion or early termination. 
• The chemistry panel includes blood urea nitrogen or urea, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, fasting glucose, ALT, total and direct bilirubin, AST, ALP, 
lactate dehydrogenase (LDH), uric acid, protein (total), albumin, creatinine, and estimated 
CrCl (per Cockcroft-Gault). Chemistry should be tested at screening (preferably within 7 
days prior to the first dose of the investigational medicine); Days 8, 15, and 22 of Cycle 1; 
Days 1 and 15 of Cycle 2; Day 1 of every cycle from Cycle 3 onwards; and at study 
completion or early termination. 
• Serum beta 2-microglobulin (β2M) should be tested at screening (preferably within 7 days 
prior to the first dose of the investigational medicine), Day 1 of every cycle from Cycle 2 
onwards and at study completion or early termination. 
• Fasting lipid profile includes total cholesterol, high-density lipoprotein, low-density 
lipoprotein, and triglycerides. It should be tested at screening (preferably within 7 days 
prior to the first dose of the investigational medicine), Day 1 of every cycle from Cycle 2 
onwards, and at study completion or early termination. 
• Serum amylase and lipase should be tested at screening (preferably within 7 days prior to 
the first dose of the investigational medicine); Days 8, 15, and 22 of Cycle 1; Days 1 and 
15 of Cycle 2; Day 1 of every cycle from Cycle 3 onwards; and at study completion or 
early termination. 
• Coagulation (INR, aPTT, and PT) should be tested at screening (preferably within 7 days 
prior to the first dose of the investigational medicine), Day 1 of every cycle from Cycle 2 
onwards, and at study completion or early termination. 
• Viral serology should be tested at screening and include the following: 

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− HIV  
− HBV (HBsAg and HBcAb; also HBsAb and HBV DNA by PCR if the patient is 
HBcAb positive) 
− HCV (HCV antibody; also, HCV RNA by PCR if the patient is HCV antibody 
positive) 
− CMV (CMV antibody; also, CMV DNA by PCR if the patient is CMV antibody 
positive) 
• Urinalysis or dipstick (pH, specific gravity, glucose, protein, ketones, and blood), should 
be tested at screening (preferably within 7 days prior to the first dose of the investigational 
medicine); Day 15 of Cycle 1; Days 1 and 15 of Cycle 2; Day 1 of every cycle from Cycle 
3 onwards; and at study completion or early termination. If protein ≥ 2+ during the period 
of study treatment, a 24-hour urine test should be conducted within 1 week.  
• Leukocyte immunophenotyping (fluorescence-activated cell sorting subsets) should be 
done at screening (preferably within 7 days prior to the first dose of the investigational 
medicine), Day 15 of Cycle 1, and Day 1 of Cycle 2, which includes: 
− Determination of T lymphocyte/B lymphocyte/natural killer cell counts (CD3, CD19, 
CD4, CD8, and CD16/56) using a standard cell marker panel. 
− Patients with CLL: 17p del/TP53 mutation status at screening (optional).  
As of Amendment 5, leukocyte immunophenotyping will not be performed from Cycle 3 
onwards. 
• All women who are not postmenopausal (no menses for at least 1 year without alternative 
medical cause) will have a serum β-HCG test at screening and study completion or early 
termination.  
• WM/LPL related testing: 
− Serum immunoglobulins assessment (quantitative immunoglobulin assessment of 
IgM, IgA, and IgG) will be performed for patients with WM/LPL at screening 
(preferably within 7 days prior to the first dose of the investigational medicine), Day 1 
of every cycle from Cycle 2 onwards, study completion or early termination, quarterly 
during the follow-up period, and at the time of CR confirmation. 
5.6.10 
Electrocardiogram  
All ECGs are required to be performed using a 12-lead tracing. Electrocardiogram measurements 
will include PR interval, QRS interval, RR interval, QT/QTcF interval, and heart rate. 
Triplicate ECGs, approximately 2 minutes apart, should be performed at screening and pre-dose 
and at 4 hours ± 15 minutes post dose on Days 1 and 15 of Cycle 1 in order to evaluate 
concentration-QT relationship for HMPL-523. Single ECGs will be conducted at any time on 
Day 1 of Cycle 2. From Cycle 3 onwards, ECGs will be performed as clinically indicated. 
Electrocardiograms will be reviewed by the investigator to determine patient eligibility at 
screening. Additional ECGs and other cardiac monitoring will be provided as clinically indicated 
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5.6.11 
Echocardiogram/Multigated Acquisition Scan  
An echocardiogram/MUGA to assess left ventricular ejection fraction will be conducted at 
screening and at study completion or early termination. 
5.6.12 
Tumor and Response Evaluation  
All evaluable lesions should be assessed and documented at screening and re-assessed at each 
subsequent tumor evaluation, using blood test, physical examination, and contrast-enhanced CT 
scans (neck, chest, abdomen, and pelvis) for indolent NHL and/or positron emission tomography 
(PET)-CT for HL and aggressive NHL. Enhanced magnetic resonance imaging (MRI) may be 
used instead of enhanced CT scans in patients for whom CT scans are contraindicated.  
Tumor assessment will be conducted every 8 weeks (±7 days) for the first 24 weeks and every 
12 weeks (±7 days) thereafter until the patient has the first progression, starts new anticancer 
therapy, or dies. Patients who discontinue study drug due to reasons other than disease 
progression will remain on the study and will be followed quarterly for tumor assessment until 
the patient has their first progression, starts new anticancer therapy, or dies or until 12 months 
after their initial dose of the study drug. Tumor assessment will also be conducted at study 
completion or early termination (for reasons other than disease progression). 
The same imaging procedure and laboratory tests used to define evaluable lesions at baseline 
should be used throughout the study for each patient. 
5.6.13 
Bone Marrow Aspirate and/or Biopsy  
A bone marrow biopsy and/or aspirate is strongly recommended to be done at screening or up to 
3 months before the Cycle 1 Day 1 and for confirmatory purposes when the patient is considered 
to be likely CR with enhanced CT and other assessments or to confirm suspected PD based 
solely upon declines in the platelet count and/or hemoglobin. 
5.7 
Participant Completion/Discontinuation  
5.7.1 
Study Completion/Early Termination Visit  
Patients who complete the study or discontinue from the study early will be asked to return to the 
clinic at 307 days after the last HMPL-523 administration for a follow-up visit. Ongoing 
TEAEs thought to be related to HMPL-523 will be followed until the event has resolved to 
baseline grade, the event is assessed as stable by the investigator, new antitumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws from the study, or it has been 
determined that the study treatment or participation is not the cause of the AE, whichever comes 
first. 
Follow-up (Extended Monitoring) 
Patients who discontinue the study drug due to reasons other than disease progression will 
remain on the study and will be followed quarterly for tumor assessment until the patient has the 
first progression, starts new anticancer therapy, dies, or until 12 months after the initial dose with 
the study drug. The assessments to be performed at the follow-up visits are listed in the Schedule 
of Activities in Appendix 1. 

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5.7.2 
Participant Discontinuation  
All study participants have the right to voluntarily withdraw from the study at any time. In 
addition, the investigator has the right to discontinue a patient from the study at any time. 
Reasons for withdrawal from the study may include the following: 
• Patient withdrawal of consent at any time  
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
• Investigator or sponsor determines it is in the best interest of the patient 
• Noncompliance (eg, frequently misses doses, visits)  
The primary reason and date for discontinuation must be recorded on the appropriate CRF. 
5.7.3 
Study Treatment Discontinuation  
Patient must discontinue the study treatment in case of: 
• Disease progression 
• Intolerable toxicity 
• Use of other antitumor therapy as described in Section 5.5.2 
• Pregnancy with onset during study 
The primary reason for study treatment discontinuation should be recorded on the appropriate 
CRF. Discontinuation from HMPL-523 treatment does not mean discontinuation from the study, 
and the remaining study procedures should be completed as indicated in the study protocol.  
5.8 
Study/Site Discontinuation and Closure  
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. The sponsor will notify the investigator if the study is placed on hold, or if the 
sponsor decides to discontinue the study or close any site. If the study is prematurely terminated 
or suspended, the principal investigator will promptly inform study participants and the IRB/IEC. 
Study participants will be contacted, as applicable, and be informed of changes to the study visit 
schedule. Reasons for suspension or termination of the study may include the following: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
• Sponsor decision to discontinue clinical development of the drug in the specific 
indication or in the specific region 
If the study was suspended for safety or quality issues, the study may resume once concerns 
about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, 
IRB/IEC and/or participating regulatory authorities. For instance, the study must comply with the 
European Medicines Agency guideline, ‘Guideline on strategies to identify and mitigate risks for 
first-in-human and early clinical trials with investigational medicinal products.’ 

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5.9 
Pharmacokinetic and Pharmacodynamic Assessments  
5.9.1 
Collection Schedule  
Blood samples will be collected at scheduled time points specified in Appendix 2 for the dose 
escalation stage and in Appendix 3 for the dose expansion stage. Upon implementation of 
Protocol Amendment 5, PK samples for measurement of plasma concentrations of HMPL-523 
 will not be collected on Cycle 5 Day 1 and beyond in the dose expansion phase. 
Additional PK samples are allowed to be collected for patients who experience a clinically 
significant safety event to facilitate the understanding of the relationship between the safety 
event and the exposure of the investigational drug. These additional samples may be obtained as 
agreed upon by the investigator and the sponsor’s medical monitor. 
After each venous blood sampling, the exact time and dates of blood sampling will be recorded 
in the patient’s source documentation such as eCRF.  
Blood samples that remain after PK analysis of HMPL-523 in the dose escalation stage or 
pharmacodynamic samples collected fresh in the dose expansion stage may be used exclusively 
for exploratory purposes. These may include pharmacodynamics biomarker study such as to 
detect the changes of expression level of chemokines (CCL22, CXCL13, CCL3, etc) in plasma 
after HMPL-523 treatment. Pharmacokinetic and pharmacodynamic biomarker correlations will 
be analyzed. 
Tumor biopsies will be collected during the screening period for all patients in the dose 
expansion cohorts for the evaluation of candidate biomarkers including, but not limited to, 
biomarkers within tumor and/or within periphery as predictive biomarkers of efficacy of 
HMPL-523 (refer to Appendix 1). If it is not feasible to collect fresh biopsy or archival tissue, 
the sponsor may waive biopsy requirement in selected patients. For archival tissue, cell block or 
10 unstained slides should be submitted. For CLL patients or patients with bone marrow 
involvement, bone marrow biopsy can be submitted to fulfill the biopsy requirement. 
Samples remaining after the predefined analysis is complete may be held for future biomarker 
analysis. 
5.9.2 
 Samples Handling and Shipment   
Pharmacokinetic and pharmacodynamic sample processing, storage, and shipment instructions 
will be detailed in the laboratory manual. 
5.9.3 
Analytical Procedures  
Plasma samples will be analyzed to determine the concentrations of HMPL-523 
 
using a validated Liquid Chromatography-Tandem Mass Spectrometry method. If required, the 
plasma samples may be analyzed to document the presence of 
 using a 
qualified research method. 
Chemokines (CCL22, CXCL13, CCL3, etc.) levels in plasma samples will be determined using a 
multiplex array. 
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6 
ASSESSMENT OF SAFETY  
6.1 
Safety Plan  
Patients will be evaluated clinically and with standard laboratory tests before and at regular 
intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of TEAEs, physical examinations, and laboratory measurements. 
No evidence available at the time of the release of this protocol indicates that special warnings or 
precautions are appropriate, other than those will be noted in the HMPL-523 IB. 
6.2 
Safety Parameters and Definitions  
Safety assessments will consist of monitoring and recording AEs and SAEs; measurement of 
protocol-specified hematologic, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study drug. 
The sponsor or the sponsor’s designee is responsible for reporting the relevant SAEs to the 
applicable regulatory authorities and participating investigators, in accordance with ICH 
guidelines and local regulatory requirements. 
6.2.1 
Adverse Event  
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except those described in Section 6.4.8 
• Recurrence of an intermittent medical condition (eg, headache) not present at baseline 
• Any deterioration in a laboratory value or other clinical test (eg, ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from the study drug 
• Related to a protocol-mandated intervention, including those that occur prior to 
assignment of study treatment (eg, screening invasive procedures such as biopsies) 
6.2.2 
Serious Adverse Events  
An SAE is any AE that meets any of the following criteria: 
• Fatal (ie, the AE actually causes or leads to death, except for deaths caused by the 
progress of the disease) 
• Life threatening (ie, the AE, in the view of the investigator, places the patient at 
immediate risk of death; it does not refer to an event that hypothetically might have 
caused death if it were more severe) 
• Requires or prolongs inpatient hospitalization (excluding emergency or outpatient 
treatment) 

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• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions) 
• A congenital anomaly/birth defect in a neonate/infant born to a female patient or female 
partner of a male patient exposed to the investigational product(s) 
• Considered a significant medical event by the investigator (eg, may jeopardize the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
All AEs that do not meet any of the criteria for serious should be regarded as nonserious AEs. 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache). “Serious” is a regulatory definition and is based on 
patient or event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or vital functions. Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
CRF. 
SAEs are required to be reported by the investigator to the sponsor immediately (ie, no more 
than 24 hours after learning of the event; see Section 6.5.1 for reporting instructions and 
Section 6.3.1 for AE reporting period). 
All SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up. Depending on the event, follow-up may require additional tests or 
medical procedures as indicated and/or referral to a general physician or a medical specialist. All 
pregnancies that occur during participation in the study should be followed to determine the 
outcome of the pregnancy. 
6.2.3 
Protocol-Defined Events of Special Interest Expedited Adverse Events  
Nonserious AEs of special interest are required to be reported by the investigator to the sponsor 
immediately (ie, no more than 24 hours after learning of the event; see Section 6.5.1 for 
reporting instructions). AEs of special interest for this study include the following: 
• Hepatotoxicity, including cases of potential drug-induced liver injury (DILI) that include 
an elevated ALT or AST in combination with either elevated bilirubin or clinical jaundice, 
as defined by Hy’s Law (see Section 6.4.5 and Appendix 13) 
• Infective pneumonia 
• Interstitial lung disease/Pneumonitis 
• Kidney injury 
6.2.4 
Reporting of Dose-Limiting Toxicity  
Investigators will be required to confirm the presence of DLT for each patient enrolled in the 
dose escalation stage of the study within 2 business days after learning of the event. Investigators 
will also participate in regular teleconference SRC meetings with the medical monitor and the 
sponsor, during which they will report any DLTs observed during the DLT assessment window 
for each patient in the dose-escalation stage of the study. The SRC recommendation form will be 
completed and signed after the dose escalation meeting by the chairperson of the SRC. 

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6.3 
Methods and Timing for Capturing and Assessing Safety Parameters  
The investigator is responsible for ensuring that all AEs and SAEs (as defined in Section 6.2) are 
recorded on the patient’s source documentations and CRF and reported to the sponsor or the 
sponsor’s designee in accordance with protocol instructions. 
6.3.1 
Adverse Event Reporting Period  
After informed consent has been obtained, all SAEs regardless of attribution will be collected 
until 30 days after the last administration of study treatment or study discontinuation/termination, 
whichever is later. 
After initiation of study medications, all AEs regardless of attribution will be collected until 
30 days after the last administration of study treatment or study discontinuation/termination, 
whichever is later. After this period, the investigators should report only SAEs that are related to 
prior HMPL-523 treatment (see Section 6.7). 
6.3.2 
Eliciting Adverse Events  
A consistent methodology of nondirective questioning for eliciting AEs at all patient evaluation 
time points should be adopted. Examples of nondirective questions include: 
• “How have you felt since your last clinic visit?” 
• “Have you had any new or changed health problems since you were last here?”  
6.3.3 
Assessment of Severity and Causality of Adverse Events  
Investigators will seek information on AEs and SAEs at each patient contact. All AEs and SAEs, 
whether reported by the patient or noted by authorized study personnel, will be recorded in the 
patient’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the source documentation and CRF, the investigator will 
make an assessment of seriousness (see Section 6.2.2 for seriousness criteria), severity, and 
causality.  
Table 4 provides guidance for grading AE severity, and Table 5 provides guidance for assessing 
the causal relationship to the investigational product. 
AE grading should be in accordance with NCI CTCAE v5.0. For AE terms that cannot be found 
in CTCAE v5.0, general guidelines for AE grading (severity), provided in Table 4, will be used 
for assessing AE severity.  
Investigators should use their knowledge of the patient, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the study drug. To ensure consistency of causality assessments, 
investigators should apply the general guidelines provided in Table 5. 

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Table 4 
AEs Grading (Severity) Scale  
Grade 
Severity 
Alternate Descriptiona 
1 
Mild (apply event-specific NCI 
CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
2 
Moderate (apply event-specific NCI 
CTCAE grading criteria) 
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADLb 
3 
Severe (apply event-specific NCI 
CTCAE grading criteria) 
Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADLc 
4 
Very severe, life threatening, or 
disabling (apply event-specific NCI 
CTCAE grading criteria) 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
 
Abbreviations: ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria 
for Adverse Events; NCI = National Cancer Institute; SAE = serious adverse event. 
Note: NCI CTCAE v5.0: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Note: Regardless of severity, some events may also meet regulatory seriousness criteria. Refer to definition of a 
SAE (see Section 6.2.2). 
a 
Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported AE is not in 
the NCI CTCAE listing. 
b 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
c 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Table 5 
Causality Attribution Guidance  
Causality 
Guidance 
Related 
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation. Factors that point toward this assessment include, but are not limited to, a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of an alternative explanation for the AE. 
Not Related 
An AE event will be considered “not related” to the use of the investigational drug if there 
is not a reasonable possibility that the event has been caused by the product under 
investigation. Factors pointing toward this assessment include, but are not limited to, the 
lack of reasonable temporal relationship between administration of the drug and the event, 
the presence of a biologically implausible relationship between the product and the AE, or 
the presence of a more likely alternative explanation for the AE. 
AE = adverse event. 
The above guidance should be taken into consideration when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
If the investigator decides that the SAE is not related to the study drug, the investigator must 
provide another cause of event for the SAE. If the investigator decides that the SAE is related to 
the study drug, the investigator should provide the rationale of causality to the study medication. 

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6.4 
Procedures for Recording Adverse Events  
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the CRF. They should avoid colloquialisms and abbreviations. 
All AEs (including SAEs) should be recorded on the AE CRF, and the check box for “Serious” 
should be ticked for entries that fit the criteria of serious. The investigator should also complete 
an SAE reporting form and submit this to the sponsor or the sponsor’s designee within 24 hours 
of knowledge of the event.  
Only 1 AE term should be recorded in each event field on the CRF. 
6.4.1 
Diagnosis Versus Signs and Symptoms  
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(eg, record only liver failure or hepatitis rather than 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 CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information. 
6.4.2 
Adverse Events 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 mild dehydration, it is 
sufficient to record only diarrhea as an AE or SAE on the CRF.  
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF. 
6.4.3 
Persistent or Recurrent Adverse Events  
A persistent AE extends continuously, without resolution, between patient evaluation time 
points. Such events should only be recorded once in the CRF unless their severity increases. If a 
persistent AE becomes more severe, it should be recorded again on an AE/SAE CRF.  
A recurrent AE occurs and resolves between patient evaluation time points and subsequently 
recurs. All recurrent AEs should be recorded on an AE/SAE CRF, respectively. 
6.4.4 
Abnormal Laboratory Values  
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (eg, abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc). 
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 recorded on the AE/SAE CRF. 

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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 CRF. 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 CRF, unless their severity, seriousness, or 
etiology changes.  
6.4.5 
Abnormal Liver Function Test Results  
The finding of an elevated ALT or AST in combination with either an elevated total bilirubin 
(> 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy’s 
Law). Therefore, investigators must report an AE of special interest upon the occurrence of 
either of the following: 
• Treatment-emergent ALT or AST ≥ 3  ULN in combination with total bilirubin 
> 2  ULN 
• Treatment-emergent ALT or AST ≥ 3 × ULN in combination with clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE CRF (see Section 6.4.1) and reported to the sponsor’s 
designee as a nonserious AE of special interest (see Section 6.5.1). 
6.4.6 
Deaths  
For this study, mortality is an efficacy endpoint. Deaths that occur during the protocol-specified 
AE reporting period (see Section 6.3.1) that are attributed by the investigator solely to 
progression of hematological malignancy under current investigation should be recorded only on 
the Study Completion/Early Discontinuation CRF. All other on-study deaths, regardless of their 
relationship to the study drug, must be recorded on the AE CRF and immediately reported to the 
sponsor (see Section 6.5.1). 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the AE CRF. Generally, only 1 such event should be reported. The term “sudden death” should 
only be used for the occurrence of an abrupt and unexpected death due to presumed cardiac 
causes in a patient with or without pre-existing heart disease, within 1 hour of the onset of acute 
symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was last seen 
alive and stable. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the AE CRF. If the cause of death later 
becomes available (eg, after autopsy), “unexplained death” should be replaced by the established 
cause of death.  
6.4.7 
Preexisting Medical Conditions  
A preexisting medical condition is present at the start of the study. Such conditions should be 
recorded on the CRF. 

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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. When recording such events on 
an AE/SAE CRF, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors (eg, “more frequent headaches”). 
6.4.8 
Worsening of Hematologic Malignancy  
Worsening and/or progression of the hematologic malignancy (eg, leukemia or lymphoma) 
should not be recorded as an AE or SAE, unless the progression directly leads to the patient’s 
death, in which case the disease progression should be reported as a CTCAE Grade 5 SAE. All 
worsening and/or progression of the hematologic malignancy data will be captured as efficacy 
assessment data. 
Hospitalization due solely to the progression of underlying lymphoma should not be reported as 
an SAE. Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy or does not fit the 
expected pattern of progression for the disease under study.  
Symptomatic deterioration may occur in some patients. In this situation, progression is evident in 
the patient’s clinical symptoms but is not supported by the tumor measurements, or the disease 
progression is so evident that the investigator may elect not to perform additional disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception, as every effort should be made to 
document the objective progression of underlying malignancy. 
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. 
6.4.9 
Hospitalization, Prolonged Hospitalization, or Surgery  
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when there is 
no occurrence of an AE. These scenarios include a planned hospitalization or prolonged 
hospitalization to: 
• Perform an efficacy measurement for the study 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical condition 
that has not changed 
• Receive scheduled therapy for the target disease of the study 
In addition, hospitalization due solely to the progression of underlying lymphoma should not be 
reported as an SAE (Section 6.2.2). 
All hospitalizations (including any overnight stay in an acute care hospital) should also be 
documented on the medical source document with the admission and discharge dates. 
6.4.10 
Pregnancy  
If a female patient becomes pregnant while receiving the study drug or within 30 days after the 
last dose of investigational product, a pregnancy report should be reported within 24 hours of 

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learning of the pregnancy to the sponsor’s drug safety department or the sponsor’s designee. 
Pregnancy should be recorded on the pregnancy CRF but not the AE CRF. 
Male patients must also be instructed to immediately inform the investigator if their partner 
becomes pregnant during the study or within 30 days after the male patient’s last dose of the 
study drug. If such an event occurs, it should be reported as described above.  
Spontaneous abortion should always be classified as an SAE (as the sponsor considers these 
medically significant), recorded on an AE CRF, and expeditiously reported to the sponsor or the 
sponsor’s designee (see Section 6.5.1). 
Any congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the study 
drug should be classified as an SAE, recorded on the AE CRF, and expeditiously reported to the 
sponsor or the sponsor’s designee (see Section 6.5.1). 
After the study period, abortions, congenital anomalies/birth defects, and pregnancy outcomes 
should still be reported expeditiously to the sponsor or the sponsor’s designee. 
6.5 
Expedited Reporting From Investigator to Sponsor  
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 on specific 
reporting forms to the sponsor (see form completion guideline for contact detail) 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 learning of the event, regardless of relationship to the study drug: 
• SAEs (see Section 6.5.1 for further details) 
• Nonserious AEs of special interest (see Section 6.5.1 for further details) 
• Pregnancies 
6.5.1 
Reporting Requirements for All Serious Adverse Events and Protocol-Defined 
Events of Special Interest  
Investigators will submit reports of all SAEs and protocol-defined events of special interest, 
regardless of attribution, to the sponsor or the sponsor’s designee via fax or email within 
24 hours of learning of the events.  
For initial SAEs and protocol-defined events of special interest reports, investigators should 
record all case details that can be gathered within 24 hours on a SAE reporting form. Relevant 
follow-up information should be submitted to the sponsor or the sponsor’s designee as soon as it 
becomes available and/or upon request within 24 hours of the investigator’s awareness of the 
events. 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/IEC. 
6.5.2 
Regulatory Reporting Requirements for Serious Adverse Events  
Prompt notification of SAEs by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of patients are met.  

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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.  
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and are forwarded to investigators 
as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will file it with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements. 
6.6 
Type and Duration of Follow-up of Patients After Adverse Events  
The investigator should follow up all unresolved AEs (including SAEs and DLTs) until the event 
resolves to baseline grade, the event is assessed by the investigator as stable, new antitumor 
treatment is initiated, the patient is lost to follow-up, the patient withdraws from the study, or it 
has been determined that the study treatment or participation is not the cause of the AE. During 
the study period, resolution of AEs (with dates) should be documented on the AE CRF and in the 
patient’s medical record to facilitate source data verification (SDV). 
All pregnancies that occur during the study should be followed to determine their outcome.  
For some SAEs, the sponsor or the sponsor’s designee may follow-up by telephone, fax, email, 
and/or a monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (eg, hospital discharge summary, consultant report, or autopsy report). 
6.7 
Post-Study Adverse Events  
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could be related 
to prior HMPL-523 treatment.  
The investigator should notify the sponsor or the sponsor’s designee of any death or other SAE 
occurring at any time after a patient has discontinued or terminated study participation if it is felt 
to be related to prior HMPL-523 treatment. The investigator is not obligated to actively monitor 
patients for AEs once the trial has ended. The sponsor or the sponsor’s designee should also be 
notified if the investigator should become aware of the development of cancer or of a congenital 
anomaly/birth defect in a subsequently conceived offspring of a patient that participated in this 
study.  

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7 
STATISTICAL ANALYSIS  
7.1 
Determination of Sample Size  
The study is closed to new enrollment; the last patient was enrolled on 
. The total 
number of patients enrolled in the dose-expansion phase of the study at the time of enrollment 
closure is 48, with 3 patients continuing on treatment. 
The sample size rationale for the study prior to closing for further enrollment is described below. 
7.1.1 
Stage 1: Dose Escalation  
The sample size for Stage 1 is based on the dose-escalation rules of the 3 + 3 design. For a given 
AE with a true rate of 10%, 5%, or 1%, the probability of observing at least 1 such AE in a given 
cohort of 6 patients is 46.9%, 26.5%, and 5.8%, respectively. 
7.1.2 
Stage 2: Dose Expansion  
The planned enrollment for Stage 2 was approximately 70 patients. A total of 70 patients will 
provide more robust safety data in the patient populations studied. For a given AE with a true 
rate of 10%, 5%, or 1%, the probability of observing at least 1 such AE in 70 patients is 99.9%, 
97.2%, and 50.5%, respectively. 
7.2 
Analysis Population  
The following analysis populations are defined for the study: 
Full Analysis Set (FAS): 
The FAS is defined as all patients who receive at least 1 dose of HMPL-523. The FAS will be 
used for analysis of safety data and efficacy data.  
DLT Evaluable Analysis Set:  
The DLT Evaluable Analysis Set is defined as all patients 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 
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Response Evaluable Set (RES): 
The RES is defined as all patients who receive at least 1 dose of HMPL-523, have either a 
baseline tumor measurement for patients with non-WM/LPL or baseline quantitative serum 
immunoglobulin assessment for patients with WM/LPL, and have at least 1 post-baseline tumor 
measurement or clinical restaging. The RES will be the primary population for the analysis of 
ORR, TTR, and DoR. 
Pharmacokinetics Analysis Set (PKAS): 
The PKAS is defined as all patients who received at least 1 dose of HMPL-523 and have at least 
1 PK sample obtained and analyzed.  
7.3 
Analysis Planned  
All statistical analysis will be performed under the direction of HUTCHMED Limited personnel. 
Details of the statistical analysis and data reporting will be provided in the Statistical Analysis 
Plan (SAP) document finalized prior to database lock. 
Data will be summarized by dose level, subtype of malignancy, and for overall, as appropriate. 
Continuous assessments will be summarized by number of patients (n), mean, standard deviation, 
median, minimum, and maximum. For categorical variables, descriptive statistics will include the 
number and percentage of patients for each category.   
The timing of analysis for each cohort may be different depending on completion of each cohort; 
final analysis of the study will be conducted at the time of the analysis of the last cohort. 
7.3.1 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics, including age, gender, race, ethnicity, weight, height, 
type of malignancy, duration of malignancy, site of disease involved, and baseline ECOG 
performance status, will be summarized descriptively for the FAS. All summaries will be 
presented for each dose level in stage 1 and type of malignancy in stage 2. 
7.3.2 
Disposition of Patients Enrolled in the Study  
The disposition of patients enrolled in the dose escalation and dose expansion stages will be 
summarized. 
Study drug administration data will be listed by dose level and type of malignancy. The total 
duration of exposure, dose intensity, and relative dose intensity of HMPL-523 will be 
summarized by descriptive statistics. 
7.3.3 
Safety Analysis  
Safety parameters, including DLTs, recorded TEAEs, clinical laboratory parameters, vital signs, 
12-lead ECG parameters, and physical examination findings, will be summarized by dose level 
in the dose escalation stage and by type of malignancy in the dose expansion stage for the FAS. 
7.3.3.1 
Dose-Limiting Toxicities  
All DLTs will be listed. 

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7.3.3.2 
Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and the 
corresponding intensity will be graded according to NCI CTCAE v5.0.  
Summaries will be presented for TEAEs. An AE is considered a TEAE if the onset date is on or 
after the start of study treatment or if the onset date is missing, or if the AE has an onset date before 
the start of study treatment but worsened in severity after the study treatment until 37 days after 
the last dose of study treatment. All TEAEs will be listed and the frequency of patients reporting 
TEAEs will be summarized by MedDRA System Organ Class and Preferred Term and NCI 
CTCAE grade. 
The same analysis will be performed for SAEs; causality-related TEAEs assessed by the 
investigators; AEs leading to dose interruption, reduction, or treatment discontinuation; and 
protocol-defined AEs of special interest.  
7.3.3.3 
Clinical Laboratory Test Values  
Descriptive statistics for each clinical laboratory test will be presented for each dose level and 
scheduled visit in the dose escalation stage and also by type of malignancy in the dose expansion 
stage. Laboratory test values from the hematology and chemistry panels, which can be graded by 
NCI CTCAE, will be summarized by the shift of NCI CTCAE grade from baseline to the highest 
grade reported during the study. 
Selected laboratory tests may be plotted over time for each patient. 
All laboratory test results will be listed. 
7.3.3.4 
Vital Signs  
Descriptive statistics for systolic and diastolic blood pressure, pulse rate, respiration rate, and 
body temperature will be summarized by dose level and type of malignancy by scheduled visit.  
Selected vital signs tests may be plotted over time for each patient. 
All vital sign data will be listed. 
7.3.3.5 
12-Lead ECGs  
Descriptive statistics for ECG parameters (PR interval, QRS interval, RR interval, QT interval, 
QTcF interval [QT interval/cube root of RR interval], and heart rate) will be presented by dose 
level and type of malignancy by visit. 
7.3.3.6 
Physical Examination  
All physical examination findings will be listed. 
7.3.4 
Pharmacokinetic Analysis  
PK parameters will be analyzed with the PKAS. A noncompartmental model analysis will be 
performed for plasma concentration data by a central laboratory using Phoenix WinNonlin. 
Individual and mean plasma concentration of HMPL-523 
 versus time data 
will be tabulated and presented. The individual and mean PK parameters determined following 
analysis of the concentration of HMPL-523 and 
 versus time data will include, but 
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not be limited to, plasma exposure (AUC0-t and AUCtau), Cmax, Tmax, Cmin, CL/F, AR, and MP 
ratio. N, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient 
of variation will be presented. The actual times of plasma sample collection will be used in the 
determination of the PK parameters. Details of PK analysis, including data handling rules and 
software used to perform PK analysis, will be provided in the statistical or PK analysis plan. 
Individual and mean HMPL-523 and 
 concentrations will be plotted by dose level. 
7.3.5 
Efficacy Analysis  
Efficacy analysis will be performed for the RES for ORR, TTR, and DoR endpoints and the FAS 
for the PFS endpoint. Efficacy endpoints will be summarized by dose level in the dose escalation 
stage and by type of malignancy (when feasible) in the dose expansion stage. 
The estimated ORR and 95% confidence interval based on the Clopper-Pearson method will be 
presented.  
Median PFS, TTR, and DoR will be summarized with the Kaplan-Meier (KM) method if data 
permits, and the corresponding KM curve will be plotted. 
BOR, PFS, TTR, and DoR data will be listed for all patients.  
Tumor assessment in different subgroups will be evaluated according to specified 
guidelines/criteria: 
• Chronic lymphocytic leukemia: the modified International Workshop on CLL guideline 
(modified IWCLL 2008, see Appendix 4) 
• WM/LPL: consensus of international workshops on WM (IWWM-7 Consensus, see 
Appendix 5) 
• Lymphoma other than CLL or WM/LPL: Lugano Response Criteria for Hodgkin and 
NHL (Cheson et al 2014, see Appendix 6) 
7.3.6 
Biomarker Analysis  
Levels of chemokines in plasma will be tabulated and summarized using descriptive statistics as 
appropriate. Correlation between drug exposure level of HMPL‑523 in plasma and chemokines 
level and biomarker changes in plasma in all subtypes or different subtypes of lymphoma will be 
analyzed using descriptive and graphical means. Exploratory data will not be included in the 
clinical study report, and a separate summary will be prepared. 
7.4 
Interim Analysis (Not Applicable)  
There is no interim analysis in this study. 
CCI

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8 ETHICS  
8.1 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and any relevant supporting 
information must be submitted to the IRB/IEC by the principal investigator for review and 
approval before the study is initiated. In addition, any patient recruitment materials must be 
approved by the IRB/IEC.  
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the regulatory 
requirements and the policies and procedures established by the IRB/IEC. Investigators are also 
responsible for promptly informing the IRB/IEC of any protocol changes or amendments and of 
any unanticipated problems involving risk to human patients or others. 
In addition to the requirements to report protocol-defined AEs to the sponsor or the sponsor’s 
designee, investigators are required to promptly report to their respective IRB/IEC all 
unanticipated problems involving risk to human patients. Some IRBs/IECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are serious, 
assessed to be related to study treatment, and are unexpected.  
8.2 
Ethical Conduct of the Study  
The study will be conducted in accordance with the protocol, ICH E6(R2) guidelines, Clinical 
Trials Regulation (EU 536/2014), the applicable regulations and guidelines governing clinical 
study conduct, and the ethical principles that have their origin in the Declaration of Helsinki. 
8.3 
Patient Information and Consent  
The investigator or his/her representative, qualified by education, training, and experience to 
comply with Good Clinical Practice (GCP) and applicable regulatory requirements, will provide 
verbal and written information to the patient explaining the nature of the study, and answering all 
questions. Prior to any study-related screening procedures being performed on the patient, the 
informed consent statement will be reviewed, signed, and dated by the patient and the person 
who administered the informed consent. The ICF must include a statement that the sponsor or its 
designee and regulatory authorities have direct access to subject records. A copy of the ICF will 
be given to the patient, and the original will be placed in the patient’s medical record and must 
be available for verification by study monitors at any time. If applicable, it will be provided in a 
certified translation of the local language. 
The ICF should be revised whenever there are changes to procedures outlined in the informed 
consent or when new information becomes available that may affect the willingness of the 
patient to participate. 
For any updated or revised ICFs, the case history for each patient shall document the informed 
consent process and that written informed consent was obtained for the updated/revised ICF for 
continued participation in the study. Signed and dated ICFs must remain in each patient’s study 
file and must be available for verification by study monitors at any time. 
The participant’s consent gives the principal investigator, sponsor, sponsor’s designees, and 
regulatory authorities, if applicable, direct access to obtain information from the patient’s 

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medical records, including electronic medical records, for the purpose of reviewing information 
about the participant’s health which is necessary as part of the implementation of the research 
project as well as for statutory control purposes, including self-regulation, quality control, and 
monitoring.  
8.4 
Data Privacy and Confidentiality  
The investigator and the sponsor or its designee must observe and adhere to any country data 
privacy laws and regulations (including country specific Data Protections Acts). The investigator 
and the sponsor or its designee are responsible for ensuring that sensitive information, transfer of 
data/research samples, and storage of biological material retained for future research are handled 
in accordance with local requirements. Appropriate consent for participation and understanding 
of the use and disclosure and/or transfer (if applicable) of protected information and research 
samples must be obtained. 
Subject names will not be supplied to the sponsor or its designee. The sponsor maintains 
confidentiality standards by coding each patient enrolled in the study through assignment of a 
unique patient identification number. This means that patient names are not included in data sets 
that are transmitted to any sponsor location. Only the subject number and subject’s initials 
(subject’s initials will only be recorded if allowable by local regulations) will be recorded in the 
CRF, where permitted; if the patient’s name appears on any other document (eg, laboratory 
report), it must be de-identified before submitting to the sponsor or its designee. 
Patient medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the ICF (or separate authorization for use and disclosure of personal 
health information) signed by the patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be informed that data generated by this study must be available for inspection 
upon request by representatives of national and local health authorities, study monitors, 
representatives, and collaborators, and the IRB/IEC for each study site, as appropriate, and that 
all personal information made available for inspection will be handled in strictest confidence and 
in accordance with local data protection laws.  
Appendix 17 describes the measures that HUTCHMED Limited has put in place to meet the 
requirements of the data protection laws for EU member states.  
 

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9 
STUDY DOCUMENTATION, CASE REPORT FORM, AND 
RECORDS  
9.1 
Source Data Documentation  
Study monitors will perform ongoing SDV to confirm that critical protocol data (ie, source data) 
entered into the CRFs by authorized site personnel are accurate, complete, and verifiable from 
source documents.  
Source documents are where patient data are recorded and documented for the first time. They 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, 
memoranda, patient diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies of transcriptions that are certified after verification as being 
accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, 
X-rays, patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial. 
Source documents that are required to verify the validity and completeness of data entered into 
the CRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the sponsor direct access to 
applicable source documents and reports for trial-related monitoring, sponsor audits, and 
IRB/IEC review. The investigational site must also allow inspection by applicable regulatory 
authorities. 
9.2 
Use of Computerized System  
When clinical observations are entered directly into an investigational site’s computerized 
medical record system (ie, in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with FDA requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system (for clinical research purposes) would be one that (1) allows data entry only by 
authorized individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (eg, modification of file); (3) protects the database 
from tampering; and (4) ensures data preservation. 
If a site’s computerized medical record system is not adequately validated for the purposes of 
clinical research (as opposed to general clinical practice), applicable hardcopy source documents 
must be maintained to ensure that critical protocol data entered into the CRFs can be verified. 
9.3 
Retention of Records  
The study should be recorded accurately by investigators so that study data can be verified. The 
study documents can be divided into 2 types: investigator documents and subject source data. 
Investigator documents include the protocol and amendments, the eCRF and data clarification 
forms, approvals, correspondence with the IRB and regulatory authorities, ICF, HMPL-523 
records, study personnel curriculum vitae, authorization forms, and any other essential 
documents. 
Subject source data documents (recording primary efficacy/safety data) include study 
site/hospital medical history, scheduled visit dates, original laboratory test results, ECGs, 

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electroencephalograms, radiological imaging, pathological and specific assessment reports, 
signed ICF(s), medical records, and subject screening forms. The documents mentioned above 
should be properly stored by the investigator for 25 years after the study is completed or longer if 
mandated by local regulatory requirements. Subject medical files will be archived in accordance 
with national law. If investigators need to transfer the documents to another party or place, the 
Sponsor must be notified in advance. It is the responsibility of the Sponsor to inform the 
investigator as to when these documents no longer need to be retained.  
The Sponsor will store the study documentation for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of HMPL-523; or until at least 25 years after the end of the study, 
whichever is longer.  
If the documents cannot be stored properly at the study site, the documents may be transferred by 
the investigator and 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. If the documents 
are still in use, they can be made available as certified copies and stored elsewhere. For remote 
visits utilizing Study Hub, study data will be retained in Study Hub until the end of the study. 
No records should be disposed of without the written approval of HUTCHMED Limited. Written 
notification should be provided to HUTCHMED Limited for transfer of any records to another 
party or moving them to another location. 

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10 
MONITORING  
Site visits will be conducted by an authorized HUTCHMED Limited’s designee to check study 
data, patients’ medical records, and CRFs. The principal investigator will permit 
monitor/sponsor’s representatives and collaborators from other regulatory agencies, IRBs/IECs, 
and the respective national or local health authorities to inspect facilities and records relevant to 
this study. 
It will be the monitor’s responsibility to check the CRFs at regular intervals throughout the study 
to verify the adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor must verify that the patient received the study drug 
assigned by the dose level. The monitor should have access to laboratory test reports and other 
patient records needed to verify the entries on the CRF. The investigator (or deputy) agrees to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 

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11 
DATA MANAGEMENT  
11.1 
Data Quality Assurance  
The overall procedures for quality assurance of clinical study data are described in the sponsor or 
designee standard operation procedures. Accurate and reliable data collection will be assured by 
verification and cross-check of the eCRFs against the investigator’s records by the study monitor 
(SDV) and the maintenance of a drug-dispensing log by the investigator. A CRO will be 
responsible for the data management of this study, including quality checking of the data. Sites 
will be responsible for data entry into the electronic data capture (EDC) system. In the event of 
discrepant data, the CRO will request data clarification from the sites. 
The sponsor will perform oversight of the data management of this study.  
11.2 
Electronic Case Report Forms  
Electronic data capture will be used for this study, meaning that all eCRF data will be entered in 
electronic forms at the study site. Data collection will be completed by authorized site staff 
designated by the investigator. Appropriate training and security measures will be completed 
with the investigator and all authorized site staff prior to the study being initiated and any data 
being entered into the system for any study patients.  
All data must be entered in English. The investigator must verify that all data entries in the eCRF 
are accurate and correct. If some assessments are not done, or if certain information is not 
available, not applicable or unknown, the investigator should indicate this in the eCRF. The 
investigator will be required to electronically sign off the clinical data. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections, and alterations are to be made by the responsible 
investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical data 
of the eCRF have been submitted to the central server, corrections to the data fields will be audit 
trailed, meaning that the reason for change, the name of the person who performed the change, 
and the time and date of the change will be logged. Roles and rights of the site personnel 
responsible for entering the clinical data into the eCRF will be determined in advance. If 
additional corrections are needed, the responsible monitor or data manager will raise a query in 
the EDC application. The appropriate investigational staff will answer queries sent to the 
investigator. This will be audit trailed by the EDC application meaning that the name of the 
investigational staff and the time and date stamps are captured. 
The investigator is responsible for maintaining source documents. These will be made available 
for inspection by the study monitor at each monitoring visit. The investigator must submit a 
completed eCRF for each patient who receives study medication, regardless of duration. All 
supportive documentation submitted with the eCRF, such as laboratory or hospital records, 
should be clearly identified with the study and patient number. Any personal information, 
including patient name, should be removed or rendered illegible to preserve individual 
confidentiality. 
The eCRF records will be automatically appended with the identification of the creator, by 
means of their unique user identification (ID). Specified records will be electronically signed by 

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the investigator to document his/her review of the data and acknowledgement that the data are 
accurate. This will be facilitated by means of the investigator’s unique user ID and password; 
date and time stamps will be added automatically at time of electronic signature. If an entry on 
an eCRF requires change, the correction should be made in accordance with the relevant 
software procedures. All changes will be fully recorded in a protected audit trail, and a reason for 
the change will be required. 
At the end of the study, the investigator will receive the data related to patients from his or her 
site in an electronically readable format (eg, on a compact disc). Data must be kept with the 
study records. 
11.3 
Coding  
AEs will be coded using MedDRA. Concomitant medications will be coded using the World 
Health Organization Drug Dictionary. Concomitant diseases/medical history will be coded using 
MedDRA. 

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12 
USE OF INFORMATION AND PUBLICATION  
12.1 
Use of Information  
All information regarding HMPL-523 and HUTCHMED Limited’s operations, such as 
HUTCHMED Limited’s patent applications, formulae, manufacturing processes, basic scientific 
data, or formulation information, supplied by HUTCHMED Limited and not previously 
published is considered confidential information. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by HUTCHMED Limited in connection with the development of 
HMPL-523. This information may be disclosed as deemed necessary by HUTCHMED Limited 
or its designee to other clinical investigators, other pharmaceutical companies, and to the 
regulatory agencies. To allow for the use of the information derived from this clinical study and 
to ensure complete and thorough analysis, the investigator is obligated to provide HUTCHMED 
Limited with complete test results and all data developed in this study and to provide direct 
access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspection. 
The investigator will maintain a confidential patient identification code list of all patients 
enrolled in the study (by name and patient number). This list will be maintained at the site and 
will not be retrieved by HUTCHMED Limited or its designee. 
12.2 
Publication  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice (see the International Committee of Medical Journal 
Editors authorship requirements at http://www.icmje.org/), the sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In this 
case, a coordinating investigator will be designated by mutual agreement. 
Irrespective of the outcome of the study, the Sponsor will submit a summary of the results of the 
clinical study to any relevant database within 1 year from the end of the global clinical study. It 
will be accompanied by a summary written in a manner that is understandable to laypersons. 
For studies conducted under Regulation (EU 536/2014) where the study has ended in all member 
states concerned in the EU/European Economic Area but is still ongoing in other regions and 
data from those regions are not available (making the statistical analysis not relevant), the 
summary of results must be submitted to the EU database as soon as it is available but no later 
than 1 year after the end of the study globally. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. Any formal publication of the study in which 
contribution of the sponsor’s personnel exceeds that of conventional monitoring will be 
considered as a joint publication by the investigator and the appropriate sponsor personnel. 
HUTCHMED Limited agrees that before it publishes any results of this study, it shall provide the 
investigator with a pre-publication manuscript for review at least 30 days prior to the submission 
of the manuscript to the publisher. 

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The investigators have the right to publish the results of the study but with due regard to the 
protection of confidential information. Accordingly, HUTCHMED Limited shall have the right 
to review and approve any paper for publication, including oral presentation and abstracts, which 
utilize data generated from this study. At least 30 days before any such paper or abstract is 
presented or submitted for publication, a complete copy shall be given to HUTCHMED Limited 
for review. HUTCHMED Limited shall review any such paper or abstract and give its comments 
to the author(s) promptly. The investigator shall comply with HUTCHMED Limited’s 
confidential information in any such paper and agree to withhold publication of the same for an 
additional 30 days in order to permit HUTCHMED Limited to obtain patent or other proprietary 
rights protection, if HUTCHMED Limited deems it necessary. 
This confidential information shall remain the sole property of HUTCHMED Limited, shall not 
be disclosed to others without the written consent of HUTCHMED Limited, and shall not be 
used except in the performance of this study. 
It is understood by the investigator that the information developed in the clinical study will be 
used by HUTCHMED Limited in connection with the development of HMPL-523 and, therefore, 
may be disclosed as required to other clinical investigators, other pharmaceutical companies, or 
regulatory agencies. It is understood that there is an obligation to provide HUTCHMED Limited 
with complete test results and all data resulting from this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection. 

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13 
REFERENCES  
Aronson et al 2022  
Aronson JH, et al. Approach to a patient with 'double refractory' chronic lymphocytic leukemia: 
"Double, double toil and trouble." Am J Hematol. 2022;97:S19–S25 
Binet et al 1981  
Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic 
leukemia derived from a multivariate survival analysis. Cancer. 1981;48(1):198-206 
Cheng et al 2011  
Cheng S, Coffey G, Zhang XH, et al. SYK inhibition and response prediction in diffuse large B-
cell lymphoma. Blood. 2011;118(24):6342-6352 
Cheson et al 2012  
Cheson B, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. J Clin Oncol. 2012; 30(23):2820-2822 
Cheson et al 2014  
Cheson B, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol. 2014;32(27):3059-3068 
Dimopoulos 2014  
Dimopoulos, MA. Treatment recommendations for patients with Waldenström 
macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 
2014;124(9):1404-1411  
FDA 2009  
Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation. FDA; 2009 
Friedberg et al 2010  
Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has 
significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. 
Blood. 2010;115:2578-2585 
Global Burden of Disease Cancer Collaboration et al 2017  
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, Regional, 
and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and 
Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for 
the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548 

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Hahn et al 2009  
Hahn, CK, Berchuck JE, Ross KN, et al. Proteomic and genetic approaches identify Syk as an 
AML target. Cancer Cell. 2009;16(4):281-294 
Hallek et al 2008  
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia. Blood. 2008;111(12):5446-5456 
Hoellenriegel et al 2012  
Hoellenriegel J, Coffey GP, Sinha U, et al. Selective, novel spleen tyrosine kinase (Syk) 
inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia. 
2012;26:1576-1583 
Hoster et al 2008  
Hoster E, Dreyling M, Klapper W., Gisselbrecht C. et al. A new prognostic index (MIPI) for 
patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2): 558-565 
Martin et al 2011  
Martin P, Salas C, Provencio M, et al. Heterogeneous expression of Src tyrosine kinases Lyn, 
Fyn and Syk in classical Hodgkin lymphoma: prognostic implications. Leuk Lymphoma. 2011; 
52(11): 2162-8 
National Cancer Institute 2018  
National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat 
facts: Non-Hodgkin Lymphoma. Accessed March 15, 2018. 
https://seer.cancer.gov/statfacts/html/nhl.html 
Rai 1975  
Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. 
Blood. 1975;46(2):219-234 
Sharman et al 2015  
Sharman J, Hawkins M, Kolibaba K, et al. An open-label Phase II trial of entospletinib 
(GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 
2015;125:2336-43 
Sharman et al 2017  
Sharman J, Kolibaba KS, Azar J, et al. Evaluating the Efficacy, Safety, and Dose Dependent 
Activities of Entospletinib in Patients with Chronic Lymphocytic Leukemia. Blood. 
2017;130:832 
Shipp et al 1993  
Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive Non-
Hodgkin’s Lymphoma. N Engl J Med. 1993;329:987-994 

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Solal-Celigny et al 2004  
Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. 
Blood. 2004;104:1258-1264 
Swerdlow et al 2017  
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization 
classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390 
TavalisseTM Prescribing Information 2018  
TavalisseTM (fostamatinib disodium hexahydrate) tablets prescribing information, 2018. 
Wierda and Tambaro 2020  
Wierda WG and Tambaro FP. How I manage CLL with venetoclax-based treatments. Blood. 
2020;135(17):1421-1427 

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14 
APPENDICES  
 

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APPENDIX 1 
SCHEDULE OF ACTIVITIES  
Study Day 
Procedures 
Screening 
Treatment2 
Follow-up3 
Cycle 1 
Cycle 2 
Cycle 3 and 
Onwards 
D-21 to 
D-1 
D-7 to 
D-1 
D1 
D8 
(±1) 
D15 
(±1) 
D22 
(±1) 
D1 
(±3) 
D15 
(±3) 
D1 (±3) 
Study Completion or 
Early Termination 
(30±7 Days After the 
End of Treatment) 
Follow-up 
on Day 1 
(±7) 
Quarterly 
After the 
End of 
Treatment 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
Demographics4 
X 
 
 
 
 
 
 
 
 
 
 
Medical history5 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Vital signs7 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication/procedure8 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis/dipstick10, 24 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Chemistry panel11, 24 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Beta 2-microglobulin24 
 
X 
 
 
 
 
X 
 
X 
X 
 
Fasting lipid profile12,24 
 
X 
 
 
 
 
X 
 
X 
X 
 
Serum amylase and lipase24 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation assay 
(INR, aPTT, PT) 24 
 
X 
 
 
 
 
X 
 
X 
X 
 
17p del/TP53 mutation13,24 
X 
 
 
 
 
 
 
 
 
 
 
Leukocyte 
immunophenotyping14,24  
X 
 
 
 
X 
 
X 
 
 
 
 

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Study Day 
Procedures 
Screening 
Treatment2 
Follow-up3 
Cycle 1 
Cycle 2 
Cycle 3 and 
Onwards 
D-21 to 
D-1 
D-7 to 
D-1 
D1 
D8 
(±1) 
D15 
(±1) 
D22 
(±1) 
D1 
(±3) 
D15 
(±3) 
D1 (±3) 
Study Completion or 
Early Termination 
(30±7 Days After the 
End of Treatment) 
Follow-up 
on Day 1 
(±7) 
Quarterly 
After the 
End of 
Treatment 
HIV, HBV, HCV, and CMV 
screening15 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy tests16 
X 
 
 
 
 
 
 
 
 
X 
 
Bone marrow examination 
(biopsy and/or aspirate)17 
X 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy25 
X 
 
 
 
 
 
 
 
 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG18 
X 
 
X 
 
X 
 
X 
 
As clinically 
needed 
X 
 
Arbor staging, IPI score, and 
Rai and/or Binet staging 
X 
 
 
 
 
 
 
 
 
 
 
Quantitative serum 
immunoglobulin levels (for 
WM/LPL)19,24 
X 
 
 
 
 
 
X 
 
X 
X 
X 
CT/PET-CT20 
X 
 
 
 
 
 
 
 
X 
X 
X 
Tumor assessment21 
X 
 
 
 
 
 
 
 
X 
X 
X 
PK and Pharmacodynamics 
plasma sampling22 
 
 
Refer to Appendix 2 and Appendix 3 
 
 
 
Plasma collection for 
exploratory biomarkers22 
 
 
X 
 
X 
 
X 
 
 
 
 
AE23 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
HMPL-523 treatment 
 
 
X 
 
 
Psychological evaluation 
X 
 
 
 
 

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β-HCG = beta human chorionic gonadotropin; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; CLL = chronic lymphocytic leukemia; CMV = cytomegalovirus; CR = complete response; 
CrCl = creatinine clearance; CT = computed tomography; D = day; DLT = dose-limiting toxicity; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; HL = Hodgkin’s lymphoma; IgA = Immunoglobulin A; IgG = Immunoglobulin G; 
IgM = immunoglobulin M; IHC = immunohistochemistry; INR = international normalized ratio; IPI = International Prognostic Index; LDH = lactate 
dehydrogenase; LPL = lymphoplasmacytic lymphoma; MUGA = multigated acquisition scan; NHL = non-Hodgkin’s lymphoma; PCR = polymerase chain 
reaction; PD = progressive disease; PET = positron-emission tomography; PK = pharmacokinetic; PR = partial response; PT = prothrombin time; 
QTcF = corrected QT interval with Fridericia; RNA = ribonucleic acid; SAE = serious adverse event; WM = Waldenström’s macroglobulinemia. 
1 
Informed consent must be documented before any study-specific screening procedure is performed.  
2 
Unless otherwise indicated, the visit window during the treatment period will be ±3 days (±1 day during the DLT assessment window). Except for the ECG, 
echocardiogram/MUGA, bone marrow biopsy, and/or aspirate and tumor assessment, all the assessments should be performed before dosing if the study 
drug is to be taken on the visit day. Unscheduled assessments could be performed if there is a clinical indication. 
3 
Patients who complete or prematurely discontinue the study need to return to the study site for a follow-up within 30±7 days after the last dose of 
HMPL-523. Patients who discontinue the study drug due to reasons other than disease progression will remain on study and be followed quarterly until the 
patient has the first progression, starts new anticancer therapy, or dies or until 12 months from the initial dose with the study drug have passed. 
4 
Demographic data include date of birth, gender, and self-reported race and ethnicity. 
5 
Medical history includes clinically significant diseases or symptoms, surgeries, cancer history (including constitutional symptoms/B symptoms [unexplained 
weight loss  ≥ 10% over previous 6 months, fever > 38°C/100.5°F for 2 or more weeks without other evidence of infection, night sweats for more than 
1 month without evidence of infection]), prior cancer diagnosis (including tumor type, initial diagnosis date, IHC, flow cytometry, and other pathological 
findings), prior cancer therapies and procedures), use of tobacco, use of alcohol, and use of drugs of abuse prior to the screening visit. 
6 
Physical examination refers to the examination of all body systems, including assessment of head, eyes, ears, nose, larynx, neck, heart, chest, abdomen, 
limbs, skin, lymph nodes, nervous system, general condition and weight. After screening, a change of physical signs from baseline, and newly presented or 
patient-reported physical signs should be evaluated. Height will be assessed only at screening. 
7 
Vital signs will include measurements of body temperature (taken under the armpit or in the mouth), heart rate, respiratory rate, and systolic and diastolic 
blood pressures while the patient is in a seated position. The patient should be seated for 5 minutes before the measurement of blood pressure.  
8 
Concomitant medications include all medications (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional 
supplements) used by the patient within 7 days prior to the screening visit and 30 days after the end of treatment. Any concomitant procedure (excluding 
bone marrow examination) within 7 days prior to the screening visit and 30 days after the end of treatment or early termination should be recorded. 
9 
Hematology consists of complete blood count, including red blood cell count, hemoglobin, hematocrit, white blood cell count with differential (neutrophils, 
lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet count. 
10 
Urinalysis or dipstick (pH, specific gravity, glucose, protein, ketones, blood). If protein ≥ 2+ during the period of study treatment, a 24-hour urine test should 
be conducted within 1 week. 
11 
The chemistry panel includes blood urea nitrogen or urea, sodium, potassium, magnesium, chloride, calcium, phosphorus, fasting glucose, creatinine and 
estimated CrCl per Cockcroft-Gault, ALT, bilirubin direct and total, AST, ALP, LDH, uric acid, protein (total), and albumin.  
12 
Fasting lipid profile includes total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. 
13 
17p del/TP53 mutation status is for patients with CLL only and optional. 
14 
Leukocyte immunophenotyping: T lymphocyte/B lymphocyte/natural killer cell counts (CD3, CD19, CD4, CD8, CD16/56) using a standard cell marker 
panel, should be tested at baseline and Weeks 3 and 5, every 4 weeks from Weeks 8-24, and then every 12 weeks thereafter until the end of treatment. 

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15 
HBV: HBsAg and HBcAb; also HBsAb and HBV DNA by PCR if the patient is HBcAb positive; HCV: also HCV RNA by PCR if the patient is HCV 
antibody positive; CMV: also CMV DNA by PCR if the patient is CMV antibody positive. 
16 
All women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) will have a serum β-HCG test at screening. In the case of 
menopausal women, the date of menopause onset should be recorded. 
17 
A bone marrow biopsy and/or aspirate is strongly recommended to be done at baseline or up to 3 months before Cycle 1 Day 1 and for confirmatory 
purposes when the patient is considered to be likely CR with CT assessment and laboratory tests results or to confirm suspected PD based solely upon 
declines in the platelet count and/or hemoglobin. If a bone marrow examination (biopsy and/or aspirate) has been performed within 3 months of Cycle 1 
Day 1, a screening bone marrow examination does not need to be performed unless an investigator feels one is clinically warranted as outlined above. For 
those patients with initial bone marrow involvement from lymphoma/leukemia at study entry, a repeat biopsy at the end of therapy is necessary to confirm 
complete clinical response if physical examination and CT scans demonstrate a clinical CR or to confirm suspected PD based solely upon declines in the 
platelet count and/or hemoglobin. The number of additional/unscheduled bone marrow examinations performed during the study will be at the discretion of 
the investigator.  
18 
A 12-lead ECG should be performed at screening and pre-dose and at 4 hours ± 15 minutes post-dose on Days 1 and 15 in Cycle 1 and at any time on Day 1 
of each cycle from Cycle 2 onwards. Triplicate ECGs, approximately 2 minutes apart, will be performed for all patients in baseline and Cycle 1. Additional 
ECGs and other cardiac monitoring will be provided as clinically indicated during the study. PR interval, QRS interval, RR interval, QT/QTcF interval, and 
heart rate will be involved in the 12-lead ECG. 
19 
Quantitative immunoglobulin assessment of IgM, IgA, and IgG for all patients with WM/LPL. Quantitative immunoglobin assessment should be repeated at 
the time of the CR confirmation.  
20 
Contrast-enhanced CT scans (neck, chest, abdomen, pelvis) should be performed for indolent NHL and/or PET-CT for HL and aggressive NHL. 
21 
The baseline tumor assessment can be completed within 21 days prior to enrolment. All measurable and evaluable lesions should be assessed and 
documented at this visit, using blood, physical examination and CT scan (neck, chest, abdomen, pelvis, liver/spleen) every 8 weeks (±7 days) for the first 
24 weeks and then every 12 (±7 days) weeks thereafter. At study termination or early termination (other than disease progression) of the patients, tumor 
assessment will be also conducted. The same imaging procedure and laboratory tests used to define measurable lesions at baseline should be used throughout 
the study for each patient. 
22 
Blood samples should be collected according to the time-point tables in Appendix 2 and Appendix 3. All patients in the dose expansion stage will be 
required to provide samples for pharmacodynamics biomarker analysis. Upon implementation of Amendment 5, PK samples for measurement of plasma 
concentrations of HMPL-523
 will not be collected on Cycle 5 Day 1 and beyond in the dose expansion phase. 
23 
After informed consent, but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be collected (eg, SAEs 
related to invasive procedures such as biopsies, medication washout, or no treatment run-in). After initiation of HMPL-523 treatment, all AEs and SAEs 
regardless of attribution will be collected until 30 days following the last administration of study treatment or study discontinuation/termination, whichever 
is later. After this period, investigators should report only SAEs that are related to prior HMPL-523 treatment. 
24 
Preferably within 7 days prior to the first dose of the study drug. 
25 
Fresh or archival tumor tissue consisting of a cell block or 10 unstained slides should be collected for patients in dose expansion cohorts during screening. 
 
CCI

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APPENDIX 2 
PK SAMPLING TIME POINTS (ONCE DAILY) (DOSE ESCALATION 
STAGE)d  
Visit Cycle and Day 
Time Point 
Cycle 1 Day 1 
Pre-dosea 
30 minutes (±5 minutes) post-dose 
1 hour (±5 minutes) post-dose 
2 hours (±10 minutes) post-dose 
4 hours (±15 minutes) post-dose 
6 hours (±15 minutes) post-dose 
8 hours (±15 minutes) post-dose 
Cycle 1 Day 2 
Pre-dosea 
Cycle 1 Day 15 
Pre-dosea 
30 minutes (±5 minutes) post-dose 
1 hour (±5 minutes) post-dose 
2 hours (±10 minutes) post-dose 
4 hours (±15 minutes) post-dose 
6 hours (±15 minutes) post-dose 
8 hours (±15 minutes) post-dose 
Cycle 1 Day 16 
Pre-dosea 
Cycle 1 Day 28b 
Pre-dosea 
30 minutes (±5 minutes) post-dose 
1 hour (±5 minutes) post-dose 
2 hours (±10 minutes) post-dose 
4 hours (±15 minutes) post-dose 
6 hours (±15 minutes) post-dose 
8 hours (±15 minutes) post-dose 
Cycle 2 Day 1c 
Pre-dosea 
PK = pharmacokinetic. 
a 
The blood samples will optimally be obtained within 5 minutes prior to dosing but may be obtained up to 
30 minutes prior to dosing.  
b 
Cycle 1 Day 28 shares the window with Cycle 2 Day 1, which is ±3 days and should be immediately followed 
by Cycle 2 Day 1. 
c 
Cycle 2 Day 1 pre-dose is the 24-hour (+15 minutes) PK sample of Cycle 1 Day 28. 
d 
Blood samples that remain after PK analysis of HMPL-523 may be used exclusively for exploratory biomarker 
purposes. 

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APPENDIX 3 
PK AND PHARMACODYNAMICS SAMPLING TIME POINTS (DOSE 
EXPANSION STAGE)e  
Visit Cycle and Dayf 
Time Pointd 
PK Sample 
Pharmacodynamics 
Sample 
Cycle 1 Day 1 
Pre-dosea 
X 
X 
30 minutes (±5 minutes) post-dose 
X 
- 
1 hour (±5 minutes) post-dose 
X 
- 
2 hours (±10 minutes) post-dose 
X 
- 
4 hours (±15 minutes) post-dose 
X 
- 
6 hours (±15 minutes) post-dose 
X 
- 
8 hours (±15 minutes) post-dose 
X 
- 
Cycle 1 Day 2 
Pre-dosea 
X 
- 
Cycle 1 Day 28b, g 
Pre-dosea 
X 
- 
30 minutes (±5 minutes) post-dose 
X 
- 
1 hour (±5 minutes) post-dose 
X 
- 
2 hours (±10 minutes) post-dose 
X 
- 
4 hours (±15 minutes) post-dose 
X 
- 
6 hours (±15 minutes) post-dose 
X 
- 
8 hours (±15 minutes) post-dose 
X 
- 
Cycle 2 Day 1c 
Pre-dosea 
X 
X 
Cycle 3 Day 1 
Pre-dosea 
X 
X 
Cycle 5 Day 1 and every 
other cycle thereafterh 
NA 
- 
 
eCRF = electronic case report form; NA = not applicable; PK = pharmacokinetic. 
a 
The blood samples will optimally be obtained within 5 minutes prior to dosing but may be obtained up to 
30 minutes prior to dosing.  
b 
Cycle 1 Day 28 shares the window with Cycle 2 Day 1, which is ±3 days and should be immediately followed 
by Cycle 2 Day 1. 
c 
Cycle 2 Day 1 pre-dose is the 24-hour (+15 mins) PK sample of Cycle 1 Day 28. 
d 
The actual date and time of the PK samples must be recorded in the eCRF. 
e 
Blood samples that remain after PK analysis of HMPL-523 may be used exclusively for exploratory biomarker 
purposes. 
f 
On PK sampling day, study drug must be taken at the investigative site under the supervision of the investigator 
or designee and should not be taken at home on the morning of the visits. The date and time of the dose 
administered on the day of PK collection and 1 day before PK collection must be recorded in the eCRF. 
g 
In case PK samples planned for Cycle 1 Day 28 does not occur due to whatever reasons, they may be 
rescheduled for collection in subsequent cycles. Please consult the sponsor for further guidance and instructions. 
h 
Upon implementation of Protocol Amendment 5, PK samples for measurement of plasma concentrations of 
HMPL-523 will not be collected on Cycle 5 Day 1 and beyond. 
 
 

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APPENDIX 4 
INTERNATIONAL WORKSHOP ON CHRONIC LYMPHOCYTIC 
LEUKEMIA UPDATE OF THE NATIONAL CANCER INSTITUTE-
WORKING GROUP GUIDELINES: RESPONSE CRITERIA  
Complete Response (CR) 
Complete response requires all of the following criteria as assessed no earlier than 2 monthsa 
after completion of therapy:  
• Peripheral blood lymphocytes (evaluated by blood and differential count) below 
4 × 109/L (4000/μL) 
• Absence of significant lymphadenopathy (nodes ≤15 mm in longest diameter or any extra 
nodal disease) by physical examination and computed tomography (CT) scan 
• No hepatomegaly or splenomegaly by physical examination or CT scan, as appropriate 
• Absence of disease or constitutional symptoms (B symptoms). 
• Blood counts above the following values: 
− Neutrophils > 1.5 × 109/L (1500/μL) (without growth factors) 
− Platelets > 100 × 109/L (100000/μL) (without platelet transfusion or growth factors) 
− Hemoglobin > 110 g/L (11 g/dL) (without blood transfusions or erythropoietin) 
• Bone marrow aspirate and biopsy should be performed 3 months after the last treatment 
when the clinical and laboratory results listed above demonstrate a CR/cytopenic CR has 
been achieved. Bone marrow should be at least normocellular for age, with < 30% of 
nucleated cells being lymphocytes. Lymphoid nodules should be absent. If the bone marrow 
is hypocellular, a repeat determination should be made in 4 weeks or when peripheral blood 
counts have recovered. However, this time interval should not exceed 6 months. A marrow 
biopsy should be compared to a pretreatment marrow if available.  
In patients who are otherwise in a complete remission but bone marrow nodules can be identified 
histologically, immunohistochemistry should be performed to define whether these nodules are 
composed primarily of T cells or lymphocytes other than chronic lymphocytic leukemia (CLL) 
cells, or CLL cells. Patients with residual CLL cells should be considered to be partial response 
(PR) (nodular partial response [nPR]).  
Complete Response with Incomplete Bone Marrow Recovery  
Patients who fulfill the criteria for CR (including bone marrow) but who have persistent 
cytopenia, anemia, thrombocytopenia, or neutropenia. The marrow evaluation described above 
should be performed with scrutiny and not show any clonal infiltrate.  
Partial Response (PR) 
To be considered PR, patients must exhibit the following features for at least 2 months from end 
of treatment: 
•  ≥ 50% decrease in peripheral blood lymphocyte count from the pre-treatment value  
AND either a 
 
a Bone marrow biopsies should be performed at least 2 months after the last treatment and if clinical and laboratory 
results demonstrate that a CR has been achieved. 

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•  ≥ 50% reduction in lymphadenopathy (sum of longest diameter of the 6 largest lymph 
nodes by physical examination and 50% reduction in the sum of product of diameter of 
the 6 largest lymph nodes measured by CT scan). No increase in any node and no new 
enlarged lymph node. In small lymph nodes (< 2 cm in diameter), an increase of less than 
25% is not considered to be significant. 
OR 
•  ≥ 50% reduction of liver enlargement if enlarged at baseline as assessed by CT scan 
OR 
•  ≥ 50% reduction of spleen enlargement if enlarged at baseline as assessed by CT scan 
Plus at least 1 of the following: 
• Neutrophils > 1.5 × 109/L [1500/μL] (without growth factors) or ≥ 50% increase of 
pretreatment value 
• Platelets > 100 × 109/L (100000/μL) (without platelet transfusion growth factors) or 
≥ 50% increase of pretreatment value 
• Hemoglobin > 110 g/L (11 g/dL) (without blood transfusions or erythropoietin) or ≥ 50% 
increase of pre-treatment value  
Partial Response with Lymphocytosis (PR-L) 
Patients achieved PR with CLL-related signs or symptoms other than lymphocytosis will be 
considered PR-L and continue on therapy until the occurrence of definitive disease progression 
other than lymphocytosis alone. 
Progressive Disease (PD) 
PD during or after therapy will be characterized by at least 1 of the following: 
• ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5×109/L. 
During treatment, the increase should be assessed against baseline using a Day 1 
(pre-cycle) nadir lymphocyte count and not interim cycle lymphocyte counts, which may 
not be stable. After treatment, increases should be assessed against the end of treatment 
response assessment.  
• Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra 
nodal lesion (regardless of size) 
• ≥ 50% increase in the longest diameter of any previous site of clinically significant 
lymphadenopathy (ie, any lesion > 10 mm at baseline). During treatment, the increase 
should be assessed against baseline. After treatment, increases should be assessed against 
the end of treatment response assessment. 
• ≥ 50% increase in the enlargement of the liver and/or spleen as determined by 
measurement below the relevant costal margin or appearance of palpable hepatomegaly or 
splenomegaly that was not previously present. During treatment, the increase should be 
assessed against baseline. After treatment, increases should be assessed against the end of 
treatment response assessment. 
• Transformation to a more aggressive histology (eg, Richter’s syndrome or plasmacytoid 
lymphocytic lymphoma with > 55% prolymphocytes). Whenever possible, this diagnosis 
should be supported by lymph node biopsy. 

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• After treatment, the progression of any cytopenia (unrelated to autoimmune cytopenia), as 
documented by either: 
− A decrease of hemoglobin levels by more than 20 g/L (2 g/dL) or to less than 100 g/L 
(10 g/dL) 
OR  
− a decrease of platelet counts by more than 50% or to less than 100 × 109/L 
(100000/μL), which occurs no earlier than 3 months after end of therapy defines 
progression if the marrow biopsy demonstrates an infiltration of clonal CLL cells. 
Stable Disease (SD) 
Patients who have not achieved a CR or a PR, or who have not exhibited PD, will be considered 
to have SD. 
Objective response rates (ORRs) classified into classical ORR defined as the proportion of 
patients with CR, CRi, nPR, or PR, as determined by the investigator; and neo-ORR defined as 
the proportion of patients with CR, CRi, nPR, PR-L, or PR, as determined by the investigator. 
Source: Adapted from Hallek et al 2008 and Cheson et al 2012. 

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APPENDIX 5 
CONSENSUS-BASED UNIFORM RESPONSE CRITERIA FOR 
WALDENSTRÖM’S MACROGLOBULINEMIA  
Developed by the IWWM, updated in the Sixth IWWM 
Response Category 
Description 
Complete response 
• 
Absence of serum monoclonal IgM protein by immunofixation  
• 
Normal serum IgM level 
• 
Complete resolution of extramedullary disease, ie, lymphadenopathy 
and splenomegaly if present at baseline 
• 
Morphologically normal bone marrow aspirate and trephine biopsy 
Very good partial response  
• 
Monoclonal IgM protein is detectable  
• 
≥ 90% reduction in serum IgM level from baselinea 
• 
Complete resolution of extramedullary disease, ie, lymphadenopathy/ 
splenomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Partial response  
• 
Monoclonal IgM protein is detectable  
• 
≥ 50% but< 90% reduction in serum IgM level from baselinea 
• 
Reduction in extramedullary disease, ie, 
lymphadenopathy/splenomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Minor response  
• 
Monoclonal IgM protein is detectable 
• 
≥ 25% but < 50% reduction in serum IgM level from baselinea 
• 
No new signs or symptoms of active disease 
Stable disease  
• 
Monoclonal IgM protein is detectable 
• 
< 25% reduction and < 25% increase in serum IgM level from baselinea 
• 
No progression in extramedullary disease, ie, 
lymphadenopathy/splenomegaly 
• 
No new signs or symptoms of active disease 
Progressive disease  
• 
≥ 25% increase in serum IgM levela,b from lowest nadir (requires 
confirmation) and/or progression in clinical features attributable the 
disease 
IgM = immunoglobulin M. 
a 
Sequential change in IgM levels may be determined either by M-protein quantitation by densitometry or total 
serum IgM quantitation by nephelometry. 
b 
An absolute increase of 0.5 g/L (0.5 g/dL) is required when the increase of IgM component is the only 
applicable criterion. 
Source: Adapted from Dimopoulos 2014 

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APPENDIX 6 
LUGANO RESPONSE CRITERIA FOR HODGKIN AND NON-HODGKIN’S LYMPHOMA  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete Response 
Complete Metabolic Response 
Complete Radiologic Response (All of the Following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3a with or without a residual mass on 5PSb 
Target nodes/nodal masses must regress to ≤1.5 cm in LDi 
It is recognized that in Waldeyer’s ring or extranodal sites with high 
physiologic uptake or with activation within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if uptake at sites of initial 
involvement is no greater than surrounding normal tissue even if the tissue 
has high physiologic uptake. 
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
Partial 
Partial metabolic response 
Partial Remission (All of the Following) 
Lymph nodes and 
extralymphatic sites 
Score 4 or 5b with reduced uptake compared with baseline and residual 
mass(es) of any size 
≥ 50% decrease in SPD of up to 6 target measurable nodes 
and extranodal sites 
At interim, these findings suggest responding disease 
When a lesion is too small to measure on CT, assign 
5 mm × 5 mm as the default value 
At end of treatment, these findings indicate residual disease 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but smaller than normal, use 
actual measurement for calculation 
Nonmeasured lesions Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 
normal 
New lesions 
None 
None 

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Response and Site 
PET-CT–Based Response 
CT-Based Response 
Bone marrow 
Residual uptake higher than uptake in normal marrow but reduced 
compared with baseline (diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration should be given 
to further evaluation with MRI or biopsy or an interval scan. 
Not applicable 
No Response or 
Stable Disease 
No Metabolic Response 
Stable Disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 with no significant change in FDG uptake from baseline at 
interim or end of treatment 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for PD 
are met 
Nonmeasured lesions Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
PD 
Progressive Metabolic Disease 
PD Requires at least 1 of the Following 
Individual target 
nodes/nodal masses 
Score 4 or 5 with an increase in intensity of uptake from baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or end-of-
treatment assessment 
An individual node/lesion must be abnormal with:  
• 
LDi > 1.5 cm and increase by ≥ 50% from PPD 
nadir and an increase in LDi or SDi from nadir 
• 
0.5 cm for lesions ≤2 cm and 1.0 cm for lesions 
> 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must increase to > 16 cm). If 
no prior splenomegaly, must increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
Nonmeasured lesions None 
New or clear progression of pre-existing nonmeasured 
lesions 

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Response and Site 
PET-CT–Based Response 
CT-Based Response 
New lesions 
New FDG-avid foci consistent with lymphoma rather than another 
etiology (eg, infection, inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; 
LDi = longest transverse diameter of a lesion; MRI = magnetic resonance imaging; PD = progressive disease; PET = positron-emission tomography; 
PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular 
diameters for multiple lesions. 
a 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured 
dominant lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions 
include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any 
disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or 
myeloid growth factors). 
b 
PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 

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APPENDIX 7 
LISTS OF PROHIBITED DRUGS AND THOSE THAT SHOULD BE 
USED WITH CAUTION  
Drugs that are known to be strong inhibitors of CYP3A4 that may increase exposure to 
HMPL-523 are as follows: 
• boceprevir 
• clarithromycin 
• conivaptan 
• elvitegravir RIT 
• fluconazole 
• grapefruit juice (double strength)* 
• indinavir 
• itraconazole 
• ketoconazole 
• lopinavir/ritonavir 
• mibefradil 
• nefazodone 
• nelfinavir 
• posaconazole 
• ritonavir 
• saquinavir 
• telaprevir 
• telithromycin 
• tipranavir/RIT 
• troleandomycin 
• voriconazole 
*Patients should abstain from eating large amounts of grapefruit and Seville oranges (and other 
products containing these fruits, eg, grapefruit juice or marmalade) during the study (eg, no more 
than a small glass of grapefruit juice [120 mL], half a grapefruit, or 1-2 teaspoons (15 g) of 
Seville orange marmalade daily). 
Drugs that are known to be strong inducers of CYP3A4 are as follows: 
• avasimibe 
• carbamazepine 
• enzalutamide 
• enzalutamide 
• mitotane 
• phenobarbital 
• phenytoin 
• rifabutin 
• rifampin 
• St John’s wort 
 

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Drugs that are known to be sensitive substrates of CYP1A2, CYP2B6, CYP3A4, P-gp, BCRP, or 
MATE1/2-K and the corresponding substrates with a narrow therapeutic range are listed in the 
table below. Co-administration with HMPL-523 may affect the levels (increase or decrease) of 
these drugs.  Patients should be counseled and monitored for changes in efficacy or toxicity of 
these drugs if given concomitantly with HMPL-523. 
CYP Enzymes/ 
Transporter  
Sensitive Substrates  
Substrates with Narrow Therapeutic 
Range  
CYP1A2 
• 
Alosetron 
• 
Duloxetine 
• 
Melatonin  
• 
Ramelteon 
• 
Tacrine 
• 
Tizanidine 
• 
Theophylline 
• 
Tizanidine  
CYP2B6 
• 
Bupropion 
• 
Efavirenz  
 
None  
CYP3A4 
• 
Levomethadyl (LAAM) 
• 
Lomitapide 
• 
Lopinavir 
• 
Lovastatin 
• 
Lumefantrine 
• 
Lurasidone 
• 
Maraviroc 
• 
Midazolam 
• 
Midostaurin  
• 
Neratinib 
• 
Nisoldipine 
• 
Perospirone 
• 
Quetiapine 
• 
Ridaforolimus 
• 
Saquinavir 
• 
Sildenafil 
• 
Simeprevir 
• 
Simvastatin 
• 
Sirolimus 
• 
Tacrolimus  
• 
Alfentanil  
• 
Astemizole 
• 
Cisapride 
• 
Cyclosporine 
• 
Dihydroergotamine 
• 
Ergotamine 
• 
Fentanyl 
• 
Pimozide 
• 
Quinidine 
• 
Sirolimus 
• 
Tacrolimus 
• 
Terfenadine  
P-gp 
• 
Aliskiren 
• 
Ambrisentan 
• 
Dabigatran 
• 
Fexofenadine 
• 
Maraviroc 
• 
Talinolol 
• 
Tolvaptan 
• 
Colchicine 
• 
Digoxin 
• 
Everolimus 
• 
Sirolimus 

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CYP Enzymes/ 
Transporter  
Sensitive Substrates  
Substrates with Narrow Therapeutic 
Range  
BCRP 
• 
Rosuvastatin 
• 
Sulfasalazine 
 
None 
MATE1/2-K 
• 
Metformin 
 
None 
Abbreviations: BCRP = breast cancer resistance protein; CYP = cytochrome P450 enzyme; MATE = multidrug 
and toxin extrusion; P-gp = P-glycoprotein 

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APPENDIX 8 
EASTERN COOPERATIVE ONCOLOGY GROUP 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, 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 
 

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APPENDIX 9 
RAI STAGING SYSTEM FOR CHRONIC LYMPHOID LEUKEMIA  
Stage 
Description 
Risk Status 
0 
Lymphocytosis, lymphocytes in blood > 15000/mm3 and 
> 40% lymphocytes in the bone marrow 
Low 
I 
Stage 0 with enlarged node(s) 
Intermediate 
II 
Stage 0-I with splenomegaly, hepatomegaly, or both 
Intermediate 
III 
Stage 0-II with hemoglobin< 11 g/dL or hematocrit < 33% 
High 
IV 
Stage 0-III with platelet < 100000/mm3 
High 
Source: Adapted from Rai 1975 
 

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APPENDIX 10 
BINET STAGING SYSTEM FOR CHRONIC LYMPHOCYTIC 
LEUKEMIA  
Binet classification: 
• Clinical stage A* CLL is characterized by no anemia or thrombocytopenia and fewer than 
3 areas of lymphoid involvement (Rai stages 0, I, and II). 
• Clinical stage B* CLL is characterized by no anemia or thrombocytopenia with 3 or more 
areas of lymphoid involvement (Rai stages I and II). 
• Clinical stage C CLL is characterized by anemia and/or thrombocytopenia regardless of 
the number of areas of lymphoid enlargement (Rai stages III and IV). 
*Lymphoid areas include cervical, axillary, inguinal, liver, and spleen. 
Adapted from Aronson et al 2022 
 

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APPENDIX 11 
ANN ARBOR CLASSIFICATION  
Revised staging system for primary nodal lymphomas 
Stage 
Involvement 
Extranodal (E) Status 
Limited 
 
 
I 
One node or a group of adjacent nodes 
Single extranodal lesions without nodal 
involvement 
II 
Two or more nodal groups on the same side of the 
diaphragm 
Stage I or II by nodal extent with limited 
contiguous extranodal involvement 
II bulkya 
II as above with “bulky” disease 
Not applicable 
Advanced 
 
 
III 
Nodes on both sides of the diaphragm; nodes 
above the diaphragm with spleen involvement 
Not applicable 
IV 
Additional noncontiguous extralymphatic 
involvement 
Not applicable 
Note: Extent of disease is determined by positron emission tomography - computed tomography for avid 
lymphomas and computed tomography for non-avid histologies. Tonsils, Waldeyer’s ring, and spleen are 
considered nodal tissue. 
a 
Whether Stage II bulky disease is treated as limited or advanced disease may be determined by histology and 
a number of prognostic factors. 
Source: Adapted from Cheson et al 2014 

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APPENDIX 12 
INTERNATIONAL PROGNOSTIC INDEX  
Follicular Lymphoma International Prognostic Index 
Risk Factors 
Ann-Arbor Stage III or IV 
 
Age ≥ 60 years 
 
Serum LDH >1 × ULN 
 
Anemia (hemoglobin < 120 g/L) 
 
Involved nodal areas >4 
 
FLIPI Risk Group  
Number of FLIPI Risk Factors 
Low  
0 or 1 
Intermediate  
2 
High 
3-5 
Abbreviations: FDG = fluorodeoxyglucose; FLIPI = Follicular Lymphoma International Prognostic Index; 
LDH = lactate dehydrogenase; PET = positron-emission tomography; ULN = upper limit of normal. 
Note: The results of FDG-PET should not be taken into account for calculation of FLIPI, as this prognostic score 
was established without FDG-PET. 
Source: Adapted from Solal-Celigny et al 2004. 
 
Diffuse Lymphoma International Prognostic Index 
Risk Factors 
Ann-Arbor Stage III or IV 
 
Age >60 years 
 
Serum LDH >1 × ULN 
 
ECOG Performance Status ≥ 2 
 
Extranodal involvement ≥ 2 
 
IPI Risk Group  
Number of IPI Risk Factors 
Low  
0 or 1 
Low-intermediate 
2 
High-intermediate  
3 
High  
4-5 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; FDG = fluorodeoxyglucose; IPI = International 
Prognostic Index; LDH = lactate dehydrogenase; PET = positron-emission tomography; ULN = upper limit 
of normal. 
Note: The results of FDG-PET should not be taken into account for calculation of IPI, as this prognostic score 
was established without FDG-PET. 
Source: Adapted from Shipp et al 1993. 

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Simplified Mantel Cell Lymphoma International Prognostic Index Score 
The simplified MIPI score will be derived based on baseline values of 4 prognostic factors: age, 
and Eastern Cooperative Oncology Group (ECOG), lactate dehydrogenase, and white blood 
cells. Points will be assigned to each of these factors as presented below, and the score will be 
derived by adding the points for all 4 factors. A score of 0-3 indicates low risk, 4-5 indicates 
intermediate risk, and 6-11 indicates high risk. 
Prognostic Factors 
0 Points 
1 Point 
2 Points 
3 Points 
Age (years)  
<50 
50-59 
60-69 
≥70 
ECOG 
0-1 
Not applicable 
2-4 
Not applicable 
LDH (relative to ULN, ie, LDH/ULN) 
<0.67 
0.67-0.99 
1.0-1.49 
≥1.5 
WBC (×109/L) 
<6.7 
6.7-9.9 
10.0-14.9 
≥15.0 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; ULN = upper 
limit of normal; WBC = white blood cells. 
Source: Adapted from Hoster et al 2008 
International Prognostic Scoring System for Waldenström’s Macroglobulinemia  
Risk Factors 
Age >65 years 
 
Hemoglobin ≤11.5 g/dL, 
 
Platelet count ≤100×109/L 
 
Beta 2-microglobulin >3 mg/L 
 
Serum monoclonal protein concentration >7.0 g/dL 
 
IPI Risk Group  
Number of IPI Risk Factors 
Low  
≤1 adverse characteristic and^#≤65 years old 
Intermediate  
2 adverse characteristics or only >65 years old 
High  
>2 adverse characteristics 
Abbreviations: IPI = International Prognostic Index. 

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APPENDIX 13 
CLINICAL EVALUATION OF POSSIBLE DRUG-INDUCED LIVER 
INJURY  
If alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is elevated to higher than 
3 × upper limit of normal (ULN) and bilirubin is elevated to higher than 2 × ULN, HMPL-523 
treatment should be discontinued immediately, and supportive treatment should be given. This 
combination of laboratory abnormalities meets the biochemical criteria for Hy’s Law, which is 
associated with a markedly increased possibility of severe drug-induced liver injury (DILI) and 
may progress to liver transplantation or death (FDA 2009). 
If the biochemical criteria for Hy’s Law are met, HMPL-523 should be immediately 
discontinued, and patients need to be very closely monitored (bilirubin, alkaline phosphatase 
(ALP), AST, and ALT measured 2-3 times weekly until the results return to baseline or normal) 
and other causes of liver injury evaluated (eg, new or worsening hepatobiliary metastases; 
nonmalignant biliary obstruction; viral hepatitis A, B, or C; alcoholic or autoimmune hepatitis; 
preexisting or acute liver disease; ischemic liver injury; right-sided congestive heart failure; new 
or worsening liver metastases; or concomitant medication that could cause the observed injury). 
Consultation with a gastroenterologist or hepatologist should be considered. 
If the biochemical criteria for Hy’s Law have been met, expedited reporting is required (see 
Section 6.5.2), before waiting for the evaluation of other causes to be completed.  
Recommended Data Collection for Suspected DILI 
The investigator is recommended to obtain the following information so as to further evaluate, 
follow up and complete the clinical data. Data should be recorded on case report forms (CRFs), 
where possible, and supplemented by investigator reporting as text in the clinical database: 
• Medical history of the patient: 
− Detailed history of current symptoms, diagnosis of complications, and medical history 
− Previous medical history (viral hepatitis, alcoholic hepatitis, autoimmune disease, 
biliary tract disease, cardiovascular disease, etc) 
− History of concomitant medication (including over-the-counter and prescription drugs, 
herbal medicines, and dietary supplements), alcohol consumption, recreational drugs, 
and special diet 
− History of exposure to potentially hepatotoxic chemicals 
• Complete the following laboratory tests: 
− Hematology 
− Clinical biochemistry: ALT, AST, bilirubin (including total bilirubin and direct 
bilirubin), ALP, albumin, prothrombin time or international normalized ratio, amylase, 
fasting blood glucose, cholesterol, and triglycerides 
− Other serum tests: Hepatitis A (anti-immunoglobulin M [IgM] and anti-IgG), hepatitis 
B (hepatitis B surface antigen, anti-HBs and hepatitis B virus deoxyribonucleic acid), 
hepatitis C (anti-hepatitis C virus [HCV]; HCV ribonucleic acid test is required for 
any patient with a positive test result), hepatitis D (anti-IgM and anti-IgG), hepatitis E 
(anti-HEV and anti-HEV IgM), and CMV (CMV DNA test is required for any patient 
with a positive test result). 

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• Complete appropriate auxiliary examination: 
− Patients with confirmed elevation of ALT/AST combined with total bilirubin are 
required to receive abdominal ultrasonography or other clinically applicable imaging 
examination within 48 hours (to exclude biliary tract, pancreatic, or intrahepatic 
causes, such as new or worsening hepatobiliary metastases or biliary calculi) and 
obtain the liver imaging result as soon as possible. If an alternative cause (such as 
biliary tract, pancreatic, or intrahepatic causes) of abnormal hepatic results cannot be 
confirmed by imaging, paracentesis is recommended for pathological examination 
after obtaining consent of the patient.  
− If suspected cardiovascular causes exist, cardiac ultrasonography is recommended to 
exclude cardiovascular dysfunction (ie, right heart failure). 
Long-term follow-up: Perform close monitoring on the patient through repetitive tests of ALT, 
AST, ALP, and bilirubin (including total bilirubin and direct bilirubin) 2 to 3 times weekly until 
the laboratory ALT and/or AST abnormality becomes stable or recovers, and then proceed 
according to the protocol. 
 

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APPENDIX 15 
RECOMMENDATIONS FOR MANAGEMENT OF TOXICITY INCLUDING DOSE MODIFICATION  
This document provides guidance to the investigators for the differential diagnosis and management of the important potential class 
toxicities noted on HMPL-523 trials and/or those associated with other SyK inhibitors. This constitutes general recommendations to 
investigators involved in HMPL-523 studies and should be supplemented with any additional protocol-specific guidance. In case of 
questions, prompt discussions with the sponsor’s clinical representative are recommended. Please see the following tables for the dose 
modification and toxicity management recommendations for pulmonary toxicities, gastrointestinal toxicities such as infectious 
diarrhea/colitis, nausea/vomiting, hepatic AEs, infection, neutropenia, thrombocytopenia, anemia, rash and cutaneous skin reactions.  
As a general principle, the recommendations are as follows: 
• Differential diagnosis for any adverse event should be diligently evaluated according to standard medical practice. 
• Recommendations provided here should be evaluated in conjunction with the local clinical standard of care, and overall 
management plan should be clearly documented and be based on the investigator’s best clinical judgment. 
• Consultation with specialty medical care is recommended as appropriate and especially prior to any invasive diagnostic or 
therapeutic procedures. 
• For events that are clearly immune-mediated, prompt initiation of steroids and gradual tapering of steroids once event has 
resolved is recommended. 
 

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Table 6 
Dose Modification/Toxicity Management Recommendations for Pulmonary Toxicities (Including 
Pneumonia/Pneumonitis)  
Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Followup 
Grade 1 
 
(Asymptomatic, 
clinical, or 
radiological 
observations 
only) 
• Educate patient to report any new respiratory symptoms 
(dyspnea, cough) immediately 
• Monitor for symptoms including SpO2 measurement (as 
clinically indicated) 
• Request test for CMV DNA and COVID-19 PCR 
• Consider pulmonary and/or infectious disease consult, as 
appropriate 
Consider 
withholding 
study drug, as 
per clinical 
judgment 
• Re-image within 3 to 4 weeks. Repeat imaging 
as clinically indicated or for those with 
radiographic evidence only or with 
noninfectious/immune-mediated pneumonitis 
• If persistent stable radiologic changes and 
asymptomatic on 1 to 2 scans, revert to normal 
restaging scans per protocol 
• If study drug withheld and no worsening, study 
drug may be resumed based on clinical 
judgment 
• In any case of worsening, treat as Grade 2, 3, or 
4 (see below) 
Grade 2 
 
(Symptomatic, 
mild-to-moderate 
new or 
worsening 
symptoms) 
• Educate patient to report any worsening symptoms 
immediately 
• Monitor for worsening symptoms (eg, 
dyspnea/exertional dyspnea, cough) every 3 days or as 
clinically indicated 
• Measure SpO2 as clinically indicated 
• Consider empiric antibiotics while evaluating the 
differential diagnosis 
• Request pulmonary and/or infectious disease consult if 
cause unclear 
• Evaluate differential diagnosis and causality 
(infection/immune-related/disease progression) with 
standard diagnostic tests, including but not limited to the 
following: 
o Infectious panel (consider cultures/PCR for bacterial, viral, 
and opportunistic infections, including PJP and CMV) 
o Chest X-ray, SpO2, and HRCT 
o PFT and BAL, as necessary 
o ILD markers (KL-6 and SP-D), if available 
Withhold 
study drug 
• Continue close follow-up and re-imaging, as 
needed 
• If considered infectious etiology or if the 
etiology is unclear: 
o If resolved in ≤7 days, resume study drug at 
same dose 
o If resolved in > 7 to 28 days, resume study 
drug at the same or a reduced dose at the 
discretion of the investigator 
− 
If symptoms recur at the original dose, 
then restart study drug at a reduced dose 
at resolution 
− 
If symptoms recur at the reduced dose, 
then permanently discontinue the study 
drug 
o If not resolved within 28 days or worsens, 
consider permanently discontinuing study 
drug 
• If considered immune-related and related to 
study treatment, promptly start systemic steroid 

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Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Followup 
o COVID-19 testing (RT-PCR), if clinically indicated 
• If determined as infectious, prompt antibiotic, antifungal, 
or appropriate treatment as per standard guidelines 
• If determined as immune-related, promptly consider systemic 
steroid treatment 
o Administer methylprednisolone IV 1 to 2 mg/kg/day or 
equivalent oral corticosteroid dose 
treatment, and permanently discontinue study 
drug 
o After sustained clinical improvement with 
steroid treatment is observed, gradually taper 
steroids (eg, by 5 to 10 mg/week over 4 to 6 
weeks) per institutional standards 
o Patients can be switched to an 
equivalent/appropriate dose of oral 
corticosteroids (eg, prednisone) during the 
steroid taper 
• Monitor closely on restarting treatment 
(regardless of whether pulmonary event is 
infectious or immune mediated);  
o If symptoms recur at the original dose, then 
restart study drug at a reduced dose at 
resolution   
o If symptoms recur at the reduced dose, then 
permanently discontinue the study drug 

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Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Followup 
Grade 3 or 
Grade 4 
 
(Severe or 
life-threatening 
symptoms, new 
or worsening 
hypoxia) 
• Hospitalize for further management 
• Request pulmonary and/or infectious disease consult 
• Evaluate differential diagnosis and causality (as 
described above) 
• Prompt treatment with antibiotic, antifungal, or 
appropriate treatment as per standard guidelines 
• Prompt treatment with systemic steroids, if considered 
immunerelated events 
o Administer 1 to 2 mg/kg/day IV methylprednisolone or 
equivalent 
• Consider bronchoscopy and lung biopsy if clinically indicated 
Withhold 
study drug 
• Continue close follow-up and re-imaging  
• If considered infectious etiology or if the 
etiology is unclear: 
o If resolved to baseline within 28 days, 
resume study drug at a reduced dose 
o If not resolved to baseline within 28 days, 
permanently discontinue study drug 
o If recurs on restarting treatment, permanently 
discontinue study drug 
• If considered immune-related: 
o Permanently discontinue study drug and treat 
promptly with steroids (including gradual 
tapering) 
− 
If not improving after 48 hours or 
worsening, consider additional 
immunosuppression 
− 
After sustained clinical improvement is 
observed, gradually taper steroids (eg, by 
5 to 10 mg/week over 4 to 6 weeks) per 
institutional standards 
− 
Patients can be switched to an 
equivalent/appropriate dose of oral 
corticosteroids (eg, prednisone) during 
the steroid taper 
BAL  =  bronchoalveolar lavage; CMV = cytomegalovirus; COVID-19 = coronavirus 2019; CTCAE = Common Terminology Criteria for Adverse Events; 
DNA = deoxyribonucleic acid; HRCT = high-resolution computed tomography; ILD = interstitial lung disease; IV = intravenous; KL-6 = Krebs von den 
Lungen-6; PCR = polymerase chain reaction; PFT = pulmonary function test; PJP = Pneumocystis jiroveci fungus; RT-PCR = real-time polymerase chain 
reaction; SP-D = serum surfactant protein D; SpO2 = oxygen saturation. 
 
 

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Table 7 
Dose Modification/Toxicity Management Recommendations for GI Toxicities  
Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 or 2 
Diarrhea 
(Mild or 
moderate, up to 
6 episodes per 
day from 
baseline, and 
responsive to 
antidiarrheal 
treatment) 
OR 
Grade 1 Colitis 
(Asymptomatic) 
• Monitor closely for any worsening of symptoms. Educate 
patient to report any worsening immediately 
• Prompt evaluation for etiologies, including infection (with 
consideration of travel history and COVID-19), dietary 
factors, and medications, followed by diagnostic testing with 
stool culture, Clostridium difficile testing, CMV, parasite 
RT-PCR (if available), and COVID-19 testing (as appropriate) 
• Consider supportive treatment (use of antidiarrheal and IV 
fluid resuscitation) and dietary optimization 
Continue 
current dose 
and reassess in 
48 hours 
• Reassess within 48 hours of starting supportive 
treatment 
• If responsive to antidiarrheal treatment: 
o No change in study drug dose 
o Monitor as clinically indicated until 
complete resolution  
• If not responsive to antidiarrheal treatment 
or worsening 
o Withhold study drug 
o Manage as per next higher CTCAE grade 
Grade 3 Diarrhea 
(Severe diarrhea, 
> 6 episodes per 
day from 
baseline) 
OR 
Grade 2 or 3 
Colitis 
(Abdominal pain, 
mucus or blood 
in stool, and 
peritoneal signs) 
• Monitor symptoms every 1 to 2 days 
• Evaluate differential diagnosis and causality (as described 
above) 
• Consider GI consult/endoscopy for atypical or refractory cases 
• Initiate supportive treatment (use of antidiarrheal and IV fluid 
resuscitation) and dietary optimization 
• Administer prophylactic antimicrobial or appropriate 
treatment as per standard guidelines 
• If determined as noninfectious (ie, immune mediated), 
promptly start (including gradual tapering) enteric acting 
steroids (eg, budesonide) or systemic steroids such as 
methylprednisolone IV 1 to 2 mg/kg/day or equivalent 
Withhold 
study drug 
 
• Continue close follow-up 
• Reassess within 48 hours of starting supportive 
treatment 
o If resolves to Grade 1 or baseline with 
antidiarrheal treatment, restart study 
drug at the same dose level  
• If considered infectious etiology (clearly not 
immune-related): 
o If event resolves to Grade 1 or baseline in 
<28 days, resume study drug at the same 
or a reduced dose at the clinical 
judgment/discretion of the investigator 
• If considered immune mediated, promptly 
start steroid treatment with gradual tapering 
of steroids and resume study drug at a 
reduced dose if resolved to Grade 1 or 
baseline as described above 

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Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
• Monitor closely on restarting treatment; if 
symptoms recur at Grade 3 or higher, 
permanently discontinue the study drug 
Grade 4 
Diarrhea or 
Colitis 
(Life threatening) 
• Hospitalize and promptly start supportive treatment 
• Consider endoscopy and GI consult, as needed 
• Evaluate differential diagnosis and causality (as described 
above) 
• Prompt treatment with systemic steroids such as 1 to 
2 mg/kg/day IV methylprednisolone or equivalent and/or 
empiric antibiotics 
Withhold 
study drug 
 
• Continue close follow-up until resolution 
• Once resolved, start with reduced dose 
•  If immune mediated, permanently discontinue 
study drug and promptly start steroid treatment 
with gradual steroid tapering 
• Monitor closely on restarting treatment of the 
diarrhea/colitis regardless of whether 
infectious or immune mediated; if at the 
reduced dose, the symptoms recur at Grade 3 
or higher, then permanently discontinue the 
study drug 
CMV = cytomegalovirus; COVID-19 = coronavirus 2019; CTCAE = Common Terminology Criteria for Adverse Events; GI = gastrointestinal; IV = intravenous; 
RT-PCR = real-time polymerase chain reaction. 
 

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Table 8 
Dose Modification/Toxicity Management Recommendations for Hepatic Adverse Events  
Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 or 2 
AST/ALT 
elevation 
(≤5 times upper 
limit of the 
normal [ULN] or 
from baseline, if 
baseline is 
abnormal) 
• Evaluate differential diagnosis and causality (including 
pre-existing liver disease and infectious etiology including 
possible COVID-19 infection [use RT-PCR for diagnosis]) 
• Close monitoring for worsening of any clinical 
signs/symptoms (eg, hyperbilirubinemia)  
• Close monitoring of transaminase and bilirubin levels until 
return to Grade 1 or < 3 times ULN 
• Manage with supportive care for symptom control 
• If the AST/ALT and bilirubin levels meet the definition of 
Hy's law, permanently discontinue the study drug 
Continue 
current dose 
• Monitor as clinically indicated and initiate 
treatment as per standard of care.  
 
Grade 3 or 4 
AST/ALT 
elevation 
(> 5 to 20 times 
ULN or from 
baseline, if 
baseline is 
abnormal) 
• Evaluate differential diagnosis and causality (including 
pre-existing liver disease and infectious etiology) 
• Close monitoring for any clinical symptoms 
• Weekly monitoring of transaminase and bilirubin levels until 
return to Grade 1 or < 3 times ULN 
• Consider hepatic consult and treat accordingly per standard 
treatment guidelines 
• Permanently discontinue study drug if the patient meets the 
definition of Hy's law 
o 
AST or ALT value > 3 × ULN and TBL > 2 × ULN 
o 
No other reason to explain combination of increased 
AST or ALT and TBL, ALP normal (ie, no initial 
findings of cholestasis) 
Withhold 
study drug 
• If resolved to Grade 1 or baseline in less than 
28 days, resume study drug at the same or a 
reduced dose at the discretion of the 
investigator 
• If not resolved to Grade 1 or baseline more 
than 28 days recommend restarting at a 
reduced dose 
• In case of Hy’s Law or if suspicious of liver 
injury permanently discontinue study drug 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; COVID-19 = coronavirus 2019; CTCAE = Common 
Terminology Criteria for Adverse Events; RT-PCR = real-time polymerase chain reaction; TBL = total bilirubin level; ULN = upper limit of normal. 
 

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Table 9 
Dose Modification/Toxicity Management Recommendations for Infection  
Adverse 
Reaction 
CTCAE v5.0  
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 or 2 
Infection 
• Evaluate differential diagnosis and causality 
(infection/immune-related/disease progression) with standard 
diagnostic tests (including but not limited to imaging, 
COVID-19 testing, chest X-ray, cultures, etc)  
• Consider supportive care, including use of growth factors for 
patients with persistent or severe myelosuppression  
• Once confirmed as infection, treat as per standard guidelines 
(including but not limited to antibiotics or antifungals) 
• Consider infectious disease consult, as appropriate 
• For patients with pulmonary or GI toxicities or 
myelosuppression, also refer to guidelines for management of 
those conditions 
Continue 
current dose 
• In case of persistent infection or worsening, 
manage as next higher grade 
Grade ≥ 3 
Infection 
• Evaluate causality and consider supportive care and/or 
anti-microbial therapy as described above 
• Obtain infectious disease consult 
Withhold 
study drug 
• If resolved to baseline within 28 days, resume 
study drug at the same or a reduced dose at the 
discretion of the investigator 
• If not resolved within 28 days or worsens or 
recurs on restarting treatment, permanently 
discontinue study drug 
Clinical CMV 
infection or 
reactivation or 
viremia  
 
Positive CMV 
PCR or antigen 
test 
• In case of symptomatic CMV viremia or end organ damage 
(such as hepatitis, colitis, pneumonitis, or retinitis) or CMV 
reactivation, promptly start appropriate antiviral treatment 
(such as ganciclovir or valganciclovir) 
• If asymptomatic, with CMV DNA > 100,000 copies or CMV 
levels increasing over multiple measurements, withhold study 
treatment. Consider antiviral treatment with guidance from 
infectious disease consult 
Withhold 
study drug 
• Monthly monitoring for CMV reactivation by 
PCR or antigen test 
• In case of symptomatic CMV viremia or 
end-organ damage (such as hepatitis, colitis, 
pneumonitis, or retinitis) or CMV 
reactivation, permanently discontinue study 
treatment 
• In case of asymptomatic CMV viremia, may 
resume study drug at the same or a reduced 
dose at the discretion of the investigator if 
viral load is negative within 28 days 

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Adverse 
Reaction 
CTCAE v5.0  
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Shingles (Herpes 
zoster 
reactivation) 
Grade 1 or 2 
infection 
• Initiate antiviral therapy with acyclovir or valacyclovir  
Continue 
current dose 
• In case of persistent or worsening infection, 
manage as next higher grade  
Shingles (Herpes 
zoster 
reactivation) 
Grade ≥ 3 
infection 
• Initiate antiviral therapy with acyclovir IV 
• Consider infectious disease consult to guide antiviral therapy 
Withhold 
study drug 
• Transition to oral antiviral therapy once 
stabilized 
• Consider as clinically indicated continuing 
antiviral prophylaxis with acyclovir or 
valacylovir, particularly during prolonged 
neutropenia 
• If resolved to baseline within 28 days, 
resume study drug at the same or a reduced 
dose at the discretion of the investigator 
• If not resolved within 28 days or worsens or 
recurs on restarting treatment, permanently 
discontinue study drug 
Pneumocytis 
jiroveci infection 
• Consider pulmonary consult and bronchoscopy. Start empiric 
treatment (also refer to management of pulmonary toxicities) 
Withhold 
study drug 
• In case of PJP diagnosis, permanently 
discontinue study treatment. 
CMV = cytomegalovirus; COVID-19 = Coronavirus 2019; CTCAE = Common Terminology Criteria for Adverse Events; GI = gastrointestinal; 
PCR = polymerase chain reaction; PJP = Pneumocystis jiroveci infection; RNA = ribonucleic acid. 
 

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Table 10 
Dose Modification/Toxicity Management Recommendations for Neutropenia  
Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 or 2 
Neutropenia 
(ANC of  
≥ 1 × 109/L) 
• Monitor for any fever 
• If persistent, consider supportive care as needed 
Continue 
current dose 
• In case of worsening of neutropenia or 
neutropenic fever, treat as Grade 3 or 4 
Grade 3 
Neutropenia 
(ANC of 0.5 to 
1 × 109/L) 
• Monitor with complete blood count every 2 weeks 
• Consider supportive care, including use of growth factors for 
patients with persistent or severe myelosuppression  
• If persistent Grade 3 recurs or worsens, withhold study drug 
Continue 
current dose 
 
• On resolution to a lower grade or baseline, 
resume at the same dose level 
• In case of recurrence after restarting 
treatment, consider next lower dose level at 
the discretion of the investigator 
• In case of worsening of neutropenia or 
neutropenic fever, treat as Grade 4 
Grade 4 
Neutropenia 
(ANC of 
< 0.5 × 109/L) 
OR 
Occurrence of 
neutropenic fever 
or infection 
• Monitor with complete blood count at least every 2 weeks 
• Strongly recommend initiation of growth factors and other 
supportive care including antibiotic prophylaxis 
Withhold 
study drug 
• On resolution to a lower grade or baseline 
(ANC of ≥ 1 × 109/L), resume at the same 
dose level or at the next lower dose level at 
the discretion of the investigator (also refer 
to treatment guidelines for infection) 
• In case of recurrence after restarting 
treatment, resume at the next lower dose 
level 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events. 
 

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Table 11 
Dose Modification/Toxicity Management Recommendations for Thrombocytopenia  
Adverse Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade ≤3 
Thrombocytopenia 
without bleeding 
(Platelet count 
> 25 × 109/L) 
• If persistent, consider supportive care as needed 
Continue 
current dose 
• In case of bleeding or worsening, manage as 
next higher grade 
Grade 4 
Thrombocytopenia 
(Platelet count 
< 25 × 109/L) 
OR 
Any grade 
thrombocytopenia 
with bleeding 
• Monitor with complete blood count at least every 2 weeks 
• Consider supportive care including platelet transfusion (as 
clinically indicated) 
• On resolution to a lower grade or baseline, resume at the same 
dose level 
Withhold 
study drug 
• In case of recurrence after restarting 
treatment, consider next lower dose level at 
the discretion of the investigator 
CTCAE = Common Terminology Criteria for Adverse Events. 
 

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Table 12 
Dose Modification/Toxicity Management Recommendations for Anemia  
Adverse Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 3 Anemia  
(Hemoglobin 
< 8.0 g/dL; 
< 4.9 mmol/L; 
< 80 g/L) 
• Transfusion is indicated, especially if symptomatic 
Withhold 
study drug 
 
• On resolution to ≤Grade 2 or baseline, 
resume at the same dose level or at the next 
lower dose level at the discretion of the 
investigator  
• In case of recurrence after restarting 
treatment, resume at the next lower dose 
level 
Grade 4 Anemia 
(Life-threatening 
consequences; 
urgent intervention 
indicated) 
• Transfusion urgently indicated 
• Monitor with complete blood count at least every 2 weeks 
Withhold 
study drug 
 
• On resolution to ≤Grade 2 or baseline, 
resume at the next lower dose level at the 
discretion of the investigator  
 
• In case of recurrence after restarting 
treatment, consider next lower dose level at 
the discretion of the investigator 
CTCAE = Common Terminology Criteria for Adverse Events. 
 

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Table 13 
Dose Modification/Toxicity Management Recommendations for Rash and Cutaneous Skin Reactions  
Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 or 2 
Rash or 
Cutaneous 
Reactions 
(Covering < 30% 
of BSA, with no 
evidence of 
superinfection) 
• Initiate supportive treatment with emollients, antihistamines 
(for pruritus), or topical steroids 
• Counsel patients to avoid skin irritants 
• Monitor closely for any worsening 
Continue 
current dose 
• In case of worsening, treat as Grade 3 or 4 
Grade 3  
Rash or 
Cutaneous 
Reactions 
(Covering > 30% 
BSA, 
moderate/severe 
symptoms, 
associated with 
local 
superinfection) 
• Initiate supportive treatment with emollients, antihistamines 
(for pruritus), or topical steroids 
• If rash does not resolve with topical steroids, consider 
low-dose systemic steroids (0.5 to 1 mg/kg/day 
methylprednisolone IV or oral equivalent per institutional 
guidelines) 
• Monitor closely for any worsening 
• Consider skin biopsy and dermatology consult 
Withhold 
study drug  
• If resolved in less than 28 days, resume study 
drug at the same or a reduced dose as per 
investigator’s discretion 
• If not resolved within 28 days after dose 
reduction, permanently discontinue study 
drug. Treat as the next higher grade 
Grade ≥ 4  
(Life threatening) 
OR 
Any grade of 
SJS, TENS, or 
DRESS 
• Obtain skin biopsy and dermatology consult  
• Treat as per the diagnosis and standard treatment guidelines 
(such as IV antibiotics and IV steroids) 
Permanently 
discontinue 
study drug 
• Continue close follow-up until resolution 
• If improves to baseline, gradually taper 
steroids as per local standard 
BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; DRESS = drug reaction with eosinophilia and systemic symptoms; 
IV = intravenous; SJS = Steven’s Johnsons’ Syndrome; TENS = toxic epidermal necrolysis. 

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Table 14 
Dose Modification/Toxicity Management Recommendations for Nausea/Vomiting  
Adverse 
Reaction 
CTCAE v5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 or 2 
Nausea or 
vomiting 
 
• Initiate dietary modification (small frequent meals, bland 
foods, sipping/eating slowly) 
• Initiate antiemetic therapy as needed 
 
Continue 
current dose 
• Reassess within 48 hours of starting supportive 
treatment 
• If responsive to antiemetic treatment: 
o No change in study drug dose 
o Monitor as clinically indicated until 
complete resolution  
• If not responsive to antiemetic treatment or 
worsening 
o Withhold study drug 
o In case of worsening, treat as Grade 3 or 4 
Grade 3 Nausea 
or vomiting  
 
• Initiate antiemetic therapy  
• IV hydration  
• Consider hospitalization  
• If persistent despite maximal supportive care and dose hold, 
investigate other causes (consider GI consult, imaging, CNS 
imaging) 
 
Withhold 
study drug  
• If resolved in less than 28 days, resume study 
drug at the same or a reduced dose as per 
investigator’s discretion 
• If not resolved within 28 days, resume study 
drug at reduced dose 
• Consider using scheduled antiemetic prior to 
HMPL-523 administration for prophylaxis 
Grade ≥ 4  
Vomiting 
• Initiate antiemetic therapy IV 
• IV hydration 
• Hospitalization for stabilization/management 
• If persistent despite maximal supportive care and dose hold, 
investigate other causes (consider GI consult, imaging, CNS 
imaging) 
Withhold 
study drug 
• If resolved in less than 28 days, resume study 
drug at the same or a reduced dose as per 
investigator’s discretion 
• If not resolved within 28 days, resume study 
drug at reduced dose 
• Consider using scheduled antiemetic prior to 
HMPL-523 administration for prophylaxis 
CTCAE = Common Terminology Criteria for Adverse Events; CNS = central nervous system; GI = gastroenterology; IV = intravenous. 
 

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APPENDIX 16 
PROHIBITED CONCOMITANT MEDICATIONS THAT HAVE A 
KNOWN RISK OF QT PROLONGATION AND/OR TORSADES DE 
POINTES (TDP)  
Generic Name 
Brand Names (Partial List) 
Drug Class 
Aclarubicin 
Aclacin and others 
Anticancer 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Trisenox 
Anticancer 
Astemizole 
Hismanal 
Antihistamine 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bepridil 
Vascor 
Antihypertensive 
Cesium Chloride 
Energy Catalyst 
Unclassified 
Chloroquine 
Aralen 
Antimalarial 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / Antiemetic 
Chlorprothixene 
Truxal 
Antipsychotic 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Cisapride 
Propulsid 
Gastroprokinetic agent 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Cocaine 
None 
Local anesthetic 
Disopyramide 
Norpace 
Antiarrhythmic 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Domperidone 
Motilium, Motillium, Motinorm Costi, Nomit 
Antinausea 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dronedarone 
Multaq 
Antiarrhythmic 

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Generic Name 
Brand Names (Partial List) 
Drug Class 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic/Antiemetic 
Erythromycin 
E.E.S and others 
Antibiotic 
Escitalopram 
Cipralex, Lexapro, Nexito,  
Antidepressant, SSRI 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic 
Fluconazole 
Diflucan, Trican 
Antifungal 
Gatifloxacin 
Tequin 
Antibiotic 
Grepafloxacin 
Raxar 
Antibiotic 
Halofantrine 
Halfan 
Antimalarial 
Haloperidol 
Haldol  
Antipsychotic 
Hydroquinidine 
Serecor 
Antiarrhythmic 
Hydroxychloroquine 
Plaquenil and others 
Antimalarial 
Ibogaine 
None 
Psychedelic 
Ibutilide 
Corvert 
Antiarrhythmic 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Levomepromazine 
(Methotrimeprazine) 
Nosinan and others 
Antipsychotic 
Levomethadyl acetate 
Orlaam 
Opioid agonist 
Levosulpiride 
Neoprad, Lesuride and others 
Antipsychotic, prokinetic agent 
Meglumine 
antimoniate 
Glucantime 
Antileishmanial 
Mesoridazine 
Serentil 
Antipsychotic 
Methadone 
Dolophine, Symoron, Amidone, Methadose, 
Physeptone, Heptadon 
Opioid agonist 
Mobocertinib 
Exkivity 
Anticancer 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 

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Generic Name 
Brand Names (Partial List) 
Drug Class 
Nifekalant 
Shinbit 
Antiarrhythmic 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, Emetron, 
Ondavell, Emeset, Ondisolv, Setronax 
Antiemetic 
Oxaliplatin 
Eloxatin 
Antineoplastic agent 
Papaverine 
Multiple 
Antispasmodic 
Pentamidine 
Pentam 
Antifungal 
Pimozide 
Orap 
Antipsychotic 
Probucol 
Lorelco 
Antihyperlipidemic 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Propofol 
Diprivan, Propoven 
Anesthetic, general 
Quinidine 
Quinaglute, Duraquin, Quinact, Quinidex, 
Cin-Quin, Quinora 
Antiarrhythmic 
Roxithromycin 
Rulide and others 
Antibiotic 
Sertindole 
Serdolect and others 
Antipsychotic 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Sparfloxacin 
Zagam 
Antibiotic 
Sulpiride 
Dogmatil and others 
Antipsychotic 
Sultopride 
Barnetil, Topral and others 
Antipsychotic 
Terfenadine 
Seldane 
Antihistamine 
Terlipressin 
Teripress and others 
Vasoactive agent 
Terodiline 
Micturin and others 
Antispasmodic 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Vandetanib 
Caprelsa 
Anticancer 

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APPENDIX 17 
EUROPEAN UNION GENERAL DATA PROTECTION 
REGULATION- AND CLINICAL TRIAL REGULATION-
COMPLIANT DATA PROTECTION  
HUTCHMED Limited, as Data Controller of this study, ensures that all processing activities 
involving personal data performed in the scope of the study comply with applicable privacy and 
data protection laws, including, but not limited to, Regulation (EU) 2016/679 (General Data 
Protection Regulation), together “Data Protection Laws.”  
HUTCHMED Limited will ensure that the technical, organizational, and contractual security 
measures described below are periodically reviewed and updated to take into account relevant 
technological developments and/or changes to the processing of personal data in conjunction 
with the study. All locations, personnel, and information systems that are used to perform 
services for the study will be covered by the measures described in this appendix. 
HUTCHMED Limited may apply additional statutory measures where required by the national 
laws that apply to the study or that HUTCHMED Limited otherwise deems appropriate, and in 
such cases, it will implement these measures even if they are not expressly listed below. 
Technical Measures 
• Restriction and monitoring of physical access to the offices and information 
processing facilities to employees, personnel, and approved visitors 
• Ensuring appropriate and restricted user access relevant to the function and type 
of activity performed in relation to the study (“role-based access”) 
• The pseudonymization and encryption of personal data, as appropriate 
• Processing personal information in accordance with the data minimization 
principle, meaning that personal data is never collected “just in case” and each 
data element collected is necessary for the purpose of conducting the study 
• The ability to ensure the ongoing confidentiality, integrity, availability, and 
resilience of processing systems and services 
• Network, application, and database security by means of firewalls and 
antivirus/antimalware 
• Ensuring the detection of malware purposed for unauthorized deletion, blocking, 
copying of information, or disabling security measures 
• The means to restore the availability and access to personal information in a 
timely manner in the event of a physical or technical incident 
• Logging of security events/incidents in information systems and implementation 
of system audit trails, where applicable 
• Ensuring that information systems, computers, and software involved in the 
performance of the services provided in the study are backed up 
• A process for regularly testing, assessing, and evaluating the effectiveness of 
technical measures 

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• Procedures to detect any personal data breach that may occur 
Study subjects will be assigned a subject identification number for the purposes of transferring 
their personal data, and names or other information that would make study subjects directly 
identifiable will not be transferred. The information technology systems used to collect, process, 
and store study-related data are secured by the technical, organizational, and contractual security 
measures described in this appendix, in particular so that identifiable personal data of study 
subjects are not processed other than as contemplated by the protocol. 
Sponsor representatives acting on behalf of HUTCHMED Limited will have read-only access to 
fully identifiable personal data only when strictly necessary, eg, in the scope of the on-site 
monitoring visits and audits, only for the source data verification mandatory under the clinical 
study framework, including the ICH-GCP obligations applicable to the conduct of the study. 
In addition, records containing fully identifiable personal data may be reviewed by national and 
international regulatory authorities. 
Organizational Measures 
HUTCHMED Limited has implemented and maintains the following organizational measures: 
• The provision of information notices to, and where required, obtaining consent 
from, data subjects (including the participants in the study) 
• Procedures and practices for data protection compliance, including policies and 
standard operating procedures relating to personal data security, data subject 
rights requests, data retention, personal data breaches, vendor contracting, and 
transfer impact assessments 
• Procedures and practices for securing the destruction of paper documents 
containing personal data after the applicable retention period, if any 
• Procedures and practices that cover reporting, analysis, monitoring, and resolution 
of security incidents 
• Business continuity procedures and practices to help ensure that HUTCHMED 
Limited can continue to provide services through operational interruption 
• Processes to ensure that cross-border transfers of personal data comply with the 
Data Protection Laws 
• Procedures and practices for employee and staff awareness and training  
• Procedures and practices for auditing compliance with the Data Protection Laws 
Contractual Measures 
When selecting vendors, HUTCHMED Limited has due diligence processes in place. In addition 
to the above-mentioned technical and organizational measures, HUTCHMED Limited, by means 
of internal measures and imposing contractual data processing clauses on relevant subcontractors 
and third parties, ensures the confidentiality of records and personal data of study subjects. In 
addition, the contracts between the Sponsor and study sites specify the responsibilities of the 
parties relating to data protection, including the handling of personal data breaches, respective 
communication, and cooperation of the parties.  

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Personal Data Breaches 
HUTCHMED Limited has put in place a process to assess and, if required, report personal data 
breaches occurring at its or its subcontractors’ facilities and premises. In the event of a data 
breach, HUTCHMED Limited will apply appropriate measures to mitigate the risks to data 
subjects based on the specific context of the data breach and taking into account the rights and 
freedoms of the individuals. If a breach is likely to result in a risk to data subjects, HUTCHMED 
Limited will determine whether it is required to notify the applicable supervisory authorities 
within 72 hours after becoming aware of the breach, and if the breach is likely to result in a high 
risk to data subjects, the relevant individuals will also be informed without undue delay. In 
addition, HUTCHMED Limited will take appropriate steps to mitigate the possible adverse 
effects of the data breach in coordination with the relevant parties involved in the study (whether 
controllers and/or processors) and those parties’ data protection officers. 
Data Transfer 
Where applicable, personal data may be transferred to third countries outside of the European 
Economic Area. HUTCHMED Limited ensures the security of the data transfer by means of an 
Adequacy Decision, where applicable, or by concluding Standard Contractual Clauses as 
provided by the European Commission in adjunction with appropriate supplementary measures. 
A Transfer Impact Assessment will be in place before the first subject data is processed. 
 
  

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APPENDIX 18 
AMENDMENT HISTORY  
Amendment 4 (12 December 2022) 
Section Number 
Summary of Change 
Rationale for Change  
Cover Page, Sponsor’s Approval, 
Document History, Header, and 
Footer 
Administrative updates made to reflect 
Amendment 4 
The administrative updates were 
made to reflect Amendment 4.  
Section 2.1 – Current Therapies and 
Unmet Medical Need 
Additional text added to review the use 
of BCL-2 inhibitor therapy in CLL and 
definition of double refractory CLL 
This information clarifies the 
current treatment landscape in 
CLL and provides background 
for requirement for prior BCL-2 
inhibitor therapy in selected 
patients in the post-BTK CLL 
cohort.   
Section 2.2.3 – Nonclinical 
Toxicology 
Additional text added to update results 
of in vitro phototoxicity studies 
Based on updated data 
Synopsis, Section 4.5 – Dose 
Expansion Stage (Stage 2) 
Language was added to indicate that as 
of 30 November 2022, patients will no 
longer be permitted to consent to enroll 
in selected lymphoma dose expansion 
cohorts (mantle cell lymphoma [MCL], 
follicular lymphoma [FL], marginal 
zone lymphoma [MZL], 
Waldenström’s 
macroglobulinemia/lymphoplasmacytic 
lymphoma [WM/LPL], peripheral T-
cell lymphoma [PTCL], and cutaneous 
B-cell lymphoma [CBCL]. Currently 
enrolled patients deriving clinical 
benefit from treatment may continue to 
participate in the study. 
 
The dose expansion cohort for chronic 
lymphocytic leukemia (CLL) post-
Bruton tyrosine kinase (BTK) exposure 
is also modified to require 
approximately 10 out of 20 patients to 
have received prior Bcell lymphoma-2 
(BCL-2) inhibitor therapy in addition 
to the BTK therapy. 
This new language confirms that 
consenting to the study, for 
selected cohorts was halted on 
30 November 2022. This 
language also confirms this 
change is not based on any 
patient safety or efficacy 
concerns, and to ensure patients 
deriving clinical benefit from 
study treatment may continue 
treatment. 
 
 
 
 
Based on emerging unmet need 
in the clinic for the management 
of patients who have failed both 
BTK and BCL-2 targeted 
therapies, so called “double 
refractory” patients 
Synopsis, Section 4.7.2 – Rationale 
for Selection of Patient Population, 
Section 5.1.1 – Inclusion Criteria 
Language regarding closing enrollment 
to all non-Hodgkin’s lymphoma (NHL) 
expansion cohorts added.  
This language was added to 
reflect changes in patient 
enrollment upon implementation 
of this protocol amendment.  
Synopsis, Section 4.8.3 – 
Pharmacokinetic Outcome 
Measures  
Removed bullet “The Accumulation 
Index based on area under the 
concentration time curve (AUC)” 
Clarification 
Section 5.4.3 – Recommendations 
for Management of Toxicity 
Including Dose Modification  
Removed phototoxicity 
management/sunlight precautions 
Results of the in vitro 
phototoxicity studies with 
HMPL-523 
 
 showed no 
phototoxic potential, indicating 
CCI
CCI

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Section Number 
Summary of Change 
Rationale for Change  
that the previously necessary 
precautions in this clinical study 
can be lifted. 
Synopsis, Section 7.1 – 
Determination of Sample Size, 
Section 7.1.2 – Stage 2: Dose 
Expansion 
Language was added to confirm the 
total expected enrollment is 
approximately 90 patients and 
approximately 70 patients are expected 
to enroll in the Dose Expansion Stage 
(stage 2). Language associated with the 
change in expected enrollment was 
removed or updated for clarity.  
The new language confirms the 
expected enrollment upon 
completion of enrollment upon 
implementation of this protocol 
amendment. 
Section 7.2 – Analysis Population  
Text added defining DLT evaluation 
Based on updated data 
Synopsis, Section 7.3 – Analysis 
Planned, Section 7.3.1 – 
Demographic and Baseline 
Characteristics, Section 7.3.2 – 
Disposition of Patients Enrolled in 
the Study, Section 7.3.3 – Safety 
Analysis, Section 7.3.3.2 – Adverse 
Events, Section 7.3.3.3 – Clinical 
Laboratory Test Values, Section 
7.3.3.4 – Vital Signs, Section 
7.3.3.5 – 12-Lead ECGs, Section 
7.3.5 – Efficacy Analysis 
Any language, headings, tables, and 
analyses related to assessments, 
objectives, and endpoints that fall 
outside of the scope of the necessary 
assessments for the Safety Review 
Committee to monitor the benefit/risk 
profile of patients remaining on trial 
were updated or removed. 
This language was updated or 
removed to clarify what 
assessments, objectives, and 
endpoints are still relevant upon 
implementation of this protocol 
amendment.   
 
 
Amendment 3 (23 July 2022) 
Section Number 
Summary of Change 
Rationale for Change  
Section 2.1 – Current Therapies 
and Unmet Medical Need 
Section 2.2.2 - Nonclinical 
Pharmacokinetics 
Section 2.2.3 - Nonclinical 
Toxicology 
Section 2.2.4 – Clinical Experience  
Section 2.3.2.1 – Risk Assessment 
Updated based on Investigator’s 
Brochure (IB) v9. 
To provide updated information. 
Section 4.5  Dose Expansion Stage 
(Stage 2) 
Overall expansion stage 
enrollment increased from 110 to 
125. 
Increased number of patients in 
Hodgkin’s lymphoma (HL) cohort 
of expansion stage from 10 to 25.  
To increase the sample size of the 
HL dose expansion cohort to further 
evaluate the efficacy and safety of 
HMPL-523 in these patients. 
Section 4.7.1 - Rationale for the 
Starting Dose and the Dose 
Schedule 
Updated status of studies as of 
10 May 2022. 
To provide updated information.  
Section 5.1.1 – Inclusion 
Criteria #4 
Added number of subjects for HL 
cohort.  
To increase the sample size of the 
HL dose expansion cohort to further 

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Section Number 
Summary of Change 
Rationale for Change  
evaluate the efficacy and safety of 
HMPL-523 in these patients. 
Section 5.1.2 – Exclusion 
Criteria #2 
Note has been updated to clarify 
patients with low complete blood 
cell count can be enrolled if they 
have splenic involvement or bone 
marrow infiltration.  
To allow splenic involvement or 
bone marrow infiltration as condition 
with sponsor approval to make 
exception for lower blood counts.  
Section 5.1.2 – Exclusion 
Criteria #14 
Appendix 1 – Schedule of 
Activities 
Appendix 13  Clinical Evaluation 
of Possible Drug-Induced Liver 
Injury 
Added cytomegalovirus (CMV) 
test at screening.  
To provide clarification that CMV 
viral antibody test should be 
performed at screening to ensure 
CMV DNA testing is negative to 
enroll patients.  
Section 5.1.2 – Exclusion Criteria 
#18 
Section 5.5.2 – Prohibited Therapy 
and Food 
Appendix 16 - Prohibited 
Concomitant Medications that 
Have a Known Risk of QT 
prolongation and/or Torsades de 
Pointes (TdP) 
Reference to 
http://www.crediblemeds.org 
removed and appendix has been 
added. 
For clarification on prohibited 
concomitant medications that have a 
known risk of QT prolongation 
and/or TdP. 
Section 5.4.3 and Appendix 15  
Recommendations for Management 
of Toxicity Including Dose 
Modification 
Added new section and appendix 
on recommendations for 
management of toxicity including 
dose modification.  
To provide guidelines for 
management of toxicities including 
dose modifications.  
Section 5.5.2 – Prohibited Therapy 
and Food 
Updated the section.  
To provide updated information 
based on findings and interpretation 
of in vitro drug-drug interaction 
studies. 
Section 5.6.9 – Laboratory 
Assessments  
Added CMV testing at screening. 
Removed reticulocyte count and 
bands as part of differential white 
blood cells count.  
For clarification. Reticulocyte count 
and bands are not part of routine 
complete blood count at many sites. 
Section 5.6.10 – Electrocardiogram 
Appendix 1 – Schedule of 
Activities 
Electrocardiogram to be performed 
at screening and at Cycle 1, Day 1. 
For clarification. 
Section 5.7.3 – Study Treatment 
Discontinuation 
Added cross reference to Section 
5.5.2 
For clarification. 
Section 5.9.3 – Analytical 
Procedures  
Updated the method for 
determination of chemokines.  
For clarification.  
Section 6.2.3 – Protocol-Defined 
Events of Special Interest 
Expedited Adverse Events 
Added adverse events of special 
interest. 
For clarification. 
Section 7.1 – Determination of 
Sample Size 
Section 7.1.2  Stage 2: Dose 
Expansion  
Planned enrollment for this study 
was updated from approximately 
116 to 140 patients to 
approximately 131 to 155 patients. 
To increase the sample size of the 
HL dose expansion cohort to further 
evaluate the efficacy and safety of 
HMPL-523 in these patients. 

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Section Number 
Summary of Change 
Rationale for Change  
Increased number of patients in 
HL cohort as noted above for 
Section 4.5. 
Sample size increased from 110 to 
125 patients.  
Probability of observing at least 
1 adverse event in expansion stage 
patients was updated. 
Section 7.2 – Analysis Population  
Definition of response evaluable 
set (RES) updated.  
For clarification.  
Appendix 7 – Lists of Prohibited 
Drugs and Those That Should Be 
Used with Caution 
Renamed/revised appendix and 
added P-gp, BCRP, and 
MATE1/2-K sensitive substrates 
and substrates with narrow 
therapeutic range. 
To avoid confusion and protocol 
deviations for prohibited 
concomitant medications and to 
specify that the substrates with 
narrow therapeutic range are 
prohibited.  
Throughout the protocol 
Administrative changes made 
throughout the protocol.  
To update company name, address, 
company logo, and amendment 
version.  
Throughout the protocol 
Minor grammatical, formatting, 
and revisions were made 
throughout the protocol.  
For better presentation.  
 
 
 
Amendment 2 (07 August 2021) 
Section Number 
Summary of Change 
Rationale for Change 
Section 4.5 - Dose Expansion 
Stage (Stage 2) 
Overall expansion stage enrollment 
increased from 70 to 110. 
Addition of new cohorts: CLL/SLL 
post-BTK exposure (n = 20) and HL 
(n = 10). 
Increased number of patients in FL 
cohort of expansion stage from 10 to 20. 
 
 
Add identified RP2D (700 mg once 
daily). 
To add a dose expansion cohort 
and increase the sample size of an 
existing dose expansion cohort to 
further evaluate the efficacy and 
safety of HMPL-523 based on 
proof of activity from a Phase I 
study in China evaluating 
HMPL‑523 in lymphoma patients. 
 
For information. 
Section 4.4.5 - Definition of 
Recommended Phase II Dose 
Added identified RP2D (700 mg once 
daily). 
For information. 

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Section 7.1 - Determination of 
Sample Size 
Section 7.1.2 - Stage 2: Dose 
Expansion 
Addition of new CLL/SLL post-BTK 
exposure and HL cohorts and increased 
number of patients in FL cohort as 
noted above for Section 4.5.  
Provided updated probability of 
observing a given adverse event based 
on increase in number of patients in 
expansion phase. 
 
Sample size (planned enrollment) 
corrected to 116-140 patients. 
To add a dose expansion cohort 
and increase the sample size of an 
existing dose expansion cohort to 
further evaluate the efficacy and 
safety of HMPL-523 based on 
proof of activity from a Phase I 
study in China evaluating 
HMPL‑523 in lymphoma patients. 
 
To be consistent with 6-30 patients 
from dose escalation stage + 
110 patients from dose expansion. 
Section 2.2.4 - Clinical 
Experience 
Section 4.7.1 - Rationale for the 
Starting Dose and the Dose 
Schedule 
Removed location “Australia” for 
2015-523-00CH1, which was conducted 
in China. 
For correction. 
Section 2.2.4.5 - Study 
2018-523-00US1 Phase I Study 
in Patients with 
Relapsed/Refractory 
Lymphoma  
Subsection added to describe the 
rationale for adding the chronic 
lymphocytic leukemia/small 
lymphocytic lymphoma (CLL/SLL) 
post-Bruton’s tyrosine kinase (BTK) 
exposure and Hodgkin lymphoma (HL) 
cohorts and increasing number of 
patients in follicular lymphoma (FL) 
cohort. 
To provide rationale for additional 
expansion phase cohorts and to 
have a larger cohort to further 
evaluate the efficacy of HMPL-
523 in FL. 
Section 2.1 - Current Therapies 
and Unmet Medical Need 
Added background regarding spleen 
tyrosine kinase expression in HL 
patients. 
To provide rationale for addition of 
HL cohort. 
Section 4.5.1 - Exploratory 
Analysis 
Section deleted and content moved to 
Section 5.9. 
To present sub-section in 
Section 5.9 for a better flow as the 
exploratory biomarker analysis 
applies to the entire study and not 
just the dose expansion stage. 
Section 5.4.2 - After 
Dose-Limiting Toxicity 
Assessment Window in Stage 1 
or in Stage 2 
Specified 600 mg and 400 mg dose as 
the first and second lower dose in case 
of toxicity. 
 
Added statement to consult with 
Sponsor if treatment hold longer than 2 
weeks is required for resolution of 
toxicity. 
 
Add requirement for additional PK 
sampling if dose is reduced for toxicity 
in Stage 2. 
For clarification. 
 
 
 
To allow longer window for 
toxicity resolution. 
 
 
To evaluate relationship of PK data 
to observed toxicity. 
Section 5.6.9 - Laboratory 
Assessments 
Removed description of 
pharmacokinetic (PK) and 
pharmacodynamic assessments. 
To minimize redundancy as these 
assessments are addressed 
separately under Section 5.9. 

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Section 5.9 - Pharmacokinetic 
and Pharmacodynamic 
Assessments 
Revised/reorganized section. 
Previously Section 5.9 title was “Assay 
Methods.”  
Included and updated text regarding 
exploratory analyses that was 
previously in Section 4.5.1. 
Reference to central laboratory 
removed. 
Method for analysis of plasma samples 
(Liquid Chromatography-Tandem Mass 
Spectrometry) identified.  
To streamline and update the 
content. 
Section 5.9.1 - Collection 
Schedule 
Included collection of additional PK 
and pharmacodynamic samples for 
steady state reached with new dose after 
treatment hold for toxicity. 
 
Specified purpose for blood samples 
that remain after PK analysis. 
 
Include statement that tumor biopsy 
(archival or fresh biopsy) will be 
collected at screening for patients in 
dose expansion cohorts. 
 
Specified purpose for tumor samples 
that remain after predefined analysis. 
To evaluate relationship of PK data 
to observed toxicity. 
 
 
 
For clarification. 
 
 
To allow evaluation of candidate 
biomarkers. 
 
 
 
For clarification. 
Section 5.1.1 - Inclusion 
Criteria # 7 
Added requirement for availability of 
tumor sample (archival or fresh biopsy) 
for patients in dose expansion cohorts. 
To allow evaluation of candidate 
biomarkers. 
Section 4.7.1 - Rationale for the 
Starting Dose and the Dose 
Schedule 
Updated study status of clinical trials 
discussed. 
 
Updated Table 2 data. 
To provide updated study status. 
 
 
To provide corrected data. 
Section 4.7.2 - Rationale for 
Selection of Patient Population 
Listed patients with CLL post-BTK 
exposure and HL with the rest of the 
cohorts. 
 
Replaced term “NHL” with 
“lymphoma.” 
To include new cohorts. 
 
 
 
To use more general term, since 
HL cohort has been added. 
Section 5.3.5 - Post-Trial 
Access to HMPL-523 
Replaced term “NHL” with 
“lymphoma.” 
To use more general term, since 
HL cohort has been added. 

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Section 4.8.3 - Pharmacokinetic 
Outcome Measures  
Removed following PK parameters: 
• 
Terminal half-life 
• 
Apparent volume of 
distribution based on the terminal 
phase 
• 
Mean residence time 
• 
Mean plasma concentration 
To update list of PK parameters. 
Section 7.3.4 - Pharmacokinetic 
Analysis 
Listed PK parameters updated as for 
Section 4.8.3. 
 
Added statement that statistical or PK 
analysis plan will source for details of 
PK analysis. 
 
Specified that HMPL-523 
 
concentrations will be plotted by dose 
level. 
To update list of PK parameters 
and related endpoints. 
 
For clarification.  
 
 
 
For clarification.  
Section 5.1.1 - Inclusion 
Criteria #4 
Addition of CLL/SLL post-BTK 
exposure and HL cohorts. 
To further evaluate the efficacy 
and safety of HMPL-523. 
Section 5.1.1 - Inclusion 
Criteria #6 
Clarified the definition of measurable 
disease to align with Lugano criteria: 
nodal disease > 1.5 cm, non-nodal 
disease > 1 cm. 
 
Added HL to disease subtypes listed in 
text describing measurable disease 
definition. 
For consistency with Lugano 
criteria as the measurable disease 
was defined as > 1.5 cm. 
 
 
To include HL, as an HL cohort 
has been added to study. 
Section 5.1.1 - Inclusion 
Criteria #10 
 
 
 
 
 
 
 
 
 
Section 5.6.9 - Laboratory 
Assessments 
Appendix 1 - Schedule of 
Activities, footnote 16 
For contraception, specified that male 
patients must use condom. Clarified 
measures to be used are highly effective 
measures as defined by Clinical Trials 
Facilitation Group, provided additional 
information regarding route of 
administration and types of 
contraceptive methods. Updated 
duration of contraceptive use from 100 
days to 30 days (based on updated 
investigator’s brochure [IB]). 
 
Clarified definition of postmenopausal 
female. 
To align with updated 
recommendation in IB and to 
match other protocols.  
Section 5.1.2 - Exclusion 
Criteria #15 
Listed urine test under pregnancy test. 
For clarification. 
CCI

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Section 2.2.1 - Nonclinical 
Pharmacology 
Section 2.2.2 - Nonclinical 
Pharmacokinetics 
Section 2.2.3 - Nonclinical 
Toxicology 
Updated based on IB v8. 
To provide updated information. 
Section 2.2.4 - Clinical 
Experience 
Updated based on IB v8. 
To provide updated information. 
Section 2.3 - Study Rationale 
and Benefit-Risk Assessment 
Added subheadings within section. 
Added important identified risks 
provided in IB v8. 
Added reference to Section 2.2.4. 
To provide updated information. 
Section 5.7.1 - Study 
Completion/Early Termination 
Visit 
Replaced “TEAE” with “AE”. 
 
Added “Extended Monitoring” to 
“Follow-up” subheading. 
For correction. 
 
For clarification. 
Appendix 14 Coronavirus 
Disease 2019 (COVID-19) Risk 
Assessment and Vaccine 
Guidance  
(New Appendix) 
 
Section 5.1.2  - Exclusion 
Criteria #12 
Added appendix providing COVID-19 
risk assessment and vaccine guidance. 
 
 
 
 
Added reference to COVID appendix. 
For guidance on COVID-19 risk 
assessment and vaccination. 
Section 5.5.2  - Prohibited 
Therapy and Food 
Added restrictions and instructions on 
the use of acid-reducing agents. 
 
 
 
 
Added exception to grapefruit 
restriction based on Appendix 7. 
To avoid co-administration of 
acid-reducing agents that may have 
a negative impact on the 
absorption of and decrease the 
bioavailability of HMPL-523 as 
the solubility of HMPL-523 is pH 
dependent.  
 
For clarification. 
Section 5.6.2 - Informed 
Consent Forms and Screening 
Log 
Section 8.3 - Patient 
Information and Consent 
Section 8.4 - Data Privacy and 
Confidentiality 
Included detailed information regarding 
data protection. 
To comply with data privacy 
regulations/guidance. 

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Appendix 1 Schedule of 
Activities 
Added row for screening tumor biopsy 
for patients in dose expansion cohorts. 
 
Added “pharmacodynamics” plasma 
sampling with PK plasma sampling 
under procedures. 
Footnote 22 revised: “All” rather than 
“some” expansion patients will provide 
samples for PD analysis; text regarding 
basis for defining scope of PD 
assessment and determination of PD 
sampling time points is deleted. 
Replaced “Cycle 1 Day 1” with 
“screening” for Footnote 6. 
For analysis of candidate 
biomarkers. 
 
For clarification. 
Appendix 2 PK Sampling 
Time Points (Once Daily) (Dose 
Escalation Stage)d 
Removed column for “Sample 
Volume.” 
 
 
 
Added footnote “d” specifying that the 
remaining blood samples may be used 
exclusively for exploratory biomarker 
purposes. 
To avoid duplication and 
discrepancy as the sample volume 
can be found in the PK laboratory 
manual. 
 
For clarification. 

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Appendix 3 PK and 
Pharmacodynamics Sampling 
Time Points (Dose Expansion 
Stage)e 
Removed column for “Sample 
Volume.” 
 
 
 
Added 2 new columns for additional 
trough PK and pharmacodynamics 
samples to be collected in the dose 
expansion phase. 
 
Added additional PK and 
pharmacodynamic sampling visit day 
and timepoints after dose reduction due 
to toxicity. 
 
Added footnotes “d” and “f” specifying 
recording of actual date and time of the 
PK samples in the electronic case report 
form, study drug intake at the 
investigative site under the supervision 
of the investigator or designee on PK 
sampling day. 
 
Added footnote “e” to specify use of 
blood samples remaining after PK 
analysis for exploratory biomarker 
purposes. 
 
Added footnote “g” for Cycle 1 Day 28 
for PK sample rescheduling in case they 
are not collected as scheduled. 
To avoid duplication and 
discrepancy as the sample volume 
can be found in the PK laboratory 
manual. 
 
For analysis of long-term PK and 
pharmacodynamics results in 
patients receiving HMPL-523. 
 
 
To evaluate relationship of PK data 
to observed toxicity. 
 
 
 
For clarification. 
Section 6.7 - Post-Study 
Adverse Events 
Revised term “congenital anomaly” to 
“congenital anomaly/birth defect.”  
For consistency with usage in other 
parts of protocol. 
Section 6.4.10 - Pregnancy 
Specified the last dose of the study drug 
as male patient’s last dose of the study 
drug. 
For clarification. 
Section 7.3.6 - Biomarker 
Analysis 
Replaced the information for biomarker 
analysis plan document with a 
high-level summary of the analysis to 
be performed. 
For correction as the biomarker 
analysis plan document is not 
available.  
Appendix 15 - Amendment 
History 
(New Appendix) 
Added summary of Amendment 1 
changes to Amendment History. 
For consistency with sponsor’s 
process and template. 
Amendment 1 (09 April 2020) 
Description and Rationale for Change 
Sections 
Updated the clinical cutoff date and inclusion of completed 
studies. 
Section 2.2.4 Clinical Experience 

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Sections 
Ongoing studies have been updated to represent the 
appropriate countries.  
New section has been added for a Phase I open-label study to 
evaluate the safety, tolerability, pharmacokinetics, and 
preliminary efficacy of HMPL-523 in patients with relapsed 
or refractory lymphoma. 
Section 2.2.4.5 Study 2018-523-00US1 Phase I 
Study in Patients with Relapsed/Refractory 
Lymphoma 
Updated to reflect the deletion of the 1000 mg dose and 
keeping the 600 mg dose.  
Section 2.3 Study Rationale 
Added an exploratory objective to explore biomarkers 
Section 3.3 Exploratory Objectives  
Added ongoing study information and updated safety data 
from completed dose escalation studies. 
Section 4.7.1 Rationale for the Starting Dose and 
the Dose Schedule 
Added peripheral T-cell lymphoma (PTCL) and cutaneous 
B-cell lymphoma (CBCL) to types of lymphoma patients that 
will be enrolled 
Section 4.7.2 Rationale for Selection of Patient 
Population  
Section 5.1.1 Inclusion Criteria 
Route of administration has been added to specify: Orally, 
with water, after meal 
Removed pharmacokinetic data from dose escalation 
decision 
Removed potential for BID dosing 
Section 4.2 Dose Escalation Stage (Stage 1) 
Table 1 Proposed Dose Escalation Scheme 
New section has been added to specify eligibility criteria for 
patient intradose-escalation 
Section 4.3 Intrapatient Dose Escalation (new 
section) 
Clarified definition of febrile neutropenia per CTCAE v5.0 
and added criteria for Hy’s Law 
Section 4.4 Definition of a Dose Limiting Toxicity 
Further clarified definition of DLT evaluable patients  
Section 4.4.1 Dose Limiting Toxicity Assessment 
Window 
Two additional cohorts have been added (PTCL and CBCL) 
with 10 patients planned for each of these cohorts. Revised 
the total number of patients from approximately 50 to 
approximately 70 patients with relapsed or refractory 
lymphomas  
Section 4.5 Dose Expansion Stage (Stage 2) 
Section 5.1.1 Inclusion Criteria 
Updated clinical trial information 
Section 4.7.1 Rationale for the Starting Dose and 
the Dose Schedule 
Added and clarified definitions of best overall response 
(BOR), time to response (TTR), and progression free 
survival (PFS). 
Section 4.8.4 Efficacy Outcome Measures 
Section 7.3.5 Efficacy Analysis 

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Sections 
The inclusion criteria have been expanded to include the 
2 additional cohorts: PTCL and CBCL. 
Clarified the definition of relapsed and refractory lymphoma 
patients as:  
e. 
Refractory to any prior regimen, defined as no 
response (complete response [CR] or partial 
response [PR]) to previous therapies, or progression 
within 6 months of completion of the last dose of 
prior therapy. 
f. 
Those who can no longer tolerate/withstand 
cytotoxic chemotherapy and or available standard 
of treatment/care. Where safety profile and risks of 
toxicity of other treatment options far outweigh any 
possible clinical benefit 
g. Those with no curative standard of treatment or 
where available treatments are not reasonable or do 
not make sense. In particular, and in the opinion of 
the attending principal investigator, those who will 
benefit from this class of compound 
Contraceptive methods were clearly defined, and language 
has been added to describe highly effective measures. 
Moved exclusion regarding prior SYK inhibitors to the 
inclusion criteria section for clarification of language 
Section 5.1.1 Inclusion Criteria 
Revised the following exclusion criteria: 
• 
Amended laboratory abnormality parameters in 
exclusion criteria #2 
• 
Changed estimated creatinine clearance (CrCl) per 
Cockcroft-Gault parameters for escalation stage 
• 
Added exclusion of patients that have used St. 
John’s wort within 3 weeks of study initiation 
• 
Consolidated exclusion criterion #7 into #5 
• 
Changed exclusion criterion #9 to clarify prohibited 
drugs and clarify exclusionary window for patients 
that have used these drugs prior to study initiation 
• 
Added patients with interstitial lung disease to 
exclusion criterion #13 
• 
Removed exclusion criterion #24 from the protocol 
body to align with the synopsis 
Added the following exclusion criteria: 
• 
#24 Ongoing psychiatric disorder, specifically 
patient with depression and/or suicidal tendencies 
• 
#25 Patients with pathological fractures, especially 
with unknown etiology 
Section 5.1.2 Exclusion Criteria 
Simplified drug labeling procedure to avoid conflicting 
information 
Section 5.3.2 Drug Labeling 
Clarified the HMPL-523 dosing window and administration 
with food 
Section 5.3.4 Dosage, Administration, and 
Compliance 

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Sections 
Clarified eligibility criteria for post-trial access to 
HMPL-523 
Section 5.3.5 Post-Trial Access to HMPL-523 
Added reference 
http://medicine.iupui.edu/clinpharm/ddis/main-table  
Section 5.5 Concomitant Therapy and Food 
Changed ECG requirement from screening and pre-dose to 
one or the other 
Section 5.6.10 Electrocardiogram  
Added +/-7 day window to tumor assessments to align with 
NTF issued to sites previously 
Section 5.6.12 Tumor and Response Evaluation 
Clarified intent of laboratory assessments window prior to 
initiating HMPL-523 dosing 
Section 5.6.9 Laboratory Assessments 
Added parameters to align with EMA guidance 
Section 5.8 Study/Site Discontinuation and Closure 
Removed DLT notification “form” to align with NTF issued 
to sites previously 
Section 6.2.4 Reporting of Dose-Limiting Toxicity 
Added a new analysis population, the response evaluable set  Section 7.2 Analysis Population 
Added text to the planned analysis for clarity 
Section 7.3 Analysis Planned 
Added description of pharmacodynamics assessments for 
certain patients at the sponsor’s discretion  
Section 5.9 Assay Methods 
Added section describing the biomarker analysis    
Section 7.3.6 Biomarker Analysis (new section) 
Updated the Schedule of Activities to align with changes in 
this amendment  
Appendix 1 Schedule of Activities 
Added an Amendments column in the Version/Amendment 
History table for clarification 
Version/Amendment History 
Added a statement a statement of compliance according to 
ICH E6(R2) guidelines 
Statement of Compliance (new section) 
Revised the Investigator’s Agreement page for compliance 
with health authority requirements and consistency with the 
sponsor’s global study protocols 
Investigator’s Agreement 
Nonsubstantive editorial and formatting changes were made 
for administrative purposes or improvements in clarity. 
Throughout entire document 
 

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