Clinical trial NCT03786926
Conditions: Lymphoma
Keywords: CLL SLL FL MZL LPL WM MCL PTCL CBCL
Sponsor: Hutchmed
Start date: 2019-08-26; Completion date: 2024-06-26
Enrollment: 53 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability and PK of HMPL-689 in patients with relapsed or refractory lymphomas

Detailed description:
This is a Phase 1, open-label, multicenter study of HMPL-689 administered orally to patients with relapsed or refractory lymphoma.

HMPL-689 is a selective and potent small molecule inhibitor targeting the isoform phosphoinositide 3'-kinase delta (PI3Kδ), a key component in the B-cell receptor signaling pathway

This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2).

Dose Escalation Stage (Stage 1):

This stage will end when any of the following criteria is met:

* The dose level 1 demonstrates an excessive toxicity, ie, 3 dose limiting toxicities (DLTs) are observed out of the first 3 patients at dose level 1.
* The maximum sample size is reached.
* The MTD and/or RP2D is confirmed.

Dose Expansion Stage (Stage 2):

To further characterize the safety and explore the preliminary anti-tumor activity of HMPL-689 at RP2D, patients with B cell lymphoma will be enrolled in the dose expansion stage.

Arms: arm 1: All patients take HMPL-689 taken daily
Interventions: intervention 1: HMPL-689
Intervention descriptions: intervention 1: HMPL-689 is a PI3Kδ inhibitor

Protocol documents:
Prot_000.pdf: 
Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 1  
 
 
 
  
A P h ase 1, O pe n -L a bel St u d y t o E v al u ate  t he S afet y, T oler a bilit y, 
P h ar m ac o ki netics , a n d Preli mi n ar y Effic ac y of H M P L -6 8 9 i n 
P atie nts wit h Rel a pse d or Refr act o r y L y m p h o m a  
 
Pr ot oc ol n u m ber:  
2 0 1 8 -6 8 9 -0 0 U S 1  
A me n d me nt n u m ber:  
5  
I n v esti gati o nal pr o d uct:  
H M P L -6 8 9  
St u d y p h ase:  
1  
S p o ns or:  
H U T C H M E D L i mited  
B uil di n g 4, 7 2 0 Cail u n R oa d  
C hi na ( S ha n g h ai) Pil ot Free Tra de Z o n e 
S ha n g hai, C hi na 2 0 1 2 0 3  
I N D: 
 
E u dra C T:  
2 0 1 8‐ 0 0 4 8 0 8‐ 1 9  
Cli nical Trials. g o v I D:  
N C T 0 3 7 8 6 9 2 6  
Iss u e Date : 
0 8  Dece m b er  2 0 2 2  
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is t he c o nfi de ntial a n d pr o prietar y i nf or mati o n of 
H U T C H M E D  Li mite d , a n d e x ce pt as ma y be re q uire d b y a p plica ble l a ws or re g ul ati o n s, ma y 
n ot be discl ose d t o ot hers wit h o ut pri or writte n per missi o n  of H U T C H M E D  Li mite d . 
 
C CI


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 2 
 
STATEMENT OF COMPLIANCE  
This study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by ICH E6(R2), and all applicable local and national regulatory 
requirements.  Enrollment at any clinical study site may not begin prior to that site receiving 
approval from the ethics committee of record for the protocol and all materials provided to 
potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Re-consent of previously enrolled participants may be 
necessary, depending on the nature of the amendment. 
The principal investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the sponsor and documented approval from the 
ethics committee of record unless such a change is necessary to eliminate an immediate hazard to 
the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP training as outlined by their governing institution. 
 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 3  
 
S P O N S O R’ S A P P R O V A L   
Title  
A  P hase 1, O pe n -La bel St u d y t o E val uate t h e Safet y, T olera bilit y, 
P har mac o ki netics, a n d Preli mi nar y Efficac y of H M P L -6 8 9 i n Patie nts wit h 
Rela pse d or Refract or y L y m p h o ma  
Pr ot oc ol 
N u m ber  
2 0 1 8 -6 8 9 -0 0 U S 1  
A me n d me nt  
5  
T he desi g n of t his st u d y as o utli ne d b y t his pr ot oc ol has bee n re vie we d a n d a p pr o ve d b y t he 
s p o ns or’s res p o nsi ble pers o n nel as i n dicate d i n t he si g nat ur e ta ble bel o w.  
N a me: [last na me, first na me] 
Title:  
, M D  
 
 
H U T C H M E D I nter nati o nal C or p.  
Si g n at ure:  
See a p pe n de d si g n at ure p a ge  
 
D ate:  [ D D-M o n -Y Y Y Y]  
P P D
P P D


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HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2018-689-00US1 
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 conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by ICH E6(R2) 
• To obtain approval for the protocol and all written materials provided to participants prior 
to initiating the study at my site 
• To obtain informed consent – and updated consent, in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any study-
specific procedures or administering investigational products to those participants 
• To maintain records of each patient’s participation and all data required by the protocol 
 
Name [Print last name, first 
name] 
Title [Title at institution] 
Institution [Address] 
 
 
 
Signature 
Date [DD Mon YYYY] 
 
 


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 5 
 
DOCUMENT HISTORY  
Amendment 
Issue Date 
Original Protocol 
13 Nov 2018 
1 
04 Aug 2020 
2 
20 Jan 2021 
3 
04 June 2021 
4 
28 March 2022 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 6  
 
A M E N D M E N T S U M M A R Y   
T his Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1 A me n d me nt 5  re places Pr ot oc ol 2 0 1 8-6 8 9 -0 0 U S 1 A me n d me nt 4 .  
T his a me n d me nt is c o nsi dere d t o b e s u bsta ntial b ase d o n t he criteria set f ort h i n Article  1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n . 
T he pri mar y p ur p ose of A me n d me nt 5  is t o pr o vi de n otificati o n t hat f urt her e nr oll me nt t o t his 
st u d y has bee n h alte d base d u p o n t he strate gi c e val uati o n of t he cli nical de vel o p me nt of 
H M P L -6 8 9 i n t he U nite d States , E ur o pe, a n d A ustralia  wit h H U T C H M E D as t he st u d y S p o ns or .  
T his c ha n ge is n ot base d o n a n y c o ncer n f or p atie nt safet y or efficac y relati ve t o H M P L -6 8 9 
treat me nt. C urre ntl y e nr olle d patie nts w h o are deri vi n g cli nical be nefit fr o m treat me nt wit h 
H M P L -6 8 9 ma y c o nti n ue t o partici pate i n t he st u d y  as per t he pr ot oc ol . T here is n o pla n ne d 
i nterr u pti o n i n t he s u p pl y of H M P L-6 8 9 t o cli nical trial sites wit h acti ve patie nts . T he c ha n ges 
ma de i n t his a me n d me nt are d escri be d i n t he ta bl e bel o w.   E dit orial a n d f or matti n g c h a n ges are 
n ot i ncl u de d i n t his s u m mar y.  
Details of pri or a m e n d me nts are s u m marize d i n A p pe n di x  1 7 . 
Secti o n N u m ber  
S u m m ar y of C h a n ge  
R ati o n ale f or C h a n ge  
C o ver P a ge, S p o ns or’s A p pr o val, 
D oc u me nt Hist or y, Hea der, a n d 
F o oter  
A d mi nistrati ve u p dates ma de t o reflect 
A me n d me nt 5 . 
 
T he a d mi nistrati ve u p dates  were  
ma de t o reflect A me n d me nt 5.   
S y n o psis,  Secti o n 4. 1. 2  –  D ose 
E x pa nsi o n Sta ge ( Sta ge 2), a n d 
Secti o n  5. 1  –  P atie nts  
La n g ua ge was a d de d t o i n dicate t hat 
c o nse nti n g t o t he st u d y  was halte d as 
of 
 C urre ntl y 
e nr olle d patie nts deri vi n g cli ni cal 
be nefit fr o m treat me nt ma y c o nti n ue 
t o partici pate i n t he st u d y.  
T his ne w la n g ua ge c o nfir ms t hat 
c o nse nti n g t o t he st u d y  was halte d  
o n 
  T his 
la n g ua ge als o c o nfir ms t his c ha n ge 
is n ot base d o n a n y patie nt safet y 
or efficac y c o ncer ns, a n d t o e ns ure 
patie nts deri vi n g cli nical be nefit 
fr o m st u d y treat me nt ma y c o nti n ue 
treat me nt.  
S y n o psis a n d 
Secti o n  4. 1. 5  –  T u m or 
Assess me nt a n d Res p o nse 
E val uati o n  
La n g ua ge i n dicati n g patie nts 
disc o nti n ui n g H M P L -6 8 9 d ue t o ot her  
reas o ns ot her t ha n disease pr o gressi o n 
will c o nti n ue t u m or assess me nts was 
re m o ve d.  
La n g ua ge a n d Secti o n  hea di n g relate d 
t o bli n de d i n de pe n de nt ce ntral re vie w 
of baseli ne a n d s u bse q ue nt t u m or 
i ma gi n g was re m o ve d. 
T his la n g ua ge was re m o ve d as it 
n o l o n ger a p plies as of 
i m ple me ntati o n of t his pr ot oc ol 
a me n d me nt.  
S y n o psis  a n d 
Secti o n  7. 1  –  Deter mi nati o n of 
Sa m ple Size  
La n g ua ge was a d de d t o c o nfir m t he 
t otal e x pecte d e nr oll me nt  is 
a p pr o xi matel y   patie nts  an d 
a p pr o xi matel y   patie nts are 
e x pecte d t o e nr oll i n t he D ose 
E x pa nsi o n Sta ge ( Sta ge 2) . La n g ua ge 
ass ociate d wit h t he c ha n ge i n  e x pecte d 
e nr oll me nt was re m o ve d or u p date d 
f or clarit y.  
T he ne w la n g ua ge c o nfir ms t he 
e x pecte d e nr ol l me nt u p o n 
c o m pleti o n of e nr oll me nt u p o n 
i m ple me ntati o n of t his pr ot oc ol 
a me n d me nt.  
S y n o psis, Secti o n 3  –  O bj ecti ves 
a n d E n d p oi nts, 
Secti o n  4. 1. 7  –  E xte n de d 
A n y l a n g ua ge , hea di n gs , ta bles, a n d 
a nal yses relate d t o assess me nts, 
o bj ecti ves, a n d e n d p oi nts  t hat fall 
T his la n g ua ge was u p date d or 
re m o ve d t o clarif y w hat 
assess me nts, o bj ecti ves, a n d 
C CI
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Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
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CONFIDENTIAL 
Page 7 
 
Section Number 
Summary of Change 
Rationale for Change 
Progression-Free Survival 
Follow-Up Period, 
Section 5.7 – Study Assessments, 
Section 5.8.2 – Extended 
Progression Free Survival 
Follow-up, 
Section 5.9 - Pharmacokinetic, 
Pharmacodynamic, and 
Pharmacogenetic Assessment 
Methods, Section 7 – Statistical 
Analysis, and Appendix 1, 2, 3, 
and 4. 
outside of the scope of the necessary 
assessments for the safety review 
committee (SRC) to monitor the 
benefit/risk of patients remaining on 
trial were updated or removed.  
endpoints are still relevant upon 
implementation of this protocol 
amendment.  
Synopsis and 
Section 5.7.2 – Informed Consent 
Forms and Screening Log 
Language regarding rescreening was 
updated to indicate that patients will 
not be rescreened upon 
implementation of Protocol 
Amendment 5. 
This language was added to clarify 
that rescreening will no longer be 
permitted upon implementation of 
this protocol amendment. 
 


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


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
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CONFIDENTIAL 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................. 1 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
DOCUMENT HISTORY............................................................................................................... 5 
AMENDMENT SUMMARY ........................................................................................................ 6 
EMERGENCY CONTACT ........................................................................................................... 8 
TABLE OF CONTENTS ............................................................................................................... 9 
LIST OF ABBREVIATIONS ...................................................................................................... 15 
1 
PROTOCOL SYNOPSIS ................................................................................................ 19 
2 
INTRODUCTION ........................................................................................................... 29 
2.1 
Current Therapies and Unmet Medical Need ............................................................... 29 
2.2 
Background on HMPL-689........................................................................................... 30 
2.2.1 
Preclinical Pharmacology .......................................................................................... 30 
2.2.2 
Preclinical Pharmacokinetics ..................................................................................... 30 
2.2.3 
Preclinical Toxicology ............................................................................................... 31 
2.3 
Clinical Experience of HMPL-689 ............................................................................... 33 
2.4 
Study Rationale and Benefit-Risk Assessment ............................................................. 35 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 38 
4 
STUDY DESIGN............................................................................................................. 39 
4.1 
Overall Study Design .................................................................................................... 39 
4.1.1 
Dose Escalation Stage (Stage 1) ................................................................................ 39 
4.1.2 
Dose Expansion Stage (Stage 2) ................................................................................ 43 
4.1.3 
Safety Monitoring ...................................................................................................... 44 
4.1.4 
Lifestyle Management ............................................................................................... 44 
4.1.5 
Tumor Assessment and Response Evaluation ........................................................... 44 
4.1.6 
Safety Follow-Up Period ........................................................................................... 44 
4.1.7 
Extended Progression-Free Survival Follow-Up Period ............................................ 44 
4.2 
Rationale for the Starting Dose and Dosing Schedule .................................................. 45 
4.3 
Rationale for Selection of Patient Population ............................................................... 45 
4.4 
End of Study ................................................................................................................. 46 


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HMPL-689 
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5 
MATERIALS AND METHODS ..................................................................................... 47 
5.1 
Patients .......................................................................................................................... 47 
5.1.1 
Inclusion Criteria ....................................................................................................... 47 
5.1.2 
Exclusion Criteria ...................................................................................................... 48 
5.2 
Study Treatment ............................................................................................................ 51 
5.2.1 
Formulation, Packaging, and Handling ..................................................................... 51 
5.2.2 
Drug Labeling ............................................................................................................ 51 
5.2.3 
Drug Accountability................................................................................................... 51 
5.2.4 
Dosage, Administration, and Compliance ................................................................. 51 
5.2.5 
Pneumocystis jiroveci Pneumonia Prophylaxis ......................................................... 51 
5.2.6 
Post-trial Access to HMPL-689 ................................................................................. 52 
5.3 
Method of Treatment Assignment ................................................................................ 52 
5.4 
Dose Delays and Modification ...................................................................................... 52 
5.4.1 
During Dose Limiting Toxicities Assessment Window ............................................ 53 
5.4.2 
After Dose Limiting Toxicities Assessment Window of Stage 1 or at Stage 2 ......... 53 
5.5 
Treatment of Overdose ................................................................................................. 54 
5.6 
Concomitant Therapy and Food.................................................................................... 54 
5.6.1 
Permitted Therapy ...................................................................................................... 54 
5.6.2 
Prohibited Therapy and Food, and Concomitant Medications Requiring Caution in 
Use ............................................................................................................................. 54 
5.7 
Study Assessments ........................................................................................................ 55 
5.7.1 
Definitions of Study Assessments ............................................................................. 55 
5.7.2 
Informed Consent Forms and Screening Log ............................................................ 55 
5.7.3 
Medical History and Demographic Data ................................................................... 55 
5.7.4 
Concomitant Medication/Concomitant Procedure ..................................................... 56 
5.7.5 
Performance Status .................................................................................................... 56 
5.7.6 
Ann Arbor Staging and Rai/Binet Staging................................................................. 56 
5.7.7 
International Prognostic Index ................................................................................... 56 
5.7.8 
Vital Signs .................................................................................................................. 57 
5.7.9 
Physical Examination................................................................................................. 57 
5.7.10 
Laboratory Assessments ............................................................................................ 57 
5.7.11 
Electrocardiogram ...................................................................................................... 59 
5.7.12 
Echocardiogram/MUGA ............................................................................................ 59 


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5.7.13 
Tumor and Response Evaluation ............................................................................... 59 
5.7.14 
Timing of Study Assessments .................................................................................... 60 
5.8 
Participant Completion/Discontinuation ....................................................................... 61 
5.8.1 
Study Completion/Early Termination Visit ............................................................... 61 
5.8.2 
Extended Progression Free Survival Follow-up ........................................................ 61 
5.8.3 
Individual Patient Discontinuation ............................................................................ 61 
5.8.4 
Study Treatment Discontinuation .............................................................................. 62 
5.8.5 
Study and Site Discontinuation .................................................................................. 63 
5.9 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Assessment Methods ..... 64 
5.9.1 
Pharmacokinetic Assay .............................................................................................. 64 
5.9.2 
Collection Schedule for Pharmacokinetic Samples ................................................... 64 
5.9.3 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Sample Handling and 
Shipment .................................................................................................................... 64 
6 
ASSESSMENT OF SAFETY .......................................................................................... 65 
6.1 
Safety Plan .................................................................................................................... 65 
6.2 
Safety Parameters and Definitions ................................................................................ 65 
6.2.1 
Adverse Event ............................................................................................................ 65 
6.2.2 
Serious Adverse Events ............................................................................................. 66 
6.2.3 
Protocol-Defined Adverse Events of Special Interest Expedited Adverse Events .... 66 
6.2.4 
Methods and Timing for Capturing and Assessing Safety Parameters ...................... 66 
6.2.5 
Adverse Event Reporting Period ............................................................................... 67 
6.2.6 
Eliciting Adverse Events............................................................................................ 67 
6.2.7 
Assessment of Severity and Causality of Adverse Events ......................................... 67 
6.3 
Procedures for Recording Adverse Events ................................................................... 69 
6.3.1 
Recording Adverse Events on the CRF ..................................................................... 69 
6.4 
Expedited Reporting Requirements for Serious Adverse Events ................................. 73 
6.4.1 
Reporting Requirements for All Serious Adverse Events and Protocol-Defined Events 
of Special Interest ...................................................................................................... 73 
6.4.2 
Regulatory reporting requirements for Serious Adverse Events ............................... 73 
6.5 
Reporting of Dose Limiting Toxicity ........................................................................... 74 
6.6 
Type and Duration of Follow-Up of Patients after Adverse Events ............................. 74 
6.7 
Post Study Adverse Events ........................................................................................... 74 


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6.8 
HMPL-689 Dose Modification and Toxicity Management Algorithm for Clinical Trials
 ...................................................................................................................................... 75 
7 
STATISTICAL ANALYSIS ........................................................................................... 86 
7.1 
Determination of Sample Size ...................................................................................... 86 
7.1.1 
Stage 1: Dose Escalation Stage .................................................................................. 86 
7.1.2 
Stage 2: Dose Expansion Stage.................................................................................. 86 
7.2 
Analysis Populations ..................................................................................................... 88 
7.3 
Statistical Methods ........................................................................................................ 89 
7.3.1 
Disposition of Patients Enrolled in the Study ............................................................ 89 
7.3.2 
Safety Analysis .......................................................................................................... 89 
7.3.3 
Pharmacokinetic Analysis .......................................................................................... 90 
7.3.4 
Efficacy Analysis ....................................................................................................... 91 
7.3.5 
Pharmacodynamics (Electrocardiogram) Analysis .................................................... 91 
7.4 
Interim Analysis ............................................................................................................ 92 
8 
ETHICS............................................................................................................................ 93 
8.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ....................... 93 
8.2 
Ethical Conduct of the Study ........................................................................................ 93 
8.3 
Patient Information and Consent .................................................................................. 93 
8.4 
Data Privacy and Confidentiality .................................................................................. 94 
9 
STUDY DOCUMENTATION, CASE REPORT FORM, AND RECORDS ................. 95 
9.1 
Source Data Documentation ......................................................................................... 95 
9.2 
Use of Computerized System........................................................................................ 95 
9.3 
Retention of Records..................................................................................................... 95 
10 
MONITORING ................................................................................................................ 96 
11 
DATA MANAGEMENT................................................................................................. 97 
11.1 
Data Quality Assurance ................................................................................................ 97 
11.2 
Electronic Case Report Forms ...................................................................................... 97 
11.3 
Coding ........................................................................................................................... 98 
12 
USE OF INFORMATION AND PUBLICATION ......................................................... 99 
12.1 
Use of Information ........................................................................................................ 99 
12.2 
Publication .................................................................................................................... 99 
13 
REFERENCES .............................................................................................................. 101 
APPENDICES ........................................................................................................................... 105 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ........................................................................................ 106 
Appendix 2 
PK Sampling Time Points (Dose Escalation Stage) .......................................... 111 
Appendix 3 
PK Sampling and ECG Time Points (Dose Expansion Stage) .......................... 112 
Appendix 4 
Time Points for Exploratory Biomarkers ........................................................... 113 
Appendix 5 
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Update of 
the National Cancer Institute-Working Group (NCI-WG) Guidelines: Response 
Criteria ............................................................................................................... 114 
Appendix 6 
Consensus-based Uniform Response Criteria for WM Developed by the IWWM, 
Updated in the Sixth IWWM ............................................................................. 117 
Appendix 7 
Lugano Response Criteria for Hodgkin and Non-Hodgkin Lymphoma ............ 118 
Appendix 8 
Lists of Drugs Prohibited and Those That Should be Used with Caution ......... 121 
Appendix 9 
ECOG Performance Status ................................................................................ 123 
Appendix 10 Ann Arbor Staging ............................................................................................. 124 
Appendix 11 Rai Staging System for Chronic Lymphoid Leukaemia .................................... 125 
Appendix 12 Binet Staging System for Chronic Lymphocytic Leukaemia ............................ 126 
Appendix 13 International Prognostic Index ........................................................................... 127 
Appendix 14 Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) .................. 129 
Appendix 15 COVID-19 Risk Assessment ............................................................................. 131 
Appendix 16 Prior Bruton’s tyrosine kinase Inhibitors ........................................................... 133 
Appendix 17 Amendment History ........................................................................................... 134 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ............................................................ 38 
Table 2 
Proposed Dose Escalation Scheme ...................................................................... 39 
Table 3 
Number of Planned Patients Enrolled Per Cohort ............................................... 43 
Table 4 
Adverse Event Grading (Severity) Scale ............................................................. 68 
Table 5 
Guidance on Causality to the IP........................................................................... 68 
Table 6 
Dose Modification/Toxicity Management Recommendations for Pulmonary 
Adverse Events Including Pneumonia/Pneumonitis ............................................ 76 
Table 7 
Dose Modification/Toxicity Management Recommendations for Diarrhea/Colitis
.............................................................................................................................. 79 


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Table 8 
Dose Modification/Toxicity Management Recommendations for Hepatic Adverse 
Events ................................................................................................................... 81 
Table 9 
Dose Modification/Toxicity Management Recommendations for Infection ....... 82 
Table 10 
Dose Modification/Toxicity Management Recommendations for Neutropenia .. 83 
Table 11 
Dose Modification/Toxicity Management Recommendations for 
Thrombocytopenia ............................................................................................... 84 
Table 12 
Dose Modification/Toxicity Management Recommendations for Rash and 
Cutaneous Skin Reactions.................................................................................... 85 
Table 13 
Number of Patients Planned to be Enrolled and Treated in Stage 2 .................... 87 
Table 14 
Calculated 95% Exact Clopper-Pearson CI Based on Different ORR in Cohort 2
.............................................................................................................................. 87 
Table 15 
Calculated 95% Exact Clopper-Pearson CI Based On Different ORR among 40 
Patients in Cohort 1, Cohort 3, and Cohort 4 ....................................................... 88 
 
LIST OF FIGURES 
Figure 1 
mTPI-2 Decision Chart for Selection of Dose ..................................................... 40 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AO 
Aldehyde oxidase 
aPTT 
Activated partial thromboplastin time 
AR 
Accumulation ratio based on AUC 
AST 
Aspartate transaminase 
AT 
Aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-24h 
Area under the plasma concentration-time curve over the last 24-h dosing interval 
AUC0-t 
Area under the concentration-time curve in a selected time interval 
BCRP 
Breast-cancer resistance protein 
BID 
Twice daily 
B-NHL 
B-cell non-Hodgkin lymphoma 
BTK 
Bruton’s tyrosine kinase 
CBCL 
Cutaneous B-Cell Lymphoma 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CL 
Clearance 
CL/F 
Apparent clearance 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum plasma concentration 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine clearance (estimated per Cockcroft-Gault) 
CRF 
Case report form 
CRi 
Complete response with incomplete bone marrow recovery 
CRO 
Contract research organization 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DILI 
Drug-induced liver injury 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 


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Abbreviation 
Definition 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EOT 
End of treatment 
EUA 
Emergency Use Authorized 
FACS 
Fluorescence activated cell sorting 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FL 
Follicular lymphoma 
FMO 
Flavin-containing monooxygenase 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HL 
Hodgkin lymphoma 
HDPE 
High density polyethylene 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Concentration of a drug required for 50% inhibition in vitro 
ICF 
Informed consent form 
ICH 
International Conference for Harmonization 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
iNHL 
Indolent non-Hodgkin lymphoma 
INR 
International normalized ratio 
IP 
Investigational product 
IPI 
International Prognostic Index 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ISSWM 
International prognostic scoring system for Waldenström’s macroglobulinemia 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWWM 
International Workshops on Waldenström’s macroglobulinemia 
KM 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 


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Abbreviation 
Definition 
LOAEL 
Low-observed-adverse-effect level 
LPL/WM 
Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIPI 
Mantle Cell Lymphoma International Prognostic Index 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTPI-2 
Modified toxicity probability interval scheme-2 
MUGA 
Multigated acquisition scan 
MZL 
Marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect level 
nPR 
Nodular partial response 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
PCR 
Polymerase chain reaction 
PD 
Progressive disease  
PET 
Positron emission tomography 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenetic 
PI3K 
Phosphatidylinositol 3-kinase 
PI3Kδ 
Phosphatidylinositol 3-kinase p110  isoform 
PI3Kγ 
Phosphatidylinositol 3-kinase γ isoform 
PJP 
Pneumocystis jiroveci pneumonia (formerly called Pneumocystis carinii pneumonia 
[PCP]) 
PKAP 
Pharmacokinetic analysis plan 
PKAS 
Pharmacokinetics analysis set 
PK 
Pharmacokinetic(s) 
PPB 
Plasma protein binding 
PR 
Partial response 
PR-L 
Partial response with lymphocytosis 
PS 
Performance status 
PT 
Prothrombin time 
PTCL 
Peripheral T-cell lymphoma 
QD 
Once daily (from the Latin quaque die) 
QTc 
Corrected QT interval 


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Abbreviation 
Definition 
QTcF 
Corrected QT interval by Fredericia 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
RR 
The time elapsed between 2 successive R-waves of the QRS signal on the ECG 
SAE 
Serious adverse event 
SD 
Stable disease 
SDV 
Source data verification 
SLL 
Small lymphocytic lymphoma 
SPD 
Sum of the product of the perpendicular diameters for multiple lesions 
SRC 
Safety review committee 
t½ 
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to reach maximum plasma concentration 
TRAE 
Treatment-related adverse event 
TRSAE 
Treatment-related serious adverse event 
TSH 
Thyroid stimulating hormone 
TTR 
Time to response  
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
Vss 
Volume of distribution at steady state 
Vz/F 
Apparent volume of distribution 
WBC 
White blood cell 
WHO-DD 
World Health Organization-Drug Dictionary 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 1 9  
 
1  
P R O T O C O L S Y N O P SI S   
Pr ot oc ol N u m ber  
2 0 1 8 -6 8 9 -0 0 U S 1  
Title  
A P hase 1, O pe n -La bel St u d y t o E val uate t he Safet y, T olera bilit y, 
P har mac o ki netics , a n d Preli mi nar y Efficac y of H M P L -6 8 9 i n P atie nt s wit h 
Rela pse d or Refract or y L y m p h o ma  
St u d y P h ase  
P hase 1  
S p o ns or  
H U T C H M E D Li mite d  
I n vesti g ati o n al pr o d uct 
H M P L -6 8 9  
St u d y St at us as of 
Pr ot oc ol A me n d me nt 5  
Pl a n ne d E nr oll me nt  
St u d y D ur ati o n  
A p pr o xi matel y 4 8 m o nt hs  
O bjecti ves a n d 
E n d p oi nts  
Tier  
O bjecti ves  
E n d p oi nts  
Pri mar y –  D ose 
Escalati o n  
T o deter mi ne M T D a n d/ or 
R P 2 D of H M P L -6 8 9 i n 
patie nts wit h rela pse d, 
refract or y or resista nt 
l y m p h o ma 
•  I nci de nce of D L Ts  
•  Safet y (i ncl u di n g b ut n ot 
li mite d t o T E A Es, 
treat me nt-relate d a d verse 
e ve nts [ T R A Es], S A Es, 
treat me nt-relate d S A Es 
[ T R S A Es], a n d la b 
a b n or malities)  
Pri mar y –  D ose 
E x pa nsi o n  
T o f urt her e val uate safet y a n d 
t olera bilit y of H M P L-6 8 9 at 
M T D i n patie nts wit h 
rela pse d, refract or y, or 
resista nt l y m p h o ma 
•  Safet y, i ncl u di n g T E A Es 
a n d T R A Es  
 
Sec o n dar y  
 
T o assess preli mi nar y efficac y 
of H M P L 6 8 9 i n patie nts wit h 
rela pse d, refract or y, or 
resista nt l y m p h o ma o verall 
a n d b y l y m p h o ma s u b -t y pes 
as assesse d b y i n vesti gat or  
•  O R R  
•  T T R  
•  D o R  
•  C B R  
•  P F S  
T o c haracterize P K 
para meters of H M P L -6 8 9 i n 
patie nts wit h rela pse d, 
refract or y, or resista nt 
l y m p h o ma at b ot h d ose 
escalati o n a n d d ose e x pa nsi o n 
sta ges 
•  C o nce ntrati o n -ti me pr ofiles 
a n d P K para meters after 
si n gle d ose a n d at stea d y 
state 
 
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To evaluate the effect of 
HMPL-689 on cardiac 
repolarization, as detected by 
changes in electrocardiogram 
(ECG) QTc intervals  
• QTc interval and 
HMPL-689 concentration 
 
Study Design 
This is a phase 1, open-label, multicenter study of HMPL-689 administered orally to 
patients with relapsed, refractory, or resistant lymphoma. 
This study will consist of a dose escalation stage (Stage 1) and a dose expansion 
stage (Stage 2).  Both Stage 1 and Stage 2 include the following periods: screening 
period, treatment period, safety follow-up period, and extended progression-free 
survival (PFS) follow-up period. 
Dose Escalation Stage (Stage 1) 
Dose escalation will be performed according to a modified toxicity probability 
interval scheme-2 (mTPI-2), and HMPL-689 will be titrated using a modified 
Fibonacci design allowing dose increments in subsequent dose levels.  The dose 
escalation is planned at 5 mg once daily (QD), 10 mg QD, 15 mg QD, 20 mg QD, 
25 mg QD, 30 mg QD, 35 mg QD, 40 mg QD, 45 mg QD, and 50 mg QD (dose 
levels 1–10).  
Design Characteristics of mTPI-2 
• 
The maximum sample size for this stage will be determined by the sponsor 
and investigators based on the accumulated data and the mTPI-2 design.  The 
maximum recommended sample size under mTPI-2 design is k × (d + 1), 
where k denotes the cohort size and d denotes the number of doses.  In this 
study, the minimum cohort size is 3.   
• 
The equivalence interval of toxicity probability for the MTD is (25%, 35%).  
This interval is derived based on the following parameters: 
– 
The target probability of toxicity (pT) is set to 30%. 
– 
Both epsilon 1 (ε1) and epsilon 2 (ε2) are set to 0.05.  
• 
This stage will end when any of the following criteria are met: 
– 
The dose level 1 demonstrates an excessive toxicity, i.e., 3 dose-limiting 
toxicities (DLTs) are observed out of the first 3 patients at dose level 1. 
– 
The maximum sample size is reached. 
– 
The MTD and/or recommended phase 2 dose (RP2D) is confirmed.   
Dose Escalation Rules 
• 
The starting dose is dose level 1: 5 mg QD. 
• 
If a lower dose is needed upon results from dose level 1, dose level -1 will 
be explored. 
• 
Three patients will be enrolled for the initial cohort (dose level 1). 
• 
At the end of the DLT assessment window for a dose level, decision on the 
dose of the next dose level will follow the mTPI-2 rule, which leads to 
enrollment of another 3 patients at the next step.   
• 
In the event that the first two patients within a given dose level experience 
DLT events but the third patient has not yet begun protocol treatment, the 
third patient should receive a lower dose per the mTPI-2 algorithm.   
At the end of Stage 1, the MTD will be determined based on the number of patients 
treated and the number of experienced DLT at each dose level.  


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Definition of Dose Limiting Toxicity 
Dose limiting toxicities are defined as the occurrence of any of the following 
treatment -emergent adverse events (TEAE) during the DLT assessment window 
(Cycle 1, Day 1 through Cycle 1, Day 28), unless equivocally due to underlying 
malignancy or an extraneous cause: 
a. 
Nonhematologic toxicity: All nonhematologic TEAEs of Grade 3 or greater 
with the exception of:  
i. 
Grade 3 nausea or vomiting that can be controlled by supportive 
therapy  
b. Hematologic toxicity: 
i. 
Grade 4 neutropenia lasting for more than 5 days 
ii. 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with 
bleeding event or requiring platelet transfusion 
iii. 
Grade ≥3 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 not explained 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, DLTs will be assessed during a DLT assessment window 
of 28 days (i.e., from Cycle 1, Day 1 [the day of the first administration of 
treatment] through Cycle 1, Day 28). 
Definition of DLT-Evaluable Patient 
For decisions on dose escalation, each dose cohort shall present the protocol-
required number of DLT-evaluable patients.  A patient is DLT evaluable if he/she:  
• 
has received at least 75% of the assigned dose of study treatment during the 
DLT assessment window (ie, Days 1 to 28); 
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 each dose cohort. 
Dosing Beyond Cycle 1 
Patients who complete the DLT assessment window and are deemed by the 
investigator to be benefiting from HMPL-689 treatment may continue with 
HMPL-689 treatment until disease progression, death, intolerable toxicity, 
investigator’s discretion that the patient can no longer benefit from the study 
treatment, withdrawal of consent, or the end of study, whichever occurs first.  
During the study treatment period, including the DLT assessment window, patients 
will not be allowed to make up missed doses. 
Definition of MTD 
The MTD is the dose with a posterior toxicity probability closest to the target 
toxicity probability pT, i.e., closest to 30%.  In case all doses have toxicity 
probabilities greater than (pT + ε2), i.e., 35%, no dose will be considered as the 
MTD. 
Posterior toxicity probability at each dose level will be estimated based on beta 
posterior distribution and application of pooled adjacent violator’s algorithm. 
 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 2 2  
 
Defi niti o n of Rec o m me n de d P h ase 2 D ose  
T he decisi o n re gar di n g t he R P 2 D will ta ke t he f oll o wi n g i nt o c o nsi derati o n:  
•  
M T D, if reac he d;  
•  
P har mac o ki netics wit h or wit h o ut ass ociate d safet y a n d preli mi nar y efficac y 
fi n di n gs. 
T hese criteria c o nstit ute t he basis f or R P 2 D deter mi nati o n.  B ot h t he s p o ns or a n d t he 
safet y re vie w c o m mittee ( S R C) m ust a gree o n t he R P 2 D.  
D ose E x p a nsi o n St a ge ( St a ge 2)  
T he safet y, t olera bilit y, P K, a n d preli mi nar y efficac y of H M P L -6 8 9 at M T D/ R P 2 D 
will b e f urt her e val uate d i n patie nts wit h rela pse d, refract or y, or resista nt n o n -
H o d g ki n l y m p h o ma [ N H L].  
A me n d me nt 4 :  
A me n d me nt 5:  
S afet y M o nit o ri n g  
Safet y m o nit ori n g a n d d ose escalati o n deter mi nati o n will be c o n d ucte d b y a n S R C, 
w hic h c o nsists of t he s p o ns or’s me dical m o nit or, dr u g safet y lea d, P K scie ntists, a n d 
t he sites’ Pri nci pal I n vesti gat ors ( PIs) or dele gate, as a p plica ble.  Safet y will be 
m o nit ore d c o nti n u o usl y t hr o u g h o ut t he c o n d uct of t his st u d y b y t he S R C.  T here 
will b e peri o dic re vie ws of e mer gi n g dat a o n safet y, P K, dr u g e x p os ure, tar get 
e n ga ge me nt, p har mac o d y na mi cs, a n d cli nical res p o nse t o deter mi ne c o nti n uati o n ( or 
ot her wise) of a n i n di vi d ual partici pa nt, c o h ort ar m, or e ntire e x pa nsi o n sta ge.  
T he S R C f or d ose escalati o n sta ge ma y e xte n d t o t he e x pa nsi o n sta ge or a ne w o ne 
ma y re place t his S R C, wit h t he sa me ma n date.   
Lifest yle M a n a ge me nt  
F ull assess me nt of e xte nsi ve n o n -cli nical st u dies i n dicate d H M P L -6 8 9 has n o 
p h ot ot o xic effects.  F urt her m ore, e x perie nce fr o m o n g oi n g cli nical st u dies i n C hi na 
a n d A ustralia als o c o nfir m t hat t his st u d y dr u g lac ks a n y p h ot ot o xic effect.  
N o net heless, patie nts  e nr olle d i n t his st u d y are a d vise d t o a v oi d u n necessar y l o n g -
ter m a n d direct e x p os ure t o s u nli g ht or a n y ot her s o urce of ultra vi olet ( U V) li g ht 
d uri n g t heir partici pati o n i n t he st u d y a n d u ntil 3 0 da ys after t he last d ose of st u d y 
dr u g.  P atie nts  are a ls o e nc o ura ge d t o wear s u n glasses a n d a p pl y s u nscree n pr o d ucts 
wit h pr otecti ve c oefficie nt of at least S P F 1 5 w he ne ver p ossi ble.  
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Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 2 3  
 
T u m or Assess me nt a n d Res p o nse E v al u ati o n  
T u m or assess me nt a n d res p o nse e val uati o n will be perf or me d usi n g t he I nter nati o nal 
W or ks h o p o n C L L g ui deli ne f or patie nts wit h C L L, t he c o ns e ns us of I nter nati o nal 
W or ks h o ps o n W M (I W W M -7 c o nse ns us) f or patie nts wit h L P L/ W M, a n d t he 
L u ga n o res p o nse criteria f or patie nts wit h ot her l y m p h o mas.  T u m or res p o nse will 
be assesse d b y i n vesti gat o rs a cc or di n g t o t he res p o nse criteria f or t he res pecti ve 
disease s u bt y pes e ver y 8 wee ks ( ± 7 da ys) f or t he first 2 4 we e ks a n d e ver y 1 2 wee ks 
( ± 7 da ys) t hereafter. 
P atie nts w h o disc o nti n ue H M P L -6 8 9 treat me nt d ue t o reas o ns ot her t ha n disease 
pr o gressi o n will  c o nti n ue t u m or assess me nt acc or di n g t o t he pre vi o us t u m or 
assess me nt sc he d ule u ntil dise ase pr o gressi o n, deat h, e n d of t he st u d y, or start of 
ne w a nti ne o plastic t hera p y, w hic he ver is earlier.  U p o n i m pl e me ntati o n of Pr ot oc ol 
A me n d me nt 5, t his assess me nt wi ll n o l o n ger be re q uire d. 
Deter mi nati o n of disease pr o gressi o n will occ ur l ocall y b y t he i n vesti gat or i n 
acc or da nce wit h res pecti ve disease criteria.  
S afet y F oll o w -U p  Peri o d  
T he safet y of all e nr olle d patie nts will be cl osel y m o nit ore d after i nf or me d c o ns e nt 
has bee n o btai ne d u ntil 3 0 da ys after t he last d ose of treat me nt or t he i nitiati o n of 
ne w a nti ne o plastic t hera p y, w hic he ver c o mes earlier.  After t he safet y f oll o w -u p 
peri o d, i n vesti gat ors s hall o nl y re p ort t he f oll o w -u p of u nres ol ve d seri o us a d verse 
eve nts ( S A Es) t hat are relate d t o pri or st u d y treat me nt of H M P L -6 8 9.  
All a d verse e ve nts ( A Es) will be gra de d i n acc or da nce wit h t he Nati o nal Ca ncer 
I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts ( N CI C T C A E) versi o n 
5. 0.  
E xte n de d P F S F oll o w -U p  Per i o d 
P atie nts w h o disc o nti n ue H M P L -6 8 9 treat me nt d ue t o reas o ns ot her t ha n disease 
pr o gressi o n will e nter t he e xte n de d P F S f oll o w -u p peri o d.  D uri n g t his peri o d, t u m or 
assess me nt will be c o n d ucte d q uarterl y u ntil disease pr o gressi o n, deat h, t he e n d of 
t he st u d y, or t he i nitiati o n of ne w a nti ne o plastic t hera p y, w hi c he ver c o mes earlier.  
U p o n i m ple me ntati o n of Pr ot oc ol A me n d me nt 5, t his assess me nt will n o l o n ger be 
re q uire d. 
E n d of St u d y  
T he e n d of t he st u d y is defi ne d as 1 8 m o nt hs after t he last p atie nt has bee n e nr olle d 
i n t he st u d y or all patie nts ha ve disc o nti n ue d t he st u d y treat me nt, w hic he ver c o mes 
earlier.  
St u d y Tre at me nt  
H M P L -6 8 9 is i n ca ps ule f or m ulati o n f or dail y oral a d mi nistr ati o n.  
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Criteria for Inclusion 
Patients must meet the following criteria to be eligible for study entry: 
1. Signed informed consent form (ICF); 
2. Age 18 years; 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 
4. Histologically confirmed NHL of the following sub-types CLL/SLL, FL 
(grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL; 
• 
Patients with CLL/SLL, FL (grade 1-3a), MCL and LPL/WM must have 
received at least 2 prior lines of systemic therapy. 
• 
Patients with MZL must have received at least 1 prior line of systemic 
therapy that includes an anti-CD20 monoclonal antibody agent. 
• 
Patients with PTCL and CBCL must have received at least 1 prior line 
of systemic therapy. 
5. Patients with relapsed, refractory, or resistant NHL, as defined below:  
• 
Refractory to any prior regimen, defined as no response (complete 
response or partial response) to previous therapies, or progression within 
6 months of completion of the last dose of prior therapy. 
• 
Those who can no longer tolerate/withstand cytotoxic chemotherapy 
and/or available standard of treatment/care (SoT/SoC), where safety 
profile and risks of toxicity of other treatment options far outweigh any 
possible clinical benefit. 
• 
Those with no curative SoT or no reasonable access to available 
treatments, in particular, those who will benefit from this class of 
compound, in the opinion of the attending investigator.  
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, or SLL is 
defined as at least 1 bi-dimensionally measurable lesion (>1.5 cm in its 
largest dimension by computerized tomography [CT] scan). 
7. Expected survival of more than 24 weeks as determined by the principal 
investigator. 
8. Patients with prior treatment with any PI3Kẟ inhibitors are eligible for dose 
escalation.  However, during dose expansion, only patients that 
discontinued PI3Kẟ inhibitor for reasons other than disease progression are 
eligible. 
9. Male patients must agree to use a condom and female patients of 
childbearing potential must agree to use highly effective contraceptive 
measures that result in a low failure rate (<1% per year) when used 
consistently and correctly, from the screening period, through the entire 
study period, and for 30 days after the last dose of study drug.  These highly 
effective contraceptive measures, as defined by the Clinical Trials 
Facilitation Group (CTFG)*, include combined estrogen and progestogen 
hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), 
intrauterine device or intrauterine hormone-releasing system, bilateral tubal 
occlusion, a vasectomized partner, or sexual abstinence if in the preferred 
and usual lifestyle of the patient.  These same criteria are applicable to 
partners of patients involved in this clinical study if that partner is of 
childbearing potential.  Postmenopausal females (no menses for 12 months 


Clinical Study Protocol 2018-689-00US1 
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CONFIDENTIAL 
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without an alternative medical cause) and surgically sterilized females are 
exempt from this criterion. 
*Note: In the context of this guidance, sexual abstinence is considered a 
highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject. 
Criteria for Exclusion 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Patients with primary central nervous system (CNS) lymphoma;  
2. Any of the following laboratory abnormalities: 
• 
Absolute neutrophil count 1.0 × 109/L  
• 
Hemoglobin 80 g/L 
• 
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 bone marrow infiltration.  The 
investigator will discuss the eligibility of such patients with the 
sponsor, and only upon approval by the sponsor will a patient with cell 
counts below the thresholds be enrolled in the study. 
NOTE: In the dose expansion stage, patients with ≤G2 neutropenia per 
CTCAE version 5.0 and/or thrombocytopenia and with confirmed bone 
marrow infiltration are eligible. 
3. Inadequate organ function, defined by the following: 
• 
Total bilirubin 1.5 times the upper limit of normal (× ULN), with the 
following exception: 
– 
Patients with known Gilbert’s disease who have serum total and 
direct bilirubin level 2.5  ULN and normal aspartate 
transaminase (AST) and alanine transaminase (ALT) can be 
enrolled. 
• 
AST 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. 
• 
Estimated creatinine clearance (CrCl) per Cockcroft-Gault 
− Dose escalation stage of trial (Stage 1) – CrCl <40 mL/min 
− Dose expansion stage of trial (Stage 2) – CrCl <30 mL/min 
4. International normalized ratio (INR) 1.5  ULN, activated partial 
thromboplastin time 1.5  ULN or prothrombin time 1.5  ULN; 
• 
Patients requiring anticoagulation therapy but with a stable INR within 
the recommended range according to the local guideline are eligible. 
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 by the sponsor will a 
patient with impaired kidney function due to underlying disease be enrolled 
in the study. 


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5. Serum amylase or lipase ULN at screening or known medical history of 
serum amylase or lipase >ULN; 
NOTE: Patients with known medical history of serum amylase or lipase 
>ULN are eligible in the dose expansion stage. 
6. Patients with presence of second primary malignant tumors within the last 2 
years, with the exception of: 
• 
Basal cell carcinoma of the skin 
• 
Squamous cell carcinoma of the skin 
• 
Carcinoma in situ of the cervix 
• 
Carcinoma in situ of the breast 
7. Clinically significant history of liver disease, including cirrhosis, current 
alcohol abuse, or current known active infection with human 
immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus 
(HBV), or hepatitis C virus (HCV).  Active infection is defined as one 
requiring treatment with antiviral therapy, presence of positive test results 
for hepatitis B (hepatitis B surface antigen and/or total hepatitis B core 
antibody), or CMV or HCV antibody. 
• 
Patients who are positive for hepatitis B core antibody are eligible only 
if test results are also positive for hepatitis B surface antibody and 
polymerase chain reaction (PCR) is negative for HBV deoxyribonucleic 
acid (DNA).  These patients will require HBV DNA PCR monitoring, 
as per local standards. 
• 
Patients who are positive for CMV or HCV serology are eligible only if 
testing for CMV DNA or HCV RNA is negative. 
8. Any anticancer therapy, including chemotherapy, hormonal therapy, 
biologic therapy, vaccine, or radiotherapy within 3 weeks prior to initiation 
of study treatment; 
9. Any granulocyte colony-stimulating factor treatment/blood transfusion 
within 7 days before the screening hematology test; 
10. Any steroid therapy or approved targeted small molecule agents for anti-
neoplastic intent within 7 days or approximately 5 half-lives, whichever is 
longer, prior to initiation of study treatment; 
11. Prior use of any drug that is a strong inducer of cytochrome P450(CYP)3A4 
or strong inhibitor of CYP3A4 within 2 weeks prior to initiation of study 
treatment (3 weeks for St John’s Wort); 
12. Prior autologous transplant within 6 months prior to initiation of study 
treatment;  
13. Prior allogeneic stem cell transplant within 6 months prior to initiation of 
study treatment or with any evidence of active graft versus host disease or 
requirement for immunosuppressants within 21 days prior to initiation of 
study treatment; 
14. Clinically significant active infection (e.g., pneumonia) or interstitial lung 
diseases; (including drug induced pneumonitis); 
15. Major surgical procedure within 4 weeks prior to initiation of study 
treatment; 
16. Treatment within a clinical study of an investigational agent or using an 
investigational device within 30 days prior to initiation of the current study 
treatment; 
17. Adverse events from prior anti-neoplastic therapy that have not resolved to 
Grade 1, except for alopecia; 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 2 7  
 
1 8.  Pre g na nt ( p ositi ve ser u m beta h u ma n c h ori o nic g o na d otr o pi n  [ β-H C G] or 
uri ne test) or lactati n g w o me n;  
1 9.  Ne w Y or k Heart Ass ociati o n ( N Y H A) Class II or greater c o n gesti ve heart 
fail ure; 
2 0.  C o n ge nital l o n g Q T s y n dr o me or Q T c > 4 7 0 msec;  
2 1.  C urre ntl y use me dicati o n k n o w n t o ca use Q T p r ol o n gati o n or t orsa d es de 
p oi ntes (see f ull list at htt p:// w w w.cre di ble me ds. or g);  
2 2.  Hist or y of m y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n 6  m o nt hs pri or t o 
i nitiati o n of st u d y treat me nt; 
2 3.  Hist or y of str o ke or tra nsie nt isc he mic attac k wit hi n 6 m o nt hs p ri or t o 
i nitiati o n of st u d y treat me nt;  
2 4.  I na bilit y t o ta ke oral 
me dicati o n, pri or s ur gical pr oce d ures affecti n g 
a bs or pti o n, or acti ve pe ptic ulcer disease;  
2 5.  Hist or y of i nfla m mat or y b o wel disease (e. g., Cr o h n’s disease or ulcerati ve 
c olitis);  
2 6.  P atie nts wit h o n g oi n g c hr o nic gastr oi ntesti nal diseases;  
2 7.  Le gall y pr otecte d a d ults;  
2 8.  A n y ot her diseases, meta b olic d ysf u ncti o n, p h ysical e xa mi nati o n fi n di n g, or 
cli nical la b orat or y fi n di n g t hat, i n t he i n vesti gat or’s o pi ni o n, gi ves 
reas o na ble s us pici o n of a dise ase or c o nditi o n t hat c o ntrai n dicates t he use of 
a n i n vesti gati o nal dr u g or t hat ma y affect t he i nter pretati o n of t he res ults or 
re n ders t he patie nt at hi g h ris k of  treat me nt c o m plicati o ns. 
St atistic al M et h o ds  
Deter mi n ati o n of S a m ple Siz e  
.  I n ge neral, t he ma xi m u m sa m ple size i n t he d ose 
escalati o n sta ge will be deter mi ne d b y s p o ns or a n d i n vesti gat or base d o n t he acc u m ulate d safet y data a n d t he m T PI -
2 desi g n.  
 
.  P atie nts w h o wit h dra w fr o m t he st u d y pri or t o c o m pleti n g t he D L T 
assess me nt wi n d o w f or reas o ns ot her t ha n D L T or recei ve less t ha n 7 5 % of assi g ne d st u d y me dicat i o n d uri n g D L T 
assess me nt wi n d o w will be re place d.  T his ma y res ult i n act ual e nr oll me nt e xcee di n g pla n ne d e nr oll me nt.  
St a ge 1: D ose Esc al ati o n St a ge  
T he ma xi m u m sa m ple size f or t his sta ge will be deter mi ne d b y t he s p o ns or a n d i n vesti gat or, base d o n t he 
acc u m ulate d safet y data a n d t he m T PI -2 desi g n.  T he ma xi m u m sa m ple size u n der m T PI -2 desi g n is k × ( d + 1), 
w here k de n otes t he c o h ort si ze a n d d de n otes t he n u m ber of d oses.  T he c o h ort size i n t his st u d y is mi ni m u m 3 
patie nts per c o h ort.  T o e ns ure t hat t h e hi g hest d ose (if nee de d) is reac he d per t he m T PI -2 desi g n a n d t he a vaila bilit y 
of a d diti o nal c o h orts, it is esti mate d t hat a p pr o xi matel y 
 patie nts will be nee de d i n t his p orti o n of t he st u d y.   
St a ge 2: D ose E x p a nsi o n St a ge  
A me n d me nt 4 : 
C CI
C CI
C CI
C CI


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 2 8  
 
A me n d me nt 5:  
St atistic al A n al ysis:  
Data will be s u m marize d b y d ose le vel, s u bt y pe of mali g na nc y a n d f or o verall as a p pr o priate.  I n Sta ge 2 of t he 
pr ot oc ol, eac h l y m p h o ma s u bt y pe c o h ort will be a nal yze d i n de pe n de ntl y a n d i n a g gre gate.  C o nti n u o us assess me nts 
will be s u m marize d i n descri pti ve statistics b y t he n u m ber of patie nts ( n), mea n, sta n dar d de viati o n, me dia n, 
mi ni m u m a n d ma xi m u m.  F or cate g orical varia bles, descri pti ve statistics will i ncl u de t he n u m ber a n d perce nta ge 
of patie nts f or eac h cate g or y.  
S afet y A n al ysis:  
E x p os ure t o st u d y dr u g will be s u m marize d a n d liste d.  
D ose li miti n g t o xicities will b e liste d.  T he i nci de nce of T E A Es, S A Es, A Es of s pecial i nt erest, T E A Es lea di n g t o 
d ose a dj ust me nt, or treat me nt disc o nti n uati o n will be prese nte d b y Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) S yste m Or ga n Class ( S O C) a n d preferre d ter m, b y relati o ns hi p t o st u d y dr u g a n d b y t o xicit y gra d e f or 
eac h d ose le vel.  S hift of la b orat or y test res ults will be s u m marize d acc or di n g t o t he N CI C T C A E gra de or n or mal 
ra n ges if n ot gra d a ble.  Descri pti ve statistics f or vital si g ns a n d 1 2-E C G pa ra meters will be prese nte d b y d ose le vel 
a n d visit.  P h ysical e xa mi nati o n fi n di n gs will be liste d.  
P h ar m ac o ki netic A n al ysis:  
N o n -c o m part me ntal m o del a n d p o p ulati o n m o del -base d a nal yses will be perf or me d f or plas ma c o nce ntrati o n data.  
I n di vi d ual a n d mea n plas ma c o nce ntrati o ns of H M P L -6 8 9 vers us ti me data will be ta b ulate d a n d prese nte d.  
Descri pti ve a nal ysis ( n, mea n, sta n dar d de viati o n, mi ni m u m, me dia n, ma xi m u m, ge o metri c mea n, a n d c oefficie nt 
of variati o n [ % C V]) f or all of t he rele va nt P K para meters of H M P L -6 8 9 will be prese nte d.  I n di vi d ual a n d mea n 
H M P L -6 8 9 c o nce ntrati o ns will b e pl otte d b y d ose le vel.  
Effic ac y A n al ysis:  
T he best perce nt c ha n ge fr o m baseli ne ( %) i n t he tar get lesi o n, O R R, C B R a n d 9 5 % CI base d o n Cl o p per -P ears o n 
met h o d will be prese nte d b y d ose le vel f or eac h t y pe of mali g na nc y.  T he P F S, T T R, a n d D o R will be esti mate d 
wit h Ka pla n -Meier ( K M) met h o d if data per mits , a n d t he c orres p o n di n g K M c ur ve will be pl otte d f or eac h t y pe of 
mali g na nc y.  
T u m or assess me nt i n differe nt t y pes of mali g na nc ies will be e val uate d acc or di n g t o s pecifi e d g ui deli nes/criteria: 
1.  C L L: t he m o difie d I nter nati o nal W or ks h o p o n C L L g ui deli ne  
2.  L P L/ W M: c o nse ns us of i nter nati o nal w or ks h o ps o n W M (I W W M -7 c o nse ns us)  
3.  Ot her l y m p h o mas: L u ga n o Res p o nse Criteria f or H o d g ki n a n d N H L  
 
C CI


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2 
INTRODUCTION  
Lymphoma is a group of blood cell tumors that develop from lymphatic cells.  The two main 
categories of lymphomas are Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL).  
Hodgkin lymphomas account for 10% of all lymphomas and less than 1% of all cancers diagnosed 
in the United States (US) yearly.  Approximately 8,500 new patients will be diagnosed with HL 
and 1,050 will die of the disease in the United States in 2018 (NCI 2018).  Non-Hodgkin 
lymphomas are a heterogeneous group of lymphoproliferative disorders originating in 
B-lymphocytes, T-lymphocytes or natural killer (NK) cells.  In the US, B-cell lymphomas account 
for 80% to 85% of lymphomas and range from slow-growing indolent and incurable diseases (such 
as follicular lymphoma [FL] or chronic lymphocytic leukemia/small lymphocytic lymphoma 
[CLL/SLL]) to more aggressive lymphomas (such as diffuse large B-cell lymphoma [DLBCL]).  
Mantle cell lymphoma (MCL) is thought to possess the worst characteristics of both indolent and 
aggressive NHL subtypes owing to incurability of disease (Teodorovic 1995).  Diffuse large B-
cell lymphoma has the highest incidence of NHL accounting for approximately 30-40% of all new 
patients, whereas FL and MCL account for approximately 20-25% and 6-10% of other lymphomas, 
respectively.  B-cell CLL is the most common chronic leukemia in adults in western countries and 
been classified as one of mature B-cell malignancy.  Lymphoplasmacytic lymphoma/ 
Waldenström’s macroglobulinemia (LPL/WM) 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 protein (IgM), thickening the blood, and infiltration 
of bone marrow with lymphoplasmacytic cells.  Approximately 74,680 new patients will be 
diagnosed with NHL and 19,910 will die of the disease in the US in 2018 (NCI 2018). 
2.1 
Current Therapies and Unmet Medical Need  
Globally, there were 465,000 incident cases of NHLs and 226,000 deaths in 2013.  Non-Hodgkin 
lymphomas caused 6.4 million disability-adjusted life years (DALYs) in 2013, with 71% 
occurring in developing countries and 29% occurring in developed countries (Fitzmaurice 2015).  
Non-Hodgkin lymphoma ranked the 8th for cancer incidence and 11th for cancer death in 2013.  In 
developed countries, it ranked 7th for incidence and 9th for mortality, and in developing countries 
it ranked 11th for both incidence and mortality (Vanhaesebroeck 2012).  Non-Hodgkin lymphoma 
is the seventh leading site of new cancer cases among men and women, accounting for 4% of 
new cancer cases and 3% of cancer-related deaths (Vanhaesebroeck 2010). 
The mainstay of treatment for NHL is anti-CD20 antibodies (including rituximab, ofatumumab, 
and obinutuzumab [GA101]) and chemotherapies such as alkylating agents, anthracyclines, 
antimitotic agents, or purine analogues either alone or in combination settings.  Although the 
current treatments for indolent NHL (iNHL) are initially effective in inducing responses in most 
patients, they are not curative and show decreasing efficacy with repeated administrations.  The 
majority of patients are elderly, and not all patients can tolerate aggressive chemotherapy.  Patients 
with high-risk cytogenetics have inferior responses to standard treatments or shorter duration of 
response (DoR).  In addition, chemotherapy-based regimens are associated with long-term toxic 
effects, including cumulative myelosuppression, neuropathy, cardiac toxicity, and secondary 
cancers (Lunning 2012, Gribben 2007, Leonard 2008). 
Investigation of the genetic abnormalities that underlie NHL is providing targets for the 
development of innovative treatments.  Several drugs have been approved for the treatment of 


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different types of relapsed NHL, most notably the B-cell signaling pathway kinase inhibitors 
ibrutinib (Imbruvica®), idelalisib (Zydelig®), copanlisib (Aliqopa®) and acalabrutinib 
(Calquence®).  However, these patients are rarely cured with these new treatments, and they still 
need options after the progression or relapse from the currently available treatment. Furthermore, 
a good candidate with good single agent tolerability and efficacy to combine with the current 
standard of care to provide better efficacy in the front line is also desired.  
2.2 
Background on HMPL-689  
2.2.1 
Preclinical Pharmacology  
HMPL-689 is a novel, highly potent and selective phosphatidylinositol 3-kinase kinase p110  
isoform (PI3Kδ) inhibitor with an IC50 of 0.0008 M in a PI3Kδ kinase enzymatic assay.  HMPL-
689 displayed excellent selectivity against a Kinase ProfilerTM panel of 323 kinases as well as in a 
CEREP panel of 80 pharmacological targets in vitro.  At the cellular level, HMPL-689 effectively 
inhibited the phosphorylation of its downstream signaling molecule AKT in Ramos (human 
Burkitt's lymphoma) cells upon anti-IgM stimulation with an IC50 value of 0.001 M.  HMPL-689 
significantly inhibited cell viability and induced apoptosis of SU-DHL-6 (human B-cell 
lymphoma) cells.  In addition, HMPL-689 inhibited the survival of multiple B-cell NHL lines, 
such as Pfeiffer, RL and REC-1 etc.  Furthermore, HMPL-689 showed potent inhibitory activity 
against anti-IgM stimulated survival of B-cells derived from CLL patients, along with potent 
inhibition of release of chemokines CCL3 and CCL4, which are involved in B-cell homing, from 
those primary cells.  At whole blood level, HMPL-689 significantly inhibited anti-IgD dependent 
B-cell activation (CD86 expression) in rat whole blood with an IC50 of 0.004 M and anti-IgE 
induced basophils activation (CD63 expression) in human whole blood with an IC50 of 0.003 M.  
The ability of HMPL-689 to inhibit the activation of B-cells in vivo was evaluated in rat using an 
ex vivo assay.  Blood samples from the rats were collected after oral administration of HMPL-689 
at various doses and different time points.  The samples were stimulated with anti-IgD overnight 
and B-cell activation in rat whole blood was examined.  The data showed that HMPL-689 inhibited 
expression of CD86 on the surface of B-cells in rat whole blood in a dose- and time- dependent 
manner, with excellent correlation to the drug exposure.  The exposure (470 h•ng/mL) at the 
potential efficacy dose was achieved through concentration values that exceeded the EC90 of B-
cell activation from in vivo target inhibition study for 24 hours. 
2.2.2 
Preclinical Pharmacokinetics  
The pharmacokinetic (PK) properties, metabolic profile, and potential for drug-drug interaction 
(DDI) of HMPL-689 were evaluated both in vitro and in vivo.  HMPL-689 was found to have high 
intrinsic membrane permeability and good oral absorption in mice, rats, dogs and monkeys.  
HMPL-689 could extensively distribute into most tissue (liver, muscle, stomach, fat, small 
intestine etc.) with higher exposure than plasma after oral administration in rats.  HMPL-689 was 
able to penetrate the blood-testis barrier and blood brain barrier, but the exposure in testis, spinal 
cord, and brain were lower than in plasma (exposure ratio between 0.1 to 1).  The volume of 
distribution at steady-state (Vss) was similar across different preclinical species (rat: 1.7 L/kg; 
mouse: 1.9 L/kg; dog: 2.4 L/kg; monkey: 1.5 L/kg).  The plasma protein binding (PPB) rates of 
HMPL-689 were concentration-independent and remained constant (around 90%) at the test 
concentration range of 0.1-20 µM among all tested species (mouse, rat, dog, monkey, and human).  


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In vivo clearance was found to be low in mouse, rat, and monkey and to be medium in dog.  The 
metabolic stability of HMPL-689 in human liver microsomes was better than in preclinical species, 
which suggest low in vivo clearance in human.  A total of 20 metabolites, including phase 1 
metabolites (M2, M4-M20) and glutathione conjugation products after mono-oxidation (M1 and 
M3), were detected in the incubation systems of liver microsomes and S9 fractions from different 
species.  
Metabolites in liver microsomal system of rat, dog, and monkey could cover most metabolites 
generated in that of human.  The relative level of metabolites in monkey was much higher than in 
human, especially M11.  The terminal half-life (t½) values in all species were around 2-3 hours 
after intravenous administration.  HMPL-689 could be metabolized by several metabolic enzymes 
including cytochrome P450 (CYP) enzymes (CYP3A4/5, CYP2C8, CYP2D6, CYP2C9, 
CYP2C19, and CYP2E1) and non-CYP450 enzymes (flavin-containing monooxygenase [FMO] 
and aldehyde oxidase [AO]).  Involvement of multiple enzymes can effectively decrease the risk 
of potential DDI in clinical trials.  HMPL-689 was found to be neither a reversible nor a time-
dependent inhibitor of major CYP450 isoforms except to be a weak reversible inhibitor on 
CYP2C8 (IC50 = 30.4 µM) and CYP2C9 (IC50 = 10.7 µM).  HMPL-689 showed low potential to 
induce the activities of CYP isoforms of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes.  
Moreover, HMPL-689 showed low potential to interfere with efflux transport (efflux ratio <2.0) 
and no inhibition of breast-cancer resistance protein (BCRP), but also showed weak inhibition on 
P-glycoprotein (P-gp) (IC50 = 22.9 µM).  Hence, the risk of drug interaction was predicted to be 
low.  The preliminary results showed that 91% of HMPL-689 and its metabolites were recovered 
from urine, bile, and feces in rat at 96 hours following a single oral dose.  In summary, HMPL-
689 showed good absorption, low to medium clearance, extensive distribution, and no obvious 
accumulation in preclinical species.  There was good agreement between the in vitro and in vivo 
studies.  In in vitro human pharmacokinetic studies, HMPL-689 showed high permeability, low 
potential of efflux transport, good metabolic stability, medium PPB, and low potential of DDI.  
Based on the results from these studies, HMPL-689 was expected to possess good oral absorption, 
low clearance, high oral bioavailability, extensive tissue distribution, and low risk of DDI in 
humans. 
2.2.3 
Preclinical Toxicology  
The safety profiles of HMPL-689 were evaluated in several in vitro and in vivo studies under GLP 
condition. 
• HMPL-689 at 30 mg/kg caused transient and recoverable increase of systolic blood 
pressure in conscious beagle dogs in single oral administration in telemetered conscious 
beagle dog.  HMPL-689 at the doses up to 10 mg/kg did not have any effect on 
cardiovascular system in conscious beagle dogs.  Therefore, the no-observed-effect level 
(NOEL) of HMPL-689 on cardiovascular parameters in conscious beagle dog is 
considered to be 10 mg/kg.  
• The hERG evaluation study results showed that HMPL-689 inhibited hERG currents with 
an IC50 of >30 μM. 
• HMPL-689 up to 150 mg/kg did not exhibit any significant effects on CNS system 
compared with animals given the vehicle in a single oral dose study in Sprague-Dawley 
rats.  The NOEL of HMPL-689 is considered to be 150 mg/kg in this rat study. 


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• HMPL-689 up to 120 mg/kg did not exhibit any significant effects on respiratory 
function in a single oral dose study in Sprague-Dawley rats compared with animals given 
the vehicle.  The NOEL of HMPL-689 is considered to be 120 mg/kg in this study.  
• The maximum tolerated dose (MTD) for HMPL-689 was 2000 mg/kg in rats, and 1000 
mg/kg in dogs, respectively, in single dose toxicity studies. 
• Sprague-Dawley rats were administrated daily of HMPL-689 at the dose of 3, 15, and 
100 mg/kg/day for 4 weeks, followed by 4-week recovery period in a 4-week toxicity 
study.  No mortality or moribund was found during the whole period of study.  No 
abnormal change was found in clinical observation, body weight and food consumption.  
Changes in clinical pathology were mainly observed in females in the 100 mg/kg group, 
including increased white blood cell (WBC) count and percentages of monocytes, 
neutrophils, and that of reticulocytes, while there was a decrease in percentage of 
lymphocytes, hemoglobin, hematocrit, glucose, total protein, albumin, and albumin-
globulin ratio.  In bone marrow smear evaluation, increased eosinophil granulocyte cell 
counts were observed in females at 100 mg/kg.  All above changes were reversible 
following a 4-week recovery period.  The HMPL-689 related histopathological changes 
were observed as follows: changes of thymus, liver, and mandibular and mesenteric 
lymph nodes were observed in female at doses ≥3 mg/kg; in addition, histopathological 
change of testes was found in male at doses ≥15 mg/kg; histopathological changes in 
spleen could be found in female at doses ≥15 mg/kg and in male at 100 mg/kg, 
respectively.  The histopathological changes in gastrointestinal system (stomach, 
duodenum, jejunum, ileum, cecum, and colon), Peyer’s patches, bone marrow of sternum, 
tongue, and adrenal glands were only found in female at 100 mg/kg.  After the 4-week 
recovery period, all those histopathological changes were recovered, except for the 
inflammatory cell infiltration in tongue, which persisted in female of 100 mg/kg with low 
incidence.  Therefore, the no-observed-adverse-effect level (NOAEL) is considered to be 
3 mg/kg with corresponding AUC0-t of 1430 h•ng/mL for male rats.  The low-observed-
adverse-effect level (LOAEL) was considered to be 3 mg/kg with corresponding AUC0-t 
of 6260 h•ng/mL for female rats.  According to the exposure of NOAEL/LOAEL, the 
safety margins compared with the potential efficacy dose in the inhibition of the 
activation of B-cells in vivo were 3.0-fold (male) and 13.3-fold (female), respectively. 
• Beagle dogs were administrated daily of HMPL-689 at the dose of 0.5, 3.5, and 25 
mg/kg/day for 4 weeks, followed by 4-week recovery period in a 4-week toxicity study.  
The HMPL-689 related abnormal finding were observed as follows: decreased activity, 
decreased the percentage of basophiles and increased fibrinogen in animals treated at 
doses ≥3.5 mg/kg; and watery feces, color change (red) of feces, decreased body weight 
and food consumption, increased WBC count, percentage of neutrophil, aspartate 
transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH), 
companied with decreased percentage of lymphocyte, total protein, albumin, and 
albumin-globulin ratio in animals at dose 25 mg/kg.  The above changes were reversible 
in surviving animals following a 4-week recovery period.  The HMPL-689 related 
histopathological changes were observed in tongue, mandibular lymph nodes, spleen, 
liver, mesenteric lymph nodes, Peyer’s patches, thymus, and testes at doses ≥3.5 mg/kg; 
in esophagus, intestines including duodenum, ileum, cecum, colon and rectum, lungs, 
bone marrow of sternum and femur at 25 mg/kg.  After the 4-week recovery period, the 
HMPL-689 related changes still persisted in Peyer’s patches at 3.5 mg/kg and in liver and 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 3 3  
 
testes at d oses ≥2 5 m g/ k g.  T he N O A E L is c o nsi d ere d t o be 0. 5 m g/ k g wit h 
c orres p o n di n g A U C 0 -t of 5 5 0 ( fe male) a n d 7 5 4 (m ale ) h•n g/ m L.  
•  H M P L -6 8 9 w as n ot ge n ot o xic i n t he i n vitr o bacterial re verse m utati o n st u d y , a n i n vi v o 
micr o n ucle u s e v al uati o n i n t he 4 -wee k re peate d d ose t o xicit y st u d y i n S pra g ue -Da wle y 
rats u p t o 1 0 0 m g/ k g, a n d a si n gle-d ose t o xicit y st u d y i n I C R mice ( n o n -G L P) u p t o 2 0 0 0 
m g/ k g.  I n a c hr o m os o me a berra nt test, H M P L -6 8 9 c o ul d i n d uce t he i ncrease t he 
i nci de nce of cells wit h a b erra nt c hr o m os o me at 2 4 0. 0 μ g/ m L (t he hi g hest c o nce ntrati o n 
teste d) wit h hi g h cell gr o wt h i n hi biti o n ( > 6 0 %) at 4 h o urs wit h or wit h o ut S 9, b ut has n o 
i m pact at all ot her c o n ce ntrati o ns.  T his c o nce ntrati o n is far great er t ha n t h e E C9 0 (e x 
vi v o, H M P L -6 8 9 o n B -cell acti vati o n i n w h ole bl o o d of nai ve fe male Wistar rats) of 1 6 
n g/ m L i n rat ( ~ 1 5, 0 0 0 f ol d).  
•  S pra g u e -D a wle y rats were orall y a d mi nistere d d ail y of H M P L -6 8 9 at d oses of 3, 1 5, a n d 
1 0 0 m g/ k g/ da y i n fertilit y a n d earl y e m br y o nic de vel o p me ntal t o xicit y st u d y.  T he n o-
o bser ve d -a d vers e-effect le vel ( N O A E L) of H M P L -6 8 9 f or ge n eral t o xicit y is c o nsi dere d 
t o be 3 m g/ k g/ da y i n pare ntal male a n d 1 5 m g/ k g/ da y i n f e male rat, res p ecti vel y.  T he 
N O A E L of H M P L -6 8 9 f or fertilit y a n d earl y e m br y o nic de vel o p me nt is c o nsi dere d t o be 
1 0 0  m g/ k g/ da y.  
•  H M P L -6 8 9 w as n ot p h ot ot o xic i n a n i n vi v o st u d y wi t h g ui nea pi gs.  I n t his st u d y, 
H M P L -6 8 9 w as a d mi nistere d  as a si n gl e d ose via oral ga va ge t o g ui n ea p i gs at 5, 2 5, or 
1 2 5 m g/ k g.  N o s ki n reacti o ns were o bser ve d at all ti me p oi nts i n b ot h n o n -irra diate d a n d 
irra diate d s ki n of all a ni mals treate d wit h t he test article.  
O verall, H M P L -6 8 9 was well t olerate d i n rat a n d d o g f oll o wi n g a si n gle d os e oral a d mi nistrati o n .  
T o xic fi n di n gs were see n i n re peat -d ose a ni mal safet y e v al uati o ns i n rats a n d d o gs at hi g h er d oses 
a n d were f o u n d t o be re v ersi ble .  T hese fi n di n gs ca n be rea dil y m o nit ore d i n t he cli nical st u dies 
a n d were f ull y or  partiall y re versi ble u p o n dr u g wit h dra wal.  
2. 3  
C li nic al E x perie nce of H M P L -6 8 9   
See t he i n vesti gat or’s br o c h ure (I B) f or u p -t o-date cli nical e x perie nce f or H M P L -6 8 9 . 
St u d y 
 (C o m plete d)  
T his was a  p hase 1 , ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d , first-i n-h u ma n, si n gle d ose 
escalati o n st u d y t o i n v esti gate t he safet y, t olera bilit y a n d P K of H M P L-6 8 9 i n A ustralia 
(c o m plete d).  T h e st u d y e nr oll e d 4 8 healt h y v ol u nteers w h o were ra n d o mize d i nt o H M P L-6 8 9 
gr o u p or pla ce b o gr o u p at a 3: 1 rati o.  S u bjects recei ve d  oral si n gle d ose s of H M P L -6 8 9 or place b o 
i n se q ue nce at d ose le vels of 1 , 2. 5, 5. 0, 1 0, 2 0, a n d 3 0 m g u n der fe d c o n diti o n .   
Of  3 6 s u bjects i n  t he H M P L-6 8 9  treat me nt gr o u p, 1 5  s u bjects (4 1. 6 7 %)  e x p erie nce d a t otal of 1 9 
a d verse e v e nts ( A Es).  A d verse e ve nts re p orte d i n at least o ne s u bject i ncl u d e d u p per res pir at or y 
tract i nfecti o n (1 3. 9 % ), hea dac he (8. 3 % ), d ys p e psia (5. 6 % ), oli g os per mia ( 5. 6 % ), flat ule nce 
(2. 8 % ), bac k pai n (2. 8 % ), m usc ul os keletal pai n (2. 8 % ), ecze ma (2. 8 % ), s ki n b ur ni n g se nsati o n 
(2. 8 % ), a n d e ye irritati o n ( 2. 8 % ).  A d v erse e ve nts t hat were assesse d b y t h e i n vesti gat or as relat e d 
t o H M P L-6 8 9  were u p per res pirat or y tr act i nfecti o n  (8. 3 % ), hea dac h e (5. 6 % ), d ys p e psia (5. 6 % ), 
flat ule nce (2. 8 % ), a n d bac k  pai n  (2. 8 % ).  Ala ni ne tra nsa mi nase i ncreas e was n otice d  i n 5. 5 6 % of 
s u bjects i n t he H M P L -6 8 9  gr o u p a n d 8. 3 3 % of s u bjects i n t he place b o gr o u p .  A s partate 
tra nsa mi nase i ncreas e was n otice d  i n 1 9. 4 4 % of s u bjects i n t he H M P L -6 8 9 gr o u p a n d 2 5 % of 
C CI


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 3 4  
 
s u bjects i n t he place b o gr o u p ; all of t he A L T/ A S T i ncreas es were of G ra d e 1.  N o Gra d e ≥3 A E 
was  re p orte d.  N o d ose li miti n g t o xicit y ( D L T ) was n ote d.  
T he si n gle d ose P K of H M P L -6 8 9 was e v al uat e d i n 3 6 healt h y  v ol u nt eers i n t he H M P L -6 8 9 
treat me nt gr o u p u n der fe d c o n diti o n .  H M P L -6 8 9 wa s a bs or be d after oral a d mi nistrati o n wit h a 
me dia n T ma x  of 1. 5 t o 3 h o urs.  T h e H M P L -6 8 9 e x p os ures, as meas ure d b y C ma x  a n d A U C, 
i ncreas e d wit h d ose i ncrease fr o m 1 t o 3 0 m g after si n gle d osi n g.  T he ge o metric mea n s of a p pare nt 
v ol u me of distri b uti o n ( V z/ F) a n d a p pare nt oral cleara n ce ( C L/ F) w ere a p pr o xi matel y 2 0 9 -2 6 8  L  
a n d 1 8. 2-2 3. 0 L/ h, res pecti vel y, acr oss all d ose l e v els .  T he ge o m etric mea n t½  val ues were si milar 
acr oss d ose l e v els, wit h val ues ra n gi n g fr o m 7. 0 6 t o 9. 3 7 h o urs.  
St u d y 
 ( C o m plete d) 
T his wa s a si n gle-ce nter, ra n d o mize d, o pe n -la bel, si n gle-d os e, 2 -peri o d cr oss o ver st u d y c o n d uct e d 
i n C hi na t o e val uate t he effects of f o o d o n t he P K of H M P L -6 8 9 .  Healt h y male  s u bjects recei ve d 
a si n gle oral d ose of H M P L -6 8 9 3 0  m g ( 3 ×  1 0  m g ca ps ules) u n der  fasti n g (at least 1 0 h o urs 
o ver ni g ht fast) a n d fe d c o n diti o n s (t otal cal ories: 8 0 0  t o 1 0 0 0  cal ories wit h fat c o ntri b uti n g t o 5 0 % 
of t he t otal cal oric c o nte nt of t he meal , c o ns u me d wit hi n 3 0  mi n utes pri or t o d osi n g).  Eac h d os e 
was se parate d b y a was h o ut peri o d of 4  da ys . 
D osi n g H M P L -6 8 9  wit h f o o d pr ol o n ge d H M P L -6 8 9  tma x  b y 3 . 0 h o urs wit h me dia n (ra n ge) of 
1. 0  ( 0. 5 t o 4. 0) h o ur u n d er faste d c o n diti o n a n d 4. 0 ( 1. 5  t o 8. 0) h o urs u n d er fe d c o n diti o n.  F e d 
c o n diti o ns  decrease d t he C ma x  b y 3 6 % b ut di d n ot alter H M P L -6 8 9  A U C 0 -i nf. T hese res ults s u g gest 
t hat H M P L -6 8 9 ca n be a d mi nistere d wit h or wit h o ut f o o d.  
St u d y 
 (O n g oi n g)  
T his is a p hase 1, o pe n -la bel st u d y t o assess t he safet y, P K,  an d preli mi nar y efficac y of H M P L -6 8 9 
a d mi nistere d orall y i n patie nts  wit h  rela pse d or refract or y l y m p h o ma.  T his st u d y i ncl u des 2 sta ges: 
a d ose escalati o n sta ge ( Sta ge 1) a n d a d os e  e x pa nsi o n sta ge ( Sta ge 2).  F or Sta ge  1, a m o difie d 
t o xicit y pr o ba bilit y i nter val sc he me-2 ( m T PI -2) desi g n is a d o pte d f or t he d ose escalati o n a n d M T D 
deter mi nati o n.  
At t he start of 2 0 1 8 -6 8 9 -0 0 U S 1, t he st u d y was o n g oi n g at S ta ge 1 a n d 1 3 patie nts ha ve recei ve d 
at least 1 d ose of H M P L -6 8 9 a n d are e v al ua ble f or safet y.  T he d ose le vel s of H M P L -6 8 9 teste d 
i ncl u ded  2. 5 m g t wice d ail y (BI D ), 5 m g BI D a n d 5 m g o nce dail y ( Q D ).  T his data  e na ble d t he 
de vel o p me nt of pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  (c urre nt pr ot oc ol). 
As of 3 0 A pr 2 0 1 8,  twel ve  patie nts ( 9 2. 3 %) treate d wit h H M P L -6 8 9 e x perie nce d at least 
1  treat me nt e mer ge nt a d v erse e v e nt  (T E A E ).  Treat me nt e mer ge nt a d verse e ve nt s t hat occ urre d i n 
m ore t ha n 1 patie nt were  bl o o d bilir u bi n i ncrease d ( 3 8. 5 %), ne utr o p e nia ( 3 8. 5 %), ast he nia 
( 3 0. 8 %), le u k o p e nia ( 3 0. 8 %), t hr o m b oc yt o pe ni a ( 3 0. 8 %), u p per res pirat or y tr act i nfecti o n 
( 3 0. 8 %), bilir u bi n c o nj u gate d i ncrease d ( 2 3. 1 %), c o u g h ( 2 3. 1 %), pr ot ei n uria ( 2 3. 1 %), a b d o mi nal 
pai n ( 1 5. 4 %), a m ylas e i ncreas e d ( 1 5. 4 %), a ne mi a ( 1 5. 4 %), h y p erte nsi o n ( 1 5. 4 %), h y p o k ale mia  
( 1 5. 4 %), i nfl ue nza s y n dr o me ( 1 5. 4 %), pai n ( 1 5. 4 %), a n d bl o o d uri ne pres e nt ( 1 5. 4 %) .  Treat me nt  
e mer ge nt a d v erse e ve nts of Gra de ≥3 re p orte d b y at least  1 patie nt i ncl u de d a m yl ase i ncrease d 
( 1 5. 4 %), h y p erte nsi o n (1 5. 4 %), A S T i ncreas e d ( 7. 7 %), bac k pai n ( 7. 7 %), bl o o d gl u c ose i ncreas e d 
( 7. 7 %), left 
ve ntric ul ar 
d ysf u ncti o n ( 7. 7 %), le u k o pe nia ( 7. 7 %), 
pai n ( 7. 7 %), 
a n d 
t hr o m b oc yt o pe ni a ( 7. 7 %).  Gra d e ≥3  T E A Es assess e d as relate d t o H M P L -6 8 9 b y t h e i n vesti gat ors 
were a m yl ase i ncrease d ( 1 5. 4 %), A S T i ncrease d ( 7. 7 %), h y perte nsi o n ( 7. 7 %), le u k o pe nia ( 7. 7 %), 
t hr o m b oc yt o pe ni a ( 7. 7 %).  T w o D L Ts  (as y m pt o matic Gra de 3 a m ylas e i ncreas e d)  were o bser ve d 
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Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 3 5  
 
i n 6 patie nts at t he d ose le vel of 5 m g BI D, a n d n o D L T was o bser ve d at t h e d ose le vels of 2. 5 m g 
BI D or 5 m g Q D.  
Se ve n  of t he 1 3  patie nts were efficac y e v al ua ble .  T he b est o verall res p o nse s were o bser ve d i n 
7  patie nts , i ncl u di n g 6 wit h partial res p o nse ( P R)/ p artial res p o ns e wit h l y m p h oc yt osis ( P R -L) a n d 
1 wit h sta ble disease ( S D).  P R/ P R -L occ urre d at 2. 5 m g BI D (1 S L L a n d 1 M C L ), 5 m g BI D 
( 2 M C L), a n d 5 m g Q D ( 1 M C L a n d 1 C L L ). 
As of 3 0 A pr.  2 0 1 8 , t he preli mi nar y P K d ata f or 2. 5 m g BI D, 5 m g BI D,  a n d 5 m g Q D o n Da y 1 
a n d Da y 1 5 w ere a v aila ble  b ut ha ve n ot bee n vali date d a n d are s u bject t o c ha n ge .  C o m pare d t o 
t he si n gle d ose P K d ata o btai ne d fr o m A ustralia n healt h y v ol u nteers i n St u d y 
, 
t he P K pr ofile o n Da y 1 i n C hi nese patie nts wit h l y m p h o ma was si milar t o t hat i n male healt h y 
v ol u nteers i n A ustralia wit h re ga r d t o t ½ a n d e x p os ures ( C ma x  a n d A U C) at t he e q ui vale nt d ose 
le vel.  After m ulti ple oral d oses f or 1 5 da ys, t he acc u m ulati o n rati o was ar o u n d 1 -2.  
As of Marc h  2 0 2 1, t his o n g oi n g P hase I trial of H M P L -6 8 9 i n C hi na (
) h as 
c o m plete d d ose escalat i o n wit h a R P 2 D of 3 0 m g Q D. As of t his c ut off, 7 9  patie nts wit h rela pse d 
or refract or y  N H L ( F L, mar gi n al z o ne l y m p h o ma [ M Z L], M C L, D L B C L) ha ve  s o far recei ve d t he 
R P 2 D d ose le vel i n t he d ose escalati o n or e x pa nsi o n p hase of t his trial.  Of t hese 6 0  patie nt s ha d 
c o m plete d at le ast o ne t u m or assess me nt. T he o bjecti ve res p o nse rate ( O R R ) rate f or t his gr o u p 
was 5 1. 7 % ( 3 1/ 6 0 ) a n d C R rate 1 3. 0 % ( 8/ 6 0).  I n 1 8  patie nts wit h F L, t he O R R was 7 7. 8 % ( 1 4/ 1 8) 
a n d C R rate 3 8. 9 % ( 7/ 1 8). I n M Z L, 6 o ut of 1 2 patie nts ha ve res p o n d e d ( O R R 5 0. 0 %). I n m a ntle 
cell l y m p h o ma, 4  o ut of 5  patie nts ha ve res p o n de d ( O R R 8 0. 0 %).   T he m ost c o m m o n A Es 
(i nci de nce ≥ 1 0 %) i n s u bjects treate d wit h t he R P 2 D ( n = 7 9) i ncl u de d ne utr o pe nia ( 2 8.8 %), 
le u k o pe nia ( 2 2. 7%), u p per res pir at or y tract i nf ect i o n ( 1 2. 1 %) a n d h y pertri gl yceri de mia ( 1 0. 6 %). 
T E A Es of Gra d e ≥3 ( ≥ 5 %) were ne utr o p e nia ( 1 3. 6 %) a n d ras h ( 6. 1 %).  T he ot her Gra d e ≥3 
T E A Es of i nterest ( < 5 %) re p orte d of were p ne u m o nia 4. 5 % a n d diarr hea 1. 5 %.  T here were n o 
re p orte d Gra de ≥3 T E A Es of i nterest of A L T/ A S T ele vati o n, h y pert e nsi o n, c olitis or p ne u m o nitis. 
2. 4  
 St u d y R ati o n ale a n d Be nefit -Ris k Assess me nt    
Class I p h os p hati d yli n osit ol 3 -ki nase ( PI 3 K ) is a li pi d ki nase wit h  a catal yti c s u b u nit t hat e xists i n 
4 differe nt is of or ms: α , β , δ , a n d γ.  Acti vati o n of PI 3 K ge nerates li pi d sec o n d messe n gers at t he 
cell me m bra ne t hat recr uit a n d acti vate m ulti ple  i ntracell ular e nz y mes t hat are re g ulat ors of cell 
pr oliferati o n, s ur vi val, a n d m otilit y .  T he α  a n d β  is of or ms are wi del y e x presse d i n ma n y tiss ues, 
a n d t he p h os p hati d yli n osit ol 3 -ki nase γ is of or m (PI 3 Kγ ) has a partic ular r ole i n T -cell acti vati o n, 
PI 3 K δ e x pressi o n is lar gel y restricte d t o he mat o p oietic cells  (Br o w n 2 0 1 4 ).  I n B-l y m p h oc yt es, 
t he δ is of or m ( PI 3 Kδ ) pla ys a ce ntral r ol e i n n or mal B-cell d e v el o p me nt  a n d f u ncti o n, tra ns d uci n g 
si g nals fr o m t he B-cell rece pt or as well as fr o m rece pt ors f or vari o us c yt o ki nes, c he m o ki nes, a n d 
i nte gri ns (D ura n d 2 0 0 9 , Bila nci o 2 0 0 6 ).  PI 3 K δ  si g nali n g pat h w a ys are c o m m o nl y h y p eracti ve i n 
B -cell mali g na n cies,  ma ki n g i n hi biti o n of PI 3 K δ  a pr o misi n g tar get i n t he t h era p y of B-cell N H L  
(La n n utti 2 0 1 1 , H oelle nrie gel 2 0 1 1 ).   
PI 3 K δ  i n hi bit ors ha ve pr o ve n acti vit y  i n rela psed /refract or y l y m p h o m a setti n g, wit h f o ur a ge nts 
recei vi n g accel erate d a p pr o val fr o m t he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) f or 
t he treat me nt of f ollic ular ly m p h o ma , (i delalisi b, c o pa nlisi b , d u velisi b  a n d u m bralisi b) .  
A d diti o nall y, u m bralisi b  is als o a p pr o ve d i n t he U nite d States f or t he treat me nt of M Z L . 
In t he i del alisi b p hase 2 st u d y i n p atie nts wit h rela pse d i N H L, 1 2 5 p atie nts, i ncl u di n g 7 2 F L, 2 8 
S L L, 1 5 
M Z L, a n d 1 0 l y m p h o plas mac ytic l y m p h o ma/ Wal de nstr ö m's 
macr o gl o b uli ne mia 
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Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 36 
 
(LPL/WM), were enrolled and treated with idelalisib as a single agent (Gopal 2014).  The ORR 
was 57% (71/125 patients), with 6% meeting the criteria for a CR.  The median time to a response 
(TTR) was 1.9 months, the median DoR was 12.5 months, and the median progression-free 
survival (PFS) was 11 months.  Similar response rates were observed across all subtypes.  The 
most common adverse events of grade 3 or higher were neutropenia (27%), elevations in 
transaminase levels (13%), diarrhea (13%), and pneumonia (7%).  For the patients with 
relapsed/refractory MCL enrolled in phase 1 study, idelalisib also showed tolerable toxicity and 
anti-tumor activities: patients without DLT and no evidence of disease progression after 48 weeks 
enrolled in the extension study (Kahl 2014).  Common Grade ≥3 AEs included diarrhea (45%), 
decreased appetite (75%), transaminase levels elevations (33%).  ORR was 40% (16/40 patients), 
with CR 5% (2/40).  Median DoR was 2.7 months, median PFS was 3.7 months, and 1-year PFS 
was 22%.  Based on this study, FDA approved idelalisib for the treatment of patients with relapsed 
FL or SLL who have received at least two prior systemic therapies. 
In the phase 3 study among patients with relapsed CLL who were less able to undergo chemo-
therapy, the combination of idelalisib and rituximab, as compared with placebo and rituximab, 
significantly improved progression-free survival (mean PFS: not reached in the idelalisib group 
and 5.5 months in the placebo group [hazard ratio for progression or death in the idelalisib group 
= 0.15; P <0.001]), ORR (81% vs. 13%; odds ratio, 29.92; P <0.001), and overall survival (OS) at 
12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02).  Serious adverse events occurred 
in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo 
and rituximab.  Based on the study results, FDA approved idelalisib for the treatment of patients 
with relapsed CLL, in combination with rituximab (Furman 2014). 
In a single-arm, multicenter, phase 2 clinical trial to evaluate the efficacy of copanlisib (PI3K α/δ 
inhibitor) in relapse NHL, a total of 142 patients were enrolled, including 104 FL patients, who 
have received at least two prior treatments, including rituximab and an alkylating agent 
(Dreyling 2017).  The ORR in FL patients was 59%, with 14% CR and 44% PR.  The median DoR 
was 12.2 months (range 0+ to 22.6 months).  The median TTR was 1.7 months (range 1.3 to 9.7 
months).  Safety data were collected in 168 adults with FL and other hematologic malignancies 
treated with copanlisib.  Serious adverse reactions were reported in 44 (26%) patients.  The most 
frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%), and 
hyperglycemia (5%).  The most common adverse reactions (≥20%) were hyperglycemia, diarrhea, 
decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower 
respiratory tract infections, and thrombocytopenia.  Based on this study, FDA approved copanlisib 
for the treatment of patients with relapsed FL who have received at least two prior systemic 
therapies. 
In a phase 2, multi-center, open-label trial to evaluate the activity and safety of duvelisib (PI3K 
α/ɣ inhibitor) in patients with relapsed/refractory iNHL a total of 129 patients were enrolled, 
including FL, MZL, and SLL.  All enrolled patients were double refractory to rituximab and to 
either chemotherapy or radioimmunotherapy.  The ORR across all indications was 47.3% (42.2% 
FL, 38.9% MZL). The estimated mDOR was 10 months with an estimated mPFS of 9.5 months. 
Safety data revealed diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and 
cough (27.1%) as the most common TEAEs.  At least one ≥ grade 3 TEAE was experienced in 
88.4% of patients, with the most common being neutropenia (24.8%), diarrhea (14.7%), anemia 
(14.7%), and thrombocytopenia (11.6%) (Flinn 2019). 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 3 7  
 
I n a p hase 2, m ulti-ce nt er, o pe n -la bel trial t o e v al uate t he safet y a n d efficac y of u m br alisi b i n 
pre vi o usl y tr eate d N H L p atie nts, a t otal of 2 0 8 pati e nts were e nr olle d, i ncl u di n g 6 9 M Z L, 1 1 7 F L, 
a n d 2 2 S L L. M Z L patie nts were refract or y t o at least o ne li ne of a nti-C D 2 0,  a n d F L/ S L L patie nts 
were refract or y t o at le ast t w o li nes of t hera p y, i n cl u di n g a n a nti -C D 2 0.  T he O R R i n F L p atie nts 
was 4 5. 3 % wit h 5. 1 % C R a n d D o R of 1 1. 1 m o nt hs (ra n ge 8. 3 -1 5. 6 m o nt hs).   T he me dia n T T R 
was 2. 8 m o nt hs (ra n ge 2. 7 t o 2. 9).  T he O R R i n M Z L patie nts was 4 9. 3 % wit h 1 5. 9 % C R a n d D o R 
n ot yet reac h e d at ti me of p u blicati o n.  T he me dia n T T R was 2. 8 m o nt hs (ra n ge 2. 7 –  2. 9). Safet y 
data re v eale d s eri o us a d verse e v e nts i n 2 8. 1 % of patie nts, wit h 2 4. 6 % ≥ gra de 3.  T h e m ost 
c o m m o n ≥ gra d e 3 A Es were n e utr o pe nia ( 1 1. 5 %), diarr hea ( 1 0. 1 %) a n d i ncrease d A L T/ A S T 
( 7. 2 %).  Ot her A Es of i nterest i ncl u de d p ne u m o nitis (all gra de 1. 4 %; ≥ gra d e 3 1. 0 %), a n d c olitis 
(all gra de 1. 4 %; ≥ gra de 3 0. 5 %) (Zi nz a ni 2 0 2 0 ). 
O verall, a p pr o ve d PI 3 k -δ  i n hi bit ors ha ve de m o nstr ate d a m o dest  O R R i n t he ra n ge of 4 0 %  t o 5 0 % 
i n F L a n d M Z L.  H o we ver, t he y d e m o nstrate a l o w C R rate of 1 -1 6 %  a n d m P F S of less t ha n 
1 2  m o nt hs.   W hile t hese  a ge nts re prese nt  a ma na gea ble  t o xicit y pr ofile , hi g h rates of diarr hea, 
c olitis, a n d he patic t o xicit y res ults i n a hi g h rate d ose re d u cti o n a n d treat me nt disc o nti n uati o n, 
t here b y i m pacti n g t he l o n g ter m be n efit.  T heref ore, t here is r o o m f or a m ore effi caci o us a n d 
t olera ble PI 3 K-δ i n hi bit or  f or treat me nt of N H L (Dre yli n g  2 0 1 7 , Zi nza ni 2 0 2 0 , Fli n n 2 0 1 9 ). 
H M P L -6 8 9 is a PI 3 K δ i n hi bit or wit h differe nt m olec ular str uct ur e as c o m p ar e d wit h i delalisi b or 
d u velisi b.  Precli nical data s h o ws t hat H M P L -6 8 9 is a s mall m olec ule i n hi bit or wit h hi g h p ote nc y, 
fa v ora bl e p har m ac o ki netic a n d dr u g s afet y pr ofile.  T he rati o of H M P L-6 8 9 bi oc he mical acti vit y 
i n PI 3 K δ was > 1 0 0 ti mes str o n ger t ha n t he ot her PI 3 K is of or ms.  Br oa d ki nase selecti vit y st u dies 
de m o nstrate d H M P L -6 8 9’s hi g h PI 3 K δ s electi vit y t hat is better t ha n i d elalisi b a n d d u velisi b.  
I m pr o v e d is of or m selecti vit y ca n mi ni mize seri o us i nfecti o n t hat is see n wit h d u velisi b as a res ult 
of i n h i biti n g PI 3 Kγ a n d ca usi n g i m m u ne s u p pressi o n.  I n t he o n g oi n g P hase I st u d y 
(
) o ut of 1 8  F L patie nts O R R of 7 7. 8 % ( 1 4/ 1 8 ) a n d C R rate 3 8. 9 % ( 7 /1 8 ) was 
ac hie ve d as of Marc h 2 0 2 1 .  I n M Z L, 6 o ut of 1 2  patie nts res p o n de d ( O R R 5 0. 0 %).   I n ma ntle cell 
l y m p h o ma, 4  o ut of 5  pati e nts res p o n de d  ( O R R 8 0. 0 %).  T he e v ol vi n g cli nical data f or H M P L-6 8 9 
fr o m St u d y 
 s u g gests e nc o ura gi n g acti vit y i n N H L s u b-t y p es s u c h as F L, M Z L, 
M C L a n d C L L/ S L L, wit h a ver y t olera ble safet y pr ofile.   Hi g h  PI K 3 -δ  e x pressi o n has als o bee n 
n ote d c o nsiste ntl y i n s o me s u b-t y pes of T -cell l y m p h o ma  s uc h as peri p heral T-cell l y m p h o ma 
( P T C L) (H ua n g  2 0 2 0 ).  C urre nt a p pr o ve d t h era pi es f or rel a pse d/refract or y P T C L d o n ot pr o vi de 
c o nsiste nt effi cac y be n efit acr oss all s u b -t y pes, res ulti n g i n a p o or o verall 5-year s ur vi val rate of 
1 0 -3 0 % ( C oiffier  2 0 1 4 ).  I n phase 1/ 2 st u dies , PI K 3 -i n hi bit ors ha ve d e m o nstrate d pr o misi n g 
cli nical acti vit y 
wit h o verall res p o nses of 
~ 3 0 % t o 
5 0 % a n d a n acce pta bl e safet y 
pr ofile  (H or witz  2 0 1 8 , Dre yli n g  2 0 1 7 ), s u g gesti n g a r ole f or PI K 3-i n hi bit ors s uc h as H M P L-6 8 9 
i n t his setti n g.  
Si milarl y, t he pa u cit y of treat me nt o pti o ns f or rela pse d/refract or y c uta ne o us B-cell l y m p h o m a 
(C B C L ) a n d t he p ote ntia l f or PI 3 K i n hi bit ors t o b e nefit t hes e patie nts s u p p orts t he e v al uati o n of 
H M P L -6 8 9 i n t he st u d y 2 0 1 8 -6 8 9 -0 0 U S 1  (D u m mer  2 0 1 2 ). 
O verall, gi ve n t he i m p orta nce of t he PI 3 K δ  pat h w a y i n t he l y m p h o mas, H M P L -6 8 9’s si g nifica nt 
effic ac y i n t he precli nical  cell li nes  a n d preli mi nar y efficac y i n l y m p h o m a patie nts , c o u ple d wit h 
its desira ble p har m ac o ki netic a n d safet y pr ofile, H M P L -6 8 9 warra nts f urt her i n vesti gati o n i n 
cli nical st u dies t o f ull y c haracteriz e its p ote ntial as a n o vel s mall -m olec ule oral t hera p y f or 
l y m p h o mas. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 
Objectives and Corresponding Endpoints  
Tier 
Objectives 
Endpoints 
Primary – Dose 
Escalation 
To determine MTD and/or RP2D of 
HMPL-689 in patients with relapsed, 
refractory, or resistant lymphoma 
• Incidence of DLTs  
• Safety (including but not limited to TEAEs, 
treatment-related adverse events [TRAEs], 
SAEs, treatment-related SAEs [TRSAEs], and 
lab abnormalities) 
Primary – Dose 
Expansion 
To further evaluate safety and 
tolerability of HMPL-689 at MTD in 
patients with relapsed, refractory, or 
resistant lymphoma 
• Safety, including TEAEs and TRAEs 
 
Secondary 
To assess preliminary efficacy of 
HMPL689 in patients with relapsed, 
refractory, or resistant lymphoma overall 
and by lymphoma sub-types as assessed 
by investigator 
• ORR 
• TTR 
• DoR 
• CBR 
• PFS 
To characterize PK parameters of 
HMPL-689 in patients with relapsed, 
refractory, or resistant lymphoma at both 
dose escalation and dose expansion 
stages 
• Concentration-time profiles and PK parameters 
after single dose and at steady state 
 
To evaluate the effect of HMPL-689 on 
cardiac repolarization, as detected by 
changes in electrocardiogram (ECG) 
QTc intervals  
• QTc interval and HMPL-689 concentration 
 
Abbreviations: CBR = clinical benefit rate; DLT = dose-limiting toxicity; DoR = duration of response; 
MTD = maximum tolerated dose; ORR = objective response rate; PD = progressive disease; 
PFS = progression-free survival; PK = pharmacokinetic; RP2D = recommended phase 2 dose; SAE = serious 
adverse event; TEAE = treatment-emergent adverse event; TRAE = treatment-related adverse event; TRSAE 
= treatment-related serious adverse event; TTR = time to response. 


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4 
STUDY DESIGN  
4.1 
Overall Study Design  
This is a phase 1, open-label, multicenter study of HMPL-689 administered orally daily to patients 
with relapsed, refractory or resistant lymphoma. 
This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2).  
Both Stage 1 and Stage 2 include the following periods: screening period, treatment period, safety 
follow-up period, and extended PFS follow-up period, if applicable, as defined in Appendix 1. 
The study duration is estimated to be approximately 48 months.  
4.1.1 
Dose Escalation Stage (Stage 1)  
Dose escalation will be performed according to an mTPI-2 (Yang 2015).  HMPL-689 dose 
escalation will be titrated using a modified Fibonacci design allowing dose increments in 
subsequent dose levels as listed in Table 2.  The guidelines used for dose escalation are shown in 
Figure 1.  
Table 2 
Proposed Dose Escalation Scheme  
Cohort 
Dose Levela 
Route of Administration 
-1 
2.5 mg QD 
Orally, with water 
1 
5 mg QD 
Orally, with water 
2 
10 mg QD 
Orally, with water 
3 
15 mg QD 
Orally, with water 
4 
20 mg QD 
Orally, with water 
5 
25 mg QD 
Orally, with water 
6 
30 mg QD 
Orally, with water 
7 
35 mg QD 
Orally, with water 
8 
40 mg QD 
Orally, with water 
9 
45 mg QD 
Orally, with water 
10 
50 mg QD 
Orally, with water 
Xb 
XXb 
Orally, with water 
Abbreviations: PK = pharmacokinetic; QD = once daily; SRC = safety review committee. 
a 
The actual next dose will be discussed and decided by the investigators and sponsors based on all previous 
available data. 
b 
The need for dose escalation beyond 50 mg QD, or other regimens, such as twice daily, will be evaluated and 
determined by the SRC based on all available cumulative clinical safety, PK, and efficacy data. 


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Figure 1 
mTPI-2 Decision Chart for Selection of Dose  
 
DLT = dose limiting toxicity, E = escalate to the next higher dose; S: Stay at the same dose, D = de-escalate to the 
previous lower dose, DU = de-escalate to the previous lower dose and the current dose will never be used again 
in the trial.  
Target toxicity probability = 30%; epsilon 1 = 0.05; epsilon 2 = 0.05. 
The design characteristics of mTPI-2 are as follows: 
• The maximum sample size for this stage will be determined by the sponsor and 
investigators, based on the accumulated data and the mTPI-2 method (Ji 2013).  The 
maximum recommended sample size under mTPI-2 design is k × (d + 1), where k 
denotes the cohort size and d denotes the number of doses.  In this study, the minimum 
cohort size is 3. 
• The equivalence interval of toxicity probability for MTD is (25%, 35%).  This interval is 
derived based on the following parameters: 
− The target probability of toxicity (pT) is set to 30%.  
− Both epsilon 1 (ε1) and epsilon 2 (ε2) are set to 0.05.  
• This stage will end when any of the following criteria is met: 
− The dose level 1 demonstrates an excessive toxicity, i.e., 3 DLTs are observed out of 
the first 3 patients at dose level 1. 


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− The maximum sample size is reached. 
− The MTD and/or RP2D are confirmed. 
The rules applied in the dose escalation stage are as follows: 
• The starting dose is dose level 1: 5 mg QD. 
• If a lower dose is needed upon results from dose level 1, dose level -1 will be explored. 
• Three patients will be enrolled for the initial cohort (dose level 1). 
• At the end of the DLT assessment window for a dose level, the decision on the dose of 
the next dose level will follow the rule specified in Figure 1, which leads to enrollment of 
another 3 patients at the next step. 
• In the event that the first two patients within a given dose level experience DLT events 
but the third patient has not yet begun protocol treatment, the third patient should receive 
a lower dose per the mTPI-2 algorithm.   
At the end of Stage 1, the MTD will be determined based on the number of patients treated and 
the number of experienced DLTs at each dose level. 
Stopping rules for individual patients in the dose escalation stage are located in Section 5.8.3.1.  
Stopping rules for dose cohorts or for the study in the dose escalation stage are available in 
Section 5.8.4.1. 
4.1.1.1 
Intra-patient Dose Escalation  
Intra-patient 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 has also been cleared of DLT (safe and tolerable) prior to the 
start of that intra-patient dose escalation.  There must be at least 28 days in-between the last dose 
of the current/lower dose level and the start of next/higher dose level and the patient must have 
tolerated the current/lower dose level.   
4.1.1.2 
Definition of Dose Limiting Toxicity  
Dose limiting toxicities are defined as the occurrence in the DLT assessment window of any of 
the following TEAEs, unless equivocally due to underlying malignancy or an extraneous cause:  
a. Non-hematologic toxicity: All non-hematologic TEAEs of Grade 3 or greater with the 
exception of:  
i. Grade 3 nausea or vomiting that can be controlled by supportive therapy  
b. Hematologic toxicity: 
i. Grade 4 neutropenia lasting for more than 5 days 
ii. Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding event or 
requiring platelet transfusion 
iii. Grade ≥3 febrile neutropenia (defined as ANC <1000/mm3 with a single 
temperature > 38.3ºC [101°F] or a sustained temperature of ≥38°C [100.4°F] for 
more than 1 hour) 
iv. Grade 4 anemia not explained by underlying disease 
c. Any TEAE requiring a dose delay of ≥15 days  
d. Any case of Hy’s Law  


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4.1.1.3 
Dose Limiting Toxicity Assessment Window  
For all patients in Stage 1, DLTs will be assessed during a DLT assessment window of 28 days 
(i.e., from Cycle 1, Day 1 [the day of first administration of treatment] through Cycle 1, Day 28). 
4.1.1.4 
Definition of a DLT-Evaluable Patient  
For decisions on dose escalation, each dose cohort shall present protocol-required number of DLT-
evaluable patients.  Any patient is DLT evaluable if he/she meets the following criteria:   
A patient is DLT evaluable if he/she:  
• has received at least 75% of the assigned dose of study treatment during the DLT 
assessment window (i.e., Days 1-28);  
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 each dose cohort. 
4.1.1.5 
Dosing Beyond Cycle 1  
Patients who complete DLT assessment window and are deemed by the investigator to be 
benefiting from HMPL-689 treatment may continue with HMPL-689 treatment until disease 
progression, death, intolerable toxicity, at investigator’s discretion that the patient can no longer 
benefit from the study treatment, withdrawal of consent, or the end of study, whichever occurs 
first.  Conversely, if, in the opinion of the attending principal investigator, the patient may receive 
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 intra-patient dose escalation 
(Section 4.1.1.1). 
During the study treatment period, including the DLT assessment window, patients will not be 
allowed to make up missed doses. 
4.1.1.6 
Definition of Maximum Tolerated Dose  
The recommended MTD is the dose with a posterior toxicity probability closest to the target 
toxicity probability pT, i.e., closest to 30%.  In case all doses have toxicity probabilities greater 
than (pT + ε2), i.e., 35%, no dose will be considered as MTD. 
Posterior toxicity probability at each dose level will be estimated based on a beta posterior 
distribution and application of pooled adjacent violator’s algorithm (Yang 2015). 
4.1.1.7 
Definition of Recommended Phase 2 Dose  
The decision regarding the RP2D will take the following into consideration: 
• MTD, if reached; 
• Pharmacokinetics with or without associated safety and preliminary efficacy findings. 
These criteria constitute the basis for RP2D determination.  Both the sponsor and the safety review 
committee (SRC) (Section 4.1.3) must agree on the RP2D. 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 4 3  
 
4. 1. 2  
D ose E x p a nsi o n St a ge (St a ge 2 )  
T he safet y, t olera bilit y, P K, a n d preli mi nar y effi cac y of H M P L -6 8 9 at t he M T D/ R P 2 D will b e 
f urt her e v al uate d i n patie nts wit h rela pse d, refract or y, or resista nt N H L .  
I n t he d ose e x pa nsi o n sta ge , a p pr o xi matel y
patie nts will be e nr olle d  i n t he f oll o wi n g c o h orts  
(Ta ble 3 ), wit h a p pr o xi matel y t h e i n dicate d n u m b er of patie nts e nr olle d per c o h ort. 
T a ble 3  
N u m ber of P l a n ne d P atie nts E nr olle d Per C o h ort   
a 
P atie nts wit h pri or B T K i n hi bit or e x p os ure s h o ul d be eit her refract or y or i nt olera nt  t o B T K i n hi bit or t hera pies 
liste d i n A p pe n di x  1 6 . 
b 
Rela pse d, refract or y, or i nt olera nt t o a B T K i n hi bit or , w here i nt olera nce  is defi ne d as treat me nt disc o nti n uati o n 
f or ≥ 1 4 da ys wit h o ut disease pr o gressi o n d ue t o ≥ 1 Gra de 3 or ≥ 2 Gra de 2 n o n-he mat ol o gic t o xicities, ≥ 
1  Gra d e 3 ne utr o pe nia wit h i nfecti o n or fe ver, or ≥ 1 Gra de 4 he mat ol o gic t o xicit y.  
T he s p o ns or, i n c o ns ultati o n wit h S R C, ma y deci d e t o i ncrease or d ecrease t he n u m ber of e nr olle d 
patie nts  i n eac h c o h ort d e pe n di n g o n preli mi nar y cli nical res p o nse, safet y si g nals, or o perati o nal 
feasi bilit y.  Patie nts  w h o are n ot efficac y e v al ua bl e i n a n y c o h ort ma y b e re place d.  
Patie nt s will recei ve ora l d oses of H M P L -6 8 9 Q D  at t he R P 2 D f or c o nti n u o us 2 8 -da y tr eat me nt 
c ycles u ntil disease pr o gressi o n, deat h, i nt olera bl e t o xicit y, at i n vesti gat or’s discreti o n t hat t he 
patie nt ca n n o l o n ger b e nefit fr o m t he st u d y treat me nt, patie nt wit h dra wal fr o m t he st u d y, or t h e 
e n d of st u d y, w hic he v er occ urs first.  
St o p pi n g r ules f or i n di vi d ual patie nts i n t he d ose e x pa nsi o n sta ge are l ocat e d i n Secti o n 5. 8. 3. 2 .  
St o p pi n g r ules f or d os e c o h orts or f or t h e st u d y i n t he d ose e x pa nsi o n sta ge are a vaila bl e i n 
Secti o n  5. 8. 4. 2 . 
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4.1.3 
Safety Monitoring  
Safety monitoring and dose escalation determination will be conducted by a SRC, which consists 
of the sponsor’s medical monitor, drug safety lead, PK scientists, and the sites’ Principal 
Investigators (PIs) or delegate, as applicable.  Safety will be monitored continuously throughout 
the conduct of this study by the SRC.  There will be periodic reviews of emerging data on safety, 
PK, drug exposure, target engagement, pharmacodynamics, and clinical response to determine 
continuation (or otherwise) of an individual participant, cohort arm, or entire expansion stage.  
The SRC for dose escalation stage may extend to the expansion stage or a new one may replace 
this SRC, with the same mandate.   
4.1.4 
Lifestyle Management  
Full assessment of extensive non-clinical studies indicated HMPL-689 has no phototoxic effects. 
Furthermore, experience from ongoing clinical studies in China and Australia also confirm that 
this study drug lacks any phototoxic effect. Nonetheless, patients enrolled in this study are advised 
to avoid unnecessary long-term and direct exposure to sunlight or any other source of ultraviolet 
(UV) light during their participation in the study and until 30 days after the last dose of study drug. 
Patients are also encouraged to wear sunglasses and apply sunscreen products with protective 
coefficient of at least SPF 15 whenever possible.  
4.1.5 
Tumor Assessment and Response Evaluation  
Tumor assessment and response evaluation will be performed using the International Workshop 
on CLL guideline for patients with CLL (Hallek 2008, Cheson 2012), the consensus of 
International Workshops on WM (IWWM-7 consensus) (Dimopoulos 2014), for patients with 
LPL/WM, and the Lugano response criteria for patients with other lymphomas (Cheson 2014).  
Tumor assessment will be conducted every 8 weeks (±7 days) for the first 24 weeks and every 12 
weeks (±7 days) thereafter. - 
Determination of disease progression will occur locally by the investigator in accordance with 
respective disease criteria. 
4.1.6 
Safety Follow-Up Period  
The safety of all enrolled patients will be closely monitored after the inform consent has been 
obtained until 30 days post last treatment dose or the initiation of new antineoplastic therapy, 
whichever comes earlier.  After the safety follow-up period, investigators shall only report the 
follow-up of unresolved SAEs that are related to prior study treatment of HMPL-689.  All AEs 
will be graded in accordance with the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 5.0. 
4.1.7 
Extended Progression-Free Survival Follow-Up Period  
Patients who discontinue HMPL-689 treatment due to reasons other than disease progression will 
enter the extended PFS follow-up period.  During this period, tumor assessment will be conducted 
quarterly until disease progression, death, the end of the study or the initiation of new 
anti-neoplastic therapy, whichever is earlier.  
Upon implementation of Protocol Amendment 5, this assessment will no longer be required. 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
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C O N FI D E N TI A L  
P a ge 4 5  
 
4. 2  
R ati o n ale f or t he St arti n g D ose a n d D osi n g Sc he d ule   
T he starti n g d ose of t his m ulti ple d oses st u d y i n h u ma n is deter mi ne d acc or di n g t o  t he fi nal res ult 
of t he si n gle d ose st u d y i n healt h y v ol u nteers, t h e preli mi nar y res ult of t h e m ulti ple d oses st u d y i n 
patie nts wit h l y m p h o m a, as well as  t he res ult of t he n o n -cli nical t o xicit y st u dies. 
I n t h e H M P L-6 8 9 si n gle d ose escal ati o n first -i n-h u ma n st u d y  (
), si n gle d ose of 
H M P L -6 8 9  3 0 m g w as well t olerate d wit h n o D L T or S A E n ote d .  T he e x p os ures of H M P L -6 8 9 
meas ure d b y ge o metric mea n A U C 0 -2 4 h val ues i n h u ma n at d ose le vels of 1, 2. 5, 5, 1 0, 2 0 a n d 3 0 
m g were  3 9. 9, 9 8. 2, 1 9 5, 4 4 6, 8 7 7, a n d 1 2 8 0  h •n g/ m L, res p ecti vel y .  T he  ge o m etric mea n  t½  of 
H M P L -6 8 9 w as ar o u n d 7 -9  h o urs.   
I n t he m ulti ple d ose escalati o n st u d y (
), 2 D L Ts were o bser ve d at 5  m g BI D, 
a n d n o D L T w as o bser ve d at 2. 5 m g BI D or 5 m g Q D .  Re -c halle n gi n g of 5  m g BI D a n d e val uati n g 
of 1 0 m g Q D were o n g oi n g at t he data c ut -off d ate  of  3 0  A pril 2 0 1 8 .  T he P K pr ofile i n C hi nese 
patie nts wit h l y m p h o ma o n Da y 1 was si milar t o t hat i n male healt h y v ol u nteers i n A ustralia wit h 
re gar d t o t½  a n d e x p os ures ( C ma x  a n d A U C) at t he e q ui vale nt d ose le vel s.  After m ulti ple oral d oses 
f or 1 5 da ys, t he acc u m ulati o n rati o was ar o u n d 1-2 .  Partial res p o nses were o bser ve d i n all d ose 
le vels teste d, i ncl u di n g 2. 5 m g BI D, 5 m g BI D a n d 5 m g Q D. 
I n H M P L -6 8 9  4 -wee k t o xicit y st u dies , t he N O A E L were 0 . 5 m g/ k g/ d a y  i n d o gs a n d 3 m g/ k g/ da y  
i n male rats, res pecti vel y.  T he A U C 0 -2 4 h was 7 5 4 h •n g/ m L i n male a n d 5 5 0 h •n g/ m L i n fe male f or 
d o gs, 1 4 3 0 h •n g/ m L i n male rats  f or c orres p o n de d N O A E Ls, res p ecti vel y. 
Acc or di n g t o t otal e x p os ure of H M P L -6 8 9 i n h u ma n a n d i n precli nical t o xicit y st u dies, a n d t he 
differe nt pr ot ei n bi n di n g rates of H M P L -6 8 9  i n rat, d o g a n d h u ma n, w hic h was ar o u n d 8 9. 1 %, 
8 8. 5 % a n d 9 3. 1 %, res pecti vel y , the  h u ma n e q ui val e nt d ose  of N O A E L , esti mate d b y  free e x p os ure 
of H M P L -6 8 9 , is li kel y t o be 2 0 -5 0 m g / da y.  
Base d o n t he data a b o ve, H M P L -6 8 9 5 m g Q D was selecte d as t he i nitial d ose i n t his st u d y.  A 
treat me nt c ycl e is defi ne d as 2 8 da ys of c o nti n u o us d osi n g.  
4. 3  
R ati o n ale f or Selecti o n of P atie nt P o p ul ati o n   
T he cli nical data ha ve i n dicate d  t hat PI 3 K is a b n or mall y acti vat e d i n B-cell l y m p h o mas .  I n vitr o 
e x peri me nts ha ve als o de m o nstrate d t hat PI 3 K m olec ule pla ys m aj or r ole i n acti vati o n a n d 
pr oliferati o n of B -N H Ls , as pre vi o usl y disc uss e d ( Secti o n  2. 3 ).  F or e x a m ple, d o w n -re g ulati o n of 
PI 3 K was a ble t o re d uce pr oliferati n g si g n al as well as t he e x pa nsi o n of D L B C L cells a n d 
s p o nta ne o us l y m p h o ma cells fr o m tra ns ge nic 
mice.  T hese e x peri me nts i n dicate t hat 
h y p eracti vat e d PI 3 K or P T E N deleti o n pla ys i m p orta nt r ole i n pr o m oti n g acti vati o n of B -N H Ls .  
T heref ore, i n hi biti o n of PI 3 K acti vati o n i n B -N H Ls ma y bl oc k si g nal tr a ns d ucti o n, res ulti n g i n 
i n hi biti o n of B l y m p h o ma cell pr oliferati o n or lea d t o i n d ucti o n of a p o pt osis i n t u m or cell.  T his 
a p pr oac h m a y pr o vi de a p o werf ul t o ol f or tr eat me nt of B -cell l y m p h o mas.  
T he patie nt p o p ulati o n of Sta ge 1 ( i.e., patie nts wit h rela pse d, refract or y or resista nt  l y m p h o ma) 
has  bee n sele cte d beca use t hese patie nts ha ve e x ha uste d all a p pr o ve d t hera p e utic o pti o ns a vaila ble, 
a n d offere d b y sta n dar d of care .  Base d o n pre vi o us cli nical data of H M P L -6 8 9 i n a si milar 
p o p ulati o n, H M P L -6 8 9 mi g ht be offere d t o t hes e patie nts as a n alter n ati ve t hera pe utic o pti o ns.  
T he i ncl usi o n criteri o n of Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma n ce stat us of 0  
or 1 has bee n selecte d t o facilitate attri b uti o n of t o xicities t o disease or t he i ntr o d ucti o n of t his 
a ge nt.  
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Patients with relapsed, refractory or resistant CLL/SLL, MCL, FL, MZL, PTCL, CBCL, and 
WM/LPL were selected for Stage 2 based on the preclinical and clinical data (Sections 2.2 and 
2.3), which suggest that patients with these types of NHL are more likely to benefit from the 
treatment of PI3Kδ inhibitor. 
4.4 
End of Study  
The end of the study is defined as 18 months after the last patient has been enrolled in the study or 
all patients have discontinued the study treatment, whichever comes earlier. 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 4 7  
 
5  
M A T E RI A L S A N D M E T H O D S   
5. 1  
P ati e nts   
5. 1. 1  
I ncl usi o n Criteri a  
Patie nts m ust meet t he f oll o wi n g criteria t o be eli gi ble f or st u d y e ntr y:  
1.  Si g ne d I nf or me d C o nse nt F or m (I C F) ;  
2.  A ge 1 8 years;  
3.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1;  
4.  Hist ol o gical l y c o nfir m e d  N H L  of t he f oll o wi n g s u b-t y pes C L L/ S L L, F L ( gra de 1-3a) , 
M C L, M Z L, L P L/ W M, P T C L or C B C L ;  
•  Patie nts wit h C L L / S L L, F L ( gra de 1-3 a), M C L  a n d L P L/ W M m ust ha ve recei ve d at 
least 2 pri or li nes of s yste mic t hera p y. 
•  Patie nts wit h M Z L m ust ha ve recei ve d at least 1 pri or li ne of s yste mic t hera p y t h at 
i ncl u des a n a nti-C D 2 0 m o n ocl o nal a nti b o d y a ge nt . 
•  Patie nts wit h P T C L a n d C B C L m us t ha ve recei ve d at least 1 pri or li ne of s yste mic 
t hera p y. 
5.  Patie nts wit h rela pse d , refract or y, or resista nt N H L , as d efi ne d b el o w: 
•  Refract or y t o a n y pri or re gi me n, defi ne d as n o res p o nse (c o m plete res p o ns e [ C R] or 
partial res p o nse [ P R]) t o pre vi o us t hera pi es, or pr o gressi o n wit hi n 6 m o nt hs of 
c o m pleti o n of t he last d ose of pri or t hera p y.  
•  T h ose w h o ca n n o l o n ger t olerate/ wit hsta n d c yt ot o xic c he m ot hera p y a n d or a vaila ble 
sta n dar d of treat me nt/care ( S o T/ S o C) , w here safet y pr ofile a n d ris ks of t o xicit y of 
ot her  treat me nt o pti o ns f ar o ut wei g h a n y p ossi ble cli nical be nefit. 
•  T h ose wit h n o c urati ve S o T or n o reas o n a ble access t o  a vaila ble treat me nts , in 
partic ular, t h ose w h o will be nefit fr o m t his class of c o m p o u n d , i n t he o pi ni o n of t he 
atte n di n g i n vesti gat or. 
6.  I n the d ose e x pa nsi o n sta ge, patie nts m ust ha v e m eas ura bl e diseas e f or o bj ecti ve res p o nse 
assess me nt, e x ce pt f or patie nts wit h C L L a n d W M/ L P L  
N O T E: meas ur a ble disease wit h F L, M C L, M Z L, P T C L, C B C L or S L L defi ne d as at 
least 1 bi-di me nsi o nall y meas ura ble l esi o n  ( > 1. 5 c m i n its lar gest di me nsi o n b y 
c o m p uterize d t o m o gra p h y [ C T] sca n), as defi n e d i n A p pe n di x 7  
7.  E x pecte d s ur vi val of m or e t ha n 2 4 wee ks  as deter mi ne d b y pri nci p al i n vesti gat or 
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8. Patients with prior treatment with any PI3Kẟ inhibitors are eligible for dose escalation.  
However, during dose expansion, only patients that discontinued PI3Kẟ inhibitor for 
reasons other than disease progression are eligible. 
9. Male patients must use a condom and female patients of childbearing potential must agree 
to use highly effective contraceptive measures that result in a low failure rate (<1% per 
year) when used consistently and correctly, from the screening period, through the entire 
study period, and for 30 days after the last dose of study drug.  These highly effective 
contraceptive measures, as defined by the Clinical Trials Facilitation Group (CTFG)*, 
include combined estrogen and progestogen hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable),  
intrauterine device (IUD) or intrauterine hormone-releasing system (IUS), bilateral tubal 
occlusion, a vasectomized partner, or sexual abstinence if in the preferred and usual 
lifestyle of the patient.  These same criteria are applicable to partners of patients involved 
in this clinical study if that partner is of childbearing potential.  Postmenopausal females 
(no menses for 12 months without an alternative medical cause) and surgically sterilized 
females are exempt from this criterion.  
*Note: In the context of this guidance, sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments.  The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject. 
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 (CNS) lymphoma;  
2. Any of the following laboratory abnormalities: 
• Absolute neutrophil count 1.0 ×109/L  
• Hemoglobin  80 g/L 
• 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 bone 
marrow infiltration.  The investigator will discuss the eligibility of such patients with the 
sponsor, and only upon approval by the sponsor will a patient with cell counts below the 
thresholds be enrolled in the study. 
NOTE: In the dose expansion stage, patients with ≤Grade 2 neutropenia per CTCAE 
version 5.0 and/or thrombocytopenia and with confirmed bone marrow infiltration are 
eligible.  
3. Inadequate organ function, defined by the following: 
• Total bilirubin 1.5 times the upper limit of normal ( ULN), with the following 
exception: 
▪ Patients with known Gilbert’s disease who have serum total and direct 
bilirubin level  2.5  ULN and normal AST and ALT can be enrolled. 


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• AST 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. 
• Estimated creatinine clearance (CrCl) per Cockcroft-Gault 
– Dose escalation stage of trial (Stage 1) – CrCl <40 mL/min 
– Dose expansion stage of trial (Stage 2) – CrCl <30 mL/min 
4. International normalized ratio (INR) 1.5  ULN, activated partial thromboplastin time 
(aPTT) 1.5  ULN; 
• Patients requiring anticoagulation therapy but with a stable INR within the 
recommended range according to the local guideline are eligible. 
NOTE: Patients may be considered for this 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 by the sponsor will a patient with impaired kidney function due to 
underlying disease be enrolled in the study. 
5. Serum amylase or lipase ULN at screening or known medical history of serum amylase 
or lipase >ULN; 
NOTE: Patients with known medical history of serum amylase or lipase ULN are 
eligible in the dose expansion stage. 
6. Patients with presence of second primary malignant tumors within the last 2 years, with 
the exception of: 
• Basal cell carcinoma of the skin 
• Squamous cell carcinoma of the skin 
• Carcinoma in situ of the cervix 
• Carcinoma in situ of the breast 
7. 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, presence of positive test results 
for hepatitis B (hepatitis B surface antigen and/or total hepatitis B core antibody), or CMV 
or HCV antibody 
• Patients who are positive for hepatitis B core antibody are eligible only if test 
results are also positive for hepatitis B surface antibody and polymerase chain 
reaction (PCR) is negative for HBV deoxyribonucleic acid (DNA).  These 
patients will require HBV DNA PCR monitoring, as per local standards 
• Patients who are positive for CMV or HCV serology are eligible only if testing for 
CMV DNA or HCV RNA is negative. 
8. Any anticancer therapy, including chemotherapy, hormonal therapy, biologic therapy, 
vaccine, or radiotherapy within 3 weeks prior to initiation of study treatment; 
9. Any granulocyte colony-stimulating factor treatment/blood transfusion within 7 days 
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10. Any steroid therapy or approved targeted small molecule agents for anti-neoplastic intent 
within 7 days or approximately 5 half-lives, whichever is longer, prior to initiation of study 
treatment; 
11. Prior use of any drug that is a strong inducer of CYP3A4 or strong inhibitor of CYP3A4 
within 2 weeks prior to initiation of study treatment (3 weeks for St John’s Wort) (refer to 
Appendix 8); 
12. Prior autologous transplant within 6 months prior to initiation of study treatment;  
13. Prior allogeneic stem cell transplant within 6 months prior to initiation of study treatment 
or with any evidence of active graft versus host disease or requirement for 
immunosuppressants within 21 days prior to initiation of study treatment; 
14. Clinically significant active infection (e.g., pneumonia) or interstitial lung diseases 
(including drug induced pneumonitis); 
15. Major surgical procedure within 4 weeks prior to initiation of study treatment; 
16. Treatment within a clinical study of an investigational agent or using an investigational 
device within 30 days prior to initiation of the current study treatment; 
17. Adverse events from prior anti-neoplastic therapy that have not resolved to Grade  1, 
except for alopecia; 
18. Pregnant (positive urine or serum beta human chorionic gonadotropin [β-HCG] test) or 
lactating women; 
19. New York Heart Association (NYHA) Class II or greater congestive heart failure; 
20. Congenital long QT syndrome or corrected QT interval (QTc) >470 msec; 
21. Currently use medication known to cause QT prolongation or torsades de pointes (see full 
list at http:// www.crediblemeds.org); 
22. History of myocardial infarction or unstable angina within 6 months prior to initiation of 
study treatment; 
23. History of stroke or transient ischemic attack within 6 months prior to initiation of study 
treatment;  
24. Inability to take oral medication, prior surgical procedures affecting absorption, or active 
peptic ulcer disease; 
25. History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis); 
26. Patients with ongoing chronic gastrointestinal diseases; 
27. Legally protected adults; 
28. 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 or that may 
affect the interpretation of the results or renders the patient at high risk of treatment 
complications. 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 5 1  
 
5. 2  
St u d y Tre at me nt   
5. 2. 1  
F or m ul ati o n, P ac k a gi n g, a n d H a n dli n g   
H M P L -6 8 9  ca ps ul es  of 2 stre n gt hs (2 .5 m g a n d 10 m g) will be use d i n t his cli nical st u d y .  T he 
ca ps ules are pac ka ge d i n w hite hi g h -d e nsit y p ol yet h yle ne ( H D P E ) b ottl es .  T h e ca ps ules are 
c o m p ose d of wi del y use d p har mace utical e x ci pie nts ( U nite d States p h ar mac o peia [ U S P ] gra d e or 
e q ui vale nt) a n d H M P L-6 8 9 dr u g s u bsta nce .  T he d r u g will  be  st ore d at tem p erat u res bet w ee n 1 0 ° C 
a n d 3 0 ° C a n d s h o ul d re mai n i n its b ottle u ntil a d mi nistrati o n i n or der t o a v oi d u n pr otecte d e x p os ure 
t o s u nli g ht.  F or f urt her details, please refer t o H M P L -6 8 9  IB  a n d t h e p har m ac y ma n ual . 
5. 2. 2  
Dr u g L a beli n g   
T he c o nte nts of t he la b el will be i n acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts.  
5. 2. 3  
Dr u g Acc o u nt a bilit y   
All I P re q uir e d f or t his st u dy will b e pr o vi de d b y H U T C H M E D Li mite d  or c o ntr acte d C o ntract 
Researc h Or ga n iz ati o n (C R O ).  T he reci pie nt will ac k n o wle d ge recei pt of t he dr u g b y c o m pleti n g 
a n d kee pi n g  t he a p pr o priate d o c u me ntati o n f or m i n dicati n g s hi p me nt c o nte nt a n d c o n diti o n.  
Da ma ge d s u p plies will b e re pla ce d.  
Acc urate rec or ds of all I P recei ve d at, dis pe nse d fr o m, ret ur ne d t o a n d dis p ose d b y t h e st u d y site 
s h o ul d be rec or de d b y usi n g t he Dr u g I n ve nt or y L o g. 
I n v esti gati o nal pr o d uct will be dis p ose d of at t he st u d y site acc or di n g t o t he st u d y site’s 
i nstit uti o nal sta n dar d o perati n g pr oce dure , a n d t h e met h o d of destr ucti o n m ust be d oc u me nte d. 
5. 2. 4  
D os a ge, A d mi nistr ati o n, a n d C o m pli a nce   
T he pr o p ose d d osa ge of H M P L -6 8 9 is s pecifie d i n Ta ble 2 .  I n vesti gati o n al pr o d uct s h o ul d be 
ta ke n at a p pr o xi matel y t h e sa me ti mes eac h da y.  I deall y, d oses i n t he Q D c o h orts s h o ul d be ta ke n 
at 2 4 -h o ur i nter val s wit h  ± 4 -h o ur  wi n d o w .  H M P L -6 8 9  ca n b e ta ke n wit h or wit h o ut f o o d wit h 
a p pr o xi matel y 8 o u n ces  (2 4 0  m L ) of wat er .  T he a d mi nistrati o n ti me s h o ul d be acc uratel y rec or de d 
i n t he patie nt diar y.  
I n t he st u d y, p atie nts will n ot be all o we d t o m a ke u p misse d d oses; patie nts will res u me d osi n g at 
t heir ne xt sc he d ule d d ose.  
G ui deli nes f or d osa ge m o dificati o n a n d tr eat me nt i nterr u pti o n or disc o nti n uati o n are pr o vi de d i n 
Secti o n 5. 3 . 
A n y o ver d ose  (S ecti o n 6. 3. 1. 6 ) or i nc orrect a d mi nistrati o n of I P s h o ul d be n ote d o n t he patie nt ’s 
s o urce d o c u me ntati o n a n d Case Re p ort F or m ( C R F) .  A d verse e ve nts ass o ciate d wit h a n o ver d ose 
or i nc orrect a d mi nistrati o n of I P s h o ul d als o be rec or de d o n t he patie nt ’s s o urce d o c u me ntati o n 
a n d A d vers e E ve nt s pa ge o n t he C R F  ( Secti o n 6. 3. 1. 6 ) a n d treate d acc or di n g t o Secti o n  5. 5 .  
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H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 5 2  
 
5. 2. 6  
P ost -tri al Access t o H M P L -6 8 9   
C urre ntl y, t he s p o ns or d oes n ot ha ve a n y sc he d ul e d pla ns t o pr o vi de H M P L -6 8 9  or a n y ot her st u d y 
i nter ve nti o ns after t he e n d of t he st u d y or f or a n y patie nt w h o has disc o nti n ue d or wit h dra w n fr o m 
t he st u d y.  T he s p o ns or  will e val uate w het her t o c o nti n ue pr o vi di n g H M P L -6 8 9  after t he st u d y is 
o ver.  
I n t he e ve nt t hat t he sp o ns or dee ms p ost -trial access t o H M P L-6 8 9  t o be a p pr o priate, t he sp o ns or 
ma y offer p ost -trial access t o t he I P ( H MP L -6 8 9 ) free of c har ge t o eli gi ble patie nts as o utli ne d 
bel o w.  
A patie nt will be eli gi ble t o recei ve I P after t he e n d of t he st u d y if all of t he  f oll o wi n g c o n diti o ns 
are met:  
•  T he patie nt has rela pse d/refract or y/r esista nt l y m p h o ma t hat re q uires c o nti n ue d I P 
treat me nt f or his or her well-bei n g.  
•  T here are n o a p pr o priat e alter nati ve treat me nts a v aila ble t o t he patie nt.  
•  T he patie nt a n d his or her d oct or c o m pl y wit h a n d satisf y a n y le gal or re g ul at or y  
re q uire me nts t hat a p pl y t o t he m. 
A patie nt will n ot be eli gi bl e t o recei ve I P after t he e n d of t he st u d y if a n y of t he f oll o wi n g 
c o n diti o ns are met:  
•  T he I P is c o m merciall y mar kete d i n t he patie nt's c o u ntr y a n d is reas o na bl y accessi ble t o 
t he patie nt (e. g., is acc o m m o date d b y t he patie nt's i ns ura nce or w o ul d n ot ot her wise 
creat e a fi n a ncial har ds hi p f or t he patie nt).  
•  T he s p o ns or has disc o nti n ue d de vel o p me nt of t he I P or data s u g gest t hat  t h e I P is n ot 
effecti ve f or l y m p h o ma. 
•  T he s p o ns or has r eas o na ble safet y c o n cer ns re gar di n g t he I P as tr eat me nt  f or l y m p h o ma. 
•  Pr o visi o n of I P is n ot per mitte d u n der t he la ws a n d re g ulati o ns of t he patie nt ’s c o u ntr y. 
5. 3  
Met h o d of Tre at me nt Assi g n me nt   
Patie nts will be assi g ne d t o d ose le vels se q ue ntiall y at d os e escal ati o n sta ge .  H o we ver, i n t he d os e 
e x pa nsi o n sta ge, patie nts will be all ocate d bas e d o n disease s u bt y pe . 
5. 4  
D ose Del a ys a n d M o dific ati o n   
Refer t o Secti o n 6. 8  f or rec o m me n dati o ns o n dia g n osis a n d ma na ge me nt of p ote ntial t o xicities 
ass ociate d wit h H M P L-6 8 9 a n d/ or n ote d wit h ot her PI 3 K δ i n hi bit ors . T he r eco m me n d ati o ns 
pr o vi de d i n Secti o n 6. 8  s h o ul d be e val uate d i n c o nj u ncti o n wit h t he l ocal cli nical sta n dar d of care, 
a n d o verall ma n a ge me nt pla n s h o ul d be base d o n t he i n vesti gat or’s best cli nical ju d g me nt . 
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5.4.1 
During Dose Limiting Toxicities Assessment Window  
If a patient experiences a DLT, dosing of HMPL-689 will be interrupted and supportive therapy 
administered as required in accordance with local practice/guidelines. Refer to Section 6.8 for 
toxicity management recommendations. 
Patients who experience a DLT may resume dosing at the same or previous lower dose level at the 
discretion of the treating physician given that the toxicity is resolved or improved to the baseline 
level.  If a patient experiences an intolerable toxicity at the reduced dose level, he/she will be 
discontinued from the study treatment.  Patient cannot be dose-reduced by more than 2 dose levels.  
Once reduced, the dose cannot be re-escalated. 
No dose reduction in patients without DLT is permitted in the DLT assessment window without 
the sponsor’s approval.  
5.4.2 
After Dose Limiting Toxicities Assessment Window of Stage 1 or at Stage 2  
After DLT assessment window of Stage 1 or at Stage 2, the dose of HMPL-689 may be interrupted 
if any of the following is observed: 
• Any grade pulmonary toxicity 
• Any grade diarrhea/colitis 
• Grade 3 or 4 hematologic toxicity 
• Grade 3 or 4 non-hematologic toxicity (except for alopecia and skin eruption, nausea, 
vomiting, diarrhea or constipation if well-controlled by systemic or topical medication) 
Refer to Section 6.8 for detailed toxicity management recommendations for potential class-related 
toxicities and dose modification of HMPL-689. 
For all other toxicities, treatment with HMPL-689 should be withheld until the toxicity resolves to 
CTCAE Grade ≤2.  Dosing may then be resumed at either the same dose level or the previously 
evaluated lower dose level if the toxicity is improved to CTCAE Grade ≤2 within 2 weeks, per 
investigator’s discretion.  If treatment is resumed at the same dose, and the patient experiences the 
same toxicity of Grade 3 or 4, the dose should be reduced following resolution of the event.  If the 
patient continues to experience intolerable toxicity, a second dose reduction to a previously 
evaluated lower dose is permitted. 
In all cases, every patient is allowed to reduce HMPL-689 dose only twice.  If a patient continues 
to experience intolerable toxicity after 2 dose reductions, or if dosing with HMPL-689 is 
interrupted for >14 consecutive days due to toxicity (except for those with additional guidance 
provided in Section 6.8), treatment should be discontinued, unless otherwise agreed by the 
investigator and the sponsor. 
Intra-patient dose escalation to a higher dose level may be permitted by the sponsor provided that 
the dose level to be escalated has already been cleared at the time of dose increase being proposed. 


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5.5 
Treatment of Overdose  
For this study, any dose of study drug greater than the intended daily dose will be considered an 
overdose (Sections 5.2.4).  Procedures for recording overdose events are available in 
Section 6.3.1.6. 
No specific information is available on treatment of overdose of HMPL-689.  Nevertheless, in the 
event of overdose, further HMPL-689 administration should be withheld and subject should be 
observed closely for clinical features of toxicities.  Appropriate supportive treatments should also 
be provided if clinically indicated.   
5.6 
Concomitant Therapy and Food  
5.6.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs or 
homeopathic remedies, 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 CRF. 
Beyond Cycle 1 of Stage 1 or in Stage 2, patients may receive treatment with corticosteroids (at 
dosages equivalent to prednisone ≤20 mg/day) and/or bisphosphonates for the treatment of bone 
metastases.  Patients may also receive palliative radiotherapy for painful bony metastases.  If a 
patient needs to undergo palliative local radiotherapy to relieve symptoms (such as local 
radiotherapy to relieve cancer bone pain), the patient may resume administration of the study IP 
7 days after the local radiotherapy is over, but should meet the following criteria:  
• The patient’s radiotherapy-related toxicity has recovered to <Grade 2; and 
• The tumor has not progressed.  
5.6.2 
Prohibited Therapy and Food, and Concomitant Medications Requiring Caution 
in Use  
Patients receiving strong inducers of CYP3A4 or strong inhibitors of CYP3A4 within 2 weeks 
before the first dose of study treatment (3 weeks for St John’s Wort) are excluded from the study.  
Concomitant use of drugs that are known to be strong inducers of CYP3A4 or strong inhibitors of 
CYP3A4 during the trial should be avoided 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 drug-drug interactions.  
Drugs that are known to be affected by P-gp should be used with caution.  
Appendix 8 provides lists of drugs prohibited and those that should be used with caution.  These 
lists are not intended to be exhaustive, please refer to full prescribing information for all drugs 
prior to concomitant use with HMPL-689. 
Other anticancer agents, investigational agents, and radiotherapy (not for painful bony lesion) 
should not be given while the patient is during the study.  
Corticosteroids are prohibited from 7 days before the date of hematologic screening test to the end 
of DLT assessment window of Cycle 1 of Stage 1. 


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Granulocyte colony stimulating factors should not be used prophylactically during the DLT 
assessment window.  Use of prophylactic colony stimulating factors may be considered after Cycle 
1 following discussion with the sponsor. 
No grapefruit or grapefruit juice or recreational drugs will be allowed during the study. 
HMPL-689 shows pH-dependent solubility (i.e., solubility at pH 4.5-6.8 < solubility at pH 1-2) 
and may be less well absorbed as gastrointestinal pH increases.  Patients should avoid using proton 
pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole) during the study.  If concomitant 
use of an acid-reducing agent is unavoidable, H2-antagonist (e.g., famotidine, ranitidine, 
nizatidine) may be used but should be administered approximately 10 hours before or 2 hours after 
HMPL-689 dosing.  Antacid may be used, but the antacid dose should be administered at least 
2 hours before or 2 hours after HMPL-689 dosing. 
5.7 
Study Assessments  
5.7.1 
Definitions of Study Assessments  
All patients will be closely monitored for safety and tolerability throughout the study.  Continued 
dosing with HMPL-689 will be offered to patients until disease progression, death, intolerable 
toxicity, or 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, whichever comes first. 
The schedule of activities is provided in Appendix 1 and the schedule of PK sample collection at 
dose escalation stage is provided in Appendix 2, the schedule of PK sample collection at dose 
expansion stage is provided in Appendix 3.  
5.7.2 
Informed Consent Forms and Screening Log  
Written informed consent for participation in the study must be obtained from the study participant 
before performing any study specific screening tests or evaluations using an ICF approved by the 
local IRB/IEC that contains all elements required by ICH E6 and in compliance with country 
specific regulations and guidelines.  One of 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. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before study treatment.  Patients who do not meet the lab testing related 
eligibility criteria might be re-screened.  Re-screening requires re-signing of the ICF and a new 
screening number will be assigned.  Upon implementation of Amendment 5, patients may not be 
rescreened. The investigator will maintain a screening log to record details of all patients’ screened 
and record reasons for screening failure.  Eligibility verification form will be maintained by 
investigator and confirmed with sponsor prior to initial study treatment. 
5.7.3 
Medical History and Demographic Data  
Medical history and demographic data will be collected at screening.  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 medical records, including 
electronic medical records, for the purpose of reviewing information about the participant’s health 


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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.  
Medical history will include clinically significant diseases, 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, night sweats for 
more than 1 month without evidence of infection]), prior cancer diagnosis (including tumor type, 
initial diagnosis date, immunohistochemistry, flow cytometry, other pathological findings), prior 
anti-neoplastic therapies and procedures and related outcome, use of tobacco, use of alcohol and 
drugs of abuse prior to the screening visit. 
Demographic data will include date of birth, sex, and self-reported race/ethnicity. 
5.7.4 
Concomitant Medication/Concomitant Procedure  
Any concomitant medication/procedure within 7 days prior to the screening visit and 30 days after 
the end of treatment or early termination will be recorded.  
5.7.5 
Performance Status  
The ECOG performance status (Appendix 9) should be assessed by the same study personnel at 
screening, Days 1 and 15 of Cycle 1, and Day 1 of every cycle from Cycle 2 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.  Additional consideration should 
be given to borderline ECOG performance status to avoid enrolling patients with significant 
impairment. 
5.7.6 
Ann Arbor Staging and Rai/Binet Staging  
Appendix 10 provides a description of Ann Arbor staging for primary nodal lymphomas.  
Appendix 11 and Appendix 12 provide a description of Rai and Binet staging respectively for 
CLL.  
Ann Arbor staging and Rai and/or Binet staging will be collected at screening.  
5.7.7 
International Prognostic Index  
Appendix 13 provides information on the different International Prognostic Indices (IPIs) for the 
patients with FL, MCL, LPL/WM and other lymphomas.  For FL, risk factors refer to Follicular 
Lymphoma International Prognostic Index (FLIPI).  For MCL, risk factors refer to Simplified 
Mental Cell Lymphoma International Prognostic Index (SMIPI).  For LPL/WM, risk factors refer 
to International prognostic scoring system for Waldenström’s macroglobulinemia (ISSWM).  For 
DLBCL and other lymphomas, risk factors refer to IPI.  
IPI score will be collected at screening. 


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5.7.8 
Vital Signs  
Vital signs will be collected at screening, Days 1, 8, 15, 22 of Cycle 1, Days 1 and 15 of Cycle 2, 
Day 1 of every cycle from Cycle 3 and onwards, and at study completion or early termination, and 
will include measurements of body temperature, heart rate, respiratory rate, systolic and diastolic 
blood pressure while the patient is in a seated position.  The patient should be seated for 5 minutes 
before the measurement of the blood pressure.  
5.7.9 
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, weight, and height.  Physical examination should be performed at screening, 
Days 1, 8, 15, 22 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of every cycle from Cycle 3 and 
onwards, and at study completion or early termination.  Weight will be assessed at screening, Day 
1 of every cycle from Cycle 2 and onwards, and at study completion or early termination, while 
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. 
5.7.10 
Laboratory Assessments  
Samples for hematology, chemistry panel, serum amylase and lipase, fasting lipid profile, 
coagulation, thyroid hormones, hemoglobin A1c, serum β-2 microglobulin, viral serology, 
urinalysis, leukocyte immunophenotyping and pregnancy testing will be analyzed at the study 
site’s local laboratory. Upon implementation of Protocol Amendment 5, some assessments will no 
longer be required. Please refer to Appendix 1 for further details. 
Laboratory assessments will include the following: 
• Hematology consists of complete blood count, including red blood cell count, 
hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, 
bands, lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet 
count.  Hematology should be tested at screening (within 7 days prior to the first dose of 
the IP), Days 8, 15 and 22 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of every cycle 
from Cycle 3 and onwards, and at study completion or early termination. 
• The chemistry panel includes blood urea nitrogen (BUN) or urea, sodium, potassium, 
magnesium, chloride, calcium, phosphorus, uric acid, fasting glucose, ALT, total and 
direct bilirubin, AST, alkaline phosphatase (ALP), LDH, protein (total), albumin, creatine 
phosphokinase, creatinine, and estimated CrCl per Cockcroft-Gault.  Chemistry should be 
tested at screening (within 7 days prior to the first dose of the IP), Days 3, 8, 15 and 22 of 
Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of every cycle from Cycle 3 and onwards, and 
at study completion or early termination. 
• Serum amylase and lipase should be tested at screening (within 7 days prior to the first 
dose of the IP), Days 8, 15 and 22 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of every 
cycle from Cycle 3 and onwards, and at study completion or early termination. 
• Fasting lipid profile: includes total cholesterol, high-density lipoprotein (HDL), low-
density lipoprotein (LDL), triglycerides, and should be tested at screening (preferably 


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within 7 days prior to the first dose of the IP), Day 1 of every odd cycle from Cycle 3 and 
onwards, and at study completion or early termination. 
• Coagulation (INR, aPTT, or PT) should be tested at screening (within 7 days prior to the 
first dose of the IP), Day 1 of every cycle from Cycle 2 and onwards, and at study 
completion or early termination. 
• Thyroid hormones include free triiodothyronine (FT3), free thyroxine (FT4) and thyroid 
stimulating hormone (TSH), and should be tested at screening (preferably within 7 days 
prior to the first dose of the IP), Day 1 of every odd cycle from Cycle 3 and onwards and 
at study completion or early termination. 
• Hemoglobin A1c should be tested at screening (preferably within 7 days prior to the first 
dose of the IP), Day 1 of every odd cycle from Cycle 3 and onwards and at study 
completion or early termination. 
• Serum β-2 microglobulin (β2M) should be tested at screening (preferably within 7 days 
prior to the first dose of the IP), Day 1 of every cycle from Cycle 2 and onwards, and at 
study completion or early termination.  
• Viral serology should be tested at screening and includes the following: 
− HIV  
− HBV (HBsAb, HBsAg and HBcAb)  
o also, HBsAb by enzyme-linked immunosorbent assay and HBV DNA by PCR if 
the patient is HBcAb positive 
− HCV (HCV antibody) 
o also HCV RNA by PCR if the patient is HCV antibody positive 
− CMV (CMV immunoglobulin G [IgG], CMV immunoglobulin M [IgM])  
o also CMV DNA by PCR if patient is CMV IgG positive 
• Urinalysis or dipstick (glucose, protein, ketones, blood), should be tested at screening 
(within 7 days prior to the first dose of the IP), Day 3 and 15 of Cycle 1, Days 1 and 15 of 
Cycle 2, Day 1 of every cycle from Cycle 3 and onwards, and at study completion or 
early termination.  If protein ≥2+ observed during the period of study treatment, a 24-
hour urine test should be conducted within 1 week. 
• Leukocyte immunophenotyping (Fluorescence-activated Cell Sorting [FACS] subsets) 
should be done at screening (preferably within 7 days prior to the first dose of the IP), 
Day 15 of Cycle 1, Day 1 of every cycle from Cycle 2 and onwards, and at study 
completion or early termination, which includes: 
− Determination of T/B/NK Counts (CD3, CD4, CD8, CD19, CD16/56) using a 
standard cell marker panel 
• Patients with CLL: (optional)  
− Tests of cytogenetic abnormality will be performed at screening (preferably within 7 
days prior to the first dose of the IP) for patients with CLL in the dose expansion stage 
only.  These tests should include but not be limited to TP53 mutation, 17p deletion, 11q 
deletion, 13q deletion, and +12 trisomy. 
− Upon implementation of Protocol Amendment 5, these assessments will no longer be 
required. 
• All women who are not postmenopausal (no menses for 12 months without an alternative 
medical cause) or surgically sterile will have a serum β-HCG or urine pregnancy test at 


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screening and at study completion or early termination.  In the case of postmenopausal 
women, the date of menopause onset should be recorded. 
• Plasma HMPL-689 concentrations (for PK evaluations) will be assessed using a validated 
assay.  Blood samples should be collected according to the time points in Appendix 2 or 
Appendix 3. 
• Exploratory biomarker assessments will be required for patients in the dose expansion 
stage and should be collected according to the time points in Appendix 4.  
− Upon implementation of Protocol Amendment 5, this assessment will no longer be 
required. 
• LPL/WM related testing 
− Serum immunoglobulins assessment (quantitative immunoglobulin assessment of 
IgM, IgA, IgG) will be performed for patients with LPL/WM at screening (preferably 
within 7 days prior to the first dose of the IP), Day 1 of every cycle from Cycle 2 and 
onwards, study completion or early termination, quarterly during the extended PFS 
follow-up period, and at the time of CR confirmation.  
5.7.11 
Electrocardiogram  
All electrocardiograms (ECGs) are required to be performed using a 12-lead tracing.  ECG 
measurements will include PR interval, QRS interval, RR interval, QT/QTcF interval, and heart 
rate. 
For dose escalation stage, triplicate ECGs, approximately 2 minutes apart, should be performed at 
screening, pre-dose, and 2 ± 0.5 and 4 ± 0.5 hours post-dose on Days 1 and 15 of Cycle 1 in order 
to evaluate concentration-QT relationship with HMPL-689.  Single ECG will be conducted at any 
time on Day 1 of every cycle from Cycle 2 and onwards, and at study completion or early 
termination.  For dose expansion stage, ECGs should be collected according to the schedule and 
time points in Appendix 3. 
Additional ECGs and other cardiac monitoring will be provided as clinically indicated during the 
study. 
5.7.12 
Echocardiogram/MUGA  
An echocardiogram/multigated acquisition scan (MUGA) to assess left ventricular ejection 
fraction (LVEF) will be conducted at screening, Day 1 of every odd cycle from Cycle 3 and 
onwards, and at study completion or early termination.  The modality of the cardiac function 
assessments must be consistent within a patient.  For example, if echocardiogram is used for the 
screening assessment, then echocardiogram should also be used for subsequent scans if required.  
5.7.13 
Tumor and Response Evaluation  
The baseline tumor assessment can be completed within 21 days prior to the first dose of IP 
(depending on the patient's disease status a window may be acceptable based on a discussion 
between the investigator and the sponsor’s medical monitor).  All measurable and evaluable 
lesions should be assessed and documented at screening and each subsequent tumor evaluation, 
using blood test, physical examination, contrast enhanced CT scans (neck, chest, abdomen, and 
pelvis) for non-fluorodeoxyglucose (FDG)-avid lymphomas (e.g., LPL/WM, CLL/SLL, and MZL) 
and/or positron emission tomography(PET)-CT scans for patients with FDG-avid lymphomas 


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(e.g., FL, MCL, and DLBCL).  Enhanced magnetic resonance imaging (MRI) may be used instead 
of 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.  Patients who discontinue HMPL-689 treatment due to reasons other 
than disease progression will continue tumor assessment according to previous tumor assessment 
schedule till disease progression, death, end of the study, or start of a new anti-neoplastic therapy, 
whichever is earlier (see Appendix 1).  Upon implementation of Protocol Amendment 5, patients 
who discontinue HMPL-689 treatment due to reasons other than disease progression will also 
discontinue from the study. 
The same imaging procedure and laboratory tests used to define measurable lesions at baseline 
should be used throughout the study for each patient. 
Bone Marrow Aspirate and Biopsy 
A bone marrow biopsy or aspirate is strongly recommended to be done at baseline or up to 
3 months before of the Cycle 1 Day 1 and for confirmatory purposes for all patients who achieved 
a radiologic CR or to confirm suspected progressive disease (PD) based solely upon declines in 
the platelet count and/or hemoglobin. Upon implementation of Protocol Amendment 5, this 
assessment will no longer be required. 
5.7.14 
Timing of Study Assessments  
5.7.14.1 
Screening and Assessment  
All screening evaluations must be completed and reviewed by the investigator and the sponsor’s 
medical monitor to confirm that patients meet all eligibility criteria before the first administration 
of HMPL-689.  
Please see Appendix 1 for the schedule of screening and pre-treatment assessments.  Screening 
and pre-treatment tests will be performed within 21 or 7 days preceding the day of first dose of IP, 
unless otherwise specified.  Results of standard of care tests performed prior to obtaining informed 
consent and within 21 days prior to study entry may be used; such tests do not need to be repeated 
for screening. 
The baseline tumor assessment can be completed within 21 days prior to the first dose of IP 
(depending on the patient’s disease status a window may be acceptable based on a discussion 
between the investigator and sponsor’s medical monitor).  A bone marrow biopsy and aspirate are 
to be done at baseline or up to 3 months before study treatment. 
5.7.14.2 
Assessment during Treatment  
All visits must occur within  3 days ( 1 day during the DLT assessment window) from the 
scheduled date, unless otherwise noted (Appendix 1).  All assessments will be performed on the 
day of the specified visit unless a time window is specified.  


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5.8 
Participant Completion/Discontinuation  
5.8.1 
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-689 administration for a follow-up visit.  Ongoing AEs 
considered by the investigator to be related to HMPL-689 will be followed up until the event has 
resolved to baseline, the event is assessed by the investigator as stable, new antineoplastic 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or when it has 
been determined that the study treatment or participation is not the cause of the event. 
5.8.2 
Extended Progression Free Survival Follow-up  
Patients who discontinue HMPL-689 treatment due to reasons other than disease progression will 
enter the extended PFS follow-up period.  During this period, tumor assessment will be conducted 
quarterly until disease progression, death, the end of the study or the initiation of new 
antineoplastic therapy, whichever comes earlier.  The assessments to be performed at the follow-up 
visits are listed in Appendix 1.  Upon implementation of Protocol Amendment 5, patients who 
discontinue HMPL-689 treatment due to reasons other than disease progression will also 
discontinue from the study. 
5.8.3 
Individual Patient 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 
• Non-compliance (e.g., frequently misses doses, visits)  
Guidance for diagnosis and management of important potential class toxicities noted on HMPL-
689 trials and/or those associated with other PI3Kδ inhibitors is provided in Section 6.8. 
The primary reason and date for discontinuation must be recorded appropriately on the CRF. 
In addition, stopping rules for individual patients during the dose escalation (Section 5.8.3.1) and 
dose expansion (Section 5.8.3.2) stages are outlined below. 
5.8.3.1 
Individual Patient Stopping Rules – Dose Escalation  
For specific guidance on the diagnosis and management of important potential class toxicities 
associated with HMPL-689 and/or other PI3Kδ inhibitors, please refer to Section 6.8. 
Dosing will stop for an individual subject, if any of the following occurs: 
• A DLT that has not returned to Grade 1 (inclusive) or lower within 14 days, or a DLT that 
re-occurs in the same subject at a de-escalated lowered dose level 
• A DLT equivalent beyond Cycle 1 that has not resolved (even with medical intervention) 
within 14 days, or that reoccurs after the patient receives a de-escalated lower dose level 


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5.8.3.2 
Individual Patient Stopping Rules – Dose Expansion  
For specific guidance on the diagnosis and management of important potential class toxicities 
associated with HMPL-689 and/or other PI3Kδ inhibitors, please refer to Section 6.8. 
• An adverse drug reaction (ADR) severity and its resolution will determine dose 
interruption, reduction, or discontinuation for an individual 
• ADR resolution will determine if subject will discontinue treatment altogether or at the 
discretion of attending physician, resume treatment at; i) the same dose level, or ii) at a 
lower dose 
• If in professional opinion and recommendation of the PI, individual patients should 
withdraw from the study  
• ADR emerging from drug-drug interaction or food-effect may lead to dose interruption, 
reduction, or discontinuation 
5.8.4 
Study Treatment Discontinuation  
Patient must discontinue the study treatment in case of: 
• Disease progression 
• Intolerable toxicity 
• Use of new antineoplastic therapy 
• Pregnancy with onset during study 
The primary reason for study treatment discontinuation should be recorded on the appropriate 
CRF.  Discontinuation from HMPL-689 treatment does not mean discontinuation from the study, 
and the remaining study procedures should be completed as indicated in the study protocol. 
In addition, stopping rules for a cohort or study during dose escalation (Section 5.8.4.1) and dose 
expansion (Section 5.8.4.2) stages are outlined below. 
5.8.4.1 
Cohort or Study Stopping Rules – Dose Escalation  
There will be no escalation to the next cohort higher dose level until all available data from the 
current cohort dose level have been reviewed and analyzed by SRC, which will then recommend 
appropriate dose escalation, de-escalation, or discontinuation.  This dose escalation stage will be 
suspended, interrupted, or discontinued before MTD is attained based on: 
• recommendation of SRC 
• analysis of emerging PK data, which suggests dose-exposure or target engagement is 
saturated 
At the end of the DLT assessment window for a cohort dose level, safety data will be evaluated to 
determine either to escalate to the next cohort of higher dose level (Figure 1) or de-escalate to a 
specific lower dose level (not necessarily pre-specified).  The need for dose escalation beyond 
50 mg QD, de-escalation to below 5 mg QD, or other regimens, such as BID, will be evaluated 
and determined by the SRC based on all available cumulative data on safety, PK, 
pharmacodynamics, and efficacy. 
Below are other scenarios that may be applicable: 


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 6 3  
 
•  O ne o ut of 3 patie nts wit h D L T will lea d t o a n i ncrease i n n u m ber of patie nts  o n t hat 
c o h ort d ose le vel  
•  T hree o ut of 6 p atie nts wit h D L Ts will lea d t o de-escalati o n t o a l o wer le vel d ose  
•  T hree or m ore o ut of 6 p atie nts wit h D L T at c urre nt d ose i n dicate t hat t he d ose is u nsafe, 
a n d t hat t his d ose s h o ul d be de-es calat e d or disc o nti n ue d.  
•  Si x o ut of 6 patie nts wit h D L Ts at c o h ort # 1 (i nitial starti n g d ose) ma y lea d t o 
ter mi nati o n of t he st u d y ar m, a me n d me nt of t h e pr ot oc ol t o reflect a ne w l o wer starti n g 
d ose or c ha n ges t o i ncl usi o n/e x cl us i o n criteria, or ter mi nati o n of t he e ntire st u d y. 
5. 8. 4. 2  
C o h ort or St u d y St o p pi n g R ules –  D ose E x pa nsi o n   
T he M T D/ R P 2 D of e x pa nsi o n sta ge 2 will be t h e d ose d eter mi ne d as s afe b y t he S R C  bas e d o n 
t he c o ncl usi o n of d ose es calati o n sta ge 1 secti o n of t his p hase 1 cli nical trial. 
T he d ose or a n y of t he treat me nt ar ms/c o h orts/t u m or t y pes ma y b e re -e v al uate d f or d ose 
i nterr u pti o n, s us pe nsi o n, or re d ucti o n base d o n re vie w of e mer gi n g safet y d ata a n d 
rec o m me n dati o n of t h e safet y c o m mittee. 
5. 8. 5  
St u d y a n d Site Disc o nti n u ati o n   
T his st u d y ma y be te m p oraril y s us pe n de d or pre mat urel y ter mi nate d if t here is s ufficie nt 
reas o na bl e ca use.  T he s p o ns or will n otif y t h e i n v esti gat or if t he st u d y is pl ace d o n h ol d, or if t he 
s p o ns or deci des t o disc o nti n ue t he st u d y or cl os e a n y site.  If t he stu d y is pre mat urel y ter mi nate d 
or s us pe n de d, t he PI  will pr o m ptl y i nf or m st u d y partici pa nts a n d t he I nstit uti o nal Re vie w 
B oar d/I n de pe n d e nt Et hics C o m mittee (I R B/I E C) .  Patie nts  will be c o ntacte d, as a p plica ble, a n d be 
i nf or me d of c ha n ges t o st u d y visit sc hed ule .  Reas o ns f or s us pe nsi o n or ter mi nati o n t he st u d y 
i ncl u de: 
•  Deter mi nati o n of u ne x pecte d, si g nifi ca nt, or u nacce pta ble ris k t o patie nts  
•  De m o nstrati o n of efficac y t hat w o ul d warra nt st o p pi n g  
•  I ns ufficie nt c o m plia n ce t o pr ot oc ol re q uire m e nts 
•  Data t hat are n ot s uffici e ntl y c o m plete a n d/ or e val ua ble  
•  Deter mi nati o n t hat t he pri mar y e n d p oi nt has bee n met  
•  Deter mi nati o n of f utilit y  
T he st u d y ma y res u me o nce c o n cer ns a b o ut safet y, pr ot o c ol c o m plia nce, a n d data q ualit y are 
a d dresse d, a n d satisf y t he s p o ns or, I R B/I E C  a n d/ or partici pati n g re g ulat or y a ut h orities.  
C CI


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5.9 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Assessment Methods  
5.9.1 
Pharmacokinetic Assay  
Plasma samples will be analyzed to determine concentrations of HMPL-689 using a validated, 
specific, and sensitive liquid chromatography-tandem mass spectrometry method.  If required, 
some plasma samples may be analyzed to document the presence of circulating metabolites using 
a qualified research method. 
5.9.2 
Collection Schedule for Pharmacokinetic Samples  
NOTE: Upon implementation of Protocol Amendment 5, PK samples for measurement of plasma 
concentrations of HMPL-689 will not be collected on C3D1 and beyond, and all pharmacodynamic 
biomarker and pharmacogenetic sample collections will be halted in the dose expansion stage.  
Blood samples will be collected at noted time points in the protocol.  During the dose escalation 
stage, the time points for PK blood collection from patients are shown in Appendix 2.  During 
the dose expansion stage, the time points for PK blood collection are shown in Appendix 3.   
Time points for pharmacodynamic biomarker collection and pharmacogenetic (PGx) collection 
are shown in Appendix 4.  In this table, the pre-dose PGx blood sample is the only collection for 
patients in dose escalation and is optional.  In the dose expansion, PGx blood samples should be 
collected in all patients to the extent possible.  If, for any reason, the sample is not drawn prior to 
dosing, it may be taken at any follow-up visit.  
After each venous blood sampling, the exact time and dates of blood sampling for PK, 
pharmacodynamic, and PGx analysis should be recorded on the patient’s source documentation 
and the CRF.  
5.9.3 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Sample Handling 
and Shipment  
Sample handling instructions will be detailed in the Laboratory Manual. 


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6 
ASSESSMENT OF SAFETY  
6.1 
Safety Plan  
HMPL-689 has not been approved for marketing, and clinical development is ongoing.  The safety 
plan for patients in this study is based on clinical experience with HMPL-689 in completed and 
ongoing studies.  Please refer to the HMPL-689 IB for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  Patients will 
undergo safety monitoring during the study, including assessment of the nature, frequency, and 
severity of AEs.  In addition, guidelines for managing AEs, including criteria for dosage 
modification and treatment interruption or discontinuation, are provided in Section 5.3. 
6.2 
Safety Parameters and Definitions  
Safety assessments will consist of monitoring and recording protocol-defined 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 IP. 
Sponsor or 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  
According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical 
occurrence in a clinical investigation patient administered a pharmaceutical product, regardless of 
causal attribution.  An AE can therefore 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 as described in Section 6.3.1.8.  
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline; 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, Xray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from IP; 
• Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies). 
• Clinical features or clinical sequelae of a suspected overdose of either study drug or a 
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6.2.2 
Serious Adverse Events  
An SAE is any AE that is any of the following: 
• Fatal (i.e., the AE actually causes or leads to death); 
• Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death); 
• Requires or prolongs inpatient hospitalization; 
• Results in persistent or significant disability/incapacity (i.e., 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 IP; 
• Considered a significant medical event by the investigator (e.g., 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 non-serious 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. 
6.2.3 
Protocol-Defined Adverse Events of Special Interest Expedited Adverse Events  
• Non-serious AEs of special interest are required to be reported by the investigator to the 
sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 
6.3.1 for reporting instructions).  
• Adverse events of special interest for this study include: Cases of potential drug-induced 
liver injury (DILI) that include an elevated ALT or AST in combination with either an 
elevated bilirubin or clinical jaundice, as defined by Hy’s law (see Section 6.3.1.5 and 
Appendix 14), and non-serious cases of interstitial lung disease/pneumonitis (see 
Section 6.8, Table 6). 
• Please refer to the latest IB for additional information. 
6.2.4 
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 CRF and reported to sponsor or sponsor’s designee in accordance with protocol 
instructions. 


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6.2.5 
Adverse Event Reporting Period  
After informed consent has been obtained but prior to initiation of study medications, only SAEs 
will be collected. 
After initiation of study medications, all AEs and SAEs regardless of causality will be collected 
until 30 days after the last administration of study treatment or start of a new treatment of anti-
neoplasm therapy, whichever is earlier.  After this period, investigators should report only SAEs 
that are related to prior study treatment of HMPL-689 (see Section 6.7). 
6.2.6 
Eliciting Adverse Events  
A consistent methodology of non-directive questioning for eliciting AEs at all patient evaluation 
time points should be adopted.  Examples of non-directive questions include: 
“How do you feel since your last clinic visit?” 
“Have you had any new or changed health problems since last visit?”  
6.2.7 
Assessment of Severity and Causality of Adverse Events  
For guidance on the diagnosis and management of important potential class toxicities noted on 
HMPL-689 trials and/or those associated with other PI3Kδ inhibitors, please refer to Section 6.8. 
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 applicable CRF, the investigator will make an assessment 
of seriousness (see Section 6.2.2) per seriousness criteria, severity, and causality.  
AE should be graded in accordance with NCI CTCAE v5.0.  For AE terms not listed in CTCAE 
v5.0, alternative guideline of 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 IP.  To ensure consistency of causality assessments, investigators 
should apply the general guidelines provided in Table 5. 


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Table 4 
Adverse Event Grading (Severity) Scale  
Grade 
Severity 
Alternative Definitionsa 
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 
None 
ADL = activities of daily living, AE = adverse event, CTCAE = Common Terminology Criteria for Adverse 
Events, NCI = National Cancer Institute. 
The NCI CTCAE v5.0 can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Regardless of severity, some events may also meet regulatory seriousness criteria.  Refer to Section 6.2.2. 
a 
The alternative definitions will be used for events of Grades 1, 2, 3, and 4 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 refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Table 5 
Guidance on Causality to the IP  
Causality 
Guidance 
Related 
An adverse event will be considered as “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation.  A 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the adverse event.  Factors that point toward this assessment include, but are not limited 
to, a positive re-challenge, 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 
adverse event, or a lack of an alternative explanation for the adverse event. 
Not Related 
An adverse event will be considered as “not related” to the use of the IP 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 adverse event, or the presence of a more 
likely alternative explanation for the adverse event. 
IP=investigational product. 
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 an investigator’s opinion of “not related to IP” is given for a SAE, another cause of event must 
be provided by the investigator for the event.  If an investigator’s opinion of “related to IP” is given 
for a SAE, the rationale of causality should be provided. 


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6.3 
Procedures for Recording Adverse Events  
6.3.1 
Recording Adverse Events on the CRF  
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the CRF.  Avoid using colloquialisms and abbreviations. 
All AEs (including SAEs) would be recorded on the AE CRF, and the check box for “Serious” 
would be ticked for entries that fit the criteria of serious.  The investigator would also complete an 
SAE report and submit it to sponsor or sponsor’s designee within 24 hours of awareness of the 
event.  
Only one AE term should be recorded in the event field on the CRF. 
6.3.1.1 
Diagnosis versus Signs and Symptoms  
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., 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. 
6.3.1.2 
Adverse Events Occurring Secondary to Other Events  
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause.  For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the 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. 
6.3.1.3 
Persistent or Recurrent Adverse Events  
A persistent AE is one that extends continuously, without resolution between patient evaluation 
time points.  Such events should only be recorded once in the CRF.  The initial severity (intensity 
or grade) of the event will be recorded at the time the event is first reported.  If a persistent adverse 
event becomes more or less severe, it should also be recorded on the Adverse Event CRF as a new 
entry. 
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  Each recurrence of an adverse event should be recorded as a separate event 
on an AE/SAE CRF. 


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6.3.1.4 
Abnormal Laboratory Values  
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require IP 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 (e.g., alkaline 
phosphatase and bilirubin 5 ULN associated with cholecystitis), only the diagnosis (e.g., 
cholecystitis) needs to be recorded on the AE/SAE CRF. 
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.  
6.3.1.5 
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).  Briefly, Hy’s Law 
cases have the following three components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo; 
2. Among trial patients showing such AT elevations, often with ATs >3 × ULN, one or more 
patients also show elevation of serum TBL to >2 × ULN, without initial findings of 
cholestasis (elevated serum ALP); 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
Therefore, investigators must report as an AE in the occurrence of either of the following: 
• Treatment-emergent ALT or AST ≥3  ULN in combination with total bilirubin ≥2  
ULN; or  
• 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 Adverse Event CRF (see Section 6.3.1.4) and reported to the 
sponsor’s designee as a non-serious AE of special interest (see Section 6.2.3). 
The guidance on diagnosis and management of hepatic AEs (including Hy’s law) can be found in 
Section 6.8, Table 8. 


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6.3.1.6 
Overdose  
In the event of accidental or intentional overdose, the investigator should inform sponsor study 
representatives immediately, or no later than 24 hours following the overdose. 
• An overdose with associated AEs/SAEs should be recorded in CRF specific module for 
AE/SAE diagnosis/symptoms. 
• An overdose with no associated clinical features should be reported only on study CRF. 
• Overdose with no associated clinical features will not be reported as an AE/SAE unless it 
is an intentional overdose with possible suicidal/self-harming intent.  Such overdoses 
should be reported regardless of sequelae. 
6.3.1.7 
Deaths  
All deaths that occur during the protocol-specified AE reporting period (see Section 6.2.5) must 
have the underlying cause reported to the Sponsor as an SAE, with death listed as the outcome.  
Deaths that occur during the protocol-specified AE reporting period due to the progression of 
disease must also be reported to the Sponsor as an SAE.  All other on study deaths, regardless of 
relationship to IP, must be recorded on the Adverse Event CRF and immediately reported to the 
sponsor (see Section 6.4.1). 
Death should be considered an outcome and not a distinct event.  The primary event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical concept 
on the Adverse Event CRF.  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 
preexisting heart disease (e.g., within 1 hour of the onset of acute symptoms).  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, or if the death was unwitnessed, 
“unexplained death”, “death of unknown cause”, or “unwitnessed death” should be recorded on 
the Adverse Event CRF.  If the cause of death later becomes available (e.g., after autopsy), 
“unexplained death” should be replaced by the established cause of death.  
6.3.1.8 
Preexisting Medical Conditions  
A preexisting medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the CRF. 
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 preexisting condition has changed 
by including applicable descriptors (e.g., “more frequent headaches”). 
6.3.1.9 
Worsening of Lymphoma  
Worsening and/or progression of the lymphoma should not be recorded as an AE or SAE, unless 
the progression directly leads to the patient’s death, then the disease progression should be reported 
as a CTCAE Grade 5 SAE.  All worsening and/or progression of the lymphoma data will be 
captured as efficacy assessment data. 
Hospitalization due solely to the progression of underlying lymphoma should not be reported as a 
serious adverse event.  Clinical symptoms of progression may be reported as AEs if the symptom 


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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.  Alternatively, 
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. 
6.3.1.10 
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 preexisting 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 a serious adverse event (Section 6.3.1.9). 
The following hospitalization scenarios are not considered to be SAEs, but should be reported as 
AEs instead: 
• Hospitalization that was necessary because of patient requirement for outpatient care 
outside of normal outpatient clinic operating hours 
6.3.1.11 
Pregnancy  
If a female patient becomes pregnant while receiving the IP or within 30 days after the last dose 
of IP, a Pregnancy Report CRF should be reported within 24 hours of learning of the pregnancy to 
sponsor’s Drug Safety Department or sponsor’s designee.  Pregnancy should not be recorded on 
the Adverse Event CRF. 
Male patients must also be instructed to inform the investigator immediately if their partner 
becomes pregnant during the study or within 30 days after the last dose of IP.  If such an event 
occurs, it should be reported as described above. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
sponsor considers these medically significant), recorded on an Adverse Event CRF, and 
expeditiously reported to sponsor or sponsor’s designee (see Section 6.4.1). 


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Any congenital anomaly/birth defect in a neonate/infant born to a mother exposed to IP should be 
classified as an SAE, recorded on the Adverse Event CRF, and expeditiously reported to the 
sponsor (see Section 6.4.1). 
After a patient discontinues study treatment due to pregnancy, abortions, congenital 
anomalies/birth defects, and pregnancy outcomes should still be reported expeditiously to the 
Sponsor or Sponsor’s designee. 
6.4 
Expedited Reporting Requirements for Serious Adverse Events  
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 IP: 
• Serious adverse events (see Section 6.4.2 for further details) 
• Non-serious adverse events of special interest (see Section 6.4.2 for further details) 
• Overdose 
• Pregnancies 
6.4.1 
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 sponsor or sponsor’s designee within 24 hours of learning of the events.  
For initial SAE 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 sponsor or sponsor’s designee as soon as it becomes available 
and/or upon request within 24 hours of investigator’s awareness. 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/IEC. 
6.4.2 
Regulatory reporting requirements for Serious Adverse Events  
Prompt notification of SAEs by the investigator to sponsor is essential so that legal obligations and 
ethical responsibilities towards the safety of patients are met.  
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.  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. 


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An investigator who receives an investigator safety report describing an SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from sponsor will file it with the IB and will 
notify the IRB/IEC, if appropriate according to local requirements. 
6.5 
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 awareness of the event.  Investigators 
will also participate in regular teleconferences with the sponsor’s medical monitor, during which 
they will report any DLTs observed during the DLT observation period for each patient in the dose 
escalation stage of the study. 
6.6 
Type and Duration of Follow-Up of Patients after Adverse Events  
The investigator should follow all unresolved AEs (including SAEs and DLTs) until the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new antineoplastic 
treatment is initiated, the patient is lost to follow up, the patient withdraws consent, or when 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 Adverse Event 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 its outcome.  
For some SAEs, the sponsor or sponsor’s designee may follow up by telephone, fax, email, and/or 
a monitoring visit to obtain additional case details deemed necessary to evaluate appropriately the 
SAE report (e.g., 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 study 
treatment. 
The investigator should notify sponsor or sponsor’s designee of any death or other SAE occurring 
at any time after a patient has discontinued or terminated study participation if related to prior 
study treatment.  The investigator is not obligated to actively monitor patients for AEs once the 
trial has ended.  Sponsor or sponsor’s designee should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a patient that participated in this study.  


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Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
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6.8 
HMPL-689 Dose Modification and Toxicity Management Algorithm for Clinical 
Trials  
This section provides guidance to the investigators for the differential diagnosis and management 
of the important potential class toxicities noted on HMPL-689 trials and/or those associated with 
other PI3Kδ inhibitors. This constitutes general recommendations to investigators involved in 
HMPL-689 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 Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, and Table 12 for 
the dose modification and toxicity management recommendations for pulmonary AEs (including 
pneumonia/pneumonitis), diarrhea/colitis, hepatic AEs, infection, neutropenia, thrombocytopenia, 
and rash and cutaneous skin reactions, respectively.  
As a general principle, the recommendations are as follows: 
• Differential diagnosis for any adverse event should be diligently evaluated according to 
standard medical practices. 
• Recommendations provided here should be evaluated in conjunction with the local 
clinical standard of care, and overall management plan should 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. 


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
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CONFIDENTIAL 
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Table 6 
Dose Modification/Toxicity Management Recommendations for Pulmonary Adverse Events Including 
Pneumonia/Pneumonitis  
Adverse 
Reaction 
CTCAE V5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
Grade 1 
 
(Asymptomatic, 
clinical or 
radiological 
observations 
only) 
• Educate patient to report any worsening immediately 
• Monitor for symptoms including SpO2 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 
non-infectious pneumonitis 
• If persistent stable radiologic changes and 
asymptomatic on 1 to 2 scans, revert to normal 
restaging scans per protocol 
• In case of 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 immediately 
• Monitor for worsening symptoms (e.g., dyspnea/exertional 
dyspnea) 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 bacterial, viral, and 
opportunistic infections, including PJP and CMV-use of 
cultures) 
o Chest X-ray, SpO2, and HRCT 
o PFT and BAL, as necessary 
o ILD markers (KL-6 and SP-D), if available 
o COVID-19 testing (RT-PCR), if clinically indicated 
• If determined as infectious, prompt antibiotic, antifungal, or 
appropriate treatment as per standard guidelines 
Withhold 
study drug 
• Continue close follow-up and re-imaging and 
increase steroid dose, as needed 
• If considered infectious etiology (clearly not 
immune related): 
o If resolved in ≤7 days, resume study drug 
o If resolved in >7 to 28 days, resume study 
drug at the same or a reduced dose at the 
discretion of the investigator 
o If not resolved within 28 days or worsens, 
consider permanently discontinuing study 
drug 
• If considered non-infectious etiology with need 
for systemic steroid treatment, permanently 
discontinue study drug 
o After sustained clinical improvement is 
observed, gradually taper steroids (e.g., 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 


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
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Adverse 
Reaction 
CTCAE V5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
• If determined as non-infectious (i.e., with immune 
component), promptly consider systemic steroid treatment 
o Administer methylprednisolone IV 1 to 2 mg/kg/day or 
equivalent oral corticosteroid dose 
corticosteroids (e.g., prednisone) during the 
steroid taper. 
• If etiology unclear and resolves without a need 
for systemic steroid treatment, then study drug 
treatment may be restarted at a reduced dose 
based on investigator’s clinical judgment 
• Monitor closely on restarting treatment; if 
symptoms recur (at either same or reduced 
dose), then permanently discontinue the study 
drug 


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
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Adverse 
Reaction 
CTCAE V5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
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 
non-infectious or for suspected immune-related 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 and 
increase steroid dose, as needed 
• If considered infectious etiology: 
o If resolved to baseline within 28 days, 
resume study drug at a reduced dose 
o If not resolved within 28 days, permanently 
discontinue study drug. 
o If worsens or recurs on restarting treatment, 
permanently discontinue study drug 
• If considered immune-related or non-infectious 
etiology: 
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 (e.g., 
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 (e.g., 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; PFT = pulmonary function test; PJP = Pneumocystis jiroveci fungus; RT-PCR = real-time polymerase chain reaction; SP-D = serum surfactant 
protein D; SpO2 = oxygen saturation. 


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 79 
 
Table 7 
Dose Modification/Toxicity Management Recommendations for Diarrhea/Colitis  
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 non-infectious (i.e., immune mediated), 
promptly start (including gradual tapering) enteric acting 
steroids (e.g., 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 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 non-infectious etiology with 
need for systemic steroid treatment, then 
permanently discontinue study drug  
o After sustained clinical improvement is 
observed, gradually taper steroids (e.g., by 5 
to 10 mg/week over 4 to 6 weeks) per 
institutional standards 


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 80 
 
Adverse 
Reaction 
CTCAE V5.0 
Grade/Severity 
Recommended Management 
Recommended 
Dosing 
Modification 
Recommended Follow-up 
o Patients can be switched to an 
equivalent/appropriate dose of oral 
corticosteroids (e.g., prednisone) during the 
steroid taper 
• If etiology unclear and resolves without a 
need for systemic steroid treatment, then 
study drug treatment may be restarted at a 
reduced dose based on investigator’s clinical 
judgment 
• 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 
Permanently 
discontinue 
study drug 
 
• Continue close follow-up until resolution 
• If improves to baseline, gradually taper steroids 
(e.g., by 5 to 10 mg/week over 4 to 6 weeks) per 
institutional standards 
• If refractory to steroids, consider other 
immunosuppression (as clinically indicated)  
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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Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
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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 infection [use RT-PCR for diagnosis]) 
• Close monitoring for worsening of any clinical 
signs/symptoms (e.g., 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 
• If likely immune mediated, seek hepatic consult 
and consider use of steroids as clinically 
indicated 
• In case of worsening, treat as Grade 3 or 4 
Grade 3 
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 (i.e., 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 or worsens or recurs after re-
initiating therapy, permanently discontinue 
study drug 
• If likely immune mediated, seek hepatic consult 
and consider use of steroids with gradual taper 
Grade ≥4 
(>20 times ULN 
or from baseline, 
if baseline is 
abnormal) 
Evaluate differential diagnosis and causality (including 
pre-existing liver disease and infectious etiology) 
Consider hepatic consult and treat accordingly per standard 
treatment guidelines 
If the AST/ALT and bilirubin levels meet the definition of Hy's 
law, permanently discontinue the study drug 
Permanently 
discontinue 
study drug 
• Continue close follow-up until resolution 
• If likely immune mediated, seek hepatic consult 
and consider use of steroids with gradual taper 
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.  


Clinical Study Protocol 2018-689-00US1 
HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 82 
 
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 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 RNA >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 
Pneumocytis 
jiroveci infection 
• Consider pulmonary consult and bronchoscopy. Start empiric 
treatment (also refer to management of pulmonary toxicities 
[Table 6]) 
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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Amendment 5 
 
 
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CONFIDENTIAL 
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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 × 10^9/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 × 10^9/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 × 10^9/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 × 10^9/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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HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
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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 × 10^9/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 × 10^9/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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HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
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Table 12 
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 and sun exposure 
• 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 doesn't 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, 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.


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 8 6  
 
7  
S T A TI S TI C A L A N A L Y SI S   
7. 1  
Deter mi n ati o n o f S a m ple Size  
.  I n ge n eral, t he ma xi m u m sa m ple 
siz e i n t he d ose-escalati o n sta ge will be deter mi ne d b y s p o ns or a n d i n v esti gat or b ase d o n t he 
acc u m ulate d s afet y dat a a n d t he m T PI-2 desi g n  (Ji 2 0 1 3).  
 
.  
Patie nts w h o wit h dra w fr o m t he st u d y pri or t o c o m pl eti n g t he D L T ass ess me nt wi n d o w f or reas o ns 
ot her t ha n D L T or recei ve less t ha n 7 5 % of assi g ne d st u d y me dicati o n d uri n g D L T assess me nt 
wi n d o w will be re place d .  T his ma y res ult i n t he act ual e nr oll me nt e x cee di n g  t he pla n ne d 
e nr oll me nt.  
7. 1. 1  
St a ge 1 : D ose Esc al ati o n St a ge   
T he ma xi m u m sa m ple size at m T PI 2  f or t his sta ge will be deter mi ne d b y s p o ns or a n d i n vesti gat or 
base d o n t he acc u m ulate d safet y data a n d m T PI -2 desi g n  (Ji 2 0 1 3).  T he  ma xi m u m sa m ple siz e 
u n der t he m T PI -2 met h o d is k ×  ( d +  1), w here k de n otes t he c o h ort siz e  a n d d de n otes t he n u m ber 
of d oses .  T he mi ni m u m  c o h ort siz e i n t his st u d y is 3 patie nts per c o h ort .  T o e ns ure t hat t he hi g hest 
d ose (if nee de d) is reac h e d per t he m T PI -2 desi g n a n d t he a v aila bilit y of a d diti o nal c o h orts , it is 
esti mate d t hat a p pr o xi matel y 
 p atie nts will be nee d e d i n t his st u d y.  
7. 1. 2  
St a ge 2 : D ose E x p a nsi o n S t a ge  
C CI
C CI
C CI
C CI
C CI


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 8 7  
 
C CI


Cli nic al St u d y Pr ot oc ol 2 0 1 8 -6 8 9 -0 0 U S 1  
H M P L -6 8 9  
A me n d me nt 5  
 
H U T C H M E D Li mite d  
 
C O N FI D E N TI A L  
P a ge 8 8  
 
7. 2  
A n al ysis  P o p ul ati o ns   
T he f oll o wi n g a nal ysis p o p ulat i o ns are defi n e d f or t he st u d y: 
F ull A nal ysis Set ( F A S ): 
T he F A S is defi ne d as all patie nts w h o recei v e at l east o ne d os e of H M P L -6 8 9 .  T he F A S  will be 
use d f or a n al ysis  of s afet y dat a a n d efficac y e n d p oi nt P F S .   
D L T E val u a ble A nal ysis Set: All patie nts e nr olle d i n t he d ose escalati o n p hase of t he st u d y w h o 
are e val u a ble f or D L T assess me nt. A s u bject is D L T e v al ua ble if he/s he meets t he f oll o wi n g 
criteria:  
− has recei ve d at least 7 5 % of t he assi g ne d d ose of st u d y me dicati o n d uri n g t he D L T 
assess me nt wi n d o w  
O R  
C CI


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− has not completed the DLT assessment period due to a DLT 
Efficacy Analysis Set (EAS):  
All patients who receive at least one dose of HMPL-689 and have a baseline tumor assessment 
and at least one post-baseline assessment will be considered evaluable for anti-tumor efficacy 
endpoints such as ORR, clinical benefit rate (CBR), TTR, and DoR. 
Pharmacokinetics Analysis Set (PKAS): 
The PKAS is defined as all patients who received at least one dose of HMPL-689 and have at least 
one PK sample obtained and analyzed. 
7.3 
Statistical Methods  
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.   
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, which will be finalized prior to database lock. 
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 
Disposition of Patients Enrolled in the Study  
The patient disposition in the dose escalation and dose expansion stages will be summarized for 
each dose level.  
Study drug administration data will be listed by dose level.  The total duration of exposure, dose 
intensity, and relative dose intensity of HMPL-689 will be summarized by descriptive statistics. 
7.3.2 
Safety Analysis  
Safety parameters, including study drug exposure, DLTs, recorded TEAEs, clinical laboratory 
parameters, vital signs, 12-lead ECG parameters and physical examination findings, will be 
summarized by dose level across different stages for the FAS. 
7.3.2.1 
Dose Limiting Toxicities  
All DLTs will be listed. 
7.3.2.2 
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 v.5.0.  Analysis of AEs will be 
performed for TEAEs, which are defined as AEs that onset or worsen in severity on or after the 
first dose of HMPL-689.  All TEAEs will be summarized in frequency and percentage of patients 
for each dose level. 


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The same analysis will be performed for SAEs, study drug–related TEAEs assessed by the 
investigators, TEAEs leading to dose adjustment, or treatment discontinuation, and AEs of special 
interest.   
7.3.2.3 
Clinical Laboratory Test Values  
Descriptive statistics for each clinical laboratory test will be presented for each dose and scheduled 
visit.  Laboratory test values from the hematology and chemistry panels, which are gradable in 
NCI CTCAE, will be summarized by the shift of NCI CTCAE grade from baseline to the worst 
grade on study treatment period. 
Selected laboratory tests will be plotted over time for each patient.  All laboratory test results will 
be listed. 
7.3.2.4 
Vital Signs  
Vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, and body temperature) 
will be summarized with descriptive statistics by dose level and visit.  
Selected vital signs tests will be plotted over time for each patient.  All vital sign data will be listed. 
7.3.2.5 
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 visit.  Refer to Section 7.3.5 for further details. 
7.3.2.6 
Physical Examination  
All physical examination findings will be listed. 
7.3.3 
Pharmacokinetic Analysis  
Pharmacokinetic parameters will be analyzed with the PKAS.  A non-compartmental model 
analysis will be performed for plasma concentration data from the escalation stage using Phoenix 
WinNonlin.  Individual and mean plasma concentration of HMPL-689 versus time data will be 
tabulated and presented.  The individual and mean PK parameters determined following analysis 
of the concentration of HMPL-689 versus time data, will include, but are not limited to AUC, Cmax, 
Tmax, Cmin, CL/F and AR.  N, mean, standard deviation, minimum, median, maximum, geometric 
mean, and coefficient of variation [%CV] will be presented.  The actual times of plasma sample 
collection will be used in the determination of the PK parameters.  Individual and mean HMPL-
689 concentrations will be plotted by dose level.  Details of the PK analysis, including data 
handling rules and software used to perform the PK analysis, will be provided in the PK analysis 
plan (PKAP). 
Plasma concentration data of HMPL-689 from the expansion stage will be tabulated and presented 
as described in the PKAP. 


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7.3.4 
Efficacy Analysis  
Efficacy endpoints will be summarized by dose level for each type of malignancy.  
The best percent change from baseline (%) in the target lesion, ORR, CBR, and the corresponding 
95% CI based on Clopper-Pearson method will be presented by dose level.  
The PFS, TTR, and DoR will be summarized with Kaplan-Meier (KM) method if data permit, and 
the corresponding KM curve will be plotted. 
ORR, CBR, PFS, TTR, and DoR data will be listed for all patients. 
Tumor assessment in different types of malignancies will be evaluated according to specified 
guidelines/criteria: 
• CLL: the modified International Workshop on CLL guideline (Hallek 2008, Cheson 
2012), see Appendix 5. 
• LPL/WM: consensus of international workshops on WM (IWWM-7 consensus) 
(Dimopoulos 2014), see Appendix 6. 
• Other lymphomas: Lugano Response Criteria for Hodgkin and NHL (Cheson 2014), see 
Appendix 7. 
In the evaluation of the tumor response endpoints (ORR, TTR, CBR, DoR, and PFS), the 
investigator-assessed data will be utilized for tumor assessment.  
7.3.5 
Pharmacodynamics (Electrocardiogram) Analysis  
Patients who 1) receive at least 1 dose of study drug and 2) have baseline and at least 1 postdose 
ECG measurement will be evaluable for pharmacodynamic (ECG) evaluation.  Patients who had 
reduced dosage, prolonged dose interruption of >2 days in cycle 1, any dose interruption within 3 
days before Cycle 1 Day 15, or were discontinued from the study prior to the completion of ECG 
data collection (Cycle 1 Day 15) will be excluded.  For each of the ECG parameters, the average 
values from the 3 readings of a triplicate ECG set will be used in the analysis. 
For all ECG parameters, the baseline will be defined as the mean values of the triplicate ECG 
measurements taken at predose on Cycle 1 Day 1. 
7.3.5.1 
Corrected QT Intervals  
The terminology QTc is used in this section as a general notation for QTc using any of the specified 
methods. 
The QT interval data will be corrected for heart rate using 2 correction methods (QTcF and 
corrected QT interval by Bazett – QTcB).  For each QTc correction method, the relationship 
between QTc and RR at baseline will be evaluated graphically by plotting the logarithm of baseline 
QTc values against the logarithm of corresponding RR intervals.  QTcF will be used as the primary 
correction method for statistical analysis.  If the correlation between QTc and RR intervals remains 
significant using the Fridericia correction method, an alternative correction method may be 
considered for statistical analysis in addition to QTcF. 
For the statistical analysis based on the primary correction method (QTcF), the mean changes from 
baseline (ΔQTc) at each time point will be summarized (mean, standard deviation, median and 


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range, and 2-sided 90% CI).  Mean values for the difference and 2 sided 90% CI for mean 
difference will be calculated at each time point. 
The primary analysis will focus on the maximum mean change from baseline in QTc (ΔQTc) on 
Cycle 1 Day 15, which will be estimated by the mean QTc change at around tmax, the time when 
the Cmax is reached (i.e., steady state).  The same analysis will be performed for ΔQT data using 
other correction methods if data warrant.  The mean change from baseline in QTc (±standard 
deviation) over time will be plotted. 
In addition, QTc will be categorized based on International Council for Harmonisation (ICH) E14 
guidelines.  Tables will present the number and percentage of patients meeting or exceeding the 
following categories: 
• QTc prolongation: 
− Absolute values >450 to ≤480 msec 
− Absolute values >480 to ≤500 msec 
− Absolute values >500 msec 
• QTc change from baseline: 
− Increase from baseline >30 to ≤60 msec 
− Increase from baseline >60 msec 
7.3.5.2 
Heart Rate, QRS, and PR Intervals  
For each treatment and time point of measurement, heart rate, QRS interval, and PR interval, as 
well as the change from baseline in heart rate, QRS, and PR (Δheart rate, ΔQRS, ΔPR), will be 
summarized using descriptive statistics (mean, standard deviation, median, range, and 90% CI).  
The number and percentage of patients with heart rate >100 bpm will be tabulated for each time 
point.  The number and percentage of patients with QRS >110 msec will be tabulated for each time 
point.  The number and percentage of patients with PR >200 msec will be tabulated for each time 
point. 
7.4 
Interim Analysis  
There is no interim analysis planned for this study. 


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8 
ETHICS  
8.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC)  
This protocol, the Informed Consent Forms, any information to be given to the patient and 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 
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 sponsor’s 
designee, investigators are required to report to their respective IRB/IEC promptly 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, International Conference on 
Harmonization (ICH) guidelines, 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 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 informed consent form 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 Informed Consent Form 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 Consent Forms, the case history for each patient shall document the 
informed consent process and that written informed consent was obtained for the updated/revised 
Consent Form for continued participation in the study.  Signed and dated Informed Consent Forms 
must remain in each patient’s study file and must be available for verification by study monitors 
at any time. 


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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 Protection 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 is 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 Informed Consent Form (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 the China FDA and other 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. 


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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 (i.e., 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.  These 
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, Xrays, 
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 (i.e., 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 (e.g., 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  
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP require that records 
and documents pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 2 years after the last marketing application approval in 
an ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of the IP. All state and local laws for retention of records also apply.  
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 designee of HUTCHMED Limited to check study 
data, patients’ medical records, and CRFs.  The Principal Investigator will permit study 
monitors/sponsor’s representatives and collaborators 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 study 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 study monitor must verify that the patient received the IP 
assigned by the dose level.  The study monitor should have access to laboratory test reports and 
other patient records needed to verify the entries on the CRF.  The investigator (or designee) agrees 
to cooperate with the study 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 
CRO standard operation procedures.  Sites will be responsible for data entry into the electronic 
data capture (EDC) system.  Accurate and reliable data collection will be assured by verification 
and crosscheck of the CRFs against the investigator’s records by the study monitor.  In the event 
of discrepant data, the CRO will request data clarification from the sites.  Sponsor and CRO will 
be responsible for the data management of this study, including quality checking of the data.  
11.2 
Electronic Case Report Forms  
Electronic data capture (EDC) will be used for this study, meaning that all CRF 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.  
The study monitor will review the CRFs and evaluate them for completeness and consistency.  The 
CRF 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.  All corrections to the data fields will be audit trailed, meaning that the reason 
for change, the name of the person who performed the change, together with the time and date will 
be logged.  If additional corrections or clarifications are needed, the responsible study monitor or 
data manager will raise a query in EDC.  The appropriate investigational staff will answer queries.  
This will also be audit trailed by the EDC. 
The investigator is responsible for maintaining source documents.  These will be made available 
for audit or inspection.  The investigator must submit a completed CRF for each patient who has 
been screened.  All supportive documentation submitted with the CRF, 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. 
Electronic case report form records will be automatically appended with the identification of the 
creator, by means of their unique User ID.  The Investigator must ensure all data entries in the 
CRF are accurate and correct and will be required to sign off electronically on the clinical data.  
This will be facilitated by means of the investigator’s unique user ID and password.  If an entry on 
a CRF 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 (e.g., on a compact disc).  Data must be kept with the study 
records. 


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11.3 
Coding  
Adverse events, medical history/surgery, concomitant procedure will be coded using MedDRA.  
Concomitant medications, anti-neoplastic medication of post-IP and pre-IP will be coded using 
World Health Organization-Drug Dictionary (WHO-DD).  


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12 
USE OF INFORMATION AND PUBLICATION  
12.1 
Use of Information  
All information regarding HMPL-689 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-689.  
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 “International Committee of Medical Journal 
Editors authorship requirements” 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. 
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 sponsor personnel exceeded 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 a pre-publication manuscript for review at least 30 days prior to the submission of the 
manuscript to the publisher. 
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' confidential 
information in any such paper and agrees 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. 


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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-689 and, therefore, may 
be disclosed as required to other clinical investigators, other pharmaceutical companies, or to 
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 
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HMPL-689 
Amendment 5 
 
 
HUTCHMED Limited 
 
CONFIDENTIAL 
Page 104 
 
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7, 2020. 


Si g nat ure Pa ge f or 
Si g nat ure Pa ge f or 
A p pr o val Tas k
1 2- Dec- 2 0 2 2 1 3: 1 3: 4 3 G M T + 0 0 0 0
P P D
C CI
C CI

SAP_001.pdf: 
H U T C H M E D Li mite d.
Statistical A nal ysis P la n V2. 0
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St atistic al A n al ysis Pl a n
A P h ase 1, O pe n -L a bel St u d y t o E v al u ate t he S afet y, 
T oler a bilit y, P h ar m ac o ki netics, a n d Preli mi n ar y Effi c ac y 
of H M P L -6 8 9 i n P atie nts wit h Rel a pse d or Refr act o r y 
L y m p h o m a
P r ot oc ol N u m ber :
2 0 1 8 -6 8 9 -0 0 U S 1
A me n d me nt n u m ber:
5
I n vesti g ati o n al Pr o d uct 
N a me :
H M P L -6 8 9
P h ase :
P hase I
S p o ns or :
H U T C H M E D Li mite d.
A d dress: B uil di n g 4, La n e 7 2 0 Cail u n R oa d, Pil ot Fr ee 
Tra de Z o n e, C hi na ( S ha n g hai) , 2 0 1 2 0 3
Tel :
Fa x:
S t atistic al a n al ysis pl a n 
versi o n:
Versi o n 2. 0
D ate ：
2 2 J ul y 2 0 2 4
Cli nic al St u d y Re gistr ati o n 
N u m ber ：
N C T 0 3 7 8 6 9 2 6
C o m pli a nce: T he st u d y descri be d i n t his re p ort was perf or me d acc or di n g t o t he pri nci ple of G o o d Cli nical 
Practice ( G C P).
C o nfi de nti alit y St ate me nt
T he  i nf or mati o n  c o ntai ne d  i n  t his  Statistical  A nal ysis  Pla n  ( S A P)  is  c o nfi de ntial  a n d  t he  i nf or mati o n 
c o ntai ne d wit hi n it ma y n ot b e re pr o d uce d or ot her wise disse mi nate d wit h o ut t he a p pr o val of H utc his o n 
Me di P har ma Li mite d, Lt d
or its s u bsi diaries.
P P D
P P D




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M O DI FI C A TI O N H I S T O R Y 
 
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T A B L E O F C O N T E N T S  
1.  
LI S T O F A B B R E VI A TI O N S  ............................................... 9  
2.  
I N T R O D U C TI O N ............................................................... 1 1  
3.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ...................... 1 2  
3. 1.  
Pri m ar y O bjec ti ve .................................................................................................................. 1 2  
D ose Escalati o n P hase ( Sta ge 1) ................................................................................................................1 2  
D ose E x pa nsi o n P hase ( Sta ge 2)  ...............................................................................................................1 2  
3. 2.  
Sec o n d ar y O bjecti ve s ............................................................................................................. 1 2  
4.  
S T U D Y D E SI G N  ................................................................ 1 4  
4. 1.  
Ge ner al Descri pti o n  ............................................................................................................... 1 4  
4. 2.  
Deter mi n ati o n of S a m pl e Siz e  ............................................................................................... 1 5  
Sta ge 1: D ose Escalati o n Sta ge  .................................................................................................................1 5  
Sta ge 2: D ose E x pa nsi o n Sta ge  .................................................................................................................1 5  
4. 3.  
Sc he d ule of E ve nts  ................................................................................................................. 1 5  
4. 4.  
C h a n ges t o A n al ysis fr o m P r ot oc ol....................................................................................... 1 6  
5.  
P L A N N E D A N A L Y S E S  .................................................... 1 6  
6.  
A N A L Y SI S S E T S  ............................................................... 1 6  
6. 1.  
All E nr olle d Set  ...................................................................................................................... 1 6  
6. 2.  
F ull A n al ysis Set ( F A S)  .......................................................................................................... 1 6  
6. 3.  
Effic ac y a n al ysis set ( E A S)  .................................................................................................... 1 6  
6. 4.  
D L T E v al u a ble A n al ysis Set ( D E A S)  ................................................................................... 1 7  
7.  
G E N E R A L C O N S I D E R A TI O N S ...................................... 1 7  
7. 1.  
Refere nce St a rt D ate a n d St u d y D a y  .................................................................................... 1 7  
7. 2.  
B aseli ne a n d C h a n ge fr o m B aseli ne  ..................................................................................... 1 7  
7. 3.  
L ast K n o w n Ali ve D ate  .......................................................................................................... 1 8  
7. 4.  
O n Tre at me nt Peri o d a n d W orst P ost -B aseli ne  .................................................................. 1 8  
7. 5.  
Retests, U nsc he d ule d Visits a n d E arl y Ter mi n ati o n D at a  .................................................. 1 9  
7. 6.  
S u b gr o u ps  ............................................................................................................................... 1 9  


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7. 7.  
Wi n d o wi n g C o n ve nti o ns  ........................................................................................................ 1 9  
7. 8.  
S oft w are Versi o n  .................................................................................................................... 1 9  
7. 9.  
D at a H a n dli n g C o n ve nti o ns  .................................................................................................. 1 9  
7. 1 0.  
Missi n g d at a  ............................................................................................................................ 2 0  
8.  
O U T P U T P R E S E N T A TI O N S  ............................................ 2 3  
9.  
DI S P O SI TI O N A N D WI T H D R A W A L S  ........................... 2 3  
9. 1.  
Dis p ositi o n  .............................................................................................................................. 2 4  
9. 2.  
Pr ot oc ol De vi ati o ns  ................................................................................................................ 2 4  
1 0.  
D E M O G R A P HI C A N D B A S E LI N E 
C H A R A C T E RI S TI C S  ................................................................ 2 4  
1 1.  
O T H E R B A S E LI N E DI S E A S E C H A R A C T E RI S TI C S  . 2 5  
1 2.  
P RI O R O N C O L O G Y T H E R A P Y  ................................... 2 6  
1 3.  
M E DI C A L HI S T O R Y  ...................................................... 2 7  
1 4.  
P I O R A N D C O N C O MI T A N T M E DI C A TI O N S A N D 
P R O C E D U R E S ........................................................................... 2 7  
1 4. 1.  
Pri or a n d C o nc o mit a nt M e dic ati o ns  .................................................................................... 2 7  
1 4. 2.  
Pri or a n d C o nc o mit a nt Pr oce d ures  ...................................................................................... 2 8  
1 4. 3.  
S u bse q ue nt M e dic ati o ns a n d N o n -dr u g Tre at me nts ........................................................... 2 8  
1 5.  
S T U D Y M E DI C A TI O N E X P O S U R E A N D 
C O M P LI A N C E ........................................................................... 2 8  
1 6.  
E F FI C A C Y O U T C O M E S  ................................................ 2 9  
1 6. 1.  
B est O ver all Res p o nse ( B O R)  ............................................................................................... 3 0  
1 6. 2.  
O bjecti ve Res p o nse R ate ( O R R)  ........................................................................................... 3 1  
1 6. 3.  
C o m plete Re s p o nse R ate ( C R r ate) ...................................................................................... 3 1  
1 6. 4.  
Cli nic al B e nefit R ate ( C B R)  .................................................................................................. 3 1  
1 6. 5.  
Pr o gressi ve -Free S ur vi v al ( P F S)  ........................................................................................... 3 1  
1 6. 6.  
D ur ati o n of Res p o nse ( D o R ) ................................................................................................. 3 4  
1 6. 7.  
Ti me t o Res p o ns e ( TT R)  ........................................................................................................ 3 4  


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1 6. 8.  
T u m or B ur de n  ........................................................................................................................ 3 5  
1 7.  
S A F E T Y O U T C O M E S  .................................................... 3 5  
1 7. 1.  
D ose Li miti n g T o xicities ( D L Ts)  ........................................................................................... 3 5  
1 7. 2.  
A d verse E ve nts  ....................................................................................................................... 3 6  
T E A E O ver vie w  ........................................................................................................................................3 7  
T E A E s u m mar y  .........................................................................................................................................3 7  
A E SI s u m mar y  ..........................................................................................................................................3 8  
1 7. 3.  
De at hs  ...................................................................................................................................... 4 0  
1 7. 4.  
L a b or at or y E v al u ati o ns  ......................................................................................................... 4 0  
1 7. 5.  
E C G E v al u ati o ns  .................................................................................................................... 4 0  
1 7. 6.  
Vit al Si g ns  ............................................................................................................................... 4 1  
1 7. 7.  
P h ysic al E x a mi n ati o n  ............................................................................................................ 4 1  
1 7. 8.  
E C O G Perf or m ace St at us  ..................................................................................................... 4 1  
1 7. 9.  
Ec h oc a r di o gr a m/ M U G A  ....................................................................................................... 4 2  
1 8.  
R E F E R E N C E S  ................................................................. 4 3  
 
 


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L I S T O F T A B L E S  
Ta ble 1 O bjecti ves a n d C orres p o n di n g E n d p oi nts  ............................................................ 1 3  
Ta ble 2  
Pr o gressi o n -Free S ur vi val Ce ns ori n g R ule  ...................................................... 3 2  
 
 


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1.  L I S T O F A B B R E VI A TI O N S  
Ter ms a n d 
A b bre vi ati o ns  
Defi niti o n  
A E  
A d verse E v e nt  
A E SI  
A d verse E v e nts of S peci al I nt erest  
C B C L  
C uta ne o us B -cell L y m p h o ma  
C B R  
Cli nical Be nefit Rate  
C F B                                              
C ha n ge  fr o m Baseli ne 
C L L  
C hr o nic L y m p h oc ytic Le u ke mia  
C R  
C o m plete Res p o nse  
C Ri  
C o m plete Res p o nse wit h I n c o m plete Marr o w Rec o ver y  
C R F  
Case Re p ort F or m  
C T M S  
Cli nical Trial Ma na ge me nt S yst e m  
D E A S  
D L T E v al ua ble A nal ysis Set  
D L T  
D ose -li miti n g T o xicit y 
D o R  
D urati o n of Res p o nse  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
F L  
F ollic ular L y m p h o ma  
I C F 
I nf or me d C o nse nt F or m 
L D H  
Lactate D e h y dr o ge nase  
L P L/ W M  
L y m p h o plas mac yti c L y m p h o ma / Wal de nstr ö m’s 
Macr o gl o b uli ne mia  
L V E F  
Left Ve ntric ul ar  Ejecti o n Fracti o n  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M R  
Mi n or Res p o nse  
m T PI -2  
M o difie d T o xicit y Pr o ba bilit y  Int er val Sc h e me -2  
M T D  
Ma xi m u m  T olerate d D ose  
M Z L  
Mar gi nal Z o ne L y m p h o ma  
N CI -C T C  
Nati o nal Ca ncer I nstit ute C o m m o n T o xicit y Criteria  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts  
N H L  
N o n -H o d g ki n  L y m p h o m a  
n P R  
N o d ular Partial Res p o nse  
O R R  
O bjecti ve Res p o nse Rate  
P C F B  
Perce nta ge C ha n ge fr o m Baseli ne  


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P D  
Pr o gressi ve Diseas e  
P F S  
Pr o gressi o n Free S ur vi val  
P K  
P har mac o ki netics  
P R  
Partial Res p o nse  
P R -L  
Partial Res p o nse wit h L y m p h oc yt osis  
P T  
Preferre d Ter m  
P T C L  
Peri p heral T -cell L y m p h o ma  
Q D  
O nce D ail y  
R P 2 D  
Rec o m me n de d P hase 2 D ose  
S A P  
Statistical A nal ysis Pla n  
S O C  
S yste m Or ga n Class  
S D  
Sta ble Disease  
S L L  
S mall L y m p h o c yti c L y m p h o ma  
S R C  
Safet y R e vie w C o m mittee  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T T R  
Ti me t o Res p o nse  
V G P R  
Ver y G o o d Partial Res p o nse  
W H O  
W orl d Healt h Or ga nizati o n  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g  Dicti o nar y  
N ote: Sta n dar d u nits s uc h as m g a n d m L as use d i n t he te xt are n ot i ncl u de d i n t he a b bre vi ati o ns list.  
 
 




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3.  S T U D Y O B J E C TI V E S  A N D E N D P OI N T S  
3. 1.  
P RI M A R Y O B J E C TI V E  
D O S E E S C A L A TI O N P H A S E  ( ST A G E 1)  
T he pri mar y o bje cti ve of t he d ose escalati o n p h ase  ( Sta ge 1) is t o deter mi ne ma xi m u m 
t olerate d d ose ( M T D) a n d/ or rec o m me n de d p h ase 2 d ose ( R P 2 D) of H M P L-6 8 9 i n patie nts 
wit h rela pse d, refract or y, or resista nt l y m p h o ma.  
D O S E E X P A N SI O N P H A S E  ( ST A G E 2)  
T he pri mar y o bje cti ve of t he d ose e x pa nsi o n p has e  ( Sta ge 2) is t o f urt her e val uate s afet y 
a n d t olera bilit y of H M P L -6 8 9 at M T D i n patie nts wit h rela pse d, refract or y, or resista nt 
l y m p h o ma. 
3. 2.  
S E C O N D A R Y O B J E C TI V E S  
T he  sec o n d ar y o bjecti ves are (f or b ot h sta ges):  
•  
T o assess preli mi nar y efficac y of H M P L -6 8 9 i n patie nts wit h rela pse d, refract or y, or 
resista nt l y m p h o ma o verall a n d b y l y m p h o ma s u b-t y pes as assesse d b y i n vesti gat or. 
•  
T o c haracterize P K para meters of H M P L -6 8 9 i n patie nts wit h rela pse d, refract or y, or 
resista nt l y m p h o ma at b ot h d ose escalati o n a n d d ose e x pa nsi o n sta ges. 
•  
T o e val uate t he effect of H M P L -6 8 9 o n car diac re p olarizati o n, as detecte d b y c ha n ges i n 
electr ocar di o gra m ( E C G) Q T c i nter vals . 
 
 




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4.  S T U D Y D E SI G N  
4. 1.  
G E N E R A L D E S C RI P TI O N  
T his is a P hase 1, o pe n -la bel, m ultice nter st u d y of H M P L-6 8 9 a d mi nistere d orall y t o  
patie nts wit h rela pse d, refract or y, or resista nt l y m p h o ma. 
T his st u d y will c o nsist of a d ose escalati o n sta ge ( Sta ge 1) a n d a d ose e x pa nsi o n sta ge 
( Sta ge 2). B ot h Sta ge 1 a n d Sta ge 2 i n cl u de t h e f oll o wi n g peri o ds: scree ni n g peri o d, 
treat me nt peri o d, safet y f oll o w-u p peri o d, a n d e xte n de d pr o gres si o n free s ur vi val ( P F S) 
f oll o w-u p peri o d , if a p pli ca ble. 
T he st u d y d urati o n is esti mate d t o be a p pr o xi matel y  4 8  m o nt hs.  
 
 
 
D ose Esc al ati o n St a ge ( St a ge 1 ) 
D ose es calati o n will be perf or me d acc or di n g t o a m o difie d t o xicit y pr o ba bilit y i nter val 
sc he me-2 ( m T PI -2). H M P L -6 8 9 will be titrate d usi n g a m o difie d Fi b o nacci d esi g n 
all o wi n g d os e i ncre me nts i n s u bse q ue nt d ose le vels. T he d os e es calati o n is pla n ne d at 5 
m g o nce dail y ( Q D), 1 0 m g Q D, 1 5 m g Q D, 2 0 m g Q D, 2 5 m g Q D, 3 0 m g Q D, 3 5 m g Q D, 
4 0 m g Q D, 4 5 m g Q D, a n d 5 0 m g Q D ( d ose le vels 1 – 1 0).  T he nee d f or d ose escalati o n 
be y o n d 5 0 m g Q D, or ot her re gi me ns, s uc h as t wice dail y, w ill be e val uate d a n d deter mi ne d 
b y t he safet y re vie w c o m mittee ( S R C) base d o n all a vaila ble c u m ulati ve cli nical safet y, 
P K, a n d effic ac y d ata . 
 
D ose E x p a nsi o n St a ge ( St a ge 2)  
T he safet y, t olera bilit y, P K, a n d preli mi nar y effi cac y of H M P L -6 8 9 at R P 2 D will b e f urt her 
e val uate d i n patie nts wit h rela pse d/r efract or y/r esista nt n o n -H o d g ki n l y m p h o ma ( N H L).  
 
Patie nts will recei ve oral d oses of H M P L -6 8 9 Q D at t he R P 2 D f or c o nti n u o us 2 8 -da y 
treat me nt c ycles u ntil disease pr o gressi o n, deat h, i nt olera ble t o xicit y, at i n vesti gat or’s 
discreti o n t hat t he patie nt ca n n o l o n ger be n efit fr o m t he st u d y treat me nt, patie nt 
wit h dra wal fr o m t he st u d y, or t he e n d of st u d y, w hic he ver occ urs first.  
C CI
C CI




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5.   P L A N N E D A N A L Y S E S  
T here is n o  f or mal i nteri m a nal ysis pla n ne d f or t his st u d y.  H o we ver, t he accr ue d data fr o m 
a n y c o h ort ma y be a nal yze d f or i nter nal decisi o n -ma ki n g  p ur p ose s.  
A  fi nal a n al ysis is pl a n n e d f or t his st u d y w hi c h will be perf or me d at t he e n d of st u d y 
(defi ne d as 1 8 m o nt hs after t he last patie nt has b ee n e nr olle d i n t he st u d y or all patie nts 
ha ve disc o nti n ue d t he st u d y tr eat me nt, w hic h e ver c o mes earlier  i n t he pr ot o c ol a me n d me nt 
5 ) a n d aft er data b ase l oc k .  
6.  A N A L Y SI S S E T S  
6. 1.  
A L L E N R O L L E D S E T  
T he all e nr olle d set will c o ntai n all patie nt s w h o pr o vi de i nf or me d c o nse nt f or t his st u d y. 
6. 2.  
F U L L A N A L Y SI S S E T (F A S ) 
T he f ull a nal ysis set ( F A S) is defi ne d as all patie nts w h o recei ve at least o ne d ose of H M P L-
6 8 9. T he F A S will be  use d f or a nal ysis of safet y d ata a n d efficac y e n d p oi nt P F S.    
 
Patie nts will be a nal yz e d b y t heir act ual d ose i nitiall y recei ve d. If patie nts ha d t heir  d ose 
re d uce d d uri n g t h e st u d y, all data will be s u m marize d/a nal yze d bas e d o n t he i nitial d ose of 
st u d y tr eat me nt recei ve d. H o we v er, s o me listi n gs s uc h as A E listi n gs ma y gi ve t he act ual 
d ose t o t he patie nt recei v e d at t he ti me of t he A E (e. g. re d uce d d ose , i nterr u pti o n etc.). 
 
6. 3.  
E F FI C A C Y A N A L Y SI S S E T  ( E A S) 
T he  effi cac y a nal ysis set ( E A S) is defi ne d as all p atie nt s w h o recei v e at least o ne d ose of 
H M P L -6 8 9 a n d ha v e a baseli ne t u m or assess me nt  a n d at least o ne e val ua ble p ost -baseli ne 
assess me nt  u nless deat h oc c urs b ef ore t he first p ost -baseli ne ass ess me nt . A nti -t u m or 
effic ac y e n d p oi nts : o bje cti ve res p o nse rate  ( O R R), cli nical be nefit rate ( C B R), ti me t o 
C CI


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res p o nse ( T T R), a n d durati o n of res p o nse  ( D o R) will be e val uate d bas e d o n t his a nal ysis 
set. 
6. 4.  
D L T  E V A L U A B L E A N A L Y SI S S E T ( D E A S) 
T he D L T E val ua ble A n al ysis Set ( D E A S) is defi ne d as all patie nts e nr olle d i n t he d ose 
escalati o n p has e of t he st u d y w h o are e val ua ble f or D L T ass ess me nt. A s u bject is D L T 
e val ua ble if h e/s he meets t he f oll o wi n g criteria:  
− has recei ve d at least 7 5 % of t he assi g n e d d ose of st u d y me di cati o n d uri n g t he 
D L T assess me nt wi n d o w  
O R  
− has n ot c o m plete d t he D L T assess me nt peri o d d u e t o a D L T  
D L T ass ess me nt wi n d o w is defi ne d as t he treat me nt peri o d of 2 8 da ys (i.e., fr o m C ycle 1, 
Da y 1 [t he da y of t he first a d mi nistrati o n of treat me nt] t hr o u g h C ycl e 1, Da y 2 8). 
 
 
7.  G E N E R A L C O N SI D E R A TI O N S  
7. 1.  
R E F E R E N C E S T A R T D A T E A N D S T U D Y D A Y  
St u d y Da y will be cal c ulate d fr o m t he refere n ce start d ate a n d  will b e use d t o s h o w 
start/st o p da y of assess m e nts a n d e ve nts.  
 
Refere n ce start date is defi ne d as t he da y of first n o n -zer o a d mi nistrati o n of treat me nt , a n d 
will a p pear i n e v er y listi n g w h ere a n assess me nt d ate or e v e nt date a p p ears.  
If t he date of t he e v e nt is o n or after t h e refere nce date, t he n:   
•  St u d y Da y = ( date of e v e nt –  refere nce date) + 1. 
If t he date of t he e v e nt is pri or t o t he refere n ce d ate, t he n:  
•  St u d y Da y = ( date of e ve nt –  refere nce date). 
I n t he sit uati o n w here t he e ve nt date is partial or missi n g, t he date will a p pear partial or 
missi n g i n t he listi n gs. St u d y d a y a n d a n y c orres p o n di n g d urati o ns will be prese nte d base d 
o n t he i m p utati o ns s pecifie d i n secti o n  7. 1 0  Missi n g Data , b ut prese nte d as missi n g i n t he 
listi n gs. 
7. 2.  
B A S E LI N E  A N D C H A N G E F R O M B A S E LI N E  
U nless ot her wise s pecifie d, baseli ne is defi ne d as t he last n o n-missi n g meas ure me nt ta ke n 
wit hi n 2 1 da ys pri or t o t he da y of first n o n -zer o  a d mi nistrati o n of treat me nt (i ncl u di n g 


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u nsc he d ule d assess me nts). B o n e marr o w bi o ps y a n d/ or as pirate are d o n e at baseli ne or u p 
t o 3 m o nt hs bef ore of t he C ycle 1 Da y 1. I n t he case w here t he l ast n o n-missi n g 
meas ure me nt is ta ke n o n t he da y of first n o n -zer o a d mi nistrati o n of treat me nt wit h o ut ti me 
p oi nt c ollecte d, t hat me as ure me nt will be c o nsi dere d b aseli ne. F or El ectr ocar di o gra m 
(E C G ) p ara met ers, last assess me nt perf or me d pri or t o or o n first n o n -zer o d ose date wit h 
ti me p oi nt mar ke d as “ pre-d ose” will be c o nsi dere d as baseli ne.  A d verse E ve nts ( A Es) a n d 
me dicati o ns c o m me nci n g o n t he  da y of first n o n -zer o a d mi nistrati o n of treat me nt  will be 
c o nsi dere d  p ost -b aseli ne.  
 
F or q ua ntitati ve meas ure me nts, c ha n ge fr o m baseli ne ( C F B) will be calc ulate d as:  
•  C F B = Assess me nt val ue at eac h visit –  Baseli ne v al ue.  
Perce nta ge C F B ( % C F B) is t o be calc ulate d as:  
•  % C F B = ( Assess m e nt val ue at eac h visit –  Bas eli ne val ue)/ Baseli ne v al ue × 1 0 0.  
 
7. 3.  
L A S T K N O W N A LI V E D A T E  
F or patie nts i n F A S w h o are ali ve at t he a n al ysis c ut -off date, t he last k n o w n ali ve date will 
be deri ve d b ase d o n t he l ast date of t he f oll o wi n g rec or d e d dates: 
•  All assess me nt / sca n / sa m ple c ollecti o n dates (e. g. la b orat or y e v al uati o n, vital si g n 
assess me nt, p h ysic al e x a mi nati o n, E C G, E C O G assess me nt, sca n dates f or t u m or 
e val uati o n, etc.);  
•  Me dicati o n dates, i ncl u di n g st u d y dr u g, c o n c o mita nt me dicati o ns;  
•  Pr oce d ure d ates;  
•  Date of s u bse q ue nt a nti -t u m or t hera p y, i n cl u di n g s u bse q ue nt c h e m ot hera p y a n d 
o nc ol o g y  me di cati o n, s ur ger y/ pr oce d ure a n d ra di ot hera p y;  
•  A d verse e v e nts start a n d e n d dates, date of c ha n ge of C T C A E gra de, S A E starte d 
date.  
F or s u b je cts w h o are c o nfir me d dea d i n t he st u d y, t he l ast k n o w n ali ve d ate will als o be 
deri ve d acc or di n g t o t he a b o ve r ules, b ut t his date will o nl y b e use d as a n alter nati ve date 
t o i m p ute date of deat h if date of deat h is missi n g. 
7. 4.  
O N T R E A T M E N T P E RI O D A N D W
O R S T P O S T -
B A S E LI N E  
F or t he a nal ysis p ur p ose, o n treat me nt peri o d is defi ne d as t he peri o d fr o m t he da y of first 
n o n -zer o d ose of treat me nt t o 3 0 da ys after t he last d ose of treat me nt pl us pr ot oc ol wi n d o w 
of 7 da ys  (7 -da y wi n d o w o nl y a p plies f or b y-visit s u m ma ries) or t he i nitiati o n of ne w 
a nti ne o plastic t hera p y, w hic he ver c o mes earlier.  
 


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T he  se verit y of a d verse e ve nts a n d la b orat or y res ults de pe n ds o n C T C A E gra de. T he w orst 
p ost baseli ne val ue is defi ne d as t he hi g h est C T C A E gra de d uri n g o n treat me nt peri o d.  
T he w orst p ost -baseli ne a b n or malit y is defi ne d i n t he or der of A b n or mal, Cli nical l y 
Si g nifica nt  ( A C S) > A b n or mal, N ot Cli nica lly  Si g nifica nt  ( A N C S) >  N or mal  d uri n g t h e 
o n -treat me nt peri o d. 
F or n u merical s u m mari es, t he w orst p ost -b aseli ne val ue is defi n e d as  t h e hi g hest a n d/or t he 
l o west n u merical val u es.  
7. 5.  
R E T E S T S , U N S C H E D U L E D V I SI T S A N D E A R L Y 
T E R MI N A TI O N D A T A  
In ge n eral, f or b y -visit s u m maries, data rec or de d at t he n o mi nal visit will be prese nt e d. 
U nsc he d ule d m eas ur e me nts will n ot be i ncl u de d i n b y -visit s u m maries b ut will c o ntri b ute 
t o t he w orst -cas e val ue w here re q uire d (e. g. s hift t a ble).  
I n t he case of a retest (sa me visit n u m ber assi g ne d), t he latest a vaila ble meas ure m e nt f or 
t hat visit will be use d f or b y-visit s u m maries.  
Listi n gs will i ncl u de sc h e d ule d, u nsc he d ule d, retest visits,  a n d earl y disc o nti n uati o n data.  
7. 6.  
S U B G R O U P S  
N ot a p plica ble.  
7. 7.  
W
I N D O WI N G C O N V E N TI O N S  
N o a nal ysis visit wi n d o wi n g will be perf or m e d f or t his st u d y.  T he pla n ne d visit wi n d o wi n g 
is prese nte d i n A p pe n di x 1 of pr ot oc ol a me n d me nt 5 . 
7. 8.  
S O F T W A R E V E R SI O N  
All a nal ys es will be c o n d ucte d usi n g S A S E nter prise ® V ersio n 8. 3  or hi g her versi o n.  
7. 9.  
D A T A H A N D LI N G C O N V E N TI O N S  
Data will be s u m marize d se paratel y f or sta ge 1 a n d 2 : b y d os e le vel  ( Sta ge 1), a n d b y 
mali g na n c y t y p e ( Sta ge 2). 
C o nti n u o us assess me nts will be s u m marize d b y n u m ber of patie nts ( n), mea n, sta n dar d 
de viati o n,  me dia n, 
mi ni m u m,  a n d 
ma xi m u m. T he deci mal places f or 
mi ni m u m a n d 
ma xi m u m will be t he sa me as t he ma x deci mal places i n ori gi nal data. Mea n a n d Me dia n will 
kee p o ne m ore dec i mal place t ha n t he deci mal places i n ori gi nal data; sta n dar d de viati o n will 
kee p 2 m ore deci mal places t ha n t he deci mal places i n ori gi nal data, b ut n o m ore t ha n 4 deci mal 
places.  
F or cat e g orical varia bles, descri pti ve statistics will i ncl u de t he  n u m ber a n d perce nta ge of 
patie nts f or eac h cate g or y.   T he de n o mi nat or f or all perce nta ges will be t he n u m ber of patie nts 


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i n t hat d ose le vel  or mali g na nc y t y pe wit hi n t he p o p ulati o n of i nterest, u nless ot her wise n ote d. 
T he perce nta ge will kee p o ne deci mal places. If t he perce nta ge is 1 0 0 %, 1 0 0 % will be re p orte d; 
if t he fre q ue nc y is 0, n o perce nta ge will be re p orte d. If nee de d, t he 2-si de d 9 5 % c o nfi de nce 
i nter val f or perce nta ge will be calc ulate d usi n g Cl o p per -Pears o n met h o d  as well, a n d t he 
deci mal places will be t he sa me as perce nta ge.  
7. 1 0.  
M I S SI N G D A T A 
I n ge neral, all a vaila ble data will be i ncl u de d i n t he a nal yses. U nl ess ot her wise s pecifi e d 
t here will be n o s u bstit uti o n of missi n g data, i.e. missi n g data will n ot be re place d b ut will 
be ha n dle d as ' missi n g' i n t he s tatistical e val uati o n. Partial dates ma y b e i m p ute d f or 
statistical a nal ys es f or s p ecific o utc o m es. I n s u c h cases, t he s pecifi c i m p utati o n r ules are 
pr o vi de d bel o w. H o we ver, as a gl o bal c o n ve nti o n, i m p ute d dates s h o ul d n ot be s h o w n i n 
listi n gs.  
 
A d verse E ve n ts  
If t he a d verse e v e nt o nset date is missi n g or partial, t he date will be c o m pare d as far as 
p ossi ble wit h t he date of first d ose of st u d y me di cati o n. A d verse e ve nts will be ass u me d t o 
be treat me nt -e mer ge nt, u nless t here is clear e vi de nce (t hr o u g h c o m paris o n of partial dat es) 
t o s u g gest t hat t he a d verse e ve nt st o p pe d pri or t o t he first d ose of st u d y me dicati o n  or 
starte d m ore t ha n 3 0  da ys after last d ose of st u d y m e dicati o n or ne w a nti ne o plastic t hera p y . 
 
Missi n g or p arti al st art d ates :  
•  If t he date h as n o missi n g year a n d m o nt h b ut t he da y is missi n g:  
1)  If t he year a n d m o nt h of first d ose date are t he s a me as t he year a n d m o nt h of 
t he start date, t he n t he d ate of first d ose will be us e d.  
2)  Ot her wise, 1st da y of t h e m o nt h will be use d.  
•  If the dat e has n o missi n g year, b ut has missi n g m o nt h, a n d t he year of first d ose date 
is t he sa me as t he year of t he start date, t he d ate of first d ose will be use d.  
•  If t he date has n o missi n g year, b ut h as missi n g m o nt h, a n d t he year of first d ose is 
n ot t he sa me as t he year of t he start date, t he n J a n uar y 1st will be use d.  
•  If t he start dat e is c o m pletel y u n k n o w n, t he n us e t he date of first d ose.  
 
Missi n g or p arti al st o p d ates:  
•  If t he d ate h as n o missi n g year a n d m o nt h b ut t he da y is missi n g, t h e n use t he last 
da y of t he m o nt h.  
•  If t he date h as n o missi n g year, b ut has missi n g m o nt h, t he n use Dece m b er 3 1st of 
t hat year.  
•  If t he st o p date is c o m pletel y u n k n o w n, d o n ot i m p ute t he st o p date. 
N ote:  If t he i m p ute d st o p date is earlier t h a n t he start date, t he n t he st o p date is i m p ute d 
wit h t he start date. If t he i m p ute d start date is after n o n-i m p ute d e n d date / S A E start date 
/ date of c ha n ge C T C A E gra de t he n s et start date t o e n d date / S A E start date / date of 


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c ha n ge C T C A E gra d e .  F or patie nts w h o die d, if t he i m p ute d start/st o p date is later t ha n 
date of deat h, t h e i m p ute d date will set t o be d ate of deat h.  If t h e i m p ute d st o p date is after 
t he last k n o w n ali ve date, t he n t he st o p date is i m p ute d wit h t he last k n o w n ali ve date.  
 
C o nc o mit a nt Me dic ati o n s/ Pr oce d ures  
If c o n c o mita nt me dicati o n starts a n d/ or st o ps d ates are missi n g or p artial, t he dates will be 
c o m pare d as far as p ossi ble wit h t he date of first d ose of st u d y m e dicati o n.   
Me dicati o ns will be ass u me d t o be c o nc o mita nt, u nless t here is cl ear e vi de nce (t hr o u g h 
c o m paris o n of partial dat es) t o s u g gest t hat t he me dicati o n st o p pe d pri or t o t he first d ose 
of st u d y me dicati o n  or starte d later t h a n 3 0  da ys after last d ose of st u d y dr u g . If t here is 
clear e vi de n ce t o s u g gest t hat t he me dicati o n starte d pri or t o t he first d ose of st u d y 
me dicati o n, t he me di cati o n will be ass u me d t o b e Pri or a n d C o nc o mita nt, u nless t here is 
clear e vi de n ce t o s u g gest t hat t he me dicati o n st o p pe d pri or t o t he first d ose of st u d y 
me dicati o n. If t here is cl ear e vi de nce t o s u g gest t hat t he me dicati o n st o p pe d pri or t o t he 
first d ose of st u d y m e dic ati o n, t he me dicati o n will be ass u me d t o be pri or.  
 
Missi n g or p arti al st art d ates:  
•  If t he date h as n o missi n g year a n d m o nt h b ut t he da y is missi n g, 1st da y of t h e m o nt h 
will be use d.  
•  If t he date has n o missi n g year, b ut has missi n g m o nt h, t he n J a n uar y 1st will be use d.  
•  If t he start dat e is c o m pletel y u n k n o w n, d o n ot i m p ute t he start date.  
Missi n g or p arti al st o p d ate s:  
•  If t he d ate h as n o missi n g year a n d m o nt h b ut t he da y is missi n g, t h e n use t he last 
da y of t he m o nt h.  
•  If t he date h as n o missi n g year, b ut has missi n g m o nt h, t he n use Dece m b er 3 1st of 
t hat year.  
•  If t he st o p date is c o m pletel y u n k n o w n, d o n ot i m p ute t he st o p date, a n d assi g n 
‘ o n g oi n g’ st at us.  
 
N ote: If t he i m p ute d st o p date is earlier t h a n t he start date, t he n t he st o p date is i m p ute d 
wit h t he start date. F or p atie nts w h o die d, if t he i m p ute d start/st o p date is later t ha n date of 
deat h, t he i m p ute d date will set t o be date of deat h. If t he i m p ute d st o p date is after t he last 
k n o w n ali ve date, t he n t h e st o p date is i m p ute d wit h t he last k n o w n ali ve date.  
 
 
De at h D ate  
•  If year a n d m o nt h of deat h date are k n o w n b ut t he da y is u n k n o w n, da y will be 
i m p ute d as 1 st (f or e x a m ple, if a patie nt is re p orte d t o die o n Dec 2 0 1 7, t he deat h 
date will be i m p ute d as 1 st Dec 2 0 1 7).  
•  If o nl y year are k n o w n, d eat h date will be i m p ute d as 1st J a n of t he gi ve n year.  
•  If t he i m p ute d deat h dat e is pri or t o t he l ast k n o w n ali ve dat e, t he n t he d eat h dat e 


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will be i m p ute d as last k n o w n ali ve date + 1.  
•  If d eat h date is t otall y missi n g, dates will be i m p ute d as t he last k n o w n ali ve date + 
1.  
N ote: if t he i m p ute d deat h date is after c ut-off dat e, t he n t h e deat h dat e will be i m p ute d as 
c ut-off dat e.  
 
L ast k n o w n ali ve d ate  
•  If year a n d m o nt h are k n o w n b ut t he da y is u n k n o w n, da y will be i m p ute d as 1st .  
•  If o nl y year is k n o w n, m o nt h a n d da y w o ul d be i m p ute d as Ja n 1st.  
 
L a st d ose d ate  
Missi n g or p arti al d ate of l ast d ose d ate of st u d y tre at me n t:  
•  If t he dat e is partiall y missi n g, t he n i m p ute t he date as t he last da y of gi ve n part of 
ori gi nal last d ose date . If t he da y is missi n g, i m p ute d date will be t he last da y of t he 
m o nt h of t he partial last d ose. If t he m o nt h is missi n g, i m p ute d date will be t he last 
da y of t he year of t he partial last d ose . If t he i m p ute d date is after t he date of deat h 
(if t he s u bject die d) / last k n o w n ali ve date (if t he s u bject is n ot k n o w n t o die) / E O T 
date / E O S date , t he n it will be re place d wit h t he earliest of t he a b o ve .  
•  If t he date is c o m plet el y missi n g, t he n i m p ute t he earliest of t he a b o ve .  
 
S u bse q ue nt a nti -c a ncer t her a p y    
M issi n g or p arti al st art d ate of a nti-c a ncer t her a p y after e n d of  st u d y tre at me nt:  
•  If t he dat e has n o missi n g year a n d m o nt h b ut t he da y is missi n g. A n d if t he date has 
sa me year a n d m o nt h as last d ose date, t he n e q ual t o last d ose date + 1, else 1 5t h da y 
of t he m o nt h will be use d.  
•  If t he date h as n o missi n g year, b ut has missi n g m o nt h, a n d t he year of l ast d ose date 
is t he sa me as t he year of t he start date, t he d ate of last d ose + 1 will be use d.  
•  If t h e date has n o missi n g year, b ut has missi n g m o nt h, a n d t he year of last d ose is 
be f ore t h e year of t he start date, t he n J ul y 1st will be use d.  
•  If t he start dat e is c o m pletel y u n k n o w n, t he n us e t he date of last d ose + 1.  
 
O nc ol o g y Di a g n osis Hist or y D ates  
•  If year is missi n g, d o n ot i m p ute.  
•  if year a n d m o nt h are k n o w n b ut t he da y is u n k n o w n, da y will be i m p ute d as 1 5.  
•  If o nl y year is k n o w n, m o nt h a n d da y w o ul d be i m p ute d as J ul y 1st.  
N ote: T he i m p ute d date will be c o m pare d t o i nf or m c o nse nt date. If it is later t ha n t he 
i nf or m c o nse nt date, t he i nc o m plete date will be i m p ute d as t he i nf or m c o nse nt date. 
 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 3  of 4 3  
 
 
D ate of Pr o gressi o n/ D ate of L ast T u m or Assess me nt  
•  If year a n d m o nt h are k n o w n b ut t he da y is u n k n o w n, da y will be i m p ute d as 1st . 
•  If b ot h t he da y a n d m o nt h are missi n g or a dat e is c o m plete missi n g, it will be 
c o nsi dere d as missi n g.  
 
Pri o r o nc ol o g y a nti -c a ncer Me dic ati o ns  
Missi n g or p arti al st art d ates:  
•  If t he date h as n o missi n g year a n d m o nt h b ut t he da y is missi n g, 1st da y of t h e m o nt h 
will be use d.  
•  If t he date has n o missi n g year, b ut has missi n g m o nt h, t he n J a n uar y 1st will be use d.  
•  If t he start dat e is c o m pletel y u n k n o w n, d o n ot i m p ute t he start date.  
Missi n g or p arti al st o p d ate s:  
•  If t he d ate h as n o missi n g year a n d m o nt h b ut t he da y is missi n g, t h e n use t he last 
da y of t he m o nt h.  
•  If t he date h as n o missi n g year, b ut has missi n g m o nt h, t he n use Dece m b er 3 1st of 
t hat year.  
•  If t he st o p date is c o m pletel y u n k n o w n, d o n ot i m p ute t he st o p date, a n d assi g n 
‘ o n g oi n g’ st at us.  
N ote: If t he i m p ute d st o p date is earlier t h a n t he start date, t he n t he st o p date is i m p ute d 
wit h t he start date. F or p atie nts w h o die d, if t he i m p ute d start/st o p date is later t ha n date of 
deat h, t he i m p ute d date will set t o be date of deat h.  If t he i m p ute d st o p date is after t he last 
k n o w n ali ve date, t he n t h e st o p date is i m p ute d wit h t he last k n o w n ali ve date.  
 
Effic ac y A n al yses D at a  
Missi n g effi cac y res p o ns e will be treate d as N ot E val ua ble ( N E) at t he visit.   
 
8.  O U T P U T P R E S E N T A TI O N S  
S u m mar y res ults will be prese nte d se p aratel y b y Sta ge 1 a n d Sta ge 2.  
E fficac y a nal ysis: F or Sta ge 1, s u m mar y will be b y d ose le vel. F or Sta ge 2, s u m mar y will 
be  b y t y p e of mali g na nc i es.  
A nal ysis ot h er t ha n effic ac y: F or Sta ge 1, s u m m ar y will be b y d os e le vel  a n d t otal . F or 
Sta ge 2, s u m mar y will be b y t y pe of mali g n a ncies  a n d t otal.  
9.  D I S P O SI TI O N A N D W
I T H D R A W A L S 
All patie nts w h o pr o vi de i nf or me d c o nse nt will be acc o u nte d f or i n t his st u d y.  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 4  of 4 3  
 
 
9. 1.  
D I S P O SI TI O N 
Patie nt  dis p ositi o n, disc o nti n uati o n as well as reas o ns f or disc o nti n uati o n will be prese nte d 
f or t he all e nr olle d set. T he n u m ber of patie nt s w h o pr o vi de d t h e i nf or m e d c o nse nt f or t he 
st u d y will be s u m marize d, Scree n faile d patie nt s a n d t he reas o n f or scree n fail ure will als o 
be s u m mariz e d.  
T he n u m ber a n d perce nta ge of patie nt s w h o recei ve d, disc o nti n ue d or are still o n t he 
treat me nt will be prese nt e d. Reas o ns f or disc o nti n uati o n fr o m st u d y tr eat m e nt as rec or de d 
o n t he “ E n d of Treat me nt” f or m will be s u m marize d. T he n u m ber a n d perce nta ge  of 
patie nts  w h o ha ve disc o nti n ue d or are still o n st u d y will be pres e nte d. Reas o ns f or 
disc o nti n uati o n fr o m st u d y  as rec or de d o n “ E n d of St u d y” f or m will be s u m marize d .  T he 
f oll o w u p ti me will be als o s u m marize d wit h mea n, me dia n, mi ni m u m, ma xi m u m  a n d 
sta n dar d de viati o n. 
F oll o w u p ti me ( m o nt hs ) = (date of d eat h (if t he s u bject die d) or  last k n o w n ali ve d ate (if 
t he s u bject is n ot k n o w n t o die) –  t he first d ose date + 1)/ 3 0. 4 3 7 5. F or t he i nt eri m e val uati o n 
of Sta ge 1 res ults, f oll o w -u p ti me ( da ys) is defi ne d as date of c ut off (e v e n if p atie nt was 
off treat me nt or die d) –  first d ose date + 1. 
I n a d diti o n, n u m ber a n d perce nt a ge of patie nts wit h < 6, > = 6, < 1 2, > = 1 2 m o nt hs f oll o w-u p 
ti me will be s u m marize d. 
 
T he n u m ber/ perce nt a ge of patie nt s i ncl u de d i n F A S, E A S, a n d D E A S  (st a ge 1 o nl y) will 
be s u m marize d base d o n F A S f or b ot h Sta ge 1 a n d Sta ge 2. A b y -patie nt listi n g will i ncl u de 
the i ncl usi o n/e x cl usi o n of patie nts i n eac h a nal ysis set.  
 
I n di vi d ual listi n gs c o ntai ni n g t he site a n d s u bject I D, i nf or me d c o ns e nt i nf or mati o n, first 
a n d last n o n -zer o st u d y me dicati o n a d mi nistrati o n date, treat me nt disc o nti n uati o n 
i nf or mati o n a n d e n d of st u d y i nf or mati o n will b e pr o vi de d se p arat el y f or Sta ge 1 a n d Sta ge 
2 . A se parate data listi n g 
will i ncl u de eli gi bilit y f or st u d y e n try bas e d o n  
i ncl usi o n/e x cl usi o n criteria.  
9. 2.  
P R O T O C O L D E VI A TI O N S  
Pr ot oc ol de viati o n will be c ollecte d b y cli nical tea m a n d e nt ere d i nt o cli nical trial 
ma na ge me nt s yste m ( C T M S).   
A  s u m mar y ta ble f or maj or pr ot oc ol de viati o ns b y de viati o n cate g or y will be prese nte d. A 
s u bject will o nl y be c o u nte d o nce wit hi n a partic ular de viati o n  cate g or y e ve n if he/s he has 
m ulti ple de viati o ns  u n der t he sa me cate g or y.  
All  pr ot oc ol de viati o n will be prese nte d i n listi n gs i ncl u di n g de viati o n cate g or y, de viati o n ter m, 
de viati o n date, se verit y ( maj or/ mi n or), acti o ns ta ke n , C O VI D -1 9 im pact relate d. 
 
C O VI D -1 9 Visit I m pact t o pla n ne d visit will be i ncl u de d i n b y-patie nt listi n gs . 
1 0.  D E M O G R A P HI C A N D B A S E LI N E C H A R A C T E RI S TI C S  
De m o gra p hic s a n d ot her baseli ne c haracteristics will be prese nte d f or t he F A S.  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 5  of 4 3  
 
 
C o nti n u o us de m o gra p hic varia bles: a ge, hei g ht  at baseli ne, wei g ht at baseli ne , a n d b o d y 
mass i n de x  at baseli ne  will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d 
de viati o n , me dia n, mi ni m u m, a n d ma xi m u m).  F or all t he ot her cat e g orical varia bles, 
res ults will be prese nte d as n u m ber a n d p erce nta ge of patie nts.  
T he f oll o wi n g d e m o gra p hic a n d baseli ne c haracteristics will be re p orte d f or t his st u d y : 
•  A ge ( years)  =  fl o or (year  of i nf or me d c o ns e nt -year  of birt h)  
•  A ge ( years) cate g or y:  
o  < 6 5  
o  ≥ 6 5  
•  Ge n der  (i ncl u di n g c hil d beari n g p ote ntial f or fe mal e patie nts)  
•  Race  
•  Et h nicit y  
•  Wei g ht at Baseli ne ( k g)  
•  Hei g ht at Bas eli ne (c m)  
•  B MI ( k g/ m 2)  at Bas eli ne  = wei g ht( k g) /( h ei g ht( m) * hei g ht( m))  
•  T o bacc o Us e Stat us  
•  Alc o h ol Use Stat us  
•  Dr u g A b use Stat us  
•  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) P erf or ma nce  Stat us at Baseli ne.   
•  B -s y m pt o ms ( Prese nt, A bse nt)  
•  B o ne Marr o w I n v ol ve me nt b y L y m p h o ma  
A ll a b o ve de m o gra p hi c i nf or mati o n , cyt o ge neti c ab n or malit y test a n d b o ne marr o w 
as pirate will be liste d.  
1 1.  O T H E R B A S E LI N E D I S E A S E C H A R A C T E RI S TI C S  
Pri or ca ncer dia g n osis i ncl u des i nitial t u m or t y p e, i m m u n o hist oc he mistr y, fl o w c yt o metr y, 
ot her pat h ol o gi cal fi n di n gs.  
F A S will be use d t o s u m mariz e baseli ne diseas e c haract eristics  as f oll o wi n g:  
•  Ti me si nce dia g n osis ( m o nt hs ): calc ulate d as  ( dat e of first d ose dat e  –  date of pri mar y 
dia g n osis + 1)/ 3 0. 4 3 7 5  
•  I nitial T u m or T y pe ( C L L, S L L, M C L, F L, W M/ L P L, M Z L, P T C L, C B C L) a n d s u b-
t y pes f or F L, M Z L, a n d P T C L, a n d pri or B T K i n hi bit or e x p os ure f or M C L o nl y. 
•  Ris k Gr o u ps  
o  F or C L L/ S L L/ M Z L: L o w , L o w -i nter m e diate, Hi g h -I nter me diat e, Hi g h  
fr o m “ Diff us e L y m p h o ma I nter n ati o nal Pr o g n osti c I n de x ” C R F pa ge 
o  F or 
F L: 
L o w, I nter m e diate, 
Hi g h fr o m “ F ollic ular 
L y m p h o m a 
I nter nati o nal Pr o g n ostic I n de x ” C R F pa ge 
o  F or 
M C L: L o w, I nter me diate, Hi g h fr o m “ Si m plifie d 
Ma ntel Cell 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 6  of 4 3  
 
 
L y m p h o ma I nt er nati o nal Pr o g n ostic I n d e x ( MI PI) Sc ore” C R F p a ge  
o  F or W M/ L P L: L o w, I nter me diate, Hi g h fr o m “I nt er nati o nal Pr o g n ostic 
Sc ori n g S yste m f or Wal d e nstr o m’s Macr o gl o b uli n e mia (I S S W M)” C R F 
pa ge  
•  Rai sta ge  ( o nl y f or patie nts wit h l y m p h o ma t y pe C L L) 
•  Bi net sta g e ( o nl y f or pati e nts wit h l y m p h o m a t y p e C L L) 
•  A n n Ar b or Sta gi n g at st u d y e ntr y (f or patie nts wit h l y m p h o ma ot her t ha n C L L)  
A ll o nc ol o g y dia g n osis i nf or mati o n a n d ot her b aseli ne disease c h aracteristics will be liste d.  
1 2.  P RI O R O N C O L O G Y  T H E R A P Y  
Pri or o nc ol o g y t h era p y will be s u m marize d f or t he F A S. Pri or o nc ol o g y t h era pi es are 
defi ne d as a n y a nti -ca ncer t hera p y ta ke n pri or t o i nitiati o n of st u d y tr eat me nt.  
Pri or o nc ol o g y t h era pi es i ncl u de pri or o n c ol o g y c he m ot hera p y a n d o nc ol o g y me di cati o n, 
pri or  o nc ol o g y ra di ot hera pies a n d pri or o nc ol o g y s ur geries/ pr o ce d ures.  
 
Pri o r o nc ol o g y s ur geries/ pr oce d ure  
Pri or o nc ol o g y s ur geries/ pr oce d ures will be c o de d usi n g Me d D R A Versi o n 2 6. 0  or hi g her 
( de pe n ds o n t he latest data c o di n g). N u m ber a n d perce nt a ge of patients ta ke n pri or 
o nc ol o g y s ur geries / pr o ce d ure will be s u m marize d.  
All  pri or o nc ol o g y s ur geries / pr oce d ure  rec or ds will be liste d wit h s yste m or ga n class 
(S O C ) a n d P T i n t he listi n g. 
 
Pr i o r o nc ol o g y r a di ot her a p y 
Ra di ot hera pies are n ot c o nsi dere d a li ne of pri or o nc ol o g y t hera p y. Ra di ot hera pies will be 
s u m marize d b y n u m bers a n d p erce nta ges of patie nts ta ke n ra di ot hera pies, a n d all 
ra di ot hera p y rec or ds will be liste d.   
 
Pri o r o nc ol o g y c he m ot h er a p y a n d o nc ol o g y me di c ati o n  
Pri or o nc ol o g y  me di cati o n  t hera pies will als o be s u m marize d as f oll o ws : 
•  N u m ber a n d p erce nta ge  of patie nt s wit h at least o ne pri or o nc ol o g y m e dicati o n  
t hera p y 
•  N u m ber of pre vi o us li nes of t hera p y  
•  N u m ber a n d p erce nta ge of patie nts wit h 1, 2, 3, a n d > 3 pre vi o us li nes of t hera p y  
•  Ti me si nce last o nc ol o g y me dicati o n  t hera p y ( m o nt h) =  (d ate of first  d ose –  last date 
f or t he last t hera p y + 1)/ 3 0. 4 3 7 5 
•  N u m ber a n d perce nt a ge of patie nts wit h Pr o gressi o n of Disease wit hi n 2 4 m o nt hs 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 7  of 4 3  
 
 
fr o m t he start of t he first li ne of pri or t hera p y ( yes/ n o). 
•  N u m ber a n d p erce nta ge of patie nts wit h a n y pri or C D 2 0  me dicati o n t hera p y  
•  N u m ber a n d perce nta ge of patie nts wit h a n y pri or B T K i n hi bit or me dicati o n t hera p y  
Pri or o nc ol o g y 
me di cati o ns will be c o de d usi n g 
W orl d Healt h Or ga nisati o n Dr u g 
Dicti o nar y E n ha n ce d ( W H O -D D E) versi o n M A R 2 0 2 3  or hi g h er.  
A ll pri or o nc ol o g y c he m ot hera p y a n d o n c ol o g y m e dicati o n rec or ds will be liste d wit h A T C 
le vel 2 te xt a n d preferre d ter m ( P T) i n t he listi n g. 
1 3.  M E DI C A L H I S T O R Y 
Me dical Hist or y i nf or mati o n will be prese nte d f or t he  F A S .  
All me dical hist or y fr o m e C R F pa ge ‘ Me dical Hist or y’ will be c o de d wit h 
Me dical 
Dicti o nar y f or Re g ulat or y A cti vities ( Me d D R A) ce ntral c o di n g dicti o nar y, Versi o n 2 6. 0  or 
hi g her.  
A ll me dical hist or y rec or ds will be liste d wit h s yst e m or ga n class ( S O C) a n d preferre d ter m 
( P T) i n t he listi n g. 
1 4.  P IO R A N D C O N C O MI T A N T M E DI C A TI O N S  A N D 
P R O C E D U R E S  
1 4. 1.  
P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S  
Me dicati o ns will be pres e nte d f or t he F A S  a n d will be c o de d usi n g W H O -D D E versi o n 
M A R 2 0 2 3  or hi g her.  
Refer t o S ecti o n 7. 1 0  f or ha n dli n g of missi n g or partial dates. , I n t he cas e w here it is n ot 
p ossi ble t o defi ne a me dicati o n as pri or or c o n c o mita nt  base d o n dates , t he me dicati o n will 
be classifie d as c o nc o mit a nt.  
•  ‘ Pri or’ me dicati o ns are me dicati o ns w hic h starte d a n d st o p pe d pri or t o t he da y of t he 
first a d mi nistrati o n.  
•  ‘ C o nc o mita nt’ me dicati o ns are t h ose w hi c h:  
o  Starte d pri or t o t he first a d mi nistrati o n date of st u d y me dicati o n a n d 
e n de d o n or after t he first a d mi nistrati o n date o n treat me nt.  
o  Starte d o n or after t he first a d mi nistrati o n date of st u d y m e dicati o n b ut 
n o later t ha n 3 0  da ys f oll o wi n g last a d mi nistrati o n date o n treat me nt . 
A ll pri or a n d c o nc o mita nt me dicati o n rec or ds will be liste d  wit h A T C le vel 2 te x t a n d P T 
i n t he listi n g. 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 8  of 4 3  
 
 
1 4. 2.  
P RI O R A N D C O N C O MI T A N T P R O C E D U R E S  
Pr oce d ures will be prese nte d f or t he F A S a n d  will be  c o de d usi n g Me d D R A Versi o n 2 6. 0  
or hi g her.  
•  ‘ Pri or’ pr oce d ure s are pr oce d ure s w hi c h starte d a n d st o p pe d pri or t o t he da y of t he 
first a d mi nistrati o n.  
•  ‘ C o nc o mita nt’ pr oce d ure s are t h ose w hi c h:  
o  Starte d pri or t o t he first a d mi nistrati o n date of st u d y me dicati o n a n d 
e n de d o n or after t he first a d mi nistrati o n date o n treat me nt.  
o  Start e d o n or after t he first a d mi nistrati o n date of st u d y m e dicati o n b ut 
n o later t ha n 3 0 da ys f oll o wi n g last a d mi nistrati o n date o n treat me nt.  
A ll pri or a n d c o n c o mita nt pr oce d ure rec or ds will be liste d wit h  s yste m or ga n class ( S O C) 
a n d preferre d ter m ( P T) i n t he listi n g. 
1 4. 3.  
S U B S E Q U E N T M E DI C A TI O N S A N D N O N -D R U G 
T R E A T M E N T S  
S u bse q ue nt o nc ol o g y t hera p y is defi ne d as a n y ne w a nti -ne o plastic t hera p y (i n cl u di n g 
c hem ot hera p y a n d me dicati o n, s ur ger y/ pr oce d ure, a n d ra di ot hera p y) start e d after last d ose 
of st u d y me di cati o n. Me dicati o ns will be c o de d usi n g W H O -D D E versi o n M A R 2 0 2 3 or 
hi g her . Pr oce d ures will be c o de d usi n g Me d D R A Versi o n 2 6. 0 or hi g her . 
S u bse q ue nt o nc ol o g y t hera p y will be liste d f or t h e F A S  wit h  A T C 2 a n d P T i n t he listi n g 
f or me dicati o ns a n d wit h S O C a n d P T i n the listi n g f or  s ur ger y a n d pr o ce d ures. 
1 5.  S T U D Y M E DI C A TI O N E X P O S U R E  A N D C O M P LI A N C E  
E x p os ure t o st u d y me di cati o n will be prese nte d f or t he F A S.  
Date of first d ose is defi ne d as t he date of first n o n -zer o st u d y m e dicati o n a d mi nistrati o n, 
w hic h  will be ta ke n fr o m t he e C R F “ H M P L -6 8 9 Treat me nt” f or m.  
Date of last d ose is defi ne d as t he date of last n o n -zer o st u d y me dicati o n o n or pri or t o 
wit h dra wal fr o m t he st u d y or c ut -off date , w hic h will be ta ke n fr o m t he e C R F “ H M P L -6 8 9 
Treat me nt ” f or m. F or missi n g or partial e n d dates, see i m p utati o n r ule i n Secti o n 7. 1 0 .  
T he e xte nt of e x p os ure t o st u d y me di cati o n will be prese nte d f or t he f oll o wi n g s u m maries:  
•  N u m ber of i nitiate d c ycl es:  
N u m ber of i nitiale d c ycles is t he n u m ber of c ycl es i n w hic h t he patie nt t o o k a n y d ose 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 2 9  of 4 3  
 
 
of st u d y me dicati o n.  
•  T otal d urati o n of e x p os ure (m o nt hs ):  
T otal d urati o n of e x p os ur e  ( m o nt hs) = ( date of last d ose  - date of first d ose + 1
3 0. 4 3 7 5
)  
•  N u m ber a n d p erce nta ge of patie nts wit h  t otal d urati o n of e x p os ure 
o  < 6 m o nt hs  
o  > = 6 t o < 1 2 m o nt hs  
o  > = 1 2 m o nt hs  
•  Act ual d urati o n of st u d y treat me nt ( m o nt hs ):  
Act ual d urati o n of st u d y treat me nt is defi ne d as t he t otal n u m ber of m o nt hs  o n t he 
st u d y me di cati o n  d uri n g t he treat me nt p hase e x cl u di n g t he peri o ds of d ose brea k or 
d ose i nterr u pti o ns.  
Act ual d urati o n of st u d y tr e at m e nt ( m o nt hs) =  
( date of last d ose  - date of first d ose  - d a ys wit h z er o d os e d u e t o a n y c a us e + 1
3 0. 4 3 7 5
)  
•  C u m ulati ve d ose ( m g):  
C u m ulati ve d ose ( m g) is defi ne d as t he s u m of t he t otal d osa ge t hat t h e patie nt  
act uall y recei ve d d uri n g a n e x p os ure peri o d.  
•  D ose i nte nsit y ( m g/ da y):  
D ose i nte nsit y ( m g/ da y) = (
𝐂𝐮𝐦𝐮𝐥𝐚𝐭𝐢𝐯𝐞 𝐝𝐨𝐬𝐞 (𝐦𝐠)
𝐭𝐨𝐭𝐚𝐥 𝐝𝐮𝐫𝐚𝐭𝐢𝐨𝐧 𝐨𝐟 𝐞𝐱𝐩𝐨𝐬𝐮𝐫𝐞(𝐝𝐚𝐲𝐬))  
•  Relati ve d ose i nte nsit y ( %):  
Relati ve d ose i nte nsit y ( %) = (
d ose i nte nsit y ( m g/ da y)
𝐩𝐥𝐚𝐧𝐧𝐞𝐝 𝐝𝐨𝐬𝐞 𝐢𝐧𝐭𝐞𝐧𝐬𝐢𝐭𝐲(𝐦𝐠/ 𝐝𝐚𝐲)) ∗𝟏𝟎𝟎 
T he pla n ne d d ose i nte nsit y is t he i nitial assi g ne d d ose i nte nsit y . 
It will be s u m marize d as a c o nti n u o us varia ble a n d als o cate g orize d i nt o gr o u ps as 
bel o w:  
o  < 5 0 %  
o  5 0 % - < 7 0 %  
o  7 0 % - < 9 0 %  
o  9 0 % - < 1 1 0 %  
o  > = 1 1 0 %   
Details of st u d y tr eat me nt a d mi nistrati o n  a n d e x p os ure e n d p oi nts  will be i ncl u de d i n 
patie nt listi n gs.  
1 6.  E F FI C A C Y O U T C O M E S  
T he E A S is t he pri mar y a nal ysis set f or disease res p o nse efficac y e n d p oi nts i ncl u di n g O R R, 
C B R , D o R a n d T T R. T he F A S is re gar de d as pri mar y a nal ysis set f or P F S . I n t he e v al uati o n 
of t he t u m or res p o nse e n d p oi nts ( O R R, T T R, C B R, D o R, a n d P F S), t he i n vesti gat or -


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 0  of 4 3  
 
 
assesse d data will be utilize d f or t u m or assess me nt . U nless ot her wise s pecifie d, all efficac y 
o utc o mes  are t o be s u m marize d b y d ose le vel  i n sta ge 1 a n d b y t he mali g na n c y t y p e i n 
sta ge 2. T u m or assess me nt will be c o n d ucte d e ver y 8 wee ks  (± 7 da ys)  f or t he first 2 4 wee ks 
a n d t he n e ver y 1 2 wee ks  (± 7 da ys)  t hereaft er. 
 
T u m or assess me nt i n differe nt t y pe s of mali g n a ncies will be e val uate d acc or di n g t o 
s pecifie d g ui deli nes/criteria: 
•  C L L: t he m o difie d I nter nati o nal W or ks h o p o n C L L g ui deli ne ( Halle k 2 0 0 8, C hes o n  
2 0 1 2), see A p p e n di x  5  of pr ot oc ol a me n d me nt 5 . 
•  L P L/ W M: c o nse ns us of i nter nati o nal w or ks h o ps o n 
W M  (I W W M-7 c o nse ns us)  
( Di m o p o ul os 2 0 1 4), see A p pe n di x 6 of pr ot oc ol a me n d me nt 5 . 
•  Ot her l y m p h o mas: L u ga n o Res p o nse Criteria f or H o d g ki n a n d N o n -H o d g ki n  
L y m p h o ma  ( C hes o n 2 0 1 4), see A p pe n di x 7 of pr ot oc ol a me n d me nt 5 . 
 
 
1 6. 1.  
B E S T O V E R A L L R E S P O N S E ( B O R) 
Best o v erall res p o nse is defi ne d as t he best res p o nse rec or de d fr o m t he st art of treat me nt 
u ntil disease pr o gressi o n  or ne w a nti -ca ncer t hera p y, w hic he ver c o mes earli er .  
 
Best o verall res p o nse is d eter mi ne d fr o m t he s e q ue nce of res p o nses ass esse d as bel o w:  
•  F or C L L g u i deli ne: C o m plete Res p o nse ( C R), C R wit h i nc o m plete b o n e marr o w 
rec o ver y ( C Ri), Partial Res p o nse ( P R), N o d ular Partial Res p o nse ( n P R), Partial 
Res p o nse wit h L y m p h oc yt osis ( P R -L), Sta ble Disease ( S D), Pr o gressi ve Disease 
( P D), N ot E val uate d ( N E).  
•  F or W M g u i deli ne: C o m plete Res p o nse ( C R), Ver y G o o d Partial Res p o nse ( V G P R), 
Partial Res p o nse ( P R), Mi n or Res p o nse ( M R), Sta ble Disease ( S D), Pr o gressi ve 
Disease ( P D) , N ot E val u ate d ( N E).  
•  F or Ot her L y m p h o mas g ui deli ne: C o m plete Res p o nse ( C R), Partial R es p o nse ( P R), 
Sta ble Disease ( S D), Pr o gressi ve Diseas e ( P D) , N ot E val uate d ( N E).  
B O R will be assi g n e d f or eac h patie nt as t he b est res p o nse rec or de d fr o m all res p o nses 
rec or de d after st u d y m e dicati o n a d mi nistrati o n u ntil disease pr o gress i o n or start  of  
s u bse q ue nt a nti-t u m or assess me nt, w hic he ver c o mes earlier. F or p atie nt s wit h m ulti ple 
assess me nt s o n differe nt dates f or t he sa me t u m or assess me nt visit , the earli est date will be 
selecte d f or P D, w hile t he latest date will be selecte d f or ot her res p o nses. 
 
Patie nts wit h B O R “ N E” will be s u m marize d b y reas o n f or ha vi n g N E stat us. T he 
f oll o wi n g reas o ns will be use d:  
•  All p ost -baseli ne assess me nts ha ve o verall res p o nse N E  
B O R  data will be liste d f or all patie nts i n E A S.  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 1  of 4 3  
 
 
 
1 6. 2.  
O B J E C TI V E R E S P O N S E R A T E ( O R R) 
O bjecti ve  res p o ns e rate ( O R R) is defi ne d as t he pr o p orti o n of patie nts w h o ha ve B O R wit h 
C R, C Ri, n P R  or P R f or C L L p atie nts; pr o p orti o n of patie nts w h o ha ve B O R wit h C R, 
V G P R, P R or M R f or W M patie nts; pr o p orti o n of patie nts w h o ha ve B O R wit h C R or P R 
f or patie nts wit h disease t y p e ot h er t ha n C L L a n d W M.  
T he defi niti o n of n e o -O R is si milar t o classical O R e x ce pt t hat partial res p o nse wit h 
l y m p h oc yt osis ( P R-L) is als o i ncl u de d f or C L L.  
T he esti mate d O R R , ne o-O R  a n d 9 5 % Cl o p per -P ears o n c o nfi de nce i nter val ( CI ) will be 
prese nte d b y d os e le vel f or Sta ge 1 a n d b y t he mali g na n c y t y p e sta ge 2. 
O R R data will be liste d f or all patie nts i n E A S.  
 
1 6. 3.  
C O M P L E T E R E S P O N S E R A T E ( C R R A T E )  
C R rate is d efi ne d as t h e pr o p orti o n of patie nts w h o ha ve B O R wit h C R or C Ri f or C L L 
patie nts , a n d C R o nl y f or ot her patie nts.  
T he esti mate d C R rate a n d 9 5 % Cl o p per -Pears o n c o nfi de nce i nter val ( CI) will be prese nte d 
b y d ose l e vel f or Sta ge 1 a n d b y t h e mali g n a nc y t y pe f or sta ge 2.   
C R  rate data will be liste d f or all patie nts i n E A S.  
 
1 6. 4.  
C LI NI C A L B E N E FI T R A T E ( C BR)  
C B R  is defi ne d as t he pr o p orti o n  of patie nts w h o ha ve B O R wit h  sta ble disease ( S D) or 
better.  
T he cli nical be n efit f or eac h t y pe of mali g na n c y is defi ne d as f oll o wi n g: 
•  C L L: B O R wit h C R, C Ri, n P R, P R , P R-L  or S D  
•  W M : B O R,  wit h C R, V G P R, P R , M R  or S D  
•  Ot her t y p es of disease : C R, P R or S D 
T he esti mate d C B R a n d t he c orres p o n di n g 9 5 % e x act CI calc ul ate d usi n g t he  Cl o p per -
Pears o n  met h o d  will be prese nte d b y d os e le vel i n Sta ge  1 a n d t y pe of t he mali g na n c y f or 
sta ge 2. 
C B R data will be liste d f or all patie nts i n E A S.  
 
1 6. 5.  
P R O G R E S SI V E -F R E E S U R VI V A L ( P F S) 
P F S is defi ne d as t he ti me (i n m o nt hs) fr o m t he date of first st u d y me dicati o n t o t he earliest 
date of diseas e pr o gressi o n or deat h  of a n y ca us e , w hic he ver occ urs first.  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 2  of 4 3  
 
 
 
Pr o gressi o n -free s ur vi val ( P F S) ( m o nt hs) = ( < date of pr o gressi o n or deat h or ce ns ori n g > 
- < date of first d ose of st u d y me dicati o n > + 1)/ 3 0. 4 3 7 5.  
A patie nt is dee me d t o be ce ns ore d, acc or di n g t o t he r ules s pecifie d i n T a bl e 4 bel o w:  
 
Ta ble 2  
Pr o gressi o n -Free S ur vi val Ce ns ori n g R ule  
 
#  
Sit uati o n  
Date of Pr o gressi o n 
or Ce ns ori n g  
O utc o me  E ve nt/ Ce ns or reas o n  
1  
Deat h ( wit h o ut pre vi o usl y 
d oc u me nte d pr o gressi ve disease 
[P D ]) wit hi n t w o e val ua ble  
t u m or assess me nts[a] fr o m last 
e val ua ble t u m or assess me nt or 
first d ose (if n o p ost-baseli ne 
t u m or assess me nt) 
Date of deat h  
E ve nt  
Deat h  
2  
Deat h ( wit h o ut pre vi o usl y 
d oc u me nte d P D) after t w o or 
m ore c o nsec uti ve misse d/ n o n -
e val ua ble t u m or assess me nts[a] 
fr o m last e val ua ble t um or 
assess me nt or first d ose (if n o 
p ost -baseli ne t u m or assess me nt)  
Date of last e val ua ble 
t u m or assess me nt or 
date of first d ose (if n o 
p ost -baseli ne t u m or 
assess me nt)  
Ce ns ore d  
Deat h after t w o or m ore 
c o nsec uti ve  misse d or 
N E t u m or assess me nts 
3  
Pr o gressi o n wit hi n t w o 
e val ua ble t u m or assess me nts [a] 
fr o m last e val ua ble t u m or 
assess me nt or first d ose (if n o 
p ost -baseli ne t u m or assess me nt 
bef ore P D)  
Date of pr o gressi o n  
E ve nt  
Disease Pr o gressi o n  
4  
Pr o gressi o n after t w o or m ore 
c o nsec uti ve misse d/ n o n -
e val ua ble t u m or assess me nts [a] 
fr o m last e val ua ble t u m or 
assess me nt or first d ose (if n o 
p ost -baseli ne t u m or assess me nt 
bef ore P D)  
Date of last e val ua ble 
t u m or assess me nt or 
date of first d ose (if n o 
p ost -baseli ne t u m or 
assess me nt bef ore P D) 
Ce n s ore d 
Pr o gressi o n after t w o or 
m ore c o nsec uti ve 
misse d or N E t u m or 
assess me nts  
5  
Pr o gressi o n after ne w a nti-
ca ncer treat me nt 
Date of last e val ua ble 
t u m or assess me nt 
bef ore ne w a nti-ca ncer 
treat me nt or date of 
first d ose (if n o p ost-
baseli ne t u m or 
assess me nt bef ore ne w 
a nti-ca ncer) 
Ce ns ore d  
Pr o gressi o n after ne w 
a nti-ca ncer t hera p y 
6  
N o baseli ne t u m or  e val ua ble  
assess me nt a n d ali ve  
Date of first d ose  
Ce ns ore d  
N o baseli ne assess me nt  
7  
N o p ost -baseli ne t u m or 
e val ua ble assess me nt a n d ali ve  
Date of first d ose  
Ce ns ore d  
N o p ost -baseli ne 
assess me nt  
8  
Ne w a nti-ca ncer treat me nt 
starte d wit h n o 
pr o gressi o n [ b]/ deat h 
Date of last e val ua ble 
t u m or assess me nt 
bef ore ne w a nti-ca ncer 
Ce ns ore d  
I nitiati o n of ne w a nti-
ca ncer t hera p y wit h o ut 
P D/ deat h o bser ve d  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 3  of 4 3  
 
 
treat me nt or date of 
first d ose (if n o p ost-
baseli ne t u m or 
assess me nt bef ore ne w 
a nti-ca ncer) 
9  
N o disease pr o gressi o n or deat h  
N ote: use last t u m or assess me nt 
bef ore t w o or m ore c o n sec uti ve 
misse d/ n o n -e val ua ble t u m or 
assess me nts (if e xists)  
Date of last e val ua ble 
t u m or assess me nt or 
date of first d ose (if n o 
p ost -baseli ne t u m or 
assess me nt)  
Ce ns ore d  
Pr o gressi o n free at ti me 
of a nal ysis: t he patie nt  is 
k n o w n t o be ali ve 
wit h o ut a n y pr o gressi o n 
ha p pe ne d at t he data c ut -
off date  
N ote:  O nl y f or t u m or  assess me nts  a n d deat h date bef ore c ut off date.  
[a] ti me peri o d t hat i de ntifies t w o c o nsec uti ve misse d/ n o n-e val ua ble t u m or assess me nts is calc ulate d as 
2 *(t he pla n ne d d urati o n bet wee n assess me nts + pr ot oc ol all o we d visit wi n d o w) fr o m t he last e val ua ble 
t u m or assess me nt or (2 *t he pla n ne d d urati o n bet wee n  assess me nts + 1 * pr ot oc ol all o we d visit wi n d o w ) 
fr o m date of first d ose (if n o p ost -baseli ne e val ua ble t u m or assess me nt) .  
Acc or di n g t o pr ot oc ol, t u m or assess me nt will be c o n d ucte d e ver y 8 wee ks f or t he first 2 4 wee ks a n d 
e ver y 1 2 wee ks t hereafter ( ± 7 da ys ). Gi ve n t he sc he d ules visit assess me nt sc he me, t he defi niti o n of t w o 
misse d c o nsec uti ve t u m or assess me nt visit ma y var y, ple ase refer t o f oll o wi n g r ule:  
•  
If t he last e val ua ble t u m or assess me nt bef ore P D/ deat h is o n or b ef ore Da y 1 0 5  ( wee k 1 5 , w hic h 
is 8 wee ks bef ore wee k 2 4 , a n d all o wi n g f or 7 da ys f or earl y visit, he nce 7 * 1 6 wee ks - 7 da ys 
f or a late visit =Da y 1 0 5 ), t he n t w o c o nsec uti ve assess me nts e q uates t o 1 2 6 da ys si nce last 
e val ua ble t u m or assess me nt , all o wi n g f or earl y a n d late visits (2 * 8 wee ks + 7 da ys f or a n earl y 
assess me nt + 7 da ys f or a late assess me nt) , or 1 1 9 da ys si nce date of first d ose, all o wi n g f or late 
visit ( 2 * 8 wee ks + 7 da ys f or a late assess me nt) . 
•  
If t he t w o misse d assess me nts occ ur o ver t he peri o d w he n t he sc he d ule d fre q ue nc y of t u m or 
assess me nts c ha n ge fr o m 8 -wee kl y t o 1 2 -wee kl y, w hic h mea ns last e val ua ble t u m or assess me nt 
is fr o m wee k 1 6 t o 2 3 (Da y 1 0 6 t o Da y 1 6 1 ), t he n t w o c o nsec uti ve assess me nts e q uates t o 1 5 4 
da ys ( 7 * 8 wee ks + 7 * 1 2 wee ks + 7 da ys f or a n earl y assess me nt + 7 da ys f or a late assess me nt)  
si nce last e val ua ble t u m or assess me nt. 
•  
Fr o m Da y 1 6 2  ( wee k 2 4 ) o n war ds ( w he n t he sc he d uli n g c ha n ges t o 1 2-wee kl y ass ess me nts) , 
t w o missi n g c o nsec uti ve ass ess me nts e q uates t o 1 8 2 da ys ( 2 * 1 2 wee ks + 7 da ys f or a n earl y 
assess me nt + 7 da ys f or a late assess me nt)  si nce last e val ua ble t u m or assess me nt. 
[ b] f or patie nt s w h o recei ve ne w a nti-ca ncer t hera p y, t he f oll o wi n g r ules will a p pl y:  
If t he start date of ne w a nti -ca ncer t hera p y is partial  or missi n g , t he i m p utati o n r ules refer t o secti o n 
7. 1 0 . 
If a n assess me nt occ urs o n t he sa me da y as t he start of ne w a nti-ca ncer t hera p y, t he assess me nt will be 
use d as it will be ass u me d t he assess me nt occ urre d pri or t o t he a d mi nistrati o n of ne w a nti-ca ncer 
t hera p y). 
 
 
T he me dia n a n d q u artiles f or P F S a n d t he P F S rates at 6 m o nt hs, 1 2 m o nt hs, t o get her wit h 
t heir t w o-si de d 9 5 % c o nfi de nce i nter vals will be esti mate d f or eac h d ose le vel ( Sta ge 1) 
a n d mali g na n c y t y pe ( Sta g e 2) usi n g t he Ka pla n -M eier met h o d. T he 9 5 % CI f or t he me dia n 
will be calc ulate d  fr o m a l o g-l o g tra nsf or mati o n base d o n t he met h o d b y Br o o k me yer a n d 
Cr o wle y ( 1 9 8 2).  
Ka pla n -Mei er c ur ves will be pl otte d. I n case t he n u m ber of res p o nses i n eac h gr o u p is ver y 
small, P F S ma y be liste d o nl y.  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 4  of 4 3  
 
 
P F S f oll o w -u p ti me will be s u m marize d b y re verse d Ka pla n -Meier m et h o d (i.e. usi n g 
differe nt ce ns ori n g r ule w hic h re verses ce ns ori n g i n dicat or of P F S, i.e. patie nts w h o 
pr o gresse d or die d i n P F S a nal ysis will be ce ns ore d at t h e date of pr o gressi o n or deat h, 
patie nts w h o are ce ns or e d i n P F S a nal ysis will be assi g ne d i n dicat or of “e ve nt” wit h t he 
sa me d urati o n f or P F S) t o calc ulate me di a n, first a n d t hir d q uartiles a n d 9 5 % CIs.  
 
Fre q u e nc y a n d perce nt a ge f or eac h t y pe of e ve nt ( P D  or deat h) a n d ce ns ori n g reas o ns will 
be prese nt e d  as cate g ories . 
T he P F S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a 
patie nt listi n g  f or F A S.   
 
1 6. 6.  
D U R A TI O N O F R E S P O N S E ( DO R ) 
D urati o n of res p o nse ( D o R ): defi ne d as t he ti me fr o m w he n t h e first res p o nse ( C R, C Ri, 
P R , n P R , V G P R , P R-L, a n d M R ) was ac hie ve d u ntil t he earlier of t he first d oc u me ntati o n 
of defi niti ve disease pr o gressi o n or deat h fr o m a n y ca use , w hi c he ver is earlier. If patie nts 
d o n ot ha ve di sease pr o gressi o n or deat h, t he y will be ce ns ore d f oll o wi n g t he sa me r ules 
as f or  P F S. O nl y patie nts wit h res p o nse of C R, C Ri, P R , n P R , V G P R , P R-L , or M R will 
be i ncl u de d i n t he a n al ysis f or D o R.  
D o R ( m o nt hs) =  ( < d ate of first d oc u me ntati o n of d efi niti ve P D or deat h  fr o m a n y ca use or 
ce ns ori n g > - < date of first res p o nse > + 1)/ 3 0. 4 3 7 5.  
Me dia n a n d q uartiles f or D o R , a n d t he D o R  rates at 6 m o nt hs, 1 2 m o nt hs, al o n g wit h t he 
t w o-si de d 9 5 % CI will b e esti mate d a n d Ka pla n-Meier c ur ve will be pl otte d b y d os e le ve l 
i n sta ge 1 a n d b y t he m ali g na n c y t y p e i n sta ge 2. T he 9 5 % CI f or t he me dia n will be 
calc ulate d fr o m a l o g-l o g tra nsf or mati o n base d o n t he met h o d b y Br o o k m e yer a n d Cr o wle y 
( 1 9 8 2).  
D o R data will be liste d f or all patie nts i n E A S.  
 
1 6. 7.  
T I M E T O R E S P O N S E ( TT R)  
T T R is defi ne d as t he ti me fr o m t he first d ose of st u d y treat me nt t o t he first occ urre n ce of 
C R, C Ri, P R , n P R, V G P R, P R-L, or M R . O nl y p atie nt wit h res p o nse of C R, Cri, P R, n P R, 
V G P R , P R-L, or M R  will be i ncl u de d i n t he a nal ysis f or T T R.  
T T R = ( < dat e of f irst r es p o nse > - < d ate of first d ose of st u d y m e dicati o n> + 1)/ 3 0. 4 3 7 5.  
T T R will be s u m marize d b y descri pti ve statistics  b y d ose le vel i n sta ge 1 a n d b y t he 
mali g na n c y t y p e i n sta ge 2.  
T T R data will be liste d f or all patie nts i n E A S.  
 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 5  of 4 3  
 
 
1 6. 8.  
T U M O R B U R D E N  
T u m or b ur de n is defi ne d as t he s u m of t he pr o d uct of dia meters of all tar get meas ura ble 
lesi o ns at eac h t u m or ass ess me nt visit.  
 
T he best perce nt c h a n ge fr o m baseli ne i n t u m or b ur de n is calc ul ate d as:  
•  ( T he mi ni m u m t u m or b ur de n a m o n g p ost-baseli ne assess me nts –  Baseli ne t u m or 
b ur de n val ue)/ Bas eli ne t u m or b ur de n val ue × 1 0 0  
T u m or b ur de n will be missi n g f or t hat assess me nt visit if t here is a missi n g v al ue of t he 
pr o d uct of dia meters. T here of a patie nt wi ll be c o nsi dere d n ot e val ua ble f or t he meas ure of 
t he best perce nt c ha n ge fr o m baseli ne i n t u m or b ur de n f or t hat visit.   
   
B est perce nt c ha n ge fr o m baseli ne i n t u m or b ur de n  will be s u m marize d b y d escri pti ve 
statistics. A waterfall pl ot of t he best perce n t c ha n ge fr o m baseli ne i n t u m or b ur de n will b e 
prese nte d  f or E A S, B O R will be la bele d i n t he pl ot. Patie nts wit h o ut a n y baseli ne or 
e val ua ble p ost -bas eli ne assess me nts will be c o m pletel y e x cl u de d fr o m t he pl ots. Patie nts 
wit h o ut a n y tar get lesi o ns at basel i ne will be e x cl u de d as well. 
 
Differe nt c ol or will be prese nte d t o differe ntiate v ari o us d ose le vels (f or sta ge 1) a n d t he 
differe nt t y pe of mali g na nc y i n sta ge 2.    
 
A listi n g wit h t he t u m or assess me nts at bas eli ne a n d eac h t u m or assess me nt visit will b e 
prese nte d , i ncl u di n g eac h c o m p o ne nt f or t u m or ass ess me nt. 
A s wi m mer pl ot of d urati o n of treat me nt will be prese nte d fr o m d ate of first d ose u ntil date 
of last d ose. Treat me nt re d ucti o n a n d i nterr u pti o n will be s h o w n  i n t he e x p os ure b o x f or 
eac h p atie nt. T u m or res p o nses f or eac h t u m or ass ess me nt will als o be la bele d i n t he pl ot.  
1 7.  S A F E T Y O U T C O M E S  
All s u m mar y res ults f or s afet y o utc o mes will be base d o n t he F A S, e x ce pt D L Ts s u m maries 
w hic h are b ase d o n t he D E A S.  
A d verse E v e nts ( A Es) will be c o de d usi n g M e d D R A versi o n 2 6. 0  or hi g her. A E a n d 
la b orat or y test res ults se verit y will be perf or m e d wit h t he Nati o nal C a ncer I nstit ute 
C o m m o n Ter mi n ol o g y criteria f or a d v erse e ve nt s ( N CI C T C A E) V 5. 0. 
 
1 7. 1.  
D O S E L I MI TI N G T O XI CI TI E S ( D L TS ) 
D L T is defi ne d as t he occ urre nce of a n y  of t he f oll o wi n g treat me nt e mer ge nt  a d verse e ve nts 
( T E A E) d uri n g t he D L T assess me nt wi n d o w ( C ycle 1, Da y 1 t hr o u g h C ycl e 1, Da y 2 8), 
u nless clearl y u nrelate d t o st u d y me dicati o n: 
a. N o n he mat ol o gic t o xicit y: All n o n he mat ol o gic T E A Es of Gra de 3 or greater  wit h t he 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 6  of 4 3  
 
 
e xce pti o n of: 
i. 
Gra de 3 na usea or v o miti n g t hat ca n be c o ntr olle d b y s u p p orti ve  t hera p y 
b.  He mat ol o gic t o xicit y:  
i. 
Gra de 4 ne utr o pe nia lasti n g f or m ore t ha n 5 da ys  
ii. 
Gra de 4 t hr o m b oc yt o pe nia or Gra de 3 t hr o m b oc yt o pe nia wit h  blee di n g e ve nt or 
re q uiri n g platelet tra nsf usi o n  
iii. 
Gra de ≥3 fe brile ne utr o pe nia ( defi ne d as A N C < 1 0 0 0/ m m 3 wit h a  si n gle 
te m perat ure of > 3 8. 3º C [ 1 0 1º F] or a s ustai ne d te m perat ure of ≥3 8º C [ 1 0 0. 4º F] 
f or m ore t ha n 1 h o ur) 
i v. 
Gra de 4 a ne mia n ot e x plai ne d b y u n derl yi n g disease  
c. A n y T E A E re q uiri n g a d ose dela y of ≥1 5 da ys  
d.  A n y case of H y’s La w  ( defi ne d as t he fi n di n g of a n ele vate d A L T or A S T i n c o m bi nati o n 
wit h eit her a n ele vate d t otal bilir u bi n ( ≥2 × U L N))  c ollecte d as A d verse E ve nt of S pecial 
I nterest. 
 
F or all patie nts i n Sta ge 1, D L Ts will be  assesse d d uri n g a D L T assess me nt wi n d o w of 2 8 
da ys (i .e. fr o m C ycl e 1, Da y 1 [t he da y of first a d mi nistrati o n of treat me nt] t hr o u g h C ycl e 
1, Da y 2 8).  D L T is c olle cte d i n t he “ D ose -Li miti n g T o xicit y Assess me nt” C R F pa ge.  
 
D L T will be c o d e d usi n g Me d D R A Versi o n 2 6. 0 or hi g her . T he n u m ber a n d perce nta ge of 
patie nts wit h D L Ts will be base d o n t he n u m ber of patie nts i n t he D E A S b y S O C , P T  a n d 
C T C A E gra d e . S O C/ P T will be s orte d i n desce n di n g fre q ue nc y of t he t otal n u m ber of 
patie nt s, S OC/ P T will be prese nte d al p ha beticall y f or S O C/ P T of t he sa me fre q ue n c y .  
B y -patie nt listi n g of D L Ts will be prese nte d  wit h S O C, P T a n d C T C A E gra d e i n t he listi n g . 
1 7. 2.  
A D V E R S E E V E N T S  
Treat me nt -e mer ge nt a d v erse e ve nts ( T E A Es ) are defi ne d as A Es wit h o nset  date o n or after 
t he first d ose of st u d y m e dicati o n a n d n o later t h a n 3 0 da ys  aft er t he dat e of l ast st u d y 
treat me nt a d mi nistrati o n or start of a ne w treat me nt of a nti -ne o plas m t hera p y, w hic he v er 
is earlier. A n e x ce pti o n is t hat st u d y m e dicati o n relate d S A E c ollecte d l ater t ha n 3 0 d a ys 
after t h e last tr eat me nt d ate  or start of a n e w tr eat me nt of a nti -ne o pl as m t hera p y  will be 
treate d as T E A Es.  
 
Refer t o Secti o n 7. 1 0  f or ha n dli n g of partial dat es f or A Es. I n t h e cas e w here it is n ot 
p ossi ble t o cl assif y a n A E as tr eat me nt -e mer ge nt or n ot, t he A E will be classifie d as  
treat me nt-e mer ge nt.  
 
All A Es will be liste d, a n d o nl y T E A E  will be s u m marize d.  
 
T he missi n g se verit y will be classifie d as gra d e 3.  Relati o ns hi p, as i n dicate d b y t he 
I n v esti gat or, is classifie d as “ N ot relate d”, “ Relat e d”. T E A Es wit h a missi n g rel ati o ns hi p 
t o st u d y me dicati o n will be re gar de d as “relate d” t o st u d y me dicati o n. 
 






H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 3 9  of 4 3  
 
 
I nfecti ve p n e u m o nia 
Me d D R A S M Q “I nfecti v e 
p ne u m o nia” ( narr o w)  
2 0 0 0 0 2 3 1  
C olitis or diarr h oea  
Me d D R A S M Q “ N o ni nfecti o us 
diarr h oea” ( narr o w + br oa d)  
2 0 0 0 0 2 1 8  
I nterstitial l u n g diseas e Me d D R A S M Q “I nterstitial l u n g 
disease” ( narr o w)  
2 0 0 0 0 0 4 2  
Se vere c ut a ne o us 
a d verse reacti o ns  
Me d D R A S M Q “ Se vere c uta ne o us 
a d verse reacti o n” ( narr o w)  
2 0 0 0 0 0 2 0  
 
All A E SIs  will be s u m marize d i n fre q ue n c y a n d perce nt b y A E SI cat e g or y, P T  a n d 
ma xi m u m C T C A E gra de ( All Gra de, Gra de ≥3, Gra de 1/ 2) . T h e f oll o wi n gs will als o b e 
s u m marize d f or eac h A E SI cate g or y:  
•  A E SI  
•  Treat me nt Relate d A E SI  
•  A E SI of C T C A E Gra d e 3 or hi g h er  
•  A E SI  me eti n g S A E criteria  
•  A E SI le a di n g t o d ose m o dificati o n  
•  A E SI le a di n g t o d ose re d ucti o n  
•  A E SI le a di n g t o d ose i nterr u pti o n  
•  A E SI le a di n g t o d ose disc o nti n uati o n  
•  A E SI le a di n g t o deat h  
 
M ore o ver, ti me t o A E SI o nset ( da ys), A E SI d urati o n ( da ys) a n d A E SI o utc o me 
(t he 
n u m ber a n d perce nt of p atie nts) will be s u m marize d descri pti vel y.  
Ti me t o A E SI o nset is defi ne d as t he ti me i nter val fr o m t he date of first d os e of st u d y dr u g 
t o t he earliest o ns et dat e a m o n g all A E SIs. T h at is, if a s u bject has m ulti ple A E SI 
occ urre n ces, t he earliest A E SI o nset dat e will be use d as t he o nset date t o calc ulate ti me t o 
o nset of A E SI.  
A E SI d urati o n ( da ys) will o nl y be cal c ulate d f or e n de d A E SI  as ( A E e n d date -A E start 
date + 1).  
 
All A E  will be liste d , i ncl u di n g A E ter m, start date, e n d date, se verit y, w het her t he A E is 
D L T, c h a n ge of C T C A E g ra d e, w het her t h e A E is S A E, classificati o n of S A E (if S A E), 
w het her t h e A E is A E SI, relati o ns hi p t o st u d y dr u g, acti o n ta ke n, o utc o me will be pres e nte d 
i n s u bject data listi ngs. If t he A E is o n g oi n g at t he data c ut -off date, it will be re p orte d as 
‘ O n g oi n g’ i n t he listi n g. 
I n a d diti o n, se parate listi n gs of all S A Es, A E SIs, A Es lea di n g t o deat h a n d A Es lea di n g t o 
disc o nti n uati o n of st u d y dr u g will be pr o vi de d.  
 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 4 0  of 4 3  
 
 
1 7. 3.  
D E A T H S  
T he i nf ormati o n rec or de d i n C R F “ Deat h D etails” pa ge will be prese nte d i n t he listi n g, a n d 
t he o n-treat me nt deat h (d efi ne d as deat h d uri n g t he date of first d ose t o 3 0 da ys after t he 
last d ose of st u d y dr u g or pri or t o t he start of a ne w a nti-ca ncer t hera p y, w hic he ver c o mes 
first) will be fla g ge d . 
1 7. 4.  
L A B O R A T O R Y E V A L U A TI O N S  
La b orat or y e v al uati o ns will be perf or me d i n t he site la b orat or y.  La b orat or y e val uati o ns t o 
be i ncl u de d i n t he o ut p uts are i ncl u de d i n t he pr ot oc ol, secti o n 5. 7. 1 0 , i ncl u di n g 
he mat ol o g y, c he mistr y p a nel, ser u m a m ylase a n d li pase, fasti n g li pi d pr ofile, c o a g ulati o n, 
t h yr oi d h or m o nes, ser u m β-2 
micr o gl o b uli n, viral ser ol o g y, uri nal ysis, le u k oc yte 
i m m u n o p he n ot y pi n g, pre g n a nc y testi n g , ser u m i m m u n o gl o b uli ns assess me nt  fr o m t he 
st u d y site’s l oc al la b orat or y.  All la b orat or y res ults (i ncl u di n g pre g na n c y t est res ults) will 
be i ncl u de d i n listi n gs.  
La b orat or y res ults will be c o n verte d t o I nter n ati o nal Sta n dar d U nits ( SI U nits), a n d all t he 
a nal ysis a n d pres e ntati o n will be b ase d o n SI u nits.  
 
T he i nci de nce of p atie nts wit h t he f oll o wi n g ele vati o ns a b n or mal li ver f u ncti o n tests ( H y’s 
La w) at p ost -b aseli ne will als o be s u m marize d:  
•  A L T or A S T > 3 x U L N a n d < = 5 x U L N ( base d o n t he w orst p ost-baseli ne case)  
•  A L T or A S T > 5 x U L N ( base d o n t he w orst p ost-baseli ne cas e)  
•  T otal bilir u bi n > = 2 x U L N ( base d o n t h e w orst p ost-baseli ne cas e)  
•  ( A L T or A S T > 3 x U L N) a n d t otal bilir u bi n >=  2 x U L N [ defi n e d as t otal bilir u bi n 
i ncreas e b y > = 2 x  U L N wit hi n 1 4 da ys after A L T or A S T i ncrease b y >  3 x  U L N]  
•  H y’s l a w: ( A S T or A L T > 3 x U L N) a n d t otal bilir u bi n >=  2 x U L N a n d A L P < 2 x 
U L N [ defi ne d as t otal bilir u bi n i ncreas e b y > = 2 x  U L N a n d A L P i ncreas e < 2 x  U L N 
wit hi n 1 4 da ys after A L T or A S T i ncrease b y > 3 x  U L N]  
 
A ll la b orat or y e v al uati o n rec or ds a n d a b n or m al li ver f u ncti o n will be liste d.  
1 7. 5.  
E C G  E V A L U A TI O N S  
Res ults fr o m t he ce ntral E C G ( Electr ocar di o gra m) Rea di n g Ce ntre will be i ncl u de d i n t he 
re p orti n g of t his st u d y.  
T he f oll o wi n g E C G p ara meters will be re p orte d:  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 4 1  of 4 3  
 
 
•  P R  I nter v al ( msec) 
•  R R I nter v al ( msec)  
•  Q R S I nter v al ( msec)  
•  Q T I nter val ( msec)  
•  Q Tc F I nter val ( msec) = Q T i nter val/c u be r o ot of R R i nter val
𝐂𝐮 (𝐦𝐮)
√𝐥𝐚 (𝐭𝐢)/ 𝐯𝐞𝐝𝐨
𝐬
 
•  H R ( b p m)  
•  O verall assess m e nt of E C G (I n vesti gat or’s j u d g me nt):  
o  N or mal  
o  A b n or mal, N ot Cli nicall y Si g nifica nt  
o  A b n or mal, Cli nicall y Si g nifica nt  
 
A ll E C G e val uati o n data will be liste d 
. 
1 7. 6.  
V I T A L S I G N S 
T he f oll o wi n g v ital si g ns meas ure me nts will be re p orte d f or t his st u d y:  
•  S yst olic Bl o o d Press ur e ( m m H g)  
•  Diast olic Bl o o d Press ure ( m m H g) 
•  P ulse Rate ( b p m)  
•  Res pirat or y Rate ( breat hs/ mi n)  
•  Te m perat ur e (⁰ C)  
A ll vital si g n data will be liste d. 
 
1 7. 7.  
P H Y SI C A L E X A MI N A TI O N  
All  p h ysical e x a mi nati o n data will be liste d. 
1 7. 8.  
E C O G  P E R F O R M A C E S T A T U S  
E C O G Perf or ma n ce Stat us Gra de List  
Gr a de  
Acti vit y Le vel  
0  
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n  
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k 
of a li g ht or se de ntar y nat ure, e .g ., li g ht h o use w or k, office w or k 
2  
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities. U p 
a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs  


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 4 2  of 4 3  
 
 
3  
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs  
4  
C o m pletel y disa ble d, ca n n ot carr y o n a n y self -care, t otall y c o nfi ne d t o be d or c hair  
5  
Deat h  
A ll E C O G perf or m a nce stat us data will be liste d.  
1 7. 9.  
E C H O C A R DI O G R A M / M U G A 
All  Ec h ocar di o gra m/ M U G A data will be liste d . 
 
 


H U T C H M E D Li mite d.  
Statistical A nal ysis P la n V2. 0  
P r ot oc ol N u m ber: 2 0 1 8 -6 8 9 -0 0 U S 1  
P a ge 4 3  of 4 3  
 
 
1 8.  R E F E R E N C E S  
E M A. ( n. d.). G ui deli ne o n Missi n g D at a i n C o nfir m at ory Cli nic al Tri als.  Retrie ve d Dece m ber 1 5, 2 0 1 1, 
fr o m E ur o pea n Me dici nes A ge nc y: 
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n
G B/ d oc u me nt li brar y/ S cie ntific g ui deli ne/ 2 0 1 0/ 0 9/ W C 5 0 0 0 9 6 7 9 3. p df  
I C H g ui da nce f or i n d ustr y E 3 Str uct ure a n d C o nte nt of Cli nical St u d y Re p orts, 1 9 9 6 
I C H g ui da nce f or i n d ustr y E 9 Statistical Pri nci ples f or Cli nical Trials, 1 9 9 8 
Cl o p per, CJ a n d P ears o n, E S. T he use of c o nfi de nce or fi d uci al li mits ill ustr ate d i n t he c ase of t he 
bi n o mi al.  Bi o metri ka 2 6: 4 0 4 -4 1 3, 1 9 3 4  
C ollett, D. M o delli n g S urviv al D at a i n Me dic al Rese arc h. L o n d o n: C h a p m a n & H all, 1 9 9 4  
L ac hi n, J. M. Bi ost atistic al Met h o ds: T he Assess me nt of Rel ative Risks.  Ne w Y or k: J o h n Wile y & S o ns, 
2 0 0 0  
B r o o k me yer, R. a n d Cr o wle y, J. A C o nfi de nce I nterv al f or t he Me di a n S urviv al Ti me . Bi o metrics, 3 8, 
2 9 – 4 1, 1 9 8 2  
Halle k M. et al. G ui deli nes f or t he dia g n osis a n d treat me nt of c hr o nic l y m p h oc ytic le u ke mia Bl o o d. 2 0 0 8 
J u n 1 5; 1 1 1( 1 2): 5 4 4 6-5 6.  
C hes o n  B. et al. N o vel tar gete d a ge nts a n d t he nee d t o refi ne cli nical e n d p oi nts i n c hr o nic l y m p h oc ytic 
le u ke mia. J o ur nal of Cli nical O nc ol o g y,  2 0 1 2 V ol 3 0, N o 2 3, 2 8 2 0-2 8 2 2