A Phase 1, Open-Label, Multicenter Study of HMPL-306 in Advanced Hematological Malignancies With Isocitrate Dehydrogenase (IDH) Mutations
Phase: PHASE1
Conditions: Isocitrate Dehydrogenase Gene Mutation
Sponsor: Hutchmed

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 1 
 
CONFIDENTIAL 
 
 
 
Clinical Study Protocol 
A Phase 1, Open-Label, Multicenter Study of HMPL-306 in 
Advanced Hematological Malignancies With Isocitrate 
Dehydrogenase (IDH) Mutations 
 
Short Title 
A Phase 1 Study of HMPL-306 in Advanced 
Hematological Malignancies With mIDH 
Investigational Product(s): 
HMPL-306 
Protocol Number: 
2020-306-GLOB1 
Clinical Phase: 
1 
Issue Date: 
02 November 2023 
Amendment: 
5 
Sponsor: 
HUTCHMED Limited 
720 Cailun Road  
China (Shanghai) Pilot Free Trade Zone 
Shanghai, China 201203 
Regulatory Agency Identifier 
Number (s) 
IND 150936 
EudraCT 2020-003751-15 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the confidential and proprietary information of 
HUTCHMED Limited, and except as may be required by applicable laws or regulation, may 
not be disclosed to others without prior written permission of HUTCHMED Limited. 

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 2 
 
CONFIDENTIAL 
 
 
STATEMENT OF COMPLIANCE  
The study will be conducted in compliance with this clinical study protocol, Good Clinical Practice 
(GCP) as outlined by International Council for Harmonization (ICH) E6(R2), and all applicable 
local and national regulatory requirements.  Enrollment at any clinical study site may not begin 
prior to that site receiving approval from the ethics committee (EC) of record for the protocol and 
all materials provided to potential patients. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Reconsent of previously enrolled patients 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 patients. 
All personnel involved in the conduct of this study have completed Human Patients Protection and 
GCP Training as outlined by their governing institution. 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
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P a ge  3  
 
C O N FI D E N TI A L  
 
 
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, M ultice nter St u d y of H M P L -3 0 6 i n A d va nce d He mat ol o gical 
Mali g na ncies W it h Is ocitrate De h y dr o ge nase (I D H) M utati o ns  
Pr ot oc ol N u m ber  
2 0 2 0 -3 0 6 -G L O B 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 h e 
S p o ns or’s res p o nsi ble pers o n nel as i n dicate d i n t h e si g nat ure ta ble b el o w.  
N a me:  
Title:  
, M D, P h D 
 
 
H U T C H M E D  I nter nati o nal C or p orati o n 
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 nt h Y Y Y Y ] 
P P D
P P D

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 4 
 
CONFIDENTIAL 
 
 
INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2020-306-GLOB1 
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 patients under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records 
of the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, 
the requirements of the ethics committee of record for my clinical site, and Good 
Clinical Practices as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to patients 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 patients enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those patients 
• To maintain records of each patient’s participation and all data required by the protocol 
 
Name: 
Title:  
Institution:  
 
 
 
Signature:  
Date:   
 
 

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 5 
 
CONFIDENTIAL 
 
 
DOCUMENT HISTORY  
Amendment 
Issue Date 
Original Protocol 
16 September 2020 
1 
20 October 2020 
2 
30 August 2021 
3 
15 October 2021 
4 
24 June 2022 
 

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C O N FI D E N TI A L  
 
 
A M E N D M E N T S U M M A R Y   
T his 
Pr ot oc ol 
2 0 2 0 -3 0 6 -G L O B 1 
A me n d me nt 
5  (date d 
0 2  N o ve m ber  2 0 2 3 ) re places 
Pr ot oc ol  2 0 2 0 -3 0 6 -G L O B 1 A me n d m ent  4  (date d 2 4 J u ne 2 0 2 2 ).  T his a m e n d me nt is c o nsi dere d 
t o be 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 h e 
E ur o pea n Parlia m e nt a n d t he C o u ncil of t he E ur o p ea n U ni o n.  
As of 2 3  Oct o b er  2 0 2 3, t he d ose es calati o n p art of t he c urre nt st u d y has e nr olle d 
 patie nts  wit h 
is ocitrate d e h y dr o ge n ase  (I D H) m uta ti o ns at i n creasi n g d ose l e vels fr o m  
 m g o nce dail y 
(Q D ).  
. T he  
 m g Q D d ose is t he hi g hest 
t olera ble d ose e v al uate d i n t he d ose escalati o n part.  All  t he patie nts e nr olle d i n t he d ose escalati o n 
p art were rela pse d or refract or y  a c ute m yel oi d le u ke mia ( R/ R A M L) patie n ts.  T he st u d y di d n ot 
e nr oll a n y p atie nts wit h m yel o d ys pl astic sy n dr o me  ( M D S) or  an gi o -i m m u n o blastic T-cell 
ly m p h o ma  ( AI T L), 2  ot her p o p ulati o ns  tar gete d f or t he ori gi nall y pla n ne d e x pa nsi o n c o h orts 
(C o h orts B a n d C ) p er Pr ot oc ol  2 0 2 0 -3 0 6 -G L O B 1 A me n d me nt  4.  
A m o n g t he R/ R A M L patie nts, cli nical res p o nses were n ote d i n patie nts w h o were naï ve t o pri or 
I D H t hera p y at H M P L-3 0 6 d oses of  
 m g Q D or hi g h er. 
 were n ote d i n 
R/ R A M L patie nts w h o  h a d 
. H o we ver, all 
b ut 
 patie nts were e nr olle d i n t he l o wer d ose c o h orts (
 m g QD ) ma ki n g it 
diffic ult t o e val uat e effic ac y a n d safet y of H M P L -3 0 6  i n t his s u b gr o u p of patie nts wit h a hi g h 
u n met nee d f or acti ve s u bse q ue nt t hera p y.  
T he pri mar y p ur p os e of A me n d me nt 5 is t o m o dif y t he d os e e x pa nsi o n  c o h orts  base d u p o n t he 
sp o ns or’s strate gic e val u ati o n of t he u n met nee d a n d t he a bilit y t o e nr oll i n selecte d p o p ulati o ns .  
I n E x pa nsi o n C o h ort A, t he st u d y will e nr oll 1 0 R/ R A M L patie nts , li mite d t o patie nts w h o ha v e 
recei v e d pri or I D H i nhi bit or t hera p y.  T he  safet y a n d t olera bilit y as well as pr o of of acti vit y will 
be e val uate d at t he hi g hest t olera ble d ose le vel e val uate d i n  t he d ose escalati o n part ( 
 m g Q D). 
If pr o of of acti vit y is esta blis he d at t h e hi g her d ose le vel  i n t his hi g h-ris k p o p ulati o n, f urt her 
e val uati o n at l o wer d os es ma y b e warr a nte d i n t he f ut ure. 
E x pa nsi o n C o h orts B ( M D S) a n d C ( AI T L) are re m o ve d, as t hes e p atie nts were n ot e v al uate d i n 
t he d ose escalati o n  p art d ue t o lac k of e nr oll me nt i n t hese p o p ulati o ns .  T his c ha n ge is n ot base d 
o n a n y c o n cer n f or patie nt safet y or efficac y rel ati ve t o H M P L‑ 3 0 6 treat me nt.   T he c ha n ges ma de 
i n t his a me n d me nt are descri be d i n t he ta ble bel o w. E dit orial a n d f or matti n g c ha n ges are n ot 
i ncl u de d i n t his s u m mar y. 
Details of c ha n ges ma de i n pri or a me n d me nts are s u m marize d i n A p pe n di x 1 8 . 
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  
S p o ns or ’s A p pr o val P a ge  
U p date d c hief me dical officer’s n a me. 
T he a d mi nistrati ve u p date  
was  ma de t o reflect t he 
c ha n ge i n t he s p o ns or’s 
si g nat or y. 
S y n o psis  
A d de d st u d y stat us as of Pr ot oc ol 
A me n d me nt 5  secti o n. 
T he secti o n was a d de d t o 
e x plai n t he st u d y stat us a n d 
reas o n f or t he a me n d me nt. 
S y n o psis , Secti o n 1. 2 –  St u d y 
Sc he matic, Secti o n 4. 1. 2 – P art 2 
( D ose E x pa nsi o n), Secti o n 5. 2 –  
U p date d  t he tar get p o p ulati o n f or t he d ose 
e x pa nsi o n part t o re m o ve hi g h -ris k M D S 
a n d AI T L c o h orts a n d t o s pecif y t hat 
C o h orts B a n d C were 
re m o ve d d ue t o lac k of 
e nr oll me nt.  C o h ort A was  
C CI
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C CI
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C CI
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
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P a ge  7  
 
C O N FI D E N TI A L  
 
 
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  
I ncl usi o n Criteria ( P art 2, c), 
Secti o n 9. 2. 7  –  Efficac y A nal ysis  
patie nts m ust  n ot ha ve  sta n dar d 
t hera p e utic o pti o ns a vaila ble a n d m ust 
ha ve recei ve d  at least 1  pri or li ne of 
t hera p y wit h I D H i n hi bit ors. 
m o difie d  base d u p o n t he 
s p o ns or’s strate gic 
e val uati o n of t he u n met 
nee d .  
S y n o psis , Secti o n 3 – O bj ecti ves 
a n d E n d p oi nts  ( T a ble 3, O bj ecti ve 
a n d C orres p o n di n g  E n d p oi nts ), 
Secti o n 4. 2. 3 –  Rati o nale f or 
Bi o mar ker T esti n g,  Secti o n 6. 1. 1 5. 1 
–  Sa m ple C ollecti o n a n d Ha n dli n g, 
Secti o n 6. 1. 1 5. 2 –  A nal ytical 
Pr oce d ures, Secti o n 9. 1. 3 –  
A nal ysis Sets, Secti o n 9. 2. 6 –  
P har mac o d y na mic A nal ysis, 
A p pe n di x 2 –  
P K/ P D / Bi o mar ker/ E C G 
Assess me nts f or E x pa nsi o n C o h orts  
Re m o ve d c ollecti o n of b o ne marr o w 
sa m ples f or c o nce ntrati o ns of 
2 -h y dr o x y gl utaric h dr oc y gl utaric aci d  
( 2-H G)  
La n g ua ge re m o ve d t o 
si m plif y bi ol o gical sa m ple 
c ollecti o n. 
S y n o p sis, Secti o n 9. 1. 2 –  Sa m ple 
Size Rati o nale  
U p date d  t otal n u m ber of patie nts t o 4 0 t o 
5 0 patie nts  (fr o m 7 5 patie nts ). 
T he u p dates were ma de t o 
reflect t he re m o val of 
C o h orts B a n d C, a n d 
m o dificati o n of C o h ort A.  
S y n o psis, Secti o n 1. 2 –  St u d y 
Sc he matic,  Secti o n 4. 1. 2 –  P art 2 
( D ose E x pa nsi o n), Secti o n 6. 2. 2. 2 –  
St o p pi n g R ules f or a C o h ort or t he 
St u d y ( D ose E x pa nsi o n P art) , a n d 
 
 
, Secti o n 9. 1. 2 –  Sa m ple Size 
Rati o nale , Secti o n 9.1. 2. 2 – D ose 
E x pa nsi o n P art  
U p date d n u m ber of patie nts  a n d/ or n u m ber 
of c o h orts, if a p plica ble,  f or Part 2 t o 
a p pr o xi matel y 1 0  patie nts (fr o m 
a p pr o xi matel y 1 5 patie nts per c o h ort or  
4 5  patie nts  t otal). 
T he u p dates were ma de t o 
reflect t he re m o val of 
C o h orts  B a n d C, a n d 
m o dificati o n of C o h ort A.  
Secti o n 1. 2 –  St u d y Sc he matic  
U p date d t o re m o ve C o h orts B a n d C a n d 
m o dif y C o h ort A.  
T he u p dates were ma de t o 
reflect t he re m o val of 
C o h orts B a n d C, a n d 
m o dificati o n of C o h ort A.  
Secti o n 1. 3 –  Sc he d ule of E ve nts , 
(T a ble 1 , Sc he d ule of E ve nts [D ose  
Escalati o n ] a n d T a ble 2, Sc he d ule 
of E ve nts [ D ose E x pa nsi o n –  
Rela pse d/ Refract or y Ac ute M yel oi d 
Le u ke mia] ) 
Re vise d  “ B o ne marr o w as pirati o n a n d/ or 
bi o ps y” t o “ Bl o o d a n d/ or b o ne marr o w 
as pirati o n a n d/ or bi o ps y.”  
Re vise d  f o ot n ote o  ( T a ble 1) a n d f o ot n ote 
n ( T a ble 2) t o “ W h ole bl o o d a n d/ or b o ne 
marr o w sa m ples will be c ollecte d a n d 
pr o vi de d t o a ce ntral la b orat or y f or 
 a nal yses.”  
A d de d f o ot n ote y  t o state t hat, “B o ne 
mar r o w as pirati o n or bi o ps y will i ncl u de 
l ocal i m m u n o p he n ot y pi n g, c yt o ge netic 
a nal ysis, a n d m olec ular ge neti c testi n g.  
A d diti o nal pr oce d ural details are a vaila ble 
i n Secti o n 6. 1. 1 0. 3, Secti o n 6. 1. 1 0. 1 3, a n d 
A p pe n di x 1 7 .” F o ot n ote y s y m b ol was 
a d de d t o “ T u m or e val uati o n/i ma gi n g .” 
Re visi o ns ma de t o clarif y 
bi ol o gical sa m ple c ollecti o n 
a n d testi n g re q uire me nts. 
C CI
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
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P a ge  8  
 
C O N FI D E N TI A L  
 
 
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  
Secti o n 1. 3 –  Sc he d ule of E ve nts, 
T a ble 2 –  Sc he d ule of E ve nts ( D ose 
E x pa nsi o n  –  Rela pse d/ Refract or y 
Ac ute M yel oi d Le u ke mia ) 
Re vise d ta ble title t o a d d, 
“Rela pse d/ Refract or y Ac ute M yel oi d 
Le u k e mia.”  
A d de d “ Mi ni mal resi d ual dise ase 
e val uati o n” wit h ti mi n g t o mat c h “ T u m or 
e val uati o n/i ma gi n g.”  
Re m o ve d  ” A n n -Ar b or sta gi n g” a n d 
ass ociate d f o ot n ote v . S u bse q ue nt f o ot n ote 
was relettere d v.  
T a ble title re visi o n was 
ma de f or clarit y.  
E val uati o n was a d de d  to 
all o w f or pr o of -of -c o nce pt 
e val uati o n of rele va nce of 
m i ni mal resi d ual disease. 
A n n -Ar b or sta gi n g re m o ve d 
beca use of t he re m o val of 
AI T L c o h ort .  
Secti o n 2. 1. 2. 2 –  M utati o ns a n d 
Mali g na ncies , Secti o n 2. 3. 1 –  
B e nefit -Ris k Assess me nt  
A d de d a state me nt t hat patie nts w h o fail 
I D H i n hi bit or t hera pies d o n ot ha ve a n y 
sta n dar d treat me nt o pti o ns a vaila ble. 
Re visi o n pr o vi des 
j ustificati o n f or 
m o dificati o n of patie nt 
p o p ulati o n f or P art 2.  
Secti o n 2. 2 –  B ac k gr o u n d  
A d de d  la n g ua ge c o nsiste nt wit h t he “ St u d y 
stat us as of Pr ot oc ol A me n d me nt 5” 
secti o n of t he s y n o psis a n d t he 
A me n d me nt  S u m mar y  
La n g ua ge  was a d de d t o 
e x plai n t he st u d y stat us a n d 
reas o n f or t he a me n d me nt. 
Secti o n 2. 3. 1 –  B e nefit -Ris k 
Assess me nt  
A d de d t he state me nt , “ A d diti o nall y, A M L 
patie nts w h o fa il I D H t hera pies d o n ot 
ha ve a n y sta n dar d treat me nt o pti o ns 
a vaila ble, ma ki n g t he m a p o p ulati o n wit h 
ver y hi g h u n met nee d ( N C C N -A M L 
2 0 2 1) .” 
A d de d t he state me nt,  “T he i nci de nce rate 
a n d se verit y of  t o xicities i n t hese F D A 
a p pr o ve d I D H 1 a n d I D H 2 i n hi bit ors is 
c o nsiste nt wit h t he safet y pr ofile of 
H M P L -3 0 6 i n patie nts wit h he mat ol o gic 
mali g na ncies. F urt her details o n i de ntifie d 
a n d p ote ntial ris ks of H M P L -3 0 6 are 
pr o vi de d i n t he I n vesti gat or’s Br oc h ure 
(I B).” 
R e vise d  t he f oll o wi n g state me nt, “I n 
s u m mar y, patie nts wit h A M L w h o ha ve 
recei ve d at least 2 pri or li nes of t hera p y 
i ncl u di n g I D H i n hi bit ors a n d patie nts 
wit h AI T L a n d  H R -M D S w h o ha ve 
recei ve d at least 1 pri or li ne of t hera p y d o 
n ot ha ve via ble treat me nt o pti o ns .” 
La n g ua ge a d de d t o pr o vi de 
clarit y f or t he i nf or mati o n 
t o s u p p ort be nefit:ris k a n d 
ali g ne d t o esta blis he d 
t hera pies. 
Secti o n 4. 1. 1 – P art 1 ( D ose 
Escalati o n) , Safet y Re vie w 
C o m mittee , Secti o n 1 1. 1. 1 –  Safet y 
Re vie w C o m mittee  
A d de d state me nt “ T he S R C, o n a n 
o n g oi n g basis, will als o m o nit or t he 
be ne fit-ris k of H M P L-3 0 6 treat me nt i n t he 
e x pa nsi o n c o h ort a n d ma ke 
rec o m me n dati o ns o n t he c o nti n uati o n of 
e nr oll me nt i n t he st u d y. ”  
Re visi o n  pr o vi des a d d e d 
safet y m o nit ori n g meas ures 
f or P art 2. 
Secti o n 4. 1. 2 –  P art 2 ( D ose 
E x pa nsi o n) , St u d y Treat me nt, 
Secti o n 7. 1. 2 –  D ose E x pa nsi o n  
Re vise d t o i n dicate t hat patie nts will 
recei ve H M P L-3 0 6 dail y at “ 
 m g Q D 
( hi g hest t olera ble d ose e val uat e d i n t he 
d ose escalati o n part.”  
Re visi o ns  reflect t he hi g hest 
t olera ble d ose fr o m P art 1. 
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Section Number 
Summary of Change 
Rationale for Change 
Section 4.2.2.1 – 
Relapsed/Refractory Acute Myeloid 
Leukemia, Section 4.2.2.2 – 
Relapsed/Refractory High-Risk 
Myelodysplastic Syndrome, Section 
4.2.2.3 – Relapsed or Refractory 
Angio-immunoblastic T-cell 
Lymphoma 
Removed “Cohort A,” “Cohort B,” and 
“Cohort C” designations, respectively. 
All the patients enrolled in 
the dose escalation part 
were R/R AML patients. 
The study did not enroll any 
patients with 
myelodysplastic syndrome 
MDS or AITL, 2 other 
populations targeted for the 
originally planned 
expansion cohorts 
(Cohorts B and C) per 
Protocol 2020-306-GLOB1 
Amendment 4. 
Section 4.2.3 – Rationale for 
Biomarker Testing 
Removed possible concomitant 
co-mutation  sample analysis and added 
instead that results of local IDH mutation 
testing at screening will be used for further 
analyses. 
Language removed for 
clarification. 
Section 5.2 – Inclusion Criteria 
(Part 2) 
Removed c, “Patients with HR-MDS must 
have an IPSS-R score of >4.5 (high and 
very high risk) 
Combined d and e to specify that patients 
will have R/R AML, no standard 
therapeutic options available, and must 
have progressed on prior IDH treatment. 
Removed patients with HR-MDS and 
AITL. 
Removed Inclusion Criterion #5 and 6 
(AITL patients). 
The updates were made to 
reflect the removal of 
Cohorts B and C, and 
modification of Cohort A. 
Section 5.3 – Exclusion Criteria 
Added Exclusion Criterion #20 for Part 2 
only. 
Addition specifies the time 
period between treatment 
with IDH inhibitor and 
study drug administration. 
Section 6.1.2 – PK Week 
Added statement that PK week for a 
particular dose cohort will be optional and 
not mandatory if PK week data from 
5 patients have been collected at the same 
dose. 
Language added to clarify 
the requirement of PK 
week. 
Section 7.6.1 – Differentiation 
Syndrome Handling Principles 
Removed statements that there are no clear 
diagnostic criteria for differentiation 
syndrome and the associated clinical 
symptoms. 
New language was added to 
replace the statements that 
were removed in order to  
provide further clarification 
on clinical diagnosis of DS 
(Differentiation Syndrome)  
Section 8.2.2 – Expedited Reporting 
Added “Hy’s Law” to list of events that 
must be reported by investigators to the 
sponsor within 24 hours of first learning of 
the event. 
Revision was made for the 
importance of ensuring 
prompt reporting of Hy’s 
law/DILI cases following 
guidance from the Health 
Authorities (FDA Guidance 

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 10 
 
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Section Number 
Summary of Change 
Rationale for Change 
2009) 
https://www.fda.gov/media/
116737/download 
Section 8.7 – Duration of Follow-up 
for Adverse Events 
Added, “start of new oncology treatment” 
as an end point for follow-up of AEs and 
SAEs. 
Revision made to provide 
further clarification on  the 
end period of safety follow 
up 
Section 9.1.2.2 – Dose Expansion 
Part 
Updated the probability of observing an 
AE or CR in Dose Expansion Part given 
the change in sample size. 
The updates were made to 
reflect the removal of 
Cohorts B and C, and 
modification of Cohort A. 
Section 9.2.1 – Patient Disposition, 
Section 9.2.3 – Prior and 
Concomitant Medications 
Updated summarization to be by overall 
and by “cohorts” (not tumor types). 
The updates were made to 
reflect the removal of 
Cohorts B and C, and 
modification of Cohort A. 
Section 9.2.7 – Efficacy Analysis 
Added a statement that the efficacy 
analysis will only be conducted for AML 
patients. Other tumor assessment data 
(HR-MDS or AITL) will be listed. 
Revised baseline transfusion dependence 
timing to 28 days (from 56 days). 
Removed efficacy data language regarding 
corresponding tumor types from Part 1. 
The updates were made to 
reflect the removal of 
Cohorts B and C, and 
modification of Cohort A 
and to reflect the response 
to FDA Information 
Request received on 
20 September 2022 for 
IND 150936. 
Section 9.2.7.2 –Tumor Response 
Endpoints for Patients with 
HR-MDS, Section 9.2.7.3 –Tumor 
Response Endpoints for Patients 
with AITL 
Sections deleted. 
The deletions were made to 
reflect the removal of 
Cohorts B and C. 
Appendix 1 – 
PK/PD/Biomarker/ECG 
Assessments for Escalation Cohorts 
Blood and Bone Marrow Samples for 
Gene Mutation Analysis – all sample 
collections removed except for screening. 
Revisions made to simplify 
biological sample collection 
and testing schedule. 
Appendix 2 – 
PK/PD/Biomarker/ECG 
Assessments for Expansion Cohort 
Added an X for blood sample collection 
for 2-HG at predose on C1D1. 
Removed X for blood sample collection 
for 2-HG at predose on C1D2 and C2D2. 
Shifted the study day for serial PK blood 
sample collection from C2D1 to C3D1. 
Shifted the study day for predose PK blood 
sample collection from C2D2 to C3D2. 
Shifted the study day for triplicate ECG 
collection from C2D1 to C3D1 
Removed footnote 4. 
Revisions made to optimize 
biological sample and ECG 
collection schedule. 
 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
DOCUMENT HISTORY............................................................................................................... 5 
AMENDMENT SUMMARY ........................................................................................................ 6 
TABLE OF CONTENTS ............................................................................................................. 11 
LIST OF TABLES ....................................................................................................................... 16 
LIST OF APPENDICES .............................................................................................................. 17 
LIST OF ABBREVIATIONS ...................................................................................................... 19 
1 
PROTOCOL SUMMARY ............................................................................................... 23 
1.1 
Synopsis ........................................................................................................................ 23 
1.2 
Study Schematic............................................................................................................ 26 
1.3 
Schedule of Events ........................................................................................................ 26 
2 
INTRODUCTION ........................................................................................................... 35 
2.1 
Study Rationale ............................................................................................................. 35 
2.1.1 
Investigational Product .............................................................................................. 35 
2.1.2 
Isocitrate Dehydrogenase ........................................................................................... 35 
2.1.2.1 
Mutations of IDH .................................................................................................... 35 
2.1.2.2 
Mutations and Malignancies ................................................................................... 35 
2.1.2.3 
Rationale and Benefits of Targeting All mIDHs Simultaneously .......................... 36 
2.2 
Background ................................................................................................................... 36 
2.2.1 
Description of HMPL-306 ......................................................................................... 37 
2.2.2 
Supportive Nonclinical Data ...................................................................................... 37 
2.2.2.1 
Pharmacology ......................................................................................................... 37 
2.2.2.2 
Pharmacokinetics .................................................................................................... 38 
2.2.2.3 
Toxicology .............................................................................................................. 39 
2.2.3 
Supportive Clinical Data ............................................................................................ 39 
2.3 
Benefit/Risk Assessment .............................................................................................. 39 
2.3.1 
Benefit-Risk Assessment ........................................................................................... 39 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 41 
4 
STUDY PLAN ................................................................................................................. 42 

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4.1 
Study Design ................................................................................................................. 42 
4.1.1 
Part 1 (Dose Escalation)............................................................................................. 42 
4.1.2 
Part 2 (Dose Expansion) ............................................................................................ 46 
4.2 
Design Rationale ........................................................................................................... 46 
4.2.1 
Rationale for Starting Dose and Dosing Regimen ..................................................... 46 
4.2.2 
Rationale for Study Population Selection .................................................................. 47 
4.2.2.1 
Relapsed/Refractory Acute Myeloid Leukemia...................................................... 48 
4.2.2.2 
Relapsed/Refractory High-Risk Myelodysplastic Syndrome ................................. 48 
4.2.2.3 
Relapsed or Refractory Angio-immunoblastic T-cell Lymphoma ......................... 49 
4.2.3 
Rationale for Biomarker Testing ............................................................................... 49 
5 
POPULATION ................................................................................................................ 50 
5.1 
Definitions..................................................................................................................... 50 
5.1.1 
Informed Consent and Screening Period ................................................................... 50 
5.1.1.1 
Pre-Screening Period .............................................................................................. 50 
5.1.1.2 
Screening Period ..................................................................................................... 50 
5.1.1.3 
Rescreening ............................................................................................................. 50 
5.2 
Inclusion Criteria .......................................................................................................... 51 
5.3 
Exclusion Criteria ......................................................................................................... 52 
6 
STUDY CONDUCT ........................................................................................................ 54 
6.1 
Study Procedures .......................................................................................................... 54 
6.1.1 
Study Drug Administration ........................................................................................ 54 
6.1.1.1 
Dose Escalation ....................................................................................................... 54 
6.1.1.2 
Dose Expansion ...................................................................................................... 54 
6.1.2 
PK Week .................................................................................................................... 54 
6.1.3 
Medical History and Demographic Information ........................................................ 54 
6.1.4 
Prior and Concomitant Medications and Concomitant Procedures ........................... 55 
6.1.5 
Lifestyle Management ............................................................................................... 55 
6.1.6 
Vital Signs .................................................................................................................. 55 
6.1.7 
Physical Examination, Weight, and Height ............................................................... 55 
6.1.8 
ECOG Performance Status ........................................................................................ 55 
6.1.9 
Ophthalmologic Examination .................................................................................... 55 
6.1.10 
Laboratory Evaluations .............................................................................................. 56 

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6.1.10.1 
Hematology – Routine ............................................................................................ 56 
6.1.10.2 
Hematology – Blood Transfusion History and Blood Transfusion Record ............ 56 
6.1.10.3 
Hematology – Bone Marrow Aspiration and/or Biopsy ......................................... 56 
6.1.10.4 
Blood Chemistry ..................................................................................................... 57 
6.1.10.5 
Blood Amylase and Lipase ..................................................................................... 57 
6.1.10.6 
Fasting Lipid Panel ................................................................................................. 57 
6.1.10.7 
Coagulation Indicators ............................................................................................ 57 
6.1.10.8 
HbA1C .................................................................................................................... 57 
6.1.10.9 
Pregnancy Test ........................................................................................................ 57 
6.1.10.10 
Urinalysis ................................................................................................................ 58 
6.1.10.11 
Virological Screening ............................................................................................. 58 
6.1.10.12 
IDH Mutational Status ............................................................................................ 58 
6.1.10.13 
Tumoral Sample for Patients with AITL ................................................................ 58 
6.1.11 
Electrocardiogram ...................................................................................................... 58 
6.1.12 
Echocardiogram/Multigated Acquisition Scan .......................................................... 58 
6.1.13 
Safety Evaluation ....................................................................................................... 58 
6.1.14 
Efficacy Evaluation .................................................................................................... 59 
6.1.14.1 
Risk Stratification/Prognostic Scoring .................................................................... 60 
6.1.14.2 
Ann-Arbor Staging.................................................................................................. 60 
6.1.15 
Pharmacokinetics and Pharmacodynamic Evaluations .............................................. 60 
6.1.15.1 
Sample Collection and Handling ............................................................................ 60 
6.1.15.2 
Analytical Procedures ............................................................................................. 60 
6.1.16 
IDH Mutation Confirmation ...................................................................................... 60 
6.1.17 
Exploratory Biomarker Evaluation ............................................................................ 61 
6.1.18 
End of Treatment Visit............................................................................................... 61 
6.1.19 
Follow-up Period ....................................................................................................... 61 
6.1.20 
End of Study .............................................................................................................. 62 
6.2 
Discontinuation or Withdrawal ..................................................................................... 62 
6.2.1 
Discontinuation of Treatment .................................................................................... 62 
6.2.1.1 
Permanent Discontinuation of Treatment ............................................................... 62 
6.2.1.2 
Temporary Treatment Discontinuation ................................................................... 62 
6.2.1.3 
Withdrawal from Study........................................................................................... 63 

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6.2.1.4 
Replacement of Patients .......................................................................................... 63 
6.2.1.5 
Patients Lost to Follow-up ...................................................................................... 63 
6.2.2 
Study Stopping Rules ................................................................................................. 63 
6.2.2.1 
Stopping Rules for Individual Patient ..................................................................... 64 
6.2.2.2 
Stopping Rules for a Cohort or the Study ............................................................... 64 
6.3 
Study Termination ........................................................................................................ 65 
7 
STUDY INTERVENTIONS ........................................................................................... 66 
7.1 
Study Drug Administration ........................................................................................... 66 
7.1.1 
Dose Escalation .......................................................................................................... 66 
7.1.2 
Dose Expansion ......................................................................................................... 66 
7.2 
Description of Products................................................................................................. 66 
7.2.1 
Formulation, Storage, Preparation, and Handling ..................................................... 66 
7.2.2 
Drug Accountability................................................................................................... 67 
7.2.2.1 
Assignment/Disposal (Study Site) .......................................................................... 67 
7.2.2.2 
Drug Return (Patient) .............................................................................................. 67 
7.3 
Assessment and Verification of Compliance ................................................................ 67 
7.4 
Prior and Concomitant Therapies ................................................................................. 68 
7.4.1 
Prohibited Therapies .................................................................................................. 68 
7.4.2 
Permitted Therapies ................................................................................................... 68 
7.4.3 
Drug-Drug Interactions .............................................................................................. 68 
7.4.4 
Rescue Therapies ....................................................................................................... 69 
7.5 
Dose Adjustments ......................................................................................................... 69 
7.5.1 
Adjustment of Dose Within the DLT Assessment Window ...................................... 69 
7.5.2 
Dose Adjustment Outside the DLT Assessment Window (Including Dose 
Expansion Part) .......................................................................................................... 69 
7.5.3 
Dose Adjustment for QT Interval Prolongation......................................................... 71 
7.5.4 
General Dose Adjustment Note ................................................................................. 71 
7.6 
Special Adverse Events Handling Principles ................................................................ 71 
7.6.1 
Differentiation Syndrome Handling Principles ......................................................... 71 
7.6.2 
Handling Principles for Noninfectious Leukocytosis ................................................ 73 
8 
SAFETY MONITORING ................................................................................................ 74 
8.1 
Definitions..................................................................................................................... 74 

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8.1.1 
Adverse Event ............................................................................................................ 74 
8.1.2 
Serious Adverse Event ............................................................................................... 74 
8.1.3 
Dose-Limiting Toxicity ............................................................................................. 74 
8.1.4 
Adverse Events of Special Interest ............................................................................ 75 
8.2 
Adverse Event Reporting .............................................................................................. 76 
8.2.1 
Adverse Event Reporting Period ............................................................................... 76 
8.2.2 
Expedited Reporting .................................................................................................. 76 
8.2.3 
Dose-Limiting Toxicity Reporting ............................................................................ 76 
8.3 
Eliciting Adverse Events............................................................................................... 76 
8.4 
Assessment of Severity ................................................................................................. 76 
8.5 
Causality Assessment.................................................................................................... 77 
8.6 
Documenting Adverse Events....................................................................................... 77 
8.6.1 
Diagnosis Versus Symptoms and Signs ..................................................................... 78 
8.6.2 
Adverse Event Occurring Secondary to Other Events ............................................... 78 
8.6.3 
Persistent or Recurrent Adverse Events ..................................................................... 78 
8.6.4 
Abnormal Laboratory Values or Abnormal Vital Signs ............................................ 78 
8.6.5 
Pre-existing Medical Condition ................................................................................. 79 
8.6.6 
Pregnancy ................................................................................................................... 79 
8.6.7 
Progression of Hematological Malignancy Under Study .......................................... 79 
8.6.8 
Death .......................................................................................................................... 80 
8.6.9 
Overdose .................................................................................................................... 80 
8.7 
Duration of Follow-up for Adverse Events .................................................................. 80 
9 
ANALYSIS ...................................................................................................................... 81 
9.1 
Statistics and Analysis Method ..................................................................................... 81 
9.1.1 
Statistical Hypothesis ................................................................................................. 81 
9.1.2 
Sample Size Rationale ............................................................................................... 81 
9.1.2.1 
Dose Escalation Part ............................................................................................... 81 
9.1.2.2 
Dose Expansion Part ............................................................................................... 81 
9.1.3 
Analysis Sets .............................................................................................................. 81 
9.2 
Statistical Analysis ........................................................................................................ 82 
9.2.1 
Patient Disposition ..................................................................................................... 82 
9.2.2 
Demographic and Other Baseline Characteristics ..................................................... 82 

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9.2.3 
Prior and Concomitant Medications .......................................................................... 83 
9.2.4 
Safety Analysis .......................................................................................................... 83 
9.2.5 
Pharmacokinetics Analysis ........................................................................................ 84 
9.2.6 
Pharmacodynamic Analysis ....................................................................................... 85 
9.2.7 
Efficacy Analysis ....................................................................................................... 85 
9.2.7.1 
Tumor Response Endpoints for Patients with AML ............................................... 86 
9.2.8 
Exploratory/Biomarker Analysis ............................................................................... 86 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 87 
10.1 
Good Clinical Practice .................................................................................................. 87 
10.2 
Ethics Review ............................................................................................................... 87 
10.3 
Informed Consent.......................................................................................................... 87 
10.4 
Data Privacy .................................................................................................................. 88 
10.5 
Disclosure ..................................................................................................................... 89 
10.6 
Data Quality Assurance ................................................................................................ 89 
11 
OVERSIGHT ................................................................................................................... 90 
11.1 
Independent Monitoring................................................................................................ 90 
11.1.1 
Safety Review Committee ......................................................................................... 90 
11.2 
Quality Control and Assurance ..................................................................................... 90 
11.2.1 
Monitoring ................................................................................................................. 91 
11.2.2 
Audits ......................................................................................................................... 91 
11.2.3 
Records ...................................................................................................................... 91 
11.2.3.1 
Data Capture and Management ............................................................................... 91 
11.2.3.2 
Source Documentation ............................................................................................ 92 
11.2.3.3 
Records Retention ................................................................................................... 92 
11.3 
Study Termination or Study Site Closure ..................................................................... 92 
12 
PUBLICATION POLICY ............................................................................................... 94 
13 
FINANCING AND INSURANCE .................................................................................. 95 
14 
REFERENCES ................................................................................................................ 96 
15 
APPENDICES ............................................................................................................... 102 
 
LIST OF TABLES  
Table 1 
Schedule of Events (Dose Escalation) ................................................................. 27 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a ge  1 7  
 
C O N FI D E N TI A L  
 
 
Ta ble  2  
Sc he d ule of E ve nts ( D os e E x pa nsi o n - Rela pse d/ Refract or y Ac ute M yel oi d 
Le u k e mia)  ............................................................................................................ 3 1  
Ta ble  3  
O bjecti ves a n d C orres p o n di n g E n d p oi nts  ............................................................ 4 1  
Ta ble  4  
Patie nt D ose Gr o u pi n g, D ose Escalati o n Pla n  ..................................................... 4 4  
Ta ble  5  
m T PI -2 D ecisi o n Ta ble f or D ose Selecti o n  ......................................................... 4 4  
Ta ble 6  
Starti n g D ose Calc ul ati o n  .................................................................................... 4 7  
Ta ble 8  
D ose A dj ust me nt f or He mat ol o gic T o xicit y  ........................................................ 7 0  
Ta ble 9  
D ose A dj ust me nt f or N o n he mat ol o gic T o xicit y  .................................................. 7 0  
Ta ble 1 0  
D ose A dj ust me nt f or Q T I nter val Pr ol o n gati o n ................................................... 7 1  
Ta ble 1 1  
Differe ntiati o n S y n dr o m e Dia g n osis a n d M o ntesi n os Gra di n g Criteria .............. 7 2  
Ta ble  1 2  
Me dicati o ns T hat Ca n Pr ol o n g Q T I nt er val ....................................................... 1 1 1  
 
LI S T O F A P P E N DI C E S   
A p pe n di x 1  
P K/ P D/ Bi o mar ker/ E C G Assess me nts f or Escalati o n C o h orts  .......................... 1 0 3  
A p pe n di x 2  
P K/ P D/ Bi o mar ker/ E C G Assess me nts f or E x pa nsi o n C o h ort  ............................ 1 0 5  
A p pe n di x  3  
E C O G Perf or ma n ce Stat us  ................................................................................ 1 0 7  
A p pe n di x  4  
C O VI D -1 9 Ris k Assess me nt  ............................................................................. 1 0 8  
A p pe n di x  5  
Ne w Y or k Heart Ass ociati o n F u ncti o n Classificati o n  ....................................... 1 1 0  
A p pe n di x  6  
Pr o hi bite d Me dicati o n  ........................................................................................ 1 1 1  
A p pe n di x  7  
 ............................................................. 1 1 2  
A p pe n di x  8  
2 0 1 7 E ur o pea n Le u ke mi a Net Effi cac y Criteria f or A M L  ................................. 1 1 3  
A p pe n di x 9  
L u ga n o R es p o nse Criteri a f or H o d g ki n a n d N o n -H o d g ki n’s L y m p h o ma  ......... 1 1 4  
A p pe n di x  1 0  List of S u bstrates of 
 . 1 1 7  
A p pe n di x 1 1  Differe ntiati o n S y n dr o m e S y m pt o ms a n d t he Na mes of P ossi ble I n cl u de d 
A d verse E v e nts, La b orat or y T ests, or Vital Si g ns A b n or malities  ..................... 1 1 8  
A p pe n di x  1 2  I N T E R N A TI O N A L W O R KI N G G R O U P R E S P O N S E C RI T E RI A I N 
M Y E L O D Y S P L A SI A  ....................................................................................... 1 1 9  
A p pe n di x 1 3  A N N -A R B O R S T A GI N G  ................................................................................. 1 2 1  
A p pe n di x 1 4  I N T E R N A TI O N A L P R O G N O S TI C I N D E X.................................................... 1 2 2  
A p pe n di x 1 5  2 0 1 7 E L N RI S K S T R A TI FI C A TI O N B Y G E N E TI C S  .................................... 1 2 3  
A p pe n di x 1 6  I N T E R N A TI O N A L P R O G N O S TI C S C O RIN G S Y S T E M R E VI S E D 
P R O G N O S TI C S C O R E V A L U E S  .................................................................... 1 2 4  
C CI
C CI
C CI

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Appendix 17 IMMUNOPHENOTYPING, CYTOGENETICS, and MOLECULAR GENETICS
............................................................................................................................ 125 
Appendix 18 Amendment History ........................................................................................... 126 
 

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LIST OF ABBREVIATIONS  
Abbreviations 
Definitions 
%AUCext 
Percentage of AUC0-inf obtained by extrapolation 
2-HG 
2-hydroxyglutaric acid 
ADL 
Activities of daily living 
AE 
Adverse event 
AITL 
Angio-immunoblastic T-cell lymphoma 
allo-HSCT 
Allogeneic hematopoietic stem cell transplantation  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
AML 
Acute myeloid leukemia 
AR 
Accumulation ratio 
AST 
Aspartate aminotransferase  
AUC0-24 
Area under the plasma concentration-time curve from time 0 to 24 hours 
AUC0-inf 
Area under the plasma concentration-time curve from time 0 to infinity 
AUC0-t 
Area under the plasma concentration-time curve from time 0 to time of the last 
measurable concentration 
AUC0-τ 
Area under the plasma concentration-time curve within the dosing interval 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
C1D1 
Cycle 1 Day 1 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CIR 
Cumulative incidence of relapse 
CL/F 
Total plasma clearance of drug after extravascular administration 
Cmax 
Maximum observed plasma concentration 
Cmaxss 
Maximum observed plasma concentration (at steady state) 
Cmin 
Minimum plasma concentration 
Cminss 
Minimum observed plasma concentration (at steady state) 
CMR 
Complete metabolic response  
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRF 
Case report form (electronic or paper) 
CRh 
Complete response with partial hematological recovery 
CRi 
Complete response with incomplete count recovery 
CRMRD- 
Complete response with negative minimal residual disease 
CRO 
Contract research organization 

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Abbreviations 
Definitions 
CRR 
Complete radiologic response 
CSR 
Clinical study report 
CT 
Computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of variation 
CYP 
Cytochrome p450 
DFS 
Disease-free survival 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DS 
Differentiation syndrome 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EFS 
Event-free survival 
EOT 
End of treatment 
ESMO 
European Society for Medical Oncology 
EUA 
Emergency use authorization 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HI 
Hematological improvement 
HIV 
Human immunodeficiency virus 
HMA 
hypomethylating agent(s) 
HNSTD 
Highest nonseverely toxic dose 
HR-MDS 
High-risk myelodysplastic syndrome 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IDH 
Isocitrate dehydrogenase 

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Abbreviations 
Definitions 
IEC 
Independent Ethics Committee 
IPSS-R 
Revised International Prognostic Scoring System 
IRB 
Institutional Review Board  
IWG 
International working group 
MATE 
Multidrug and toxin extrusion 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mIDH 
Mutant IDH 
MLFS 
Morphologically leukemia-free state 
MPN 
Myeloproliferative neoplasm 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTPI-2 
Modified toxicity probability interval-2 
MUGA 
Multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
Next generation sequence 
NOAEL 
No-observed-adverse-effect level 
OATP 
Organic anion transporting polypeptide 
OCT 
Optical coherence tomography 
ORR 
Objective response rate 
OS 
Overall survival 
OTC 
Over-the-counter 
PD 
Pharmacodynamic(s) 
PET-CT 
Positron emission tomography-computed tomography 
PFS 
Progression-free survival 
PrD 
Progressive disease 
P-gp 
P-glycoproteins 
PK 
Pharmacokinetic(s) 
PMR 
Partial metabolic response 
PO 
Orally 
PR 
Partial response 
PRe 
Partial remission 
PS 
Performance status 
PT 
Prothrombin time 
QD 
Once daily 
QTc 
Corrected QT 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a ge  2 2  
 
C O N FI D E N TI A L  
 
 
A b bre vi ati o ns  
Defi niti o ns  
Q T c F  
Q T i nter val c orrecte d  f or heart rate usi n g Fri dericia's f or m ula 
R/ R  
Rela pse d/refract or y  
R B C  
Re d bl o o d cell  
R P 2 D  
Rec o m me n de d p hase 2 d ose  
R P E  
Reti nal p i g me nt epit heli u m  
S A E  
Seri o us a d verse e ve nt  
S D  
Sta ble disease  
S O C  
S yste m Or ga n Class  
S R C  
Safet y Re vie w C o m mittee  
t1/ 2 
Eli mi nati o n half -life 
T E  
T ar get e n ga ge me nt  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T L S  
T u m or l ysis s y n dr o me  
T ma x  
Ti me t o reac h t he ma xi m u m plas ma c o nce ntrati o n  
T T R  
Ti me t o res p o nse  
U L N  
U p per li mit of n or mal  
V z/ F 
A p pare nt v ol u me of distri b uti o n  
W B C  
W hite bl o o d cell  
α -K G  
α -K et o gl utaric aci d 
λ Z  
A p pare nt first -or der rate c o nsta nt ass ociate d wit h t he ter mi nal p orti o n of t he c ur ve  
 
C CI

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a ge  2 3  
 
C O N FI D E N TI A L  
 
 
1  
P R O T O C O L S U M M A R Y   
1. 1  
S y n o psis   
Title  
A P hase 1, O pe n -La bel, M ulti ce nter St u d y of H M P L -3 0 6 i n A d va nce d 
He mat ol o gical Mali g na ncies W it h Is ocitrate De h y dr o ge nas e (I D H) M utati o ns 
S h ort Title  
A P hase 1 St u d y of H M P L -3 0 6 i n A d va nce d He mat ol o gical Mali g na ncies 
W it h mI D H  
P h ase  
1  
St u d y St at us as of  Pr ot oc ol 
A me n d me nt 5  
As of 2 3  Oct o ber  2 0 2 3, t he d ose e x pa nsi o n c o h orts of S t u d y 2 0 2 0‑ 3 0 6‑ G L O B 1 
will b e m o difie d  base d u p o n t he strate gic e val uati o n of t he u n met  nee d a n d t he 
a bilit y t o e nr oll i n selecte d p o p ulati o ns . I n E x pa nsi o n C o h ort A, t he st u d y will 
e nr oll 1 0  rela pse d or refract or y ac ute m yel o i d le u ke mia (R/ R A M L)  patie nts , 
li mite d t o patie nts w h o ha ve r ecei ve d pri or I D H i n hi b it or t hera p y. T he safet y 
a n d t olera bilit y as well as pr o of of acti vit y will be e val uate d at t he hi g hest 
t olera ble d ose le vel e val uate d i n t he d ose escalati o n p art ( 
 m g o nce dail y 
[Q D ]). E x pa nsi o n C o h orts B (m y el o d ys plastic s y n dr o me [ M D S ]) a n d C 
(a n gi o -i m m n o blastic T-cell l y m p h o ma [ AI T L ]) are re m o ve d , as t hese patie nts 
were n ot e val uate d i n t he d ose escalati o n  p art d ue t o lac k  of e nr oll me nt i n 
t hese p o p ulati o ns .  T his c ha n ge is n ot base d o n a n y c o ncer n f or patie nt safet y 
or efficac y relati ve t o H M P L‑ 3 0 6 treat me nt.  
R ati o n ale  
Is ocitrate de h y dr o ge nase is t he e nz y me t hat catal yzes 1 of  4  rate-li miti n g ste ps 
i n t he Kre bs  c ycle, or citric aci d c ycle .  I D H m utati o n pla ys a maj or r ole i n 
carci n o ge nesis a n d has bee n f o u n d i n m ulti ple t u m ors, i ncl u di n g he mat ol o gical 
mali g na ncies , s uc h as A M L, hi g h -ris k m yel o d ys plastic sy n dr o me  (H R -M D S ), 
m yel o pr oliferati ve ne o plas m  (M P N ), a n d AI T L, a n d s oli d t u m ors s uc h as 
gli o ma, c h o n dr osarc o ma, a n d c h ola n gi ocarci n o ma .  Cli nical de vel o p me nt of 
a n i n hi bit or s uc h as H M P L -3 0 6 t hat tar gets, i n hi bits , a n d s u p presses m ulti ple 
m uta nt I D Hs ( mI D Hs ) c o nc urre ntl y c o ul d lea d t o si g nifica nt a n d d ura ble 
cli nical be nefit.   
T ar g et P o p ul ati o n  
A d ult male a n d fe male patie nt s ≥1 8 years of a ge  wit h a d va nce d rela pse d, 
refract or y, or resista nt he mat ol o gical mali g na ncies t hat har b or I D H m utati o ns  
( or c o-m utati o n) .  D ose  e x pa nsi o n p art will e nr oll R/ R  A M L patie nts  w h o m ust  
n ot ha ve sta n dar d t hera pe utic o pti o ns a vaila ble. T he patie nts m ust ha ve 
recei ve d at least 1 pri or li ne of t hera p y wit h I D H i n hi bit ors.  
I nter v e nti o n 
P art 1 ( D ose escalati o n) : 
 m g 
H M P L -3 0 6 orall y  (P O ) o nce dail y ( Q D ) 
P art 2 ( D ose e x pa nsi o n) : Rec o m me n de d p hase 2 d ose ( R P 2 D ) or  m a xi m u m 
t olerate d d ose (M T D ) fr o m P art  1 P O Q D  
Descri pti o n of Sites  
A p pr o xi matel y 4 0 st u d y sites i n t he U nite d States, E ur o pe, A ustralia , a n d Asia.  
O bjecti ves a n d E n d p oi nts  
O bjecti ves  
C orres p o n di n g E n d p oi nts  
Pri m ar y : 
•  P art 1 : T o e val uate t he safet y a n d t olera bilit y of 
H M P L -3 0 6 i n patie nt s wit h a d va nce d 
he mat ol o gical mali g na ncies t hat har b or I D H 
m utati o ns  
Pri m ar y:  
•  M T D a n d/ or R P 2 D  
•  Safet y i ncl u di n g d ose -li miti n g t o xicities (D L Ts ), 
treat me nt-e mer ge nt a d verse e ve nts  (T E A Es ), 
seri o us a d verse e ve nts (S A Es ), deat hs, 
electr ocar di o gra ms (E C Gs ), a n d cli nical la b orat or y 
a b n or malities  
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Amendment 5 
 
 
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• Part 2: To characterize safety and tolerability and to 
determine RP2D of HMPL-306 in patients with 
advanced hematological malignancies that harbor 
IDH mutations 
• Safety including DLTs, TEAEs, SAEs, deaths, 
ECGs, and clinical laboratory abnormalities 
Secondary: 
• To assess preliminary antitumor activity of 
HMPL-306 in patients with advanced 
hematological malignancies that harbor IDH 
mutations 
Secondary: 
• Best overall response, objective response rate 
(ORR), time to response (TTR), duration of 
response (DoR), clinical benefit rate (CBR), 
progression-free survival (PFS), overall survival 
(OS), disease free survival (DFS), event-free 
survival (EFS), and post-baseline transfusion 
independence 
• To assess pharmacokinetics (PK) of HMPL-306 in 
patients with advanced hematological 
malignancies that harbor IDH mutations 
• Observed plasma concentrations and drug exposure 
parameters of HMPL-306 
• To assess pharmacodynamics (PD) of HMPL-306 
in patients with advanced hematological 
malignancies that harbor IDH mutations 
• Observed plasma concentrations of 
2-hydroxyglutarichydroxyglutaric acid (2-HG) 
Exploratory: 
• 
To explore relationships between changes in 
frequency of genetic mutations, efficacy, PK, PD, 
and safety after HMPL-306 treatment 
Exploratory: 
• 
Changes from baseline in tumor markers, 
correlation with drug exposure, target engagement, 
and efficacy and safety outcomes 
• 
To explore relationships between HMPL-306 PK 
drug exposure, target engagement (TE), 2-HG 
levels, and percentage inhibition 
• 
To explore the influence of genetic abnormalities 
(other than IDH mutations) on safety, efficacy, 
PD, PK, and clinical response to HMPL-306 
treatment 
Brief Summary: 
This is a phase 1, open-label, multicenter, single-arm study to evaluate safety, tolerability, PK, PD, and 
preliminary efficacy of HMPL-306 administered orally in treatment of patients with advanced relapsed, 
refractory, or resistant hematological malignancies that harbor IDH mutations (or co-mutations).  The study 
consists of 2 parts: a dose escalation part (Part 1) and a dose expansion part (Part 2).  The dose escalation part will 
determine the MTD/R2PD.  The dose expansion part will administer the MTD/RP2D to: 
• 
R/R AML patients  who do not have standard therapeutic options available. The patients must have received 
at least 1 prior line of therapy with IDH inhibitors 
Condition/Disease 
Advanced relapsed, refractory, or resistant hematological malignancies that 
harbor IDH mutations  
Study Duration 
Approximately 36 months  
Treatment Duration 
28-day continuous dosing treatment cycle 
Health 
Measurement/Observation 
This study will determine the MTD and/or RP2D as well as safety assessments 
including DLTs, TEAEs, SAEs, ECGs, and clinical laboratory abnormalities.  
During the dose expansion part, patients will receive HMPL-306 daily at 
MTD/RP2D, for treatment cycles of 28 days until disease progression, death, 
intolerable toxicity, withdrawal of consent, lost to follow-up, conditions are 
met per Section 6.2.1, or end of study, whichever comes first. 
Visit Frequency 
PK week: every day for 1 week (Part 1 only) 
Cycle 1: every week (±1 day, except D1) 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a ge  2 5  
 
C O N FI D E N TI A L  
 
 
C ycle 2:  e ver y 2 wee ks ( ± 1  da y)  
C ycle 3 a n d o n war ds: da y 1 ( ± 3 da ys)  
Treat me nt c o m pleti o n: wit hi n  7 da ys  ( ± 3 da ys) after t he last d ose  
N u m ber of P atie nt s 
A t otal of a p pr o xi matel y 4 0  t o 5 0 e val ua ble patie nts e x pecte d bet wee n P arts 1 
a n d 2.  
P art  1: at least 3 patie nt s will be e nr olle d at eac h d ose le vel; a p pr o xi matel y 
2 4  t o 3 0 e val ua ble patie nt s 
P art  2: a p pr o xi matel y 1 0 patie nts  
I nter v e nti o n Gr o u ps a n d 
D ur ati o n  
P art  1: 
 m g of H M P L -3 0 6 P O Q D 
a d mi nistere d t o gr o u ps of at le ast 3 patie nt s f or 2 8-da y  c ycle s  
P art  2: M T D/ R P 2 D as deter mi ne d  i n P art  1 , a d mi nistere d P O Q D t o 
a p pr o xi mate l y 1 0  patie nt s f or 2 8-da y  c ycle s 
D at a M o nit ori n g/ Ot her 
C o m mittee  
Yes  
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Clinical Study Protocol 2020-306-GLOB1
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Amendment 5
HUTCHMED Limited
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CONFIDENTIAL
1.2
Study Schematic
AML=acute myeloid leukemia; ECOG PS=Eastern Cooperative Oncology Group Performance Status; IDH=isocitrate 
dehydrogenase; mTPI2=modified toxicity probability interval-2; QD=once daily; RP2D = recommended phase 2 
dose R/R = relapsed/refractory.
Note: Patients in dose expansion must have documented IDH1 or IDH2 mutations. Patients must not have any standard 
therapeutic options available and must have received at least 1 prior line of therapy with IDH inhibitors.
1.3
Schedule of Events
The Schedules of Events are presented in Table 1 (dose escalation) and Table 2 (dose expansion).
CCI
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Table 1 
Schedule of Events (Dose Escalation)  
Cycle/Period 
Pre-
screening 
Screening 
PK 
Weeka 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Survival 
Follow-up 
Visit 
Single 
Dose 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 days 
after 
last 
dose 
30 days 
after 
EOT 
Visit 
Every 
12 weeks 
from EOT 
Visit 
Every 
12 weeks 
from EOT 
Visit 
Visit window (days) 
 
-28 to -1 
0 
0 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-screening informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main informed consentb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
mIDH statusc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographicsd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
and concomitant procedurese 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Heightf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs, and 
weightf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance statusf 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Ophthalmologic examinationg 
 
X 
 
 
 
 
 
X 
(±1 
week) 
 
Every 12 weeks 
from C4D1 
(±7 days) 
X 
 
 
Laboratory evaluations:f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistryi 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood amylase and lipase 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Fasting lipid panelj 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Coagulation indicatorsk 
 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
 
HbA1C 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Pregnancy testl 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
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CONFIDENTIAL 
 
 
Cycle/Period 
Pre-
screening 
Screening 
PK 
Weeka 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Survival 
Follow-up 
Visit 
Single 
Dose 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 days 
after 
last 
dose 
30 days 
after 
EOT 
Visit 
Every 
12 weeks 
from EOT 
Visit 
Every 
12 weeks 
from EOT 
Visit 
Visit window (days) 
 
-28 to -1 
0 
0 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysism 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Virological screeningn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood and/or bone marrow aspiration 
and/or biopsyo 
 
 
Refer to Appendix 1 
 
PK and PD assessments 
 
 
Refer to Appendix 1 
 
12-lead ECGp 
 
 
Refer to Appendix 1   
 
ECHO/MUGA scanq 
 
X 
 
X 
 
 
 
X 
 
Cycle 3 
Day 1 
then 
Day 1 of 
every 
odd cycle 
X 
 
 
 
Tumor evaluation/imagingy 
 
X 
 
Every 8 weeks (±7 days) during the first 24 weeks and 
every 12 weeks (±14 days) thereafter 
X 
 
X 
 
Blood transfusion historyr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood transfusion records 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug/dispense/returnv  
 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
Study drug administration 
 
 
Refer to Table 4 
 
 
 
 
AEst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival follow-upu 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ann-Arbor stagingw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Risk stratification/Prognostic scoringx 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a ge 2 9  
 
C O N FI D E N TI A L  
 
 
2 -H G = 2 -h y dr o x y gl utaric aci d; A E =a d verse e ve nt; AI T L =a n gi o -i m m u n o blastic T-cell l y m p h o ma; a P T T =acti vate d partial t hr o m b o plasti n ti me;  C =c ycle; D = da y; 
E C G =electr ocar di o gra m; E C H O =ec h 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; E O T =e n d of treat me nt; H b A 1 C = he m o gl o bi n A 1 C; 
I C F =i nf or me d c o nse nt f or m; I D H =is ocitrate de h y dr o ge nase; I N R =i nter nati o nal n or malize d rati o; I PI =i nter nati o nal pr o g n ostic i n de x; I P S S-R Sc ore = R e vise d 
I nter nati o nal Pr o g n ostic Sc ori n g S yste m; H R -M D S = hi g h -ris k m yel o d ys plastic s y n dr o me; mI D H = m uta nt I D H; M U G A = m ulti gate d ac q uisiti o n; O C T = o ptical 
c o here nce t o m o gra p h y; P D = p har mac o d y na mics; P K = p har mac o ki netics; P R = partial res p o nse; P T = pr ot hr o m bi n ti me.  
a 
P K wee k is a p plica ble t o t he d ose escalati o n c o h orts o nl y .  See A p pe n di x 1  f or details.  F or patie nt s e nr olle d i n d ose es calati o n, a si n gle d ose of H M P L-3 0 6 
will be a d mi nistere d o n D 1 of t he P K wee k ( 7 da ys pri or t o C 1 D 1)  f or eac h d ose le vel, a n d serial bl o o d sa m ples will be c ollecte d (f or a nal ysis of plas ma 
c o nce ntrati o ns of H M P L -3 0 6 , 2 -H G , a n d ot her bi ol o gical mar kers as defi ne d b y t he s p o ns or ) a n d E C G  as s pecifie d i n A p pe n di x 1 . 
b 
Pr oce d ural d etails are a vaila bl e i n Secti o n 5. 1. 1 .   
c 
P atie nt s s h o ul d ha ve a l ocal re p ort of I D H m utati o nal a nal ysis, c o nfir mi n g mI D H .   
d   
Pr oce d ural details f or me dical hist or y  a n d de m o gra p hics  are a vaila ble i n Secti o n  6. 1. 3 . 
e 
Pr oce d ural details f or pri or a n d c o nc o mita nt me dicati o ns/tre at me nts are a vaila ble i n Secti o n 6. 1. 4 . 
f 
Pr oce d ural details are a vaila ble i n Secti o n 6. 1. 6  ( vital si g ns), Secti o n 6. 1. 7  ( p h ysical e xa mi nati o n, wei g ht, a n d hei g ht), Secti o n 6. 1. 8  ( E C O G perf or ma nce 
stat us), a n d Secti o n  6. 1. 1 0  (la b orat or y e val uati o ns). 
g 
O p ht hal m ol o gic assess me nts, i ncl u di n g e ye a p peara nce, slit la m p e xa mi nati o n, best c orrecte d vis ual ac uit y, vis ual fiel d, e ye m o ve me nt, p u pil refle x, O C T, 
a n d i ntra oc ular press ure will be perf or me d d uri n g t he Scre e ni n g P eri o d .  If t he s u bj ect has u n der g o ne t he rele va nt e xa mi nati o ns 6 0 da ys bef ore t he start of 
st u d y treat me nt ( C 1 D 1), t he y nee d n ot be re peate d.  After t he start of st u d y dr u g a d mi nistr ati o n, O C T will be perf or me d at 6 wee ks ( ± 1 wee k), t he n O C T, e ye 
a p peara nce, a n d slit la m p e xa mi nati o ns will be perf or me d e ver y 1 2 wee ks ( ± 1 wee k) fr o m C 4 D 1 a n d at t he E O T visit .  Ot her o p ht hal m ol o gic a l e xa mi nati o ns 
are t o be perf or me d w he n cli nicall y i n dicate d .  If t he s u bj ect de vel o ps a n o p ht hal mic A E relate d t o H M P L-3 0 6, t he fre q ue nc y of t he e xa mi nati o n s h o ul d be 
i ncrease d t o o nce e ver y c ycle u ntil t he A E is relie ve d or sta ble  
h 
Pr oce d ural details f or he mat ol o g y are a vai la ble i n Secti o n 6. 1. 1 0. 1 .   
i 
Pr oce d ural details f or b l o o d c he mistr y are a vaila ble i n Secti o n 6. 1. 1 0. 4 . 
j 
Pr oce d ural details f or f asti n g li pi d pa nel  are a vaila ble i n Secti o n 6. 1. 1 0. 6 . 
k  
C oa g ulati o n tests i ncl u de P T, I N R, a n d a P T T .  A d diti o nal pr oce d ural details f or c oa g ulati o n i n dicat ors  are a vaila ble i n S ecti o n 6. 1. 1 0. 7 .   
l 
A d diti o nal pr oce d ural details f or pre g na nc y testi n g are a vaila ble i n Secti o n 6. 1. 1 0. 9 . 
m  
Uri nal ysis i ncl u des uri ne gl uc ose, pr otei n, ket o ne b o d y, re d bl o o d cells, w hite bl o o d cells, a n d ur o bili n o ge n .  A d diti o nal pr oce d ural details are a vaila ble i n 
Secti o n 6. 1. 1 0. 1 0 . 
n 
A d diti o nal pr oce d ural details f or vir ol o gical scree ni n g are a vaila ble i n Secti o n 6. 1. 1 0. 1 1 . 
o 
W h ole bl o o d  a n d/ or b o ne marr o w sa m ples will be c ollecte d a n d pr o vi de d  t o a ce ntral la b orat or y f or 
 a nal yses. See A p pe n di x 1  f or 
details.  
p 
E val uati o n ti me p oi nts are s h o w n i n A p pe n di x 1  a n d A p pe n di x 2 .  A d diti o nal pr oce d ural details f or t he 1 2 -lea d E C G are a vaila ble i n Secti o n 6. 1. 1 1 . 
q  
A d diti o nal pr oce d ural details are pr o vi de d f or E C H O a n d M U G A i n S ecti o n 6. 1. 1 2 . 
r 
A d diti o nal pr oce d ural details f or b l o o d tra nsf usi o n hist or y are pr o vi de d i n Secti o n 6. 1. 1 0. 2 . 
s 
A d diti o nal pr oce d ural details f or b l o o d tra nsf usi o n rec or d are pr o vi de d i n Secti o n 6. 1. 1 0. 2 . 
t 
A Es d ue t o t he pr ot oc ol -re q uire d i nter ve nti o n will be c ollecte d fr o m si g nat ure of t he I C F.  A d diti o nal details are pr o vi de d i n Secti o n 5. 1. 1 .   
u 
S ur vi val f oll o w -u p s h o ul d be perf or me d e ver y 1 2 wee ks ( ± 2 wee ks) after t he E O T Visit .  A d diti o nal details are pr o vi de d i n Secti o n 6. 1. 1 9 . 
v 
If t u m or e val uati o n s h o ws pr o gressi ve disease d uri n g pre vi o us c ycle  a n d ne w dr u g has be e n dis pe nse d, patie nt  m ust ret ur n all u n use d st u d y dr u g o n 3 0 -da y 
safet y visit after E O T. 
w  
A p plica ble f or patie nts wit h AI T L ; see A p pe n di x 1 3  f or a descri pti o n of A n n-Ar b or sta gi n g . 
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Clinical Study Protocol 2020-306-GLOB1 
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x 
Additional procedural details for risk stratification/prognostic stratification and scoring are available in Section 6.1.14.1.  
y 
Bone marrow aspiration or biopsy will include local immunophenotyping, cytogenetic analysis, and molecular genetic testing.  Additional procedural details 
are available in Section 6.1.10.3, Section 6.1.10.13, and Appendix 17.  

Clinical Study Protocol 2020-306-GLOB1 
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Table 2 
Schedule of Events (Dose Expansion - Relapsed/Refractory Acute Myeloid Leukemia)  
Cycle/Period 
Pre-screening 
Screening 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Survival 
Follow-up 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 days 
after 
last 
dose 
30 days 
after 
EOT 
Visit 
Every 
12 weeks 
from 
EOT 
Visit 
Every 
12 weeks 
from 
EOT 
Visit 
Visit window (days) 
 
-28 to 
-1 
-7 to 
-1 
0 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-screening 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main informed consenta 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
mIDH statusb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographicsc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications and 
concomitant proceduresd 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Heighte 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination, 
vital signs, and weighte 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG 
performance 
statuse 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Ophthalmologic 
examinationf 
 
X 
 
 
 
 
 
X  
(±1 
week) 
 
Every 12 weeks 
from C4D1 
(±7 days) 
 
 
 
Laboratory evaluations:e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyg 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistryh 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood 
amylase 
and 
lipase 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 32 
 
CONFIDENTIAL 
 
 
Cycle/Period 
Pre-screening 
Screening 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Survival 
Follow-up 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 days 
after 
last 
dose 
30 days 
after 
EOT 
Visit 
Every 
12 weeks 
from 
EOT 
Visit 
Every 
12 weeks 
from 
EOT 
Visit 
Visit window (days) 
 
-28 to 
-1 
-7 to 
-1 
0 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid paneli 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Coagulation indicatorsj 
 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
 
HbA1C 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Pregnancy testk 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
Urinalysisl 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Virological screeningm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration 
and/or biopsyn 
 
 
Refer to Appendix 2 
 
PK and PD assessments 
 
 
Refer to Appendix 2 
 
12-lead ECG o 
 
 
Refer to Appendix 2 
 
ECHO/MUGA scanp 
 
X 
 
X 
 
 
 
X 
 
Cycle 3 
Day 1 
and 
every 
odd 
cycle 
thereafter 
X 
 
 
 
Tumor 
evaluation/imaging 
 
X 
 
Every 8 weeks (±7 days) during the first 24 weeks and every 12 weeks 
(±14 days) thereafter 
X 
 
X 
 
Minimal residual disease 
evaluation 
 
X 
 
Every 8 weeks (±7 days) during the first 24 weeks and every 12 weeks 
(±14 days) thereafter 
X 
 
X 
 
Blood transfusion historyq 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood transfusion recordr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug/dispense/returnu  
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 33 
 
CONFIDENTIAL 
 
 
Cycle/Period 
Pre-screening 
Screening 
C1 
C2 
C3+ 
EOT 
Safety 
Follow-up 
Efficacy 
Follow-up 
Survival 
Follow-up 
Visit 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
Within 
7 days 
after 
last 
dose 
30 days 
after 
EOT 
Visit 
Every 
12 weeks 
from 
EOT 
Visit 
Every 
12 weeks 
from 
EOT 
Visit 
Visit window (days) 
 
-28 to 
-1 
-7 to 
-1 
0 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
±14 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
 
Refer to Table 4 
 
 
 
 
AEss 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival Follow-upt 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Risk 
stratification/Prognostic 
scoringv 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; D=day; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOT=end of treatment; HbA1C=hemoglobin A1C; ICF=informed consent form; IDH=isocitrate dehydrogenase; INR=international normalized ratio; mIDH=mutant IDH; 
MUGA=multigated acquisition; OCT=optical coherence tomography; PD=pharmacodynamics; PK=pharmacokinetics; PR=partial response; PT=prothrombin time. 
a 
Procedural details are available in Section 5.1.1. 
b 
Patients should have a local report of IDH mutational analysis, confirming mIDH. 
c  
Procedural details for medical history and demographics are available in Section 6.1.3. 
d 
Procedural details for prior and concomitant medications/treatments are available in Section 6.1.4. 
e 
Procedural details are available in Section 6.1.6 (vital signs), Section 6.1.7 (physical examination, weight, and height), Section 6.1.8 (ECOG performance 
status), and Section 6.1.10 (laboratory evaluations). 
f 
Ophthalmologic assessments, including eye appearance, slit lamp examination, best corrected visual acuity, visual field, eye movement, pupil reflex, OCT, 
and intraocular pressure will be performed during the Screening Period.  If the subject has undergone the relevant examinations 60 days before the start of 
study treatment (C1D1), they need not be repeated.  After the start of study drug administration, OCT will be performed at 6 weeks (±1 week), then OCT, eye 
appearance, and slit lamp examinations will be performed every 12 weeks (±1 week) from C4D1 and at the EOT visit.  Other ophthalmologic examinations 
are to be performed when clinically indicated.  If the subject develops an ophthalmic AE related to HMPL-306, the frequency of the examination should be 
increased to once every cycle until the AE is relieved or stable  
g 
Procedural details for hematology are available in Section 6.1.10.1.   
h 
Procedural details for blood chemistry are available in Section 6.1.10.4. 
i 
Procedural details for fasting lipid panel are available in Section 6.1.10.6. 
j 
Coagulation tests include PT, INR, and aPTT.  Additional procedural details for coagulation indicators are available in Section 6.1.10.7. 
k 
Additional procedural details for pregnancy testing are available in Section 6.1.10.9. 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
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A me n d me nt 5  
 
 
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P a ge 3 4  
 
C O N FI D E N TI A L  
 
 
l 
Uri nal ysis i ncl u des uri ne gl uc ose, pr otei n, ket o ne b o d y, re d bl o o d cells, w hite bl o o d cells, a n d ur o bili n o ge n .  A d diti o nal pr oce d ural details are a vaila ble i n 
Secti o n 6. 1. 1 0. 1 0 . 
m  
A d diti o nal pr oce d ural details f or vir ol o gical scree ni n g are a vaila ble i n Secti o n 6. 1. 1 0. 1 1 . 
n 
W h ole bl o o d a n d/ or b o ne marr o w sa m ples will be c ollecte d  a n d pr o vi de d t o a ce ntral la b orat or y f or 
 a nal yses. See  A p pe n di x  1  f or 
details . 
o 
E val uati o n ti me p oi nts are s h o w n i n A p pe n di x 2 .  A d diti o nal pr oce d ural details f or t he 1 2 -lea d E C G are a vaila ble i n Secti o n 6. 1. 1 1 . 
 p  
A d diti o nal pr oce d ural details are pr o vi d e d f or E C H O a n d M U G A i n Secti o n 6. 1. 1 2 . 
q 
A d diti o nal pr oce d ural details f or bl o o d tra nsf usi o n hist or y are pr o vi de d i n Secti o n 6. 1. 1 0. 2 . 
r 
A d diti o nal pr oce d ural details f or b l o o d tra nsf usi o n rec or d are pr o vi de d i n Secti o n 6. 1. 1 0. 2 . 
s 
A Es d ue t o t he pr ot oc ol -re q uire d i nter ve nti o n will be c ollecte d fr o m si g nat ure of t he I C F.  A d diti o nal details are pr o vi de d i n Secti o n 5. 1. 1 . 
t 
S ur vi val f oll o w -u p s h o ul d be perf or me d e ver y 1 2 wee ks ( ± 2 wee ks) after t he E O T Visit .  A d diti o nal  details are pr o vi de d i n Secti o n 6. 1. 1 9 . 
u 
If t u m or e val uati o n s h o ws pr o gressi ve disease d uri n g pre vi o us c ycle  a n d ne w dr u g has be e n dis pe nse d, patie nt  m ust ret ur n all u n use d st u d y dr u g o n 3 0 -da y 
safet y visit after E O T. 
v  
A d diti o nal pr oce d ural details f or ris k stratificati o n/ pr o g n osti c stratificati o n a n d sc ori n g are a vaila ble i n Secti o n 6. 1. 1 4. 1 . 
 
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Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
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2 
INTRODUCTION  
2.1 
Study Rationale  
2.1.1 Investigational Product  
HMPL-306 is an innovative, small-molecule, orally available, highly selective, and potent 
inhibitor of IDH1 and IDH2 mutations. 
2.1.2 Isocitrate Dehydrogenase  
Isocitrate dehydrogenase (IDH) is the enzyme that catalyzes 1 of 4 rate-limiting steps in 
tricarboxylic acid cycle.  Tricarboxylic acid cycle, also called Krebs cycle and/or citric acid cycle, 
is the second stage of cellular respiration, a three-stage process by which living cells break down 
organic fuel molecules in the presence of oxygen to harvest energy they need to grow and divide.  
Specifically, IDH catalyzes the rate-limiting, irreversible, oxidative decarboxylation of isocitrate 
to produce: i) (D)-α-ketoglutaric acid (α-KG), ii) nicotinamide adenine dinucleotide + hydrogen 
(NADH) (2.5 adenosine triphosphate [ATP]), and iii) carbon dioxide.  There are 3 isoforms of 
IDH enzyme in the human: 1) IDH1 in cytoplasm, 2) IDH2 in mitochondria, and 3) IDH3 in 
mitochondria (Thall 1994, Wang 2013, Yonal-Hindilerden 2016, Yoshihara 2001).   
2.1.2.1 Mutations of IDH  
IDH mutation plays a major role in carcinogenesis.  Mutation of normal IDH enzymes, in 
particular, IDH1 and IDH2 (IDH3 has not been associated with mutation), leads to loss of 
physiological functions of these IDH enzymes.  The resultant mutant IDHs (mIDHs) acquire new 
metabolic capabilities, that is, the catalytic metabolism of α-KG into oncogenic metabolite 
(R)-2-hydroxyglutaric acid (2-HG) (Dang 2009, Fathi 2012).  Intracellular accumulation of 2-HG 
leads to a series of epigenetic changes, including hypermethylation of deoxyribonucleic acid 
(DNA) and  histones proteins, which causes a blockade of cell differentiation and the consequent 
malignant transformation and proliferation of tumor cells (Chowdhury 2011, Ivanova 2005, 
Koivunen 2012, Xu 2011). 
2.1.2.2 Mutations and Malignancies  
Mutant IDHs have been found in multiple tumors, including acute myeloid leukemia (AML), 
myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), angio-immunoblastic 
T-cell lymphoma (AITL), glioma, chondrosarcoma, and cholangiocarcinoma (Delahousse 2018, 
Haferlach 2008, Harding 2018, Odejide 2014, Parsons 2008, Kosmider 2010, Marcucci 2010, 
Papaemmanuil 2016, Pardanani 2010, Yan 2009).  Pharmacological intervention and therapeutic 
targeting of mIDH should therefore be logical in the treatment of certain cancers.  Hematological 
malignancies (such as AML, AITL, and MDS) and solid tumors (such as primary brain cancer 
[Grade 2/3 glioma], secondary glioblastoma, chondrosarcoma, and cholangiocarcinoma) are tumor 
types with a documented high incidence of recurrent expression of mIDH. 
The clinical efficacy of the FDA-approved single-target inhibitors ivosidenib and enasidenib for 
IDH1 or IDH2 mutations, respectively, has been validated in patients with relapsed or refractory 
AML that harbor corresponding IDH mutation (Stein 2017, Devillier 2015, DiNardo 2018).  
Ivosidenib is approved for newly diagnosed patients with AML who are ≥75 years old or who have 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
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A me n d me nt 5  
 
 
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P a g e 3 6  
 
C O N FI D E N TI A L  
 
 
c o m or bi dities t hat precl u de t he use of i n te nsi ve i n d ucti o n c he m ot hera p y (R o b oz 2 0 2 0 ).  Patie nts 
w h o fail 
I D H i n hi bit or t hera pies d o n ot ha v e a n y sta n dar d tr eat me nt o pti o ns a vaila ble 
(N C C N -A M L  2 0 2 1 ).  
2. 1. 2. 3  Rati o nale a n d Be nefits of Tar geti n g All mI D Hs S i m ulta ne o usl y  
M uta nt I D Hs  ca n c o -e xist  a n d c o-m utate c o nc urre ntl y a n d i n a n y c o m bi n ati o n i n patie nt s wit h 
a d va nce d rela ps e d, refract or y, or resista nt he mat ol o gical mali g na n cies .  F or e x a m ple, s o me A M L 
patie nt s e x presse d c o-m utati o ns of differe nt c o m bi nati o ns of mI D H c o nc urre ntl y.  I n a d diti o n, 
mI D H is of or m s witc hi n g  lea di n g t o resista nce h as bee n re p orte d w here patie nt s bec o me resista nt 
t o I D H 1 i n hi bit or b y u pre g ulati n g a n d o ver -e x pressi n g ot her is ot y pes of mI D H, s pecificall y 
mI D H 2 .  C o n versel y, resista nce t o I D H 2 i n h i bit or occ urre d w he n tu m or cells u pre g ulat e d a n d 
o ver -e x presse d ot her is ot y p es of mI D H, i n t his cas e mI D H 1.  T heref ore, sel ecti ve a n d si n gle mI D H 
is ot y pe i n hi bit ors s uc h as  iv osi de ni b f or mI D H 1 or enasi de ni b  f or m I D H 2 are n ot i deal or a de q u ate 
a n d t h us lead t o u nacce pta ble a n d i ns ufficie nt efficac y, a n d a b o v e all, resista nce  (C h oe  2 0 1 9 , 
Ya n g  2 0 1 5 ). 
Cli nical de vel o p me nt of a n i n hi bit or s uc h as H M P L -3 0 6 t hat tar gets, i n hi bits , a n d s u p press es 
m ulti ple mI D H s c o n c urre ntl y c o ul d lea d t o si g nifi ca nt a n d d ura ble cli nical be nefit.  
H M P L -3 0 6 is a  n o vel, orall y a v aila ble, s mall -m olec ule, hi g hl y selecti ve, a n d p ote nt i n hi bit or of 
I D H 1 a n d I D H 2 m uta nts.  It de m o nstrate d re mar ka ble i n hi bit or y effect o n 2-H G i n t u m or cells 
wit h a n y I D H m utati o ns, a n d t heref ore, t his p hase 1 , o pe n -la bel st u d y is pl a n ne d t o e val uate t h e 
safet y, t olera bilit y, p har mac o ki netics ( P K), p h ar mac o d y na mics ( P D), a n d preli mi nar y efficac y of 
H M P L -3 0 6 i n patie nt s 
wit h a d va nce d, rela pse d, refract or y, or resista nt he mat ol o gical 
mali g na n cies t hat har b or I D H m utati o ns.  
2. 2  
B ac k gr o u n d   
As of 2 3  Oct o ber  2 0 2 3, t he d ose escalati o n p art of t he c urre nt st u d y h as e nr olle d 
 patie nts wit h 
I D H m utat i o ns at i ncreasi n g d ose le vels fr o m 
 m g  
 m g o nce dail y ( Q D ).  
 
 
 All of  t he p atie nts e nr olle d i n t h e d ose 
escalati o n p art were rela pse d or refract or y ac ute m yel oi d le u ke mia ( R/ R A M L) patie nts.  T he st u d y 
di d n ot e nr oll a n y patie nts wit h m yel o d ys plastic sy n dr o me ( M D S) or an gi o -i m m u n o blastic T-cell 
L y m p h o ma  ( AI T L), 2  ot her p o p ulati o ns tar gete d f or t he ori gi nall y pla n ne d e x pa nsi o n c o h orts 
(C o h orts B a n d C) per Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1 A me n d me nt  4.  
A m o n g t he  R/ R A M L patie nt s, cli nical res p o nses were n ote d i n patie nts w h o were naï ve t o pri or 
I D H t hera p y at H M P L -3 0 6 d oses of  
 m g Q D or hi g h er . 
 
 
were e nr olle d i n t he l o wer d ose c o h orts ( 
 m g Q D) ma ki n g it 
diffic ult t o e val uat e effic ac y a n d safet y of H M P L -3 0 6  i n t his s u b gr o u p of patie nts wit h a hi g h 
u n met nee d f or acti ve s u bse q ue nt t hera p y .   
T he pri mar y p ur p os e of A me n d me nt 5 is t o m o dif y t he d os e e x pa nsi o n c o h orts base d u p o n t he 
s p o ns or’s strate gic e val u ati o n of t he u n met nee d a n d t he a bilit y t o e nr oll i n selecte d p o p ulati o ns .   
I n E x pa nsi o n C o h ort A, t he st u d y will e nr oll 1 0 R/ R A M L patie nts, li mite d t o patie nts w h o ha v e 
recei v e d pri or I D H i n hi bit or t hera p y (e g,  e nasi d e ni b, i v osi de ni b, or ol utasi de ni b) . T he safet y a n d 
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 3 7  
 
C O N FI D E N TI A L  
 
 
pr o of of acti vit y will be e val uat e d at t he hi g h est t olera ble d ose le vel e val uate d i n t he d ose 
escalati o n p art ( 
 m g Q D). If pr o of of acti vit y is esta blis he d at t he hi g her d ose le vel i n t his hi g h-
ris k p o p ulati o n, f urt her e val uati o n at l o wer d oses ma y b e warra nte d i n f ut ure. 
E x pa nsi o n C o h orts B ( M D S) a n d C ( AI T L) are re m o ve d , as t hes e p atie nts were n ot e v al uate d in 
t he d ose escalati o n d ue t o lac k of e nr oll me nt i n t hese p o p ulati o ns . 
2. 2. 1  Descri pti o n of H M P L -3 0 6   
H M P L -3 0 6 is a hi g hl y s electi ve a n d p ote nt  i n hi bit or of b ot h I D H 1 a n d I D H 2 m uta nts , whic h is 
c haracteriz e d b y hi g h oral bi oa vaila bilit y, l o w cl eara n ce, e xte nsi ve tiss ue distri b uti o n, relati vel y 
l o w ris k of dr u g i nteracti o ns, a n d satisfact or y precli nical safet y feat ures.  H M P L -3 0 6 is a vaila ble 
i n ta blet f or m ulati o n of  2 stre n gt hs: 
 m g a n d  
 m g.  
2. 2. 2  S u p p orti ve N o ncli nic al D at a   
2. 2. 2. 1  P har mac ol o g y   
2. 2. 2. 1. 1  
I n vitr o P har mac o d y na mi c s  
At t he cell ular le v el, usi n g  i n vitr o e x peri me nts i n cell li nes t h at c o ntai n m I D Hs [
, 
I D H 1 R 1 3 2H , I D H 2 R 1 4 0Q , a n d I D H 2 R 1 7 2 K], H M P L -3 0 6 si g nifica ntl y i n hi bit e d pr o d ucti o n of 
2 -H G a n d s h o w e d a str o n g i n hi bit or y effect o n t hese mI D H s. 
H M P L -3 0 6 h as 
 effect o n 
 (at t he c o nce ntr ati o n of 
 μ M, t he i n hi biti o n rat e was  
) or  o n 3 2 2 ki nases i n t he Select Scree n T M  platf or m (at t he 
c o nce ntr ati o n of 
 μ M ), s h o wi n g hi g h ki nase s electi vit y.  O n t he C E R E P platf or m, H M P L -3 0 6 
di d 
 
 μ M).  C o m pare d t o t he refere nce c o m p o u n d A G-2 2 1, H M P L -3 0 6 s h o we d 
greater  selecti vit y. 
I n cell f u ncti o nal st u dies, H M P L-3 0 6 s u p presse d pr o d ucti o n of 2 -H G b y i n hi biti n g t hese m I D Hs 
[
, I D H 1 R 1 3 2 H, I D H 2 R 1 4 0 Q, a n d I D H 2 R 1 7 2 K].  T his lea d s t o differe ntiati o n of 
t u m or cells fr o m i m mat ure mali g n a nt cells t o mat ure n or mal cells. 
2. 2. 2. 1. 2  
I n vi v o P har m ac ol o g y   
T ar get i n hi biti o n effect of 2 -H G wit h H M P L -3 0 6 i n U 8 7 M G -I D H 2 R 1 4 0 Q-M 3 1 t u m or m o del  
I n si n gle-d os e a d mi nistrat i o n st u dies, vari o us  patie nt -deri ve d x e n o graft  t u m or m o dels 
t hat 
c o ntai ne d mI D H w ere us ed .  At a 
 m g/ k g , i n all mI D H m o dels us e d, t he 
st u d y dr u g mai ntai ne d s ustai ne d s up pressi o n of 2 -H G pr o d ucti o n at > 9 5 % fr o m 1 6 t o 2 4 h o urs; 
t his effect beca me s tr o n ger after 2 4 h o urs a n d reac he d 9 8 %, a near -c o m plete i n hi biti o n of all 
mI D Hs use d i n t hese st u d ies. 
I n 
 st u dies, the i n hi bit or y effect of H M P L -3 0 6 o n 2 -H G pr o d ucti o n after 
oral a d mi nistrati o n of H M P L -3 0 6 at 
 m g/ k g 
 
was i n vesti gate d  i n a t u m or m o del t hat c o ntai ne d mI D H .  T he res ults s h o we d t hat a fter  
 of 
d osi n g, wit hi n 2 t o 2 4 h o urs after t he last d ose, t he i n hi bit or y rate of H M P L-3 0 6 o n 2 -H G was 
mai ntai ne d a t m ore t ha n 96 %  f or all 3 d osa ges, a n d t he i n hi bit or y rate was si g nifica ntl y hi g her 
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 3 8  
 
C O N FI D E N TI A L  
 
 
t ha n t hat 
.  In crease i n 2 -H G i n hi biti o n rate was d u e t o a n 
i ncreas e i n dr u g e x p os ure a n d tar get e n ga ge me nt ( T E) aft er re peat e d a d mi nistrati o n. 
T ar get in hi bit ory effect of H M P L -3 0 6 o n 2 -H G i n H T 1 0 8 0 t u m or m o del  
I n t he I D H 1 m utati o n t u m or m o del H T 1 0 8 0 ( R 1 3 2 C m utati o n), H M P L-3 0 6 was a d mi nistere d at  
 m g/ k g, a n d t he tar get i n hi biti o n of H M P L-3 0 6 o n I D H 1 m utati o n 
was e v al uate d b y meas uri n g  c ha n ges of 2 -H G l e v els after 2 t o 4 0 h o urs .  T he res ults s h o w e d t hat 
at 1 6 a n d 2 4 h o urs aft er d osi n g i n all 3  d os e gr o u ps, t he i n hi bi t or y rate of H M P L-3 0 6 a gai nst 2 -H G 
i n t u m or tiss ues reac he d m ore t ha n 9 0 %, a n d 
 m g/ k g  
 ac hie ve d al m ost 
c o m plete i n hi biti o n ( 9 7% t o 9 8 % ) at 1 6 t o 2 4 h o urs . 
T he tar get i n hi bit or y effect of H M P L -3 0 6 o n 2 -H G was f urt her assess e d i n t he H T 1 0 8 0 t u m or 
m o del .  After  
 m g/ k g 
, 2-H G i n hi biti o n rate i n t u m or tiss ues 
reac h e d 9 7 %, a n d its i n hi bit or y effect o n t he tar get was str o n ger wit h t he i ncrease i n dr u g e x p os ure 
a n d T E  after  
 d oses . 
2. 2. 2. 1. 3  
Safet y P h ar mac ol o g y   
T he effect of H M P L -3 0 6 o n h E R G p otassi u m c ha n nels was e val uate d usi n g H E K 2 9 3 cell  li ne.  
T he  half -ma xi mal  i n hi bit or y c o ncen trati o n of H M P L -3 0 6 was  
 μ M o n h E R G p otassi u m 
c ha n nels , 
. 
 i n u nrestrai ne d a n d 
tele metere d Bea gle d o gs at si n gle d os es u p t o 
 m g/ k g, t he hi g h est d ose e m pl o ye d, f urt her 
s u p p orti n g a l o w ris k of H M P L-3 0 6 o n t he car di o vasc ular s yste m .   
S i n gle d oses u p t o 
 m g/ k g , t he hi g h est d ose use d, were a d mi nistere d via oral ga v a ge t o 
S pra g u e -D a wle y rats .  
 
. 
C ollecti vel y, t he res u lts of t he safet y p h ar mac ol o g y st u dies i n dicate t hat H M P L-3 0 6 is l o w ris k t o 
t he car di o vas c ular, res pir at or y, a n d ce ntral ner v o us s yste m.  
2. 2. 2. 2  P har mac o ki netics   
H M P L -3 0 6 h as g o o d i n vitr o per mea bilit y a n d is n ot a s u bstrate of effl u x tra ns p orter s.  Cleara n ce 
of H M P L -3 0 6 i n rats a n d d o gs was 
.  
 
 
H M P L -3 0 6  is sta bl y m eta b oliz e d i n i n vitr o 
 i n vari o us 
s pecies, a n d t he maj or i n vitr o meta b olite  o bser ve d was t he  
.  
I n vitr o gl uc ur o n yl tra nsf erase st u d y res ults s h o we d t hat 
 
 
 were  t he mai n meta b olic e nz y m es t hat me diate t he ge nerati o n of gl uc ur o nic aci d 
c o nj u gate.  
I n vitr o st u dies s h o we d t h at H M P L-3 0 6 e x hi bit s a relati vel y 
 
 
.  H M P L -3 0 6 s h o we d relati vel y  
 
 
.  H M P L -3 0 6 has a n 
 
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 3 9  
 
C O N FI D E N TI A L  
 
 
.  H M P L -3 0 6 
.  H M P L -3 0 6 is 
 
. 
2. 2. 2. 3  T o xic ol o g y   
T he c o m plete d H M P L -3 0 6 t o xic ol o g y stu dies  i n cl u de d si n gle-d os e t o xicit y st u dies i n rats a n d 
d o gs, 4 -w ee k re peat -d os e t o xicit y st u dies wit h a n 8 -wee k rec o v er y peri o d i n rats a n d d o gs, 
ge n ot o xicit y st u dies ( bacterial re vers e m utati o n test, i n vitr o c hr o m os o mal a berrati o n test, a n d a n 
i n vi v o micr o n ucle us t est), a n d a p h ot ot o xicit y st u d y i n rats.  T he res ults s h o we d t hat si n gle -d os e 
a d mi nistrati o ns of H M P L -3 0 6 i n rats a n d d o gs were 
wit h m a xi m u m  t olerate d d oses 
of  
 m g/ k g a n d  
m g/ k g, res p ecti vel y.  
I n t he 4-wee k re peat -d os e t o xicit y st u dies of rats a n d d o gs, 
 
 was o bs er ve d i n eit her of t he 2  s pecies.  I n t he rats, 
 
 
 were o bser ve d.  T here were 
 o bser ve d 
i n t he d o gs.  T he c o m m o n tar get or ga n was 
 
.  C ha n ges i n t he 
 
 were als o o bser ve d at t he hi g h d ose of rats at t he e n d of t he d osi n g peri o d.  
After t he 8 -wee k rec o ver y peri o d, 
 
was still o bser ve d i n t h e hi g h -d ose fe mal e rats, a n d all of t he ot her af ore me nti o ne d c ha n ges 
rec o vere d. 
H M P L -3 0 6 w as n ot 
.   
F urt her  d etails o n p har mac ol o g y , p har mac o ki n etics, a n d t o xic ol o g y are pr o vi de d i n t he 
I n v esti gat or’s Br oc h ure (I B). 
2. 2. 3  S u p p orti ve Cli nic al D at a   
A p hase 1 st u d y is c urre ntl y o n g oi n g  i n C hi na t o e val uate safet y, t olera bilit y, an d preli mi nar y 
a nti-t u m or acti vit y of H M P L-3 0 6 i n patie nt s wit h a d va nce d he mat ol o gical mali g na n cies t hat 
har b or mI D H 1/ 2  ( N C T 0 4 2 7 2 9 5 7).  Refer t o t he latest H M P L -3 0 6 I B f or t h e m ost u p date d cli nical 
data s u m mar y .   
2. 3  
Be nefit/ Ris k Assess me nt   
2. 3. 1  Be nefit -Ris k Assess me nt   
T he patie nt s t o be e nr olle d i n t his st u d y will be t h ose wit h a d va nce d, relapse d, refract or y, or 
resista nt he mat ol o gi cal mali g na n cies a n d, t heref ore, ha ve a n  u n met me di cal nee d .   
F or patie nt s wit h refract or y A M L, t he me dia n o verall s ur vi val ( O S) is a p pr o xi matel y 1. 5 m o nt hs 
wit h o nl y 8 % o ne -year  s ur vi val (G ale 2 0 0 8 , Giles 2 0 0 5 ).  Nati o nal C o m pre he nsi ve Ca ncer 
Net w or k ( N C C N ) a n d E ur o pea n S ociet y f or 
Me dical O nc ol o g y ( E S M O ) practice g ui d eli ne s 
rec o m me n d 
c o nsi deri n g 
cli nical 
trial 
f or 
patie nt s 
wit h 
pri mar y 
refract or y 
A M L 
(N C C N -A M L  2 0 2 1 , H e user 2 0 2 0 ).  I n t he e v e nt t hat n o cli nical trial is a v aila ble, t he n t h e i nte nt 
of a sec o n d sal va ge c he m ot hera p y i n t hese patie nt s, h o we ver, is o nl y s u p p orti ve at best .  T heref ore, 
patie nt s wit h A M L w h o ha ve recei ve d at least 2 pri or li nes of t hera p y d o n ot ha ve a via ble 
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CONFIDENTIAL 
 
 
treatment option available. Additionally, AML patients who fail IDH inhibitor therapies do not 
have any standard treatment options available, making them a population with very high unmet 
need (NCCN-AML 2021).  
High-risk MDS (HR-MDS) carries a major risk of progression to AML and short survival.  There 
are no standard treatment options for patients with relapsed or refractory HR-MDS.  Patients 
ineligible for allo-HSCT have no approved second-line treatment options after failure of an 
approved hypomethylating agent (HMA), and clinical trials are the recommended option as per 
NCCN and ESMO guidelines (NCCN-MDS 2021, ELN 2017, Fenaux 2020). 
Similarly, ESMO and NCCN practice guidelines recommend considering clinical trial for patients 
with relapsed or refractory AITL because of the poor survival rate with available single agent 
palliative therapy options (NCCN-MDS 2021, NCCN-PTCL 2021, d’Amore 2015).   
HMPL-306 is a dual inhibitor of IDH1 and IDH2, which, in preclinical studies, has demonstrated 
similar efficacy to single target IDH inhibitors (ivosidenib and enasidenib), and may have similar 
benefit to other IDH1 and/or IDH2 inhibitors in the same class.  Preclinical studies, including 
toxicology studies, indicate that HMPL-306 is well tolerated.  Additionally, there are no approved 
therapies for the treatment of hematological malignancies that have been previously treated with 
an mIDH1 or mIDH2 inhibitor, thus providing a potential treatment option in an area of unmet 
medical need. 
Most toxicities associated with the use of FDA-approved IDH1 and IDH2 inhibitors are considered 
to be mild and are well managed.  Incidence of Grade 3 and Grade 4 events have been observed to 
occur at a lower frequency with these agents compared to other available treatments for AML.  
The most common toxicities associated with IDH1 and IDH2 inhibitors include differentiation 
syndrome, 
tumor 
lysis 
syndrome, 
hyperbilirubinemia, 
anemia, 
febrile 
neutropenia, 
thrombocytopenia, fatigue, nausea, and diarrhea (Stein 2017, DiNardo 2018).  The incidence rate 
and severity of  toxicities in these FDA approved IDH1 and IDH2 inhibitors is consistent with the 
safety profile of HMPL-306 in patients with hematologic malignancies. Further details on 
identified and potential risks of HMPL-306 are provided in the Investigator’s Brochure (IB). 
Taking into account the measures taken to minimize risk to patients in this study as defined in 
Section 7.4, Section 7.5, Section 7.6, and Appendix 11, the risks identified in association with 
HMPL-306 are justified by the anticipated benefits that may be afforded to patients with solid 
tumors with IDH mutations as defined in Section 5.2.  
In summary, patients with AML who have received at least 2 prior lines of therapy including IDH 
inhibitors and patients with AITL and HR-MDS who have received at least 1 prior line of therapy 
do not have viable treatment options.  This study provides an opportunity for these patients to 
participate in a study of HMPL-306, a novel agent that targets mutations that are common among 
these tumors.  Thus, HMPL-306 can potentially provide clinical benefit to patients with advanced, 
relapsed, refractory, or resistant hematological malignancies.   
Refer to the latest HMPL-306 IB for the most updated clinical and safety data.   

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3 
OBJECTIVES AND ENDPOINTS  
The objectives and corresponding endpoints are summarized in Table 3. 
Table 3 
Objectives and Corresponding Endpoints   
Tier 
Objectives 
Endpoints 
Primary 
Part 1: To evaluate the safety and tolerability of 
HMPL-306 in patients with advanced hematological 
malignancies that harbor IDH mutations 
MTD and/or RP2D 
Safety, including DLTs, TEAEs, 
SAEs, deaths, ECGs, and clinical 
laboratory abnormalities 
Part 2: To characterize safety and tolerability, and to 
determine RP2D of HMPL-306 in patients with 
advanced hematological malignancies that harbor 
IDH mutations 
Safety including DLTs, TEAEs, 
SAEs, deaths, ECGs, and clinical 
laboratory abnormalities 
Secondary 
To assess preliminary antitumor activity of 
HMPL-306 in patients with advanced hematological 
malignancies that harbor IDH mutations 
Best overall response, ORR, TTR, 
DoR, CBR, PFS, OS, DFS, EFS, 
and postbaseline transfusion 
independence 
To assess the PK of HMPL-306 in patients with 
advanced hematological malignancies that harbor 
IDH mutations 
Observed plasma concentrations and 
exposure parameters of HMPL-306 
To assess PD of HMPL-306 in patients with 
advanced hematological malignancies that harbor 
IDH mutations 
Observed plasma concentrations of 
2-HG 
Exploratory 
To explore relationships between changes in 
frequency of genetic mutation, efficacy, PK, PD, 
and safety after HMPL-306 treatment 
Changes from baseline in tumor 
markers, correlation with drug 
exposure, target engagement, and 
efficacy and safety outcomes 
To explore relationships between HMPL-306 PK 
exposure, TE, 2-HG levels, and percent inhibition 
To explore the influence of genetic abnormalities 
other than IDH mutations on safety, efficacy, PD 
and PK, and clinical response to HMPL-306 
treatment 
2-HG=2-hydroxyglutaric acid; CBR=clinical benefit rate; DFS=disease-free survival; DLT=dose-limiting toxicity; 
DoR=duration 
of 
response; 
ECG=electrocardiogram; 
EFS=event-free 
survival; 
IDH=isocitrate 
dehydrogenase; MTD=maximum tolerated dose; ORR=objective response rate; OS=overall survival; 
PK=pharmacokinetics; PD=pharmacodynamics; PFS=progression-free survival; PR=partial response; 
RP2D=recommended phase 2 dose; SAE=serious adverse event; SD=stable disease; TE=target engagement; 
TEAE=treatment-emergent adverse event; TTR=time to response. 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 4 2  
 
C O N FI D E N TI A L  
 
 
4  
S T U D Y P L A N   
4. 1  
St u d y Desi g n   
T his is a p hase 1, o pe n -la bel, m ultice nter, si n gle-ar m  st u d y t o e v al uate safet y, t olera bilit y, P K , P D , 
a n d preli mi nar y efficac y of H M P L -3 0 6 a d mi nistere d orall y i n treat me nt of patie nt s wit h a d va n ce d 
rela pse d, refract or y, or resista nt  he mat ol o gical mali g na n cies t hat har b or I D H m utati o ns . 
T he st u d y c o nsists of 2 parts : d ose escalati o n part  (Part 1 ) a n d d ose e x pa nsi o n part  (Part 2 ). 
4. 1. 1  P art 1  ( D os e Esc al ati o n)  
T he first part  of t h e st u d y is d ose escalati o n , w here c o h orts of patie nt s will recei ve asce n di n g 
oral d oses of H M P L -3 0 6 t o deter mi ne  M T D a n d/ or t he rec o m me n de d p has e 2  d ose  ( R P 2 D).  T he 
m o difie d t o xicit y pr o ba bilit y i nter val-2 ( m T PI -2)  (Gree n b er g 2 0 1 2 , G u o  2 0 1 7 ) d esi g n will be 
use d t o perf or m d os e escalati o n a n d M T D/ R P 2 D det er mi nati o n .  Bri efl y, t he m T PI -2 met h o d 
uses a Ba yesia n fra me w or k a n d a hierarc hical m o d el t o c o m p ute t he d ose es calati o n base d o n t he 
i nter val bet wee n t he t o xicit y rate of eac h d os e le vel a n d tar get pr o ba bilit y (Gree n b er g 2 0 1 2 , 
G u o  2 0 1 7 ).  T his st u d y is desi g ne d tar geti n g a d os e -li miti n g t o xicit y (D L T ) rate of 2 0 % wit h a n 
e q ui vale nce i nter val of 1 5 % t o 2 5 % .   
Li ke t he 3 + 3 desi g n, t he m T PI -2 met h o d i nc or p orates pres pecifie d es calati o n r ules t hat ca n b e 
prese nte d i n a ta ble ( T a bl e  5 ).  As s h o w n i n T a ble  5 , t he n u m ber of p atie nt s d ose d at a gi ve n d os e 
le vel are s h o w n i n t he c ol u m ns, w hile t he r o ws i n dicate t he n u m ber of D L Ts e x perie n ce d.  T h e 
escalati o n/ de-escal ati o n r ules fr o m t he ta ble will b e use d f or eac h d ose l e vel e val uate d; t he p atie nt  
n u m bers a n d D L Ts d o n ot carr y o v er fr o m c o h ort t o c o h ort .  As a n e x a m ple, wit hi n a c o h ort:  
•  If n o ne of t he 3 patie nt s e x perie nce a D L T→escal ate t he d ose (“ E ” at c ol u m n  3 
r o w 0) t o t he ne xt d ose le vel c o h ort . 
•  If 1 o ut of 3 patie nt s e x perie nce a D L T→d e -es cal ate t o a l o wer d ose le vel (“ D” at 
c ol u m n 3 r o w 1) . 
•  If 2 o ut of 3 patie nt s e x perie nce a D LT →t h e d ose is deter mi ne d t o be u nacce pta bl y 
t o xic a n d will n ot be use d a gai n, de-escal ate t o a l o wer d ose le vel (“ D U” a t c ol u m n 3 
r o w 2). 
•  If 1 o ut of 5 patie nt s e x perie nce a D L T →sta y at t he sa me d ose le vel (“ S” at c ol u m n 5 
r o w 1) .   
T he f oll o wi n g r ules a p pl y d uri n g d ose escalati o n:  
•  Starti n g d ose at C o h ort 1 is 
 m g.  
•  Alt h o u g h i n t he m T PI -2 met h o d t he c o h ort siz e is n ot fi x e d, at least  3  p atie nt s will be 
e nr olle d at eac h d ose le v el .  W he n all p atie nt s at a d ose l e vel c o m plet e D L T assess me nt, 
t he st u d y will es calate t o  t he n e xt d ose le vel  a n d a n ot her mi ni m u m of 3  p atie nt s will be 
recr uite d i n t his or der u ntil R P 2 D or  M T D  (Ta ble  5 ).   
•  T he sa m ple siz e of a d os e c o h ort t h at has alrea d y passe d t he preli mi nar y D L T assess me nt 
( 3 t o 6 patie nt s) a n d s h o w n efficac y (e g, t o i ncl u de ot her efficac y si g nal f or eac h t u m or 
t y pe) ca n be e xte n de d t o 1 2 patie nt s i n or der t o f urt her e v al uate t he safet y a n d efficac y 
si g nals of t hat partic ular d ose.  
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A me n d me nt 5  
 
 
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P a g e 4 3  
 
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•  If a gree d u p o n b y t he i n v esti gat ors a n d t he s p o ns or (e g, bas e d o n safet y, P K, e x p os ure, a n d 
T E a n d/ or P D data fr o m pri or a n d c urre nt c o h orts) t hat i ncreasi n g t he d os e f urt her ma y  n ot 
yi el d a d diti o nal be nefit, t he d ose ma y st a y at t he c urre nt d ose le vel , be de -escalate d  t o a n y 
d ose , or n o f ut ure escalati o n ma y be m a de , e v e n if t he r ule i n dicates “ E” t o escalate. 
•  Bef ore M T D is reac h e d, if P K e vi de nce s u g gests t he d ose -e x p os ure a n d T E relati o ns hi p is 
sat urate d, d ose escal ati o n ma y b e disc o nti n ue d. 
•  T he nee d f or d ose escalati o n t o a s pecific d ose be y o n d  
 m g Q D or de -escalati o n t o a n 
i nter me diate d ose le v el will be e val uate d j oi ntl y b y i n vesti gat ors a n d t h e s p o ns or base d o n 
c u m ulati ve cli nical safet y, P K, a n d preli mi nar y efficac y d ata.  
T he st o p pi n g r ules f or t his p orti o n of t he st u d y are defi ne d i n Secti o n 6. 2. 2 .   
P K w ee k : T he P K wee k is defi ne d as 7  da ys pri or t o cycle 1 d a y 1 (C 1 D 1 ), d uri n g w hic h a si n gle 
d ose of H M P L -3 0 6 will be a d mi nistere d o n Da y 1 of P K wee k ( Da y - 7 relati ve t o C 1 D 1) .  Serial 
bl o o d sa m ples will be c ollecte d fr o m Da ys  1 t o 7 of t he P K wee k f or a nal ysis of pl as ma 
c o nce ntr ati o ns of H M P L -3 0 6 , 2 -H G , a n d ot h er bi ol o gical mar kers as defi n e d b y t h e s p o ns or . 
St u d y tre at me nt : O ne  c ycl e of st u d y tr eat me nt is defi ne d as 2 8 da ys of c o nti n u o us , dail y  d osi n g .  
A fter t he P K wee k , d ose e scalati o n will start at 
 m g Q D  orall y  (P O ) f or C o h ort 1  a n d t he n 
escalate i n t he se q u e nce of 
 m g Q D,  
 m g  Q D,  
 m g Q D ,
 m g Q D, 
 m g Q D, 
 m g 
Q D, a n d  
 m g Q D  (s ee Ta ble  4 ).  T he m o difie d Fi b o nacci se q u e nce will be use d t o  i ncre m e nt 
t he d ose (see Ta ble  5  f or details o n t he d ose escalati o n decisi o n). 
N o D L Ts or s afet y c o ncer ns  were  n ote d i n d ose l e vels 1 t o 3 .  Base d o n t he c ollecti ve res ults of 
t he precli nical  i n vitr o a n d i n vi v o safet y p har mac ol o g y, at a cli nical d ose of  
 m g, t he ris k f or 
p ote ntial effects o n t he car di o vasc ular, res pirat or y, a n d ce ntral ner v o us s yste ms is c o nsi dere d l o w 
after a d mi nistrati o n of H M P L -3 0 6 .T he a ntici p ate d  h u ma n e x p os ure ( as deter mi ne d b y area u n der 
t he c ur ve [A U C ]) at a cli nical d ose of  
 m g  Q D di d n ot res ult i n se vere t o xic fi n di n gs  i n t he 
4 -wee k t o xic ol o g y st u di es a n d is  e x pecte d t o be well  bel o w t he e x p os ures at t he hi g hest d oses 
st u die d.  Please refer t o t he m ost rece nt I B f or a d diti o nal i nf or mati o n .   
Sa fet y m o nit ori n g a n d e v al uati o n of eac h d ose es calati o n  c o h ort will be carrie d o ut b y t he Safet y 
Re vie w C o m mittee ( S R C), w hic h is c o m prise d of t he s p o ns or a n d i n vesti gat ors.  T h e e nr ollme nt 
of d ose le vels 5 t o 8 will be  base d o n t he c u m ulati ve safet y a n d pr eli mi nar y P K a n d P D data 
o bser ve d at 
 m g, a n d re vie w will be c o n d u cte d b y t he s p o ns or a n d t he S R C me m bers .   
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H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 4 4  
 
C O N FI D E N TI A L  
 
 
T a ble  4  
P ati e nt  D ose Gr o u pi n g, D ose E scal ati o n P l a n  
C o h ort #/ D ose L e v el 
D ose of H M P L -3 0 6  (P O Q D wit h W ater ) 
1  
 m g 
2  
m g  
3  
m g  
4  
m g  
5  
m g  
6  
m g  
7  
m g  
8  
m g  
P O = orall y ; Q D = o nce dail y . 
N ote: P atie nt s i n d ose escalati o n will recei ve 1  si n gle-d ose of H M P L -3 0 6 7 da ys pri or t o C 1 D 1 . 
T a ble  5  
m T PI -2 D ecisi o n T a b le f or D ose S electi o n   
Tar get t o xicit y pr o ba bilit y : p T = 2 0 %; ε 1 = 0. 0 5; ε 2 = 0. 0 5  
 
E =escalate t o t he ne xt hi g her d ose; S = sta y at t he sa me d ose; D = De-escalate t o t he pre vi o us l o wer d ose; 
D L T = d ose -li miti n g t o xicit y; D U = De -escalate t o t he pre vi o us l o wer d ose a n d t he c urre nt d ose will n ot be use d 
a gai n i n t his st u d y; M T D = ma xi m u m t olerate d d ose. 
N ote: T he h oriz o ntal a xis i n dicates t he n u m ber of patie nt s w h o are treate d at t he c urre nt d ose a n d t he l o n git u di nal a xis 
is t he n u m ber of o bser ve d d ose-li miti n g t o xicities.  ε 1 a n d ε 2 are fracti o ns use d t o defi ne  a n e q ui vale nce i nter val 
of M T D.  
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Safety Review Committee 
Safety monitoring and evaluation of dose escalation will be carried out by the Safety Review 
Committee (SRC), which is comprised of the sponsor and investigators.  The SRC will determine 
whether it is safe to continue to next predefined higher dose level, stay at the currently assigned 
dose level or whether the dose should be de-escalated to any lower dose, and finally, to determine 
RP2D based on evaluation of safety, PK, and PD data. The SRC, on an ongoing basis, will also 
monitor the benefit-risk of HMPL-306 treatment in the expansion cohort and make 
recommendations on the continuation of enrollment in the study. 
Dose-Limiting Toxicity 
DLT is defined as occurrence of any treatment-emergent adverse event (TEAE) as described in 
Section 8.1.3 during the DLT assessment window, unless clearly unrelated to the study drug as per 
investigator’s discretion. 
DLT Assessment Window: 
For all patients in dose escalation, DLTs will be assessed during the DLT assessment window.  
This is the first 28 days of continuous study treatment (C1D1 through C1D28), and does not 
include the dose administered during PK week. 
DLT-Evaluable Patient: 
A patient is DLT-evaluable if the following criteria are met:  
• has received at least 75% of the assigned dose of study drug during the DLT assessment 
window 
OR  
• has not completed DLT assessment period due to a DLT 
For decisions on dose escalation, each dose cohort shall present the protocol-required numbers of 
DLT-evaluable patients.  Patients who are not DLT-evaluable in a dose cohort may be replaced to 
guarantee the protocol-required number of DLT-evaluable patients for dose escalation evaluations. 
Patients who complete the DLT assessment window will be allowed to continue treatment until 
disease progression, intolerable toxicity, withdrawal of consent, lost to follow-up, end of study, 
conditions are met per Section 6.2.1, or death, whichever comes first. 
Maximum Tolerated Dose 
The MTD determination will be driven by the mTPI-2 method.  The MTD will be any doses with 
true toxicity probability in the equivalence interval.  For this study, the equivalence interval is 
defined as 15% to 25%. 
Recommended Dose of the Expansion Cohort and Phase 2 Clinical Study (RP2D) 
RP2D determination will take the following criteria under consideration: 
• Determination of MTD achieved during the dose escalation part 
• Assessment of safety, PK, and PD  

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
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4. 1. 2  P art 2  ( D os e E x p a nsi o n)  
I n t he d ose  e x pa nsi o n part , H M P L -3 0 6 will be a d mi nistere d at t he M T D  a n d/ or R P 2 D t o e val uate 
f urt her t he safet y, t olera bilit y, P K, P D, a n d preli mi nar y efficac y i n a p pr o xi matel y  1 0  patie nt s wit h 
a d va nce d rela ps e d, refract or y, or resista nt he mat ol o gical mali g n a ncies  wit h  I D H m utati o ns. 
Patie nts e nr olle d i n t he d ose  e x pa nsi o n p art m ust n ot ha ve sta n dar d t h era p e utic o pti o ns a vaila ble 
(i ncl u di n g I D H i n hi bit ors w here a p pr o ve d) a n d m ust ha ve  t he f oll o wi ng : 
o  Rela pse d A M L u ns uita ble f or i nte nsi ve c h e m ot hera p y or ve net o cla x -ba se d 
re gi me n or tar get a ge nts; 
o  Pri mar y refract or y A M L u ns uita ble f or i nte nsi ve c he m ot hera p y or 
ve net ocla x -base d re gi me n or tar get a ge nts ; 
o  Rela pse d/ refract or y A M L t hat has pr o gress e d o n pri or I D H tr eat me nt  
T he s p o ns or , i n c o ns ultati o n wit h S R C , ma y decid e  to i ncrease or d ecrease t he n u m ber of e nr olle d 
patie nt s d e pe n di n g o n preli mi nar y cli nical res p o nse , safet y si g n als, or o perati o nal feasi bilit y.  
Patie nt s w h o are n ot efficac y e v al ua ble i n a n y c o h ort ma y b e re pl ace d.  
St u d y Tre at me nt  
Patie nt s will recei ve H M P L-3 0 6 d ail y  at 
 m g Q D ( hi g hest t olera ble d ose eval uat e d  i n t he d ose 
escalati o n p art) f or 2 8-da y  c ycles u ntil disease pr o gressi o n, deat h, i nt olera ble t o xicit y, wit h dra wal 
of c o nse nt, l os t t o f oll o w-u p, c o n diti o ns are met per Secti o n 6 . 2. 1, or e n d of st u d y, w hic h e ver 
c o mes first.  
S afet y M o nit ori n g  
C o nti n u o us  safet y m o nit ori n g f or all e nr olle d patie nt s will be carri e d o ut b y partici p ati n g 
i n vesti gat ors a n d t he s p o ns or .  T he s e verit y of a ll A Es will be gra de d i n acc or da nce wit h Nati o nal 
Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or  A d verse E ve nts ( C T C A E) versi o n 5. 0.  
4. 2  
Desi g n R ati o n ale   
4. 2. 1  R ati o n ale f or S t arti n g D ose a n d D osi n g R e gi me n   
H M P L -3 0 6 is i nte n de d f or us e i n patie nt s wit h a d va nce d rela pse d, refract or y, or resista nt 
he mat ol o gic al mali g n a ncies .  He nce, t he starti n g d ose is calc ulat e d base d o n t he S 9 g ui d eli nes 
fr o m I C H of Tec h nical Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n Us e, usi n g 
t he H N S T D, a n d N O AE L d ose (fe m ale) .  T h e cal c ulati o n met h o d is s h o w n  i n Ta ble 6  bel o w:  
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C O N FI D E N TI A L  
 
 
T a ble 6  
St arti n g D ose C alc ul ati o n   
 
A 4 -W ee k S t u d y of H M P L-
3 0 6 O r all y A d mi nistere d t o 
S D R ats W it h a n 
 
R ec o ver y P eri o d 
A 4 -W ee k S t u d y of H M P L-
3 0 6 O r all y A d mi nistere d t o 
B e a gles W it h a n 
 
R ec o ver y P eri o d 
A ni mal d ose ( m g/ k g)  
H N S T D ≥
 
Fe male: N O A E L =
 
Male: H N S T D =
 
E q ui vale nt d ose rati o c o n verte d base d o n b o d y 
s urface area ( h u ma n/a ni mal) 
E q ui vale nt d ose i n h u ma n b o d y c o n verte d base d o n 
b o d y s urface area ( m g/ k g/ da y)  
E q ui vale nt d ose i n 6 0 k g of h u ma n b o d y c o n verte d 
base d o n b o d y s urface area ( m g/ da y)  
I nitial d ose calc ulate d base d o n I C H S 9 ( m g/ da y) 
Pr o p ose d i nitial d ose of p hase I cli nical trial 
( m g/ da y) 
Safet y fact or  
H N S T D = hi g hest  
n o n se verel y 
t o xic  
d ose; 
I C H =I nter nati o nal 
C o u ncil  
f or  
Har m o nizati o n , 
N O A E L = n o -o bser ve d -a d vers e -effect le vel; S D = S pra g ue -D a wle y  
T he H N S T D w as cal c ulate d fr o m re peat e d d ose t o xic ol o g y st u d ies i n r u mi na nt (rat) a n d 
n o n -r u mi nan t ( d o g), a n d it s h o we d safe d oses o bt ai ne d  t hat were  e q ui v ale nt t o h u ma n s ki n s urface 
area d os a ges of 
 m g/ da y (rat) a n d  
 m g/ da y ( d o g) .  I n acc or da nce wit h I C H S 9, t he i nitial 
d ose f or first -i n-h u ma n ( FI H) st u d y s h o ul d be 1/ 1 0 of H N S T D  i n rats or 1/ 6 of H N S T D i n d o gs.  
C o nse q ue ntl y, t he starti n g d os e calc ulate d f or t he FI H st u d y s h o ul d b e 
 m g/ da y or  
 m g/ da y .  
Ne vert hel ess, i nitial d ose f or t his FI H p hase 1  cli ni cal st u d y is set at 
 m g Q D P O .  T his pr o vi de s 
a safet y wi n d o w of m ore t ha n 1 4 ti mes a n d a b o ut 3 9 ti mes as calc ulate d fr o m t he res ults of t hese 
st u dies i n rats a n d d o gs, res pecti vel y. 
F urt her m ore, a n d  i n acc or da nce wit h I C H S 9, t he d osi n g i nter val of t he FI H st u d y s h o ul d b e b ase d 
o n t he d osi n g i nter val of n o ncli nical re peat -d ose t o xicit y st u dies a n d t he esti mate d half -life i n t he 
h u ma n b o d y .  T h e d osi n g i nter val of H M P L -3 0 6 i n t he 4 -wee k re p eate d d ose t o xicit y st u dies was 
Q D .  T he esti mate d half -life of H M L P-3 0 6 was si milar t o t hat of a p pr o ve d pr o d ucts o n mar ket , 
w hic h all use a re gi me n of Q D .  T heref ore, a re gi m e n of Q D  will be i nitiall y e x pl o re d i n t his st u d y.  
E x pl orati o n of a n ot her d osi n g re gi me n ma y be i m ple me nte d , if i n dicate d, base d o n a nal ysis of 
e mer gi n g data.  
4. 2. 2  R ati o n a le f or St u d y P o p ul ati o n Selecti o n   
M utati o ns  i n v ol vi n g I D H e nz y mes pla y a r ole i n t he pat h o ge n esis a n d de vel o p me nt as s u bset of 
s o me he mat ol o gic al mali g na n cies  s uc h as A M L, M D S , M P N, a n d  AI T L .  I D H m utati o ns ha ve 
bee n re p ort e d i n 7 % of M D S cases, 3 %  t o 4 % of M P N cases, a n d 2 0%  t o 3 0 % of AI T L cases 
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(Tefferi 2010, Breems 2008, Cairns 2012, Wang 2015, Yonal-Hindilerden 2016, Wang 2017).  
These mutations are critical in patient selection, clinical response, and even prognosis of these 
patients.  Currently, ivosidenib (mIDH1 inhibitor) and enasidenib (mIDH2 inhibitor) are the only 
approved treatments available for patients in the United States with relapsed/refractory AML that 
harbor IDH1 and/or IDH2 mutations.  Therefore, this study plans to enroll patients that harbor IDH 
mutations, co-mutation, or any combination thereof. Discussion of rationale including specific 
hematological malignancies for which IDH1 and/or IDH2 mutations play a role in some cases of 
disease, appears in the following sections.   
4.2.2.1 Relapsed/Refractory Acute Myeloid Leukemia  
This study plans to enroll AML patients who have received at least 1 prior line of therapy.  The 
median overall survival for patients with refractory AML is 1.5 months with only 8% one-year 
survival (Giles 2005).  Current guidelines recommend enrollment in a clinical trial for the 
management of relapse and/or refractory AML.   
For patients with IDH mutations who are ineligible for standard chemotherapy and have failed 
standard of care first-line treatment (eg, low-dose cytarabine or HMA in combination with 
venetoclax), and for whom targeted therapy or salvage chemotherapy is not appropriate or have 
not had IDH isoform switching after prior treatment with IDH inhibitor, current guidelines 
recommend a clinical trial (NCCN-AML 2021, Heuser 2020). 
Treatment options for primary refractory and relapsed AML in those patients who have undergone 
prior standard induction chemotherapy and consolidation, including allogeneic hematopoietic stem 
cell transplantation (allo-HSCT) and are not fit for further intensive or targeted treatment is limited.  
In the event that no clinical study is available, then the intent of second salvage chemotherapy in 
these patients, however, is only supportive at best.   
Patients who have received at least 1 prior line of therapy, where an established standard of care 
with proven benefit for which the patient is eligible is not available at the time of enrollment, is an 
appropriate population for this 2020-306-GLOB1 study. 
4.2.2.2 Relapsed/Refractory High-Risk Myelodysplastic Syndrome  
This study plans to enroll HR-MDS patients who have relapsed after or are refractory to first-line 
treatment.  High-risk MDS carries a major risk of progression to AML and short survival.  
Treatment options at diagnosis are limited to allo-HSCT, HMAs, and intensive chemotherapy 
(mainly intensive anthracycline-cytarabine combinations).  For patients with HR-MDS who are 
not a candidate for intensive chemotherapy or allo-HSCT, HMAs are the only current approved 
treatment option.  Once patients relapse or are refractory to an HMA, there is no approved second-
line therapy, and the outlook is poor with a median survival of less than 6 months (Pratcorona 
2013, Prebet 2011, Jabbour 2010) Clinical studies are, therefore, the recommended second-line 
option as per NCCN and ESMO guidelines (NCCN-MDS 2021, Fenaux 2020).  For patients who 
are refractory to or have relapsed after allo-HSCT, clinical trials are also a recommended option 
as per the NCCN and ESMO guidelines.  Therefore, patients with HR-MDS who have received at 
least 1 prior line of therapy are an appropriate population for this 2020-306-GLOB1 study. 

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4. 2. 2. 3  Rela pse d or Refract or y A n gi o -i m m u n o blastic T-cell L y m p h o ma   
T his st u d y pl a ns t o e nr oll patie nts wit h AI T L  w h o ha ve recei ve d at least 1  pri or li ne of s yst e mic 
a ntica ncer t hera p y.  F or patie nt s wit h rela pse d/refract or y (R/ R ) AI T L, N C C N a n d E S M O cli nical 
practice g ui d eli nes rec o m me n d c o nsi deri n g a cli nical st u d y b eca use of t h e p o or o verall s ur vi val 
wit h a vaila ble sal va ge t hera p y o pti o ns ( N C C N -P T C L 2 0 2 1 , d’ A m ore 2 0 1 5 ).  T heref ore, patie nt s 
wit h R/ R AI T L w h o ha ve recei ve d at least 1  pri or li ne of t hera p y are a n a p pr o priate p o p ulati o n f or 
t his 2 0 2 0-3 0 6 -G L O B 1 st u d y. 
4. 2. 3  R ati o n ale f or Bi o m ar ker Testi n g   
T he mec ha nis m  of acti o n of H M P L -3 0 6 is  selecti ve tar get i n hi biti o n of m ulti ple is ot y p es of mI D H.  
S pecificall y, H M P L -3 0 6  is a hi g hl y selecti ve , ver y p ote nt i n hi bit or of mI D H.  Res ults of l ocal I D H 
m utati o n testi n g at scree ni n g will be use d i n f urt h er a nal ys es.  
 a n d 
 ma y b e 
i m p orta nt meta b olic 
e nz y m es f or i n vi v o meta b olis m of 
H M P L -3 0 6 .  T he ref ore, m utati o n of  
 a n d  
 ma y affect  P K , dr u g e x p os ure, T E , 
a n d P D of t he st u d y dr u g.  F or  t his reas o n, sa m ples c ollecte d will be teste d f or 
 a n d 
 as des cri be d  i n Secti o n 6. 1. 1 7 . 
M uta nt I D H  is ot y pes (a b o ve) catal yz e α -K G, a n d pr o d uce 2 -H G  –  a n o nc o ge nic  m eta b olite , 
acc u m ulati o n of w hic h pla ys a cr uci al r ole i n  pat h o ge n esi s of he mat ol o gi cal mali g na n cies i n t h is 
patie nt  p o p ulati o n .  T h er ef ore, this st u d y will m o nit or c h a n ges i n le vels of 2 -H G i n t he bl o o d .  T his 
ma y be us ef ul f or : i) P D  a n d ii ) c orrel ati o n bet wee n P K, dr u g e x p os ure, T E , a n d cli nical res p o nse  
as s pecifie d i n T a ble  1  a n d Secti o n 6. 1. 1 5 . 
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5 
POPULATION  
5.1 
Definitions  
Patients officially enter the Screening Period by signing the main informed consent either directly 
or via a legally authorized representative wherever permitted by local law. 
An enrolled patient is one who has been deemed eligible without waiver of patient population 
criteria and has been assigned to a treatment group. 
5.1.1 Informed Consent and Screening Period  
5.1.1.1 Pre-Screening Period  
Pre-screening period is defined from the signing of the pre-screening informed consent, to 
obtaining the IDH mutational status report, or to withdrawal of consent.  Patients who have already 
tested positive for mIDH may enter the Screening Period directly. 
Patients who fail pre-screening will have the following information recorded: demographic 
information, disease diagnosis, mIDH status results (if available), and reason for pre-screening 
failure. 
5.1.1.2 Screening Period  
Screening Period is defined as the period from main study consent until the first dose of HMPL-306 
(Part 1: Day 1 of PK week, Part 2: C1D1). 
A screen failure is a consented patient who has been deemed ineligible on the basis of 1 or more 
eligibility criteria or who has withdrawn consent prior to treatment.  Screen failures may be 
rescreened.   
Before informed consent is obtained, examinations for standard treatment performed within 
28 days before planned C1D1 (60 days for ophthalmologic exams) can be used to replace 
assessments required for eligibility, except for assessments that need to be performed 7 days prior 
to study drug administration in the dose expansion part as specified in Table 2.  For patients 
enrolled in dose escalation, all screening assessments must be completed before study drug 
administration on Day 1 of PK week. 
5.1.1.3 Rescreening  
Patients who cannot complete the procedures within the screening window may be rescreened, and 
certain screening procedures may not need to be repeated, including certain procedures that were 
obtained as part of the patient’s standard care prior to providing informed consent for this study, 
with documented sponsor approval. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, only after discussion with and permission from the HUTCHMED clinical research 
physician or designee.   
Patients may be eligible for rescreening up to 2 times in any of the following circumstances: 
• Patients who have become eligible to enroll in the study as the result of a protocol 
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• Patients whose status has changed such that the eligibility criterion that caused the 
patient to screen fail would no longer cause the patient to screen fail again. 
• Patients who complete screening and meet all inclusion and exclusion requirements but 
are unable to be enrolled due to extenuating circumstances (such as severe weather or 
child illness). 
Each time rescreening is performed, the individual must sign a new informed consent form (ICF) 
and will be assigned a new identification number. 
5.2 
Inclusion Criteria  
Patients may be enrolled in this study only if they satisfy all the following criteria: 
1. Patients aged ≥18 years. 
2. Patients with advanced relapsed, refractory, or resistant hematological malignancies, as 
defined below: 
Part 1:  
a. Patients with documented IDH mutation per local or institutional next generation 
sequence (NGS). 
b. Patients must be refractory to or intolerant of established therapies known to 
provide clinical benefit. 
c. Patients who have received prior IDH inhibitor treatment may be enrolled in the 
escalation part of the protocol. 
Part 2:  
a. Patients with documented IDH mutation of any of these subsets: IDH1 (R132C), 
IDH1 (R132H), IDH2 (R140Q), and IDH2 (R172K), including co-mutations and 
any combination thereof per local or institutional NGS. 
b. Patients must have received at least 1 prior line of therapy.  An established standard 
of care with proven benefit for which the patient is eligible, must not be available 
at the time of enrollment. 
c. Patients with R/R AML must have progressed on prior IDH treatment. Patients with 
AML must not have standard therapeutic options available (including IDH 
inhibitors where approved) and have the following: 
i. Relapsed AML unsuitable for intensive chemotherapy or 
venetoclax-based regimen or target agents; 
ii. Primary refractory AML unsuitable for intensive chemotherapy or 
venetoclax-based regimen or target agents. 
d. Patients with relapsed/refractory AML/ include the following:  
i. Subjects who relapse after transplantation; 
ii. Subjects in second or later relapse; 
iii. Subjects who are refractory to initial induction or re-induction 
treatment. 
3. Patients must agree to bone marrow aspiration or biopsy performed before and during the 
treatment as specified in Appendix 1 (Part 1) or Appendix 2 (Part 2). 
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
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5. Patients must have adequate hepatic function as evidenced by: aspartate aminotransferase 
(AST), and alanine aminotransferase (ALT), ≤3.0 × upper limit of normal (ULN), unless 
considered due to leukemic disease and serum total bilirubin ≤1.5 × ULN. 
6. Patients must have creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault 
formula. 
7. Patients must recover to Grade <1 from any clinically relevant toxic effects of prior 
surgery, radiotherapy, or other therapies intended for the treatment of cancer. 
8. Female patients of childbearing potential must have a negative serum pregnancy test within 
7 days of study drug administration. 
NOTE: Postmenopausal is defined as at least 12 months of amenorrhea without alternative 
medical cause. 
9. Male patients with partners of childbearing potential must agree to use a condom, and 
female patients of childbearing potential must agree to use highly effective form(s) of 
contraception that result in a low failure rate (<1% per year) when used consistently and 
correctly starting in the Screening Period, continuing throughout the entire study period, 
and for 30 days after taking the last dose of study drug.  Such methods include combined 
hormonal contraception (estrogen/progestogen) associated with the inhibition of ovulation 
(oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or implantable), intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, or 
sexual abstinence, if this is the normal and preferred lifestyle.  Any hormonal method of 
highly effective contraception should always be combined with a condom because HMPL-
306 may reduce their effectiveness.   
5.3 
Exclusion Criteria  
Patients are not eligible for enrollment into this study if they meet any of the following criteria: 
1. Patients who have undergone hematopoietic stem cell transplantation (HSCT) within 
60 days of the first dose of HMPL-306, or with clinically significant active 
graft-versus-host disease  
2. Patients who received an investigational agent <14 days prior to their first day of study 
drug administration 
3. Patients who are pregnant or breastfeeding 
4. Patients with an active severe infection or with an unexplained fever >38.3°C during 
screening visits or on their first day of study drug administration (at the discretion of the 
Investigator, patients with an infection that is controlled with appropriate therapy are 
eligible); see Appendix 4 for coronavirus disease 2019 (COVID-19) risk assessment. 
5. Patients with New York Heart Association Class III or IV congestive heart failure, left 
ventricular ejection fraction <40% by echocardiogram (ECHO), or a multigated acquisition 
(MUGA) scan within approximately 28 days of C1D1 (Appendix 5) 
6. Patients with a history of myocardial infarction within the last 6 months of screening 
7. Patients with a known unstable or uncontrolled angina pectoris 
8. Patients with congenital long QT syndrome or a known history of severe and/or 
uncontrolled ventricular arrhythmias 
9. Electrocardiogram without any clinically significant findings, and for QT interval 
corrected for heart rate using Fridericia's formula (QTcF - interval from the start of the Q 

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wa ve t o t he e n d of t he T wa v e [Q T ] c orrecte d f or heart rate usi n g Fri dericia's f or m ula ) 
i nter val > 4 7 0 ms (f or w o me n) a n d > 4 5 0 ms (f or me n) , or ot her fact ors t hat i ncrease t h e 
ris k of Q T prol o n gati o n or arr h yt h mic e v e nts  a n d per t he i n vesti gat or’s assess me nt  
1 0.  Patie nt s ta ki n g me dicati o ns t hat are k n o w n t o pr ol o n g t he Q T i nter val (A p pe n di x  6 ) N O T E: 
Patie nt s ma y partici pate if me dicati o ns are c ha n ge d t o acce pt a ble alter nati ves 
1 1.  Patie nt s wit h k n o w n acti ve/ u ntreate d i nf ecti o n wit h h u ma n i m m u n o deficie nc y vir us (HI V ), 
acti ve he p atitis B  vir us ( H B V ), or he p atitis C  vir us ( H C V)  
1 2.  Patie nt s wit h i m me diatel y life-t hr eate ni n g, se v ere c o m plicati o ns of le u ke mia s uc h as 
u nc o ntr olle d blee di n g, p ne u m o nia 
wit h h y p o xia or s h oc k, a n d/ or disse mi nate d 
i ntra vasc ular c oa g ulati o n 
1 3.  Patie nt s ta ki n g 
me dicati o ns t hat ca n i n hi bit or i n d uce  
 a n d/ or  
 
(A p pe n di x  7 ) wit hi n 1 w ee k or 5 half -li ves ( w hic he ver is l o n ger) b ef ore t h e start of st u d y 
treat me nt 
1 4.  Patie nt s w h o recei ve d s mall-m olec ule or lar ge -m olec ule (s uc h as a nti b o d y -b ase d dr u g) 
dr u gs i n pre vi o us cli nical  st u dies f or < 2 we e ks, or < 4 wee ks, res pecti vel y , fr o m t he ti me 
of start of t he st u d y treat me nt t o t he last use  
1 5.  Patie nt s wit h cli nicall y si g nifica nt, or se v ere gastr oi ntesti nal disease or c o n diti o n t hat 
i n vesti gat ors s us pect ma y affect dr u g a bs or pti o n, i ncl u di n g, b ut n ot limite d t o, acti ve 
gastri c a n d d u o de n al ulc ers, ulcerati ve c olitis a n d ot her di gesti ve diseas e, gastr oi ntesti nal 
t u m or wit h acti ve blee di n g, or ot her gastr oi ntesti nal c o n diti o ns t hat ma y ca use blee di n g or 
perf orati o n, b y i n vesti gat or’s discreti o n  
1 6.  Patie nt s wit h a cli nic all y si g nifica nt li ver disease or c o n diti o n s uc h as Gil bert s y n dr o me, 
a n d at t he discreti o n of t he i n vesti gat or, ma y affect dr u g met a b olis m  
1 7.  Patie nt s wit h a me dical c o n diti o n, p h ysical e x a mi nati o n fi n di n g, or cli nical la b orat or y 
fi n di n g t h at, i n t he In vesti gat or’s o pi ni o n , 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 pret ati o n of t he res ults or re n ders t he patie nt  at hi g h ris k fr o m 
treat me nt c o m plicati o ns 
1 8.  Patie nt s wit h a k n o w n h y perse nsiti vit y t o H M P L -3 0 6 or t o a n y of its e xci pie nts  
1 9.  Patie nt s wit h prese n ce of sec o n d pri mar y m ali g n a nt t u m ors wit hi n t he last 2 years, wit h 
t he e x ce pti o n of t he f oll o wi n g, if m e dicall y c o ntr olle d: b asal cell carci n o ma of t he s ki n, 
sq ua m o us cell carci n o ma of t he s ki n, carci n o ma i n sit u of t he cer vi x, a n d carci n o ma i n sit u 
of t he breast  
2 0.  Part 2 O nl y: T he ti me si n ce t he l ast d ose  of pri or I D H i n hi bit or treat me nt  is wit hi n 3 0 da ys  
pri or t o t he first da y of st u d y dr u g a d mi nistrati o n  
C CI
C CI

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6 
STUDY CONDUCT  
Recruitment is estimated to take approximately 18 months.  The estimated duration for the entire 
study from the time the study is open to enrollment until completion of data analyses is 
approximately 36 months.  During the study, assessments at each study visit will be performed as 
listed in Table 1 and Table 2 as described in this section. 
6.1 
Study Procedures  
If there is dosing on assessment day, all assessment examinations must be completed before study 
drug administration, except for 12-lead electrocardiogram (ECG), ECHO/MUGA scan, 
ophthalmologic examination, and efficacy assessments. 
6.1.1 Study Drug Administration  
6.1.1.1 Dose Escalation  
A single dose of HMPL-306 will be administered on Day 1 of PK week (Section 6.1.2) for each 
cohort in the dose escalation part.  After PK week, all patients will receive continuous, daily 
administration of HMPL-306 beginning at C1D1.   
6.1.1.2 Dose Expansion  
All patients will receive continuous, daily administration of HMPL-306 at RP2D and/or MTD, 
beginning at C1D1. 
6.1.2 PK Week  
The PK week is defined as 7 days prior to C1D1 where a single dose of HMPL-306 will be 
administered on Day 1 of PK week (Day -7 relative to C1D1).  Blood samples and ECG 
assessments will be collected at intervals as specified in Appendix 1.  These samples will be 
analyzed for plasma concentrations of HMPL-306, 2-HG, and other biological markers as defined 
by the sponsor.  PK week is applicable to every cohort in the dose escalation part only.  See 
Appendix 1 for more details.  PK week for a particular dose cohort will be considered optional and 
not mandatory if PK week data from 5 patients have been collected at the same dose. 
6.1.3 Medical History and Demographic Information  
Medical history data will be collected at Screening and will include significant clinical disease or 
symptoms, surgical history, history of malignancy (including date of diagnosis, classification, 
prognostic evaluation, treatment performed and outcome; tumor types and outcomes of any other 
previous malignancies), history of smoking, alcohol consumption, drug abuse, and other medically 
relevant history.   
At pre-screening, only demographic information and diagnosis of disease will be collected.  This 
demographic information will include gender, race, and in some countries, year of birth.  If patients 
go on to participate in screening, demographic information on record will be used unless an update 
is warranted. 

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6.1.4 Prior and Concomitant Medications and Concomitant Procedures  
Concomitant medications may include any prescription or over-the-counter (OTC) medications 
used by a patient.  During the Screening Period, all medications taken by a patient within 28 days 
prior to HMPL-306 administration should be recorded in a case report form (CRF).  At scheduled 
subsequent visits, any drugs taken during that period and within 30 days after end of treatment 
should be recorded in the CRF.  Subsequent new transplantation pretreatment regimens and new 
antitumor treatment regimens, including HSCT, during the Safety and Efficacy Follow-up Periods 
will also be recorded.  Prior and concomitant therapies are discussed in detail in Section 7.4.1 and 
Section 7.4.2. 
6.1.5 Lifestyle Management  
Patients enrolled in this study are advised to avoid unnecessary exposure to sunlight or any other 
source of ultraviolet light during their participation in this study through to 30 days after the end 
of treatment.  Patients are encouraged to wear sunglasses and apply sunscreen products with a sun 
protective factor of at least 15.  Safety of HMPL-306 under sunlight is not yet fully understood.  
Further nonclinical studies are planned to fully assess the phototoxicity effects of HMPL-306 in 
detail. 
6.1.6 Vital Signs  
Vital signs, including blood pressure, body temperature, heart rate, and respiratory rate, will be 
monitored as per Schedule of Events (Table 1 and Table 2).  Patients need to sit still for 5 minutes 
before blood pressure measurement.  Unscheduled examinations may be performed if clinically 
indicated. 
6.1.7 Physical Examination, Weight, and Height  
Physical examination and weight measurement will be conducted as per Schedule of Events 
(Table 1 and Table 2).  Physical examination includes head, neck, ears, nose, eyes, throat, skin, 
mucous membranes, and gastrointestinal tract, as well as cardiovascular, renal, musculoskeletal, 
respiratory, and nervous systems. 
Height will only be measured at screening. 
6.1.8 ECOG Performance Status  
ECOG PS scoring will be performed per Schedule of Events (Table 1 and Table 2).  ECOG PS 
will be carefully scored in strict accordance with criteria (Appendix 3), especially to determine 
eligibility for enrollment. 
6.1.9 Ophthalmologic Examination  
Ophthalmologic examinations, including eye appearance, slit lamp examination, best corrected 
visual acuity, visual field, eye movement, pupil reflex, optical coherence tomography (OCT) 
examination, and intraocular pressure will be performed per Schedule of Events (Table 1 and 
Table 2).  If a patient has undergone the relevant examinations 60 days before treatment (C1D1), 
they do not need to be repeated.  After starting administration of the study drug, eye appearance 
and slit lamp examinations will be performed per Schedule of Events (Table 1 and Table 2).  Other 

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ophthalmic examinations are to be performed if clinically indicated.  If a patient develops an 
ophthalmic AE related to HMPL-306, the frequency of eye examinations should be increased to 
once per cycle until AE is resolved or stable.  If retinal pigment epithelium (RPE) detachment is 
noted during an OCT examination, the patient may remain on the study drug with a follow-up 
OCT examination 2 weeks later.  If RPE detachment is still observed during re-examination, the 
study drug dose should be reduced and an OCT examination performed again 2 weeks later.  If 
RPE detachment is not resolving upon re-examination, the study drug dose should be further 
reduced or held until the RPE detachment is shown to be resolving. 
6.1.10 Laboratory Evaluations  
Laboratory assessments will be performed locally.  The range of normal values of all study sites 
will be collected prior to start of the study. 
6.1.10.1 
Hematology – Routine  
Hematology cell counts include red blood cells, platelets, reticulocytes, white blood cells and 
differentials (neutrophils, lymphocytes, eosinophils, monocytes, and basophils), hemoglobin and 
hematocrit levels will all be performed per Schedule of Events (Table 1 and Table 2).  Any 
additional routine blood tests during the study shall be arranged by the investigator on an as-needed 
basis. 
6.1.10.2 
Hematology – Blood Transfusion History and Blood Transfusion Record  
Blood transfusion history, including red blood cell and/or platelet infusion within 8 weeks prior to 
HMPL-306 administration, will be recorded during Screening.  The type of infusion, number of 
infusion unit(s), and date of infusion should be recorded.  The pre-infusion hemoglobin level 
and/or platelet count should also be recorded if obtainable (either is acceptable, both are not 
required). 
Blood transfusion record will include red blood cell and/or platelet infusion after the start of study 
drug administration until end of treatment (EOT) visit.  The type of infusion, number of infusion 
unit(s), and date of infusion should be recorded.  The pre-infusion hemoglobin level and/or platelet 
count should also be recorded if obtainable (either is acceptable, both are not required). 
6.1.10.3 
Hematology – Bone Marrow Aspiration and/or Biopsy  
It is necessary to perform either bone marrow aspiration or biopsy, both are not mandatory.  
Patients with AITL that have fluorodeoxyglucose (FDG)-avid disease and will undergo positron 
emission tomography-computed tomography (PET-CT) imaging for screening and efficacy 
evaluation are not required to have a bone marrow aspiration or biopsy.   
Bone marrow aspiration and/or biopsy examinations will be performed during screening, on Day 1 
of Cycles 3, 5, and 7 (every 8 weeks ±7 days, for the first 24 weeks), then every 3 cycles (±14 days) 
thereafter (ie, Day 1 of Cycles 10, 13, and so on), at the EOT visit, and at every efficacy follow-
up assessment for applicable patients.  Additional bone marrow examinations may be performed 
at the investigator’s discretion on as-needed basis. 

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Results of the analyses of the morphology examination, immunophenotyping, cytogenetics, and 
molecular genetic testing performed during screening will be collected in the electronic case report 
form (eCRF). 
Please refer to Appendix 17 for a description of the immunophenotyping, cytogenetics, and 
molecular genetic testing for AML, HR-MDS, and AITL. 
6.1.10.4 
Blood Chemistry  
Blood chemistry will all be performed per Schedule of Events (Table 1 and Table 2).  This 
assessment should include blood urea nitrogen, creatinine, glomerular filtration rate, creatinine 
clearance rate; uric acid, electrolytes such as sodium, potassium, magnesium, chloride, calcium, 
and phosphorus, and glucose, creatine phosphokinase, and liver function tests such as total 
bilirubin, direct bilirubin, indirect bilirubin, ALT, AST, ALP (alkaline phosphatase), lactate 
dehydrogenase, total protein, and albumin. 
6.1.10.5 
Blood Amylase and Lipase  
Tests for blood amylase and lipase will be performed as per Schedule of Events (Table 1 and 
Table 2). 
6.1.10.6 
Fasting Lipid Panel  
Fasting lipid panel, including total cholesterol, high-density lipoprotein, low-density lipoprotein, 
and triglycerides, will be performed as per Schedule of Events (Table 1 and Table 2). 
6.1.10.7 
Coagulation Indicators  
Tests for coagulation indicators, including prothrombin time (PT), activated partial thromboplastin 
time, and international normalized rate (INR), will be performed as per Schedule of Events 
(Table 1 and Table 2). 
6.1.10.8 
HbA1C  
Tests for glycated hemoglobin (HbA1C) will be performed as per Schedule of Events (Table 1 and 
Table 2).   
6.1.10.9 
Pregnancy Test  
Female patients of childbearing potential (including those who have undergone tubal ligation) 
must undergo serum pregnancy test within 7 days of study drug administration (as well as prior to 
HMPL-306 administration on Day 1 of PK week in dose escalation) and record a negative result.  
After enrollment, serum or urine pregnancy test will be performed as per Schedule of Events 
(Table 1 and Table 2).   
NOTE: Postmenopausal is defined as at least 12 months of amenorrhea without alternative medical 
cause. 

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6.1.10.10 
Urinalysis  
Urinalysis (or dipstick), including urine glucose, protein, ketone body, red blood cells, white blood 
cells (WBCs), and urobilinogen, will be performed as per Schedule of Events (Table 1 and 
Table 2).   
6.1.10.11 
Virological Screening  
Viral serology should be tested at screening for all patients and includes HIV, HBV (HBsAg, 
HBsAb, HBeAg, HBeAb, and HBcAb), cytomegalovirus (CMV) (CMV antibody), and HCV 
(HCV antibody).  If HBsAg, HBcAb, or CMV antibody is positive, CMV DNA or HBV DNA is 
also required to be assayed by PCR method.  If CMV DNA or HBV DNA is negative, patients 
may be enrolled and their CMV DNA or HBV DNA should be monitored every cycle.  If HCV 
antibody is positive, HCV ribonucleic acid is required to undergo PCR testing.   
6.1.10.12 
IDH Mutational Status  
Patients who have reports of positive mIDH status may directly enter Screening Period without 
pre-screening.  Patients who have not been tested for mIDH should be tested locally (via biopsy 
tissue collection) to determine mIDH status before enrollment.   
All patients will be required to provide samples for IDH mutational status confirmation as outlined 
in Section 6.1.16.   
6.1.10.13 
Tumoral Sample for Patients with AITL  
Results of any analyses performed by local testing on previous tumoral samples taken for 
confirmation of PrD prior to screening or during screening, including immunophenotyping, 
cytogenetics, molecular genetic testing, and Epstein-Barr virus (EBV) status, will be collected in 
the eCRF. 
Please refer to Appendix 17 for a description of the immunophenotyping, cytogenetics, and 
molecular genetic testing for AITL. 
6.1.11 Electrocardiogram  
The 12-lead ECG indicators include PR interval, QRS interval, RR interval, QT or QTcF, and 
heart rate.  Evaluation time points are shown in Appendix 1 (dose escalation) and Appendix 2 
(dose expansion).   
6.1.12 Echocardiogram/Multigated Acquisition Scan  
To evaluate ejection fraction of patients, ECHO (preferred method) or MUGA will be performed 
during the Screening Period, on Day 1 of every treatment cycle for the first 3 cycles, every other 
cycle thereafter, and at EOT visit.  It is recommended to use the same assessment method 
throughout the study for each patient for consistent and uniform interpretation of the results. 
6.1.13 Safety Evaluation  
AEs emerging as a result of protocol-required procedure(s) are collected, even during 
pre-screening period if applicable.  AEs are collected from the signing of the ICF until 30 days 
after the end of treatment or initiation of new antitumor therapy.  Related AEs will be followed 

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until they are recovered to the baseline status, already in a stable state as assessed by the 
investigator, start of new antitumor therapy, lost to follow-up, death, withdrawal of informed 
consent, end of study, or it has been confirmed the AEs are unrelated to the study drug. 
Serious adverse events (SAEs) are collected from the signing of the ICF (pre-screening ICF if 
applicable) until 30 days after the end of treatment or initiation of new antitumor therapy, 
whichever is earlier.  After this 30-day period, and if the patient has not started any other antitumor 
treatment, investigators should report only SAEs considered to be related to the study drug. 
6.1.14 Efficacy Evaluation  
Efficacy evaluation of AML will be performed based on 2017 European LeukemiaNet (ELN) 
criteria (Appendix 8).  Efficacy evaluation of HR-MDS will be performed based on the 
International Working Group response criteria in myelodysplasia (Appendix 12).  Efficacy 
evaluation of AITL will be performed based on Lugano Classification (Cheson 2014) for Hodgkin 
and Non-Hodgkin’s Lymphoma (Appendix 9).   
Tumor evaluations will be conducted at screening, every 8 weeks (±7 days) during the first 
24 weeks (ie, Day 1 of Cycles 3, 5, and 7), and every 12 weeks (±14 days) thereafter (ie, Day 1 of 
Cycles 10, 13, and so on) through EOT, or end of Efficacy Follow-up period (if applicable).  
Patients who discontinue HMPL-306 treatment due to reasons other than disease progression will 
continue tumor assessment according to previous tumor evaluation schedule until disease 
progression, as defined in Appendix 8 and Appendix 9, or start of new antineoplastic therapy (see 
Table 1).  The same imaging procedure and laboratory tests used to define measurable lesions at 
baseline should be used throughout the study for each patient. 
The baseline tumor assessment should be completed within 28 days prior to the first dose of study 
treatment (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).  Tumor assessments 
completed as standard of care, prior to signing of the informed consent and within 28 days of first 
dose of study treatment, may be used as baseline assessment. 
Response evaluation of patients will be based on the most recent results of physical, bone marrow 
(if applicable), imaging, and hematological examinations, per local assessment.  If a patient needs 
to delay the study drug after bone marrow examination and wait for recovery of peripheral blood 
count, then routine blood test results within 2 weeks after bone marrow analysis can be used to 
determine response. 
For patients with myeloid malignancies, this assessment should be done using a blood test, bone 
marrow aspiration and/or biopsy, and physical examination as per the Schedule of Events (see 
Table 1).   
For patients with hematological malignancies that are non-myeloid (eg, AITL), all measurable and 
evaluable lesions should be assessed and documented at screening and each subsequent efficacy 
evaluation using contrast-enhanced CT scans (neck, chest, abdomen, and pelvis) for non-FDG-
avid disease and/or PET-CT scans for patients with FDG-avid disease.  Enhanced magnetic 
resonance imaging (MRI) may be used instead of CT scans in patients for whom CT scans are 
contraindicated.   
If a patient with non–FDG-avid disease has documented bone marrow involvement at screening, 
a bone marrow aspirate and/or biopsy will be required at each efficacy evaluation.   

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6.1.14.1 
Risk Stratification/Prognostic Scoring  
Prognostic stratification will be collected at screening as follows: 
• AML: ELN Risk stratification by genetics (Appendix 15) 
• HR-MDS: IPSS-R (Appendix 16) 
• AITL: International Prognostic Index (Appendix 14) 
6.1.14.2 
Ann-Arbor Staging  
Please refer to Appendix 13 for a description of Ann-Arbor staging for patients with AITL 
collected at screening. 
6.1.15 Pharmacokinetics and Pharmacodynamic Evaluations  
6.1.15.1 
Sample Collection and Handling  
Blood samples will be collected for PK and PD analysis of HMPL-306 and 2-HG levels in plasma, 
respectively.  The full PK and PD evaluation schedule of dose escalation and expansion cohorts is 
presented in Appendix 1 and Appendix 2, respectively. 
The collection, handling, and transportation of biological samples should be performed in 
accordance with required processes as provided in study-specific laboratory manual. 
6.1.15.2 
Analytical Procedures  
Plasma samples will be analyzed to determine concentrations of HMPL-306 using a validated, 
specific, and sensitive liquid chromatography-tandem mass spectrometry method.  Plasma samples 
will be analyzed to determine concentrations of 2-HG using a validated method. 
Plasma samples may also be analyzed to document the presence of circulating metabolites of 
HMPL-306 using a qualified research method.  If conducted, metabolite analysis will be reported 
outside of the clinical study report (CSR). 
6.1.16 IDH Mutation Confirmation  
Samples will be collected for central confirmation of mIDH status in order to validate local results 
and reports used by sites to determine eligibility for the study.  Collected samples will follow 
specified procedures as indicated in laboratory manual.  Bone marrow and/or whole blood will be 
collected for analysis as described in Appendix 1 (dose escalation) and Appendix 2 (dose 
expansion).  This independent confirmation will use NGS by the central laboratory at prespecified 
intervals as determined by the sponsor.  All samples should be prepared, labeled, handled, 
packaged, stored, and transported in accordance with required processes as provided in study-
specific laboratory manual. 

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6.1.17 Exploratory Biomarker Evaluation  
In this study, bone marrow and/or blood samples collected will be tested and analyzed for possible 
biologic marker(s) as specified/identified by the sponsor.  Results from these tests and analysis of 
its data will be used to determine correlation between possible biomarkers of HMPL-306, 
hematological malignancies under study, and their relationship to PK, drug exposure, TE, PD, and 
clinical response, as well as potential mechanism of drug resistance. 
Bone marrow/blood samples collected as per Appendix 1 (dose escalation) and Appendix 2 (dose 
expansion) will be tested further for a spectrum of levels and abundance of molecular mutations 
and genetic aberrations (as determined by the sponsor) to evaluate their association with all tumor 
types under study.  Results from these tests, and the analyses thereof, will be used to further 
characterize and fully understand biological relationship between expression levels of these 
molecular mutations and genetic aberrations and their correlation to PK, drug exposure, TE, PD, 
and clinical response of HMPL-306, as well as potential mechanisms of drug resistance. 
All related analyses will be performed by the central laboratory, and all samples should be 
prepared, labeled, handled, packaged, stored, and transported in accordance with required 
processes as provided in study-specific laboratory manual. 
6.1.18 End of Treatment Visit  
Patients who have completed the study or have discontinued study treatment will be asked to return 
to the investigational site to have safety examinations and assessments within 7 days (±3 days) 
after the last dose of the study drug. 
6.1.19 Follow-up Period  
Safety Follow-up 
All patients who have completed an EOT Visit will have a Safety Follow-up Visit.  The Safety 
Follow-up Visit will be conducted at 30 days (±7 days) from EOT Visit.   
AEs related to the study drug will be followed until resolution and SAEs will be followed until 
resolution regardless of the relationship to the study drug. 
All female patients of childbearing potential must complete a pregnancy test (serum or urine) 
during the Safety Follow-up Visit.  Pregnancy testing should be repeated for patients with 
suspected pregnancy.  This is not applicable for postmenopausal female patients (defined as at 
least 12 months of amenorrhea without alternative medical cause), and the date of menopause 
should be recorded instead. 
Efficacy Follow-up 
Patients who discontinue the study drug due to reasons other than disease progression, death, lost 
to follow-up, or withdrawal of consent will remain on study for tumor assessments and will be 
followed every 12 weeks (±14 days) from the EOT visit or last assessment, until disease 
progression, initiation of new anticancer therapy, withdrawal of consent, lost to follow-up, death, 
conditions are met per Section 6.2.1, or the end of the study, whichever comes first. 

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Survival Follow-up 
All patients will be followed for survival status every 12 weeks (±14 days), until death, lost to 
follow-up, or withdrawal of consent.  Survival information can be obtained via phone and 
information will be documented in the source documents and relevant CRFs. 
6.1.20 End of Study  
The end of study is defined as the date on which all patients have their last visit or 1 year after the 
last patient has their first visit, whichever comes first. 
6.2 
Discontinuation or Withdrawal  
6.2.1 Discontinuation of Treatment  
6.2.1.1 Permanent Discontinuation of Treatment  
The investigator has the right to discontinue a patient from the study for any medical condition 
that the investigator or sponsor determines is in the best interest of the patient; reasons may include 
non-compliance (eg, missed doses, visits) or pregnancy. 
Any patient who discontinues treatment should be encouraged to return to the study site for an 
EOT Visit and continue with the remaining study visits.  The primary reason(s) for discontinuation 
must be recorded on appropriate CRF. 
Patients must be discontinued from treatment for disease progression, withdrawal of consent, 
intolerable toxicity, as outlined in Table 8, Table 9, and Table 10, repeated non-compliance or 
poor compliance, commencement of other antitumor treatment during the study, pregnancy, loss 
to follow-up, termination of the study by the sponsor, death, or end of the study. 
Patients may receive a maximum of 6 cycles of therapy unless the following are met: 
• Patients with AML must have a partial response (PR) or better based on the 2017 
ELN criteria (Appendix 8).   
• Patients with HR-MDS must have a hematological response or better based on the 
IWG Criteria (Appendix 12) 
• Patients with AITL must have a stable disease (SD) or better based on the Lugano 
Classification (Appendix 9).   
6.2.1.2 Temporary Treatment Discontinuation  
Patients who achieved adequate response after HMPL-306 treatment and meet other criteria for 
HSCT treatment can undergo HSCT after discontinuing HMPL-306 treatment, but they will 
continue to be retained in the study to perform efficacy follow-up and subsequent treatment 
recorded (Section 6.1.19).  If the patient discontinues HMPL-306 treatment for HSCT treatment 
but eventually fails to receive HSCT treatment, HMPL-306 therapy can resume after sponsor 
approval; if the patient fails HSCT treatment and has recurrent hematological malignancy with 
mIDH and then HMPL-306 treatment can resume after request from the investigator and sponsor 
approval. 

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6.2.1.3 Withdrawal from Study  
All study patients have the right to voluntarily withdraw from study at any time.  During the period 
of treatment and follow-up, a patient who withdraws consent to continue participation in the study 
will not be followed for any reason after consent has been withdrawn.  Every effort should be made 
to obtain information on patients who discontinue the study drug but who do not withdraw consent 
to continue participation in the study.  If a patient withdraws consent for disclosure of future 
information, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
If a patient withdraws from the study, such a patient may request destruction of any samples taken 
and not tested.  The investigator must also document requested destruction in the site study records. 
6.2.1.4 Replacement of Patients  
Patients who are not DLT-evaluable in a dose cohort may be replaced to guarantee the protocol-
required number of DLT-evaluable patients for dose escalation evaluations.  Patients who are not 
eligible for response assessment (defined as those patients who completed a follow-up tumor 
assessment after cycle 2) in Part 2 of the study may be replaced.   
6.2.1.5 Patients Lost to Follow-up  
A patient will be considered lost to follow-up if the patient repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
Before a patient is deemed lost to follow-up, the investigator or designee must make every effort 
to regain contact with such patient (where possible, 3 telephone calls and, if necessary, a certified 
letter to patient’s last known mailing address or local equivalent methods).  These contact attempts 
should be documented in that patient’s medical record.  Should a patient continue to be 
unreachable, such patient will be considered withdrawn from the study. 
6.2.2 Study Stopping Rules  
Safety will be monitored continuously throughout the conduct of the study by a standing SRC.  
There will be periodic review of emerging data on safety, PK, drug exposure, TE, PD, and clinical 
response to determine continuation (or otherwise) of individual patient, cohorts, arms, or entire 
dose expansion part.  If the study is halted as per Study Stopping Rules (Section 6.2.2.2) in either 
the dose escalation part or the dose expansion part, the study will only be restarted after Regulatory 
Approval as per local regulations.   
Dose stopping rules for individual patients common to both dose escalation and dose expansion 
parts include: 
1. DLTs that occur outside the DLT assessment window (DLT-equivalent) that have not 
resolved to Grade 1 or lower within 14 days, or after medical intervention as specified in 
Section 4.1.1. 
2. Progression of disease that leads to treatment discontinuation 
3. In the opinion and recommendation of the PI, or individual patient on their own, may 
withdraw from study at any time 
4. If there is documented evidence of repeated non-compliance  

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6.2.2.1 Stopping Rules for Individual Patient  
Dose Escalation: 
Dosing will stop for an individual patient if: 
DLT has not returned to Grade 1 or lower within 14 days 
See Section 4.1.1 for details on dose escalation Part 1, DLT, and safety assessment. 
Dose Expansion:  
1. DLT-equivalent event has not resolved (even with medical intervention) within 14 days, 
or has re-occurred again at a de-escalated dose level 
2. Resolution in severity (down-grade) and/or duration (within 14 days) of DLT-equivalent 
event will determine dose interruption, reduction, or discontinuation for the individual 
3. Resolution of DLT-equivalent event will determine if the patient will resume treatment, at 
the discretion of investigator, at; 
the same dose level 
a lower dose  
discontinue treatment altogether 
6.2.2.2 Stopping Rules for a Cohort or the Study  
Dose Escalation Part 
The stopping rules at a cohort level are based on mTPI-2 method and defined in Table 5.  There 
will be no escalation to the next higher dose level cohort, until all available data from the current 
dose level cohort have been reviewed by SRC, who will then recommend appropriate dose 
escalation, de-escalation, or discontinuation.   
This dose escalation part will be suspended, interrupted, or discontinued before MTD is attained 
based on: 
 Recommendation of SRC, and/or  
 Results of the analysis of emerging PK data suggesting that drug exposure or TE is 
saturated. 
The dose escalation part of the study will prematurely end when any of the following conditions 
are met: 
1. Excessive toxicity is present in the initial dose, ie, if DLT is observed in 1 out of 3 patients 
at the first dose level.  If this occurs at the initial dose level, data will be reviewed by the 
SRC to determine next steps for the study. 
2. Although no excessive toxicity is present in the first dose level cohort, if the dose returns 
to the initial dose according to the rules in Table 5 and excessive toxicity is present at the 
initial dose (for example, 2 or more patients with a DLT are observed in 6 patients). 

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D ose E x p a nsi o n P art : 
T his part  utilizes M T D or R P 2 D t hat has bee n deter mi ne d as safe b y S R C base d o n t he c o ncl usi o n 
of d ose esca lati o n p art .  T he s p o ns or will peri o dicall y re vie w e v ol vi n g a g gre gate safet y data b y 
a p pr o priate m et h o ds.  
6. 3  
St u d y Ter mi n ati o n   
T he s p o ns or has t h e ri g ht t o te r mi nate st u d y pre m at urel y.  Reas o ns m a y i n cl u de efficac y, s afe t y, 
or f utilit y, a m o n g ot hers .  S h o ul d t he s p o ns or deci de t o ter mi nate st u d y, t he i n vesti gat or(s) will be 
n otifie d i n writi n g . 
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7  
S T U D Y I N T E R V E N TI O N S   
7. 1  
St u d y Dr u g A d mi nistr ati o n   
Patie nt s wi ll receive  H M P L -3 0 6  P O Q D  i n a 2 8 -d a y c ycle . 
Patie nt s s h o ul d ta ke H M P L-3 0 6 o n a n e m pt y st o mac h (n o f o o d 2 h o urs b ef ore a n d 2 h o urs after 
d osi n g ) at a relati vel y fi x e d ti me e ver y da y wit h a b o ut 2 4 0  m L of wat er .  T he acc urate act ual ti me 
of d osi n g s h o ul d be rec or de d i n patie nt ’s pill diar y eac h ti me.  
T he best eff ort s h o ul d be e x erte d t o e ns ure patie nts are me dicate d acc or di n g t o t he st u d y pr ot oc ol .  
If t he patie nt misses t he st u d y dr u g f or m ore t ha n 4 h o urs d ue t o vari o us reas o ns, it m ust n ot be 
s u p ple me nte d.  T he misse d d ose m ust be  rec or de d, a n d t he dr u g will be c o nti n ue d at t he n e xt 
sc he d ule d d osi n g ti me.  T he misse d dr u g m ust be rec or de d .  If v o miti n g o cc urs after dr u g 
a d mi nist rati o n, it s h o ul d als o be rec or de d, a n d t h e dr u g will be c o nti n ue d at t he n e xt sc he d ule d 
d osi n g ti me.  
Patie nt s i n d ose escalati o n will recei ve a si n gle d ose of H M P L -3 0 6 f or t hat c o h ort d ose le vel, o n 
Da y 1 of P K wee k ( 7 da ys pri or t o C 1 D 1).  
7. 1. 1  D ose E sc al ati o n  
I n d os e escalati o n, dosa ge will be acc or di n g t o d ose  le vel (see Ta ble  4 ). 
D ose escalati o n will be gi n at 
 m g Q D of H M P L -3 0 6 i n a 2 8 -da y c o nti n u o us d osi n g treat me nt 
c ycle.  T he d ose will escalate s uccessi vel y acc or d i n g t o t h e se q u e nce of  
 m g Q D, 
 m g Q D, 
a n d 
 m g Q D,  
 m g Q D,  
 m g Q D,  
 m g Q D, a n d  
 m g Q D.  
P K w ee k : A  si n gl e oral d ose of H M P L -3 0 6 will be a d mi nistere d o n Da y 1  of t he P K wee k ( 7  d a ys 
pri or t o C 1 D 1)  f or eac h d ose le vel i n d ose escalati o n . 
7. 1. 2  D ose E x p a nsi o n   
I n d os e e x pa nsi o n, H M P L -3 0 6  will be a d mi nistere d  P O Q D  i n a 2 8-d a y c o nti n u o us d osi n g 
treat me nt c ycl e at 
 m g Q D d os e . 
7. 2  
Descri pti o n of Pr o d ucts   
H M P L -3 0 6 will be pr o vi de d as a ta blet f or m ulati o n of  2 stre n gt hs: 
 m g a n d 
 m g.  
7. 2. 1  F or m ul ati o n, St or a ge, Pre p ar ati o n, a n d H a n dli n g   
H M P L -3 0 6  is f or m ulate d as ta blets, w hi c h are p ac k a ge d i n hi g h -d e nsit y , p ol yet h yle ne b ottles , wit h 
3 0 ta blets per b ottle .  T h e c o nte nts of t he la bel will be i n acc or da n ce wit h all a p plica ble re g ulat or y 
re q uire me nts. 
H M P L -3 0 6 s h o ul d b e s eale d a n d st ore d i n a s ec ure, li mite d-access area u n der a p pr o priate 
c o n diti o ns .  S t ora ge te m p erat ur e s h o ul d be bet wee n 
℃ a n d  
℃ wit h 
 
.  H M P L -3 0 6 s h o ul d n ot be use d be y o n d t he e x pirati o n  date pr o vi de d b y t h e s p o ns or. 
Te m perat ur e -m o nit ori n g l o g s h o ul d be rec or de d a n d file d i n t he st u d y bi n d er. 
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7.2.2 Drug Accountability  
7.2.2.1 Assignment/Disposal (Study Site)  
All study drug required for this study will be provided by HUTCHMED Limited.  The recipient 
will acknowledge receipt of the study drug by returning the appropriate documentation form 
indicating shipment content and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to, and disposed of by the 
study site should be recorded by using study Drug Inventory Log. 
Study drug will be disposed of at the study site according to the study site’s institutional standard 
operating procedure or returned to HUTCHMED Limited or a HUTCHMED Limited-identified 
entity with appropriate documentation, as determined by the study site.  If the study site chooses 
to destroy/dispose study drug, then the method of destruction/disposal must be documented. 
7.2.2.2 Drug Return (Patient)  
On Day -2 to Day 1, drug assignment will be performed.  The first dose of study drug should be 
administered on C1D1, except for patients participating in escalation, where they will participate 
in a mandatory PK week and receive a single dose of HMPL-306 on Day 1 of PK week.  Patients 
will be provided with a pill diary and be instructed on how to account for each day’s dose 
appropriately.  Patients should return all unused study drug and containers from the previous cycle 
on Day 1 (date of scheduled visits) of each subsequent cycle, and new study drug will be dispensed 
on same day.  Site study staff should review patient’s pill diary and provide a new diary if 
necessary on Day 1 visit of each cycle. 
If a dose adjustment is required, the patient must return to study site and return all unused study 
drug.  The site must log into the CRF, adjust the dose, reassign the drug serial number, and dispense 
new study drug dose to the patient.  If dose is adjusted a second time, then the site must log into 
CRF and record the second dose adjustment.  On this occasion, it is not necessary to reassign a 
new drug serial number.  If tumor evaluation shows PrD during the previous cycle and the new 
drug has been dispensed, patient must return all unused study drug on 30-day (±7 days) safety visit 
after EOT. 
7.3 
Assessment and Verification of Compliance  
The investigator is responsible for ensuring that patients comply with the treatment schedule.  The 
sponsor will provide supervision through on-site monitoring visits made by its representatives.  
Investigators should maintain complete and accurate records of drug use.  Dosing regimen and 
patient’s actual dosing should be recorded in original treatment records as well as in the CRF.  At 
each treatment visit, the investigator or study staff should comprehensively assess the patient's 
treatment compliance according to drug dispensing and return status at each visit and actual dosing 
conditions, such as missed doses and overdosing reported by patient.  Study patients must return 
all drug bottles/containers and remaining capsules at the end of the study.  Study sites must return 
all remaining supplies and drugs to the sponsor or provide evidence of destruction at conclusion 
of study. 

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7. 4  
Pri o r a n d C o nc o mit a nt T her a pies   
7. 4. 1  Pr o hi bite d T her a pies   
A n y  t h era p y i nte n de d f or ca ncer tr eat me nt  ( wit h e x ce pti o ns i n Secti o n 7. 4. 2 ), w het h er c urre ntl y 
mar kete d or e x peri me nt al, is pr o hi bite d .  T his i ncl u des, b ut is n ot li mite d t o, t he f oll o wi n g: 
c he m ot hera p y, h or m o nal t hera p y, bi ol o gi c t hera p y, ra di ot hera p y, or her bal t he ra p y. 
C o nc o mita nt use of me dicati o ns t hat ha ve a k n o w n ris k of ca usi n g Q T pr ol o n gati o n (refer t o 
A p pe n di x  6 ), a n d/ or t orsa des de p oi ntes is pr o hi bite d. 
H M P L -3 0 6 is a s u bstrate of 
.  T he p ote ntial effects of me dicati o ns t hat 
affect P K of H M P L-3 0 6 via 
 pat h wa ys h a ve n ot bee n teste d i n h u ma n s.  
T heref ore, d uri n g treat me nt peri o d, t he use of i n d ucers or i n hi bit ors of 
 
(A p pe n di x  7 ) s h o ul d be a v oi de d, a n d s uc h dr u gs s h o ul d b e disc o nti n u e d at least 1  wee k or 
5  h alf-li ves ( w hic he v er is l o n ger) b ef ore t he start of st u d y treat me nt.  Pr o p h ylactic us e of 
a ntie metic dr u gs, gra n ul oc yt e c ol o n y sti m ulati n g fact ors ( G -C S F), platelet -acti vati n g fact or s, or 
er yt hr o p oieti n is n ot all o we d d uri n g t h e D L T ass ess me nt wi n d o w .  O utsi de t he D L T ass ess me nt 
wi n d o w, it ma y be all o w e d if t he i n vesti gat or c o nsi ders it necessar y.  
7. 4. 2  Per mitte d T her a pie s  
C o nc o mita nt t hera p y i ncl u des a n y prescri pti o n me dicati o ns or O T C  me dicati o ns  use d b y a patie nt .  
All c o nc o mita nt me dicati o ns s h o ul d be re p orte d t o t he i n vesti gat or a n d rec or de d o n t he a p pr o priate 
C R F . 
Patie nt s w h o use oral c o ntrace pti ves, h or m o ne-re pl ace me nt t hera p y, or ot her all o we d mai nte na nce  
t hera p y ma y c o nti n ue t h eir use if i n dicate d. 
P atie nts wi t h i ncreas e d peri p heral W B C  c o u nt ( W B C > 2 5 × 1 0 9/ L) a n d/ or w h o de vel o p 
differe ntiati o n s y n dr o me  ( D S) d uri n g t he st u d y treat me nt peri o d ma y  recei v e h y dr o x y urea 
treat me nt t o re d uce peri p heral W B Cs .  I n a d diti o n, gl uc oc ortic oi d treat me nt f or D S  is als o all o wed  
(Secti o n  7. 6. 1 ). 
T u m or l ysis s y n dr o me  ( T L S) is a p ot e ntial seri o us c o m plicati o n of treat me nt, c haracteriz e d b y 
lar ge a m o u nt of a p o pt osis or necr osis of t u m or cells wit hi n a s h ort ti me b y treat me nt, ca usi n g 
c yt ol o gic al c o nte nts t o be s u d de nl y release d t o bl o o d a n d ca use meta b olic a b n or malities .  
Pre ve nti ve me dicati o ns f or t his s y n dr o me s h o ul d als o be rec or de d i n c o nc o mita nt me dicati o n f or m . 
Pr o p h yla ctic use of a ntie metic dr u gs, G -C S F, plat elet -acti vati n g fact o rs, or er yt hr o p oieti n is n ot 
all o we d d uri n g t he D L T assess me nt wi n d o w .  O utsi de t he D L T assess me nt wi n d o w, it ma y be 
all o we d if t he i n vesti gat or c o nsi ders it necessar y . 
All s u p p orti ve meas ures c o nsiste nt wit h o pti mal patie nt  care will be gi ve n t hr o u g h o ut t he st u d y . 
7. 4. 3  Dr u g -Dr u g I nter a cti o ns   
T here are c urre ntl y n o d ata o n a dr u g d e m o nstrati n g clear i nteracti o ns wit h H M P L -3 0 6 i n  t he 
h u ma n b o d y .  I n vitr o data i n dicate t hat H M P L-3 0 6 e x h i bits 
 
 
 
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. 
D uri n g st u d y treat me nt, t he use of me dicati o ns t hat are s u bstrates of 
 
 (
) s h o ul d be a v oi de d.  If t he i n vesti gat or belie v es it is 
necessar y t o use t hese me dicati o ns, c o nse nt of t he s p o ns or s h o ul d be o btai ne d bef ore use, a n d cl ose 
o bser vati o n s h o ul d b e p erf or me d d uri n g use f or pr o ba ble re d ucti o n i n effi cac y or p ossi ble i ncrease 
i n li keli h o o d of t o xicit y d ue t o dr u g i nteracti o ns. 
I n vitr o d ata s h o w t h at H M P L-3 0 6 h as t he p ote ntial 
.  Cl ose a n d fre q ue nt 
m o nit ori n g of a d verse reacti o ns is rec o m me n de d wit h c o nc o mita n t use of a n y me di cati o n t hat is a 
 a n d has a narr o w t hera pe uti c i n de x. 
7. 4. 4  Resc ue T her a pies   
N ot a p plica ble.  
7. 5  
D ose  A dj ust me nts   
7. 5. 1  A dj ust me nt of D ose W it hi n t he D L T Assess me nt Wi n d o w  
I n t he D L T assess me nt wi n d o w, patie nt s wit h o ut D L T m ust n ot u n d er g o d ose re d ucti o n  of 
H M P L -3 0 6.  
•  If a D L T o cc urs, H M P L-3 0 6 a d mi nistrati o n will be s us pe n de d a n d a p pr o pri ate 
s u p p orti ve treat me nt will be gi v e n. 
•  If a D L T ret ur ns t o G ra d e 1 (i ncl usi ve) or l o w er wit hi n 1 4  da ys, H M P L -3 0 6 ma y b e 
res u me d at t he pre vi o us l o wer d os e if t he i n vesti gat or assesses t h at t he p atie nt  ma y still 
be nefit.  
•  If a D L T has n ot ret ur n e d t o G ra de 1 (i n cl usi ve) or l o w er wit hi n 1 4  da ys, or D L T 
re occ urs at t he l o were d d ose, H M P L-3 0 6 treat me nt will be ter mi nate d.  
•  If a p atie nt  e x perie nces a Gra de 4 n o n he mat ol o gic t o xicit y, H M P L -3 0 6 tr eat me nt will 
be ter mi nate d.  
7. 5. 2  D ose A dj ust me nt O utsi de t he D L T Assess me nt Wi n d o w (I ncl u di n g D ose 
E x p a nsi o n  P art )  
D ose a dj ust me nts are t o be ma de f or a n y A E  d ee me d at least p ossi bl y relate d t o H M P L-3 0 6 .  
D ose a dj ust me nts are t o be ma de as o utli ne d i n T a ble 8  a n d Ta bl e 9 . 
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Table 8 
Dose Adjustment for Hematologic Toxicity  
CTCAE v5.0 Grade 
Action 
Grade 1 or 2 
None  
Grade 3 or 4 
(believed to be related to 
HMPL-306 and NOT 
underlying disease) 
• Hold drug. 
• If the toxicity improves to Grade ≤2 within 7 days, then resume at original dose. 
• If the toxicity recurs at original dose, then resume 1 dose level lower provided 
the toxicity improves to Grade ≤2 within 7 days. 
• If the toxicity recurs in setting of prior dose level reduction, then resume 
1 additional dose level lower provided the toxicity improves to Grade ≤2 within 
7 days. 
• In the event the toxicity does not improve to Grade ≤2 within 7 days or toxicity 
recurs despite 2 dose reductions, HMPL-306 treatment is to be permanently 
discontinued. 
CTCAE=Common Terminology Criteria for Adverse Events. 
Table 9 
Dose Adjustment for Nonhematologic Toxicity  
CTCAE v5.0 Grade 
Action 
Grade 1 or 2 
None 
Grade 3 
• Hold drug. 
• If the toxicity improves to Grade ≤2 within 7 days, then resume at original dose. 
• If the toxicity recurs at original dose, then resume 1 dose level lower provided 
the toxicity improves to Grade ≤2 within 7 days. 
• If the toxicity recurs in setting of prior dose level reduction, then resume 
1 additional dose level lower provided the toxicity improves to Grade ≤2 within 
7 days. 
• In the event the toxicity does not improve to Grade ≤2 within 7 days or toxicity 
recurs despite 2 dose reductions, HMPL-306 treatment is to be permanently 
discontinued. 
Grade 4 
Permanently discontinue treatment with HMPL-306. 
CTCAE=Common Terminology Criteria for Adverse Events. 

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7.5.3 Dose Adjustment for QT Interval Prolongation  
Table 10 
Dose Adjustment for QT Interval Prolongation  
Degree of QTcF 
Prolongation 
Action 
QTcF greater than 480 ms 
to 500 ms 
• 
Hold drug. 
• 
Monitor and supplement electrolyte levels as clinically indicated. 
• 
Review and adjust concomitant medications with known QTcF interval-
prolonging effects. 
• 
Restart HMPL-306 at original dose if QTcF interval returns to less than or 
equal to 480 ms. 
• 
Monitor ECGs at least weekly for 2 weeks following resolution of QTcF 
prolongation. 
QTcF greater than 500 ms 
and/or QTcF interval 
prolongation with 
signs/symptoms of life-
threatening arrhythmia 
• 
Discontinue HMPL-306 permanently. 
• 
Initiate continuous ECG monitoring and immediate clinical evaluation. 
ECG=electrocardiogram; QT=interval from the start of the Q wave to the end of the T wave; QTcF=QT interval 
corrected for heart rate using Fridericia's formula. 
7.5.4 General Dose Adjustment Note  
The severity of DLTs/AEs will be graded according to the NCI CTCAE v5.0.  Reasons for dose 
modifications or delays, the supportive measures taken, and outcome should be documented in 
patient’s chart and recorded in the CRF. 
• For any concomitant conditions already apparent at baseline, dose modifications will 
apply according to corresponding shift in toxicity grade, if investigator feels it is 
appropriate.  For example, if a patient has Grade 1 asthenia at baseline that increases to 
Grade 2 during treatment, this will be considered a shift of 1 grade and treated as 
Grade 1 toxicity for dose-modification purposes. 
• For toxicities that are considered by investigators to be unlikely to develop into serious 
or life-threatening events, treatment can be continued at the same dose. 
• To recover from acute toxicity, unless otherwise indicated, treatment can be delayed 
for up to 14 days.  If a treatment delay is required for 14 days or longer, treatment 
should be discontinued.  Continuation/resumption of treatment after an interruption of 
14 days or more must be discussed with the sponsor. 
• Where several toxicities with different grades or severity occur at the same time, dose 
modifications should be according to highest grade observed. 
7.6 
Special Adverse Events Handling Principles  
7.6.1 Differentiation Syndrome Handling Principles  
Patients receiving HMPL-306 treatment are at risk of developing DS.  According to relevant 
literature (Montesinos 2009), it is recommended that for patients with ≥2 items of the following 

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8 clinical symptoms, when related symptoms cannot be explained by other reasonable reasons, 
they should be diagnosed with DS and furthermore, in addition to grading as based on the NCI 
CTCAE v5.0, DS Montesinos grading also needs to be performed as per Table 11.  The 8 clinical 
symptoms include unexplained fever, dyspnea, weight gain (>5 kg), unexplained hypotension, 
acute renal failure, interstitial lung infiltration, pleural effusion, or pericardial effusion.  
Symptoms, laboratory tests, or abnormal vital signs for each AE by name may be referred to in 
Table 11.  Patients who do not meet aforementioned criteria but are assessed by the investigator to 
have suspected DS should also be reported as having DS (Section 8.1.4).  For patients who have 
or are suspected of having developed DS, the investigator must report AEs as per the requirements 
in Section 8.2, for which patients should be closely monitored, and treated using following 
measures in a timely manner: 
• Dexamethasone 10 mg and hemodynamic monitoring every 12 hours are immediately 
administered for at least 3 days or until symptoms disappear. 
• Interrupt HMPL-306 if severe pulmonary symptoms requiring intubation or ventilator 
support and/or renal dysfunction persist for more than 48 hours after initiation of 
dexamethasone. 
• Based on peripheral WBC count, hydroxyurea up to 2000 to 3000 mg twice daily (BID) is 
given orally for treatment. 
• If clinically necessary, patient is given furosemide for treatment. 
• Leukapheresis is performed if clinically necessary. 
When the above treatment measures are unable to effectively control clinical features of DS, 
HMPL-306 treatment should be suspended.  HMPL-306 administration can resume when signs 
and symptoms improve to Grade 2 or lower at a dose that should be decided after discussion with 
the sponsor. 
Table 11 
Differentiation Syndrome Diagnosis and Montesinos Grading Criteria  
Diagnosis 
Montesinos Grading 
Moderate 
Severe 
Differentiation syndrome 
(≥2 symptoms) 
2-3 symptoms 
≥4 symptoms 
Symptoms: Unexplained fever, dyspnea, weight gain (>5 kg), unexplained hypotension, acute renal failure, 
interstitial lung infiltration, pleural effusion, or pericardial effusion 

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7.6.2 Handling Principles for Noninfectious Leukocytosis  
Noninfectious leukocytosis is defined as WBC >25 × 109/L or an absolute increase in total WBC 
of >15 × 109/L from baseline.  Patients should be treated using following measures in a timely 
manner: 
• Hydroxyurea oral therapy per institutional standards 
• Leukapheresis is performed if clinically necessary 
When above treatment measures are unable to effectively control the clinical symptoms, 
HMPL-306 treatment should be suspended.  Prior to resuming study drug WBC should be 
<30 × 109/L in addition to resolution of clinical features of DS.  After clinical features have been 
fully relieved, HMPL-306 administration can resume at a dose that should be decided after 
discussion with the sponsor.   

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8 
SAFETY MONITORING  
8.1 
Definitions  
8.1.1 Adverse Event  
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product or other protocol-imposed intervention, whether or 
not considered related to study drug.   
8.1.2 Serious Adverse Event  
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in any 
of the following outcomes:  
• Death. 
• A life-threatening AE.  An event is considered “life-threatening” if, in the view of the 
investigator, its occurrence places the patient at immediate risk of death.  It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• An abnormal pregnancy outcome (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, or ectopic pregnancy) in a child born to a female patient 
or female partner of a male patient exposed to study drug. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
8.1.3 Dose-Limiting Toxicity  
DLT is defined as occurrence of any of the following TEAEs during the DLT assessment window, 
unless clearly unrelated to the study drug as per investigator’s discretion: 
• Nonhematologic toxicity:  
− TEAEs of Grade ≥4 
− Grade ≥3 with the exception of those that resolve within 72 hours of onset 
• Hematologic toxicity, with the exception of neutropenia or thrombocytopenia that occurs 
with active leukemic disease: 

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− Grade 3 or 4 neutropenia lasting more than 7 days 
− Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or any 
requirement for platelets transfusion 
− Grade 3 or greater febrile neutropenia defined as absolute neutrophil count 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 
• Any TEAE requiring a dose delay of ≥14 days 
• Cases of confirmed Hy’s law  
8.1.4 Adverse Events of Special Interest  
All adverse events of special interest (AESIs) must be collected in the eCRF using the AESI option 
on the AE page of the eCRF.  If they meet the seriousness criteria, they should also be reported as 
SAEs via the eCRF and SAE Report Form (see Section 8.1.2).  Adverse events of special interest  
in this study include the following: 
Differentiation syndrome 
For patients who experience or have suspected DS, various symptoms and their NCI CTCAE v5.0 
criteria grades should be recorded as an AE in the applicable eCRF (Appendix 11).  Further, DS 
diagnosis time and gradation judged based on the NCI CTCAE v5.0 criteria in Table 11 should be 
recorded in the eCRF as Differentiation Syndrome. 
Noninfectious leukocytosis 
Noninfectious leukocytosis is defined as WBC >25 × 109/L or an absolute increase in total WBC 
of >15 × 109/L from baseline. 
Potential drug-induced liver injury 
According to Hy’s law, ALT or AST elevations <3 × ULN accompanied by elevated total bilirubin 
(>2 × ULN) is considered as a sign of severe liver damage provided that cholestasis or other 
clinical jaundice causing hyperbilirubinemia are excluded.  Therefore, the investigator must report 
AEs when elevation in ALT or AST levels during treatment are <3 × ULN and are accompanied 
by total bilirubin elevation to above 2 × ULN.  The most appropriate diagnosis (when diagnosis 
cannot be confirmed) or laboratory abnormal values shall be recorded on the AE form of the eCRF 
and reported to the sponsor within 24 hours of learning of this event, regardless of whether it is an 
SAE or not. 

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8.2 
Adverse Event Reporting  
8.2.1 Adverse Event Reporting Period  
After informed consent, but prior to initiation of study drug, all AEs and SAEs regardless of 
attribution will be collected.  After initiation of study drug, all SAEs and AEs regardless of 
attribution will be collected until 30 days after the end of treatment or start of a new antitumor 
therapy, whichever is earlier.  After this 30-day period, and if the patient has not started any other 
antitumor treatment, then investigators should report only SAEs that are considered to be related 
to the study drug until study discontinuation. 
8.2.2 Expedited Reporting  
Certain events require immediate reporting to allow the sponsor to take appropriate measures to 
address potential new risks in a clinical study.  The investigator must report such events (both 
initial and follow-up) to the sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list of events 
that the investigator must report to the sponsor within 24 hours after first learning of the event, 
regardless of relationship to study drug: 
• SAEs 
• Pregnancy 
• Hy’s Law 
8.2.3 Dose-Limiting Toxicity Reporting  
For each DLT event that occurs in dose escalation part, investigator must confirm this event, and 
inform sponsor within 2 business days after becoming aware of it and should conduct phone or 
online meetings with the medical monitor and report any DLT events observed in DLT evaluation 
window. 
8.3 
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 have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
8.4 
Assessment of Severity  
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs and SAEs, 
whether reported by 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 severity through clinical description by referring to the 5-grade determination standard in NCI 
CTCAE v5.0.  Use the guidelines below for assessment of severity when observed or reported AE 
is not listed in the NCI CTCAE v5.0: 

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• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).  Note: Instrumental ADL 
refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.  Note: Self-care ADL refers to bathing, dressing, and undressing, feeding 
self, using the toilet, taking medications, and not bedridden. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
8.5 
Causality Assessment  
Investigators should use their knowledge of the patient, circumstances surrounding AE, and an 
evaluation of any potential alternative causes to determine whether or not an AE is considered to 
be related to study drug.  To ensure consistency of causality assessments, investigators should 
apply general guidelines provided as below: 
• Related: An AE is considered related if there is a reasonable possibility that the drug 
caused the AE.  A ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the AE.  Factors used in this assessment include but 
are not limited to: There is a reasonable temporal relationship between AE and study 
drug; the AE resolves after de-challenge and/or AE recurs after re-challenge; the impact 
or presence of other contributing factors (eg, underlying study disease, medical 
conditions, concomitant medications) are either not present or ruled out; biological 
plausibility/mechanism of action of the study drug can explain the AE.   
• Unrelated: If there is no reasonable possibility of correlation between an event and 
study drug, the AE will be deemed “unrelated” to study drug.  Factors used in this 
assessment factor include but are not limited to: The AE(s) can be reasonably explained 
by the influence of underlying disease, or concurrent medical conditions, or other 
drugs; there is no temporal relationship between AEs and study drug; the AE worsens 
or does not improve after de-challenge; and/or the AE improves or does not recur after 
re-challenge.   
8.6 
Documenting Adverse Events  
When an AE or SAE is recorded, preferred medical terminology or concept should be used.  
Abbreviations and colloquialisms (eg, jargon or slang) should be avoided. 
All AEs (including SAEs) should be recorded on the applicable CRF, and check box for “serious” 
should be ticked for entries that fit criteria for SAEs.  Investigators must also complete an SAE 
report and submit this to the sponsor within 24 hours of knowledge of that event.   
Only 1 medical concept should be recorded in event field on the CRF. 

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8.6.1 Diagnosis Versus Symptoms and Signs  
If known, a diagnosis should be recorded in the CRF rather than individual signs and symptoms 
(eg, hepatic failure should be recorded instead of jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at time of reporting, each individual event should be recorded as an AE or 
SAE in the CRF.  If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
8.6.2 Adverse Event Occurring Secondary to Other Events  
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause with exception of severe or serious secondary events.  
For example, if severe diarrhea is known to have resulted in dehydration, it is sufficient to record 
only diarrhea as an AE or SAE in the CRF if dehydration is mild. 
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events in the CRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF. 
8.6.3 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 unless severity changes.  If a 
persistent AE becomes more or less severe, it should be recorded again as a new CRF entry.   
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded in the CRF as separate events, 
respectively. 
8.6.4 Abnormal Laboratory Values or Abnormal Vital Signs  
Not every laboratory abnormality/abnormal vital sign qualifies as an AE.  An abnormal laboratory 
test result/abnormal vital sign must be reported as an AE if it is a change from baseline and meets 
any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (eg, dosage modification, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or 
a change in concomitant therapy 
• Is clinically significant by in the opinion of investigator 
Investigators are responsible for reviewing all laboratory findings and abnormal vital signs and 
determining whether or not each abnormality should be reported as an AE. 
If clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, ALP and 
bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (eg, cholecystitis) needs to be 
recorded in the CRF. 

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If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, that 
abnormality itself should be recorded as an AE or SAE in the CRF.  If the laboratory abnormality 
can be characterized by a precise clinical term, that clinical term should be recorded as 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 in the CRF, unless their severity, seriousness, or 
etiology changes. 
8.6.5 Pre-existing Medical Condition  
A pre-existing medical condition is one that is present at screening.  Such conditions (not tumor 
type under study) should be recorded in the applicable CRF as medical history.  A pre-existing 
medical condition should be recorded as an AE or SAE only if frequency, severity, or character of 
such condition worsens during study (excluding deterioration of study disease conditions).  When 
such events are recorded in the CRF, it is important to convey the concept that such pre-existing 
condition has changed by including applicable descriptors (eg, “more frequent headaches”). 
8.6.6 Pregnancy  
A female patient must be instructed to stop taking study drug and immediately inform the 
investigator if she becomes pregnant during her participation in this study.  The investigator should 
report all pregnancies within 24 hours of awareness to sponsor (reporting period for pregnancy 
continues up to 30 days after the end of treatment).  The investigator should counsel the patient 
and discuss risks of continuing with pregnancy and possible effects on the fetus.  Monitoring of 
the patient should continue to determine the outcome of that pregnancy.  Pregnancies occurring up 
to 30 days after the end of treatment must also be reported to the investigator. 
Male patients must also be instructed to inform the investigator immediately if their partner 
becomes pregnant during his participation in this study or within 30 days after the end of treatment.  
If such an event occurs, it should be reported as described above. 
Pregnancy loss of any kind should always be classified as serious AE (as the sponsor considers 
these medically significant), recorded in the CRF, and expeditiously reported to sponsor. 
Any abnormal pregnancy outcome (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomaly, birth defect, or ectopic pregnancy) in a child born to a female patient or female partner 
of a male patient exposed to study drug should be recorded and reported as an SAE. 
8.6.7 Progression of Hematological Malignancy Under Study  
Events that clearly conform to expected progression of underlying disease should not be recorded 
as AEs.  These data are only used for efficacy evaluation.  Determination of clinical progression 
is at the discretion of the investigator and may include both objective and subjective data.  The 
continuation decision should be made by the investigator in consultation with the sponsor.  In most 
cases, expected mode of progression will be evaluated based on efficacy evaluation criteria 
suitable for studied tumor type.  In a small number of cases, clinical progression is determined 
based on aggregation of clinical features.  However, progression should be demonstrated using 
objective criteria.  If it is uncertain whether a certain event is caused by progression of disease, it 

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should be reported as an AE.  If such event leads to death, then it should be reported with reference 
to description of “Death” (see Section 8.6.8). 
8.6.8 Death  
All deaths that occur during protocol-specified AE reporting period must have their primary 
underlying cause reported to sponsor as an SAE with death listed as outcome.  Deaths due to 
progression of disease must also be reported to the sponsor as an SAE.  If primary cause of death 
is unknown at the time of reporting and/or if the death was unwitnessed, please record “death of 
unknown cause,” or “unwitnessed death” in the eCRF and on the SAE report form.  The eCRF and 
SAE report form should be updated when the cause of death has been determined.  Death events 
that occur after 30 days following the end of treatment must be reported to the sponsor as an SAE 
only if it is confirmed as related to study drug.   
8.6.9 Overdose  
For this study, any dose of HMPL-306 greater than the intended dose will be considered an 
overdose.  No specific information is available on treatment of overdose of HMPL-306.  In the 
event of overdose, further HMPL-306 administration should be held, and patients should be 
observed closely for signs of toxicities.  Appropriate supportive treatment should also be provided 
if clinically indicated.  In the event of accidental or intentional overdose, the investigator or other 
site personnel should inform sponsor immediately, or no later than 24 hours.   
• An overdose with associated AEs/SAEs should be recorded as the AE 
diagnosis/symptoms in the relevant AE/SAE CRF and in the study drug CRF. 
• An overdose with no associated signs or symptoms should only be reported in the 
study drug CRF. 
• Overdose with no associated signs or symptoms will not be reported as an AE/SAE 
unless it is an intentional overdose taken with possible suicidal/self-harming intent.  
Such overdoses should be reported regardless of sequelae. 
8.7 
Duration of Follow-up for Adverse Events  
The investigator will follow all unresolved AEs and SAEs until events are resolved or stabilized, 
patient is lost to follow-up, patient death, start of new oncology treatment, or end of study.  
Resolution of AEs and SAEs (with dates) should be documented in the appropriate CRF and in the 
patient’s medical record to facilitate source data verification.  For SAEs, if, after follow-up, return 
to baseline status or stabilization cannot be established, an explanation should be recorded in 
additional case details section of the CRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate SAE report 
(eg, hospital discharge summary, consultant report, or autopsy report) may be followed-up by 
telephone, fax, email, and/or a monitoring visit. 
All pregnancies that occur during participation in the study should be followed to determine their 
outcome.   

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9 
ANALYSIS  
9.1 
Statistics and Analysis Method  
All statistical analysis will be performed under the direction of sponsor’s personnel.  Details of 
statistical analysis and data reporting will be provided in Statistical Analysis Plan, which will be 
finalized prior to database lock.   
The timing of analysis for each cohort may be different depending on completion of each cohort, 
and final analysis of study will be conducted at the time of analysis of last cohort.  No formal 
interim analysis is planned.  However, accrued data from any cohort may be analyzed for internal 
decision-making purposes; for example, to provide information for a potential phase 2 study 
design. 
9.1.1 Statistical Hypothesis  
No formal hypothesis testing is planned for this study.  For efficacy endpoints, the study will 
provide estimates and associated 95% confidence interval (CI) for precision. 
9.1.2 Sample Size Rationale  
Approximately 40 to 50 patients are to be enrolled in this study (approximately 24 to 30 evaluable 
patients are expected in the dose escalation part and approximately 10 patients are estimated for 
the dose expansion part). 
9.1.2.1 Dose Escalation Part  
The maximum sample size in this part will be determined jointly by the sponsor and investigator.  
The exact sample size of mTPI-2 design in dose escalation part cannot be prespecified due to 
dynamic nature of Bayesian allocation procedure.  Patients not evaluable for DLT may be replaced, 
and this may result in the number of patients enrolled being more than expected.  An estimated 24 
to 30 evaluable patients may be enrolled in this part. 
9.1.2.2 Dose Expansion Part  
In order to better describe the safety of the recommended single-dose of HMPL-306 for future 
studies, approximately10 AML patients are expected to be treated with HMPL-306 in this part.  
For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least 1 AE in 
10 patients is 65%, 40%, and 9.6%, respectively. 
Assuming that the true CR rate is 20%, then probability that at least 1 case of CR is observed in a 
cohort of 10 patients is 89%, the probability that at least 2 cases of CR are observed is 62.4%, and 
the probability that no CR is observed is 11%.  If further evaluation of safety and efficacy signals 
is warranted, then more patients may be enrolled in the dose expansion cohort.   
9.1.3 Analysis Sets  
The following analysis sets are defined for this study: 
• Safety analysis set: All enrolled patients who received at least 1 dose of study treatment 
will be included in safety analysis population.  Safety evaluation will be performed based 

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on first dose of study treatment received by a patient.  This is the primary population for 
safety and efficacy analyses. 
• DLT-evaluable analysis set: All patients enrolled in dose escalation part who are evaluable 
for DLT assessment.  A patient is DLT-evaluable if such a patient meets the following 
criteria:  
− Has received at least 75% of the assigned dose of study drug during DLT 
assessment window 
− OR  
− Has not completed the DLT assessment period due to a DLT 
• Response (efficacy) evaluable analysis set: All patients who receive study treatment and 
have a baseline tumor assessment, followed by at least 1 post-baseline assessment (usually 
after C3D1) will be considered evaluable for antitumor clinical response or efficacy 
endpoints. 
• PK analysis set: All patients with at least 1 quantifiable plasma concentrations of 
HMPL‑306 will be included in PK population analysis. 
• PD analysis set: All patients with at least 1 quantifiable level of 2-HG in plasma will be 
included in PD population analysis. 
9.2 
Statistical Analysis  
Data will be summarized by dose/disease cohorts.  Continuous variables will be described using 
observed number, mean, median, standard deviation, minimum, and maximum; categorical 
variables will be described using frequency.  Kaplan-Meier method will be used to summarize 
time-to-event data. 
9.2.1 Patient Disposition  
The number and percentage of patients that were enrolled in the study, treated, and discontinued 
from study treatment will be presented for the Safety Analysis Set.  The primary reason for 
treatment discontinuation will be summarized according to the categories in the CRF.  Patient 
disposition will be summarized overall and by cohorts. 
Important protocol deviations will be summarized and listed by category. 
9.2.2 Demographic and Other Baseline Characteristics   
Demographic and other baseline characteristics will be summarized for the Safety Analysis Set 
using descriptive statistics. 
A summary of baseline patient and disease characteristics, diagnosis, medical history, prior 
therapies will be reported using descriptive statistics. 
Other patient characteristics will be summarized as deemed appropriate. 

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9.2.3 Prior and Concomitant Medications   
Prior medications will be defined as medications that stopped before the day of first dose of study 
treatment.  Concomitant medications will be defined as medications that 1) started before the first 
dose of study treatment and were continuing at the time of the first dose of study treatment, or 
2) started on or after the date of the first dose of study treatment up to 30 days after the end of 
treatment.  Concomitant medications will be coded using the World Health Organization Drug 
Dictionary drug codes and will be further coded to the appropriate Anatomical Therapeutic 
Chemical code indicating therapeutic classification.  Prior and concomitant medications will be 
summarized and listed by drug and drug class.  Prior and concomitant medication will be 
summarized overall and by cohorts.  A listing of prior and concomitant medications will be 
provided. 
9.2.4 Safety Analysis  
The summary of the exposure to study treatment, AEs, AESIs, AEs leading to drug modification 
or discontinuation including DLTs, changes in laboratory results, and changes in vital signs, etc, 
will be presented.  The severity of all AEs will be graded according to NCI CTCAE v5.0, and the 
AE verbatim term will be coded by the Medical Dictionary for Regulatory Activities (MedDRA).   
TEAEs are defined as AEs that started or worsened in severity on or after the first dose of study 
treatment and no later than 30 days after the end of treatment.   
Only those AEs that were treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in patient data listings.  The number and 
frequency of patients experiencing adverse events will be summarized according to system organ 
class (SOC) and preferred terms.  If a patient reports a TEAE more than once within that 
SOC/preferred term, the AE with the highest severity will be used in the corresponding severity 
summaries. 
The following safety summaries will be produced: 
• Overview of AEs 
• Summary of DLTs (dose escalation part)  
• Summary of TEAEs  
• Summary of serious TEAEs 
• Summary of AESIs  
• Summary of TEAEs leading to dose interruption, dose reduction, or termination of 
treatment 
The above summaries will be repeated for TEAEs related to study treatment. 
Drug exposure including number of cycles received, total duration of exposure, cumulative dose 
received (mg), dose intensity, and relative dose intensity will be summarized.  The number and 
percentage of patients requiring dose interruption, dose delay, dose reduction, and treatment 
discontinuation because of AEs will be summarized.  Reasons for dose modifications will also be 
summarized. 

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For laboratory tests that are graded by NCI CTCAE v5.0 or higher, results will be summarized by 
grade.  Treatment-emergent changes will be summarized by maximum post-baseline grade.  A 
shift table summarizing the shift from baseline to maximum post-baseline grade will be presented. 
The changes in vital signs and ECOG PS scores from baseline will be summarized.  Changes in 
12-lead ECG (for example, changes in QTcF) will be summarized. 
9.2.5 Pharmacokinetics Analysis  
Evaluation on PK will be performed on PK analysis set.  Plasma concentrations of HMPL-306 will 
be tabulated and summarized using descriptive statistics (number of patients [n], arithmetic mean 
with standard deviation, coefficient of variation [CV%], and geometric mean, median, minimum, 
and maximum) as appropriate.  PK parameters will be tabulated and summarized by treatment 
using descriptive statistics (number of patients, arithmetic mean with standard deviation, CV%, 
geometric mean, median, minimum, and maximum), as appropriate. 
The following plasma PK parameters of HMPL-306 will be determined: 
AUC0-t 
area under the plasma concentration-time curve from time 0 to time of the 
last measurable concentration 
AUC0-inf 
area under the plasma concentration-time curve from time 0 to infinity 
AUC0-τ 
area under the plasma concentration-time curve within the dosing interval 
Cmax 
maximum observed plasma concentration 
Cmax,ss 
maximum observed plasma concentration (at steady state) 
Cmin,ss 
minimum observed plasma concentration (at steady state) 
Ctrough 
observed plasma concentration at the end of a dosing interval (taken 
directly before the next dose administration) 
Tmax 
time to reach the maximum plasma concentration 
Cmin 
minimum plasma concentration 
%AUCext 
percentage of AUC0-inf obtained by extrapolation 
λZ 
apparent first-order rate constant associated with the terminal portion of 
the curve, determined as the negative slope of the terminal log-linear 
phase of the plasma concentration-time curve 
t1/2 
associated with the terminal slope (λZ) of the semi-logarithmic drug 
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CL/F 
total plasma clearance of drug after extravascular administration, 
uncorrected for absolute bioavailability, calculated as dose/AUC0-inf after 
single dose or dose/AUC0-τ after multiple doses 
Vz/F 
apparent volume of distribution 
AR 
accumulation ratio 
Pharmacokinetic analysis will be performed using actual blood collection times relative to dosing 
times recorded in the raw data.  If an actual blood collection time or a dosing time is missing, the 
nominal time may be used. 
Additional PK parameters may be included if deemed appropriate.  Details of PK analysis, 
including data handling rules and software used to perform PK analysis will be provided in the 
Statistical Analysis Plan. 
9.2.6 Pharmacodynamic Analysis  
Levels of 2-HG in plasma will be tabulated and summarized using descriptive statistics (n, 
arithmetic mean with standard deviation, CV%, geometric mean, median, minimum, and 
maximum) as appropriate.  Correlation between drug exposure level of HMPL-306 in plasma and 
2-HG level and % inhibition in plasma will be analyzed using descriptive and graphical means. 
9.2.7 Efficacy Analysis  
Tumor assessment for patients with AML, HR-MDS, or AITL will be evaluated by the investigator 
according to the specific guidelines outlined in Section 9.2.7.1. However, the efficacy analysis will 
only be conducted for AML patients; for patients with HR-MDS or AITL, if enrolled, the tumor 
assessment data will be listed.  
The following efficacy endpoints will be derived and analyzed using the safety analysis set for 
patients with AML: 
• OS: defined as the time from the start of the study drug until death from any cause. 
• Progression-free survival (PFS): defined as the time from the start of study treatment 
to disease progression, or death due to any cause, whichever occurs first. 
• Baseline transfusion dependence: transfusions of red blood cells (RBCs) or platelets 
within 28 days prior to the first dose of treatment. 
• Post-baseline transfusion independence (summarized through the following 2 ways): 
− No RBC or platelet transfusion for at least ≥4 weeks during treatment period; 
or 
− No RBC or platelet transfusion for at least ≥8 weeks during treatment period.   
Patients with AML treated at the RP2D from Part 1 will be included in the data summary of the 
cohort in Part 2, unless otherwise specified. A patient data listing will be prepared for all patients. 

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Tumor response endpoints as defined in Section 9.2.7.1 (eg, best overall response, objective 
response rate [ORR], clinical benefit rate [CBR], and duration of response [DoR]) will be analyzed 
using the safety analysis set.  For binary response endpoints such as ORR and CBR, the estimate 
and its 95% CI will be calculated using the Clopper-Pearson method for each cohort.  The response 
(efficacy) evaluable analysis set will be used to conduct sensitivity analysis for tumor response.   
For the time-to-event endpoints, such as PFS, OS, and DoR, the median, 25%, and 75% percentile 
of time-to-event will be estimated using Kaplan-Meier method with their corresponding 95% CI.  
Additionally, for PFS and OS, estimates will be provided for the survival probability along with 
their 95% CIs, which are calculated using linear transformation (Brookmeyer 1982) at selected 
landmarks, for example, at 3, 6, 9, 12, and 18 months.  The Kaplan-Meier plots will be produced 
for PFS and OS.  The duration of follow-up will be calculated descriptively using the Kaplan-
Meier method.  In order to assess duration of follow-up for PFS and OS, Kaplan-Meier estimates 
will be calculated in the same way as in their analysis, while using a different censoring rule which 
reverses censoring indicator instead (ie, patients who have an event will be censored at the date of 
event).  Patients who are censored will be assigned as an “event.” 
9.2.7.1 Tumor Response Endpoints for Patients with AML  
Patients with AML will be evaluated according to the 2017 ELN criteria (Appendix 8).  The 
antitumor efficacy endpoints will include the following: 
• Best overall response (CR, complete response with negative minimal residual disease 
[CRMRD-], CRi, CR with partial hematological recovery [CRh], morphologic 
leukemia-free state [MLFS], PR, SD, and PrD) 
• ORR (including CR, CRMRD-, CRi, CRh, MLFS, and PR)  
• CBR: including ORR and SD 
• Rate of CR + CRh (where CR was based on investigator assessment of response and 
CRh can be derived from relevant data including investigator-collected bone marrow 
and hematology data among responders) 
• Duration of CR + CRh 
• Time to CR + CRh 
• Duration of CR  
• Time to CR 
• DoR 
• Time to response (TTR) 
• Disease-free survival (DFS): (Only for patients achieving CR or CRMRD-, or CRi, or 
CRh) defined as the time from achieving response (CR or CRMRD-, or CRi, or CRh) to 
disease relapse or death due to any cause  
• Time to hematologic recurrence: (Only for patients achieving CR or CR MRD-, or CRi, 
or CRh) defined as the time from when the patient achieves response for the first time 
(CR, CRMRD-, CRi, or CRh) to disease recurrence 
9.2.8 Exploratory/Biomarker Analysis  
This study will conduct detection and analysis on related biomarkers and explore biomarkers 
predicting PK-PD correlation and antitumor effects.  Exploratory biomarker evaluations may not 
be included in the CSR, and a separate summary report may instead be prepared.   

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10 
ETHICAL CONSIDERATIONS  
10.1 
Good Clinical Practice  
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct, consensus and the ethical principles 
derived from international guidelines, including the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
Applicable ICH Good Clinical Practice (GCP) Guidelines that have their origin in the Declaration 
of Helsinki, and applicable regulations and guidelines governing clinical study conduct. 
10.2 
Ethics Review  
The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) must review the 
protocol and amendments, IB, ICF, study-relevant materials (such as advertisements for patient 
recruitment), and any other essential documents.  IEC/IRB approval is to be obtained prior to the 
start of the study at the investigator site. 
All amendments are to be reviewed and approved by the IEC/IRB and applicable regulatory 
authorities (as required) and documented.  All SAEs other significant safety findings should be 
reported to the sponsor, the IEC/IRB, and applicable regulatory authorities as required.  During 
the study, protocol deviations that may increase a patient’s risk should be reported to the IEC/IRB 
in a timely manner. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study patients. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations. 
10.3 
Informed Consent  
• Investigators or designees qualified by education, training, and experience to comply 
with GCP, and applicable regulatory requirements must obtain the signed ICF from 
patients prior to conducting any study-related procedures.   
• The investigator or his/her representative will explain the nature of the study to the 
patient or to their legally authorized representative and answer all questions regarding 
the study. 
• Patients must be informed that their participation is voluntary.  Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 

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

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• The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.5 
Disclosure  
Final study results will be published on a public clinical study website according to applicable 
local guidelines and regulations. 
10.6 
Data Quality Assurance  
• To ensure the safety of patients in the study, and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and 
patient medical records in the patient files as original source documents for the study. 
• All patient data relating to the study will be recorded on a CRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of non-
compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations [CRO]). 

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11 
OVERSIGHT  
11.1 
Independent Monitoring  
11.1.1 Safety Review Committee  
• Patient safety will be continuously monitored by the SRC, which includes safety signal 
detection at any time during the study. 
• In addition, an early aggregated safety data review will be performed, the goal of which is 
to allow for a cautious, stepwise approach to HMPL-306 administration.  An initial safety 
review for this study is planned for the first 3 patients who are dosed and have provided 
safety data for 28 days after administration of Dose specified in Table 4 depending on the 
assigned cohort. The SRC, on an ongoing basis, will also monitor the benefit-risk of 
HMPL-306 treatment in the expansion cohort and make recommendations on the 
continuation of enrollment in the study. 
• All safety data collected will be summarized and reviewed by the SRC for agreement of 
next steps. 
• In particular, data will be reviewed by the sponsor for identification of the following events 
that would potentially contribute to a requirement to re-evaluate the study.   
• Any deaths, regardless of causality. 
• In addition, safety data will be reviewed on an ongoing basis during study conduct.  At 
a minimum of twice a year study data will be summarized and reviewed with 
investigators to identify potential safety signals.  Additional safety review meetings 
may be scheduled based upon concerns of the sponsor or investigators. 
• Enrollment will be paused during the review.  If a stopping rule is met, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to resume.  
If the study is halted as per Study Stopping Rules in either the dose escalation part or the 
dose expansion part, the study will only be restarted after Regulatory Approval as per local 
regulations. 
11.2 
Quality Control and Assurance  
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements and applicable standard operating procedures, including quality control of 
documents.   
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site.  The sponsor and 
investigator will ensure that any individual or party who performs study-related duties or functions 
on behalf of the sponsor/investigator is qualified to perform the study-related duties or functions. 
The overall procedures for quality assurance of clinical study data are described in the sponsor or 
designee’s standard operational procedures.  The planned quality assurance and quality control 
procedures for the study are described in the following sections. 

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

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

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Sponsor’s Decision 
Sponsor will notify the investigator(s) of a decision to close out a study site in writing.  Reasons 
may include any of the following, among others: 
• The investigator has received all items and information necessary to the perform study 
but has not enrolled any patient within a reasonable period of time. 
• The investigator has violated any fundamental obligation in study agreement, 
including, but not limited to, breach of this protocol (and any applicable amendments), 
breach of applicable laws and regulations, or breach of any applicable ICH guidelines. 
• The total number of patients required for the study are enrolled earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the appropriate regulatory authorities, and any CROs involved in the 
conduct of this study of any reason(s) leading to termination or suspension, as specified by 
applicable regulatory requirements.  The investigator shall promptly inform all patients in their 
care and should ensure appropriate patient therapy and/or follow-up. 

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

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

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14 
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deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.  
Blood.  2020 Feb 13;135(7):463-471. 
Rücker 2012  
Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, et al.  TP53 alterations in acute 
myeloid leukemia with complex karyotype correlate with specific copy number alterations, 
monosomal karyotype, and dismal outcome.  Blood.  2012 Mar 1;119(9):2114-21. 
Schlenk 2014  
Schlenk RF, Kayser S, Bullinger L, et al;German-Austrian AML Study Group.  Differential impact 
of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic 
transplantation.  Blood.  2014;124(23):3441-9. 
Shipp 1993  
Shipp MA, Harrington DP, Anderson JR, et al.  A predictive model for aggressive Non-Hodgkin’s 
Lymphoma.  N Engl J Med.  1993;329:987-94. 
Stein 2017  
Stein EM, DiNardo CD, Pollyea DA, et al.  Enasidenib in mutant IDH2 relapsed or refractory 
acute myeloid leukemia.  Blood.  2017; 130(6):722-731. 
Tefferi 2010  
Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D, et al.  IDH1 and 
IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential 
thrombocythemia, polycythemia vera or myelofibrosis.  Leukemia.  2010 Jul; 24(7):1302-9.   
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Thall PF, Simon R.  A Bayesian approach to establishing sample size and monitoring criteria for 
phase II clinical trials.  Control Clin Trials.  1994 Dec; 15(6):463-81.   
Wang 2013  
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al.  Targeted 
Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation.  Science.  May 
2013; 340(6132):622-6. 
Wang 2015  
Wang C, McKeithan TW, Gong Q, Zhang W, Bouska A, Rosenwald A, et al.  IDH2R172 
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Wang 2017  
Wang N, Wang F, Shan N, Sui X, Xu H.  IDH1 Mutation is an independent inferior prognostic 
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Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al.  Oncometabolite 2-hydroxyglutarate is a 
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19(1):17-30. 
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Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al.  IDH1 and IDH2 mutations 
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Yang S, Wang SJ, Ji Y.  An integrated dose-finding tool for phase I trials in oncology.  Contemp 
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Yonal-Hindilerden I, Daglar-Aday A, Hindilerden F, Akadam-Teker B, Yilmaz C, Nalcaci M, 
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Yoshihara T, Hamamoto T, Munakata R, Tajiri R, Ohsumi M, Yokota S.  Localization of cytosolic 
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15 
APPENDICES  

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APPENDIX 1 
PK/PD/BIOMARKER/ECG 
ASSESSMENTS 
FOR 
ESCALATION 
COHORTS  
Study Day 
Time Relative to 
Dosing 
Study 
Drug 
Intake 
Blood 
Sample for 
PK 
Blood 
Sample for 
2-HG 
Bone 
Marrow 
Sample for 
2-HG 
Blood and Bone 
Marrow 
Samples for 
Gene Mutation 
Analysis 
ECG 
Screening 
 
 
 
X 
X 
X2 
X 
PK week 
Day 1 
Predose1 
 
X 
 
 
 
X3 
0 h 
X 
 
 
 
 
 
0.5 h (±2 min) 
 
X 
 
 
 
 
1 h (±5 min) 
 
X 
 
 
 
X3 
2 h (±10 min) 
 
X 
 
 
 
X3 
3 h (±10 min) 
 
X 
 
 
 
 
4 h (±15 min) 
 
X 
 
 
 
X3 
6 h (±15 min) 
 
X 
 
 
 
 
8 h (±15 min) 
 
X 
 
 
 
 
Day 2 
24 h (±60 min) 
 
X 
X 
 
 
 
Day 3 
48 h (±60 min) 
 
X 
X 
 
 
 
Day 4 
72 h (±60 min) 
 
X 
X 
 
 
 
Day 5 
96 h (±60 min) 
 
X 
X 
 
 
 
Day 6 
120 h (±60 min) 
 
X 
X 
 
 
 
Day 7 
144 h (±60 min) 
 
X 
X 
 
 
 
C1D1 
Predose1 
 
X 
X 
 
 
 
0h 
X 
 
 
 
 
 
C1D8 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
C1D15 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
C1D22 
Predose1 
 
X 
X 
 
 
 
0 h 
X 
 
 
 
 
 
C2D1 
Predose1 
 
X 
X 
 
X2 
X3 
0 h 
X 
 
 
 
 
 
0.5 h (±2 min) 
 
X 
 
 
 
 
1 h (±5 min) 
 
X 
 
 
 
X3 
2 h (±10 min) 
 
X 
 
 
 
X3 
3 h (±10 min) 
 
X 
 
 
 
 
4 h (±15 min) 
 
X 
 
 
 
X3 
6 h (±15 min) 
 
X 
 
 
 
 
8 h (±15 min) 
 
X 
 
 
 
 
C2D2 
Predose1 
 
X 
 
 
 
 
0 h 
X 
 
 
 
 
 
C2D8 
Predose1 
 
X 
X 
 
 
 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 0 4  
 
C O N FI D E N TI A L  
 
 
St u d y D a y  
Ti me Rel ati ve t o 
D osi n g  
St u d y 
Dr u g 
I nt a ke 
Bl o o d 
S a m pl e f or 
P K  
Bl o o d 
S a m pl e f or  
2 -H G  
B o ne  
M arr o w 
S a m pl e f or  
2 -H G  
Bl o o d a n d B o ne 
M arr o w 
S a m pl es f or 
Ge ne M ut ati o n 
A n al ysis  
E C G  
0 h  
X  
 
 
 
 
 
C 2 D 1 5  
Pre d ose 1 
 
X  
X  
 
 
 
0 h  
X  
 
 
 
 
 
C 3 D 1  
Pre d ose 1 
 
X  
X  
X  
X 2 
X  
0 h  
X  
 
 
 
 
 
C 5 D 1  
Pre d ose 1 
 
X  
X  
X  
X 2 
X  
0 h  
X  
 
 
 
 
 
C 7 D 1 a n d 
e ver y 3 -c ycles 
t h ereafter 
Pre d ose 1 
 
X  
X  
X  
X 2 
X  
0 h  
X  
 
 
 
 
 
E O T ( 7 ± 3 
da ys after last 
d ose)  
A n yti me  
 
 
X  
X  
X 2 
 
Safet y F oll o w -
u p visit  
( 3 0 ± 7 da ys 
after e n d of 
treat me nt) 
A n yti me  
 
 
 
 
 
X  
2 -H G = 2 -h y dr o x y gl utaric aci d; C =c ycl e;  D = da y; E C G =ele ctr o car di o gra m; E O T =e n d of treat me nt; I D H =is ocitrate de h y dr o ge nase; 
P D = p har mac o d y na mic(s); P K = p har ma c o ki n etic(s); 
 
. 
1 
Bl o o d sa m ple c ollecti o n s h o ul d be perf or me d wit hi n 3 0 mi n utes bef ore t h e d osi n g o n t hat da y a n d a p pr o xi mat el y 2 4 ( ± 6 0 
mi n utes) h o urs after d osi n g o n t he pre vi o us da y (ie , Da y 1 of C ycles 1 or 2) .  Pre -d ose b o ne marr o w s a m ple c ollecti o n  s h o ul d 
be perf or me d  wit hi n 2 4 h o urs pri or t o  d osi n g . 
2 
B o ne marr o w a n d/ or  w h ole bl o o d will be c ollecte d f or a nal ysis of ge ne m utati o n a b u n da nce, s uc h as I D H 1, I D H 2 ( R 1 4 0 a n d 
R 1 7 2), D N M T 3 A, N P M 1, S R S F 2, R U N X 1, N R A S, K R A S, A S X L 1, T P 5 3, F L T 3, P T P N 1 1, 
, etc.  
A nal ysis f or 
 ge ne s will be perf or me d at baseli ne o nl y . 
3 
T o be perf or me d i n tri plicate wit h i nter vals of a p pr o xi matel y 5 mi n utes.  
C CI
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APPENDIX 2 
PK/PD/BIOMARKER/ECG 
ASSESSMENTS 
FOR 
EXPANSION 
COHORT  
Study Day 
Time Relative 
to Dosing 
Study 
Drug 
Intake 
Blood 
Sample 
for PK 
Blood 
Sample for 
2-HG 
Blood and Bone Marrow 
Samples for Gene Mutation 
Analysis 
ECG 
Screening 
 
 
 
X 
X2 
X 
C1D1 
Predose1 
 
X 
X 
 
X3 
0 h 
X 
 
 
 
 
0.5 h (±2 min) 
 
X 
 
 
 
1 h (±5 min) 
 
X 
 
 
X3 
2 h (±10 min) 
 
X 
 
 
X3 
3 h (±10 min) 
 
X 
 
 
 
4 h (±15 min) 
 
X 
 
 
X3 
6 h (±15 min) 
 
X 
 
 
 
8 h (±15 min) 
 
X 
 
 
 
C1D2 
Predose1 
 
X 
 
 
 
0h 
X 
 
 
 
 
C1D8 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C1D15 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C1D22 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C2D1 
Predose1 
 
X 
X 
 
X 
0 h 
X 
 
 
 
 
C2D8 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C2D15 
Predose1 
 
X 
X 
 
 
0 h 
X 
 
 
 
 
C3D1 
Predose1 
 
X 
X 
 
X3 
0.5 h 
X 
X 
 
 
 
 
1 h 
 
X 
 
 
X3 
 
2 h 
 
X 
 
 
X3 
 
3 h 
 
X 
 
 
 
 
4 h 
 
X 
 
 
X3 
 
6 h 
 
X 
 
 
 
 
8 h 
 
X 
 
 
 
C3D2 
Predose 
 
X 
 
 
 
C5D1 
Predose1 
 
X 
X 
 
X 
 
X 
 
 
 
 
C7D1 and every 
3 cycles 
thereafter 
Predose1 
 
X 
X 
 
X 
0 h 
X 
 
 
 
 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 0 6  
 
C O N FI D E N TI A L  
 
 
St u d y D a y  
Ti me Rel ati ve 
t o D osi n g 
St u d y 
Dr u g 
I nt a ke 
Bl o o d 
S a m pl e 
f or P K 
Bl o o d 
S a m pl e f or  
2 -H G  
Bl o o d a n d B o ne M arr o w 
S a m pl es f or G e ne M ut ati o n 
A n al ysis  
E C G  
E O T ( 7  ± 3  da ys 
after last d ose)  
A n yti me  
 
 
X  
 
 
Safet y F oll o w -
u p visit  
( 3 0 ± 7  da ys after 
ter mi n ati o n of 
treat me nt) 
A n yti me  
 
 
 
 
X  
2 -H G = 2 -h y dr o x y gl utaric aci d; 
AI T L =a n gi o -i m m u n o blastic T-cell l y m p h o ma; 
C =c ycle; 
D = da y; E C G =ele ctr o car di o gra m; 
E O T =e n d of treat me nt; I D H =is ocitrate de h y dr o ge nase; P D = p har mac o d y na mi c(s); P K = p har mac o ki n etic (s); 
 
. 
1 
Bl o o d sa m ple c ollecti o n s h o ul d be perf or me d wit hi n 3 0 mi n utes bef ore t h e d osi n g o n t hat da y a n d a p pr o xi matel y 2 4 
( ±6 0  mi n utes) h o urs after d osi n g o n t h e pre vi o us da y (ie , Da y 1 of C ycles 1 or 2) .  Pre -d ose b o ne marr o w sa m ple c ollecti o n 
s h o ul d be perf or me d wit hi n 2 4 h o urs pri or t o  d osi n g . 
2 
B o ne marr o w a n d/ or w h ole bl o o d will be c ollecte d f or a nal ysis of ge ne m utati o n a b u n da nce, s uc h as I D H 1, I D H 2 ( R 1 4 0 a n d 
R 1 7 2), D N M T 3 A, N P M 1, S R S F 2, R U N X 1, N R A S, K R A S, A S X L 1, T P 5 3, F L T 3, P T P N 1 1, 
, etc.  
A nal ysis f or 
 ge ne s will be perf or me d at baseli ne o nl y . 
3 
T o be perf or me d i n tri plicate wit h i nter vals of a p pr o xi matel y 5 mi n utes . 
C CI
C CI
C CI

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APPENDIX 3 
ECOG PERFORMANCE STATUS  
Grade 
Activity Level 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed or chair 
5 
Death 
 

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

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3. Management of protocol deviations due to the COVID-19 pandemic 
HUTCHMED Limited and its designee will adhere to all applicable regulatory authority 
requirements and country-specific guidelines for documenting and reporting any protocol 
deviations due to the COVID-19 pandemic.  The deviations will be reported as instructed 
to the authorities and/or ECs. 
4. Remote monitoring 
HUTCHMED Limited and its designee agree to perform remote monitoring where feasible 
and permitted.  For remote source data verification, country legislation will be followed 
and performed only where allowed with written agreement of the Principal Investigator.  
The planned site-level procedures will be described in detail and approvals sought as 
required.  If a site cannot support remote monitoring with electronic medical records 
(EMR) access, the site will not be permitted to consent new patients.  Remote visits will 
also be conducted to facilitate site selection and training. 
5. COVID-19 Vaccine Guidance 
HUTCHMED Limited presents the following guidance on the administration of COVID-
19 vaccines for patients on study. 
Patients who are enrolled on 2018-689-00US1 can receive currently approved (including 
Emergency Use Authorized [EUA]) inactivated vaccines based on investigator’s clinical 
judgment.  Given limited data, the possible interactions between the investigational drug 
and COVID-19 vaccines are unknown as this time.   
The following should be taken into consideration: 
• 
Follow any relevant regulatory guidelines which are applicable or may become 
applicable in your country or region 
• 
Administer only approved or EUA vaccines 
• 
Experimental and/or non-approved COVID-19 vaccines are prohibited per protocol 
• 
Report the vaccine name and batch number (if available) in the applicable eCRF 
• 
Record and follow any AEs related to the vaccine (including administration of) to 
resolution in the applicable eCRF 
The risk-benefit ratio for patients enrolled according to the inclusion and exclusion criteria defined 
in the study protocol and according to the defined COVID-19 risk mitigation measures continues 
to be favorable. 
HUTCHMED Limited and its designee will continue to evaluate the impact of COVID-19 on the 
ability of each country and site to initiate and execute the study.  Site-specific positions will be 
evaluated prior to the Site Initiation Visit, with the outcomes and any resultant actions documented 
and filed in the Trial Master File.   
As the COVID-19 situation may be temporary, regulatory guidance will be continuously re-
evaluated and any changes will be communicated as necessary.   
 

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APPENDIX 5 
NEW YORK HEART ASSOCIATION FUNCTION CLASSIFICATION  
Grading  
Description 
Level I 
There is no restriction on physical activity: Daily physical activities do not cause asthenia, 
palpitations, dyspnea, or angina. 
Level II 
Mild limitation of physical activity: Feel good during rest, but daily physical activities can cause 
asthenia, palpitations, dyspnea, or angina. 
Level III 
Significantly limited physical activity: There is no subjective symptom when resting, but activities 
that are less than daily physical activities can cause the above symptoms. 
Level IV 
Unable to engage in any physical activities without discomfort: Symptoms occur even when resting.  
There will be increased discomfort when performing any physical activities. 
Source: New York Heart Association, Naming and Diagnostic Criteria for Cardiovascular Disease Version 9, Boston 
Mass: Little, Brown & Co; 1994: 253-256. 
 

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APPENDIX 6 
PROHIBITED MEDICATION  
Medications that can prolong QT interval are listed in Table 12: 
Table 12 Medications That Can Prolong QT Interval 
Aclarubicin 
Amiodarone 
Anagrelide 
Arsenic trioxide 
Azithromycin 
Chloroquine 
Chlorpromazine 
Cilostazol 
Ciprofloxacin 
Citalopram 
Clarithromycin 
Cocaine 
Disopyramide 
Dofetilide 
Domperidone 
Donepezil 
Dronedarone 
Droperidol 
Erythromycin 
Escitalopram 
Flecainide 
Fluconazole 
Halofantrine 
Haloperidol 
Ibogaine 
Ibutilide 
Levofloxacin 
Levomepromazine 
Levosulpiride 
Methadone 
Moxifloxacin 
Ondansetron 
Oxaliplatin 
Papaverine hydrochloride 
Pentamidine 
Pimozide 
Procainamide 
Propofol 
Quinidine 
Roxithromycin 
Sevoflurane 
Sotalol 
Sulpiride 
Sultopride 
Terlipressin 
Terodiline 
Thioridazine 
Vandetanib 
This is not an exhaustive list of drugs that can prolong QT intervals.  The investigator should carefully consider the 
concomitant medication of each patient, assess the risk-benefit ratio, and perform appropriate monitoring. 
 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 1 2  
 
C O N FI D E N TI A L  
 
 
A P P E N DI X  7  
  
N ote: T his is n ot a n e x ha usti ve list c o ntai ni n g all 
 i n hi bit ors/i n d ucers.  T he i n vesti gat or s h o ul d 
caref ull y c o nsi der t he c o nc o mita nt me dicati o n of eac h patie nt , assess t he ris k-be nefit rati o , a n d perf or m 
a p pr o priate m o nit ori n g .   
S o urce: htt ps:// w w w. dr u g ba n k.ca  
 
C CI
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APPENDIX 8 
2017 EUROPEAN LEUKEMIANET EFFICACY CRITERIA FOR AML  
Treatment Response 
Efficacy Criteria 
Complete response (CR) 
• Myeloblast percentage <5% 
• Blast cells without Auer bodies 
• No blast cells in peripheral blood 
• No extramedullary lesion 
• ANC ≥1.0×109/L, PLT ≥100×109/L 
Complete response with negative minimal 
residual disease (CRMRD-) 
• CR with negative RT-qPCR or CR with negative MFC 
Complete response with incomplete count 
recovery (CRi) 
• Meets all other criteria of CR but ANC <1.0×109/L or 
PLT <100×109/L 
Morphologically leukemia-free status 
(MLFS)a 
• Myeloblast percentage <5% 
• Blast cells without Auer bodies 
• No extramedullary lesion 
• No hematological recovery requirements 
Partial response (PR) 
• Meets all hematological criteria for CR 
• The percentage of myeloblasts decreases from baseline by least 
50% and reaches 5% to 25% 
Stable disease (SD)b 
• Fails to meet criteria for CR, CRi, CRMRD-, MLFS, PR, or 
progressive disease 
Progressive diseasec, d 
 
• Increase in bone marrow blast percentage and/or absolute 
peripheral blood blast cells 
− 
The percentage of myeloblasts increases from baseline by 
>50% (if blast cells at baseline are <30%, net increased 
value needs to be ≥15%); or percentage of myeloblasts 
>70% continues for at least 3 months; ANC is not seen to 
be improved by at least 100%, reaching (>0.5×109/L and/or 
PLT reaches >50×109/L, without blood transfusion); or 
− 
The absolute peripheral blood blast cell count (WBC×blast 
cell ratio) increases by >50% and reaches >25×109/L 
(without differentiation syndrome); or 
• New extramedullary diseases 
Hematologic recurrence 
• After achieving CR/CRMRD-/CRi, ≥5% of the blast cells recur in 
the bone marrow; or 
• Blast cells occur in the peripheral blood; or 
• Extramedullary lesions occur 
AML=acute myeloid leukemia; ANC=absolute neutrophil count; CR=complete response; MFC=multiparameter flow 
cytometry; PLT=platelet; RT-qPCR=quantitative reverse transcription polymerase chain reaction; WBC=white 
blood cell. 
a 
Marrow should not merely be “aplastic”; at least 200 cells should be enumerated or cellularity should be at least 10% 
b 
Period of stable disease should last at least 3 months 
c 
Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, 
that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts; in the 
setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD 
d 
“Progressive disease” is usually accompanied by a decline in ANC and platelets and increased transfusion requirement 
and decline in performance status or increase in symptoms: 
Source: Döhner al 2017 

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APPENDIX 9 
LUGANO RESPONSE CRITERIA FOR HODGKIN AND NON-
HODGKIN’S LYMPHOMA  
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Response 
Complete Metabolic Response 
Complete Radiologic Response (All of 
the Following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3a with or without a residual mass on 
5PSb 
Target nodes/nodal masses must regress to 
≤1.5 cm in LDi 
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver.  In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake. 
No extralymphatic sites of disease 
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, 
IHC negative 
Partial 
Partial Metabolic Response 
Partial Remission (All of the Following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5b with reduced uptake compared with 
baseline and residual mass(es) of any size 
≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
At interim, these findings suggest responding disease When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value 
At end of treatment, these findings indicate residual 
disease 
When no longer visible, 0 × 0 mm 
For a node >5 mm × 5 mm, but smaller 
than normal, use actual measurement for 
calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by >50% in 
length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline (diffuse 
uptake compatible with reactive changes from 
Not applicable 

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

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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
be unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS=5-point scale, CT=computed tomography, FDG=fluorodeoxyglucose, 
IHC=immunohistochemistry, LDi=longest transverse diameter of a lesion, MRI=magnetic resonance imaging, 
PET=positron emission tomography, PPD=cross product of the LDi and perpendicular diameter, SDi=shortest 
axis perpendicular to the LDi, SPD=sum of the product of the perpendicular diameters for multiple lesions. 
a 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan.  However, in studies involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment).  Measured dominant lesions: Up to 6 of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 
2 diameters.  Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs (eg, liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation.  Nonmeasured lesions: 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not 
measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in 
extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response but should be no higher than surrounding normal physiologic uptake (eg, with 
marrow activation as a result of chemotherapy or myeloid growth factors).   
b 
PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake >mediastinum but ≤liver; 
4, uptake moderately >liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
Source: Cheson 2014. 
 

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APPENDIX 11 
Differentiation Syndrome Symptoms and the Names of Possible Included 
Adverse Events, Laboratory Tests, or Vital Signs Abnormalities  
Symptoms 
Names of Possible Included Adverse Events, Laboratory Tests, or Vital 
Signs Abnormalities 
Unexplained fever 
Fever, febrile neutropenia, or body temperature ≥38.3°C, etc. 
Dyspnea 
Acute respiratory failure, heart and lung failure, cardiopulmonary distress, 
cough, dyspnea, respiratory distress, respiratory failure, or respiratory arrest, 
etc. 
Weight gain (>5 kg) 
Capillary leakage, fluid retention, excessive body fluid, systemic edema, 
excessive blood volume, increased blood volume, edema, peripheral edema, 
or weight gain >5 kg from baseline 
Unexplained hypotension 
Hypotension or systolic blood pressure <90 mmHg, etc. 
Acute renal failure 
Acute kidney injury, anuria, cardiorenal syndrome, liver and kidney failure, 
prerenal failure, renal failure, acute renal failure, renal insufficiency, kidney 
injury, or serum creatinine increased from baseline and is >26.52 µmol/L or 
increased to 1.5 times that of baseline 
Interstitial lung infiltration or 
pericardial effusion 
Acute pulmonary edema, acute respiratory distress syndrome, non-
cardiogenic pulmonary edema, pulmonary edema, pulmonary congestion, 
pleural effusion, pericardial effusion, acute interstitial pneumonia, acute lung 
injury, atypical pneumonia, lower respiratory tract infection, pulmonary 
infection, pulmonary infiltration, pneumonia, pulmonary toxicity, etc. 
 

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APPENDIX 12 
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA IN 
MYELODYSPLASIA  
Proposed Modified International Working Group Response Criteria for Altering Natural 
History of MDS 
Category 
Response Criteria (Responses Must be at Least 4 Weeks) 
Complete remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines* 
Persistent dysplasia will be noted*† 
Peripheral blood‡ 
Hgb ≥ 11 g/dL 
Platelets ≥ 100 × 109/L 
Neutrophils ≥ 1.0 × 109/L† 
Blasts 0% 
Partial remission 
All CR criteria if abnormal before treatment except:  
Bone marrow blasts decreased by ≥50% over pretreatment but still >5% 
Cellularity and morphology not relevant 
Marrow CR† 
Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment† 
Peripheral blood: if HI responses, they will be noted in addition to marrow CR† 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for >8 weeks 
Failure 
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a more 
advanced MDS FAB subtype than pretreatment 
Relapse after CR or PR 
At least 1 of the following: 
Return to pretreatment bone marrow blast percentage 
Decrement of ≥50% from maximum remission/response levels in granulocytes or 
platelets 
Reduction in Hgb concentration by ≥1.5 g/dL or transfusion dependence 
Cytogenetic response 
Complete 
Disappearance of the chromosomal abnormality without appearance of new ones  
Partial 
At least 50% reduction of the chromosomal abnormality 
Disease progression 
For patients with: 
Less than 5% blasts: ≥50% increase in blasts to >5% blasts 
5%-10% blasts: ≥50% increase to >10% blasts 
10%-20% blasts: ≥50% increase to >20% blasts 
20%-30% blasts: ≥50% increase to >30% blasts 
Any of the following: 
At least 50% decrement from maximum remission/response in granulocytes or 
platelets 
Reduction in Hgb by ≥2 g/dL 
Transfusion dependence 

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Proposed Modified International Working Group Response Criteria for Altering Natural 
History of MDS (Continued) 
Survival 
Endpoints: 
Overall: death from any cause 
Event-free: failure or death from any cause 
PFS: disease progression or death from MDS 
DFS: time to relapse 
Cause-specific death: death related to MDS 
AML=acute myeloid leukemia; CR=complete remission; DFS=disease-free survival; FAB=French-American British; 
HI=hematologic improvement; Hgb=hemoglobin; IWG=International Working Group; MDS=myelodysplastic 
syndromes; PFS=progression-free survival; PR=partial remission. 
Note: Deletions to IWG response criteria are not shown.  To convert hemoglobin from grams per deciliter to grams 
per liter, multiply grams per deciliter by 10. 
*Dysplastic changes should consider the normal range of dysplastic changes (modification) (Ramos 1999). 
†Modification to IWG response criteria. 
‡In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period.  Such patients can be included in the response category into which they 
fit at the time the therapy is started.  Transient cytopenias during repeated chemotherapy courses should not be 
considered as interrupting durability of response, as long as they recover to the improved counts of the previous 
course. 
Source: Cheson 2006 
Proposed Modified International Working Group Response Criteria for Hematologic Improvement 
Hematologic Improvement* 
Response Criteria (Responses Must Last for at Least 8 Weeks)† 
Erythroid response 
(pretreatment, <11 g/dL) 
Hgb increase by ≥1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 week compared with the pretreatment transfusion 
number in the previous 8 weeks.  Only RBC transfusions given for a Hgb of 
≤9.0 g/dL 
Pretreatment will count in the RBC transfusion response evaluation† 
Platelet response (pretreatment, 
<100 × 109/L) 
Absolute increase of ≥30 × 109/L for patients starting with >20 × 109/L 
platelets 
Increase from <20 ×109/L to >20 × 109/L and by at least 100%† 
Neutrophil response 
(pretreatment, <1.0 × 109/L) 
At least 100% increase and an absolute increase >0.5 × 109/L† 
Progression or relapse after HI‡ 
At least 1 of the following: 
At least 50% decrement from maximum response levels in granulocytes or 
platelets 
Reduction in Hgb by ≥1.5 g/dL 
Transfusion dependence 
HI=hematologic improvement; Hgb=hemoglobin; IWG=International Working Group; RBC=red blood cell. 
Note: Deletions to the IWG response criteria are not shown. 
To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10. 
*Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥ 1 week apart 
(modification). 
†Modification to IWG response criteria. 
‡In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet 
responses be reported overall as well as by the individual response pattern. 
Source: Cheson 2006 

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APPENDIX 13 
ANN-ARBOR STAGING  
Revised Staging System for Primary Nodal Lymphomas 
Stage  
Involvement  
Extranodal (E) Status 
Limited 
I  
One node or a group of adjacent nodes 
Single extranodal lesions without nodal 
involvement 
II 
Two or more nodal groups on the same 
side of the diaphragm 
 
Stage I or II by nodal extent with limited 
contiguous extranodal involvement 
II bulkya 
II as above with “bulky” disease 
Not applicable 
Advanced 
III  
 
Nodes on both sides of the diaphragm; 
nodes above the diaphragm with spleen 
involvement 
Not applicable 
IV 
Additional noncontiguous extralymphatic 
involvement 
Not applicable 
Note: Extent of disease is determined by positron emission tomography– computerized tomography for avid 
lymphomas and computerized tomography for non-avid histologies.  Tonsils, Waldeyer’s ring, and spleen are 
considered nodal tissue. 
a 
Whether Stage II bulky disease is treated as limited or advanced disease may be determined by histology and a 
number of prognostic factors. 
Source: Cheson 2014 

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APPENDIX 14 
INTERNATIONAL PROGNOSTIC INDEX  
International Prognostic Index  
Risk Factors 
IPI Risk Group  
Number of IPI Risk Factors 
Ann-Arbor Stage III or IV 
Age >60 years 
Serum LDH >1×ULN 
ECOG Performance Status ≥2 
Extranodal involvement ≥2 
Low  
0 or 1 
Low-intermediate 
2 
High-intermediate  
3 
High 
4-5 
ECOG=Eastern Cooperative Oncology Group; FDG-PET=fluorodeoxyglucose-positron emission tomography; 
IPI=International Prognostic Index; LDH=lactate dehydrogenase; ULN=upper limit of normal. 
The results of FDG-PET should not be taken into account for calculation of IPI as this prognostic score was established 
without FDG-PET. 
Source: Shipp 1993.   
 

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APPENDIX 15 
2017 ELN RISK STRATIFICATION BY GENETICS  
Risk Category* 
Genetic Abnormality 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow† 
Biallelic mutated CEBPA 
Intermediate 
Mutated NPM1 and FLT3-ITDhigh† 
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk genetic 
lesions) 
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ 
Cytogenetic abnormalities not classified as favorable or adverse 
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214 
t(v;11q23.3); KMT2A rearranged 
t(9;22)(q34.1;q11.2); BCR-ABL1 
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) 
25 or del(5q); 27; 217/abn(17p) 
Complex karyotype,§ monosomal karyotype|| 
Wild-type NPM1 and FLT3-ITDhigh† 
Mutated RUNX1¶ 
Mutated ASXL1¶ 
Mutated TP53# 
AML=acute myeloid leukemia; ELN=European Leukemia Net; HCT=Hematopoietic cell transplantation; 
WHO=World Health Organization. 
Note: Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient 
numbers are available, by specific genetic lesions indicated. 
*Prognostic impact of a marker is treatment-dependent and may change with new therapies. 
†Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD allelic ratio 
(using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by area 
under the curve “FLT3- wild type”; recent studies indicate that AML with NPM1 mutation and FLT3-ITD low 
allelic ratio may also have a more favorable prognosis and patients should not routinely be assigned to allogeneic 
HCT (Gale 2008, Pratcorona 2013,Schlenk 2014, Ho 2016). 
‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations. 
§Three or more unrelated chromosome abnormalities in the absence of one of the WHO-designated recurring 
translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); 
AML with BCR-ABL1. 
||Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional 
monosomy or structural chromosome abnormality (excluding core-binding factor AML) (Breems 2008). 
¶These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML 
subtypes. 
#TP53 mutations are significantly associated with AML with complex and monosomal karyotype 
(Papaemmanuil 2016, Haferlach 2008, Bowen 2009, Rücker 2012, Devillier 2015). 
Source: ELN 2017 

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APPENDIX 16 
INTERNATIONAL PROGNOSTIC SCORING SYSTEM REVISED 
PROGNOSTIC SCORE VALUES  
IPSS-R Prognostic Score Values 
Prognostic 
Variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very good 
— 
Good 
— 
Intermediate 
Poor 
Very poor 
BM Blast, % 
≤ 2 
— 
>2%- < 5% 
— 
5%-10% 
> 10% 
— 
Hemoglobin 
≥ 10 
— 
8- < 10  
< 8 
— 
— 
— 
Platelets 
≥ 100 
50-< 100 
< 50 
— 
— 
— 
— 
ANC 
≥ 0.8 
< 0.8 
— 
— 
— 
— 
— 
ANC=absolute neutrophil count; BM=bone marrow. 
— indicates not applicable 
Source: Greenberg 2012. 
 

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APPENDIX 17 
IMMUNOPHENOTYPING, CYTOGENETICS, and MOLECULAR 
GENETICS  
Acute Myeloid Leukemia(AML) 
 
Immunophenotyping 
CD34; CD117; CD33; CD65; CD14; CD36; CD64; CD41; CD61; CD235a; 
CD36; HLA-DR 
Cytogenetics 
inv(16); t(16;16); del (16q); t(8;21); t(15;17); +8; t(9;11); -5/del (5q)  
-7/ del(7q); t (4;11); inv(3); t (3;3); t(6;9); t(9;22); Abn 3q; Abn 9q; 
del (20q); del (21q); del (17p); +6; -Y; del (12p) 
Molecular genetics 
CEBPA; FLT3-ITD; FLT3-TKD; KIT; NPM1; RUNX1; NRAS; KRAS; 
MLL; PML-RARA; ASXL1; JAK2; BCOR; DNMT3A;TP53; SF3B1; 
TET2; SRSF2; PTPN11 
 
Myelodysplastic Syndrome (MDS) 
 
Immunophenotyping 
CD34; CD117; CD33; CD65; CD14; CD36; CD64; CD41; CD61; CD235a; 
CD36; HLA-DR 
Cytogenetics 
-5 or del (5q); -7 or del(7q); i(17q) or t(17p); del(12p) or t(12p); del(11q); 
-13 or del(13q); del(9q); Idic(X)(q13); Inv(3)(q21q26.2) ;t(6;9)(p23;q34) 
t(3:21)(q26.2;q22.1); t(1;3)(p36.3;q21.2) ;t(11:16)(q23;p13.3); 
t(2;11)(p21;q23) 
Molecular genetics 
JAK2 V617F; JAK3; CALR;MPL; NRAS; KRAS; PTPN11; NF1; FLT3; 
CSF3R; CBL; KIT; TET2; ASXL1; DNMT3A; UTX; EZH2; SETBP1; 
SF3B1; U2AF1; SRSF2; NPM1; TP53; RUNX1 
 
Angio-immunoblastic T-cell lymphoma (AITL) 
 
Immunophenotyping 
CD3; Loss of CD3; CD7; Loss of surface CD7; sCD3(/dim)/CD4+/CD10; 
CD20 ; CD4; CD8; CD21; CD23; CD28; CD10; CD2; CD5; CD7; CD30; 
CD200; CD279 
Cytogenetics 
Trisomy 3; Trisomy 5; Trisomy 21; Additional X chromosome; Loss of 6q ; 
T(5;9)(q33;q22);ITK-SYK 
Molecular genetics 
TET2; DNMT3A; RHOA; PLCG1; FYN; VAV1 ; RHOAG17V; BCL6; 
PD1; ICOS; PAX5; SAP; C-MAF; CXCL13; CXCR5; Plasma cell light 
chain restriction [κ and λ] 
EBV viral load 
EBV Viral titer 
 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 2 6  
 
C O N FI D E N TI A L  
 
 
A P P E N DI X 1 8  A me n d me nt Hist or y   
A me n d me nt 4 ( 2 4 J u ne 2 0 2 2)  
Secti o n N u m ber  
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R ati o n ale f or C h a n ge  
Title P a ge, F o oters, Si g nat ure P a ge, 
a n d Gl o ball y 
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a d dress, a n d l o g o w here a p pr o priate 
t hr o u g h o ut. 
T he a d mi nistrati ve u p dates 
were ma de t o a p pr o priatel y 
reflect t he c ha n ge of 
s p o ns or c o m pa n y na me. 
S y n o psis  
La n g ua ge i n t he descri pti o n of sites was 
u p date d t o i n dicate a p pr o xi matel y 4 0 st u d y 
sites i n  E ur o pe,  Asia P acific, a n d t he 
U nite d States.  
T he descri pti o n of sites 
u p dates was ma de t o be 
c o nsiste nt wit h t he 
descri pti o n i n ot her st u d y 
trials.   
La n g ua ge i n tar get p o p ulati o n was u p date d 
t o re m o ve “after at least 2 li nes of 
t hera pies” a n d u p date d t he se nte nce t o 
“ P atie nts wit h ac ute m yel oi d le u ke mia 
( A M L) ( C o h ort A) a n d w h o ha ve recei ve d 
at least 2 pri or li nes of t hera p y a n d patie nts 
wit h hi g h -ris k m yel o d ys plasti c s y n dr o me 
( H R-M D S)  ( C o h ort B) a n d 
a n gi o -i m m u n o blastic T-cell l y m p h o ma 
( AI T L) ( C o h ort C) w h o ha ve r ecei ve d at 
least 1 pri or li ne of t hera p y.”  
T he la n g ua ge u p dates f or 
t he tar get p o p ulati o n were 
ma de t o pr o vi de clarit y of 
eli gi ble patie nt p o p ulati o ns 
a n d li nes of t hera p y.   
S y n o psis, Secti o n 1. 2 –  St u d y 
Sc he matic, a n d Secti o n 4. 1. 1 –  
P art  1 ( D ose Escalati o n), T a ble 4 –  
P atie nt D ose Gr o u pi n g, D ose 
Escalati o n Pla n  
P art 1 d ose escalati o n la n g ua ge was 
u p date d t o reflect t he a d diti o n of d ose 
le vels 5, 6, 7, a n d 8, or 
 
 m g d ose le vels, res pecti vel y. 
T he u p dates were ma de t o 
f urt her i n vesti gate 
t olera bilit y, 
p har mac o ki netic ( P K) 
e x p os ure a n d 
p har mac o d y na mic ( P D) 
effects at hi g her d ose le vels.  
S y n o psis a n d Secti o n 3 –  
O bj ecti ves a n d E n d p oi nts  
La n g ua ge was u p date d i n t he sec o n dar y 
e n d p oi nt t o s u m marize t he e n d p oi nts.   
T he la n g ua ge u p dates t o t he 
sec o n dar y e n d p oi nts were 
ma de t o reflect c ha n ges t o 
t he statistics secti o n f or 
clarit y.  
S y n o psis, Secti o n 1. 2  –  St u d y 
Sc he matic, Secti o n 2. 3. 1 –  Be nef it-
Ris k Assess me nt, 
Secti o n  4. 1. 2  –  P art 2 ( D ose 
E x pa nsi o n), 
Secti o n  4. 2. 2. 2  –  C o h ort B: 
Rela pse d/ Refract or y Hi g h -Ris k 
M yel o d ys plastic S y n dr o me, 
Secti o n  6. 1. 1 4  –  Efficac y 
E val uati o n, Secti o n  6. 2. 1. 1  –  
P er ma ne nt Disc o nti n uati o n of 
Treat me nt, Secti o n  1 4  –  Re fer e nces, 
a n d A p pe n di x 9 –  2 0 1 5 I W G 
Criteria f or Meas ure me nt of 
Treat me nt Res p o nse i n A d ult 
M D S/ M P N  
La n g ua ge was u p date d t o re m o ve 
m yel o pr oliferati ve ne o plas m ( M P N) fr o m 
C o h ort B a n d t he re q uire me nt f or at least 
2  pri or li nes of t hera p y f or hi g h -ris k 
m yel o d ys plastic s y n dr o me ( H R -M D S).  
Ass ociate d la n g ua ge was als o u p date d; 
i ncl u di n g, b ut n ot li mite d t o t he f oll o wi n g:  
•  
La n g ua ge was a d de d t o clarif y t hat 
n o a p pr o ve d sec o n d -li ne t hera p y 
e xists f or patie nts wit h H R -M D S t hat 
are rela pse d or refract or y t o 
h y p o met h ylati n g a ge nts ( H M As) a n d 
are n ot eli gi ble f or i nte nsi ve 
c he m ot hera p y or all o ge nic  
T he la n g ua ge was u p date d 
as t he eli gi ble patie nt 
p o p ulati o n u p dates i ncl u de d 
t he re m o val of M P N, 
he mat ol o gical mali g na ncies 
are n ot r o u ti nel y teste d f or 
I D H (is ocitrate 
de h y dr o ge nase) m utati o ns, 
n or d o t he y fre q ue ntl y 
de m o nstrate I D H m utati o ns.  
T he n u m ber of a p pr o ve d 
sec o n d-li ne t hera pies was 
c orrecte d. 
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Section Number 
Summary of Change 
Rationale for Change 
hematopoietic stem cell transplant 
(allo-HSCT). 
• 
Language was added to clarify that 
patients HR-MDS who have received 
at least 1 prior line of therapy do not 
have viable treatment options and are 
eligible for the 2020-306-GLOB1 
study.   
• 
Appendix 9 and the Savona 2015 
reference were removed.   
Synopsis and Section 4.2.2.3 
Cohort C: Relapsed or Refractory 
Angio-immunoblastic T-cell 
Lymphoma 
Language was updated to indicate that the 
study plans to enroll patients with AITL 
receiving at least 1 prior line of systemic 
therapy. 
The language was updated 
as there is only 1 line of 
systemic therapy available 
to patients with AITL.   
Synopsis, Section 1.2 – Study 
Schematic, Section 4.1.2 – Part 2 
(Dose Expansion), 
Section 9.1.2 – Sample Size 
Rationale, and Section 9.1.2.2 – 
Dose Expansion Part 
Language was updated to remove 
Cohort D from the study.  Associated 
language was updated to reflect the 
removal of Cohort D, including, but not 
limited to the following: 
• 
The number of cohorts was reduced 
from 4 to 3 cohorts. 
• 
The approximate enrollment for 
Part 2 was reduced from 60 to 
45 patients.   
• 
The probability of observing at least 
1 adverse event (AE) was updated to 
reflect the change from 60 to 
45 patients.  For a given AE with a 
true rate of 10%, 5%, or 1%, the 
probability of observing at least 1 AE 
in 45 patients is 99%, 90%, and 36%, 
respectively.   
The language updates 
including and related to the 
removal of Cohort D are 
due to very few 
hematological malignancies 
outside of Cohorts A, B, 
and C having IDH 
mutations or receiving 
routine testing for IDH 
mutations. 
Synopsis and Section 3 – 
Objectives and Endpoints 
Language was added to the secondary 
objectives to include the complete 
response with partial hematological 
recovery (CRh). 
The updates to the 
secondary objectives were 
made to reflect changes to 
efficacy response 
assessment for patients with 
AML. 
Synopsis, Section 9.1.2 – Sample 
Size Rationale and Section 9.1.2.1 – 
Dose Escalation Part 
Language was updated to reflect the 
updated approximate number of patient 
enrollment from 60 patients to 
approximately 75 patients.  The dose 
escalation part estimate of evaluable 
patients was updated from 12 to 
approximately 15 patients to 24 to 
approximately 40 patients.   
The updates were made to 
reflect the additional 
cohorts added to the dose 
escalation (Part 1). 
Section 1.3 – Schedule of Events; 
Table 1 – Schedule of Events (Dose 
Escalation) and Table 2 –Schedule 
of Events (Dose Expansion)  
Language was added to the Schedule of 
Events (SOE) to reflect the addition of 
Ann-Arbor staging and Risk 
stratification/Prognostic scoring at 
screening staging assessment.  The 
The updates to the SOE 
were for clarity and to 
reflect changes to study 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 2 8  
 
C O N FI D E N TI A L  
 
 
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  
f o ot n otes “ w” a n d “ x” were a d de d i n t he 
D ose Escalati o n S O E a n d t he f o ot n otes 
“ v” a n d “ w” were a d de d t o t he D ose 
E x pa nsi o n S O E t o pr o vi de f urt her 
g ui da nce o n t he A n n -Ar b or sta gi n g a n d 
Ris k stratificati o n/ Pr o g n ostic sc ori n g 
assess me nts, res pecti vel y.   
C ycle 2 Da y 1 ( ± 1 wee k) O p ht hal m ol o g ic 
e xa mi nati o n was a d de d, a n d t he 
c orres p o n di n g f o ot n ote was u p date d t o 
i ncl u de a descri pti o n of t he pr oce d ures.   
A d diti o nal c ollecti o n of he mat ol o g y, bl o o d 
a m ylase a n d li pase, fasti n g li pi d pa nel, 
c o a g ulati o n i n dicat ors, H b A 1c, a n d bl o o d 
tra nsf usi o n rec or di n g were a d de d t o safet y 
f oll o w-u p visit.   
assess me nts/ data c ollecti o n 
a n d per re g ulat or y re q uest.  
Secti o n 1. 3 –  Sc he d ule of E ve nts; 
T a ble 1 –  Sc he d ule of E ve nts ( D ose 
Escalati o n) a n d T a ble 2 –  Sc he d ule 
of E ve nts ( D ose E x pa nsi o n), 
Secti o n 6. 1. 1 0. 3 –  He mat ol o g y –  
B o ne Marr o w As pirati o n a n d/ or 
Bi o ps y, Secti o n 6. 1. 1 0. 1 3 –  
T u m oral Sa m ple f or P atie nts wit h 
AI T L  
La n g ua ge a n d refere nces were u p date d t o 
i n dicate t hat b o ne marr o w as pirati o n will 
i ncl u de l ocal i m m u n o p he n ot y pi n g, 
c yt o ge netic a nal ysis, a n d m ole c ular testi n g 
i n T a ble 1 f o ot n ote “ o” a n d T a ble 2 
f o ot n ote “ n.”  
La n g ua ge was u p date d t o pr o vi de 
pr oce d ural refere nces l ocate d i n Secti o ns 
6. 1. 1 0. 3 a n d 6. 1. 1 0. 1 3 a n d A p pe n di x 1 7.  
T he u p dat es t o t he b o ne 
marr o w as pirati o n, 
i m m u n o p he n ot y pi n g, 
c yt o ge netic a nal ysis, a n d 
m olec ular testi n g were 
ma de t o pr o vi de clarit y t o 
t he pr ocess of c ollecti o n 
a n d a nal ysis.   
Secti o n  2. 1. 2. 2 –  M utati o ns a n d 
Mali g na ncies a n d Secti o n 1 4 –  
Refere nces  
La n g ua ge wa s a d de d t o i n dicate t hat 
i v osi de ni b was als o a p pr o ve d f or use i n 
ne wl y dia g n ose d patie nts wit h A M L w h o 
are ≥7 5 years ol d or w h o ha ve 
c o m or bi dities t hat precl u de t he use of 
i nte nsi ve i n d ucti o n c he m ot her a p y.  T he 
c orres p o n di n g refere nce ( R o b oz 2 0 2 0) was 
a d de d t o t he refere nces a n d i n -te xt citati o n.   
T he i v osi de ni b u p dates 
were ma de t o reflect 
c ha n ges i n I v osi de ni b F D A 
a p pr o val acc urac y.  
Secti o n 4. 1. 1 –  P art 1 ( D ose 
Escalati o n)  
T he la n g ua ge disc ussi n g t he nee d f or d ose 
escalati o n “ be y o n d  
 m g Q D …” was 
u p d ate d t o “ be y o n d  
 m g Q D …”.  
T he la n g ua ge t hat disc usses t he rati o nale 
be hi n d t he a d diti o n of d ose le vels 5 t o 8 
was a d de d.  
T he u p date d la n g ua ge is t o 
reflect t he a d diti o nal d ose 
escalati o n c o h orts u p t o 
 m g.  
 
D ose le vels 5 t o 8 rati o nale 
was a d de d f or clarit y.   
Secti o n 4. 1. 1 –  P art 1 ( D ose 
Escalati o n), Secti o n 6. 2. 1. 4 –  
Re place me nt of P atie nts, a n d 
Secti o n 9. 1. 2. 1 –  D ose  Escalati o n 
P art  
T he la n g ua ge disc ussi n g w het her patie nts 
w h o are n ot d ose -li miti n g t o xi cit y 
( D L T)-e val ua ble i n a d ose c o h ort “ will” be 
re place d was u p date d t o “ ma y” be 
re place d.   
T he la n g ua ge u p date is t o 
reflect t he p ossi bilit y t hat 
n ot all n o n -D L T -e val ua ble 
patie nts ma y be re place d.   
Secti o n 5. 1. 1. 3 –  Rescree ni n g  
La n g ua ge a n d secti o n were a d de d t o 
pr o vi de t he p ossi bilit y t o rescr ee n patie nts 
w h o were u na ble t o c o m plete t he 
pr oce d ures wit hi n t he scree ni n g wi n d o w, 
scree n faile d, or beca me eli gi ble as t he 
T he a d diti o n of rescree ni n g 
la n g ua ge was t o pr o vi de 
clarit y a n d g ui da nce o n 
patie nt rescree ni n g.   
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Section Number 
Summary of Change 
Rationale for Change 
result of an amendment, status change, or 
change in extenuating circumstances.   
Section 5.2 – Inclusion Criteria; 
Part 2 
Language was added to “b” to clarify that 
patients with AML must have received at 
least 1 prior lines of therapy for their 
hematologic malignancy.   
Language was added to “e” to clarify the 
number and acceptable prior lines of 
therapy.  
Inclusion criterion 6 was added to indicate 
that patients with AITL must have 
measurable lesion as defined in Lugano 
2014.   
The updates to “b” and “e” 
were to clarify the number 
of lines of therapy and 
acceptable prior lines of 
therapy for each population.  
The addition of inclusion 
criterion 6 was to clarify the 
requirement of measurable 
lesions for patients with 
AITL.   
Section 5.3 – Exclusion Criteria 
Language for criterion 8 was updated to 
exclude patients with congenital long QT 
syndrome.   
Language for criterion 9 was updated to 
exclude patients with electrocardiogram 
results showing no clinically significant 
findings and a QTcF interval of >470 ms 
for women and >450 ms for men.   
The language updates were 
made per regulatory 
request.   
Section 6.1.10.3 – Hematology – 
Bone Marrow Aspiration and/or 
Biopsy and Appendix 17 – 
Immunophenotyping/Cytogenetics/
Molecular Genetics 
Language was added to indicate that 
patients with AITL that have 
fluorodeoxyglucose (FDG)-avid disease 
and will undergo positron emission 
tomography-computed tomography (PET-
CT) imaging for screening and efficacy 
evaluation are not required to have a bone 
marrow aspiration or biopsy. 
Language was added to indicate that the 
results of the analyses of the morphology 
examination, immunophenotyping, 
cytogenetics, and molecular genetic testing 
performed during screening will be 
collected in the electronic case report form 
(eCRF). 
Appendix 17 was added to provide a 
reference and description for 
immunophenotyping, cytogenetics, and 
molecular genetic testing for AML, 
HR-MDS, and AITL. 
The language updates were 
made to provide references 
and guidance on assessment 
procedures and reporting 
requirements.   
Section 6.1.10.11 – Virological 
Screening  
Language was updated to indicate that 
viral serology testing should be done at 
screening for all patients.   
The language was updated 
to provide clarity on the 
virology screening 
requirement. 
Section 6.1.10.13 – Tumoral 
Sample for Patients with AITL 
Section was added and language was 
included to indicate that the results of any 
analyses performed by local testing on 
previous tumoral samples taken for 
confirmation of progressive disease (PrD) 
prior to screening or during screening 
The addition of this section 
and language is to provide 
guidance on reporting 
requirements of the results 
of previous tumor analysis 
in patients with AITL. 

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Section Number 
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Rationale for Change 
including immunophenotyping, 
cytogenetics, molecular genetic testing, 
and Epstein-Barr virus (EBV) status will 
be collected in the eCRF. 
Section 6.1.14 – Efficacy 
Evaluation and Section 15 – 
Appendices; Appendix 12 – 
International Working Group 
(IWG) Response Criteria in 
Myelodysplasia 
Language was added to indicate that the 
evaluation of HR-MDS will be performed 
based on IWG response criteria in 
myelodysplasia as indicated in the new 
Appendix 12.   
Language was removed indicating that all 
measurable and evaluable lesions should 
be assessed and documented at screening 
and each subsequent tumor evaluation.   
Language was added to indicate that for 
patients with hematological malignancies, 
all measurable and evaluable lesions 
should be assessed and documented at 
screening and each subsequent efficacy 
evaluation using contrast-enhanced CT 
scans for non-FDG-avid disease and/or 
PET-CT for patients with FDG-avid 
disease.  Furthermore, patients with non–
FDG-avid disease who have documented 
bone marrow involvement at screening, a 
bone marrow aspirate and/or biopsy will 
be required at each efficacy evaluation. 
These language updates 
were made to provide 
clarity on the efficacy 
evaluation of patients with 
HR-MDS and AITL. 
Section 6.1.14.1 – Risk 
Stratification/Prognostic Scoring 
Section and language were added to define 
how AML, HR-MDS, and AITL 
prognostic stratification at screening will 
be collected.   
These language updates 
were made to provide 
clarity on study 
assessments/data collection. 
Section 6.1.14.2 – Ann-Arbor 
Staging  
Section and language were added to 
provide guidance on Ann-Arbor staging.   
The addition of this section 
and language was to reflect 
study assessments/data 
collection updates. 
Section – 6.2.1.1 – Permanent 
Discontinuation of Treatment 
Language was added to discuss patients 
with HR-MDS based on the IWG criteria.   
Language was removed with unspecific 
references to other hematological 
malignancies.   
The language updates were 
made to describe and clarify 
the patient population and 
associated efficacy 
evaluation. 
Section 7.1 – Study Drug 
Administration 
Language was added to indicate course of 
action for patients missing a dose of study 
drug by more than 4 hours.   
The language was added for 
guidance and clarity.   
Section 7.2.1 – Formulation, 
Storage, Preparation, and Handling 
Language was added to indicate that 
storage procedures for study drug should 
include protection from light and moisture.   
The language was added for 
clarity and guidance.   
Section 7.5.3 – Dose Adjustment 
for QT Interval Prolongation, 
Table 10 
Language for Table 10 was updated to 
require discontinuation of HMPL-306 
permanently in response to a QTcF greater 
than 500 ms. 
The language updates were 
made per regulatory 
recommendation.   

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 3 1  
 
C O N FI D E N TI A L  
 
 
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  
La n g u a ge was re m o ve d f or Q T c i nter val 
pr ol o n gati o n wit h si g ns/s y m pt o ms of 
life-t hreate ni n g arr h yt h mia. 
Secti o n 8. 1. 4 –  A d verse E ve nt of 
S pecial I nterest  
Secti o n a n d la n g ua ge a d de d t o disc uss 
a d verse e ve nts of s pecial i nterest ( A E SIs).  
A E SIs s h o ul d be re p orte d i m me diatel y.  
Differe ntiati o n S y n dr o me is a n A E SI a n d 
m o ve d here fr o m Secti o n 8. 6. 4 f or 
c o nsiste nc y.   
T he a d diti o n of t his secti o n 
a n d ass ociate d la n g ua ge 
was t o pr o vi de g ui da nce o n 
A E SIs.  
Secti o n 8. 2. 1 –  A d verse E ve nt 
Re p orti n g P eri o d  
La n g ua ge u p date d t o i n dicate t hat A Es 
re gar dless of attri b uti o n will be c ollecte d 
u ntil 3 7 da ys after last d ose of st u d y dr u g 
i nstea d of 3 0.   
T he c ha n ge i n c ollecti o n 
da ys was ma de t o c orrect 
t he le n gt h of collecti o n.  
Secti o n 9. 1. 2. 2 –  D ose E x pa nsi o n 
P art  
La n g ua ge was u p date d t o i n dicate t hat 
m ore patie nts ma y be e nr olle d i n t his 
c o h ort if f urt her a nal ysis of safet y a n d 
efficac y si g nals are nee de d.  
T his la n g ua ge was a d de d 
f or clarit y o n e nr oll me nt.   
Secti o n 9. 2. 4 –  Safet y A nal ysis  
La n g ua ge was u p date d t o i n dicate t hat a 
s u m mar y of A E SIs will be pr o d uce d.   
T he a d diti o n of A E SI 
s u m mar y was f or 
c o nsiste nc y wit h ot her 
H U T C H M E D pr ot oc ols.   
Secti o n 9. 2. 7 –  Efficac y A nal ysis  
La n g ua ge was e xtra p olate d u p o n  a n d 
u p date d f or clarit y.   
T he la n g ua ge c ha n ges were 
t he u p dates ma de t o t he 
st u d y eli gi ble patie nt 
p o p ulati o ns a n d ass ociate d 
efficac y e val uati o ns f or 
clarit y.  
A p pe n di x 1 4 –  I nter nati o nal 
Pr o g n ostic I n de x  
I nter nati o nal Pr o g n ostic I n de x was a d de d 
as A p pe n di x 1 4.  
T he I nter nati o nal 
Pr o g n ostic I n de x was a d de d 
as a n a p pe n di x f or 
refere nce. 
A me n d me nt 3 ( 1 5 Oct o b er 2 0 2 1)  
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  
Secti o n 2. 2. 2. 1. 3 –  Safet y 
P har mac ol o g y  
La n g ua ge c o m pari n g t he half -ma xi mal 
H M P L -3 0 6 i n hi biti o n o n h E R G 
p otassi u m c ha n nels wit h c o m plete 
i n hi biti o n of 2-H G was c ha n ge d t o 
 
 
La n g ua ge descri bi n g t he ne gati ve res ult 
of t he bacterial re verse m utati o n test 
a n d ma m malia n c hr o m os o me 
a b errati o n test  were re m o ve d .   
La n g ua ge was u p date d descri bi n g t he 
effects of H M P L -3 0 6 o n tele metere d 
B ea gle d o gs was u p date d t o clarif y t hat 
t he 
 m g/ k g) 
s h o we d l o w ris k o n t he car di o vasc ular 
s yste m. 
La n g ua ge u p date d f or clarit y.  
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 3 2  
 
C O N FI D E N TI A L  
 
 
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  
La n g ua ge was a d de d descri bi n g t he 
effects of H M P L -3 0 6 o n S pra g ue -
Da wle y rats was u p date d t o clarif y t hat 
t he 
 m g/ k g) 
s h o we d n o H M P L-3 0 6 -relate d effects 
o n t he res pirat or y a n d ce ntral ner v o us 
s yste m. 
C o ncl usi o n la n g ua ge was u p d ate d t o 
descri be t he res ults of t hese 
p har mac ol o g y  st u dies c ollecti vel y 
i n dicati n g t hat H M P L-3 0 6 is l o w ris k 
t o t he car di o vasc ular, res pirat or y, a n d 
ce ntral ner v o us s yste m.  
Secti o n 2. 2. 2. 2 –  
P har mac o ki netics  
La n g ua ge was u p date d f or ge neral 
clarit y.   
La n g ua ge was a d de d t o i n dicate t hat 
H M P L -3 0 6 has a n 
 
.   
La n g ua ge s u g gesti n g t hat H M P L -3 0 6 
ma y 
 
 was re m o ve d.   
La n g ua ge u p date d f or clarit y.  
Secti o n 2. 2. 2. 3 –  T o xic ol o g y  
T o xic ol o g y Secti o n was m o ve d fr o m 
Secti o n 2. 2. 2. 2 t o Secti o n 2. 2. 2. 3 t o 
reflect C T D str uct ure.   
La n g ua ge was ge nerall y u p dat e d t o 
m ore s ucci nctl y s u m marize t he res ults 
of t he c o m plete d H M P L -3 0 6 
t o xic ol o g y st u dies a n d t o c o ncl u de t hat 
H M P L -3 0 6 was 
 
 
U p date d wit h t he res ults of t he i n 
vi v o p h ot ot o xicit y st u d y a n d f or 
clarit y.  
Secti o n 2. 2. 3 –  S u p p orti ve 
Cli nical Data  
Re m o ve d la n g ua ge descri bi n g c urre nt 
e nr oll me nt a n d stat us of d ose li miti n g 
t o xicities a n d i nstea d refer t he rea der t o 
t he I B f or t he m ost c urre nt i nf or mati o n.   
La n g ua ge u p date d f or clarit y.  
Secti o n 2. 3. 1 B e nefit -Ris k 
Assess me nt  
Secti o n 2. 3. 1 Ris k Assess me nt hea di n g 
was u p date d t o Secti o n 2. 3. 1 
B e nefit -Ris k Assess me nt .   
I ntr o d uct or y la n g ua ge t o T a ble 3 
S u m mar y of P ote ntial Ris ks of 
H M P L -3 0 6 a n d T a ble 3 itself was 
re m o ve d.   
Secti o n 2. 3. 2 Be nefit Assess me nt 
hea di n g was re m o ve d a n d t he secti o n 
la n g ua ge was i nc or p orate d u n der 
Secti o n  2. 3. 1 Be nefit -Ris k hea di n g .   
T he s u b hea di n g ‘ O verall Be nefit/ Ris k 
C o ncl usi o n’ was re m o ve d .   
La n g ua ge was a d de d descr i bi n g 
t o xicities ass ociate d wit h t he use of 
F D A -a p pr o ve d I D H 1 a n d I D H 2 
i n hi bit ors a n d t heir i nci de nces.   
D ue t o li mite d h u ma n e x p os ur e, 
n o a d verse dr u g reacti o ns of 
H M P L -3 0 6 ha ve bee n i de ntifi e d 
as of I n vesti gat or Br oc h ure (I B) 
versi o n 3 .  T a ble 3, w hic h 
c o ntai ne d t he oretical effects of 
H M P L -3 0 6, is s u bj ect t o c ha n ge 
a n d/ or bec o me o ut date d a n n uall y 
base d o n u p date d h u ma n 
e x perie nce .  T he secti o n has bee n 
u p date d t o pr o vi de a hi g h -le vel 
s u m mar y of be nefits a n d ris ks 
ass ociate d wit h a p pr o ve d I D H 
i n hi bit ors, w hile referri n g t he 
rea der t o t he I B f or a d diti o nal 
i nf or mati o n. 
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 3 3  
 
C O N FI D E N TI A L  
 
 
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  
S u m mar y la n g ua ge was m o ve d t o t he 
e n d of t he secti o n a n d a refere nce t o t he 
I B f or t he m ost u p date d cli nic al data 
was a d de d .   
Secti o n 4. 2. 2 –  Rati o nale f or 
St u d y P o p ulati o n Selecti o n  
Secti o n 4. 2. 2. 1 –  C o h ort A: 
Rela pse d/ Refract or y Ac ute 
M yel oi d Le u ke mia  
Secti o n 4. 2. 2. 2 –  C o h ort B: 
Rela pse d/ Refract or y Hi g h -Ris k 
M ylel o d ys platic 
S y n dr o me/ M yel o pr oliferati ve 
Ne o plas m  
Secti o n 4. 2. 2. 3 –  C o h ort C: 
Rela pse d or Refract or y 
A n gi o -I m m u n o blastic T-Cell 
L y m p h o ma  
La n g ua ge was a d de d t o Secti o n 4. 2. 2 t o 
i ntr o d uce s u bsecti o ns 4. 2. 2. 1, 4. 2. 2. 2, 
a n d 4. 2. 2. 3 .   
Secti o ns 4. 2. 2. 1, 4. 2. 2. 2, a n d 4. 2. 2. 3 
were a d de d t o disc uss e nr oll me nt of 
C o h orts A, B, a n d C, res pecti vel y .   
La n g ua ge a d de d per Healt h 
A ut h orit y  re q uest.   
Secti o n 5. 2 –  I ncl usi o n Criteri a, 
Criteri o n # 1 0  
Criteri o n # 1 0 c o ntrace pti o n la n g ua ge 
was u p date d t o i n dicate t hat 
a p pr o priate c o ntrace pti o n practices 
s h o ul d be use d f or 3 0 da ys aft er t he last 
d ose of st u d y dr u g i nstea d of 1 8 0 da ys.  
La n g ua ge f o r descri bi n g t he use of 
h or m o nal c o ntrace pti o n was u p date d t o 
f urt her s pecif y t he ki n ds of 
c o ntrace pti o n a n d met h o ds of 
a d mi nistrati o n .  S pecifie d t hat t hese 
h or m o nal f or ms of c o ntrace pti o n 
s h o ul d be use d i n c o m bi nati o n wit h a 
barrier met h o d as H M P L -3 0 5 ma y 
re d uce t heir effecti ve ness.   
T o ali g n wit h Cli nical Trials 
Facilitati o n Gr o u p ( C T F G) 
re q uire me nts relate d t o t he 
acce pta ble c o ntrace pti ve met h o ds 
f or males a n d fe males of 
c hil d beari n g p ote ntial, a n d t he 
d urati o n of c o ntrace pti o n f or 
I M Ps wit h 
 
 base d o n data i n t he 
I M Ps I B. 
Secti o n 6. 2. 1. 1 –  P er ma ne nt 
Disc o nti n uati o n of Treat me nt  
Re vise d la n g ua ge f or patie nts t hat 
c o ul d be disc o nti n ue d fr o m tre at me nt 
fr o m “ P atie nts c o ul d be 
disc o nti n ue d …” t o “ P atie nts m ust be 
disc o nti n ue d.”  
L a n g ua ge u p date d per Healt h 
A ut h orit y re q uest .   
Secti o n 7. 4. 3 –  Dr u g -Dr u g 
I nteracti o ns 
La n g ua ge was u p date d t o i ncl u de 
 
.  La n g ua ge was re m o ve d 
s u g gesti n g H M P L-3 0 6 ma y  
 
   
La n g ua ge u p date d f or 
c o nsiste nc y a n d clarit y .   
Secti o n 8. 6. 7 –  Pre g na nc y  
U p date d d urati o n of c o ntrace pti o n 
( 1 0 0 da ys t o 3 0 da ys) a n d pre g na nc y 
re p orti n g base d o n t he res ults of n o n-
cli nical st u dies i n t he H M P L -3 0 6 I B, 
i ncl u di n g ge n ot o xicit y, e m br y ofetal 
de vel o p me nt, fertilit y, a n d e m br y o nic 
de vel o p me nt .   
T o ali g n wit h C T F G 
re q uire me nts relate d t o t he 
acce pta ble c o ntrace pti ve met h o ds 
f or males a n d fe males of 
c hil d beari n g p ote ntial, a n d t he 
d urati o n of c o ntrace pti o n f or 
I M Ps wit h 
 
l base d o n data i n t he 
I M Ps I B. 
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Section Number 
Summary of Change 
Rationale for Change 
Section 8.7 – Duration of 
Follow-up for Adverse Events 
Language was updated to clarify that 
all pregnancies that occur during study 
participation should be followed to 
determine their outcome. 
Language was updated for 
clarity.   
Appendix 2 – 
PK/PD/BIOMARKER/ECG 
ASSESSMENTS FOR 
EXPANSION COHORTS 
Footnote 4 was added to C2D1 under 
Blood and Bone Marrow Samples for 
Gene Mutation Analysis.   
This was added for accuracy and 
clarity.   
Appendix 9 – 2015 IWG 
CRITERIA FOR 
MEASUREMENT OF 
TREATMENT RESPONSE IN 
ADULT MDS/MPN 
Footnote was updated to reference the 
MPN-SAF TSS tool. 
Language was updated as the 
MPN-SAF TSS is a validated 
tool.   
Amendment 2 (30 August 2021) 
Section Number 
Summary of Change 
Rationale for Change 
Section 2.3.2 – Benefit 
Assessment 
Added information from currently 
available published data and a 
reference to the National 
Comprehensive Cancer Network 
(NCCN) and European Society for 
Medical Oncology (ESMO) treatment 
guidelines to support the current 
eligibility criteria for each cohort in 
this study. 
Request by Health Authority 
Section 5.1.1.2 – Screening 
Period 
Moved the statement, “If there is 
dosing on assessment day, all 
assessment examinations must be 
completed before study drug 
administration, except for 12-lead 
electrocardiogram (ECG), 
ECHO/MUGA scan, ophthalmologic 
examination” from this section to 
Section 6.1. 
Request by Health Authority 
Section 6.1 – Study Procedures 
Moved the statement, “If there is 
dosing on assessment day, all 
assessment examinations must be 
completed before study drug 
administration, except for 12-lead 
electrocardiogram (ECG), 
ECHO/MUGA scan, ophthalmologic 
examination” from Section 5.1.1.2 to 
this section. 
Request by Health Authority 
Section 5.2 – Inclusion Criteria 
#7 
Removed the following language from 
inclusion criterion #7, “Alternative 
methods of kidney function assessment 
may be reviewed with the Sponsor to 
determine validity and correspondence 
with other standard methods.ˮ 
Request by Health Authority 

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Section Number 
Summary of Change 
Rationale for Change 
Section 5.2 – Exclusion Criteria 
#17, #18, #19 
Added exclusion criteria #17, #18, and 
#19, respectively: 
Subjects with a medical condition, 
physical examination finding, or 
clinical laboratory finding that, in the 
Investigator’s opinion, contraindicates 
the use of an investigational drug or 
that may affect the interpretation of the 
results or renders the patient at high 
risk from treatment complications. 
Subjects with a known hypersensitivity 
to HMPL-306 or to any of its 
excipients. 
Subjects with presence of second 
primary malignant tumors within the 
last 2 years, with the exception of the 
following, if medically controlled: 
basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, 
carcinoma in situ of the cervix, and 
carcinoma in situ of the breast. 
Request by Health Authority 
Section 6.1.10.4 – Blood 
Chemistry 
Revised to add blood glucose as part of 
the safety monitoring tests. 
Request by Health Authority 
Section 6.2.1.1 – Permanent 
Discontinuation of Treatment 
Revised language for subjects that 
would be discontinued from treatment 
from “may be discontinuedˮ to “could 
be discontinuedˮ and added reference 
to Table 9, Table 10, and Table 11. 
Request by Health Authority 
Section 6.2.2 – Study Stopping 
Rules 
 
Revised language to clarify that if the 
study is halted as per Stopping Rules in 
either the dose escalation part or the 
dose expansion part, the study will only 
be restarted after Regulatory Approval 
as per local regulations. 
Request by Health Authority 
Section 11.1.1 – Safety Review 
Committee 
 
In Section 6.2.2, clarified that the 
provided dose stopping rules common 
to both dose escalation and dose 
expansion parts are applicable to 
individual subjects. 
To improve clarity 
Appendix 1 – 
PK/PD/Biomarker/ECG 
Assessments for Escalation 
Cohorts 
Appendix 2 - 
PK/PD/Biomarker/ECG 
Assessments for Expansion 
Cohorts 
Revised to include an ECG at screening 
in order to confirm eligibility. 
Request by Health Authority 
Revised to include blood and bone 
marrow samples for gene mutation 
analysis at cycle 2 day 1 (C2D1). 
Updated table title to include 
PK/PD/Biomarker/ECG assessments 
for escalation and expansion cohorts 
To improve clarity 
 
Updated footnote 1 to add “Pre-dose 
bone marrow sample collection should 
be performed within 24 hours prior to 
A 24-hour pre-dose window was 
added to provide sufficient 
flexibility in the clinic to 

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Section Number 
Summary of Change 
Rationale for Change 
dosing” and to clarify that sample 
collected 30 minutes before dosing is 
blood sample 
schedule and perform a bone 
marrow biopsy 
Section 5.2 – Inclusion Criteria 
#2 
Updated inclusion criteria #2 to add the 
following: 
Part 1 Inclusion Criterion #2c: 
Subjects who have received prior IDH 
inhibitor treatment may be enrolled in 
the escalation phase of the protocol. 
 
 
To clarify the inclusion criteria 
that patients who received prior 
IDH therapy are allowed for Part 
1 (dose escalation phase) if they 
do not have other viable 
treatment option.   
 
Part 2 Inclusion Criterion #2d: 
Subjects must not have progressed on 
prior IDH treatment unless isoform 
switching of the IDH mutation has 
been documented following 
progression on the prior IDH inhibitor. 
To exclude patients with 
progression on prior IDH therapy 
in Part 2 unless there is a valid 
clinical rationale.   
Section 5.2 – Inclusion Criteria 
#9 
Section 6.1.10.9 – Pregnancy Test 
Section 6.1.19 – Follow-up 
Period 
Updated definition of postmenopausal 
to “at least 12 months of amenorrhea 
without alternative medical cause.” 
To align with the Clinical Trial 
Facilitation Group (CTFG) 
definition 
Section 2.3.1 – Benefit-Risk 
Assessment, Table 3 
Section 5.2 – Inclusion Criteria 
#10 
Updated to clarify that “male subjects 
with partners of childbearing potential 
must agree to use a condomˮ and will 
be included in the study only if they 
agree to “use a condom”. 
To improve clarity 
Section 2.2.3 – Supportive 
Clinical Data 
Updated to provide current status of the 
ongoing phase 1 study NCT04272957 
as of 03 August 2021. 
To provide updated information 
Section 3 – Objectives and 
Endpoints, Table 4 
Updated to include “deaths” within 
safety primary endpoints for Part 1 and 
2 of the study, to be consistent with 
existing synopsis text. 
For correction. 
Section 6.1.14 – Efficacy 
Evaluation 
Revised to add imaging as part of the 
response evaluation 
Added language for completion of 
baseline tumor assessment during the 
screening period 
Added additional details defining the 
time points, imaging procedures, and 
laboratory tests for measurable and 
evaluable lesions throughout the study. 
Added details for assessment of 
myeloid malignancies using blood test, 
bone marrow aspiration and/or biopsy, 
and physical examination. 
Added details for assessment of 
hematological malignancies that are 
To improve clarity 

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Section Number 
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Rationale for Change 
non-myeloid (eg, AITL), using contrast 
enhanced CT scans (neck, chest, 
abdomen, and pelvis) and/or PET-CT 
scans.  Enhanced magnetic resonance 
imaging (MRI) may be used instead of 
CT scans in patients for whom CT 
scans are contraindicated. 
Revised to state that efficacy 
evaluation of AITL will be performed 
based on Lugano Classification 
(Cheson 2014) for Hodgkin and 
Non-Hodgkin’s Lymphoma and not the 
2007 IWG criteria. 
To provide updated information 
Appendix 10 – Lugano Response 
Criteria for Hodgkin and Non-
Hodgkin’s Lymphoma 
Replaced Appendix 10 with the 
Lugano Classification (previously 2007 
IWG Response). 
To provide updated information 
Section 6.2.1.1 –.Permanent 
Discontinuation of Treatment 
Updated reference from 2007 IWG 
Response for patients with AITL to the 
Lugano Classification. 
To provide updated information 
Section 8.5 – Causality 
Assessment 
Updated general guidelines for 
causality assessments. 
To align with the Sponsor’s 
protocol template 
Section 8.6.9 – Death  
Updated guidelines for reporting all 
deaths that occur during protocol-
specified AE reporting period. 
To align with the Sponsor’s 
protocol template 
Section 8.6.3 – Persistent or 
Recurrent Adverse Events  
Clarified that all recurrent AEs should 
be recorded in the CRF “as separate 
events”, respectively. 
To improve clarity 
Section 1.3 – Schedule of Events 
Table 1 (Dose Escalation) and 
Table 2 (Dose Expansion) 
Added tumor evaluation/imaging at the 
screening period time points for Part 1 
(dose escalation) and Part 2 (dose 
expansion). 
Added ECHO/MUGA scan at the cycle 
1 day 1 (C1D1) time points for Part 1 
(dose escalation) and Part 2 (dose 
expansion). 
To improve clarity 
Section 1.3 – Schedule of Events 
Table 1 (Dose Escalation) 
Updated footnote a, to clarify that the 
analysis of serial blood samples 
collected from Days 1 to 7 of the PK 
week will include “other biological 
markers as defined by the Sponsor.ˮ 
To improve clarity 
Section 4.1.1 – Part 1 (Dose 
Escalation) 
Defined the PK week as “7 days prior 
to cycle 1 day 1 (C1D1) during which a 
single dose of HMPL-306 will be 
administered on day 1 of PK week (day 
-7 relative to C1D1).ˮ 
Updated to clarify that the analysis of 
serial blood samples collected from 
Days 1 to 7 of the PK week will 
include “other biological markers as 
defined by the Sponsor.ˮ 
To improve clarity 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 3 8  
 
C O N FI D E N TI A L  
 
 
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  
Secti o n 5. 1. 1. 2 –  Scree ni n g 
P eri o d  
Re vise d defi niti o n of scree ni n g peri o d 
t o i n dicate t hat the peri o d be gi ns at t he 
ti me of mai n st u d y c o nse nt u ntil t he 
first d ose of H M P L-3 0 6 ( pre vi o usl y, 
t he peri o d was defi ne d t o be gi n at “first 
scree ni n g visit t o bef ore t he first d ose 
of H M P L -3 0 6.”)  
T o i m pr o ve clarit y  
Secti o n 1 0. 3 –  I nf or me d C o ns e nt 
Clarifie d  t hat i n vesti gat ors or desi g nees 
w h o o btai n t he si g ne d I C F m ust be 
“ q ualifie d b y e d ucati o n, trai ni n g, a n d 
e x perie nce t o c o m pl y wit h G C P a n d 
a p plica ble re g ulat or y re q uire me nts”  
T o c o m pl y wit h data pri vac y 
re g ulati o ns/ g ui da nce 
Secti o n 1 0. 4 –  Data Pri vac y  
A d de d t he f oll o wi n g clarificati o n: “ T he 
i n vesti gat or a n d t he s p o ns or or its 
desi g nee are res p o nsi ble f or e ns uri n g 
t hat se nsiti ve i nf or mati o n, tra nsfer of 
data/researc h sa m ples, a n d st ora ge of 
bi ol o gical material retai ne d f or f ut ure 
researc h is ha n dle d i n acc or da nce wit h 
l ocal re q uire me nts.” 
T o c o m pl y wit h data pri vac y 
re g ulati o ns/ g ui da nce 
A p pe n di x 4 –  C O VI D -1 9 Ris k 
Assess me nt  
A d de d a secti o n f or g ui da nce o n 
a d mi nistrati o n of C O VI D -1 9 vacci nes 
f or patie nts partici pati n g i n t he st u d y.   
T o pr o vi de u p date d g u i da nce 
A p pe n di x 7 –  
 
I n hi bit ors/I n d ucers 
Se veral 
 
i n hi bit ors/i n d ucers were delet e d fr o m 
A p pe n di x 7 list, a n d 3  
 
i n hi bit or were a d de d. 
List was re vise d base d o n cli nical 
rele va nce.   
A p pe n di x 8 –  2 0 1 7 E ur o pea n 
Le u ke mia Net E fficac y Criteri a 
f or A M L 
•  
F or treat me nt res p o nse C R a n d 
M L F S, c ha n ge d criteria “ N o 
e xtrat hecal lesi o n” t o “ N o 
e xtra me d ullar y lesi o n”.  
•  
Re vise d criteri o n t o i ncl u de 
C R M R D - f or treat me nt res p o nse S D, 
as f oll o ws: “ Fails t o meet criteria 
f or C R, C Ri, C RM R D -, M L F S, P R, 
or pr o gressi ve disease”  
T o ali g n wit h t he 2 0 1 7 E ur o pea n 
Le u ke mia Net ( E L N) 
rec o m me n dati o ns. 
D oc u me nt Hist or y  
U p date d ta ble t o delete u na p pr o ve d 
versi o ns fr o m t he d oc u me nt hist or y.  
T his deleti o n is t o i m pr o ve clarit y 
a n d ali g n wit h t he S p o ns or’s 
a p pr o ve d te m plate si nce t he 
versi o n n u m beri n g is f or t he 
S p o ns or’s d oc u me nt trac ki n g 
p ur p oses o nl y.  
A p pe n di x 1 3 - A me n d me nt 
Hist or y ( Ne w A p pe n di x)  
A d de d s u m mar y of A me n d me nt 1 
c ha n ges t o A me n d me nt Hist or y  
C o nsiste nc y wit h S p o ns or’s 
pr ocess a n d te m plate  
 
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Amendment 1 (20 October 2020) 
Section Number 
Summary of Change 
Rationale for Change 
Section 5.2 - Inclusion Criteria 
#2 
Table 4 Objectives and 
Corresponding Endpoints 
Section 4.1 - Study Design 
Added additional details in the inclusion criteria 
regarding definition of “advanced” and “locally 
advanced.”  
Specified that subjects in the dose escalation 
portion must be refractory to or intolerant of 
established therapies known to provide clinical 
benefit.  Specified that subjects in the dose 
expansion portion must have received at least 
2 prior lines of therapy for their hematological 
malignancy.  Specified that subjects with MDS 
must be considered high or very high risk by 
IPSS-R. 
Clarification and addition in 
response to request by FDA 
Section 4.1.1 - Part 1 (Dose 
Escalation) 
Table 6 mTPI-2 Decision 
Table for Dose Selection 
Revised text to end the study if DLT is observed 
in 1 of 3 subjects at the initial dose and included 
guidance on next steps if this occurs.  Also 
moved this text to Section 6.2.2.2. 
Updated the mTPI-2 table to include at DLT rate 
of 20% with an equivalence interval of 15% to 
25%. 
Request by FDA 
Section 8.1.3 - Dose-Limiting 
Toxicity 
Revised the DLT criteria to add the following: 
• Any Grade ≥4 nonhematologic toxicity 
• Any Grade ≥3 nonhematologic toxicity 
unless they resolve within 72 hours of onset 
• Grade 3 or 4 neutropenia lasting more than 
7 days 
• Confirmed cases of Hy’s law 
For hematologic toxicities, neutropenia or 
thrombocytopenia that occurs with active 
leukemia may be excluded. 
Request by FDA 
Section 6.2.2.2 - Stopping 
Rules for a Cohort or the 
Study 
Table 8 Bayesian Continuous 
Safety Monitoring Boundaries 
for n=15 (added) 
Added formal rules for the dose expansion 
portion with Bayesian Continuous Safety 
Monitoring boundaries specifying that accrual in 
each respective cohort will be paused if the 
number of DLTs exceeds the threshold boundary 
and next steps will be determined based on SRC 
recommendations.  The continuous safety 
monitoring rules have been revised based on a 
20% DLT rate. 
Request by FDA 
Section 4.1.1 - Part 1 (Dose 
Escalation) 
Section 4.1.2 - Part 2 (Dose 
Expansion) 
Section 1.1 - Synopsis 
Removed language allowing investigator 
discretion in decisions allowing patients to 
continue or discontinue treatment based on 
investigator judgment of whether or not subjects 
are benefiting from treatment. 
Request by FDA 
Section 5.2 - Inclusion Criteria 
#7  
Revised inclusion criterion for creatinine 
clearance to ≥60 mL/min for both dose 
escalation and dose expansion. 
Request by FDA 

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 4 0  
 
C O N FI D E N TI A L  
 
 
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  
Secti o n 5. 2 - I ncl usi o n Criteri a 
# 5  
Re vise d te xt t o s pecif y t hat AI T L s u bj ects m ust 
ha ve a platelet c o u nt ≥2 0, 0 0 0/ µ L f or eli gi bilit y; 
h o we ver, platelet tra nsf usi o ns are per mitte d t o 
reac h t his le vel. 
Re q uest b y F D A  
Secti o n 7. 4. 2 - P er mitte d 
T hera pies  
A d de d a li n k t o t he treat me nt of differe ntiati o n 
s y n dr o me.   
R e q uest b y F D A  
Secti o n 7. 4. 3 - Dr u g -Dr u g 
I nteracti o ns 
A d de d te xt t o s pecif y cl ose a n d fre q ue nt 
m o nit ori n g of a d verse e ve nts wit h c o nc o mita nt 
use of a n y me dicati o n t hat is a s u bstrate of 
 a n d has a narr o w t hera pe utic i n de x. 
Re q uest b y F D A  
Secti o n 7. 5. 1 A dj ust me nt of 
D ose wit hi n t he D L T 
Assess me nt Wi n d o w  
Re vise d t o eli mi nate t he o pti o n t o restart st u d y 
dr u g after Gra de  4 e ve nts . 
Delete d te xt all o wi n g s u bj ects t o c o nti n ue 
treat me nt if a n A E d oes n ot meet t he D L T 
criteria or is a Gra de 3 or 4 n o n -D L T .   
Re q uest b y F D A  
Secti o n 7. 5. 2 - D ose 
A dj ust me nt O utsi de t he D L T 
Assess me nt Wi n d o w 
(I ncl u di n g D ose E x pa nsi o n 
P art)  
T a ble 9  D ose A dj ust me nt f or 
He mat ol o gic T o xicit y (a d de d)  
T a ble 1 0 D ose A dj ust me nt f or 
N o n he mat ol o gic T o xicit y 
(a d de d) 
Re vise d t he g ui da nce f or d ose a dj ust me nt f or 
he mat ol o gic a n d n o n he mat ol o gic t o xicit y 
o utsi de t he D L T assess me nt wi n d o w wit h 
a d diti o n of ne w ta bles f or d ose a dj ust me nt.  
Re q uest b y F D A  
Secti o n  7. 5. 3 - I ntra-D ose 
Escalati o n ( delete d secti o n)  
Delete d pr o visi o n f or all o wi n g i ntra -s u bj ect 
d ose escalati o n.  
R e q uest b y F D A  
Secti o n 7. 6. 1 - Differe ntiati o n 
S y n dr o me Ha n dli n g Pri nci ples  
A d de d te xt stati n g t he f oll o wi n g: 
•  He m o d y na mic m o nit ori n g will als o be 
perf or me d wit h de xa met has o ne 
a d mi nistrati o n.  
•  H M P L -3 0 6 will be i nterr u pte d i n t he e ve nt of 
se vere p ul m o nar y s y m pt o ms or re nal 
d ysf u ncti o n.  
Re vise d c o n diti o n u n der w hic h H M P L -3 0 6 ma y 
res u me t o s pecif y res u m pti o n will occ ur after 
s y m pt o ms i m pr o ve t o Gra de 2 or l o wer.  
R e q uest b y F D A  
Secti o n 7. 6. 2 - Ha n dli n g 
Pri nci ples f or N o ni nfecti o us 
Le u k oc yt osis (re vise d 
hea di n g)  
•  Defi ne d n o ni nfecti o us le u k oc yt osis as W B C 
> 2 5 × 1 0 9/ L or a n a bs ol ute i ncr ease i n t otal 
W B C of > 1 5 ×  1 0 9/ L fr o m bas eli ne. 
•  S pecifie d t hat res u mi n g st u d y dr u g W B C 
c o u nt s h o ul d be < 3 0 ×  1 0 9/ L i n a d diti o n t o 
res ol uti o n of cli nical feat ures of 
differe ntiati o n s y n dr o me.  
Re q uest b y F D A  
C CI

Cli nic al St u d y Pr ot oc ol 2 0 2 0 -3 0 6 -G L O B 1  
H M P L -3 0 6  
A me n d me nt 5  
 
 
H U T C H M E D Li mit e d 
 
P a g e 1 4 1  
 
C O N FI D E N TI A L  
 
 
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  
Secti o n 7. 6. 2 - Ha n dli n g 
Pri nci ples f or N o ni nfecti o us 
Le u k oc yt osis (re vise d 
h ea di n g)  
Re vise d h y dr o x y urea oral t hera p y i nstr ucti o ns t o 
ali g n wit h i nstit uti o nal sta n dar ds .   
Clarificati o n  
Secti o n 7. 5. 3 - D ose 
A dj ust me nt f or Q T I nter val 
Pr ol o n gati o n (secti o n a d de d)  
T a ble 1 1  D ose A dj ust me nt f or 
Q T I nter val Pr ol o n gati o n 
(ta ble a d de d) 
A d de d g ui da nce f or d ose a dj ust me nt f or Q T 
i nter val pr ol o n gati o n. 
R e q uest b y F D A  
Secti o n 6. 1. 1 0. 4 - Bl o o d 
C he mistr y  
A d de d uric aci d t o list of bl o o d c he mistr y tests.  
R e q uest b y F D A  
Secti o n 6. 1. 9 - 
O p ht hal m ol o gic E xa mi nati o n  
A d de d O C T t o list of o p ht hal mic  e xa mi nati o ns.  
S pecifie d d ose a dj ust me nts re q uire d if R P E 
detac h me nt is n ote d.  
Re q uest b y F D A  
A p pe n di x 1
 
P K/ P D/ Bi o mar ker/ E C G 
Assess me nts f or Escalati o n 
C o h orts  
A p pe n di x 2
 
P K/ P D/ Bi o mar ker/ E C G 
Assess me nts f or E x pa nsi o n 
C o h orts  
Secti o n 4. 2. 3 - Rati o nale f or 
Bi o mar ker T esti n g  
A d de d m utati o nal a nal ysis f or  
.  
Re q uest b y F D A  
Secti o n 6. 2. 1. 1 - P er ma ne nt 
Disc o nti n uati o n of Treat me nt  
Re vise d c o n diti o ns f or per ma ne nt 
disc o nti n uati o n of treat me nt t o s pecif y t hat all 
patie nts ma y recei ve a ma xi m u m of 6 treat me nt  
c ycles.  Defi ne d c o n diti o ns u n der w hic h patie nts 
ma y n ot recei ve t he ma xi m u m n u m ber of 
treat me nt c ycles. 
Re q uest b y F D A  
Secti o n 7. 5. 2 - D ose 
A dj ust me nt O utsi de t he D L T 
Assess me nt Wi n d o w 
(I ncl u di n g D ose E x pa nsi o n 
P art)  
S pecifie d t hat d ose a dj ust me nts are t o be ma de 
f or a n y a d verse e ve nt dee me d at least p ossi bl y 
relate d t o H M P L-3 0 6 . 
Re q uest b y F D A  
Secti o n 7. 5. 3 - D ose 
A dj ust me nt f or Q T I nter val 
Pr ol o n gati o n  
T a ble 1 1 D ose A dj ust me nt f or 
Q T I nter val Pr ol o n gati o n  
M o difie d t he d ose a dj ust me nt f or Q T c 
pr ol o n gat i o n base d o n t he U S PI f or i v osi de ni b. 
Re q uest b y F D A  
Secti o n 4. 2. 2 - Rati o nale f or 
St u d y P o p ulati o n Selecti o n  
A d de d te xt a n d refere nces t o clarif y rati o nale f or 
use of H M P L -3 0 6 f or treat me nt of M D S, M P N, 
a n d AI T L. 
S u g gesti o n b y F D A  
C CI

Clinical Study Protocol 2020-306-GLOB1 
HMPL-306 
Amendment 5 
 
 
HUTCHMED Limited 
 
Page 142 
 
CONFIDENTIAL 
 
 
Section Number 
Summary of Change 
Rationale for Change 
Table 3 Summary of Potential 
Risks of HMPL-306 
Changed frequency of WBC monitoring from 
weekly in Cycle 2 to every other week in 
Cycle 2. 
Removed text “medication” from “patient 
medication guide.” 
To align with the schedule 
of events 
To align with operational 
conduct of the trial 
Appendix 4 COVID-19 Risk 
Assessment 
Remove text “#5.” 
Correct discrepancy with 
exclusion criterion # 
Section 4.1 - Study Design 
Removed specification that patients need to be 
refractory to 2 prior lines of therapy to qualify 
for enrollment. 
This text only applies to the 
dose expansion. 
 

Si g nat ure Pa ge f or V V- C LI N- 0 1 2 2 7 4 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 2 2 7 4 v 1. 0
A p pr o val Tas k
0 6- N o v- 2 0 2 3 2 3: 0 7: 5 0 G M T + 0 0 0 0
P P D