A Phase 1b Study of ARQ 751 as a Single Agent or in Combination With Other Anti-cancer Agents in Adult Subjects With Advanced Solid Tumors With PIK3CA / AKT / PTEN Mutations
Phase: PHASE1
Conditions: Cancer, Solid Tumors
Sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

Offici al Pr ot oc ol Title:  
N C T n u m ber:  
D oc u me nt D ate:  
A P hase 1 b St u d y of A R Q 7 5 1 as a Si n gle A ge nt or i n 
C o m bi nati o n wit h Ot her A nti-ca ncer A ge nts i n A d ult 
S u bjects wit h A d va nce d S oli d T u m ors wit h PI K 3 C A/ A K T/
P T E N M utati o ns
0 9 A pril 2 0 1 9
N C T 0 2 7 6 1 6 9 4

0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1  of 1 1 7  
 
 
 
Title:  
A P hase 1 b  St u d y  of A R Q 7 5 1 as a Si n gle A ge nt or i n 
C o m bi nati o n wit h Ot her A nti -ca ncer A ge nts i n A d ult S u bjects 
wit h A d va nce d S oli d T u m ors wit h PI K 3 C A/ A K T/ P T E N 
M utati o ns  
Pr ot oc ol N u m ber:  
A R Q 7 5 1 -1 0 1  
St u d y Dr u g : 
A R Q 7 5 1  
IN D N u m ber:  
1 2 7 8 9 9  
S p o ns or:  
Ar Q ule, I nc.  
O ne Wall Street  
B urli n gt o n, M A 0 1 8 0 3  
Tele p h o ne: 
 
Fa x: 
 
Me dic al M o nit or:  
 
S afet y F a x : 
N ort h A merica: 
 
D ate of Pr ot oc ol : 
Ori gi nal: 1 0 N o ve m ber 2 0 1 5  
A me n d me nt  1: 1 2  Ja n uar y 2 0 1 6 
A me n d me nt 2: 2 9 Marc h  2 0 1 7  
A me n d me nt 3: 2 8  J u ne 2 0 1 7  
A me n d me nt 4: 0 5 Ja n uar y 2 0 1 8  
A me n d me nt 5: 1 6 Ma y  2 0 1 8  
A me n d me nt 6: 1 8  Dece m ber 2 0 1 8  
A me n d me nt 7: 0 9  A pril  2 0 1 9  
 
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt i s c o nfi de ntial a n d t he pr o prietar y pr o pert y of 
Ar Q ule, I nc.  A n y u na ut h orize d use or discl os ure of s uc h i nf or mati o n wit h o ut t he pri or 
writte n a ut h orizati o n of Ar Q ule, I nc. is pr o hi bite d.   
P P D
P P D
P P D
P P D
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Ar Q ule, I nc.  
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C RI TI C A L S T U D Y C O N T A C T LI S T  
St u d y Pri nci pal I n vesti gat or  
S h u b ha m Pa nt, M. D.  
T he U ni versit y of Te xas  
M D A n ders o n Ca ncer Ce nter  
H o ust o n , T X, U S A  
Me dical M o nit or  
 
Me dical Direct or, Cli nical De vel o p me nt   
Ar Q ule, I nc.  
O ne Wall Street  
B urli n gt o n, M A , U S A 
 
 
P P D
0 7 Y 3 G R

Ar Q ule, I nc. 
5. 3 Pr ot oc ol or A me n d me nt 
A R Q 7 5 1- 1 0 1 
1 6. 1. 1 Pr ot oc ol A me n d me nt 7 
 
0 9 A pril 2 0 1 9  
C o nfi de ntial  
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S Y N O P SI S 
St u d y Title: 
A P hase 1 b St u d y of A R Q 7 5 1 as a Si n gle A ge nt or i n 
C o m bi nati o n wit h Ot her A n ti-ca ncer A ge nts i n A d ult 
S u bjects wit h A d va nce d S oli d T u m ors wit h 
PI K 3 C A/ A K T/ P T E N  M utati o ns 
St u d y N u m ber: 
A R Q 7 5 1- 1 0 1 
St u d y P h ase:  
1 b 
R ati o n ale f or t he St u d y 
M ulti ple  ge netic  alterati o ns  i n  t he  p h os p hati d yli n osit ol- 3-
ki nase  ( PI 3 K )/  v- A kt  m uri ne  t h y m o ma  viral  o nc o ge ne 
h o m ol o g  ( A K T )/  ma m malia n  tar get  of  ra pa m yci n  (m T O R ) 
si g nali n g pat h wa y ha ve bee n i de ntifie d i n s oli d t u m ors a n d 
he mat ol o gic  mali g na ncies.  U n der  n or mal  c o n diti o n,  PI 3 K 
pat h wa y  re g ulates  cell  gr o wt h, s ur vi val,  a n d  pr oliferati o n 
wit h PI 3 K  a n d te nsi n h o m ol o g (P T E N ) bei n g p ositi ve a n d 
ne gati ve  re g ulat ors  of  PI 3 K  pat h wa y,  res pecti vel y.  B ot h 
ge nes de pe n d o n A K T si g nali n g. T h us, A K T  is a n attracti ve 
tar get  f or  dr u g  de vel o p me nt.  C urre ntl y,  a  n u m ber  of 
i n hi bit ors,  tar geti n g  ke y  n o des  of  t his  pat h wa y,  i ncl u di n g 
A K T  i n hi bit ors,  are  i n  vari o us  sta ges  of  cli nical 
de vel o p me nt.  
 
I n  ge neral, s o me  cli nical  acti vit y wit h  tar gete d  a ge nts  has 
bee n  re p orte d  i n  m o n ot hera p y  trials,  h o we ver,  t he 
c o m bi nati o n t hera p y of dr u gs wit h differe nt mec ha nis m of 
acti o n has s h o w n m ore pr o misi n g cli nical o utc o mes, s uc h as 
i m pr o ve me nt  o n  efficac y  a n d  o verc o mi n g  resista nce  or 
rec urre nce.  T h us,  c o m bi nati o n  of  PI 3 K/ A K T  pat h wa y 
i n hi bit ors  wit h  ot her  a nti-ca ncer  a ge nts  (e. g.,  c yt ot o xic, 
e n d ocri ne, or ot her tar gete d a ge nts) ma y e n ha nce t he gr o wt h 
i n hi biti o n  effect  of  a  si n gle  a ge nt,  all o w  t o  o verc o me 
resista nce  t o  a  si n gle  a ge nt  t hera p y,  rest ore  se nsiti vit y  t o 
c he m ot hera p y or tar gete d/e n d oc ri ne t hera p y, a n d t heref ore 
aff or d  a  d ura ble  res p o nse,  partic ularl y  i n  t u m ors  wit h 
PI K 3 C A/ A K T/ P T E N  ge netic alterati o ns. 
 
T his st u d y c o nsists of t w o part s; Part 1, t hat was ori gi nall y 
desi g ne d as a d ose escalati o n a n d e x pa nsi o n st u d y of A R Q 
7 5 1 as a si n gle a ge nt, a n d Part 2,t hat is desi g ne d pri maril y 
t o deter mi ne rec o m me n de d p hase 2 d ose ( R P 2 D) of A R Q 
7 5 1 i n c o m bi nati o n wit h ot her a nti-ca ncer a ge nts.   
 
Ori gi nall y, t he A R Q 7 5 1- 1 0 1 st u d y was na me d “ A P hase 1 
D ose Escalati o n St u d y  of A R Q 7 5 1 i n A d ult S u bjects wit h 
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Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
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A d va nce d S oli d 
T u m ors 
wit h 
A K T 1, 2, 3 
Ge n etic 
Alterati o ns, Acti vati n g PI 3 K M utati o ns  or P T E N -n ull ” a n d 
was i nitiate d as a  si n gle a ge nt d ose -escalati o n , safet y, a n d 
t olera bilit y trial. S u bse q ue ntl y, t his st u d y was a me n de d t o 
als o i ncl u de s u bjects wit h ot her k n o w n acti o na ble P T E N 
m utati o n s (“A P has e 1 D ose Escalati o n St u d y of A R Q  7 5 1 
i n A d ult S u bjects wit h A d va nce d S oli d T u m ors wit h 
A K T 1, 
2, 
3 
Ge netic 
Alterati o ns, 
Acti vati n g 
PI 3 K 
M utati o ns, P T E N -n ull, or ot her k n o w n acti o na ble P T E N 
m utati o ns ”). 
 
T h e d ose escalati o n c o h orts of A R Q 7 5 1 as a si n gle a ge n t 
were c o m plete d a n d t he R P 2 D of A R Q 7 5 1 as a si n gle 
a ge nt has bee n deter mi ne d t o be 7 5 m g Q D . T o f urt her 
e val uate safet y a n d t olera bilit y, a n d t o assess preli mi nar y 
efficac y of A R Q 7 5 1 as a si n gle a ge nt , u p t o 3 0 s u bjects are 
pla n ne d t o be e nr olle d a n d t reate d wit h A R Q 7 5 1 at t he 
R P 2 D le vel i n Ar m A (e x pa nsi o n c o h ort).  It is pla n ne d t o 
e nr oll u p t o 1 5 s u bjects wit h s oli d t u m ors wit h PI K 3 C A or 
P T E N acti o na ble m utati o ns  a n d u p t o 1 5 s u bjects wit h 
A K T ge netic alterati o ns.  
As disc usse d a b o ve,  a si n gle dr u g  ap pr oac h ma y n ot be 
s ufficie nt t o i n hi bit t u m or gr o wt h, a si m ulta ne o us 
i n hi biti o n of t he m ulti ple pat h wa ys ma y be nee de d t o 
ge nerate d ura ble a nti -ne o plastic effect.  Part 2 is desi g ne d 
t o deter mi ne R P 2 D a n d t o assess safet y, t olera bilit y, a n d 
preli mi nar y efficac y of A R Q 7 5 1 i n c o m bi nati o n wit h 
ot her a nti -ca ncer a ge nts. T h us, t he pr ot oc ol has bee n re -
na me d as “ A P hase 1 b St u d y of A R Q 7 5 1 as a Si n gle A ge nt 
or i n C o m bi nati o n wit h Ot her A nti -ca ncer A ge nts i n A d ult 
S u bjects 
wit h 
A d va nce d 
S oli d 
T u m ors 
wit h 
PI K 3 C A/ A K T/ P T E N M utati o ns”  
 
Part 2  c o nsists of  t w o c o m bi nati o n t hera p y ar ms, Ar m B 
( paclita xel) a n d Ar m C  (f ul vestra nt). 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
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St u d y Desi g n a n d Tre at me nt:  
 
A R Q 7 5 1 -1 0 1 is a m ulti -ce nter, o pe n la bel, st u d y of a 
sec o n d-ge nerati o n 
pa n -A K T 
i n hi bit or 
A R Q 
7 5 1 
a d mi nister e d orall y as a si n gle a ge nt or i n c o m bi nati o n wit h 
paclita xel  or  f ul vestra nt i n s u bjects 
wit h a d va nce d, 
i n o pera ble, metastatic a n d/ or rec urre nt s oli d t u m ors  wit h 
PI K 3 C A/ A K T/ P T E N  m utati o ns .  
 
P art 1:  T he d ose escalati o n of A R Q 7 5 1 as si n gle a ge nt is 
c o m plet e d . T h e st u d y was i nitiate d i n A u g ust 2 0 1 6  as a n 
o pe n -la bel, p hase 1, first-i n-h u ma n, d ose escalati o n st u d y. 
Se ve n d ose le vels of A R Q 7 5 1 (fr o m 5 m g Q D t o 1 0 0 m g 
Q D) were e val uate d a n d R P 2 D was deter mi ne d t o be 7 5 m g 
Q D. All e nr olle d s u bjects ha d a d va nce d  o r i n o pera ble s oli d 
t u m ors wit h PI 3 K/ A K T/ P T E N  ge netic alterati o ns .  T we nt y 
t w o of t he 3 4  s u bjects i n si n gle a ge nt d ose escalati o n were 
e val ua ble f or res p o nse, i n t w o s u bjects t he best res p o nse 
was P R ( b ot h wit h H R +/ H E R 2 - breast ca ncer  wit h P T E N 
C 2 9 6fs * 2  an d  PI K 3 C A H 1 0 4 7 R, res pecti vel y), i n ei g ht S D, 
a n d i n t wel ve P D.  A d ura ble sta ble disease of > 4 0 wee ks 
was ac hie ve d i n t w o s u bjects, o ne wit h e n d o metrial ca ncer 
a n d o ne wit h breast ca ncer , wit h A K T 1 E 1 7 K  a n d PI K 3 C A  
m utati o ns, res pecti vel y .   E nr oll me nt is o n g oi n g i n t h e si n gle 
a ge nt d ose e x pa nsi o n  c o h ort ( Ar m A).   S u bjects e nr olle d i n 
Ar m A recei ve A R Q 7 5 1 at 7 5 m g Q D, c o nti n u o usl y. 
 
P art 2  is desi g ne d t o deter mi ne R P 2 D a n d t o assess safet y, 
t olera bilit y, a n d preli mi nar y efficac y of 
A R Q 7 5 1 i n 
c o m bi nati o n w ith paclita xel ( Ar m B) a n d f ul vestra n t ( Ar m 
C).    
 
E nr oll me nt i n eac h ar m will be i nitiate d per S p o ns or 
discreti o n.  T he c h oice of treat me nt Ar m will be ma de at t he 
discreti o n of t he I n vesti gat or, pr o vi de d  t hat t he c o m bi nati o n 
t hera p y 
wit h paclita xel or  f ulve stra nt rat her t ha n a 
m o n ot hera p y ( Ar m A, A R Q 7 5 1)  w o ul d be a p pr o priate f or 
t heir patie nts’ disease.  
De pe n di n g o n t he st u d y safet y a n d efficac y data, t he 
S p o ns or ma y li mit t he n u m ber of s u bjects wit h a s pecific 
t u m or t y pe(s) or PI K 3 C A/ A K T/ P T E N  m utati o n s tat us t o be 
e nr olle d . 
M utati o n stat us m ust be d oc u me nte d pri or t o t he first d ose  
of A R Q 7 5 1 . If t he stat us is u n k n o w n, arc hi val or fres h 
t u m or bi o ps y 
m ust be c ollecte d a n d teste d t o verif y 
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5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
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C o nfi de ntial  
Pa ge 6  of 1 1 7  
 
eli gi bilit y; re dacte d c o pies of all ge netic testi n g re p orts will  
be  collecte d.  
 
T o deter mi ne R P 2 D of A R Q 7 5 1 i n c o m bi nati o n wit h 
paclita xel ( Ar m B) or f ul vest ra nt ( Ar m C), sta n dar d 3 + 3 
d ose fi n di n g desi g n will be use d. Assess me nt of t he safet y 
a n d t olera bilit y of c o m bi nati o n re gi me ns will i ncl u de all 
s u bjects treate d i n Ar m B a n d Ar m C i n de pe n de nt of t he 
A R Q 7 5 1  d ose le vel s u bjects ma y recei ve. A d diti o nal ar ms 
ma y be a d de d t o assess A R Q 7 5 1 i n c o m bi nati o n wit h ot her 
a nti-ca ncer a ge nts.   
 
I n Ar ms B a n d C, d ose deter mi nati o n will be d o ne as 
f oll o ws: 
C o h ort  
A R Q 7 5 1  
( or all y, P O )  
P aclit a xel  
( Ar m B) 
F ul vestr a nt  
( Ar m C) 
-1  
2 5 m g Q D  
8 0 m g/ m 2 (I V)  
Da ys 1, 8, 1 5 
f oll o we d b y a 
wee k of rest  
5 0 0 m g (I M)  
Da ys 1 & 1 5 of 
C ycle 1, a n d Da y 
1 of all 
s u bse q ue nt 
c ycles 
1  
5 0 m g Q D  
2  
7 5 m g Q D  
E x p a nsi o n  
R P 2 D  
D ose escalati o n will pr oce e d t o 7 5 m g Q D, t he d ose t hat was 
defi ne d t o be t he A R Q 7 5 1 R P 2 D as a si n gle a ge nt. O nce 
M T D/ R P 2 D f or eac h c o m bi nati o n t hera p y 
Ar m is 
deter mi ne d,  a p pr o xi matel y 6 -9  s u bjects will be e nr olle d i n 
eac h ar m (e x pa nsi o n c o h ort). I ntra-s u bject d ose escalati o n 
will  be  per mitte d if t he ne xt hi g her d ose of A R Q 7 5 1 f or t hat  
re gi me n is deter mi ne d t o be safe. 
 
A p pr o xi matel y 9 4 s u bjects will be e nr olle d i n t his st u d y at 
4 -1 0  sites i n t he U S A; 6 4 s u bjects i n Part 1 ( D ose escalati o n 
c o h orts a n d Ar m A) a n d 3 0 i n Part 2 ( Ar m B a n d Ar m C). 
T hirt y f o ur s u bjects 
were e nr olle d i n d ose escalati o n 
c o h orts. It is pla n ne d t hat u p t o 3 0 s u bjects wit h a d va nce d, 
i n o pera ble, metastatic, or rec urre nt s oli d t u m ors will be 
e nr olle d i n Ar m A, u p t o 1 5 s u bjects wit h PI K 3 C A/ P T E N 
acti vati n g  m uta ti ons a n d u p t o 1 5 s u bjects wit h A K T ge netic 
alterati o ns. I n Part 2, a p pr o xi matel y 1 5 s u bjects will be 
e nr olle d i n eac h c o m bi nati o n t hera p y ar m ( Ar m B, A R Q 
7 5 1 + paclita xel a n d Ar m C, A R Q 7 5 1 +f ul vestra nt) . 
 
Assess me nt of safet y a n d t olera bilit y of A R Q  7 5 1 as  a 
si n gle a ge nt a n d i n c o m bi nati o n 
wit h paclita xel or  
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Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7  of 1 1 7  
 
f ul vestra nt will be base d o n c o nti n u o us e val uati o n of 
a d verse 
e ve nts, 
p h ysical 
e xa mi nati o n fi n di n g s 
a n d 
la b orat or y tests. All cli nical assess me nts a n d la b orat or y 
tests will be perf or me d acc or di n g t o t he pr ot oc ol -defi ne d 
ti me p oi nts. If cli nicall y i n dicate d, u nsc he d ule d la b orat or y 
tests a n d a n y cli nical assess me nts or e val uati o ns ma y be 
perf or me d per dis creti o n of t he I n vesti gat or.  
T u m or assess me nts ( C T o r 
M RI) 
will be perf or me d 
acc or di n g t o pr ot oc ol -defi n e d ti me p oi nts, or as ot her wise 
cli nicall y i n dicate d. T u m or res p o nse will be e val uate d 
acc or di n g t o R E CI S T 1. 1 g ui deli nes.  
P har mac o ki netic ( P K ) sa m ples will be c ollecte d pre-d ose 
a n d at differe nt ti me p oi nts p ost -d ose as defi ne d i n t he 
pr ot oc ol  ( See A p pe n di x 3 ). A d diti o nal u nsc he d ule d bl o o d 
sa m ple(s) f or P K ma y be c ollecte d o n a n y st u d y da y(s) u p o n 
a gree me nt bet wee n t he I n vesti gat or a n d t he S p o ns or.  T w o  
bas eli ne si n gle bl o o d sa m ples t o deter mi ne  C Y P 2 D 6 
ge n ot y pe a n d PI K 3 C A/ A K T/ P T E N  m utati o n i n circ ulati n g 
t u m or (ct) D N A will be c ollecte d . 
Treat me nt 
will 
c o nti n ue 
u ntil 
disease 
pr o gressi o n, 
u nacce pta ble t o xicit y or ot her treat me nt disc o nti n uati o n 
criteri o n is me t.  
Pri m ar y O bjecti ve:  
P art 1:  
T he pri mar y o bjecti ve is t o assess t he safet y a n d t olera bilit y 
of A R Q  7 5 1 i n s u bjects wit h a d va nce d s oli d t u m ors wit h 
A K T 1, 2, 3 ge netic alterati o ns, acti vati n g PI 3 K m utati o ns, 
P T E N -n ull , or ot her k n o w n acti o na ble P T E N m utati o ns. 
 
P art 2:  
T he pri mar y o bjecti ve is t o assess t he safet y a n d t olera bilit y 
of A R Q 7 5 1  i n c o m bi nati o n wit h paclita xel  or  f ul vestra nt i n 
s u bjects 
wit h a d va nce d, i n o pera ble, 
metastatic a n d/ or 
rec urre nt s oli d t u m ors 
wit h PI K 3 C A / PT E N  acti o na ble 
m utati o ns  a n d/ or A K T ge netic alterati o ns  
Sec o n d ar y O bjecti ves:  
P art 1:  
•  
T o assess t he p har mac o ki netic ( P K) pr ofile of  A R Q 7 5 1  
•  
T o assess t he p har mac o d y na mic acti vit y of A R Q 7 5 1 i n 
bl o o d s peci me ns o btai ne d fr o m s u bjects wit h a d va nce d 
s oli d t u m ors 
wit h 
A K T 1, 2, 3 ge netic alterati o ns, 
acti vati n g PI 3 K m utati o ns, P T E N -n ull, or ot her k n o w n 
acti o na ble P T E N m utati o ns  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8  of 1 1 7  
 
•  
T o deter mi ne  t he 
ma xi m u m t olerate d d ose ( M T D) 
a n d/ or t he rec o m me n de d P hase 2 d os e ( R P 2 D) of 
A R Q  7 5 1  as si n gle a ge nt  
•  
T o ge nerate preli mi nar y e vi de nce of a nti -t u m or acti vit y  
 
P art 2:  
•  
T o  deter mi ne 
M T D/ R P 2 D  d ose  of 
A R Q  7 5 1  i n 
c o m bi nati o n wit h paclita xel  or  f ul vestra nt  
•  
T o a ssess t he P K pr ofile of A R Q 7 5 1 i n c o m bi nati o n 
wit h paclita xel  or  f ul vestra nt  
•  
T o ge nerate preli mi nar y e vi de nce of a nti -t u m or acti vit y 
of 
A R Q 7 5 1 i n c o m bi nati o n 
wit h paclita xel or  
f ul vestra nt i n s u bjects 
wit h a d va nce d, i n o pera ble, 
metastatic 
a n d/ or 
rec urrent 
s oli d 
t u m ors  
wit h  
PI K 3 C A /P T E N  acti o na ble  m utati o ns  a n d/ or 
A K T 
ge netic alterati o ns  
 
St u d y E n d p oi nts:  
P art 1:  
T he pri mar y e n d p oi nt is safet y a n d t olera bilit y a n d is 
meas ure d b y safet y varia bles w hic h i ncl u de t he re p orte d 
A Es, la b orat or y tests, vital si gns, E C O G perf or ma nce stat us, 
a n d p h ysical e xa mi nati o n.  
Sec o n dar y a n d e x pl orat or y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  P har mac o ki netics w hic h are meas ure d b y ma xi m u m 
plas ma dr u g c o nce ntrati o n ( C ma x ), area u n der t he c ur ve 
( A U C), a n d eli mi nati o n half-life (t1/ 2) 
•  P har mac o d y na mic acti vit y  will be e val uate d b y c ha n ges 
i n ser u m gl uc ose a n d i ns uli n le vels, a n d b y c ha n ges i n 
cell-free ct D N A. 
•  R P 2 D will be deter mi ne d f oll o wi n g re vie w of all safet y, 
p har mac o d y na mic 
data  
a n d 
a nti -t u m or 
acti vit y 
ge nerate d i n t he d ose esc alati o n p orti o n of t he st u d y.  
T o get her wit h t he I n vesti gat ors, t he R P 2 D will be set at 
or 
bel o w t he 
M T D a n d at a 
d ose at 
w hic h 
p har mac o d y na mic acti vit y or a nti -t u m or acti vit y is 
de m o nstrate d.   
•  Preli mi nar y e vi de nce of a nti -t u m or acti vit y will be 
e val uate d  b y  R E CI S T v 1. 1 Res p o nse Criteria.  
 
P art 2:  
Pri mar y e n d p oi nt:  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9  of 1 1 7  
 
Safet y a n d t olera bilit y as assesse d b y t he fre q ue nc y, 
d urati o n, a n d se verit y of a d verse e ve nts ( A Es) fr o m t he first 
d ose of st u d y treat me nt t hr o u g h 3 0 da ys after t he last d ose 
of t hera p y.  
Sec o n d ar y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  P har mac o ki netics as meas ure d b y ma xi m u m plas ma 
dr u g(s) c o nce ntrati o n ( C ma x ), ti me t o ma xi m u m plas ma 
dr u g c o nce ntrati o n [ T ma x ], area u n der t he c ur ve ( A U C), 
a n d eli mi nati o n  half -life (t1/ 2) 
•  R P 2 D as deter mi ne d f oll o wi n g re vie w of all safet y  data 
ge nerate d i n t he d ose escalati o n c o h ort(s) f or eac h 
c o m bi nati o n t hera p y Ar m.  T he R P 2 D will be set at or 
bel o w t he M T D.   
•  Preli mi nar y e vi de nce of a nti -t u m or acti vit y as assesse d  
b y R E CI S T v. 1. 1.  
St u d y P o p ul ati o n:  
 
A d ult s u bjects w it h a d va nce d s oli d t u m ors wit h d oc u me nte d 
A K T  ge netic alter ati o ns , PI K 3 C A  or P T E N  acti o na ble 
m utati o ns w h ose ca ncer has pr o gresse d f oll o wi n g sta n dar d 
t hera p y, or f or w h o m sta n dar d t hera p y is n ot a vaila ble or is 
n ot t olera ble will be e nr olle d. . 
T o be e nr ol le d, s u bjects m ust meet all eli gi bilit y criteria. 
I ncl usi o n Criteri a 
1.  Si g ne d 
writte n i nf or me d c o nse nt gra nte d pri or t o 
i nitiati o n of a n y st u d y-s pecific pr oce d ures 
2.  1 8 years of a ge a n d ol der  
3.  Hist ol o gicall y 
a n d/ or 
c yt ol o gicall y 
d oc u me nte d 
dia g n osis of a select e d t u m or t y pe t hat is l ocall y 
a d va nce d, i n o pera ble, metastatic or rec urre nt (i ncl u di n g 
b ut n ot restricte d t o breast ca n cer, T N B C [tri ple 
ne gat i ve]; H R-p os iti ve [ H R +]/ H E R 2-ne g ati ve [ H E R 2-] 
or e n d o metrial ca ncer ) 
4.  D oc u me nte d 
A K T  ge netic 
alterati o ns 
or 
k n o w n 
actio na ble PI K 3 C A /P T E N  m utati o ns b y ge netic testi n g   
•  
s u bjects wit h t u m ors wit h P T E N n ull/ P T E N l oss-of -
f u ncti o n m utati o ns are n ot eli gi ble  
5.  F or Ar ms B  or  C, s u bjects s h o ul d be eli gi ble f or 
paclita xel  or  f ul vestra nt t hera p y as per I n vesti gat or 
assess me nt  
6.  Fail ure  t o res p o n d t o sta n dar d s yste mic t hera p y, or f or 
w h o m sta n dar d or c urati ve  s yste mic t hera p y d oes n ot 
e xist or is n ot t olera ble.  
•  S u bjects  i n Ar m A ( wit h A K T  ge netic alterati o ns) 
a n d s u bjects  i n d ose escalati o n c o h orts of Ar ms B 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0  of 1 1 7  
 
a n d C  s h o ul d ha ve at least one li ne of sta n dar d 
s yste mic t hera p y 
•  S u bjects i n  Ar m A ( wit h PI K 3 C A/ P T E N  acti o na ble 
m utati o ns) a n d s u bjects i n t he e x pa nsi o n c o h orts of 
Ar m s B a n d  C  s h o ul d ha ve n o m ore t ha n 3 pri or 
s yste mic re gi me ns f or t he a d va nce d disease  
•  Ne oa dj u va nt 
a n d 
a dj u va nt 
c hem ot hera p y 
are 
c o nsi dere d o ne re gi me n if t he y are a c o nti n uati o n of 
t he sa me re gi me n wit h i nter val de b ul ki n g s ur ger y 
•  If t he s u bject is refract or y or has disease pr o gressi o n 
wit hi n 6 m o nt hs after c o m pleti o n of t he a dj u va nt 
treat me nt, t he n t he a dj u va nt treat me nt s h o ul d be 
c o nsi dere d as t he li ne of treat me nt rat her t ha n a n 
a dj u va nt t hera p y.  
•  E n d ocri ne ( h or m o nal) t hera p y d oes n ot c o u nt 
t o war d t otal li nes of t hera p y 
•  Mai nte na nce t hera p y is c o nsi dere d part of t he 
prece di n g re gi me n if o ne or m ore of t he sa me dr u gs  
are c o nti n ue d  
7.  Has at least o ne meas ura ble tar get lesi o n acc or di n g t o 
R E CI S T v. 1. 1  
8.  Easter n 
C o o perati ve 
O nc ol o g y 
Gr o u p 
( E C O G) 
perf or ma nce stat us ( P S) ≤ 1  
9.  A de q uate or ga n f u ncti o n as i n dicate d b y t he f oll o wi n g 
la b orat or y val ues. (All la b orat or y tests m ust b e obtai ne d 
wit hi n 1 4  da ys pri or t o t he first d ose of st u d y treat me nt ): 
a. He mat ol o gical  
•  A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 x 1 0 9/ L 
•  Platelet c o u nt ( Plt) ≥ 1 0 0 x 1 0 9/ L 
•  He m o gl o bi n ( H b) ≥ 9 g/ d L  
•  I nter nati o nal n or malize d rati o (I N R) 0. 8 t o u p per 
li mit of n or mal (U L N) or ≤ 3 f or s u bjects 
recei vi n g 
a ntic oa g ula nt 
t hera p y 
s uc h 
as 
C o u ma di n or he pari n  
b.  Re nal  
•  Ser u m creati ni ne ≤ 1. 5 x U L N or calc ulate d 
creati ni ne cleara nce ≥ 6 0 m L/ mi n/ 1. 7 3 m 2 f or 
s u bjects wit h ser u m creati ni ne le vels > 1. 5 x 
i nstit uti o nal U L N 
c. He patic  
•  T o tal bilir u bi n ≤ 1. 5 x U L N  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1  of 1 1 7  
 
•  As partate a mi n otra nsferase ( A S T) a n d ala ni ne 
a mi n otra nsferase ( A L T) ≤ 3 x U L N or ≤ 5 x U L N 
f or s u bjects wit h k n o w n li ver metastases  
d.  Meta b olic  
•  Gl ycate d he m o gl o bi n ( H b A 1c) ≤ 8 % 
( ≤ 6 4 
m m ol/ m ol)   
1 0.  If a s u bject is c urre ntl y recei vi n g bis p h os p h o nates  or 
a n y ot her dr u g f or treat me nt of oste o p or osis, treat me nt -
i n d uce d b o ne l oss a n d metastases t o b o ne, t he s u bject 
m ust ha ve recei ve d t he bis p h os p h o nates f or at least f o ur 
wee ks pri or t o t he first d ose of st u d y treat me nt.  
•  I nitiati o n of bis p hos p h o nates or si milar a ge nts 
d uri n g t he st u d y ma y be all o we d pr o vi de d t he 
s u bject c o m pletes t he first c ycle of treat me nt 
wit h o ut a n y d ose li miti n g t o xicit y ( D L T) a n d t he 
I n vesti gat or r ules o ut t u m or pr o gressi o n. 
1 1.  Male or fe male s u bjects of c hil d -pr o d uc i n g p ote ntial 
m ust a gree t o use a de q uate c o ntrace pti o n , i ncl u di n g 
d o u ble -barrier  
c o ntrace pti ve  
meas ures,  
oral 
c o ntrace pti o n, or a v oi da nce o f i nterc o urse d uri n g t he 
st u d y a n d f or 9 0 da ys after t he last d ose of st u d y 
treat me nt.  
1 2. W o me n of c hil d beari n g p ot e ntial m ust ha ve a ne gati ve 
ser u m pre g na nc y test d uri n g Scree ni n g Peri o d a n d 
wit hi n 4 8 h o urs of t he first d ose of st u d y treat me nt. 
“ W o me n o f c hil d beari n g p ote ntial” is defi ne d as 
se x uall y mat ure w o me n w h o ha ve n ot u n der g o ne a 
h ysterect o m y 
or 
w h o 
ha ve 
n o t 
bee n 
nat urall y 
p ost me n o pa usal f or at least 1 2  c o nsec uti ve m o nt hs pri or 
t o t he first d ose of st u d y treat me nt. 
E xcl usi o n Criteri a  
1.  A nti -ca ncer 
t hera p y, 
s uc h 
as 
c he m ot hera p y, 
i m m u n ot hera p y, h or m o nal t hera p y, tar gete d t hera p y, 
or i n vesti gati o nal a ge nts wit hi n  five half -li ves or f o ur 
wee ks, w hic he ver is s h orter, pri or t o a d mi nistrati o n 
of t he first d ose of st u d y treat me nt  
•  T o be eli gi ble f or st u d y treat me nt, t o xicit y fr o m 
pri or treat me nt(s) m ust rec o ver t o Gra de ≤ 1, e xce pt 
f or al o pecia 
•  C o nc urre nt s yste mic hi g h -d ose c ortic oster oi ds ( i n 
d osi n g 
e xcee di n g 
1 0 
m g 
Q D 
of 
pre d nis o ne 
e q ui vale nt) 
w he n 
use d i nter mitte ntl y i n 
a n 
a ntie me tic re gi me n, f or ce ntral ner v o us s yste m 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 2  of 1 1 7  
 
( C N S) metastases ma na ge me nt, or as a part of t he 
pre me dicati o n re gi me n are all o we d  
2.  Ra diati o n t hera p y wit hi n f o ur wee ks, or palliati ve 
ra diati o n t hera p y 
wit hi n t w o wee ks, pri or t o 
a d mi nistrati o n of t he first d ose of s t u d y treat me nt  
•  T o be eli gi ble f or st u d y treat me nt, ra diati o n 
t hera p y-relate d t o xicit y m ust rec o ver t o Gra de ≤ 1 
pri or t o a d mi nistrati o n of t he first d ose of st u d y 
treat me nt 
•  C o nc urre nt palliati ve ra di ot h era p y f or l ocal pai n -
c o ntr ol or pre ve nti o n of fract ure (f or k n o w n b o n e 
metastases) ma y be all o we d pr o vi de d t he s u bject 
c o m pletes t he first c ycle of treat me nt, d oes n ot meet 
criteria of pr o gressi ve disease, a n d treate d lesi o ns 
will n ot be i ncl u de d i n t he ta r get/ n o n-tar get lesi o n 
assess me nt.  
3.  Maj or s ur gical pr oce d ure wit hi n f o ur wee ks pri or t o 
a d mi nistrati o n of t he first d ose of st u d y treat me nt  
•  T o be eli gi ble f or t he st u d y treat me nt, all s ur gical 
w o u n ds m ust be f ull y heale d, a n d a n y s ur ger y-
relate d a d verse e ve nts m ust rec o ver t o Gra de ≤ 1.  
4.  U na ble or u n willi n g t o s wall o w t he c o m plete dail y 
d ose of A R Q 7 5 1  
5.  Pre vi o us treat me nt wit h  
•  A K T i n hi bit ors (e. g., 
A R Q 0 9 2, 
M K -2 2 0 6, 
G S K 2 1 4 1 7 9 5, A Z D 5 3 6 3 ; pri or treat me nt wit h 
PI 3 K or m T O R i n hi bit or are  all o we d)  
•  Pri or ta xa ne t hera p y f or t he a d va nce d, metastatic 
disease  (f or s u bjects c o nsi dered f or Ar m B , A R Q 
7 5 1 + paclita xel,  o nl y)  
6.  K n o w n pri or aller gic reacti o n t o or se vere i nt olera nce 
of paclita xel  or f ul vestra nt. I nt olera nce is defi ne d as 
a seri o us a d ver se e ve nt, a gra de 3 or 4 A E per 
C T C A E  
v. 4. 0 3,  
or  
per ma ne nt  
treat me nt 
disc o nti n uati o n  
7.  Hist or y of T y pe 1  dia betes 
mellit us  or T y pe 2 
dia betes mellit us re q uiri n g re g ular me dicati o n ( ot her 
t ha n oral h y p o gl yce mic a ge nts) or fasti n g gl uc ose ≥ 
1 6 0 m g/ d L at Scree ni n g visit.  
8.  Si g nifica nt gastr oi ntesti nal dis or der(s) t hat c o ul d, i n t he 
o pi ni o n 
of t he I n vesti gat or, i nterfere 
wit h t he 
a bs or pti o n, meta b olis m, or e xcreti o n of A R Q  7 5 1 (e. g., 
i nfla m mat or y 
b o wel 
disease, 
Cr o h n’s 
disease, 
ulcerati ve c olitis, e xte nsi ve gastric resecti o n)  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 3  of 1 1 7  
 
9.  K n o w n u ntreate d or acti ve C N S metastases a n d/ or 
carci n o mat o us me ni n gitis  
•  T o be eli gi ble f or t he st u d y treat me nt, s u b jects m ust 
ha ve sta ble disease ≥ 1 
m o nt h, c o nfir me d b y 
ma g netic res o na nce i ma gi n g ( M RI) or c o m p ute d 
t o m o gra p h y ( C T) sca n, a n d ha ve C N S metastases 
well 
c o ntr olle d 
b y l o w -d ose 
ster oi ds, 
a nti -
e pile ptics, or ot her s y m pt o m -relie vi n g me dicati o ns. 
1 0.  Hist or y of m y oc ar dial i nfarcti o n ( MI) or Ne w Y or k 
Heart Ass ociati o n ( N Y H A) Class II -I V c o n gesti ve 
heart fail ure wit hi n 6 m o nt hs of t he a d mi nistrati o n of 
t he first d ose of st u d y treat me nt ( MI occ urri n g > 6 
m o nt hs of t he first d ose of st u d y treat me nt will be 
per mitte d); Gr a de 2 or w orse c o n d ucti o n defect (e. g., 
ri g ht or left b u n dle bra nc h bl oc k). 
1 1.  A heart rate c orrecte d Q T ( Q Tc) i nter val ≥ 4 8 0 msec, 
usi n g t he Fri dericia's f or m ula Q Tc F  
1 2.  Left ve ntric ular ejecti o n fracti o n ( L V E F) < 5 0 % as 
deter mi ne d b y M ulti ple Gate d Ac q uisiti o n ( M U G A) 
sca n or ec h ocar di o gra m ( E C H O) i n s u bjects w h o 
recei ve d pri or treat me nt wit h a nt hrac ycli nes  
1 3.  C o nc urre nt se vere a n d/ or u nc o ntr olle d ill ness n ot 
relate d t o ca ncer a n d/ or s ocial sit uati o n t hat w o ul d 
li mit co m plia nce wit h st u d y re q uire me nts, i ncl u di n g 
b ut n ot li mite d t o:  
•  Ps yc hiatric ill ness, s u bsta nce a b use  
•  O n g oi n g or acti ve k n o w n i nfecti o n, i ncl u di n g 
h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n, 
he patitis B or C vir us  
•  Si g nifica nt p ul m o nar y d ysf u ncti o n, i ncl u di n g 
p ne u m o nitis, i nterstitial l u n g disease (I L D), 
i di o pat hic p ul m o nar y fi br osis, c ystic fi br osis, 
se vere C O P D 
•  Peri p heral ne ur o pat h y gra de ≥2 ( Ar m B, A R Q 
7 5 1 + paclita xel)  
•  Blee di n g 
diat hesis, 
t hr o m b oc yt o pe nia 
or 
c oa g ulati o n  
dis or ders  
( Ar m  
C , 
A R Q 
7 5 1 +f ul vest ra nt) 
•  T hr o m b otic/c oa g ulati o n 
dis or ders 
wit hi n 
6 
m o nt hs pri or t o t he first d ose of st u d y treat me nt 
u nless sta ble o n a ntic oa g ulati o n f or > 3 m o nt hs  
1 4.  Acti ve or hist or y of ot her mali g na nc y ot her t ha n t he 
c urre nt ca ncer wit hi n 2  years of t he first d ose of st u d y 
treat me nt, wit h t he e xce pti o n of carci n o ma i n-sit u of 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 4  of 1 1 7  
 
t he cer vi x, basal cell carci n o ma, a n d s u perficial 
bla d der t u m ors c ura ti vel y treate d  
1 5.  Bl o o d tra nsf usi o n or a d mi nistrati o n of gr o wt h fact ors 
wit hi n 5 da ys pri or t o a bl o o d dra w bei n g use d t o 
c o nfir m eli gi bilit y  
1 6.  Pre g na nt or breastfee di n g  
St u d y Dr u gs, D oses, a n d 
A d mi nistr ati o n:  
 
P art 1 : 
T he i n vesti gati o nal dr u g A R Q  7 5 1 is s u p p lie d as ca ps ules 
f or oral a d mi nistrati o n. A R Q 7 5 1 is pac ka ge d i n m ulti ple 
stre n gt hs of 5 m g a n d 2 5 m g a n d is s u p plie d directl y  t o t he 
p har mac y 
at t he cli nical site. 
 A R Q  7 5 1 
m ust 
be 
a d mi nistere d u n der faste d c o n diti o ns ( o ne h o ur pri or t o or 
t w o h o urs after t he meal). T he d osi n g be g an at 5 m g o nce a 
da y ( Q D) a n d escalate d  u ntil t he M T D a n d/ or R P 2 D wa s 
deter mi ne d. S u bjects recei ve 
A R Q  7 5 1 at d ose le vels 
s pecifie d f or t heir res pecti ve d ose c o h orts.  
Treat me nt 
c o nti n ue s 
u ntil 
u nacce pta ble 
t o xicit y, 
d oc u me nte d d isease pr o gressi o n (cli nical or ra di ol o gical), 
or a n ot her disc o nti n uati o n criteri o n is met.  
 
P art 2 : 
T he i n vesti gati o nal dr u g A R Q  7 5 1 is s u p plie d as ca ps ules 
f or oral a d mi nistrati o n. A R Q 7 5 1 is pac ka ge d i n stre n gt h of 
2 5 m g a n d is s u p plie d  directl y  t o t he p har mac y at t he cli nical 
site.  A R Q  7 5 1 
m ust 
be a d mi nistere d 
u n der faste d 
c o n diti o ns ( o ne h o ur pri or t o or t w o h o urs after t he meal), 
s u bjects will recei ve A R Q 7 5 1 at d ose le vels s pecifie d f or 
their res pecti ve Ar m/c o h ort d ose.  
I n ge neral, a d mi nistrati o n of paclita xel a n d f ul vestra nt 
s h o ul d f oll o w t he F D A a p pr o ve d la bel, N C C N g ui deli nes, 
or i nstit uti o nal practice.  
•  Paclita xel: 8 0 m g/ m 2 (I V), Da ys 1, 8, 1 5 f oll o we d b y 
a wee k of rest of eac h c ycle  
•  F ul vestra nt: 5 0 0 m g (I M), Da ys 1, 1 5 of C ycle 1 & 
Da y 1  of eac h c ycle  t hereafter 
Paclita xel a n d f ul vestra nt will be o btai ne d fr o m c o m mercial 
s o urces. 
Criteri a f or Deter mi n ati o n of 
D ose -Li miti n g T o xicit y:  
 
P art 1:  
D ose -li miti n g t o xicities ( D L T) were  deter mi ne d d uri n g t he 
first c ycle (f o ur wee ks/ 2 8 da ys) of treat me nt. A D L T wa s 
defi ne d b y t he occ urre nce of a n y of t he f oll o wi n g t o xicities 
relate d, pr o ba bl y relate d, or p ossi bl y relate d t o A R Q 7 5 1  
wit hi n t he fir st c ycle of treat me nt a n d gra de d acc or di n g t o 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 5  of 1 1 7  
 
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 4. 0 3:  
•  Gra de  4 a ne mia  
•  Gra de 4 ne utr o pe nia  
•  Gra de 4 t hr o m b oc yt o pe nia  
•  Gra de 3 ne utr o pe nia lasti n g l o n ger t ha n 7 da ys des pite 
o pti mal treat me nt 
•  Gra de 3 t hr o m b oc yt o pe nia i n t he prese nce of blee di n g  
•  ≥ Gra de 3 h y per gl yce mia (fasti n g bl o o d gl uc ose > 2 5 0 
m g/ d L or n o n -fasti n g > 5 0 0 m g/ d L) re q uiri n g i ns uli n 
( u nc o ntr olle d wit h oral h y p o gl yce mic a ge nts) 
•  ≥ Gra de 3 n o n -he mat ol o gical t o xicit y of a n y d urati o n, 
e xce pt f or t he f oll o wi n g:  
o  Na usea, v o miti n g, or diarr hea res p o n di n g t o 
o pti mal me dical ma na ge me nt wit hi n 4 8 h o urs  
o  Al o pecia  
•  A n y ot her t o xicit y t hat i n t he vie w of t he I n vesti gat or 
re prese nts a cli nicall y si g nifica nt hazar d t o t he 
s u bject 
 
P art 2:  
D ose -li miti n g t o xicities will be deter mi ne d d uri n g t he first 
cycle ( 2 8 da ys) of c o m bi nati o n t hera p y . A D L T is defi ne d 
b y t he occ urre nce of a n y of t he f oll o wi n g t o xicities relate d, 
pr o ba bl y relate d, or p ossi bl y relate d t o A R Q  7 5 1  w he n 
a d mi nistere d i n c o m bi nati o n wit h paclita xel or f ul vestra nt  
wit hi n t he first c ycle of  treat me nt a n d gra de d acc or di n g t o 
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 4. 0 3:  
•  Gra de  4 a ne mia  
•  Gra de 4 ne utr o pe nia  
•  Gra de 4 t hr o m b oc yt o pe nia  
•  Gra de 3 ne utr o pe nia lasti n g l o n ger t ha n 7 da ys des pite 
o pti mal treat me nt  
•  Gra de 3 t hr o m b o c yt o pe nia i n t he prese nce of blee di n g  
•  ≥ Gra de 3 h y per gl yce mia (fasti n g bl o o d gl uc ose > 2 5 0 
m g/ d L or n o n -fasti n g > 5 0 0 m g/ d L) re q uiri n g i ns uli n 
( u nc o ntr olle d wit h oral h y p o gl yce mic a ge nts)  
•  ≥ Gra de 3 n o n -he mat ol o gical t o xicit y of a n y d urati o n, 
e xce pt f or t he f oll o wi n g:  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 6  of 1 1 7  
 
o  Na usea, v o miti n g, or diarr hea res p o n di n g t o 
o pti mal me dical ma na ge me nt wit hi n 4 8 h o urs  
o  A l o pecia  
•  T he I n vesti gat or t o assess A L T a n d A S T c ha n ges t o 
deter mi ne if t hese c ha n ges ma y be a D L T  
•  ≥ Gra de 3 A L T or A S T ele vati o n f or s u bjects wit h 
A L T/ A S T ≤ 3 U L N at Baseli ne  
•  A L T/ A S T le vels f or  s u bjects wit h k n o w n li ver 
metastases a n d A L T/ A S T ≤ 5 x U L N at  Baseli ne  
•  Gra de 2 A L T/ A S T ele vati o n acc o m pa nie d b y ≥ 
Gra de 2 ele vati o n i n bilir u bi n  
•  A n y ot her t o xicit y t hat i n t he vie w of t he I n vesti gat or 
re prese nts a cli nicall y si g nifica nt hazar d t o t he s u bject 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 7  of 1 1 7  
 
P art 1 - Criteri a f or D ose 
Esc al ati o n:  
E nr oll me nt at t he ne xt d ose le vel a n d/ or e nr oll me nt of 
a d diti o nal s u bjects i nt o t he o n g oi n g c o h ort  occ ur red  
acc or di n g t o t he f oll o wi n g criteria:  
•  If zer o of t hree i nitiall y treate d s u bjects e x perie nce a 
D L T ( A R Q  7 5 1 -relate d, pr o ba bl y relate d, or p ossibl y 
relate d) b y Da y 2 9 of d osi n g, t he n d ose escalati o n will 
occ ur  
•  If o ne of t hree i nitiall y treate d s u bjects e x perie nces a 
D L T b y Da y 2 9 of d osi n g, t he n a n a d diti o nal t hree 
s u bjects will be e nr olle d f or a t otal of si x s u bjects treate d 
at t he sa me d ose le ve l.  Escalati o n will occ ur if n o 
a d diti o nal D L Ts are see n i n t hat c o h ort ( D L T i n o ne of 
si x s u bjects). 
•  If t w o or m ore treate d s u bjects at a d ose le vel e x perie nce 
a D L T b y Da y  2 9 of c o nti n u o us d osi n g, d ose escalati o n 
wi ll st o p a n d t he pri or d ose le vel a n d/ or a less fre q ue nt 
dr u g a d mi nistrati o n sc he d ule will be c o nsi dere d t he 
M T D. If t he first d ose res ults i n  2 or m ore s u bjects 
e x perie nci n g D L T , s u bse q ue nt s u bjects will be e nr olle d 
at a less fre q ue nt dr u g a d mi nistrati o n sc he d ule (e. g., 5 
m g Q O D).  
•  If a s u bject wit h dra ws fr o m t he st u d y treat me nt f or a n y 
reas o n ot her t ha n a D L T d uri n g t he first c ycle ( 4 
wee ks/ 2 8 da ys), t hat s u bject will be re place d.  
 
T he M T D was  defi ne d as t he d ose le vel at w hic h n o m ore 
t ha n o ne o ut of si x s u bjects has a n o bser va ble D L T. 
Ar Q ule’s Me dical M o nit or a n d t he I n vesti gat or(s) re vie we d 
all si g nifica nt A R Q  7 5 1 -relate d t o xicities t o deter mi ne if t he 
d ose  
escalati o n  
sc he d ule  
re q uires  
m o dificati o n. 
I nter me diate d oses a n d alter nati ve d osi n g sc he d ules c o ul d 
be assi g ne d t o a c o h ort after a gree me nt bet wee n t he Me dical 
M o nit or a n d t he I n vesti gat or(s).   
D uri n g t he d ose escalati o n peri o d, i ntra -s u bject d ose 
escalati o n was  o nl y per mitte d if t he f oll o wi n g criteria were  
met:  
1.  T he ne xt hi g her d ose f or t his re gi me n  has de m o nstrate d 
t o be safe b y at least 3 s u bjects a n d t he last s u bject 
c o mplete d o ne c ycle wit h o ut e xcee di n g a D L T.  
2.  T he s u bject i n q uesti o n has n ot e x perie nce d a D L T.  
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 8  of 1 1 7  
 
O nce t he M T D w s deter mi ne d, i ntra-s u bject d ose escalati o n 
t o t he M T D was  c o nsi dere d t o o pti mize t he treat me nt i n 
s u bjects e nr olle d at l o wer d ose le vels. M ulti ple i ntra-s u bject 
d ose escalati o ns per s u bject was  c o nsi dere d. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 9  of 1 1 7  
 
P art 2 - Criteri a f or 
Deter mi n ati o n of R P 2 D of 
A R Q 7 5 1 i n c o m bi n ati o n wit h 
ot her a nti -c a ncer a ge nts : 
T o deter mi ne R P 2 D of A R Q 7 5 1 i n c o m bi nati o n wit h 
paclita xel  a n d f ul vestra nt, a mi ni m u m of t w o d ose le vels 
will be teste d. E nr olle d s u bjects will i nitiall y be treate d wit h 
5 0 m g Q D of A R Q 7 5 1 ( C o h ort 1  of Ar ms B  a n d C). 
E nr oll me nt at t he ne xt d ose le vel a n d/ or e nr oll me nt of 
a d diti o nal s u bjects i nt o t he o n g oi n g c o h ort will occ ur 
acc or di n g t o t he f oll o wi n g criteria:  
•  If zer o of t hree i nitiall y treate d s u bjects e x perie nce a 
D L T ( A R Q  7 5 1 -relate d, pr o ba bl y relate d, or p ossi bl y 
relate d) b y Da y 2 9 of d osi n g, t he n d ose escalati o n will  
occ ur (i.e., C o h ort 2)  
•  If o ne of t hree i nitiall y treate d s u bjects e x perie nce a 
D L T b y Da y 2 9 of d osi n g, t he n a n a d diti o nal t hree 
s u bjects will be e nr olle d f or a t otal of si x s u bjects treate d 
at t he sa me d ose le vel.  Escala ti o n will occ ur if n o 
a d diti o nal D L Ts are see n i n t hat c o h ort ( D L T i n o ne of 
si x s u bjects). 
•  If t w o or m ore treate d s u bjects at a d ose le vel e x perie nce 
a D L T b y Da y  2 9 of c o nti n u o us d osi n g, f urt her d ose 
escalati o n will n ot be i nitiate d, a n d t he pri or d ose l e vel 
a n d/ or a less fre q ue nt dr u g a d mi nistrati o n sc he d ule will 
be c o nsi dere d t he M T D. If t he first d ose le vel of st u d y 
treat me nt res ults i n  2  or m ore  s u bjects e x perie nci n g a 
D L T , s u bse q ue nt s u bjects will be e nr olle d at 2 5 m g Q D 
(i.e., C o h ort -1).  
•  If a s u bject wit h dra ws fr o m t he st u d y treat me nt f or a n y 
reas o n ot her t ha n a D L T d uri n g t he first c ycle ( 2 8 da ys), 
t hat s u bject will be re place d. 
 
T he M T D is defi ne d as t he d ose le vel at w hic h n o m ore t ha n 
o ne o ut of si x s u bjects ha ve a n o bser va ble D L T.  
T he d ose  le vels f or paclita xel a n d f ul vestra nt will sta y t he 
sa me f or all c o h orts.   
Ar Q ule’s 
Me dical 
M o nit or a n d t he I n vesti gat or(s) will 
re vie w 
all si g nifica nt treat me nt-relate d t o xicities t o 
deter mi ne if t he 
d ose escalati o n sc he d ule re q uires 
m o dificati o n. I nter me diate d oses a n d alter nati ve d osi n g 
sc he d ules ma y be assi g ne d t o a c o h ort after a gree me nt 
bet wee n t he 
Me dical 
M o nit or a n d t he I n vesti gat or(s).   
D uri n g re g ular calls, t he S p o ns or a n d t he I n vesti gat or(s) will 
als o m o nit or s u bjects’ safet y b y re vie wi n g a n d e val uati n g 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 2 0  of 1 1 7  
 
st u d y data a n d a n y e mer gi ng safet y data/si g nals o n a n 
o n g oi n g basis.  
D ur ati o n of Tre at me nt:  
F or a n i n di vi d ual s u bject, treat me nt wit h A R Q 7 5 1 as a 
si n gle a ge nt or i n c o m bi nati o n wit h paclita xel or  f ul vestra nt 
will 
c o nti n ue 
u ntil 
u nacce pta ble 
t o xicit y, 
disease 
pr o gressi o n 
(cli nica l 
or 
ra di ol o gical), 
or 
a n ot her 
disc o nti n uati o n criteri o n is met.  It is e x pecte d t hat m ost 
s u bjects will recei ve bet wee n o ne ( 4 wee ks) a n d si x c ycles  
( 2 4 wee ks) of treat me nt wit h A R Q 75 1 as a si n gle a ge nt or 
i n c o m bi nati o n wit h ot her a nti -ca ncer a ge nts .  A  treat me nt 
c ycle is defi ne d as 2 8 da ys.   
P h ar m ac o ki netic V ari a bles:  
P K varia bles will i ncl u de C ma x , A U C, a n d t1/ 2.  Bl o o d 
sa m ples f or P K a nal ysis will be dra w n at ti me p oi nts defi ne d 
i n t he pr ot oc ol . A d diti o nal u nsc he d ule d bl o o d sa m ple(s) f or 
P K ma y be c o llecte d o n a n y st u d y da y(s) u p o n a gree me nt 
bet wee n t he I n vesti gat or a n d S p o ns or.  
C o nc o mit a nt Me dic ati o ns:  
Per mitte d Tre at me nts  
•  Sta n dar d t hera pies f or c o nc urre nt me dical c o n diti o ns  
•  Er yt hr o p oieti n Sti m ulati n g A ge nts ( E S A): Please f oll o w 
A merica n S ociet y of Cli nical O nc ol o g y ( A S C O) or 
M E DI C A R E g ui deli nes f or t he use of E S A i n patie nts 
dia g n ose d wit h ca ncer, dr u g la bels, a n d t he F o o d a n d 
Dr u g A d mi nistrati o n ( F D A)  
•  He mat o p oietic gr o wt h f act ors i ncl u di n g fil grasti m 
( Ne u p o ge n ®) 
or 
ot her c ol o n y-sti m ulati n g fact ors. 
A S C O g ui deli nes s h o ul d be f oll o we d f or t he use of 
w hite bl o o d cell ( W B C) gr o wt h fact ors  
•  Pr o p h ylactic a n d s u p p orti ve a nti -e metics or l o w-d ose 
c ortic oster oi ds 
ma y be a d mi nistere d ac c or di n g t o 
sta n dar d practice  
•  H y p o gl yce mic a ge nts f or ele vate d bl o o d gl uc os e ma y be 
a d mi nistere d  
acc or di n g  
t o  
sta n dar d  
practice 
(a d mi nistrati o n of i ns uli n is n ot all o we d at baseli ne b ut 
ma y be a d mi nistere d d uri n g t he st u d y)    
•  Bis p h os p h o nates or a n y ot her dr u g f or treat me nt of 
oste o p or osis, 
treat me nt -i n d uce d 
b o ne 
l oss 
a n d 
metasta ses t o b o ne if starte d at least f o ur wee ks bef ore 
t he first d ose of st u d y treat me nt, or u p o n c o m pleti o n of 
t he first c ycle of treat me nt wit h o ut a n y D L T, a n d if t he 
I n vesti gat or r ules o ut t u m or pr o gressi o n. 
•  Palliati ve ra di ot hera p y f or l ocal pai n c o ntr ol or 
pre ve nti o n of fract ure (f or k n o w n b o ne metastases) ma y 
be all o we d, pr o vi de d t he s u bject c o m pletes t he first 
c ycle of treat me nt, d oes n ot meet criteria o f pr o gressi ve 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 2 1  of 1 1 7  
 
disease a n d treate d lesi o ns will n ot be i ncl u de d i n t he 
tar get/ n o n-tar get lesi o n assess me nt. 
 
Pr o hi bite d Tre at me nt  
T he f oll o wi n g treat me nts are n ot all o we d  d uri n g t he st u d y:  
•  A n y c o nc urre nt a ntica ncer t hera p y i ncl u di n g, b ut n ot 
li mite d 
t o, 
c he m ot hera p y, 
ra di ot hera p y 
(e xce pt 
palliati ve ra di ot hera p y f or l ocal pai n c o ntr ol), h or m o nal 
t hera p y, i m m un ot hera p y, or l oc ore gi o nal t hera p y  
•  I m m u n os u p pressi ve t hera pies i ncl u di n g c o nti n u o us 
hi g h -d ose 
c ortic oster oi ds 
(e xce pt 
w he n 
use d 
i nter mitte ntl y i n a n a ntie metic re gi me n, f or 
C N S 
metastases ma na ge me nt or as a part of t he pre me dicati o n 
re gi me n) 
•  Ot her i n vesti gati o nal a ge nts  
Tre at me nt t o Be A v oi de d or Use d wit h C a uti o n  
A R Q  7 5 1 de m o nstrate d s u b sta ntial i n hi biti o n of C Y P 2 C 1 9 
a n d C Y P 2 D 6 a n d sli g ht meta b olis m -de pe n de nt i n hi biti o n of 
C Y P 3 A 4/ 3 A 5 e nz y me acti vit y. Se nsiti ve s u bstrates f or 
t hese c yt oc hr o me P 4 5 0 ( C Y P) isoe nz y mes s h o ul d be 
a v oi de d or use d wit h ca uti o n d uri n g e nr oll me nt i n t he trial.  
A R Q 7 5 1 was deter mi ne d t o be b ot h a s u bstrate a n d 
i n hi bit or 
of 
P-gl yc o pr otei n 
( P -g p), 
t heref ore 
c o -
a d mi nistrati o n of A R Q 7 5 1 wit h dr u gs k n o w n t o be P -g p 
s u bstrates wit h narr o w t hera pe utic i n de x s h o ul d be a v oi de d 
or use d wit h ca uti o n.  
T he f oll o wi n g treat me nts s h o ul d be a v oi de d, if p ossi ble, or 
use d wit h ca uti o n d uri n g t he st u d y:  
•  C Y P 2 C 1 9 s u bstrates a n d i n d ucers  
•  C Y P 2 D 6 i n hi bit ors a n d i n d ucers  
•  C Y P 3 A 4/ 3 A 5 i n hi bit ors a n d i n d ucers  
•  P -g p s u bstrates, i n hi bit ors, a n d i n d ucers  
•  Gra pefr uit j uice  
P ote nti al Dr u g Dr u g I nter acti o n ( D DI)  
T he p ote ntial f or D DI re p orte d here are preli mi nar y a n d 
base d o n i n vitr o A R Q 7 5 1 data a n d a vaila ble p u blis he d data 
o n 
paclita xel  a n d f ul vestra nt. 
T he 
h u ma n i n 
vi v o 
meta b olis m a n d ass ociate d c o ntri b uti o ns of i m p orta nt  
meta b olic pat h wa ys of A R Q 7 5 1 ha ve n ot yet bee n f ull y 
i n vesti gate d. F urt her, n o cli nical D DI st u dies wit h A R Q 7 5 1 
ha ve bee n perf or me d.   
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 2 2  of 1 1 7  
 
C o m bi nati o n T hera p y: p ote ntial effect wit h A R Q 7 5 1 ( A R Q 
7 5 1 as a victi m)  
C o m bi n ati o n 
dr u g  
I n hi bite d b y 
C Y Ps  
A R Q  
7 5 1 
me t a b olize d 
b y 
C Y Ps  
D DI  
paclita xel  
n ot re p orte d  
2 D 6, 3 A 4  
u n k n o w n  
f ul vestra nt 
1 A 2,  
2 C 9, 
a n d 3 A 4 
2 D 6, 3 A 4  
l o w/ p ossi ble * 
* P ossi ble if C Y P 3 A 4 meta b olis m is t he pri mar y r o ute of eli mi nati o n of A R Q 
7 5 1  
C o m bi nati o n T hera p y: p ote ntial effect o n A R Q 7 5 1 ( A R Q 
7 5 1 as a per petrat or)  
C o m bi n ati o n 
dr u g  
Met a b olize d b y 
C Y Ps  
A R Q  
7 5 1 
i n hi bite d 
b y 
C Y Ps  
D DI  
paclita xel  
2 C 8 a n d 3 A 4  
2 D 6, 2 C 1 9  
l o w 
f ul vestra nt 
3 A 4  
2 D 6, 2 C 1 9  
l o w 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 2 3  of 1 1 7  
 
St atistic al Met h o ds:  
 
All s u bjects ( Part 1 a n d Part 2) w h o ha ve recei ve d  at least 
o ne d ose of A R Q  7 5 1 will be i ncl u de d i n t he safet y a nal ysis  
(safet y p o p ulati o n). Als o, t he safet y a nal ysis f or A R Q 7 5 1 
as a si n gle a ge nt or i n c o m bi nati o n wit h ot her a nti-ca ncer 
a ge nts will be perf or me d . I n a d diti o n t o t he e val uati o n a n d 
cate g orizati o n of a d verse e ve nts, listi n gs of la b orat or y test 
res ults c ollecte d at B aseli ne a n d d uri n g t he st u d y will be 
ge nerate d.  Descri pti ve statistics s u m marizi n g t he c ha n ges 
i n t h ose la b orat or y tests o ver ti me will be prese n te d.  
T he t otal n u m ber of s u bjects e x pecte d t o e nr oll i n Part 1 is 
a p pr o xi matel y 6 4 s u bjects, i ncl u di n g 3 4 s u bjects i n si n gle 
a ge nt d ose escalati o n c o h orts a n d u p t o 3 0 s u bjects i n Ar m 
A (e x pa nsi o n c o h ort of A R Q 7 5 1 si n gle a ge nt); Ar m A will 
c o nsi st of u p t o 1 5 s u bjects 
wit h l ocall y a d va nce d , 
i n o pera ble, 
metastatic or rec urre nt s oli d t u m ors 
wit h 
PI K 3 C A/ P T E N acti o na ble m utati o ns a n d u p t o 1 5 s u bjects 
wit h A K T ge netic alterati o ns w h o will be treate d wit h A R Q 
7 5 1 as a si n gle a ge nt at t he R P 2 D le vel.  
 
•  T he t ot al n u m ber of s u bjects e x pecte d t o e nr oll i n Part 2 
is a p pr o xi matel y 3 0 s u bjects: u p t o 1 5 s u bjects i n 
c o m bi nati o n t hera p y ar ms, eac h:  
o  Ar m B ( A R Q 7 5 1 + paclita xel) –  d ose escalati o n 
c o h orts ( 3 + 3 desi g n) a n d 6 -9 s u bjects at t he 
R P 2 D  (e x pansi o n c o h ort)  
o  Ar m C ( A R Q 7 5 1 + f ul vestra nt) –  d ose escalati o n 
c o h orts ( 3 + 3 desi g n) a n d 6 -9 s u bjects at t he 
R P 2 D  (e x pa nsi o n c o h ort) 
Si nce t he sa m ple size is li mite d (a p pr o xi matel y 1 5 s u bjects 
per s ub gr o u p ), f or mal sa m ple size j ustificati o n is n ot 
feasi ble, t heref ore t he descri pti ve statistics will be use d. 
H o we ver, i n a d diti o n t o o verall assess me nt of safet y 
p o p ulati o n, eac h ar m 
will b e a nal yze d se paratel y f or 
safet y/t olera bilit y a n d preli mi nar y efficac y. 
• 
H 1 –  A R Q 7 5 1 as a si n gle a ge nt t hera p y or i n 
c o m bi nati o n 
wit h 
paclita xel  
or  
i n 
c o m bi nati o n 
wit h f ul vestra nt is s ufficie ntl y 
well t olerate d t o per mit 
f urt her cli nical i n vesti gati o n 
• 
H 0 –  A R Q 7 5 1 as a si n gle a ge nt t hera p y or i n 
c o m bi nati o n 
wit h 
paclita xel  
or 
i n 
c o m bi nati o n 
wit h f ul vestra nt is n ot t olerate d. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 2 4  of 1 1 7  
 
S u bjects w h o ha ve recei ve d at least o ne c ycle of A R Q 7 5 1 
a n d ha ve ha d at least o ne disease assess me nt f oll o wi n g t he 
i nitiati o n of t hera p y 
will be c o nsi dere d e val ua ble f or 
res p o nse.  T he a nti-t u m or acti vit y will be e val uate d o n a n 
e x pl orat or y basis a n d will be s u m marize d usi n g desc ri pti ve 
statistics or gra p hics.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
C o nfi de ntial  
Pa ge 2 5  of 1 1 7  
 
T A B L E O F C O N T E N T S  
S Y N O P SI S  .......................................................................................................................................3  
T A B L E O F C O N T E N T S  ...............................................................................................................2 5  
LI S T O F T A B L E S  .........................................................................................................................2 8  
LI S T O F A B B R E VI A TI O N S  ........................................................................................................2 9  
1  
I N T R O D U C TI O N ........................................................................................................3 3  
1. 1  
P har mac o ki netic C haracteristics  .......................................................................3 5  
1. 2  
Meta b olis m of A R Q 7 5 1  ...................................................................................3 5  
1. 3  
N o ncli nical T o xic ol o g y  .....................................................................................3 6  
2  
I N V E S TI G A TI O N A L P L A N .......................................................................................3 9  
2. 1  
Criteria f or A R Q 7 5 1 D ose Escalati o n a n d Deter mi nati o n of D ose -
Li miti n g T o xicit y f or Part 1  ..............................................................................4 3  
2. 2  
Criteria f or A R Q 7 5 1 D ose Escalati o n a n d Deter mi nati o n of D ose -
Li miti n g T o xicit y f or Part 2  ..............................................................................4 4  
2. 3  
A R Q 7 5 1 D ose Li miti n g T o xicit y –  Part 1  .......................................................4 5  
2. 4  
A R Q 7 5 1 D ose Li miti n g T o xicit y ( Ar ms B a n d C)  –  Part 2  ............................4 5  
3  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ..................................................................4 7  
3. 1  
I ncl usi o n Criteria ...............................................................................................4 7  
3. 2  
E xcl usi o n Criteria ..............................................................................................4 8  
4  
S T U D Y VI SI T S  ............................................................................................................5 1  
4. 1  
I nf or me d C o nse nt ..............................................................................................5 1  
4. 2  
St u d y Visits  .......................................................................................................5 2  
4. 3  
S u bject Disc o nti n uati o n  ....................................................................................5 5  
4. 3. 1  
S u bject Disc o nti n uati o n fr o m Treat me nt  ..........................................................5 5  
4. 3. 2  
S u bject Disc o nti n uati o n fr o m t he St u d y  ...........................................................5 5  
4. 4  
St u d y Disc o nti n uati o n  .......................................................................................5 5  
5  
S T U D Y P R O C E D U R E S  ..............................................................................................5 7  
5. 1  
Me dical Hist or y  .................................................................................................5 7  
5. 2  
P h ysical E xa mi nati o n  ........................................................................................5 7  
5. 3  
1 2 -lea d E C G a n d Ec h ocar di o gra m/ M UG A Sca n  .............................................5 7  
5. 4  
Cli nical La b orat or y Tests  ..................................................................................5 7  
5. 5  
P har mac o ki netic/ P har mac o d y na mic Assess me nts  ............................................5 8  
5. 6  
H o me Bl o o d Gl uc ose M o nit ori n g  .....................................................................5 9  
5. 7  
T u m or E val uati o n  .............................................................................................5 9  
6  
T R E A T M E N T  ..............................................................................................................6 0  
6. 1  
A R Q 7 5 1  ...........................................................................................................6 0  
6. 2  
I n vesti gati o nal Pr o d uct Acc o u nta bilit y .............................................................6 0  
6. 3  
St ora ge a n d Ha n dli n g  ........................................................................................6 1  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
C o nfi de ntial  
Pa ge 2 6  of 1 1 7  
 
6. 4  
Misse d or V o mite d D ose  ...................................................................................6 1  
6. 5  
D ose M o dificati o ns  ...........................................................................................6 1  
6. 6  
Treat me nt C o m plia nce wit h A R Q 7 5 1  .............................................................6 4  
6. 7  
Bli n di n g  .............................................................................................................6 5  
6. 8  
C o nc o mita nt Me dicat i o n ...................................................................................6 5  
6. 8. 1  
Per mitte d Treat me nt  ..........................................................................................6 5  
6. 8. 2  
Pr o hi bite d Treat me nt  .........................................................................................6 6  
6. 8. 3  
Treat me nt t o be A v oi de d or Use d wit h Ca uti o n W hile o n St u d y  .....................6 6  
6. 9  
P ote ntial Be nefit a n d Ris ks f or St u d y S u bjects  ................................................6 6  
7  
S A F E T Y A S S E S S M E N T S  ...........................................................................................6 8  
7. 1  
Defi niti o ns  .........................................................................................................6 8  
7. 1. 1  
A d verse E ve nt  ...................................................................................................6 8  
7. 1. 2  
A d verse Reacti o n  ..............................................................................................6 8  
7. 1. 3  
S us pecte d A d verse Reacti o n  .............................................................................6 8  
7. 1. 4  
U ne x pecte d A d verse E ve nt or U ne x pecte d S us pecte d A d verse Reacti o n  ........6 8  
7. 1. 5  
Seri o us A d verse E ve nt or U ne x pecte d S us pecte d A d verse Reacti o n  ...............6 9  
7. 1. 6  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  ............................................6 9  
7. 1. 7  
I n patie nt H os pitalizati o n ...................................................................................6 9  
7. 1. 8  
St u d y Dr u g -relate d A d verse E ve nt or Seri o us A d verse E ve nt .........................6 9  
7. 1. 9  
A d verse E ve nts of P ote ntial Ris k  ......................................................................6 9  
7. 1. 1 0  
F urt her I nstr ucti o ns o n Re p orti n g A d verse E ve nts or Seri o us A d verse 
E ve nts  6 9  
7. 2  
Res p o nsi bilities a n d Pr oce d ures  ........................................................................7 0  
7. 3  
A d verse E ve nt or Seri o u s A d verse E ve nt Assess me nt Criteria ........................7 1  
7. 4  
Seri o us A d verse E ve nt Re p orti n g  .....................................................................7 1  
7. 5  
P ost -treat me nt Safet y F oll o w-u p  ......................................................................7 2  
7. 6  
Gra di n g of Se verit y  ...........................................................................................7 2  
7. 7  
Assess me nt of Ca usalit y  ...................................................................................7 3  
7. 7. 1  
Relate d A d verse E ve nts  ....................................................................................7 3  
7. 7. 2  
N ot Relate d A d verse E ve nts  .............................................................................7 3  
8  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  ...............................................................7 4  
9  
P L A N N E D S T A TI S TI C A L M E T H O D S  .....................................................................7 5  
9. 1  
Deter mi nati o n of Sa m ple Size  ..........................................................................7 5  
9. 2  
A nal ysis Varia bles  ............................................................................................7 5  
9. 2. 1  
De m o gra p hics a n d Baseli ne C haracteristics  .....................................................7 5  
9. 2. 2  
Safet y  7 5  
9. 2. 3  
P har mac o ki netics  ..............................................................................................7 5  
9. 3  
Statistical Met h o ds  ............................................................................................7 5  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
C o nfi de ntial  
Pa ge 2 7  of 1 1 7  
 
9. 3. 1  
De m o gra p hic a n d Baseli ne C haracteristics  .......................................................7 5  
9. 3. 2  
E xte nt of Treat me nt E x p os ure  ..........................................................................7 6  
9. 3. 3  
A nal yses of Safet y Varia bles  ............................................................................7 6  
9. 3. 4  
P har mac o ki netics a n d P har mac o d y na mics  .......................................................7 7  
9. 3. 5  
I nteri m A nal ysis ................................................................................................7 7  
1 0  
C O M P LI A N C E WI T H G O O D  C LI NI C A L P R A C TI C E A N D E T HI C A L 
C O N SI D E R A TI O N S  ....................................................................................................7 8  
1 0. 1  
I nstit uti o nal Re vie w B oar d or I n de pe n de nt Et hics C o m mittee A p pr o val ........7 8  
1 0. 2  
C o m plia nce wit h G o o d Cli nical Practice a n d Et hic al C o nsi derati o ns  ..............7 8  
1 0. 3  
S u bject I nf or mati o n a n d C o nse nt  ......................................................................7 8  
1 1  
S T U D Y M A N A G E M E N T A N D  M A T E RI A L S  ..........................................................8 0  
1 1. 1  
M o nit ori n g, Verificati o n of Data, A u dit, a n d I ns pecti o n  ..................................8 0  
1 1. 2  
Data Rec or di n g a n d Rete nti o n of St u d y Data  ...................................................8 0  
1 1. 3  
Electr o nic Case Re p ort F or ms  ..........................................................................8 0  
1 1. 4  
C o nfi de ntialit y, P u blicati o n, a n d Discl os ure P olic y  .........................................8 1  
1 2  
R E F E R E N C E LI S T  ......................................................................................................8 2  
A P P E N DI X 1  
S C H E D U L E O F A S S E S S M E N T S  ...................................................................8 5  
A P P E N DI X 2  
P E R F O R M A N C E S T A T U S  .............................................................................8 7  
A P P E N DI X 3  
P H A R M A C O KI N E TI C, P H A R M A C O D Y N A MI C, G L U C O S E 
M E T A B O LI S M ( G M) S A M P LI N G A N D E C G S C H E D U L E  ....................................8 8  
A.  
Bl o o d C ollecti o n Sc he d ule f or P K a n d G M (i ns uli n & gl uc ose) a n d E C G 
sc he d ule .............................................................................................................8 8  
B.  
Bl o o d Sa m ple C ollecti o n f or C Y P 2 D 6 a n d ct D N A  ..........................................8 9  
A P P E N DI X 4  
E X A M P L E S O F I N VI V O S U B S T R A T E S, I N HI BI T O R S, A N D 
I N D U C E R S F O R S P E CI FIC C Y P E N Z Y M E S A N D P -G L Y C O P R O T EI N S  ............9 0  
A P P E N DI X 5  
A S S E S S M E N T O F A N TI -T U M O R A C TI VI T Y  .............................................9 2  
A N N E X 1 .....................................................................................................................................1 0 1  
E LI GI BI LI T Y F O R P A R T  1 S U BJ E C T S E N R O L L E D  U N D E R A M E N D M E N T 5.  ...............1 0 2  
S C H E D U L E O F E V E N T S F O R P A R T 1 S U BJ E C T S E N R O L L E D U N D E R 
A M E N D M E N T 5  ........................................................................................................1 0 6  
S T U D Y VI SI T S F O R P A R T 1  S U BJ E C T S E N R O L L E D U N D E R A M E N D M E N T 5  .............1 0 8  
P K, P D, A N D G L U C O S E M E T A B O LI S M S A M P LI N G S C H E D U L E S F O R P A R T 1  
S U BJ E C T S E N R O L L E D U N D E R A M E N D M E N T 5  ...............................................1 1 4  
S P O N S O R’ S SI G N A T U R E  ........................................................................................................1 1 6  
I N V E S TI G A T O R’ S SI G N AT U R E  .............................................................................................1 1 7  
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
C o nfi de ntial  
Pa ge 2 8  of 1 1 7  
 
LI S T O F T A B L E S  
Ta ble 1  
D ose Dela ys/ Re d ucti o ns f or A R Q 7 5 1 -Relate d T o xicit y E xce pt H y per gl yce mia  .......6 2  
Ta ble 2  
D ose M o dificati o n f or A R Q 7 5 1 -relate d H y per gl yce mia a n d S u g geste d Cli nical 
Treat me nt a n d Ma na ge me nt of H y per gl yce mia  ............................................................6 3  
Ta ble 3  
S u g geste d Cli nical Treat me nt a n d Ma na g e me nt of H y per gl yce mia .............................6 4  
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 2 9  of 1 1 7  
 
LI S T O F A B B R E VI A TI O N S  
A C  
bef ore meals  
A E  
a d verse e ve nt  
A K T  
v -A kt m uri ne t h y m o ma viral o nc o ge ne h o m ol o g  
A L P  
al kali ne p h os p hatase 
A L T  
ala ni ne a mi n otra nsferase  
A N 3 C A  
h u ma n e n d o metrial ca ncer cell li ne  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A R Q 7 5 1  
N -[ 1-( 3-{ 3 -[ 4-( 1-ami n oc ycl o b ut yl) p he n yl] -2 -( 2-a mi n o p yri di n -3 -yl) -3 H -i mi daz o[ 4, 5-
b] p yri di n -5 -yl } p he n yl) pi peri di n -4 -yl] -N -met h ylaceta mi de ( 2 R , 3R )-tartrate 
A S C O  
A merica n S ociet y of Cli nical O nc ol o g y  
A S T  
as partate a mi n otra nsferase  
A U C  
area u n der t he c ur ve  
A U C 0 -2 4 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs after d ose a d mi nistrati o n  
B C R P  
breast ca ncer resista nt pr otei n  
BI D  
t wice a da y 
B S A  
b o d y s urface area  
B U N  
bl o o d urea nitr o ge n  
C B C  
c o m plete bl o o d c o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
C ma x  
ma xi m u m plas ma dr u g c o nce ntrati o n  
C N S  
ce ntral ner v o us s yste m  
C R  
c o m plete res p o nse  
C T  
c o m p ute d t o m o gra p h y  
C T C  
circ ulati n g t u m or cells  
C T C A E  
C o m m o n Ter mi n ol o g y Cri teria f or A d verse E ve nts 
ct D N A 
circ ulati n g t u m or de o x yri b o n ucleic aci d  
C Y P  
c yt oc hr o me P 4 5 0  
D L T  
d ose li miti n g t o xicit y  
E C 5 0 
half ma xi mal effect i ve c o nce ntrati o n 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 0  of 1 1 7  
 
E C G  
electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
electr o nic case re p ort  f or m 
E D C  
electr o nic data ca pt ure  
E O T  
e n d of treat me nt 
E S A  
Er yt hr o p oieti n Sti m ulati n g A ge nts  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nic al Practice 
GI  
gastr oi ntesti nal  
GI 5 0 
c o nce ntrati o n f or 5 0 % of ma xi mal i n hi biti o n of cell pr oliferati o n  
G n R H  
G o na d otr o pi n -releasi n g h or m o ne 
G S K 3  
gl yc o ge n s y nt hase ki nase 3  
H b  
he m o gl o bi n  
H b A 1c  
gl ycate d he m o gl o bi n  
H D L  
hi g h -de nsit y li p o pr otei n  
H E R 2  
h u m a n e pi der mal gr o wt h fact or rece pt or 2  
h E R G  
h u ma n et her -a-g o -g o -relate d ge ne 
HI P A A  
Healt h I nf or mati o n P orta bi lit y a n d Acc o u nta bilit y Act 
HI V  
h u ma n i m m u n o deficie nc y vir us  
H N S T D  
hi g hest n o n -se verel y t o xic d ose 
I B 
I n vesti gat or’s Br oc h ure 
I C5 0 
i n hi bit or co nce ntrati o n re q uire d f or 5 0 % i n hi biti o n  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisatio n  
I E C 
i n de pe n de nt et hics c o m mittee  
I N R 
i nter nati o nal n or malize d rati o 
I R B 
i nstit uti o nal re vie w b oar d 
I T T 
i nte nt t o treat 
I V 
i ntra ve n o us 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 1  of 1 1 7  
 
I V F 
i ntra ve n o us fl ui ds 
K i 
i n hi bit or y c o nsta nt 
L D H  
lactate de h y dr o ge nase 
L D L  
l o w-de nsit y li p o pr otei n  
L F T  
li ver f u ncti o n tests 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
MI  
m y ocar dial i nfarcti o n  
mi n  
mi n ute  
M N B W  
mea n net b o d y wei g ht  
M RI  
ma g neti c res o na nce i ma gi n g  
M T D  
ma xi m u m t olerate d d ose  
m T O R  
ma m malia n tar get of ra pa m yci n  
m T O R C 2  
ma m malia n tar get o f ra pa m yci n c o m ple x 2  
M U G A  
M ulti ple Gate d Ac q uisiti o n  
N E  
n ot e val ua ble  
N O A E L  
n o o bser ve d a d verse effect le vel  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O R R  
o verall res p o nse rate  
p - 
p h os p h or ylate d - 
P D  
pr o gressi ve disease, p har mac o d y na mic  
P E T  
p ositr o n e missi o n t o m o gra p h y 
P -g p  
P -gl yc o pr otei n  
P H  
plec kstri n h o m ol o g y  
PI 3 K  
p h os p hati d yli n osit ol 3 -ki nase  
PI K 3 C A  
P h os p hati d yli n osit ol -4, 5 -Bis p h os p hate 3 -Ki nas e, Catal ytic S u b u nit Al p ha  
P K  
p har mac o ki netics  
Plt  
platelet  
P O  
b y m o ut h, per os  
P R  
partial res p o nse 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 2  of 1 1 7  
 
P R A S 4 0  
pr oli ne -ric h A kt s u bstrate of 4 0 kil o dalt o ns 
P S  
perf or ma nce stat us  
P T  
pr ot hr o m bi n ti me  
P T E N  
p h os p hatase a n d te nsi n h o m ol o g delete d o n c hr o m os o me te n  
P T T  
partial pr ot hr o m bi n ti me  
Q D  
dail y  
Q H S  
bef ore e ver y be dti me  
Q O D  
e ver y ot her da y  
Q Tc  
heart rate  c orrecte d Q T 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R P 2 D  
rec o m me n de d P hase 2 d ose 
S A E  
seri o us a d verse e ve nt 
S D  
sta ble disease 
S er 4 7 3 
seri ne 4 7 3 
S T D 1 0 
se verel y t o xic d ose i n 1 0 % of a ni mals 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reac ti o ns 
t1/ 2 
eli mi nati o n half -life 
T B D  
t o be deter mi ne d 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T GI  
t u m or gr o wt h i n hi biti o n 
T hr 3 0 8  
t hre o ni ne 3 0 8  
TI D  
t hree ti mes dail y 
T ma x  
ti me t o ma xi m u m plas ma c o nce ntrati o n 
U L N  
u p per li mit of n or mal  
W B C  
w hite bl o o d cells 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 3  of 1 1 7  
 
1  
I N T R O D U C TI O N 
T he p h os p hati d yli n osit ol -3 -ki nase ( P I 3 K)/ v -A kt m uri ne t h y m o ma viral o nc o ge ne h o m ol o g 
(A K T )/ ma mmalia n tar get of ra pa m yci n ( m T O R) si g nali n g pat h wa y pla ys a maj or r ole i n 
p h ysi ol o gical pr ocesses re g ulati n g cell ular gr o wt h, pr oliferati o n,  a n gi o ge n esis, s ur vi val, a n d 
meta b olis m  (Brazil, 2 0 0 4 ; Bellac osa, 2 0 0 5 ; E n gel ma n, 2 0 0 6 ).  T he PI 3 K/ A K T/ m T O R ( PI 3 K) 
pat h wa y is fre q ue ntl y altere d i n s oli d m ali g na ncies, pr o m oti n g t u m or gr o wt h, pr oliferati o n a n d 
s ur vi val. T he pat h wa y’s t hree critical n o des, PI 3 K, A K T a n d m T O R, ha ve bee n rec o g nize d as 
i m p orta nt t hera pe utic tar gets. Rece ntl y, a n u m ber of PI 3 K pat h wa y i n hi bit ors has bee n teste d i n 
cli nic al trials (Die nst ma n n, 2 0 1 4 ; L o R uss o, 2 0 1 6 ; Li, 2 0 1 8 ). U nf ort u natel y,  t he si n gle-a ge nt 
acti vit y of t hese i n hi bit ors has bee n li mite d b y c o m pe nsat or y acti vati o n of ot her pat h wa ys, e. g., 
gr o wt h fact or rece pt or si g nali n g t hat all o ws b y passi n g t he tar gete d i n hi biti o n. (Fr u ma n, 2 0 1 4 ; 
L o R uss o, 2 0 1 6 ). T h us , it see ms reas o na ble t o su g gest t hat c o m bi nati o n t her a pies ma y i m pr o ve 
cli nical res p o nse b y tar geti n g m ulti ple  t u m or-s pecific pat h wa ys  b y si m ulta ne o us i n h i biti o n of t he 
cr osstal k bet wee n t hese a cti vate d pat h wa ys . 
I n vitr o a n d i n viv o st u dies s h o we d t hat PI 3 K pat h wa y i n hi bit ors mi g ht se nsitize t u m ors t o 
c he m ot hera p y b y alteri n g s urr o u n di n g vasc ulat ure a n d t u m or perf usi o n (F o kas, 2 0 1 2 ), t h us 
i ncreasi n g e x p os ure t o s yste mic t hera pies a n d s y ner gisticall y i n d uci n g a p o pt osis  (Be n der, 2 0 1 1,  
Kilic -Ere n, 2 0 1 3 ). I n cli nical trials, a ntit u m or acti vit y was o bser ve d i n N S C L C s u bjects  treate d 
wit h pictilis i b, car b o plati n a n d paclita xel, wit h or wit h o ut be vaciz u ma b (S oria, 2 0 1 7 ) a n d i n 
H E R 2 -ne gati ve gastric ca ncer s u bjects treat e d wit h i pataserti b pl us m F O L F O X 6 (Ba n g, 2 0 1 4)  
st u d y. Als o,  paclita xel, as a si n gle a ge nt or i n c o m bi nati o n wit h ot her a ge nts, is t he sta n dar d 
c he m ot hera pe utic a ge nt f or patie nts wit h ot her a d va nce d s oli d t u m ors, i ncl u di n g o varia n, 
e n d o metrial, cer vical, an d tri ple -ne gati ve b reast ca ncer.  PI 3 K  pat h wa y has bee n i m plicate d  i n t he 
de vel o p me nt of a n u m ber of g y nec ol o gical ca ncers, e. g., it is acti vate d i n a p pr o xi matel y 3 5 % of 
H R -p ositi ve breast ca ncers  (Ste m ke -Hale, 2 0 0 8 ) a n d is ass ociate d wit h de vel o p me nt of resista nce 
t o e n d ocri ne t hera p y (Miller, 2 0 1 1 ). T h us, c o m bi nat i o n of PI 3 K/ A K T/ m T O R i n hi bit ors wit h 
c he m ot hera p e utic a ge nts, a n d e n d ocri ne t hera p y ma y rest ore se nsiti vit y t o a n d i m pr o ve efficac y 
of t hese t hera pies c o m par e d t o  a si n gle a ge nt t hera p y. 
 
A R Q 7 5 1  
A n o vel clas s of A K T i n hi bit ors ha ve bee n disc o vere d a n d de vel o pe d at Ar Q ule, I nc.  O ne of t hese 
i n hi bit ors, A R Q  7 5 1, is a p ote nt all osteric pa n -A K T i n hi bi tor wit h bi oc he mica l I C5 0 val ues of 0. 5 5 , 
0. 8 1, a n d 1. 3 1 n M  a gai nst A K T 1, A K T 2, a n d A K T 3, res pecti v el y a n d is hi g hl y selecti ve a m o n g 
t he ki n o me. O ut of 2 4 5 ki nases scree ne d, A R Q  7 5 1 di d n o t i n hi bit a n y ki nase ot her t ha n A K T 1 b y 
m ore t ha n 5 0 % at a c o nce ntrati o n of 5  µ M.  
A R Q 7 5 1 effect i vel y i n hi bits t he p h os p h or ylati o n of A K T 1 a n d its d o w nstrea m tar get P R A S 4 0 as 
well as t he gr o wt h of ca ncer cell li nes wit h ele vate d A K T si g nali n g.  T he a bilit y of A R Q  7 5 1 t o 
i n hi bit t he A K T pat h wa y was assesse d i n a h u ma n e n d o metrial ca ncer cell li ne ( A N 3 C A).  A N 3 C A 
cells d o n ot e x press P T E N a n d e x hi bit  c o nstit uti ve acti vat i o n of A K T (B yr o n , 2 0 0 8 ). A R Q  7 5 1 
was a ble t o  i n hi bit t he p h os p h or ylati o n of A K T ( T hr 3 0 8) a n d A K T( Ser 4 7 3) as well as t he 
p h os p h or ylati o n of t h e d o w nstrea m s u bstrate P R A S 4 0( T hr 2 4 6).  T he half ma xi mal effecti ve 
c o nce nt rati o n ( E C5 0) val ues f or i n hi biti o n of p h os p h or ylate d -A K T( T hr 3 0 8) ( p -A K T[ T hr 3 0 8]),  
p -A K T( Ser 4 7 3), a n d p -P R A S 4 0( T hr 2 4 6)  were 5. 1 0, 1 0. 2 0, a n d 4 8. 5 5 n M,  res pecti vel y, i n 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 4  of 1 1 7  
 
A N 3 C A cel ls.  T hese results s u g gest t hat A R Q 7 5 1 effecti vel y i n hi bits t he A K T pat h wa y i n  h u ma n 
ca ncer cells.  
T he a nti -pr oliferat i ve acti vit y of A R Q 7 5 1 was e val uate d  i n 2 3 9 h u ma n ca ncer cell li nes usi n g 
O nc o P a nel™ 2 4 0.  T he c o nce ntrati o n f or 5 0 % of ma xi mal i n hi biti o n of cell pr oliferati o n ( GI 5 0) 
val ues f or bre ast T 4 7 D, M C F 7, B T 4 7 4, e n d o metri al A N 3 C A, o varia n O V C A R 3, a n d pr ostate 
L N Ca P ca ncer cell li nes were 1. 0 5, 2. 2 0, 3. 2 5, 1 1. 0 9, 1 3. 0 0, a n d 1 5. 0 0 n M, res pecti vel y. A N 3 C A 
a n d L N Ca P cel ls are P T E N-deficie nt; (B yr o n , 2 0 0 8 ) w hile B T 4 7 4 cells, M C F 7, a n d T 4 7 D cells 
har b or acti o na ble  m utati o ns of  PI K 3 C A  (Br u g ge , 2 0 0 7 ).  All  of t he af ore m enti o ne d cell li nes ha ve 
c o nstit uti ve acti vati o n of A K T.  F urt her m ore , 7 3 % of ca ncer cells beari n g PI K 3 C A/ R 1 m utati o ns 
were se nsiti ve t o A R Q 7 5 1, w hereas o nl y 4 2 % cells wit h wil d t y pe PI K 3 C A/ R 1, s u g gesti n g t hat 
ca ncer cells wit h PI K 3 C A/ R 1 m utati o ns are m ore  res p o nsi ve t o A R Q 7 51 ( Y u, 2 0 1 5 ). T hese data 
s u g gest t hat A RQ  7 5 1 is eff ecti ve i n i n hi biti n g t he gr o wt h of ca ncer cell  li nes wit h d ysre g ulate d 
A K T si g nali n g.  
T he A N 3 C A h u ma n e n d o metrial cell li ne was e xte nsi vel y use d f or t he de vel o p me nt of t he cell 
pr olif erati o n assa ys a n d t he i n viv o p har mac o d y na mic assa y i n t he st u d y of  A R Q 7 5 1.  
A d diti o nall y , the a nti -t u m or i n viv o acti vity of A R Q  7 5 1 was teste d i n a n at h y mic m o use xe n o graft 
m o del  e x pla nte d  wit h t he A N 3 C A cell s.  T u mor gr o wt h i n hi biti o n ( T GI) of A R Q  7 5 1  after te n 
da ys oral treat me nt at 1 2 0  m g/ k g dail y  t o 5 mg/ k g ra n ge d fr o m  9 2 %  t o 2 9 %.  T his was 
acc o m pa nie d b y a mea n net b o d y wei g ht ( M N B W) of n ot m ore t ha n  1 0 %.  I n an  e n d o metrial P D X 
m o del d ri ve n b y acti o na ble  m utati o n of A K T 1 ( A K T 1  E 1 7 K), A R Q 7 5 1 treat m e nt res ult e d i n T GI 
of 6 8, 7 8 a n d 9 8 % ( Y u et al 2 0 1 5). T hese data i n dicate t hat A R Q 7 5 1 has t he p ote ntial t o e xert 
si g nifica nt a nti-t u m or effects o n h u ma n t u m ors wit h d ysre g ulate d A K T si g nali n g.  
T he p har ma c o d y na mic effect of A R Q  7 5 1 was de m o nstrate d i n A N 3 C A xe n o graft m o dels. I n 
A N 3 C A t u m ors, p h os p h o -A K T( T hr 3 0 8 ), p h os p h o-A K T( Ser 4 7 3), a n d p h os p h o -P R A S 4 0 ( T hr 2 4 6) 
le vels were re d uce d 6 3. 9 -9 9. 7 %, , b y W ester n bl otti n g a nal ysis, 6 h o urs af ter 1 0 t o 1 2 0 m g/ k g 
d osi n g. At 2 4 h o urs p ost -d ose, A K T p h os p h or ylati o n a n d P R A S 4 0 p h os p h or ylati o n ha d decrease d 
at all d oses le vels i n t he ra n ge of 3 2. 3 -9 8. 1 % f or p h os p h o -A K T( T hr 3 0 8), 0 -9 9. 2 % f or p h os p h o -
A K T( Ser 4 7 3), a n d 8. 6 -6 6 % f or p h os p h o -P R A S 4 0 ( T hr 2 4 6).  A t oral d ose le vels of A R Q 7 5 1 ≥ 2 0 
m g/ k g, ma xi m u m plas ma dr u g c o nce ntrat i o ns ( Cma x ) of A R Q 7 5 1 were ≥ 1. 6 µ M.  I n s u m mar y, 
A R Q  7 5 1 s h o we d a mar ke d i n hi biti o n of t he A K T pat h wa y as de ter mi ne d b y Wester n bl otti n g i n 
a n A N 3 C A xe n o gr aft m o del.  
A n  i n vitr o c o mbi nati o n st u d y of A R Q 7 5 1 wit h ar o mata se i n hi bit or, a nastr oz ole or E R a nta g o nist, 
f ul vestra nt was perf or me d i n E R p ositi v e e n d o metrial  ca ncer cells wit h d ysre g ulate d PI 3 K/ A K T 
pat h wa y . C o m bi nati o n of A R Q 7 5 1 at defi ne d c o nce nt rati o ns wit h f ul vestra nt ( 1 0 µ M ) or 
a nastr oz ole ( 2 0 0 µ  M)  s h o we d si g nifica nt e n ha nce me nt i n a nti -pr oliferati ve acti vit y  i n M F E-2 8 0 
( E R +, 
PI K 3 C A H 1 0 4 7 R), 
H E C -1 B 
( E R +, 
PI K 3 C A G 1 0 4 9 R), 
a n d 
Is h ka wa 
( E R +, 
PI K 3 R 1 T 3 1 9fs * 1 & V 2 9 0fs * 1 ), c o m pare d t o si n gle a ge nts (Data o n file). F urt her m ore, in viv o  
efficac y st u d y of A R Q 7 5 1 i n c o m bi nati o n wit h a nti -P D 1 a nti b o d y was perf or me d i n a s y n ge neic 
m o use C T 2 6 c ol o n t u m or m o del. C o m bi nat i o n of A R Q 7 5 1 wit h a nti-P D 1 a nti b o d y e xerte d T GI  
(% T reate d/ ve hicle) of 5 1 %, w hereas A R Q 7 5 1 a n d a nti-P D 1 a nti b o d y  as si n gle a ge nts  s h o we d 
little or n o T GI (1 0 2 % a n d 8 9 % res pecti v el y). (Data o n file .) 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 5  of 1 1 7  
 
1. 1  
P h ar m ac o ki netic C h ar acteri stics 
T he p har mac o ki netics ( P K) of A R Q 7 5 1 f oll o wi n g oral a d mi nistrati o n t o rats  a n d m o n ke ys were 
e val uate d.  T he mea n oral bi oa vaila bilit y of A R Q  7 5 1 was  3 3. 1 % i n rats, a n d was 1 6. 1 % or 1 3. 7 % 
i n m o n ke ys d ose d wit h a s ol uti o n f or m ulati o n or p o w der fille d ca ps ule, res pecti vel y.  I n a 4 -wee k 
re peat-d ose rat st u d y after oral a d mi nistrati o n, A R Q  7 5 1 was rea dil y a bs or be d, wit h ti me t o 
ma xi m u m plas ma c o nce ntrati o n ( T ma x ) val ues ra n gi n g fr o m 4. 0 0 t o 8. 0 0  h o urs o n Da y 1 a n d fr o m 
4. 0 0 t o 6. 0 0 h o urs o n Da y 2 8.  Afte r reac hi n g Cma x , A R Q 7 5 1 c o nce ntrati o ns stea dil y decli ne d, 
wit h t he eli mi nati o n half -life (t1/ 2) val ues ra n gi n g fr o m 3. 8 1 t o 6. 2 4 h o urs o n Da y 1 a n d fr o m 3. 5 1 
t o 7. 5 6 h o urs o n Da y 2 8.  E x p os ure t o A R Q  7 5 1 i nc rease d wit h t he i ncrease i n A R Q 7 5 1 d ose 
le vel fr o m 2. 5 t o 4 0 m g/ k g/ da y o n Da y 1 a n d fr o m 2. 5 t o 1 0 m g/ k g/ da y o n Da y 2 8.  Se x di ffere nces 
i n Cma x  a n d area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs after d ose 
a d mi nistrati o n ( A U C 0 -2 4) val ues were less t ha n 2 -f ol d. Val ues for C ma x  a n d A U C 0 -2 4 were si milar 
t o sli g htl y l o wer o n Da y 2 8 t ha n o n Da y 1 at t he 2. 5  a n d 1 0 m g/ k g/ da y d ose le vels, i n dicati n g n o 
acc u m ulati o n of A R Q 7 5 1 after m ulti ple d osi n g of rats at t hese d oses.  T he i ncreases i n Cma x  a n d 
A U C 0 -2 4 f or males a n d fe males were greater t ha n d ose pr o p orti o nal. Si milar  fi n di n gs were n ote d 
i n t he 1 4-da y re peat -d ose  rat st u d y.  
I n t he 4-w ee k re peat -d ose m o n ke y st u d y, after oral ga va ge a d mi nist rati o n, A R Q 7 5 1 was rea dil y 
a bs or be d, wit h mea n T ma x  val ues ra n gi n g fr o m 2. 0 0 t o 4. 4 0 h o urs  o n Da y 1 a n d fr o m 2. 0 0 t o 
2. 0 2  h o urs d uri n g Wee k 4. After reac hi n g C ma x , A R Q 7 5 1 c o nce ntrati o ns rea dil y decli ne d, wit h 
mea n t 1/ 2 val ues ra n gi n g fr o m 4. 5 2 t o 6. 5 9 h o urs o n Da y 1 a n d fr o m 3. 5 6 t o 6. 9 5 h o urs d uri n g 
Wee k 4.  E x p os ure t o A R Q 7 5 1 i ncrease d  wit h t he i ncrease i n A R Q 7 5 1 d ose le vel fr o m 2. 5 t o 4 0 
m g/ k g/ da y o n Da y 1 a n d fr o m 2. 5 t o 1 0 m g / k g/ da y d uri n g Wee k 4. N o c o nsiste nt se x differe nces 
i n mea n Cma x  a n d A U C 0 -2 4 val ues were o bser ve d, a n d a n y differe nces were ge nerall y less t ha n 2 -
f ol d. T here were n o c o nsiste nt c ha n ges i n mea n C ma x  a n d A U C 0 -2 4 val ues after m ulti ple d osi n g at 
t he 2. 5 a n d 10 m g/ k g d ose le vels b ut t he res ults, i n ge neral, i n dicate n o acc u m ulati o n of A R Q 7 5 1 
after m ulti ple d osi n g of A R Q 7 5 1 i n m o n ke ys at t hese le vels. T he i ncreases i n mea n Cma x  a n d 
A U C 0 -2 4 f or males a n d fe males were greater t ha n d ose pr o p orti o nal. Si milar fi n di n gs were n ote d 
i n t he 1 4-d a y re peat -d ose  m o n ke y  st u d y. 
1. 2  
Met a b olis m of A R Q 7 5 1  
Data fr o m  i n vitr o meta b olis m st u dies i n pri mar y he pat oc ytes s u g geste d t hat [ 3H] -A R Q 7 5 1 was 
meta b olize d t o a s mall e xte nt, 1 6. 4 t o 3 1. 5 % ( 8 3. 6 t o 6 8. 5 % pare nt re mai ni n g) i n i nc u bati o ns 
c o ntai ni n g rat, m o n ke y, a n d h u ma n he pat oc ytes wit h t he hi g hest le v el of meta b olis m o bser ve d i n 
m o n ke y he pat oc yte i nc u bati o ns, f oll o we d b y h u ma n he pat oc yte i nc u bati o ns, a n d t he l o west i n rat 
he pat oc yte i nc u bati o ns. A t otal of  f o ur meta b olite pea ks (M 2, M 3, M 4, a n d M 5) were o bser ve d i n 
rat he pat oc yte i nc u bati o ns, t hree meta b olite pea ks ( M 1, M 2,  a n d M 4) were o bser ve d i n m o n ke y  
he pat oc yte i nc u bati o ns, a n d si x meta b olite pea ks ( M 1, M 2, M 3, M 4, M 6, a n d M 7) were  o bser ve d 
i n h u ma n he pat oc yte i nc u bati o ns. 
I nc u bati o ns wit h i n di vi d uall y e x presse d h u ma n rec o m bi na nt c yt oc hr o me P 4 5 0 ( C Y P ) is oe nz y mes, 
i n dicate d t hat C Y P 2 D 6, C Y P 3 A 4, a n d C Y P 3 A 5 were t he maj or e nz y mes i n v ol ve d i n t he 
meta b olis m of [ 3H] -A R Q 7 5 1. [ 3H] -A R Q 7 5 1 was meta b olize d t o a s mall e xte nt, a p pr o xi ma tel y 
3 0 % i n i nc u bati o ns c o ntai ni n g 1 m g/ m L micr os o mal pr otei n a n d a n i nc u b ati o n ti me of 6 0 mi n ut es, 
i n p o ole d h u ma n li ver micr os o mal i nc u bati o ns. A t otal of f o ur disti nct meta b olites ( M 1, M 2, M 3, 
a n d M 4) were o bser ve d i n p o ole d li ver micr os o mal i nc u bati o ns . Base d o n t he 1 m g/ m L h u ma n 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 6  of 1 1 7  
 
li ver micr os o mal pr otei n i nc u bati o ns c o n d ucted f or 6 0 mi n utes, meta b olite f or mati o n was ra n k 
or dere d as 
M 2 ~ M 3 > M 1 > M 4. 
Meta b olite 
M 1 
was 
mai nl y f or me d b y C Y P 2 D 6, 
w hereas 
meta b olites M 2, M 3, M 4 a p peare d t o be f or me d mai nl y b y C Y P 3 A 4 a n d C Y P 3 A 5. A n a d diti o nal 
meta b olite, M 5, was o bser ve d i n i nc u bati o ns w it h rec o m bi na nt C Y P 3 A 4 a n d C Y P 3 A 5, b ut n ot i n 
p o ole d li ver micr os o mal i nc u bati o ns.  
Base d o n t he fact t hat t he I C 5 0 val ues were all greater t ha n 3 0 µ M, A R Q 7 5 1 is n ot li kel y t o ca use  
dr u g -dr u g i nteracti o ns d ue t o i n hi biti o n of C Y P 1 A 2, C Y P 2 A 6, C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, 
C Y P 2 E 1, a n d  C Y P 3 A 4/ 5 e nz y me acti vities i n viv o i n h u ma ns. H o we ver, A R Q 7 5 1 s h o we d 
s u bsta ntial i n hi biti o n of C Y P 2 C 1 9 a n d C Y P 2 D 6 e nz y me acti vities. T he I C 5 0 val ues were 
calculate d t o be 1 6. 5 a n d 1 4. 5 μ M, res pecti vel y. A d diti o nal e x peri me nts were c o n d ucte d t o 
e val uate t he ki netics of i n hi biti o n. A R Q 7 5 1 s h o we d c o m petiti ve -f ull i n hi biti o n t o war ds C Y P 2 C 1 9 
a n d t he i n hi bit or y c o nsta nt ( K i) was calc ulate d t o be 6. 8 μ M. A R Q 7 5 1 s h o we d mi xe d -partial 
i n hi biti o n t o war ds C Y P 2 D 6 a n d t he K i was calc ulate d t o be  3. 1 μ M. T heref ore, A R Q 7 5 1 ma y 
ca use dr u g -dr u g i nteracti o ns b y i n hi biti o n of C Y P 2 C 1 9 a n d C Y P 2 D 6. A R Q 7 5 1 di d n ot s h o w 
meta b olis m -de pe n de nt i n hi biti o n of 
C Y P 1 A 2, 
C Y P 2 A 6, 
C Y P 2 B 6, 
C Y P 2 C 8, 
C Y P 2 C 9, 
C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 2 E 1 e nz y me acti vities i n p o ole d h u ma n li ver micr os o mes. Sli ght 
meta b olis m -de pe n de nt i n hi biti o n of C Y P 3 A 4/ 5 e nz y me acti vities was o bser ve d. Base d o n t hese 
data, A R Q 7 5 1 is n ot li kel y t o ca use dr u g -dr u g i nteracti o ns d ue t o  meta b olis m -de pe n de nt 
i n hi biti o n of C Y P e nz y me acti vities i n viv o, i n h u mans. A R Q 7 5 1 was deter m i ne d t o be b ot h a 
s u bstrate a n d i n hi bit or of P-gl yc o pr otei n ( P -g p), b ut n ot a s u bstrate of breast ca ncer resista nt 
pr otei n ( B C R P). A R Q 7 5 1 di d n ot i n d uce C Y P 1 A 2 , C Y P 2 B 6, or C Y P 3 A 4 e nz y me acti vit y.  A R Q 
7 5 1 was f o u n d t o be hi g hl y b o u n d  t o pr otei ns i n h u ma n plas ma ( 9 5. 3 t o 9 6. 9 %).  
1. 3  
N o ncli nic al T o xic ol o g y  
T he t o xicit y pr ofile of orall y a d mi nistere d A R Q 7 5 1 i n b ot h rats a n d m o n ke ys was c haracterize d 
pri nci pall y b y fi n di n gs i n t he i m m u ne s yste m a n d ki d ne y (rats, hi g h d ose o nl y). I n rats at t he hi g h 
d ose ( 4 0/ 3 0 
m g / k g), 
n ota ble cli nical 
pat h ol o g y fi n di n gs 
were c o nsiste nt 
wit h re nal 
d ysf u ncti o n/t o xicit y, de h y drati o n, a n d p o or healt h. 
M o deratel y t o mar ke dl y i ncrease d urea 
n itr o ge n a n d creati ni ne o bser ve d i n m ost of t hese a ni mals were c o nsiste nt wit h re nal da ma ge a n d 
correlate d wit h ki d ne y micr osc o pic fi n di n gs (re nal t u b ule de ge nerati o n/ necr osis, t u b ule cell 
vac u olati o n, a n d pr otei nace o us casts). A d diti o nal n ota ble cli nical p at h ol o g y fi n di n gs i n t hese 
a ni mals i ncl u de d mil dl y t o mar ke dl y i ncrease d g l uc ose a n d i ns uli n, mini mall y t o mil dl y i ncrease d 
w hite bl o o d cell ( W B C) a n d a bs ol ute ne utr o p hil c o u nts, a n d mi ni mall y t o m o deratel y i ncrease d 
re d cell mass (e. g., re d bl o o d cell c o unt, he m o gl o bi n, a n d he mat ocrit). It s h o ul d be n ote d t hat t he 
m yel os u p press i ve effects of A R Q 7 5 1 n ote d at 4 0/ 3 0 m g/ k g/ da y res ulte d i n i ncrease d re d cell mass 
a n d W B C, w hic h are c o nsi dere d sec o n dar y effects of A R Q 7 5 1 d ue t o de h y drati o n a n d/ or p o or 
healt h. I n rats, all o bser vati o ns re verse d at 2. 5 a n d 1 0 m g/ k g d uri n g t he rec o ver y p hase.  I n 
m o n ke ys, A R Q 7 5 1 -relate d micr osc o pic fi n di n gs were restricte d t o decrease d l y m p h oc ytes i n t he 
t h y m us, s pl ee n, a n d l y m p h n o des. Decrease d l y m p h oc ytes were n ote d i n males gi ve n 4 0/ 3 0 
m g/ k g/ da y a n d fe males gi ve n >  1 0 m g/ k g/ da y, wit h rec o ver y of l y m p h oc ytes at t he rec o v er y 
sacrifice.  
I n rats, no A R Q 7 5 1 -relate d effects occ urre d o n f u ncti o nal o bser vati o n batter y tests or l oc o m ot or 
acti vit y, n o A R Q 7 5 1 -relate d lesi o ns were n oted d uri n g o p ht hal mic e xa mi nati o ns f or a ni mals 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 7  of 1 1 7  
a d mi niste re d 2. 5 or 1 0 m g/ k g/ da y, a n d A R Q 7 5 1-relate d plet h ys m o gra p h y fi n di n gs were li mite d 
t o decrease d res pirati o n rate ( 1 6 %) f or a ni mals a dmi nistere d 4 0 m g/ k g. 
I ncrease d plas ma  gl uc ose  a n d i ns ulin  le vels w hich  were  o bser ve d  i n b ot h s pecies ha ve bee n 
re p orte d f or ot her A K T i n hi bit ors a n d ma y be a c haracteristic of t his class of ki nase i n hi bit ors. 
( Ta n, 2 0 1 1). 
A R Q 7 5 1 s h o we d p ote ntial t o i n hi bit h u ma n et her-a- g o- g o-relate d ge ne ( h E R G) i n i n vitr o st u dies 
(I C5 0 = 1 4. 9 µ M).  A d diti o nall y, i n t he 4- wee k re peat- d ose m o n ke y st u d y, a d mi nistrati o n of A R Q 
7 5 1 was ass oc iate d wit h  l o n ger heart rat e -c orrecte d Q T  ( Q Tc) i nter vals i n a ni mals  gi ve n 1 0 or 
4 0/ 3 0 m g/ k g/ da y. Mea n Q Tc i nt er vals o n Da y 2 1 of t he d osi n g p hase were 2 5 ms ec ( 7 %) l o n ger 
i n males a n d 5 1 msec ( 1 5 %) l o n ger i n females  gi ve n  4 0/ 3 0 m g/ k g/ da y  c o m pare d  wit h t heir 
res pecti ve pre- d ose p hase val ues. Mea n Q Tc i nter vals 3 h o urs p ost- d ose o n Da y 2 2 of t he d osi n g 
p hase were 1 2 msec ( 4 %) l o n ger i n males a n d 3 1 msec ( 9 %) l o n ger i n fe males gi ve n 1 0 m g/ k g/ da y 
c o m pare d  wit h  c o ntr ols. L o n ger  Q Tc  i nter vals were  re verse d i n a ni mals gi ve n 1 0 m g/ k g/ da y  b y 
2 4 h o urs  p ost- d ose  o n Da y 2 2 of t he d osi n g  p hase  a n d Da y 2 2 of t he rec o ve r y p hase.  N o A R Q 
7 5 1-relate d c ha n ges  i n Q Tc i nter val wer e o bser ve d i n a ni mals gi ve n 2. 5 m g/ k g/ da y. H o we ver, i n 
m o n ke y  tele metr y st u dies, car dio vasc ular  f u ncti o n was assesse d i n f o ur male  c y n o m ol g us 
m o n ke ys gi ve n a si n gle oral ga va ge d ose of ve hicle c o ntr ol article or 2. 5, 1 0, or 4 0 m g/ k g of A R Q 
7 5 1 a n d n o a b n or mal electr ocar di o gra m ( E C G) wa vef or ms or arr h yt h mias were attri b ute d t o A R Q 
7 5 1. A d diti o nall y,  a d mi nistrati o n of  A R Q 7 5 1 ha d n o effect  o n Q R S  d urati o n  or P R  or Q Tc 
i nter val, diast olic or p ulse press ure, or b o d y te m perat ure. T he o nl y A R Q 7 5 1-relate d effects were 
o bser ve d  at 4 0 m g/ k g a n d c o nsiste d of hi g her  heart  rate a n d  hi g her  s yst olic a n d mea n arterial 
press ures. I n hi biti o n of h E R G a n d Q T pr ol o n gati o n ha ve bee n re p orte d f or ot her A K T i n hi bit ors 
a n d ma y be a n o n-tar get t o xicit y ass ociate d wit h t his class of ki nase i n hi bit ors. ( K o n o ple va, 
2 0 1 4)  (Z ha n g Y., 2 0 0 6 ).
A R Q 7 5 1 w as e val uate d f or p h ot ot o xic p ot e ntial o n Bal b/c 3 T 3 fi br o blasts us i n g t he Ne utral Re d 
U pta ke assa y a n d is c o nsi dere d t o ha ve p h ot ot o xic p ote ntial. 
Base d o n t he 4- wee k rat st u d y,  t he se verel y t o xic d ose i n 1 0 % of rats ( S T D1 0) of A R Q 7 5 1 was 
deter mi ne d t o be greater t ha n 1 0 m g/ k g/ da y b ut less t ha n 3 0 m g/ k g/ da y w he n gi ve n via oral ga va ge 
dail y.  C o nser vati vel y,  t he 1 0 m g/ k g/ da y  d ose le v el will be use d  as t he S T D 1 0 i n rats. T his c orrelates 
t o a h u ma n e q ui vale nt  d ose of 6 0 m g/ m 2/ da y.  Base d o n t he 4- wee k  m o n ke y  st u d y, b ot h  t he 
N O A E L a n d t he hi g hest n o n-se verel y t o xic d ose ( H N S T D) of A R Q 7 5 1 were deter mi ne d i n males 
a n d fe males t o be 1 0 m g/ k g/ da y a n d 2. 5 m g/ k g/ da y, res pecti vel y. T heref ore, t he N O A E L/ H N S T D 
d ose of 2. 5 m g/ k g/ da y fr o m fe males will be use d. T his c orrelates t o a h u ma n e q ui vale nt d ose of 
3 0 m g/ m 2/ da y. Base d o n t his  i nf or mati o n, t he m o n ke y is c o nsi dere d t o be t he m ore  se nsiti ve 
s pecies f or p ur p oses of calc ulati n g a safe starti n g d ose f or t he First  i n H u ma n st u d y i n s u bjects 
wit h a d va nce d mali g na ncies.  As descri be d i n t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) 
g ui da nce  d oc u me nt:  S 9 N o ncli nic al  Ev al u ati o n  f or A ntic a ncer  P h ar m ace utic als,  a safe h u ma n 
starti n g d ose base d o n assess me nt of t o xicit y i n m o n ke y s pecies is 1/ 6 t h of t he H N S T D. T heref ore, 
t he P hase 1 starti n g d ose i was calc ulate d t o be 5 m g/ m2/ da y or 8. 1 m g/ da y ( base d o n a b o d y s urface 
area [ B S A] of 1. 6 2 m 2).  He nce, t he i nitial starti n g d ose of A R Q 7 5 1 i n h u ma ns was 5 m g dail y 
( Q D). 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 8  of 1 1 7  
In s u m mar y,  t he n o ncli nical p har mac ol o g y data s u p p ort t hat A R Q 7 5 1 has the p ote nti al t o e xert 
si g nifica nt a nti-t u m or effects o n h u ma n t u m ors wit h d ysre g ulate d A K T si g nali n g.  
Detaile d n o n -cli nical a n d cli nical data ca n be f o u n d i n t he A R Q 7 5 1 I n vesti gat or’s Br oc h ure (I B).  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 3 9  of 1 1 7  
2  
I N V E S TI G A TI O N A L P L A N  
As disc usse d i n t he I ntr o d ucti o n se cti o n of t he pr ot oc ol a n d i n t he I B, t he c urre nt u n dersta n di n g of 
t he t u m or bi olo g y, s pecificall y t he PI 3 K/ A K T/ m T O R pat h wa y i n breast a n d g y nec ol o gical  
ca ncers, has pr o vi de d rati o nale f or c o m bi nati o n of tar gete d , e nd ocri ne  a n d c he m ot hera pe utic  
a ge nts.  
S uc h c o m bi nati o n re gi me ns ma y e n ha nce t he gr o wt h i n hi biti o n effect of a si n gle a ge nt, all o w t o 
o verc o me res ista nce t o a si n gle a ge nt t hera p y, rest ore se nsiti vit y t o c he m ot hera p y or 
tar geted/e n d ocri ne t hera p y, a n d/ or aff or d a d ura ble res p o nse, partic ularl y i n m olec ularl y selecte d 
t u m ors. 
T h is st u d y c o nsists of t w o parts: Part 1 t hat i ncl u des all s u bjects e nr olle d i n t he si n gle a ge nt d ose 
escalati o n  c o h ort s a n d si n gle a ge nt e x pa nsi o n c o h ort  ( Ar m A) a n d Part 2  t hat i ncl u des all  s u bjects 
i n t he c o m bi nati o n tr eatme nt ar m s ( Ar ms B a n d C). 
A R Q 7 5 1 -1 0 1 st u d y was i nitiate d i n A u g ust  2 0 1 6  as a n o pe n -la bel, p hase 1, first -i n-h u ma n, d ose 
escalati o n st u d y. T he pr o p ose d A R Q 7 5 1 d ose le vels a n d a d mi nist rati o n sc he d ule f or t he 
c o m bi nati o n t her a p y ar ms ha ve bee n i nitial l y teste d i n t he m o n ot hera p y si n gle a ge nt D ose 
Escalati o n c o h orts  of t his tria l. T hirt y -f o ur s u bjects wit h a d va nce d s oli d t u m ors wit h d oc u me nte d  
PI K 3 C A/ A K T/ P T E N  ge netic a lterati o ns were e nr olle d i n t he si n gle a ge nt d ose escalati o n  c o h orts . 
D ose escalati o n f oll o we d t he tra diti o nal escalati o n desi g n ( 3 + 3 s u bjects) wit h t he i nitial d ose of 5 
m g Q D a n d t he hi g hest teste d d ose of 1 0 0 m g Q D , c o nti n u o usl y. D ose li mit i n g t o xicities ( D L Ts) 
were assess e d d uri n g t he first  c ycle ( 2 8 da ys) of treat me nt wit h A R Q 7 5 1 . 
O ver all , A R Q 7 5 1 as a si n gle a ge nt de m o nstrate d ma na gea ble safet y pr ofile. Re versi ble gra de 3 
pr uritic ras h  was t he o nl y D L T o bser ve d i n t he st u d y. T he d ose of  1 0 0 m g Q D  was dee me d t o be 
i nt olera ble  a n d a n i nt er me diate d ose c o h ort was i ntr o d uce d . Ei g ht s u bjects w ere treate d at t he 
i nter me diate d ose le vel of 7 5 m g Q D, se ve n c o m plete d t he first c ycle wit h o ut a n y D L T, o ne s u bject 
was disc o nti n ue d d ue t o cli nical disease pr o gressi o n.  Base d o n t he tolera bil it y a n d safet y of A R Q 
7 5 1 , R P 2 D of A R Q 7 5 1 as a si n gle a ge nt  ha s bee n defi ne d as 7 5 m g Q D, c o nti n u o usl y u n der 
fasti n g c o n diti o ns.  
T o f urt her e val uate safet y a n d t olera bilit y, a n d t o assess preli mi nar y e fficac y of A R Q 7 5 1 as a 
si n gle a ge nt, u p t o 3 0 s u bjects ar e pla n ne d t o be e nr olle d a n d treate d wit h A R Q 7 5 1 at t he R P 2 D 
le vel i n Arm A (e x pa nsi o n c o h ort).  It is pla n ne d t o e nr oll u p t o 1 5 s u bjects wit h s oli d t u m ors 
wit h PI K 3 C A or P T E N acti o na ble  m utati o ns  a n d u p t o 1 5 s u bj ects wit h A K T ge netic alte rati o ns. 
S u bjects e nr olle d i n Ar m A will recei ve A R Q 7 5 1 at 7 5 m g Q D, c o nti n u o usl y.  
Si nce a si n gle dr u g a p pr oac h ma y n ot be s ufficie nt  t o i n hi bit t u m or gr o wt h, a si m ulta ne o us 
i n hi biti o n of t he m ulti ple pat h wa ys ma y be nee de d t o ge nerate d ura ble a nti-ne o p lastic effect.  Part 
2 is desi g ne d t o deter mi ne R P 2 D a n d t o assess safet y, t olera bilit y, a n d preli mi nar y efficac y of 
A R Q 7 5 1 i n c o m bi nat i o n wit h ot her a nti-ca ncer a ge nts.   Part 2 c o nsists of t w o c o m bi nati o n 
t hera p y ar ms, Ar m B ( paclita xel) a n d Ar m C (f ul ve stra nt). 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 0  of 1 1 7  
 
T his pr ot oc ol  is a m ulti-ce nter, o pe n la bel, st u d y of oral A R Q 7 5 1 i n s u bjects wit h a d va nce d, 
i n o pera ble, metastatic a n d/ or rec urre nt s oli d t u m ors wit h, A K T  ge netic alterati o ns, a n d PI K 3 C A  
a n d P T E N  acti o na ble m utati o ns.    
 
E nr oll me nt i n eac h ar m will be i nitiate d per S p o ns or discreti o n. T he c h oice of treat me nt Ar m  will 
be ma de at t he discreti o n of t he I n vesti gat or, pr o vi de d c o m bi nati o n t hera p y wit h paclita xel  or  
f ul vestra nt w o ul d be a p pr o priate f or t heir patie nts’ disease f or Ar ms B a n d C. De pe ndi n g o n t he 
st u d y safet y a n d efficac y data, t he S p o ns or ma y li mit t he nu m ber of s u bjects wit h a s pecific t u m or 
t y pe(s) or PI K 3 C A/ A K T/ P T E N m utati o n stat us t o be e nr olle d.  
T o deter mi ne R P 2 D of A R Q 7 5 1 i n c o m bi nati o n wit h paclita xel ( Ar m B) or f ul vestra nt ( A r m C) 
i n Part 2, sta n dar d 3 + 3 d ose fi n di n g desi g n will be use d. Assess m e nt of t he safet y a n d t olera bilit y 
of c o m bi nati o n re gi me ns will i ncl u de all s u bjects treate d i n Ar m B a n d Ar m C i n de pe n de nt of t he 
A R Q 7 5 1 d ose le vel s u bjects ma y recei ve.  A d diti o nal ar ms ma y be a d de d t o assess A R Q 7 5 1 i n 
c o m bi nati o n wit h ot her a nt i-ca ncer a ge nts.   
I n Ar ms B a n d C, d ose deter mi nati o n will be d o ne as f oll o ws:  
 
C o h ort  
A R Q 7 5 1  
( or all y, P O)  
P aclit a xel  
( Ar m B) 
F ul vestr a nt  
( Ar m C) 
-1  
2 5 m g Q D  
 
8 0 m g/ m 2 (I V)  
Da ys 1, 8, 1 5 f oll o we d b y a 
wee k of rest  
  
5 0 0 m g (I M)  
Da ys 1 & 1 5 of C ycle 1, a n d Da y 1  
of all s u bse q ue nt c ycles  
1  
5 0 m g Q D  
2  
7 5 m g Q D  
E x p a nsi o n  
R P 2 D  
 
D ose escalati o n will pr ocee d t o 7 5 m g Q D, t he d ose t hat was defi ne d t o be t he A R Q 7 5 1 R P 2 D as 
a si n gle a ge nt. O nce M T D/ R P 2 D f or eac h c o m bi nati o n t hera p y Ar m is deter mi ne d, a d diti o na l si x 
s u bjects will be e nr olle d. I ntra-s u bject d ose escalati o n will be per mitte d if t he ne xt hi g her d ose of 
A R Q 7 5 1 f or t hat re gi me n is deter mi ne d t o be safe. Paclita xel  a n d f ul vestra nt a d mi nistrati o n a n d 
pre me dicati o n t hera p y if re q uire d s h o ul d f oll o w t he  F D A a p pr o ve d re gi me ns (see dr u g la bels), 
N C C N g ui deli nes, or i nstit uti o nal S O C.  
 
A p pr o xi matel y 9 4 s u bjects will be e nr olle d i n t his st u d y at 4 -1 0  sites i n t he U S A; 6 4 s u bjects i n 
Part  1 ( D ose escalati o n c o h orts a n d Ar m A) a n d 3 0 i n Part 2 ( Ar m B a n d Ar m C). T hirt y f o ur 
s u bjects were e nr olle d i n d ose escalati o n c o h orts. It is pla n ne d t hat u p t o 3 0 s u bjects wit h a d va nce d, 
i n o pera ble, metastatic, or rec urre nt s oli d t u m ors will be e nr olle d i n Ar m A, u p t o 1 5 s u bjects wit h 
PI K 3 C A/ P T E N acti vati n g  m utati o ns a n d u p t o 1 5 s u bjects wit h A K T ge netic alterati o ns. I n Part 
2, a p pr o xi matel y 1 5 s u bjects will be e nr olle d i n eac h c o m bi nati o n t hera p y ar m ( Ar m B, A R Q 
7 5 1 + paclita xel a n d Ar m C, A R Q 7 5 1 +f ul ve stra nt). 
 
Assess me nt of safet y a n d t olera bilit y of A R Q 7 5 1 as a si n gle a ge nt a n d i n c o m bi nati o n wit h 
paclita xel  or  f ul vestra nt will be base d o n c o nti n u o us e val uati o n of a d verse e ve nts, p h ysical 
e xa mi nati o n fi n di n gs a n d la b orat or y tests. All cli nical asse ssme nts a n d la b orat or y tests will be 
perf or me d acc or di n g t o t he pr ot oc ol -defi ne d ti me p oi nts. If cli nicall y i n dicate d, u nsc he d ule d 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 1  of 1 1 7  
 
la b orat or y tests a n d a n y cli nical assess me nts or e val uati o ns ma y be perf or me d per discreti o n of 
t he I n vesti gat or. 
 
T u m or asses s me nts ( C T or M RI) will be perf or me d acc or di n g t o pr ot oc ol -defi ne d ti me p o i nts, or 
as ot her wise cli nicall y i n dicate d. T u m or res p o nse will be e val uate d acc or di n g t o R E CI S T 1. 1 
g ui deli nes.  
 
P har mac o ki netic ( P K) sa m ples will be c ollecte d pre -d ose a n d at differ e nt ti me p oi nts p ost-d ose as 
defi ne d i n t he pr ot oc ol. A d diti o nal u nsc he d ul e d bl o o d sa m ple(s) f or P K ma y be c ollecte d o n a n y 
st u d y da y(s) u p o n a gree me nt bet wee n t he I n vesti gat or a n d t he S p o ns or. T w o si n gle bl o o d sa m ples 
t o deter mi ne C Y P 2 D 6 ge n ot y pe a n d PI K 3 C A/ A K T/ P T E N m utati o n i n ct D N A will be c ollecte d.  
 
F or a n i n di vi d ual s u bjec t, treat me nt will c o nti n ue u ntil u nacce pta ble t o xicit y, disease pr o gressi o n 
(cli nical or ra di ol o gical), or a n ot her disc o nti n uati o n criteri o n is met.  It is e x pecte d t hat m ost 
s u bjects w ill recei ve bet wee n o ne a n d si x c ycles (f o ur t o 2 4 wee ks).   A treat me n t c ycle is defi ne d 
as 2 8 da ys.   
 
St u d y O bjecti ves  
T he st u d y o bjecti ves f or Part 1 are  
T he pri m ar y o bjecti ve  is t o assess t he safet y a n d t olera bilit y of A R Q 7 5 1 i n s u bjects wit h 
a d va nce d s oli d t u m ors wit h A K T 1, 2, 3 ge netic alterati o ns, acti vati n g PI 3 K m ut ati o ns, P T E N-n ull , 
or ot her k n o w n acti o na ble P T E N m utati o ns . 
Sec o n d ar y a n d e x pl or at or y o bjecti ves  i ncl u de t he f oll o wi n g: 
▪ T o assess t he p har mac o ki netic ( P K) pr ofile of A R Q 7 5 1  
▪ T o assess t he p har mac o d y na mic acti vit y of A R Q 7 5 1 i n bl o o d s peci me ns 
o btai ne d fr o m s u bjects wit h a d va nce d s oli d t u m ors wit h A K T 1, 2, 3 ge netic 
alterati o ns, acti vati n g PI 3 K m utati o ns, P T E N -n ull,  or ot her k n o w n acti o na ble 
P T E N m utati o ns  
▪ T o deter mi ne t he ma xi m u m t olera te d d ose ( M T D) a n d/ or t he rec o m me n de d 
P hase 2 d ose ( R P 2 D) of A R Q  7 5 1  as si n gle a ge nt 
▪ T o ge nerate preli mi nar y e vi de nce of a nti -t u m or acti vit y  
 
T he st u d y o bjecti ves f or Part 2 are: 
T he pri m ar y o bjecti ve  is t o assess t he safet y a n d t olera bilit y of A R Q 7 5 1 i n c o m bi nati o n wit h 
paclita xel  or  f ul vestra nt i n s u bjects wit h a d va nce d, i n o pera ble, metastatic a n d/ or rec urre nt s oli d 
t u m ors wit h PI K 3 C A  / P T E N actio na ble  m utati o ns  a n d/ or A K T ge netic alterati o ns .  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 2  of 1 1 7  
 
Sec o n d ar y a n d e x pl or at or y o bjecti ves  i ncl u de t he f oll o wi n g: 
•  T o deter mi ne M T D/ R P 2 D d ose of A R Q  7 5 1 i n c o m bi nati o n wit h paclita xel  or  
f ul vestra nt  
•  T o assess t he P K pr ofile of A R Q i n c o m bi nati o n wit h paclita xel or  f ul vestra nt  
•  T o ge nerate preli mi nar y e vi de nce of a nti -t u m or acti vit y of A R Q 7 5 1 i n 
c o m bi nati o n 
w it h paclita xel or  f ul vestra nt i n s u bjects 
wit h a d va nce d, 
i n o pera ble, metastatic a n d/ or rec urre nt s oli d t u m ors wit h PI K 3 C A /P T E N 
actio na ble  m utati o ns  a n d/ or A K T ge netic alterati o ns  
•  T o deter mi ne C Y P 2 D 6 ge n ot y pe  
•  T o deter mi ne PI K 3 C A/ A K T/ P T E N  m utati o n stat us b y ct D N A   
 
S t u d y E n d p oi nts f or P art 1 
Pri m ar y e n d p oi nt : 
T he pri mar y e n d p oi nt of t he  st u d y is safet y a n d t olera bilit y a n d is meas ure d b y safet y varia bles 
w hic h i ncl u de t he re p orte d A Es, la b orat or y tests, vital si g ns, E C O G perf or ma nce stat us, a n d 
p h ysical e xa mi nati o n . 
 
Sec o n d ar y a n d e x pl or at or y e n d p oi nts  i ncl u de t he f oll o wi n g: 
•  P har mac o ki ne tics w hic h are meas ure d b y ma xi m u m plas ma dr u g c o nce ntrati o n ( C ma x ), area 
u n der t he c ur ve ( A U C), a n d eli mi nati o n half -life (t1/ 2) 
•  P har mac o d y na mic p har mac o d y na mics will be e val uate d b y c ha n ges i n ser u m gl uc ose a n d 
i ns uli n le vels, a n d b y c ha n ges i n cell-free ct D N A. 
•  R P 2 D will be deter mi ne d f oll o wi n g re vie w of all safet y, p har mac o d y na mic data a n d a nti -t u m or 
acti vit y ge nerate d i n t he d ose escalati o n p orti o n of t he st u d y.  T o get her wit h t he I n vesti gat ors, 
t he R P 2 D will be set at or bel o w t he M T D a n d at a d ose at w hic h p h ar mac o d y na mic acti vit y 
or a nti -t u m or acti vit y is de m o nstrate d.   
•  Preli mi nar y e vi de nce of a nti -t u m or acti vit y will be e val uate d b y R E CI S T v 1. 1 Res p o nse 
Criteria  
•   
St u d y E n d p oi nts  f or P art 2 
Pri m ar y e n d p oi nt : 
Safet y a n d t olera bilit y as assesse d b y t h e fre q uenc y, d urati o n, a n d se verit y of a d verse e ve nts ( A Es) 
fr o m t he first d ose of st u d y treat me nt t hr o u g h 3 0 da ys after t he last d ose of t hera p y. 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 3  of 1 1 7  
 
Sec o n d ar y e n d p oi nts  i ncl u de t he f oll o wi n g: 
•  P har mac o ki netics as meas ure d b y ma xi m u m plas ma dr u g(s) c o nce ntrat i o n 
( Cma x ), ti me t o ma xi m u m plas ma dr u g c o nce ntrati o n [ Tma x ], area u n der t he 
c ur ve ( A U C), a n d eli mi nati o n half -life (t1/ 2 ) 
•  R P 2 D as deter mi ne d f oll o wi n g re vie w of all safet y ge nerate d i n t he d ose 
escalati o n c o h ort(s) f or eac h c o m bi nati o n t hera p y Ar m.  T he R P 2 D will be set 
at or bel o w t he M T D.   
•  Preli mi nar y e vi de nce of a nti -t u m or acti vit y as assesse d b y R E CI S T v. 1. 1 
 
E x pl or at or y e n d p oi nts are as f oll o ws:  
•  T o e val uate t he effect of C Y P 2 D 6  p o l y m or p his m o n A R Q 7 5 1  e x p os ure 
•  T o deter mi ne prese nce of PI K 3 C A/ A K T/ P T E N  m utati o n(s) b y ct D N A i n bl o o d 
 
2. 1  
Criteri a f or A R Q 7 5 1 D ose Esc al ati o n a n d Deter mi n ati o n of D ose -Li miti n g T o xicit y  
f or P art 1 
E nr oll me nt at t he ne xt d ose le vel a n d/ or e nr oll me nt of a d diti o nal s u bjects i nt o t he o n g oi n g c o h ort  
occ ur re d acc or di n g t o t he f oll o wi n g criteria : 
•  If zer o of t hree i nitiall y treate d s u bjects e x perie nce a D L T ( A R Q 7 5 1 -relate d, pr o ba bl y relate d, 
or p ossi bl y r elate d) b y Da y 2 9 of d osi n g, t he n d ose escalati o n will occ ur  
•  If o ne of t hree i nitiall y treate d s u bjects e x perie nces a D L T b y Da y 29 of d osi n g, t he n a n 
a d diti o nal t hree s u bjects will be e nr olle d f or a t otal of si x s u bjects treate d at t he sa me d ose 
le vel.  Escalati o n will occ ur if n o a d diti o nal D L Ts are see n i n t hat co h ort ( D L T i n o ne of si x 
s u bjects). 
•  If t w o or m ore treate d s u bjects at a d ose le vel e x perie nce a D L T b y Da y 2 9 of c o nti n u o us 
d osi n g, d ose escalati o n will st o p a n d t he pri or d ose le vel a n d/ or a le ss fre q ue nt dr u g 
a d mi nistrati o n sc he d ule will be c o nsi dere d t he M T D. If t he first d ose res ults i n  2 or m ore 
s u bjects e x perie nci n g D L T , s u bse q ue nt s u bjects will be e nr olle d at a less fre q ue nt dr u g 
a d mi nistrati o n sc he d ule (e. g., 5 m g Q O D).  
•  If a s u bject wit h dra ws fr o m t he st u d y treat me nt f or a n y reas o n ot her t ha n a D L T d uri n g t he 
first c ycle ( 4 wee ks/ 2 8 da ys), t hat s u bject will be re place d. 
 
T he M T D was  defi ne d as t he d ose le vel at w hic h n o m ore t ha n o ne o ut of si x s u bjects has a n 
o bser va ble D L T.  
Ar Q ule’s 
Me di cal 
M o nit or a n d t he I n vesti gat or(s) re vie w e d all si g nifica nt A R Q  7 5 1 -relate d 
t o xicities t o deter mi ne if t he d ose escalati o n sc he d ule re q uires m o dificati o n. I nter me diate d oses 
a n d alter nati ve d osi n g sc he d ules c o ul d be assi g ne d t o a c o h ort after a gree me nt be t wee n t he 
Me dical M o nit or a n d t he I n vesti gat or(s).   
D uri n g t he d ose escalati o n peri o d, i ntra -s u bject d ose escalati o n was  o nl y per mitte d if t he f oll o wi n g 
criteria were  met :  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 4  of 1 1 7  
 
1.  T he ne xt hi g her d ose f or t his re gi me n has de m o nstrate d t o be safe b y at least 3 s u bjects a n d 
t he last s u bject c o m plete d o ne c ycle wit h o ut e xceedi n g a D L T.  
2.  T he s u bject i n q uesti o n has n ot e x perie nce d a D L T.  
 
O nce  t he M T D w as deter mi ne d, i ntra-s u bject d ose escalati o n t o t he M T D was  c o nsi dere d t o 
o pti mize t he treat me nt i n s u bjects e nr olle d at l o wer d ose le vels. M ulti ple i ntra -s u bject d ose 
escalati o ns per s u bject was  c o nsi dere d . 
2. 2  
Criteri a f or A R Q 7 5 1 D ose Esc al ati o n a n d Deter mi n ati o n of D ose -Li miti n g T o xicit y  
f or P art 2 
T o deter mi ne R P 2 D of A R Q 7 5 1 i n c o m bi nati o n wit h paclita xel  a n d f ul vestra nt, a mi ni m u m of 
t w o d ose le vels will be teste d. E nr olle d s ubjects will i nitiall y be treate d wit h 5 0 m g Q D of A R Q 
7 5 1 ( C o h ort 1 of Ar ms B  an d  C). E val ua ble s u bjects are defi ne d as ha vi n g bee n e x p ose d t o A R Q 
7 5 1 f or 2 8 da ys ( o ne c ycle/first c ycle of treat me nt). E nr oll me nt at t he ne xt d ose le vel a n d/ or 
e nr oll me nt of a d diti o nal s u bjects i nt o t he o n g oi n g c o h ort will occ ur acc or di n g t o t he f oll o win g 
criteria: 
•  If zer o of t hree i nitiall y treate d s u bjects e x perie nce a D L T ( A R Q 7 5 1 -relate d, 
pr o ba bl y relate d, or p ossi bl y relate d) b y Da y 2 9 of d osi n g, t he n d ose escalati o n 
will  occ ur (i.e., C o h ort 2)  
•  If o ne of t hree i nitiall y treate d s u bjects ex perie nce a  D L T b y Da y 2 9 of d osi n g, 
t he n a n a d diti o nal t hree s u bjects will be e nr olle d f or a t otal of si x s u bjects 
treate d at t he sa me d ose le vel.  Escalati o n will occ ur if n o a d diti o nal D L Ts are 
see n i n t hat c o h ort ( D L T i n o ne of si x s u bjects). 
•  If t w o or m ore treat e d s u bjects at a d ose le vel e x perie nce a D L T b y Da y  2 9 of 
c o nti n u o us d osi n g, f urt her d ose escalati o n will n ot be i nitiate d, a n d t he pri or 
d ose le vel a n d/ or a less fre q ue nt dr u g a d mi nistrati o n sc he d ule 
will be 
c o nsi dere d t he M T D. If t he first d os e le vel of st u d y treat me nt res ults i n 2 or 
m ore s u bjects e x perie nci n g a D L T , s u bse q ue nt s u bjects will be e nr olle d at 2 5 
m g Q D (i.e., C o h ort -1).  
•  If a s u bject wit h dra ws fr o m t he st u d y treatme nt f or a n y reas o n ot her t ha n a D L T 
d uri n g t he first c ycle ( 2 8 da ys ), t hat s u bject will be re place d. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 5  of 1 1 7  
 
 
T he M T D is defi ne d as t he d ose le vel at w hic h n o m ore t ha n o ne o ut of si x s u bjects ha ve a n 
o bser va ble D L T.  
T he d ose le vels f or paclita xel  a n d f ul vestra nt will sta y t he sa me f or all c o h orts.   
Ar Q ule’s Me dical M o nit or a n d t he I n vesti gat or(s) will re vie w all si g nifica nt treat me nt-relate d 
t o xicities t o deter mi ne if t he d ose escalati o n sc he d ule re q uires m o dificati o n. I nter me diate d oses 
a n d alter nati ve d osi n g s c he d ules ma y be assi g ne d t o a c o h ort after a gree me nt bet wee n t he Me d ical 
M o nit or a n d t he I n vesti gat or(s).  
D uri n g re g ular calls, t he S p o ns or  a n d t he I n vesti gat or (s) will als o m o nit or patie nts’ safet y b y 
re vie wi n g a n d e val uati n g st u d y data a n d a n y e mer gi n g safet y data/si g nals o n a n o n g oi n g basis.   
2. 3  
A R Q 7 5 1 D ose Li miti n g T o xi city  –  P art 1  
D ose -li miti n g t o xicities ( D L T) were  deter mi ne d d uri n g t he first c ycle (f o ur wee ks/ 2 8 da ys) of 
treat me nt. A D L T wa s defi ne d b y t he occ urre nce of a n y of t he f oll o wi n g t o xicities relate d, 
pr o ba bl y relate d, or p ossi bl y relate d t o A R Q  7 5 1  wit hi n t he first c ycle of treat me nt a n d gra de d 
acc or di n g t o 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 4. 0 3:  
•  Gra de 4 a ne mia  
•  Gra de 4 ne utr o pe nia  
•  Gra de 4 t hr o m b oc yt o pe nia  
•  Gra de 3  ne utr o pe nia lasti n g l o n ger t ha n 7 da ys des pite o pti mal treat me nt  
•  G ra de 3 t hr o m b oc yt o pe nia i n t he prese nce of blee di n g 
•  ≥ Gra de 3 h y per gl yce mia (fasti n g bl o o d gl uc ose > 2 5 0 m g/ d L or n o n -fasti n g > 5 0 0  m g/ d L) 
re q uiri n g i ns uli n ( u nc o ntr olle d wit h oral h y p o gl yce mic a ge nts)  
•  ≥ Gra de 3 n o n -he mat ol o gical t o xicit y of a n y d urati o n, e xce pt f or t he f oll o wi n g:  
o  Na usea, v o miti n g , or diarr hea res p o n di n g t o o pti mal me dical ma na ge me nt wit hi n 
4 8  h o urs  
o  Al o pecia  
•  A n y ot her t o xicit y t hat i n t he vie w of t he I n vesti gat or re prese nts a cli nicall y si g nifica nt 
hazar d t o t he s u bjec t 
2. 4  
A R Q 7 5 1 D ose Li miti n g T o xicit y  ( Ar ms B a n d  C)  –  P art 2  
D ose -li miti n g t ox icities will be deter mi ne d d uri n g t he first c ycle ( 2 8 da ys) of c o m bi nati o n t hera p y . 
A D L T is defi ne d b y t he occ urre nce of a n y of t he f oll o wi n g t o xicities relate d, pr o ba bl y relate d, or 
p ossi bl y relate d t o A R Q 7 5 1  w he n a d mi nistere d i n c o m bi nati o n wit h pacli ta xel or f ul vestra nt  
wit hi n t he first c ycle of treat me nt a n d gra de d acc or di n g t o 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 4. 0 3:  
•  Gra de 4 a ne mia  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 6  of 1 1 7  
 
•  Gra de 4 ne utr o pe nia  
•  Gra de 4 t hr o m b oc yt o pe nia  
•  Gra de 3 ne utr o pe nia lasti n g l o n ger t ha n 7 d a ys des pite o pti mal treat me nt  
•  Gra de 3 t hr o m b oc yt o pe nia i n t he prese nce of blee di n g   
•  ≥ Gra de 3 h y per gl yce mia (fasti n g bl o o d gl uc ose > 2 5 0 m g/ d L or n o n -fasti n g > 
5 0 0 m g/ d L) re q uiri n g i ns uli n ( u nc o ntr olle d wit h oral h y p o gl yce mic a ge nts)  
•  ≥ Gra de 3 n o n -he mat ol o gical t o xicit y of a n y d urati o n, e xce pt f or t he f oll o wi n g:  
o  Na usea, v o miti n g, or di arr hea res p o n di n g t o o pti mal 
me dical 
ma na ge me nt wit hi n 4 8 h o urs  
o  Al o pecia  
•  T he I n vesti gat or t o assess A L T a n d A S T c ha n ges t o deter mi ne if t hese c ha n ges 
ma y be a D L T  
o  ≥ Gra de 3 A L T or A S T ele vati o n f or s u bjects wit h A L T/ A S T ≤ 3 U L N 
at Baseli ne 
o  A L T/ A S T 
le vels f or s u bjects 
wit h k n o w n li ver 
metastases a n d 
A L T/ A S T ≤ 5 x U L N at Baseli ne  
o  Gra de 2 A L T/ A S T ele vati o n acc o m pa nie d b y ≥ Gra de 2 ele vati o n i n 
bilir u bi n  
•  A n y ot her t o xicit y t hat i n t he vie w of t he I n vesti gat or re prese nts a cli nicall y 
si g nifica nt hazar d to t he s u b ject 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 7  of 1 1 7  
 
3  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  
A d ult s u bjects wit h a d va nce d s oli d t u m ors wit h d oc u me nte d A K T  ge netic alte rati o ns, PI K 3 C A  or 
P T E N  actio na ble  m utati o ns w h ose ca ncer has pr o gresse d f oll o wi n g sta n dar d t hera p y, or f or w h o m 
sta n dar d t hera p y is n ot a vaila ble or is n ot t olera ble will be e nr olle d.  
 
Part 1 of t h is st u d y i ncl u des all s u bjects e nr olle d i n t he si n gle a ge nt d ose escalati o n c o h orts a n d 
e x pansi o n c o h ort  ( Ar m A) a n d Part 2 i ncl u des all s u bjects i n t he c o m bi nati o n treat me nts ar ms 
( Ar ms B a n d C).   
 
See  A n ne x 1 f or i ncl usi o n/e xcl usi o n criteria f or s u bjects e nr olle d u n der A me n d me nt 5. 
 
T o be e nr olle d, s u bjects m ust meet all eli gi bilit y criteria.  
3. 1  
I ncl usi o n Criteri a 
1.  Si g ne d writte n i nf or me d c o nse nt gra nte d p ri or t o i nitiati o n of a n y st u d y-s pecific 
pr oce d ure s 
2.  1 8 years of a ge a n d ol der  
3.  Hist ol o gicall y a n d/ or c y t ol o gicall y d oc u me nte d dia g n osis of a selecte d t u m or t y pe t hat 
is l ocall y a dva nce d, i n o pera ble, metastatic or rec urre nt (i ncl u di n g b ut n ot restricte d t o 
breast ca ncer, T N B C [tri ple ne gati ve]; H R -p ositi ve [ H R +]/ H E R 2-ne gati ve [ H E R 2 -] or 
e n d o metrial ca ncer) 
4.  D oc u me nte d A K T  ge netic alterati o n s or k n o w n acti o na ble PI K 3 C A /P T E N  m utati o ns 
b y ge netic testi n g  
•  
s u bjects wit h t u mors wit h P T E N n ull/ P T E N l os s-of -f u ncti o n mutati o ns are n ot eli gi ble   
5.  F or Ar ms B or C, s u bjects s h o uld be eli gi ble f or paclita xel or f ul vestra nt  t hera p y as per 
I n vesti gat or assess me nt  
6.  Fail ure t o res p o n d t o sta n dar d s yste mic t hera p y, or f or w h o m sta n dar d or c urati ve 
s yste mic t hera p y d oes n ot e xist or is n ot t olera ble.  
•  S u bjects i n Ar m A ( wit h A K T  g e netic alterati o ns)  a n d s u bjects i n d ose 
escalati o n c o h orts of Ar ms B a n d C s h o ul d ha ve at least o ne li ne of sta n dar d 
s yste mic t hera p y  
•  S u bjects i n Ar m A ( wit h PI K 3 C A/ P T E N  acti o na ble m utat i o ns) a n d s u bjects i n 
t he e x pa nsi o n c o h orts of Ar ms B a n d C s h o ul d ha ve no m ore t ha n 3 pri or 
s yste mic re gi me ns f or t he a d va nce d disease 
•  Ne oa dj u va nt a n d a dj u va nt c he m ot hera p y are c o nsi dere d o ne re gi me n if t he y are 
a c o nti n uati o n of t he s a me re gi me n wit h i nter val de b ul ki n g s ur ger y  
•  If t he s u bject is refract or y or has disease pr o gressi o n wi t hi n 6 m o nt hs after 
c o m pleti o n of t he a dj u va nt treat me nt, t he n t he a dj u va nt treat me nt s h o ul d be 
c o nsi dere d as t he l i ne of treat me nt rat her t ha n a n a dj u va nt thera p y.  
•  E n d ocri ne ( h or m o nal)  t hera p y d oes n ot c o u nt t o war d t otal li nes of t hera p y 
•  Mai nte na nce t hera p y is c o nsi dere d part of t he prece di n g re gi me n if o ne or m ore 
of t he sa me dr u gs ar e c o nti n ue d  
7.  Has at least o ne meas ura ble tar get lesi o n acc or di n g t o R E CI S T v . 1. 1  
8.  Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G) perf or ma nce stat us ( P S) ≤ 1  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 8  of 1 1 7  
 
9.  A de q uate or ga n f u ncti o n as i n dicate d b y t he f oll o wi n g la b orat or y val ues. ( All 
la b orat or y tests m ust be o btai ne d wit hi n 1 4 da ys pri or t o t he first d ose of st u d y 
treat me nt): 
a. He mat ol o gical  
•  A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 x 1 0 9/ L  
•  Platelet c o u nt ( Plt) ≥ 1 0 0 x 1 0 9/ L  
•  He m o gl o bi n ( H b) ≥ 9 g/ d L  
•  I nter nati o nal n or malize d rati o (I N R) 0. 8 t o u p per li mit of n or mal ( U L N) or ≤ 3 
f or s u bjects recei vi n g a ntic oa g ula nt t hera p y s uc h as C o u ma di n or he par i n 
 
b.  Re nal  
•  Ser u m creati ni ne ≤ 1. 5 x U L N or calc ulate d creati ni ne cleara nce ≥ 6 0 
m L/ mi n/ 1. 7 3 m 2 f or s u bjects wit h ser u m creati ni ne le vels >  1. 5 x i nstit uti o nal 
U L N  
•  He patic  
•  T otal bilir u bi n ≤ 1. 5 x U L N  
•  As partate a mi n otra nsferase ( A S T) a n d ala n i ne a mi n otra nsferase ( A L T) ≤ 3 x 
U L N or ≤ 5 x U L N f or s u bjects wit h k n o w n li ver metastases  
•  Meta b olic  
•  Gl ycate d he m o gl o bi n ( H b A 1c) ≤ 8 % ( ≤ 6 4 m m ol/ m ol)  
1 0.  If a s u bject is c urre ntl y recei vi n g bis p h os p h o nates or a n y ot her dr u g f or treat me nt of 
oste o p or osis, tre at me nt -i n d uce d b one l oss a n d metastases t o b o ne, t he s u bject m ust 
ha ve recei ve d t he bis p h os p h o nates f or at least f o ur wee ks pri or t o t he first d ose of st u d y 
treat me nt. 
•  I nitiati o n of bis p h os p h o nates or si milar a ge nts d uri n g t he st u d y ma y be all o we d 
pr o vi de d  t he s u bject c o m pletes t he first c ycle of treat me nt wit h o ut a n y d ose 
li miti n g t o xicit y ( D L T) a n d t he I n vesti gat or r ules o ut t u m or pr o gressi o n. 
1 1.  Male or fe male s u bjects of c hil d -pr o d uci n g p ote ntial m ust a gree t o use a de q uate 
c o ntrace pti o n , i ncl u di n g d o u ble -barrier c o ntrace pt i ve meas ures, oral c o ntrace pti o n, or 
a v oi da nce of i nterc o urse d uri n g t he st u d y a n d f or 9 0 da ys after t he last d ose of st u d y 
treat me nt.  
1 2.  W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na nc y test d uri n g 
Scr ee ni n g Peri o d a n d wit hi n 4 8 h o urs of  t he first d ose of st u d y treat me nt. “ W o me n of 
c hil d beari n g p ote ntial” is defi ne d as se x uall y mat ure w o me n w h o ha ve n ot u n der g o ne 
a h ysterect o m y or 
w h o ha ve n ot bee n nat urall y p ost me n o pa usal f or at least 
1 2  c o nsec uti ve m o nt hs pri or t o t he first d ose of st u d y treat me nt  
 
 
3. 2  
E xcl usi o n Criteri a  
1.  A nti -ca ncer t hera p y, s uc h as c he m ot hera p y, i m m u n ot hera p y, h or m o nal t hera p y, 
tar gete d t hera p y, or i n vesti gati o nal a ge nts wit hi n fi ve half-li ves or f o ur wee ks, 
w hic he ver is s h orter, pri or t o a d mi nistrati o n of t he first d ose o f st u d y treat me nt  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4 9  of 1 1 7  
 
•  T o be eli gi ble f or st u d y treat me nt, t o xicit y fr o m pri or treat me nt(s) m ust rec o ver 
t o Gra de ≤ 1, e xce pt f or al o pecia 
•  C o nc urre nt s yste mic hi g h -d ose c ortic oster oi ds (i n d osi n g e xcee di n g 1 0 m g Q D 
of pre d nis o ne e q ui vale nt) w he n use d i nter mitte ntl y i n a n a ntie me tic re gi me n, 
f or ce ntral ner v o us s yste m ( C N S) metastases ma na ge me nt, or as a part of t he 
pre me dicati o n re gi me n are all o we d  
2.  Ra diati o n t hera p y wit hi n f o ur wee ks, or palliati ve ra diati o n t hera p y wit hi n t w o wee ks, 
pri or t o  a d mi nistrati o n of t he first d ose of s t u d y treat me nt  
•  T o be eli gi ble f or st u d y treat me nt, ra diati o n t hera p y -relate d t o xicit y m ust 
rec o ver t o Gra de ≤ 1 pri or t o a d mi nistrati o n of t he first d ose of st u d y treat me nt 
•  C o nc urre nt palliati ve ra di ot hera p y f or l ocal  pai n -c o ntr ol or pre ve nti o n of 
fract ure (f or k n o w n b o ne metastases) ma y be all o we d pr o vi de d t he s u bject 
c o m pletes t he first c ycle of treat me nt, d oes n ot meet criteria of pr o gressi ve 
disease, a n d treate d lesi o ns will n ot be i ncl u de d i n t he tar get/ n o n -tar get lesi o n 
assess me nt.  
3.  Maj or s ur gical pr oce d ure wit hi n f o ur wee ks pri or t o a d mi nistrati o n of t he first d ose of 
st u d y treat me nt 
•  T o be eli gi ble f or t he st u d y treat me nt, all s ur gical w o u n ds m ust be f ull y heale d, 
a n d a n y s ur ger y -relate d a d verse e ve nts m ust rec o ver t o Gra de ≤ 1.  
4.  U na ble or u n willi n g t o s wall o w t he c o m plete dail y d ose of A R Q 7 5 1  
5.  Pre vi o us treat me nt wit h  
•  A K T i n hi bit ors (e. g., A R Q 0 9 2, M K -2 2 0 6, G S K 2 1 4 1 7 9 5, A Z D 5 3 6 3; pri or 
treat me nt wit h PI 3 K or m T O R i n hi bit or are all o we d) 
•  Pri or ta xa ne  t hera p y f or t he a d va nce d, 
metastatic disease  (f or s u bjects 
c o nsi dere d f or Ar m B, A R Q 7 5 1 + paclita xel, o nl y)  
6.  K n o w n pri or aller gic reacti o n t o or se vere i nt olera nce of paclita xel  or  f ul vestra nt. 
I nt olera nce is defi ne d as a seri o us a d verse e ve nt, a gra de 3 or 4 A E per C T C A E v. 4. 0 3, 
or per ma ne nt treat me nt  disc o nti n uati o n  
7.  Hist or y of T y pe 1  dia betes mellit us  or T y pe 2 dia betes mellit us re q uiri n g re g ular 
me dicati o n ( ot her t ha n oral h y p o gl yce mic a ge nts) or fasti n g gl u c ose ≥ 1 6 0 m g/ d L at 
Scree ni n g visit.  
8.  Si g nifica nt gastr oi ntesti nal dis or der(s) t hat c o ul d, i n t he o pi ni o n of t he I n vesti gat or, 
i nterfere wit h t he a bs or pti o n, meta b olis m, or e xcreti o n of A R Q 7 5 1 (e. g., i nfla m mat or y 
b o wel disease, Cr o h n’s disease, ulcerati ve  c olitis, e xte nsi ve gastric resecti o n)  
9.  K n o w n u ntreate d or acti ve C N S metastases a n d/ or carci n o mat o us me ni n gitis  
•  T o be eli gi ble f or t he st u d y treat me nt, s u bjects m ust ha ve sta ble disease ≥ 1 
m o nt h, c o nfir me d b y 
ma g netic res o na nce i ma gi n g ( M RI) or 
c o m p ute d 
to m o gra p h y ( C T) sca n, a n d ha ve C N S metastases well c o ntr olle d b y l o w -d ose 
ster oi ds, a nti-e pile ptics, or ot her s y m pt o m -relie vi n g me dicati o ns. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 0  of 1 1 7  
 
1 0.  Hist or y of m y ocar dial i nfarcti o n ( MI) or Ne w Y or k Heart Ass ociati o n ( N Y H A) Class 
II-I V c o n gesti ve heart fail ure wit hi n 6 m o nt hs of t he a d mi nistrati o n of t he first d ose of 
st u d y treat me nt ( MI occ urri n g > 6 m o nt hs of t he first d ose of st u d y treat me nt will be 
per mitte d); Gra de 2 or w orse c o n d ucti o n defect (e. g., ri g ht or left b u n dle bra nc h bl oc k).  
1 1.  A heart rate c o rrecte d Q T ( Q Tc) i nter val ≥ 4 8 0 msec, usi n g t he Fri dericia's f or m ula 
Q Tc F  
1 2.  Left ve ntric ular ejecti o n fracti o n ( L V E F) < 5 0 % as deter mi ne d b y M ulti ple Gate d 
Ac q uisiti o n ( M U G A) sca n or ec h ocar di o gra m ( E C H O) i n s u bjects w h o recei ve d pri or 
treat me nt wit h a nt hrac ycli nes  
1 3.  C o nc urre nt se vere a n d/ or u nc o ntr olle d ill ness n ot relate d t o ca ncer a n d/ or s ocial 
sit uati o n t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts, i ncl u di n g b ut n ot 
li mite d t o: 
•  Ps yc hiatric ill ness, s u bsta nce a b use  
•  O n g oi n g or acti ve k n o w n i nfe cti o n, i ncl u di n g h u ma n i m m u n o deficie nc y vir us 
( HI V) i nfecti o n, he patitis B or C vir us 
•  Si g nifica nt p ul m o nar y d ysf u ncti o n, i ncl u di n g p ne u m o nitis, i nterstitial l u n g 
disease (I L D), i di o pat hic p ul m o nar y fi br osis, c ystic fi br osis, se vere C O P D  
•  Peri p heral ne ur o pat h y gra de ≥2 ( Ar m B, A R Q 7 5 1 + paclita xel)  
•  Blee di n g diat hesis, t hr o m b oc yt o pe nia or c oa g ulati o n dis or ders ( Ar m C , A R Q 
7 5 1 +f ul vestra nt)  
•  T hr o m b otic/c oa g ulati o n dis or ders wit hi n 6 m o nt hs pri or t o t he first d ose of 
st u d y treat me nt u nless sta ble o n a ntic oa g ulati o n f or > 3 m o nt hs 
1 4.  Acti ve or hist or y of ot her mali g na nc y ot her t ha n t he c urre nt ca ncer wit hi n 2  years of 
t he first d ose of st u d y treat me nt, wit h t he e xce pti o n of carci n o ma i n-sit u of t he cer vi x, 
basal cell carci n o ma, a n d s u perficial bla d der t u m ors c urati vel y t reate d  
1 5.  Bl o o d tra nsf usi o n or a d mi nistrati o n of gr o wt h fact ors wit hi n 5 da ys pri or t o a bl o o d 
dra w bei n g use d t o c o nfir m eli gi bilit y  
1 6.  Pre g na nt or breastfee di n g  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt  7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 1  of 1 1 7  
 
4  
S T U D Y VI SI T S  
Bef ore t he start of a n y st u d y re q uire d pr oce d ures, t he I n vesti gat or or desi g nee m ust o btai n a si g ne d 
writte n i nf or me d c o nse nt f or m (I C F) f or t he st u d y fr o m eac h pr os pecti ve st u d y s u bject or his/ her 
le gal re prese ntati ve.  
F or Part 1, all o n g oi n g s u bjects e nr olle d i n t he  si n gle d ose escalati o n c o h ort  will c o nti n ue treat me nt  
per Sc he d ule of E ve nts  (see  A n ne x  1 ).  All o n g oi n g s u bjects e nr olle d i n t he  si n gle a ge nt d ose 
e x pa nsi o n c o h ort  ( Ar m A ) will f oll o w t he re vise d visit sc he d ule o utli ne d bel o w o nce rec o nse nte d.  
F or Part 2, s t u d y visits will c o nsist of a Scree ni n g  Visit , d uri n g w hic h t he s u bject’s eli gi bilit y f or 
t he st u d y a n d baseli ne disease state will be e val uate d; o n-treat me nt (w ee kl y, b i-wee kl y  or m o nt hl y) 
visits  de pe n di n g o n t he c ycle a n d treat me nt Ar m t he s u bject is e nr olle d , t he E n d of Treat me nt 
Visit , a n d a 3 0 -Da y  Safet y F oll o w -u p.    
F oll o wi n g t he Scree ni n g  Visit  a n d a deter mi nati o n b y t he I n vesti gat or t hat t he s u bject meets all 
eli gi bilit y  criteria, t he s u bject will be c o nsi dere d e ntere d i nt o t he st u d y.   
4. 1  
I nf or me d C o nse nt  
A sa m ple I C F wit h c ore i nf or mati o n will be pr o vi de d t o eac h st u d y site.  Pri or t o st u d y i nitiati o n 
at a gi ve n st u d y site, eac h site/I n vesti gat or m ust o btai n a writte n a p pr o val/fa v ora ble o pi ni o n fr o m 
its res pecti ve i nstit uti o nal re vie w b oar d (I R B)/ i n de pe n de nt et hics c o m mittee (I E C) f or t he I C F 
a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o s u bjects.  All I C Fs m ust be c o m plia nt wit h 
I C H G o o d Cli nical Practice  (G C P ) g ui deli nes a n d l ocal re g ulati o ns a n d m ust be a p pr o ve d b y t he 
S p o ns or  or desi g nee  pri or t o s u b missi o n t o t he I R B/I E C. T he writte n a p pr o val of t he I R B/I E C, 
t o get her wit h t he a p pr o ve d s u bject i nf or mati o n/I C F, m ust be mai ntai ne d i n t he st u d y master files.  
Writte n i nf or me d c o nse nt m us t be o btai ne d fr o m a pr os pecti ve s u bject bef ore a n y st u d y-s pecific 
pr oce d ures are perf or me d o n t hat i n di vi d ual. S u bjects w h o a g ree t o partici pate i n t he st u d y will 
si g n t he m ost rece ntl y a p pr o ve d I C F a n d will be pr o vi de d wit h a c o p y of t he f ull y e xec ute d 
d oc u me nt. T he ori gi nal, e xec ute d I C F will be mai ntai ne d i n t he res pecti ve s u bject’s cli nical st u d y 
file.   T he I C F ca n be si g ne d  greater t ha n 1 4 da ys pri or t o d osi n g,  a n d d oes n ot nee d t o be re -si g ne d 
pri or t o d osi n g u nless s pecific reas o ns a p pl y (e. g. , a ne w c o nse nt versi o n has bee n iss ue d a n d 
a p pr o ve d b y t he I R B/I E C).
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9 A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 2  of 1 1 7  
 
4. 2  
St u d y Visit s 
4. 2. 1 Ar m A ( A R Q 7 5 1 as a si n gle a ge nt)  
Scree ni n g  
C ycle 1  
C ycle 2 +   
E O T  
3 0 -d a y S afet y 
F oll o w u p  
(-1 4 t o -1  da ys)  
D a y 1  (-1 t o 0 da ys)  
D a y 1 5  ( ± 3 da ys) 
D a y 1   ( ± 3 da ys) 
( wit hi n 7 da ys of 
decisi o n t o per ma ne ntl y 
disc o nti n ue)  
( 3 0 da ys + after last 
d ose)  
 
Si g ne d I C F  
 
Me dical hist or y  
 
P h ysical e xa m, i ncl. s ki n  
 
Vital si g ns (te m perat ure, 
bl o o d press ure, 
res pirati o n rate,  p ulse) &  
hei g ht, wei g ht  
 
E C O G P S  
 
Fasti n g cli nical bl o o d 
tests 
 
T u m or mar kers 5  
 
Uri nal ysis  
 
1 2 -lea d E C G2 
 
Rec or d c o nc o mita nt 
me dicati o n s (c o n me ds) 
 
T u m or meas ure me nt a n d 
sta gi n g 
 
Ec h ocar di o gra m or 
M U G A sca n t o assess 
L V E F 3 
 
B o ne sca n  
 
Ser u m pre g na nc y test  
 
C ollect  re dacte d c o p y of 
t u m or ge ne se q ue nci n g 
re p ort 
 
 
P h ysical e xa m, i ncl. 
s ki n 
 
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate,  p ulse) &  
w ei g ht  
 
E C O G P S  
 
Fasti n g cli nical 
bl o o d tests 1  
 
T u m o r mar kers5  
 
Bl o o d sa m ples f or 
P K 4 
 
Tri plicate 1 2 -lea d 
E C G 2 
 
A d mi nister A R Q 7 5 1  
 
Dis pe nse A R Q 7 5 1  
 
Rec or d c o n me ds  
 
Assess A Es  
 
Bl o o d sa m ple f or 
C Y P 2 D 6  
 
Bl o o d sa m ple f or 
ct D N A 
 
P h ysical e xa m, 
i ncl. s ki n 
 
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate,  
p ulse)  
 
E C O G P S  
 
Fasti n g cli nical 
bl o o d tests 1  
 
T u m or mar kers 5  
 
Bl o o d sa m ples f or 
P K 4 
 
Tri plicate 1 2 -lea d 
E C G 2 
 
A d mi nister A R Q 
7 5 1  
 
Rec or d c o n me ds  
 
Assess A Es  
 
P h ysical e xa m, i ncl. 
s ki n 
 
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate, p ulse) & w ei g ht  
 
E C O G P S  
 
Fasti n g cli nical bl o o d 
tests1  
 
T u m or mar kers 5  
 
Bl o o d sa m ples f or P K 4  
( O N L Y at C ycles 2, 3 
a n d 4) 
 
Tri plicate 1 2 -lea d 
E C G 2  ( O N L Y at 
C y cles 2, 3 a n d 4  a n d 
if cli nicall y i n dicate d) 
 
Ra di o gra p hic t u m or 
assess me nt  ( per 
Secti o n 5. 8)  
 
A d mi nister A R Q 7 5 1  
 
Di s pe nse A R Q 7 5 1 
 
Rec or d c o n me ds  
 
Assess A Es  
 
 
P h ysical e xa m, i ncl. 
s ki n 
 
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate, p ulse) & wei g ht  
 
E C O G P S  
 
Fasti n g cli nical bl o o d 
tests 1 
 
T u m or mar kers 5  
 
Uri nal ysis  
 
Ser u m pre g na nc y test  
 
1 2 -lea d E C G2 
 
Ra di o gra p hi c t u m or 
assess me nt  (if P D n ot 
see n o n pri or sca n)  
 
Rec or d c o n me ds  
 
Assess A Es  
 
 
Rec or d c o n me ds  
 
Rec or d A Es  
 
1  Fasti n g cli nical bl o o d tests  (see Secti o n 5. 4) ma y be o btai ne d wit hi n 2 4 h o urs of t he visit (e xce pt  f or ti me p oi nts w here i ns uli n a n d gl uc ose sa m ples t hat are c ollecte d seriall y –  see A p pe n di x 3)  
2 C ollect  re dacte d c o pies of all E C G traci n gs.  See  A p pe n di x 3 f or details o n E C G ti me p oi nts.   
3  O nl y f or s u bjects w h o recei ve d pri or t hera p y wit h a nt hrac ycli nes           4  See A p p e n di x 3 f or details o n P K ti m e p oi nts. 
5 T u m or mar kers (if a p plica ble) -  at Scree ni n g a n d fre q ue nc y of testi n g w hile o n treat me nt  as per F D A/ N C C N g ui deli nes, or  i nstit uti o nal sta n dar ds 
 
 
0 7 Y 3 G R

Ar Q ule, I nc. 
5. 3 Pr ot oc ol or A me n d m e nt 
A R Q 7 5 1- 1 0 1 
1 6. 1. 1 Pr ot oc ol A me n d me nt 7 
 
0 9 A pril 2 0 1 9 
C o nfi de ntial 
Pa g e 5 3  of 1 1 7  
 
4. 2. 2 Ar m B ( A R Q 7 5 1 + p aclit a xel) 
Scree ni n g 
C ycle 1 
C ycle 2 +  
C y cle 2 + 
E O T  
3 0- d a y S afet y 
F oll o w u p 
(- 1 4 t o - 1 da ys) 
D a y 1 (- 1 t o 0 da ys)  
D a y 8 a n d D a y 1 5 
( ± 2 da ys) 
D a y 1  ( ± 2 da ys) 
 
D a y 8 a n d D a y 1 5  
( ± 2 da ys) 
 
( wit hi n 7 da ys of 
decisi o n t o 
per ma ne ntl y 
disc o nti n ue) 
( 3 0 da ys + after 
last d ose) 
  
Si g ne d I C F 
  
Me dical hist or y 
  
P h ysical e xa m, i ncl. 
s ki n 
  
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate, p ulse) & 
hei g ht, wei g ht 
  
E C O G P S 
  
Fasti n g cli nical 
bl o o d tests 
  
T u m or mar kers 5  
  
Uri nal ysis 
  
1 2-lea d E C G 2 
  
Rec or d c o nc o mita nt 
me dicati o ns 
(c o n me ds) 
  
T u m or 
meas ure me nt a n d 
sta gi n g 
  
Ec h ocar di o gra m or 
M U G A sca n t o 
assess L V E F 3 
  
B o ne sca n  
  
Ser u m pre g na nc y 
test  
  
C ollect re dacte d 
c o p y of t u m or ge ne 
se q ue nci n g re p ort 
 
  
P h ysical e xa m, 
i ncl. s ki n 
  
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate, 
p ulse) & wei g ht  
  
E C O G P S 
  
Fasti n g cli nical 
bl o o d tests 1  
  
T u m or mar kers 5  
  
Bl o o d sa m ples 
f or P K4 
  
Tri plicate 1 2-lea d 
E C G 2 
  
A d mi nister A R Q 
7 5 1  
  
A d mi nister 
paclita xel 
  
Dis pe nse A R Q 
7 5 1 
  
Rec or d c o n me ds 
  
Assess A Es 
  
Bl o o d sa m ple f or 
C Y P 2 D 6 
  
Bl o o d sa m ple f or 
ct D N A 
  
P h ysical e xa m, 
i ncl. s ki n 
  
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate, a 
p ulse) & wei g ht 
  
E C O G P S 
  
Fasti n g cli nical 
bl o o d tests 1  
  
T u m or mar kers 5  
  
Bl o o d sa m ples 
f or P K4 ( Da y 1 5 
O N L Y) 
  
Tri plicate 1 2-lea d 
E C G 2 ( Da y 1 5 
O N L Y) 
  
A d mi nister A R Q 
7 5 1  
  
A d mi nister 
paclita xel 
  
Rec or d c o n me ds 
  
Assess A Es 
 
  
P h ysical e xa m, i ncl. 
s ki n 
  
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate, a p ulse) & 
wei g ht  
  
E C O G P S 
  
Fasti n g cli nical 
bl o o d tests 1  
  
T u m or mar kers 5  
  
Bl o o d sa m ples f or 
P K 4 ( O N L Y at 
C y cles 2, 3 a n d 4) 
  
Tri plicate 1 2-lea d 
E C G 2 ( O N L Y at 
C y cles 2, 3 a n d 4 
a n d if cli nicall y 
i n dicate d) 
  
Ra di o gra p hic t u m or 
assess me nt ( per 
Secti o n 5. 8) 
  
A d mi nister A R Q 
7 5 1 
  
A d mi nister 
paclita xel  
  
Dis pe nse A R Q 7 5 1 
  
Rec or d c o n me ds 
  
Assess A Es 
 
  
P h ysical e xa m, 
i ncl. s ki n 
  
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate, 
p ulse) & wei g ht 
  
E C O G P S 
  
Fasti n g cli nical 
bl o o d tests 1  
  
T u m or mar kers 5  
  
A d mi nister 
A R Q 7 5 1  
  
A d mi nister 
paclita xel 
  
Rec or d c o n me ds 
  
Assess A Es 
 
  
P h ysical e xa m, 
i ncl. s ki n 
  
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate, 
p ulse) & wei g ht 
  
E C O G P S 
  
Fasti n g cli nical 
bl o o d tests 1 
  
T u m or mar kers 5  
  
Uri nal ysis 
  
Ser u m 
pre g na nc y test  
  
1 2-lea d E C G 2 
  
Ra di o gra p hic 
t u m or 
assess me nt (if 
P D n ot see n o n 
pri or sca n) 
  
Rec or d c o n me ds 
  
Assess A Es 
 
  
Rec or d 
c o n me ds  
  
Rec or d 
A Es 
 
1 Fasti n g cli nical bl o o d tests (s ee Secti o n 5. 4)  ma y be o btai n e d wit hi n 2 4 h o urs of t he visit (e xce pt f or ti me p oi nts w here i n s uli n a n d gl uc ose sa m ples t hat are c ollecte d seriall y – see A p pen di x 3)  
2 C ollect re dacte d c o pies of  all E C G traci n gs.  See A p p e n di x 3  f or details o n E C G ti me p oi nts. 
3 O nl y f or s u bjects w h o recei ve d pri or t hera p y wit h a nt hrac ycli nes                             4 See A p pe n di x 3 f or details o n  P K ti me p oi nts  
5 T u m or mar kers (if a p plica ble) - at S cree ni n g a n d fre q ue nc y of  testi n g w hile o n treat me nt as per F D A/ N C C N g ui deli nes, or i nstit uti o nal sta n dar ds 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 4  of 1 1 7  
 
4. 2. 3 Ar m C ( A R Q 7 5 1 +f ul vestr a nt)  
 
Scree ni n g  
C ycle 1  
C ycle 2 +   
C ycle 2  ( o nl y) 
E O T  
3 0 -d a y 
S afet y 
F oll o w u p  
(-1 4 t o -1  da ys)  
D a y 1  (-1 t o 0 da ys)  
D a y 1 5  ( ± 3 da ys) 
D a y 1  ( ± 3 da ys) 
D a y 1 5  ( ± 3 da ys) 
( wit hi n 7 da ys of 
decisi o n t o 
per ma ne ntl y 
disc o n ti n ue) 
( 3 0 da ys + 
after last 
d ose)  
 
Si g ne d I C F  
 
Me dical hist or y  
 
P h ysical e xa m, i ncl. 
s ki n 
 
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate, p ulse) & hei g ht, 
wei g ht  
 
E C O G P S  
 
Fasti n g cli nical bl o o d 
tests 
 
T u m or mar kers 5  
 
Uri nal ysis  
 
1 2 -lea d E C G2 
 
Rec or d c o nc o mita nt 
me dicati o ns (c o n me ds)  
 
T u m or meas ure me nt 
a n d sta gi n g 
 
Ec h ocar di o gra m or 
M U G A sca n t o assess 
L V E F 3 
 
B o ne sca n  
 
Ser u m pre g na nc y test  
 
C ollect  re dacte d c o p y 
of  t u m or ge ne 
se q ue nci n g re p ort 
 
P h ysical e xa m, 
i ncl. s ki n 
 
Vital si g ns 
(te m perat ure, bl o o d 
pre ss ure, 
res pirati o n rate, 
p ulse) & w ei g ht  
 
E C O G P S  
 
Fasti n g cli nical 
bl o o d tests 1  
 
T u m or mar kers 5  
 
Bl o o d sa m ples f or 
P K 4 
 
Tri plicate 1 2 -lea d 
E C G 2 
 
A d mi nister A R Q 
7 5 1  
 
A d mi nister 
f ul vestra nt 
 
Dis pe nse A R Q 7 5 1  
 
Rec or d c o n me ds 
 
Assess A Es  
 
Bl o o d sa m ple f or 
C Y P 2 D 6  
 
Bl o o d sa m ple f or 
ct D N A 
 
P h ysical e xa m, 
i ncl. s ki n 
 
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate, 
p ulse)  
 
E C O G P S  
 
Fasti n g cli nical 
bl o o d tests 1  
 
T u m or 
mar kers 5  
 
Bl o o d sa m ples 
f or P K4 
 
Tri plicate 1 2 -
lea d E C G2 
 
A d mi nister 
A R Q 7 5 1  
 
A d mi nister 
f ul vestra nt 
 
Rec or d 
c o n me ds 
 
Assess A Es  
 
P h ysical e xa m, i ncl. 
s ki n 
 
Vital si g ns 
(te m perat ure, bl o o d 
press ure, res pirati o n 
rate, p ulse) & wei g ht  
 
E C O G P S  
 
Fasti n g cli nical bl o o d 
tests1  
 
T u m or mar kers 5  
 
B l o o d sa m ples f or 
P K 4  ( O N L Y at 
C y cles 2, 3 a n d 4)  
 
Tri plicate 1 2 -lea d 
E C G 2  ( O N L Y at 
C y cles 2, 3 a n d 4  a n d 
if cli nicall y 
i n dicate d) 
 
Ra di o gra p hic t u m or 
assess me nt  ( per 
Secti o n 5. 8  
 
A d mi nister A R Q 7 5 1  
 
A d mi nister 
f ul vestra nt 
 
Dis pe nse A R Q 7 5 1  
 
Rec or d c o n me ds 
 
Assess A Es  
 
 
P h ysical e xa m, 
i ncl. s ki n 
 
Vital si g ns 
(te m perat ure, 
bl o o d pres s ure, 
res pirati o n rate, 
p ulse)  
 
E C O G P S  
 
Fasti n g cli nical 
bl o o d tests 1  
 
T u m or mar kers 5  
 
A d mi nister 
A R Q 7 5 1  
 
Rec or d 
c o n me ds 
 
Assess A Es  
 
P h ysical e xa m, 
i ncl. s ki n 
 
Vital si g ns 
(te m perat ure, 
bl o o d press ure, 
res pirati o n rate, 
p ulse) & 
wei g ht  
 
E C O G P S  
 
Fasti n g cli ni cal 
bl o o d tests 1 
 
T u m or 
mar kers 5  
 
Uri nal ysis  
 
Ser u m 
pre g na nc y test  
 
1 2 -lea d E C G2 
 
Ra di o gra p hic 
t u m or 
assess me nt  (if 
P D n ot see n o n 
pri or sca n)  
 
Rec or d 
c o n me ds 
 
Assess A Es  
 
 
Rec or d 
c o n me ds  
 
Rec or d 
A Es  
 
1  Fasti n g cli nical bl o o d tests (see Secti o n 5. 4) ma y be o btai ne d wit hi n 2 4 h o urs of t he visit (e xce pt  f or ti me p oi nts w here i ns uli n a n d gl uc ose sa m ples t hat are c ollecte d seriall y –  see A p pe n di x 3)  
2 C ollect  re dacte d c o pies of all  E C G traci n gs .  See  A p pe n di x 3 f or details o n E C G ti me p oi nts.  
3 O nl y  f or s u bjects w h o recei ve d pri or t hera p y wit h a nt hrac ycli nes                   
4  See  A p pe n di x 3 f or details o n P K ti me p oi nts    
5 T u m or mar kers (if a p plica ble) -  at Scree ni n g a n d fre q ue nc y of testi n g w hile o n treat me nt as per F D A/ N C C N g ui deli nes, or i nstit uti o nal sta n dar ds  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d m e nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 5  of 1 1 7  
 
 
 
4. 3  
S u bject Disc o nti n u ati o n  
S u bjects will be re m o ve d fr o m t he tre at me nt or t he st u d y at a n y ti me if t he y meet a n y of t he 
f oll o wi n g criteria: 
4. 3. 1  
S u bject Disc o nti n uati o n fr o m Treat me nt  
•  D oc u me nte d ra di o gra p hic pr o gressi o n of disease  
o  S u bjects ma y re mai n o n st u d y tre at me nt if, i n t he o pi ni o n of t he I n vesti gat or 
a n d wit h t he a gree me nt of t he Me dical M o nit or, t he y c o nti n ue t o deri ve 
be nefit fr o m t he st u d y dr u g  ( A R Q 7 5 1) 
•  D oc u me nte d cli nical pr o gressi o n of disease  
•  Cli nicall y u nacce pta ble t o xicities des pite o pti mal treat me nt or d ose re d ucti o n  
•  Wit h dra wal of c o nse nt  
•  N o nc o m plia nce wit h a n y part of t he st u d y, as assesse d b y t he I n vesti gat or or 
Me dical M o nit or  
•  I n vesti gat or’s decisi o n (wit h t he  a gree me nt wit h t he S p o ns or/ Me dical M o nit or 
or desi g nee)  
•  Deat h  
 
4. 3. 2  
S u bject Disc o nti n uati o n  fr o m t he St u d y 
•  Safet y f oll o w -u p visit is c o m plete d per t he pr ot oc ol a n d dr u g -relate d A Es ha ve 
res ol ve d t o baseli ne, N CI 
C T C A E 
Gra de 1, sta bilize d, or are dee me d 
irre versi ble 
•  Wit h dra wal of c o nse nt  
•  L ost t o f oll o w -u p  
•  Deat h  
 
4. 4  
St u d y Disc o nti n u ati o n  
T he S p o ns or reser ves t he ri g ht t o te m p oraril y or per ma ne ntl y disc o nti n ue t he st u d y at a n y site a n d 
at a n y ti me.  Reas o ns f or st u d y disc o nti n uati o n ma y i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  Safet y c o ncer ns  
•  P o or e nr oll me nt  
•  N o n -c o m plia nce wit h t he p r ot oc ol, G C P g ui deli nes, or ot her re g ulat or y 
re q uire me nts b y t he I n vesti gat or(s) 
•  Re q uest t o disc o nti n ue t he trial b y a re g ulat or y or healt h a ut h orit y  
•  Disc o nti n uati o n of pr o d uct de vel o p me nt  
•  Ma n ufact uri n g diffic ulties/c o ncer ns  
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 6  of 1 1 7  
 
T he S p o ns or a n d/ or desi g nee wi ll pr o m ptl y i nf or m all I n vesti gat ors a n d t he a p pr o priate re g ulat or y 
a ut h orities if t he st u d y is s us pe n de d or ter mi nate d f or safet y reas o ns. I n t he case of s uc h 
ter mi nati o n, t he I n vesti gat or will n otif y t he I R B or I E C, as a p pr o priate. 
If a n y s u bject i n Ar ms B or C per m a ne ntl y disc o nti n ues A R Q 7 5 1, t he y will at t hat ti me 
disc o nti n ue fr o m t he st u d y.  If a n y s u bject i n Ar ms B or C per ma ne ntl y disc o nti n ues t he 
c o m bi nati o n t hera p y ( paclita xel or f ul vestr a nt) t he s u bject will be all o we d c o nti n ue i n t he st u d y 
ta ki ng A R Q 7 5 1 u n til o ne of t he disc o nti n uati o n criteria is met.  
 
 
 
 
 
 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 7  of 1 1 7  
 
5  
S T U D Y P R O C E D U R E S  
Detaile d i nf or mati o n o n sc he d ule of assess me nts, a n d i nstr ucti o ns o n c ollecti o n a n d s hi p me nt of 
st u d y-relate d sa m ples a n d la b orat or y/testi n g re p orts ca n be f o u n d i n secti o n 4. 2 ( St u d y Visits) a n d 
A p pe n dices (1 a n d 3 ). 
 
All c ollecte d bi ol o gical sa m ples , cli nical re p orts a n d C T/ M RI sca ns will be la bele d b y pers o n nel 
fr o m t he i nstit uti o n wit h s u bjects’ st u d y I D a n d t heir i de ntit y will n ot be ma de k n o w n t o e m pl o yees 
fr o m t he S p o ns or, a d diti o nal c olla b orat ors, or ot her I n vesti gat ors. Sa m ples will o nl y be use d f or 
t he p ur p oses of t he pr ot oc ol a n d will o nl y be use d b y t he S p o ns or’s pers o n nel or b y a n e xter nal 
la b orat or y c h ose n b y t he S p o ns or t o o uts o urce t he a nal ysis acc or di n g t o i nter nal g ui d eli nes. 
Sa m ples will be ke pt u ntil all pr ot oc ol -relate d a nal yses are c o m plete d, f or a peri o d n ot e xcee di n g 
1 0 years  or as re q uire d b y l ocal la w . 
5. 1  
Me dic al Hist or y  
Me dical hist or y will i ncl u d e, b ut is n ot li mite d t o t he f oll o wi n g:  
•  De m o gra p h y: date of birt h, s e x, race, et h nic ori gi n 
•  Cli nicall y si g nifica nt pri or dia g n oses, s ur geries, a n d c o nc o mita nt me dicati o ns  
o  Me dicati o ns use d wit hi n 3 0 da ys pri or t o t he first d ose of A R Q 7 5 1 
s h o ul d be re p orte d 
•  C urre nt ca ncer hist or y:  dia g n osis, t u m or sta ge at ti me of dia g n osis  a n d st u d y 
e nr ol me nt; t u m or 
mar kers; pre vi o us a nti -ca ncer t hera p (ies) f or a d va nce d 
disease , i ncl u di n g dates, d urati o n a n d o utc o me of treat me nt; pre vi o us ra diati o n 
t hera p y, i ncl u di n g a nat o mic site, d ose a n d dates of treat me nt; pre vi o us 
ne oa dj u va nt, a dj u va nt  a n d mai nte na nce t hera p(ies), i ncl u di n g dates, d urati o n 
a n d o utc o me of treat me nt ; pre vi o us ca ncer -relate d s ur gical pr oce d ures, 
i ncl u di n g t y pe of t he pr oce d ures a n d dates. 
5. 2  
P h ysic al E x a mi n at i o n 
C o m plete p h ysical e xa mi nati o n of t he maj or b o d y s yste ms, i ncl u di n g s ki n, hei g ht, wei g ht, vital 
si g ns (t o i ncl u de bl o o d press ure, heart rate, res pirat or y rate, te m perat ure [ oral, a xillar y or 
t y m pa nic]), a n d E C O G P S (see A p pe n di x 2).  
5. 3  
1 2 -le a d E C G a n d Ec h oc ar di o gr a m/ M U G A Sc a n  
A n  ec h ocar di o gra m/ M U G A s h o ul d be c o n d ucte d at t he scree ni n g visit O N L Y f or S u bjects w h o 
recei ve d pri or t hera p y wit h a nt hrac ycli nes.  1 2 -lea d E C Gs (eit her si n gle or tri plicate) s h o ul d be 
c o n d ucte d at t he pr ot oc ol defi ne d ti me p oi nts (see A p pe n di x 3 ).  A d diti o nal E C G(s) a n d 
ec h ocar di o gra m/ M U G A sca n(s) ma y  be c o n d ucte d if cli nicall y  i n dicate d. C o pies of E C G traci n gs 
s h o ul d be pr o vi de d t o t he S p o ns or. 
5. 4  
Cli nic al L a b or at or y Tests  
Safet y la b orat or y deter mi nati o ns will i ncl u de he mat ol o g y, bl o o d c he mistr y, a n d uri nal yses.  All 
la b orat or y tests re q uire d d uri n g t he st u d y m ust be o btai ne d at t he l ocal la b orat or y at t he 
i n vesti gati o nal site.  C he mistr y sa m ples s h o ul d be ta ke n i n a fasti n g state (fasti n g f or at least 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 8  of 1 1 7  
 
8  h o urs) a n d pri or t o a d mi nistra ti o n of st u d y treat me nt (e xce pt f or ti me p oi nts w here i ns uli n a n d 
gl uc ose  sa m ples t hat are c ollecte d seriall y, see A p pe n di x 3).  If, i n err or, s u bject has eate n a hea d 
of testi n g, t his s h o ul d be d oc u me nte d as a fe d rat her t ha n as a fasti n g sa m ple i n t he electr o nic case 
re p ort f or m (e C R F) a n d o n t he req uisiti o n f or m.  
•  He mat ol o g y: c o m plete bl o o d c o u nt ( C B C) i ncl u di n g he m o gl o bi n, he mat ocrit, 
w hite bl o o d cell c o u nt wit h 5 -part differe ntial, re d bl o o d cell, a n d platelet c o u nt  
•  C oa g ulati o n t ests: (at Scree ni n g  a n d E n d of Treat me nt  visits , a n d if cli nicall y 
i n dicate d): pr ot hr o m bi n ti me ( PT), I N R, a n d partial pr ot hr o m bi n ti me ( P T T) 
•  Bl o o d c he mistr y: H b A 1c (at Scree ni n g  visit o nl y), bicar b o nate, bl o o d urea 
nitr o ge n ( B U N), calci u m, c hl ori de, creat i ni ne, gl uc ose, i ns uli n, ma g nesi u m, 
p otassi u m, t otal pr otei n, s o di u m, uric aci d  
•  Li ver f u ncti o n tes ts: al b u mi n, A L T, A S T, al kali ne p h os p hatase ( A L P), t otal a n d 
direct bilir u bi n, lactate de h y dr o ge nase ( L D H)  
•  Li pi ds: c h olester ol, hi g h -de nsit y li p o pr otei n ( H D L) , l o w-de nsit y li p o pr otei n 
( L D L), a n d tri gl yceri des 
•  T u m or mar k ers (if a p plica ble) t o m o nit or diseas e stat us (at scree ni n g a n d d uri n g 
t he treat me nt).  Fre q ue nc y of testi n g will be as per t he F D A/ N C C N g ui deli nes, 
or i nstit uti o nal sta n dar d of care  
•  R o uti ne uri nal ysis (at Scree ni n g  a n d E n d of Treat me nt  visits , a n d if cli nicall y 
i n dicate d): di pstic k a n d microsc o p y ( o nl y if cli nicall y i n dicate d or di pstic k is 
n ot d o ne)  
•  Ser u m pre g na nc y test (at Scree ni n g  a n d E n d of Treat me nt  visits  o nl y): f or 
fe male s u bjects of c hil d beari n g p ote ntial  
N ote: Fasti n g cli nical bl o o d tests ma y be o btai ne d wit hi n 2 4 h o urs of t he visi t (e xce pt f or 
ti me p oi nts w here i ns uli n a n d gl uc ose sa m ples t hat are c ollecte d seriall y, see A p pe n di x 3) 
5. 5  
P h ar m ac o ki netic / P h ar m ac o d y n a mic Assess me nts  
P K varia bles meas ure d will i ncl u de C ma x , A U C, a n d t1/ 2.   
F or s u bjects e nr olle d i n t he si n gle d ose escalati o n c o h orts a n d s u bjects e nr olle d i n si n gle a ge nt 
d ose e x pa nsi o n  (Ar m A ) u n der A me n d me nt 5 , b l o o d sa m ples f or P K a nal ysis were  c ollecte d 
d uri n g C ycle 1 Da y 1 ( 2 4 -h o ur f ull assess me nt, i ncl u di n g t he 2 4 -h o ur c ollecti o n o n t he m or ni n g 
of Da y 2), Da y 8, Da y 1 5, Da y 2 2 ( Da y 2 1 f or s u bjects recei vi n g A R Q 7 5 1 Q O D ) ( 2 4-h o ur f ull 
assess me nt, i ncl u di n g t he 2 4 h o ur c ollecti o n o n t he m or ni n g  of Da y 2 3  [Da y 2 2  f or s u bjects 
recei vi n g A R Q 7 5 1 Q O D] ) a n d o n C ycle 2 Da y 1 a n d Da y  1 5 . 
F or su bjects i n Ar m A (e nr olle d a n d/ or rec onse nte d u n der A me n d me nts 6 or later ) a n d su b jects i n 
Ar m s B a n d C, b l o o d sa m ples f or P K a nal ysis will be c ollecte d acc or di n g t o pr ot oc ol defi ne d 
ti me p oi nts (see A p pe n di x 3). 
T he bl o o d sa m ple c ollecti o n date a n d ti me, a n d t he ti me of d osi n g of A R Q  7 5 1 , paclita xel a n d  
f ul vestra nt a d mi nistrati o n o n t he da ys of P K m ust be rec o r de d o n t he e C R F. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 5 9  of 1 1 7  
 
A d diti o nal u nsc he d ule d bl o o d sa m ple(s) f or P K ma y be c ollecte d o n a n y st u d y da y(s) u p o n 
a gree me nt bet wee n t he I n vesti gat or a n d t he S p o ns or.  
Detaile d i nstr ucti o ns f or c ol lecti o n a n d s hi p me nt of plas ma P K sa m ples will be pr o vi de d i n t he 
lab orat or y ma n ual.  
A bl o o d sa m ple t o deter mi ne C Y P 2 D 6 ge n ot y pe will be c ollecte d.  Patie nt C Y P 2 D 6 stat us will be 
deter mi ne d a n d t he effect o n P K e x p os ure will be e val uate d.  
 
A  bl o o d sa m ple t o deter mi ne m utati o n stat us b y li q ui d bi o ps y (ct D N A) will be c ollecte d. 
Detaile d i nstr ucti o ns f or c ollecti o n a n d s hi p me nt of bi ol o gical  sa m ples is pr o vi de d i n t he 
la b orat or y ma n ual. 
5. 6  
H o me Bl o o d Gl uc ose M o nit ori n g  
S u bjects s h o ul d perf or m a h o me fasti n g bl o o d gl uc ose test at least o nce per da y ( bef ore brea kfast) 
f or t he first f o ur wee ks e xce pt f or da ys w here t he s u bject has gl uc ose teste d at t he site . If t he fasti n g 
gl uc ose le vel is >  1 6 0 m g/ d L b ut ≤ 2 5 0 m g/ d L, s u bjects are t o test a gai n bef ore di n ner.  If t h e 
fasti n g gl uc ose le vel is > 2 5 0 m g/ d L, s u bjects are t o call t heir I n vesti gat or. After t he first f o ur 
wee ks of treat me nt, t he I n vesti gat or will d eter mi ne if a s u bject s h o ul d c o nti n ue h o me gl uc ose 
testi n g a n d t he testi n g fre q ue nc y. 
5. 7  
T u m or E v al u ati o n  
Sta n dar d i ma gi n g st u dies ( C T sca n or 
M RI) s h o ul d be perf or me d acc or di n g t o i nstit uti o nal 
pr oce d ures a n d/ or sta n dar d of care.  T u m or res p o nse will be e val uate d usi n g t he g ui deli nes f or 
Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) v. 1. 1 o utli ne d i n A p pe n di x 5.  
F or all s u bjects, a b o ne sca n s h o ul d be perf or me d d uri n g  Scree ni n g peri o d  a n d if cli nicall y 
i n dicate d t hereafter.  
I ma gi n g st u dies ca n be use d as t he baseli ne assess me nt if t he y were perf or me d wit hi n f o ur wee ks 
( 2 8 da ys) pri or t o t he first d ose of A R Q 7 5 1. 
W hile o n st u d y, t u m or e val uati o ns will be perf or me d e ver y 2 c ycles d uri n g first 1 2 c ycles. F or 
s u bjects w h o d o n ot e x perie nce disease pr o gressi o n a n d c o nti n ue t o be nefit fr o m t he treat me nt 
after 1 2 c ycles, t u m or e val uati o n ma y be perf or me d e ver y 3 c ycles u p o n a gree me nt bet wee n t he 
I n vesti gat or a n d t he Me dical M o nit or.  T u m or e val uati o n will als o be perf or me d at t he E n d of 
Treat me nt visit u nle ss t he pri or sca n s h o we d ra di o gra p hic disease pr o gressi o n. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 0  of 1 1 7  
 
6  
T R E A T M E N T  
A R Q 7 5 1, P aclit a xel  a n d  F ul vestr a nt A d mi nistr ati o n  
 
T he S p o ns or will pr o vi de A R Q 7 5 1 re q uire d f or t his st u d y.  Paclita xel a n d f ul vestra nt will be 
o btai ne d b y t he s u bject fr o m c o m mer cial so urces. F or a d mi nistrati ve reas o ns, t he treat me nt peri o d 
is di vi de d i nt o 4-wee k c ycles ( 2 8 da ys).  
S u bjects e nr olle d i n Ar m A will recei ve A R Q 7 5 1 at 7 5 m g Q D, c o nti n u o usl y.  
 
I n Ar ms B  a n d C , d ose deter mi nati o n will be gi n wit h c o h ort 1 ( 5 0 m g A R Q 7 5 1 ) a n d will be d o ne 
as f oll o ws: 
 
C o h ort  
A R Q 7 5 1  
( or all y, P O)  
P aclit a xel  
( Ar m B) 
F ul vestr a nt  
( Ar m C) 
-1  
2 5 m g Q D  
 
8 0 m g/ m 2 (I V)  
Da ys 1, 8, 1 5 f oll o we d b y 
a wee k of rest 
 
5 0 0 m g (I M)  
Da ys 1 & 1 5 of C ycle 1, a n d Da y 1 of all 
s u bse q ue nt c ycles 
1  
5 0 m g Q D  
2  
7 5 m g  Q D  
E x p a nsi o n  
R P 2 D  
 
A R Q  7 5 1 will be a d mi nistere d b y m o ut h u n der faste d c o n diti o n ( o ne h o ur pri or t o or t w o h o urs 
after t he meal). T he d ose of A R Q  7 5 1 t o be a d mi nistere d de pe n ds o n t he d ose le vel c o h ort t o w hic h 
t he s u bject is e nr olle d.  A R Q 7 5 1 s h o u l d be ta ke n at a p pr o xi matel y t he sa me ti me eac h da y, 
es peciall y o n P K sa m pli n g da ys . O n n o n -P K sa m pli n g da ys, A R Q  s h o ul d be ta ke n wit hi n 4 -6 h o urs 
of t he sc he d ule d d osi n g ti me.   
It is e x pecte d t hat m ost s u bjects will recei ve A R Q  7 5 1 as a si n gle a ge nt or i n  c o m bi nati o n wit h 
paclita xel  or  f ul vestra nt f or f o ur t o 2 4 wee ks. 
Paclita xel  a n d f ul vestra nt a d mi nistrati o n a n d a d mi nistrati o n of pre me dic ati o n t hera p y if re q uire d 
s h o ul d f oll o w t he F D A a p pr o ve d re gi me ns, N C C N g ui deli nes, or i nstit uti o nal S O C.  
6. 1  
A R Q 7 5 1  
T he i n vesti gati o nal dr u g A R Q 7 5 1 is s u p plie d as ca ps ules f or oral a d mi nistrati o n. A R Q 7 5 1 is 
pac ka ge d i n stre n gt h of 2 5 m g a n d is s u p plie d t o t he p har mac y at t he cli nical site.  A R Q 7 5 1 is 
la bele d as a n i n vesti gati o nal a ge nt, li mite d b y fe deral a n d ot her ap pli ca ble la ws.  T he a p pr o priate 
q ua ntit y of ca ps ules s h o ul d be dis pe nse d t o t he s u bject acc or di n g t o t he c o h ort d osi n g le vel a n d 
sc he d ule of a d mi nistrati o n t he s u bject is e nr olle d t o. A R Q  7 5 1 s h o ul d be st ore d acc or di n g t o t he 
i nstr ucti o ns pr o vi de d o n t he dr u g  la bel.  
6. 2  
I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he reci pie nt will ac k n o wle d ge recei pt of A R Q 7 5 1 b y i n dicati n g s hi p me nt c o nte nt a n d c o n diti o n.  
Da ma ge d s u p plies will be re place d. U ntil dis pe nse d t o t he s u bjects, t he st u d y dr u g will be st ore d 
i n a sec ure area, accessi ble t o a ut h orize d pers o n nel o nl y. 
0 7 Y 3 G R

Ar Q ule, I nc. 
5. 3 Pr ot oc ol or A me n d me nt 
A R Q 7 5 1- 1 0 1 
1 6. 1. 1 Pr ot oc ol A me n d me nt 7 
 
0 9 A pril 2 0 1 9  
C o nfi de ntial  
Pa g e 6 1  of 1 1 7  
 
Dr u g  acc o u nta bilit y  rec or ds  will  be  mai ntai ne d  f or  A R Q  7 5 1.    T h ese  rec or ds  s h o ul d  rec or d 
q ua ntities of st u d y dr u g recei ve d  a n d q ua ntities dis pe nse d t o su bjects, i ncl u di n g l ot n u m ber, date 
recei ve d a n d dis pe nse d, s u bject i de ntifier n u m ber, s u bject i nitials, pr ot oc ol n u m ber, d ose, q ua ntit y 
ret ur ne d, bala nce re mai ni n g, a n d t he i nitials of t he pers o n dispe nsi n g t he dr u g.  Acc urate rec or ds 
of all st u d y dr u g dis pe nse d fr o m a n d ret ur ne d t o t he st u d y site  are t o be mai ntai ne d. T he st u d y site 
m ust  s u p pl y  a  c o p y  of  t heir  dr u g destr ucti o n  p olic y  t o  t he  S p o n s or  bef ore  a ut h orizati o n  f or 
destr ucti o n will be gra nte d. Pr o d uct acc o u nta bilit y will be m o n it ore d t hr o u g h o ut t he st u d y. U p o n 
c o m pleti o n or ter mi nati o n of t he st u d y a n d after i n ve nt or y veri ficati o n b y a n Ar Q ule m o nit or or 
desi g nate d re prese ntati ve, all u n o pe ne d, u n dis pe nse d i n vesti gat i o nal pr o d uct is to be ret ur ne d t o 
Ar Q ule  i n  t he  ori gi nal  c o ntai ners  u nless  a p pr o val  has  bee n  gra n te d  t o  destr o y  u n use d 
i n vesti gati o nal pr o d uct at t he site or l ocal destr ucti o n facilit y. 
6. 3  
St or a ge a n d H a n dli n g 
At a st u d y site, A R Q 7 5 1 s h o ul d be  st ore d at c o ntr olle d r o o m tem perat ure ( 2 0° C- 2 5° C; 6 8° F- 7 7° F) 
acc or di n g t o t he st ora ge i nstr ucti o ns pr o vi de d o n t he la bel, u n til dis pe nse d t o t he s u bject.  
 
At a st u d y site, st ora ge a n d ha n dli n g of paclita xel a n d f ul vest ra nt s h o ul d f oll o w t he F D A a p pr o ve d 
la bel or i nstit uti o nal p har mac y g ui deli nes. 
 
6. 4  
Misse d or V o mite d D ose 
A misse d d ose ma y be ta ke n wit hi n a 4- 6 h o ur wi n d o w of t he re g u lar, sc he d ule d d ose. A v o mite d 
d ose s h o ul d n ot be re place d. T h e s u bject s h o ul d be i nstr ucte d t o ta ke t he ne xt sc he d ule d d ose at 
t he re g ularl y sc he d ule d ti me. If t he s u bject v o mite d t he ver y first d ose of st u d y dr u g ( A R Q 7 5 1), 
t he s u bject ma y be re-c halle n ge d at t he discreti o n of t he I n vesti gat or. 
6. 5  
D ose M o dific ati o ns 
I n ge neral, o nce t he d ose of A R Q 7 5 1 has bee n m o difie d f or a s ubject, all s u bse q ue nt d oses s h o ul d 
be a d mi nistere d t o t hat s u bject a t t he m o difie d d ose le vel a n d d ose a d mi nistrati o n sc he d ule.  
W he n  a  A R Q  7 5 1-relate d  t o xicit y  (a n y  t o xicit y  c o nsi dere d  t o  be  relate d,  pr o ba bl y  relate d,  or 
p ossi bl y  relate d  t o  A R Q  7 5 1)  is  o bser ve d,  d ose  dela ys  a n d/ or  re d ucti o ns  i n  A R Q 7 5 1 
a d mi nistrati o n are all o we d.  If d ose re d ucti o n is i n dicate d, t h e s u bject s h o ul d be assi g ne d t o t he 
pre vi o us (l o wer) c o h ort d ose a n d sc he d ule ( d ose re-escalati o n is n ot per mitte d) or t o a d ose a n d 
sc he d ule a gree d u p o n b y t he S p o ns or a n d t he I n vesti gat or. I n t he e ve nt of a d ose m o dificati o n, t he 
d ose c ha n ge(s) m ust be ca pt ure d i n t he electr o nic data ca pt ure ( E D C) s yste m.  
O nce t he R P 2 D A R Q 7 5 1 d ose i n c o m bi nati o n wit h paclita xel or f u l vestra nt is deter mi ne d, i ntra-
s u bject  d ose  escalati o n  of  A R Q  7 5 1  ma y  be  c o nsi dere d  t o  o pti mize  t he  treat me nt  i n  s u bjects 
e nr olle d at l o wer d ose le vels.  
T he  d ose  le vel  f or  paclita xel  a n d  f ul vestra nt  will  sta y  t he  sa m e  f or  all  c o h orts.    Paclita xel  a n d 
f ul vestra nt d ose m o dificati o ns or dela ys s h o ul d f oll o w t he F D A a p pr o ve d la bel, N C C N g ui deli nes, 
or i nstit uti o nal sta n dar d of practice. 
I n  case  of  n o n- A R Q  7 5 1-relate d  t o xicit y  a n d  if  treat me nt  wit h  paclita xel  or  f ul vestra nt  is 
i nterr u pte d, t he s u bject ma y c o nti n ue ta ki n g A R Q 7 5 1 u p o n a greeme nt bet wee n t he I n vesti gat or 
a n d t he S p o ns or’s Me dical M o nit o r. I n case of A R Q 7 5 1-relate d to xicit y t hat re q uire d A R Q 7 5 1-
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 2  of 1 1 7  
 
treat me nt i nterr u pti o n, t he s u bject ma y c o nti n ue treat me nt wit h paclita xel  or  f ul vestra nt u p o n 
a gree me nt bet wee n t he I n vesti gat or a n d t he S p o ns or’s Me dical M o nit or.  
T a ble 1  
D ose Del a ys/ Re d ucti o ns f or A R Q 7 5 1 -Rel ate d T o xicit y E xce pt 
H y per gl yce mi a  
E ve nt Gr a de  
Acti o n  
Al o peci a  
C o nti n ue c urre nt d ose le vel  
Gr a de 1 or 2  
C o nti n ue c urre nt d ose le vel, h o we ver, at t he discreti o n of t he I n vesti gat or, d ose 
i nterr u pti o n/ m o dificati o n ma y be i m ple me nte d (e. g., ras h).  If rec o ver y occ urs after 
m ore t ha n 2 1 da ys o n dr u g h ol d, per ma ne ntl y disc o nti n ue A R Q  7 5 1 . 
Gr a de 3 -4 (e xce pt 
Gr a de 3 n a use a, 
v o miti n g , or di arr he a 
l asti n g less t h a n 
2 4  h o urs)  
Wit h h ol d A R Q 7 5 1 u ntil rec o ver y t o Gra de 1 or baseli ne. If rec o ver y occ urs wit hi n 
2 1 da ys, restart A R Q 7 5 1 at t he d ose a n d sc he d ule of t he pre v i o us c o h ort f or 
s u bse q ue nt d oses, u nless f urt her d ose re d ucti o n is re q uire d. If rec o ver y occ urs after 
m ore t ha n 2 1 da ys o n dr u g h o l d, per ma ne ntl y disc o nti n ue A R Q 7 5 1.  
Gr a de 3 n a use a, 
v o miti n g , or di arr he a 
l asti n g less t h a n 
2 4  h o urs  
Wit h h ol d A R Q 7 5 1 u ntil rec o ver y t o Gra de 1 or baseli ne. If rec o ver y occ urs wit hi n 
2 4 h o urs, restart A R Q 7 5 1 at t he c urre nt d ose le vel. If rec o ver y occ urs after 2 4 h o urs 
a n d wit hi n 2 1 da ys, restart A R Q 7 5 1 at t he d ose a n d sc he d ule of t he pre vi o us c o h ort 
f or s u bse q ue nt d oses, u nless f urt her d ose re d ucti o n is re q uire d. If rec o ver y occ urs 
after m ore t ha n 2 1 da ys o n dr u g h ol d, per ma ne ntl y disc o nt i n ue A R Q 7 5 1.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 3  of 1 1 7  
 
T a ble 2  
D ose M o dific ati o n f or A R Q 7 5 1 -rel ate d H y per gl yce mi a a n d S u g geste d 
Cli nic al Tre at me nt a n d M a n a g e me nt of  H y per gl yce mi a  
E ve nt Gr a de  
A R Q 7 5 1 D ose M o dific ati o n  
S u g geste d Cli nic al Tre a t me nt a n d 
M a n a ge me nt of H y per gl y ce mi a 
Gr a de 1  
C o nti n ue treat me nt wit h c urre nt d ose 
le vel a n d sc he d ule 
Start o nce per da y h o m e gl uc ose m o nit ori n g 
(alter nate bet wee n bef ore  brea kfast a n d bef ore 
di n ner ; prefera bl y fasti n g)  
N o treat me nt nee de d  
Gr a de 2  
C o nti n ue treat me nt wit h t he c urre nt 
d ose le vel a n d sc he d ule  
Start h o me gl u c ose m o nit ori n g t wice per da y 
( bef ore brea kfast a n d di n ner ; prefera bl y fasti n g).  
Treat h y per gl yce m ia f oll o win g t he al g orit h m i n 
Secti o n A  of  Ta ble 3  or per t he I n v esti gat or’s 
discreti o n.  
Gr a de 3 
( As y m pt o m atic) 
C o nti n ue treat me nt wit h c urre nt d ose 
le vel a n d sc he d ule 
Start h o me gl u c ose m o nit ori n g t wice per da y 
( before brea kfa st a n d di n ner; prefera bl y fasti n g)  
Treat h y per gl yce m ia f oll o wi n g t he al g orit h m i n 
Secti o n B  of  Ta ble 3  or per t he I n v esti gat or’s 
discreti o n.  
Gr a de 3 
( S y m pt o m atic) 
or  
Gr a de 4 
( As y m pt o m atic) 
If im pr o ve d ( gl uc ose <  2 5 0  m g/ d L) 
wit h i n o ne wee k, c o nti n ue A R Q  7 5 1 
treat me nt at t he c urre nt d ose le vel u nti l 
d ose re d uct i o n is re q uire d.   
If not i m pr o ve d ( gl uc ose ≥ 2 5 0  m g/ d L) 
wit h i n o ne wee k, wit h h ol d st u d y dr u g 
a n d restart A R Q  7 5 1 treat me nt at t he 
ne xt l o we r d ose  le vel w he n gl uc ose is 
< 2 5 0  m g/ d L a n d t here are n o 
s y m pto ms . 
Start h o me gl u c ose m o nit ori n g t h ree ti mes per 
da y a n d bef ore e v er y be d ti me ; prefera bl y fasti n g  
Treat h y per gl yce m ia f oll o wi n g t he al g orit h m i n 
Secti o n C  of  Ta ble 3  or per t he I n v esti gat or’s 
discreti o n.  
Gr a de 4 
( S y m pt o m atic) 
Wit h h ol d st u d y dr u g.  
If i m pr o ved ( gl uc ose < 2 5 0 m g/ d L) 
wit hi n 7 da ys, restart A R Q 7 5 1 at t he 
ne xt l o we r d ose le vel u nti l f urt her d ose 
re d ucti o n is re q uire d.  
If n ot i mpr o ve d ( gl uc ose ≥ 2 5 0  m g/ d L) 
wit hi n 7 da ys, disc o nti n ue st u d y 
treat me nt per ma ne ntl y 
Refer t o a n e n d ocri n ol o g y or dia betes treati n g 
s pecialist 
S o urce: B usai d y N L, Far o o ki A, D o wlati A, et al. Ma na ge me nt of meta b olic effects ass ociate d wit h a ntica ncer a ge nt tar get i n g t he 
PI 3 K -A kt -m T O R pat h wa y. J Cli n O nc ol . 2 0 1 2; 3 0( 2 3): 2 9 1 9-2 8.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 4  of 1 1 7  
 
T a ble 3  
S u g geste d Cli nic al Tre at me nt a n d M a n a ge me nt of H y per gl yce mi a  
A  
Ma na ge me nt f or Gra de 2 h y per gl yce mia  
( 1 6 1-2 5 0 m g/ d L)  
C hec k h o me bl o o d gl uc oses A C BI D  
Lifest yl e c ha n ge ( T L C)  
 Metf or mi n *  
 
 
 
After 2 wee ks: If t he fasti n g gl uc ose is Gra de 2 or ra n d o m gl uc ose is > 2 0 0 m g/ d L  
C o nti n ue metf or mi n *  
 
A d d s ulf o n yl urea a n d titrate  
 
 
 
After a n a d diti o nal 1 wee k: If fasti n g gl uc ose is > 1 6 0 m g/ d L or ra n d o m gl uc ose is >  2 0 0 m g/ d L  
C o nti n ue t w o oral a ge nts  
 
A d d basal i ns uli n  
 
 
 
St o p oral a ge nts. Be gi n basal b ol us i ns uli n f o ur i njecti o ns/ da y. 
 
B  
Ma na ge me nt f or as y m pt o matic Gra de 3 h y per gl yce mia  
( 2 5 0-5 0 0 m g/ d L)  
Be gi n metf or mi n * a n d s ulf o n yl urea  
C hec k h o me bl o o d gl uc os e A C BI D 
 Ra pi dl y titrate oral a ge nts  
 
 
 
After 1 wee k: If fasti n g gl uc ose is > 1 6 0 m g/ d L or ra n d o m gl uc ose is > 2 0 0 m g/ d L  
A d d basal i ns uli n t o oral a ge nts  
 
Titrate basal i ns uli n t o fasti n g gl uc ose  
 
 
 
After a n a d diti o nal 1 wee k: If fasti n g gl uc ose is  > 1 6 0 m g/ d L or ra n d o m gl uc ose is > 2 0 0 m g/ d L  
St o p oral a ge nts; a d d pre -meal i ns uli n  
 
C hec k gl uc ose A C TI D a n d Q H S  
 
C  
Ma na ge me nt f or s y m pt o matic Gra de 3 h y per gl yce mia ( 2 5 0 -5 0 0 m g/ d L)  
or Gra de 4 h y per gl yce mia ( > 5 0 0 m g/ d L)  
C o nsi der I V F a n d/ or a d mit if h y p o v ole mic si g ns/s y m pt o ms  
Dia betes c o ns ultati o n  
 F o ur -i njecti o n basal b ol us i ns uli n re gi me n 
 
 
 
C hec k h o me gl uc ose A C TI D a n d Q H S  
After 1 wee k: If fasti n g or ra n d o m gl uc ose > 2 5 0 m g/ d L  
D L T a n d h ol d A R Q 7 5 1  
 
Restart w he n gl uc ose < 2 5 0 m g/ d L a n d  
n o s y m pt o ms  
Ma na ge me nt of ( A) Gra de 2 h y per gl yce mia ( 1 6 1 t o 2 5 0 m g/ d L), ( B) as y m pt o matic Gra de 3 h y per gl yce mia ( 2 5 0  t o 
5 0 0  m g/ d L), ( C) s y m pt o matic Gra de 3 h y per gl yce mia ( 2 5 0 t o 5 0 0 m g/ d L) or as y m pt o matic Gra de 4 h y per gl yce mia ( > 5 0 0 
m g/ d L).  
A b bre viati o ns: A C: bef ore meals, D L T: d ose -li miti n g t o xicit y, I V F: i ntra ve n o us fl ui ds, Q H S: bef ore e ver y be dti me, TI D: 
t hree ti mes dail y  
( *) D o n ot use metf or mi n if creati ne is 1. 3 m g/ d L ( w o me n) or 1. 4 m g/ d L ( me n) or if a n y state of decrease d tiss ue perf usi o n or  
he m o d y na mic i n sta bilit y is prese nt (e. g., heart fail ure); h ol d metf or mi n f or C T  sca ns; GI s y m pt o ms ma y occ ur wit h i nitiati o n 
b ut u s uall y s u bsi de after t he first wee k. 
S o urce: B usai d y N L, Far o o ki A, D o wlati A, et al. Ma na ge me nt of meta b olic effects ass ociate d wit h a ntica ncer a ge nt tar geti n g 
t he PI 3 K-A kt -m T O R pat h wa y. J Cli n O nc ol. 2 0 1 2; 3 0( 2 3): 2 9 1 9-2 8.  
 
 
6. 6  
Tre at me nt C o m pli a nce  wit h A R Q 7 5 1  
A s u bject is c o nsi dere d c o m plia nt wit h t he st u d y pr ot oc ol w he n st u d y me dicati o n is a d mi nistere d 
at a c o m plia nce le vel of ≥ 8 0 %.  I n or de r t o e val uate t he safet y of A R Q 7 5 1, re place me nt of n o n -
c o m plia nt s u bjects will be all o we d d uri n g t he firs t 2 8 da ys of dosi n g.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 5  of 1 1 7  
 
C o m plia nce will be calc ulate d usi n g t he f oll o wi n g e q uati o n:  
( N u m ber of ca ps ules act uall y i n geste d / n u m ber of ca ps ules t hat s h o ul d ha ve bee n i n geste d per 
d ose le vel) x 1 0 0  = % c o m plia nce  
6. 7  
Bli n di n g  
T his is a n o pe n -la bel st u d y.  Neit her t he s u bject n or t he I n vesti gat or or site staff will be bli n de d t o 
t he treat me nt a d mi nistere d. 
6. 8  
C o nc o mit a nt Me dic ati o n  
6. 8. 1  
Per mitte d Treat me nt  
All i nf or mati o n re gar di n g c o nc o mita nt treat me nts ( me dicati o ns, bl o o d tra nsf usi o ns , or pr oce d ures) 
m ust be rec or de d o n t he s u bject’s e C R F (i ncl u di n g t he na me of t he me dicati o n or pr oce d ure a n d 
d urati o n of treat me nt). Palliati ve a n d s u p p orti ve care f or disease -relate d s y m pt o ms will be offere d 
t o all s u bjects i n t his st u d y.  
T he f oll o wi n g treat me nts are all o we d:  
•  Sta n d ar d t hera pies f or c o nc ur re nt me dical c o n diti o ns 
•  Er yt hr o p oieti n Sti m ulati n g A ge nts ( E S A): Please f oll o w A merica n S ociet y of 
Cli nical O nc ol o g y ( A S C O ) or M E DI C A R E g ui deli nes f or t he use of E S A i n 
patie nts dia g n ose d 
wit h ca ncer, dr u g la bels , a n d t he F o o d a n d 
D r u g 
A d mi nistrati o n ( F D A)   
•  He mat o p oietic gr o wt h fact ors i ncl u di n g fil grasti m ( Ne u p o ge n ®) or ot her 
c ol o n y -sti m ulati n g fact ors. A S C O g ui deli nes s h o ul d be f oll o we d f or t he use of 
W B C gr o wt h fact ors  
•  Pr o p h ylactic a n d s u p p orti ve a nti -e metics or l o w-d ose c ortic ost er oi ds ma y be 
a d mi nister e d acc or di n g t o sta n dar d practice  
•  H y p o gl yce mic a ge nts f or ele vate d bl o o d gl uc ose 
ma y be a d mi nistere d 
acc or di n g t o sta n dar d practice (a d mi nistrati o n of i ns uli n is n ot all o we d at 
baseli ne b ut ma y be a d mi nistere d d uri n g t he st u d y)    
•  Bis p h os p h o nates or a n y o t her dr u g f or treat me nt of oste o p or osis, treat me nt-
i n d uce d b o ne l oss a n d metastases t o b o ne if starte d at least f o ur wee ks bef ore 
t he first d ose of A R Q 7 5 1, or u p o n c o m pleti o n of t he first c ycle of treat me nt 
wit h o ut a n y D L T, a n d if t he I n vesti gat or r ules out t u m or pr o gressi o n.  
•  Palliati ve ra di ot hera p y f or l ocal pai n c o ntr ol ma y be all o we d, pr o vi de d t he 
s u bject c o m pletes t he first c ycle of treat me nt, d oes n ot meet criteria of 
pr o gressi ve disease a n d treate d lesi o ns will n ot be i ncl u de d  i n t he tar get/ n o n-
tar get lesi o n assess me nt. 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 6  of 1 1 7  
 
6. 8. 2  
Pr o hi bite d Treat me nt  
T he f oll o wi n g treat me nts are n ot all o we d d uri n g t he st u d y:  
•  A n y c o nc urre nt a ntica ncer t hera p y i ncl u di n g, b ut n ot li mite d t o, c he m ot hera p y, 
ra di ot hera p y (e xce pt palliati ve ra di ot hera p y f or local pai n c o ntr ol), h or m o nal 
t hera p y, i m m u n ot hera p y, or l oc ore gi o nal t hera p y 
•  I m m u n os u p pressi ve t hera pies i ncl u di n g c o nti n u o us hi g h-d ose c ortic oster oi ds 
(e xce pt w he n use d i nter mitte ntl y i n a n a ntie metic re gi me n, f or C N S metastases 
ma na ge me nt or as a part of  t he pre me dicati o n re gi me n)  
•  Ot her i n vesti gati o nal a ge nts  
6. 8. 3  
Treat me nt t o be A v oi de d or Use d wit h Ca uti o n W hile o n St u d y  
A R Q 7 5 1 de m o nstrate d s u bsta ntial i n hi biti o n of C Y P 2 C 1 9 a n d C Y P 2 D 6 , a n d sli g ht meta b olis m-
de pe n de nt i n hi biti o n of C Y P 3 A 4/ 3 A 5  e nz y me acti vit y . Se nsiti ve s u bstrates for t hese C Y P 
is oe nz y mes s h o ul d be a v oi de d or use d wit h ca uti o n d uri n g e nr oll me nt i n t he trial.  
A R Q 7 5 1 was deter mi ne d t o be b ot h a s u bstrate a n d i n hi bit or of P -g p, t heref ore c o -a d mi nistrati o n 
of A R Q 7 5 1 wit h dr u gs k n o w n t o be P -g p s u bstrates wit h narr o w t hera pe utic i n de x s h o ul d be 
a v oi de d or use d wit h ca uti o n.  
T he f oll o wi n g treat me nts s h o ul d be a v oi de d, if p ossi ble , or use d wit h ca uti o n d uri n g t he st u d y:  
•  C Y P 2 C 1 9 s u bstrates a n d i n d ucers (see A p pe n di x 4 f or details)  
•  C Y P 2 D 6 i n hi bit ors a n d i n d ucers (see A p pe ndi x 4 f or details)  
•  C Y P 3 A 4/ 3 A 5 i n hi bit ors a n d i n d ucers (see A p pe n di x 4 f or details)  
•  P -g p s u bstrates, i n hi bit ors , a n d i n d ucers (see A p pe n di x 4 f or details)  
•  Gra pefr uit j uice  
6. 9  
P ote nti al Be nefit a n d Ris ks f or St u d y S u bjects  
Deta ile d n o n-cli nical a n d cli nical dat a ca n be f o u n d i n t he A R Q 7 5 1 I B.  
P reli mi nar y efficac y data s u g gest t hat A R Q 7 5 1 ma y be cli nicall y acti ve i n ca ncer s u bjects w h ose 
t u m ors har b or PI K 3 C A , A K T  a n d P T E N  m u tati o ns. T he c urre nt pr ot oc ol a me n d me nt see ks t o test 
a n u m ber of c o m bi nati o n re gi me ns i n t u m or t y pes wit h s pecific m olec ular c haracteristics t hat ma y 
i de ntif y s pecific patie nt p o p ulati o n(s) m ost li kel y t o deri ve be nefit fr o m t hese t hera pies.  
I n a ni mal m o dels, t he t o xicit y pr ofile of orall y a d mi nistere d A R Q 7 5 1 was c haracterize d 
pri nci pall y b y fi n di n gs i n t he he mat o p oietic s yste m, GI tract, a n d ki d ne y, s o me of w hic h were 
sec o n dar y t o re d uce d f o o d c o ns u m pti o n, wei g ht l oss, a n d/ or de h y drati o n.  Als o, b ase d o n 
n o ncli nical data, it has bee n s u g geste d t hat A R Q  7 5 1  ma y ca use a p h ot ot o xic reacti o n i n s o me 
s u bjects e x p ose d t o t he dr u g a n d s u nli g ht. T he a m o u nt of A R Q 7 5 1 t hat ma y be re q uire d t o ca use 
s uc h a reacti o n is u n k n o w n. All s u bjects s h o ul d be i nstr ucte d t o a v oi d t he e x p os ure t o s u nli g ht, t o 
use s u nscree n t o pr o tect e x p ose d areas of t he b o d y (e.g., f ore hea d, n ose, li ps, a n d ha n ds), a n d t o 
re p ort s y m pt o ms t hat ma y be ass ociate d wit h p h ot ot o xic reacti o n (e. g., re d ness, pr urit us, s welli n g, 
a n d blister f or mati o n).  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 7  of 1 1 7  
 
A n u m ber of A K T i n hi bi t ors (e. g., M K-2 2 0 6, G S K 6 9 0 6 9 3,  i pataserti b) ha ve bee n teste d i n 
cli nical trials (Nit ulesc u, 2 0 1 6 ) a n d class -relate d, o n-tar get t o xicities ha ve bee n re p orte d . T he 
m ost c o m m o nl y re p orte d a d verse e ve nts t hat ma y be ass ociate d wit h  t his class of ki nase 
i n hi bit ors are h y per gl yce mia, s ki n ra s h, pr urit us, na usea a n d diarr hea. (Ta n , 2 0 1 1 ) (Ya p , 2 0 1 1 ) 
Car di o vasc ular  t o xicit y has n ot bee n o bser ve d i n n o n -cli nical A R Q 7 5 1 st u dies , h o we ver, 
i n hi biti o n of h E R G a n d Q T pr ol o n gati o n ha ve bee n re p orte d f or ot her A K T i n hi bit ors a n d ma y 
be a n o n -tar get t o xicit y s pecific f or t his class of ki nase i n hi bit ors. (K o n o ple va , 2 0 1 4)  (Z ha n g Y ., 
2 0 0 6 ) 
I n t he Part 1, D ose Escalati o n C o h orts  of A R Q 7 5 1 a d m i nistere d as a si n gle a ge nt, 3 3 o ut of 3 4 
s u bjects e x perie nce d T E A Es, i ncl u di n g 2 4 e ve nts assesse d as A R Q 7 5 1 -relate d. I n o ne  s u bject 
treat me nt was i nte rr u pte d, a n d i n t hree s u bjects’ treat me nt was i nterr u pte d a n d s u bse q ue ntl y d ose 
was m o difie d d ue t o A R Q 7 5 1 -relate d A Es, a n d o ne  s u bjects with A R Q 7 5 1 -relate d gra de 1 h ot 
fl us h a n d na usea was disc o nti n ue d fr o m  t he st u d y treat me nt.  T he m ost c o m m o n A Es ( ≥1 0 %) of 
all gra des were GI dis or ders ( diarr hea, c o nsti pati o n, na usea, v o miti n g a n d a b d o mi nal pai n), 
fati g ue, peri p heral e de ma, uri nar y tract  infecti o n , A S T i ncrease, decrease a p petite, h y p o natre mia, 
hea dac he, c o u g h, d ys p nea, a n d ras h.  T he m ost c o m m o n gra de 3  A Es ( ≥1 0 %) were c o nsti pati o n 
a n d A S T i ncrease, t here was o nl y o ne re p orte d gra de 4 A E of t hr o m b oc yt o pe nia. T he m ost 
c o m m o n A R Q 7 5 1 -relate d A Es (≥5 %) of all gra des i ncl u de d  GI dis or ders ( diarr hea, na use a, 
v o miti n g  a n d st o mati tis), fati g ue, m uc osal i nfla m mati o n, h y per gl yce mia, a n d ras h.  T he m ost 
c o m m o n gra de 3 A R Q 7 5 1 -relate d A Es ( ≥5 %) were diarr hea a n d h y per gl yce mia, t here were n o 
re p orte d gra de 4 e ve nts. T here were 3 2 S A E re p orts  i n 1 7 s u bjects, i ncl u di n g 8 deat hs t hat were 
all d ue t o disease pr o g ressi o n; in t hree s u bjects , t he S A Es were re p orte d as A R Q 7 5 1 -relate d 
( h y per gl ycemia, diarr hea, a n d diarr hea/ v o miti n g) , t hese e ve nts were ma na ge d wit h d ose 
i nterr u pti o n a n d i n o ne s u bject als o wit h d ose m o dificati o n.   
 
I n s u m mar y, all s u bjects e nr olle d i n t he A R Q 7 5 1 -1 0 1 st u d y s h o u l d be cl osel y m o nit ore d  f or 
A R Q 7 5 1 -relate d A Es s uc h as h y per gl yce m ia, ras h, st o matitis/ m uc ositis, a n d gastr oi ntesti n al 
t o xicit y (diarr hea,  na usea , v o miti n g). 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 8  of 1 1 7  
 
7  
S A F E T Y A S S E S S M E N T S  
7. 1  
Defi niti o ns  
7. 1. 1  
A d verse E ve nt  
A n A E is defi ne d as a n y u nt o war d m e dical occ urre nce i n a s u bject or cli nical i n vesti gati o nal 
s u bject a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal relati o ns hi p 
wit h st u d y -dr u g treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora b le a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he me dici nal 
pr o d uct.  
7. 1. 2  
A d verse Reacti o n  
A n a d verse reacti o n is defi ne d as a n y e ve nt f or w hic h t here is a reas o na ble p ossi bilit y t hat t he dr u g 
ca use d t he e ve nt.  
7. 1. 3  
S us pecte d A d verse Reacti o n  
A s us pecte d a d verse reacti o n is defi ne d as a n y a d verse e ve nt f or w hic h t here is a reas o na ble 
p ossi bilit y t hat t he dr u g ca use d t he  a d verse e ve nt.  Reas o na ble p ossi b ilit y mea ns t hat t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he a d verse e ve nt.  
7. 1. 4  
U ne x pecte d A d verse E ve nt or U ne x pecte d S us pecte d A d verse Reacti o n  
A n a d verse e ve nt or s us pecte d a d verse reacti o n i s c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n t he 
I n vesti gat or’s Br oc h ure or is n ot liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d.  
“ U ne x pecte d” als o refers t o a d verse e ve nts or s us pecte d a d verse reacti o ns t hat are me nti o ne d i n 
t he I n vesti gat or’s Br oc h ure as occ urri n g wit h t he class of dr u gs or as a ntici pate d fr o m t he 
p har mac ol o gical pr o perties of t he dr u g b ut  are n ot s pecificall y me nti o ne d as occ urri n g wit h t he 
partic ular dr u g u n der i n vesti gati o n.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 6 9  of 1 1 7  
 
7. 1. 5  
Seri o us A d verse E ve nt or U ne x pecte d S us pe cte d A d verse Reacti o n  
A n a d verse e ve nt or s us pecte d a d verse reacti o n is c o nsi dere d “seri o us” if, i n t he vie w of eit her t he 
I n vesti gat or or S p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h  
•  Life -t hreate ni n g 
•  Re q uires ne w i n patie nt h os pitalizati o n d efi ne d as a h os pital a d missi o n las ti n g 
≥ 2 4 h o urs ( n ot i ncl u di n g e mer ge nc y r o o m visit wit h o ut h os pital a d missi o n), or 
pr ol o n gati o n of e xisti n g h os pitalizati o n  
•  Persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  C o n ge nital a n o mal y/ birt h defect  
•  Ot her i m p orta nt m e dical e ve nts t hat ma y n ot res ult i n de at h, be life-t hreate ni n g, 
or re q uire h os pitalizati o n , b ut ma y be c o nsi dere d seri o us w he n, base d u p o n 
a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire 
me dical or s ur gical i nter ve nti o n t o pr e ve nt o ne of t he o utc o mes liste d. A n 
i mp orta nt me dical e ve nt ma y be c o nsi dere d a seri o us a d verse e ve nt ( S A E ) 
base d u p o n a p pr o priate me dical j u d g me nt.  
7. 1. 6  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
All a d verse e ve nts t hat are deter mi ne d b y t he I n vesti gat or o r b y t he S p o ns or as ha vi n g a reas o na ble 
s us pecte d ca usal relati o ns hi p ( p ossi bl y, pr o ba bl y, or defi nitel y relate d) t o a st u d y dr u g i ncl u di n g 
place b o a n d t hat are b ot h u ne x pecte d a n d seri o us are c o nsi dere d t o be s us pecte d u ne x pecte d 
seri o us a d verse reacti o ns ( S U S A R) a n d are s u bject t o e x pe dite d re g ulat or y re p orti n g.  
7. 1. 7  
I n patie nt H os pitalizati o n 
A n i n patie nt h os pitalizati o n is a h os pital a d missi o n t hat lasts m ore t ha n 2 4 h o urs.  
7. 1. 8  
St u d y Dr u g -relate d A d verse E ve nt or Seri o us A d verse E ve nt 
St u d y dr u g -relate d A E or S A E is defi ne d as a n A E or S A E t hat is relate d, pr o ba bl y relate d, or 
p ossi bl y relate d  t o t he treat me nt wit h A R Q 7 5 1  a n d/ or wit h o ne of t he c o m bi nati o n dr u gs . 
7. 1. 9  
A d verse E ve nts of P ote ntial Ris k  
A d verse e ve nt s of p ote ntial ris k i ncl u de h y per gl yce mia, ras h , diarr hea, L F Ts i ncrease a n d Q Tc 
pr ol o n gati o n . T hese A Es  s h o ul d be cl osel y m o nit or e d a n d rec or de d i n t he E D C s yste m of t his 
st u d y a n d disc usse d wit h t he s p o ns or d uri n g t he s p o ns or/i n vesti gat or calls . 
7. 1. 1 0  
F urt her  I nstr ucti o ns o n Re p orti n g A d verse E ve nt s or Seri o us A d verse E ve nt s 
W here ver p ossi ble, a s pecif ic disease or s y n dr o me rat her t ha n i n di vi d ual ass ociate d si g ns a n d 
s y m pt o ms s h o ul d be i de ntifie d.  H o we ver, if a n o bser ve d or re p orte d si g n or s y m pt o m is n ot 
c o nsi dere d a c o m p o ne nt of a s pecific disease or s y n dr o me b y t he I n vesti gat or, it s h o ul d be rec or de d 
as a se parate A E.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 0  of 1 1 7  
 
La b orat or y data  are t o be c ollecte d as sti p ulate d i n t his pr ot oc ol.  Cli nical s y n dr o mes ass ociate d 
wit h la b orat or y a b n or m alities are t o be rec or de d as a p pr o priate (e. g., dia betes mellit us i nstea d of 
h y per gl yce mia) . 
Sc he d ule d h os pi talizati o ns or electi ve s ur gical pr oce d ures will n ot be c o nsi dere d as A Es or S A Es.   
Pr ol o n gati o n of a sc he d ule d h os pitali zati o n ca n be c o nsi dere d a n S A E.   
C o m plicat i o ns ass ociate d wit h sc he d ule d pr oce d ures are c o nsi dere d A Es or S A Es. 
Pr o gressi o n of dise ase is c o nsi dere d a n efficac y o utc o me para meter a n d s h o ul d n ot be ca pt ure d as 
a n A E or a S A E u nless its o utc o m e is deat h.   
E x p os ure i n uter o d uri n g cli nical  st u dies: Alt h o u g h pre g na nc y is n ot tec h nicall y a n A E, all 
pre g na ncies w hile recei vi n g t he st u d y treat me nt or wit hi n 3 0  da ys after t he last d ose of t he st u d y 
treat me nt m ust be re p orte d as a  S A E a n d m ust be f oll o we d t o c o ncl usi o n t o deter mi ne t heir 
o utc o me. T he I n vesti gat or s h o ul d ma ke e ver y eff ort t o f oll o w t he s u bject u ntil c o m pleti o n of t he 
pre g na nc y. If t he o utc o me of t he pre g na nc y meets t he criteria f or i m me diate classificati o n as a 
S A E (e. g., p ost-part u m c o m plicati o ns, s p o nta ne o us a b orti o n, still birt h, ne o natal deat h, or 
c o n ge nital a n o mal y, i ncl u di n g t hat i n a n a b orte d fet us), t he I n vesti gat or s h o ul d f oll ow t he 
pr oce d ures f or S A E re p orti n g.  
A dverse eve nts , i ncl u di n g S AEs t h at occ ur f oll o wi n g t he e xec uti o n of t he I C F b ut pri or t o d osi n g 
will n ot be rec or de d as A Es or S A Es , t hey h ave t o be re p orte d as p art of Me dic al Hist ory.  
A d verse e ve nts i ncl u di n g S A Es t hat occ ur after s u bjects recei ve a n y a ntica ncer t hera p y ot her t ha n 
t he st u d y-defi ne d treat me nt( s) will n ot be rec or de d as A Es or S A Es. 
7. 2  
Res p o nsi bilities a n d Pr oce d ures  
T he res p o nsi b ilit y f or t he safet y of a n i n di vi d ual s u bject lies i n all cases wit h t he I n vesti gat or.  T his 
i ncl u des t he ti mel y re vie w of all safet y data o btai ne d d uri n g t he c o urse of t he st u d y. 
A n I n vesti gat or m ust i nstr uct his/ her s u bjects t o re p ort a n y A E a n d S A Es t he y e x perie nce.   
I n vesti gat ors ca pt ure, e val uate a n d d oc u me nt all A Es a n d S A Es  occ urri n g d u ri n g a s u bject’s 
e nr oll me nt i n t he trial, c o mme nci n g wit h t he first da y of treat me nt a n d i ncl u di n g t he pr ot oc ol -
defi ne d 3 0 -da y p ost -treat me nt f oll o w-u p peri o d ( C o de of Fe deral Re g ulati o ns [ C F R] 2 1 
§ 3 1 2. 6 4[ b]) as s o urce d oc u me nts a n d o n desi g nate d e C R F pa ges. T hese A Es/ S A Es m ust be 
rec or de d i n t he E D C s yste m of t his st u d y.  
I n vesti gat ors s h o ul d assess A Es at eac h sc he d ule d a n d n o n-sc he d ule d visit, b y t he use of o pe n-
e n de d q uesti o ni n g, p h ysical e xa m i nati o n, a n d re vie w of la b orat or y res ults.  
N ote : It is i mp orta nt t o rec or d all A Es a n d S A Es t hat r es ult i n te m p ora r y a n d per ma ne nt 
disc o nti n uati o n of st u d y treat me nt, re gar dless of se verit y.  
I n vesti gat ors m ust re p ort all S A Es, w het her or n ot t he y are c o nsi dere d st u d y -dr u g relate d, t o t he 
S p o ns or or de si g nee wit hi n 2 4 h o urs fr o m k n o wle d ge of t he e ve nt (see Se cti o n 7. 4 ).   
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 1  of 1 1 7  
 
I n cases of S U S A R, I n vesti gat ors are res p o nsi ble for re p orti n g t o t heir l ocal I R B /I E C.  The 
S p o ns or or desi g nee(s) is res p o nsi b le f or n otifyi n g re g ulat or y a ut h orities a n d all rele va nt 
I n vesti gat ors of S U S A Rs. 
7. 3  
A d verse E ve nt or Seri o us A d verse E ve nt Assess me nt Criteri a  
A d verse e ve nts a n d S A Es are e val uate d a n d gra de d usi n g N CI C T C A E g ui deli nes, v ersi o n 4. 0 3.  
7. 4  
Seri o us A d verse E ve nt Re p orti n g  
T he I n vesti gat ors are o bli gate d t o i m me diatel y re p ort t o t he S p o ns or ( or t he dr u g safet y desi g nee 
of t he S p o ns or ), eac h S A E t hat occurs d uri n g t his i n vesti gati o n, wit hi n 2 4  h o urs fr o m k n o wle d ge 
of t he e ve nt, w het her or n ot it is c o nsi dere d st u d y -dr u g relate d. All ne w a n d/ or u p date d i nf or mati o n 
m ust be  f or war de d t o t he S p o ns or or desi g nee as s o o n as it bec o mes a vaila ble. If a n y q uesti o ns or 
c o nsi derati o ns re gar di n g a S A E arise, t he Me dical M o nit or or desi g nee s h o ul d be c o ns ulte d.  
C 3i S ol uti o ns  S A E Re p ort  
 S p o ns o r’s 
Me dic al M o nit or  
E mail: 
 
Fa x f or N ort h A merica: 
 
F or  fa x or e mail iss ues, e mail 
 or call 
. 
 
Tele p h o ne: 
 
e mail: 
T he i nf or mati o n pr o vi de d i n a S A E re p ort s h o ul d be as c o m plete as p ossi ble b ut c o ntai n a 
mi ni m u m of:  
•  A s h ort descri pti o n of t he A E ( dia g n osis) a n d t he reas o n w h y t he A E was 
cate g orize d as seri o us  
•  S u bject i de ntificati o n a n d treat me nt (if a p plica ble)  
•  I nvesti gat or’s na me a n d p h o ne n u m ber (if a p plica ble)  
•  Na me of t he s us pect me dici nal pr o d uct a n d dates of a d mi nistrati o n  
•  Assess me nt of ca usalit y  
If all i nf or mati o n a b o ut t he S A E is n ot yet k n o w n, t he I n vesti gat or will be re q uire d t o re p ort a n y 
a d diti o nal i nf or mati o n wit hi n 2 4 h o urs as it bec o mes a vaila ble.  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 2  of 1 1 7  
 
All S A Es will be e val uate d b y t he  Me dical M o nit or or desi g nee.  T he S p o ns or wil l deter mi ne 
re p orta bilit y re gar dless of t he I n ve sti gat or’s assess me nt.  I n t he case of a S U S A R, t he S p o ns or or 
desi g nee will  re p ort t he e ve nt t o all perti ne nt re g ulat or y a ut h orities ha vi n g j uris dicti o n o ver 
o n g oi n g A R Q  7 5 1 trials i n a n e x pe dite d ma n ner ( wit hi n 7 da ys or 1 5  da ys of k n o wle d ge)  a n d t o 
all I n vesti gat ors i n v ol ve d i n A R Q 7 5 1 cli nica l trials.1 
T he I n vesti gat ors m ust i n t ur n n otif y t heir g o ver ni n g I R B/I E C  i n acc or da nce wit h t heir b yla ws . 
7. 5  
P ost -tre at me nt S afet y F oll o w -u p  
I n t his st u d y, t he p ost-treat me nt safet y f oll o w-u p peri o d is defi ne d as 3 0 d a ys after  t he last d ose 
of assi g ne d treat m e nt. All A Es occ urri n g d uri n g t he st u d y peri o d fr o m t he ti me of t he first d ose 
of A R Q 7 5 1  a d mi nistratio n t o t he last da y of t he 3 0 -da y p ost -treat me nt S afet y F oll o w -u p peri o d 
will be ca pt ure d.  
All s u bjects will be f oll o w e d f or a mi ni mu m of 3 0 da ys after disc o nti n uati o n of A R Q 7 5 1 . All 
s u bjects sh o ul d be i nstr ucte d t o re p ort  A Es or S A Es occ ur ri n g d uri n g t he 3 0-da y p ost -treat me nt 
S afet y F oll o w -u p peri o d.   
U nres ol ve d st u d y dr u g-relate d (see Secti o n 7. 1. 8  f or defi niti on) A Es a n d S A Es at t he ti me of 
treat me nt disc o nti n uati o n or ne w st u d y dr u g-relate d A Es a n d S A Es t hat occ ur d uri n g t he 3 0 -da y 
safet y f oll o w-u p peri o d will be f ol l o we d u ntil t he y ha ve, i n t he o pi ni o n of t he I n vesti gat or, 
res ol ve d t o baseli ne, stabilize d, or are dee me d t o be irre versi ble.  
If a s u bject recei ves ot her a ntica ncer t hera p y wit hi n t he 3 0-da y S afet y F oll o w -u p peri o d, t he 
f oll o w-u p f or A Es will ceas e, be gi n ni n g o n t he first da y of t he ne w t hera p y. 
7. 6  
Gr a di n g of Se verit y  
Eac h A E or S A E will be gr a de d f or se verit y acc or di n g t o N CI C T C A E v ersi o n 4. 0 3.   
F or A Es n ot liste d i n t he N CI C T C A E v ersi o n 4. 0 3, a si milar gra di n g s yste m s h o ul d be use d as 
f oll o ws: 
•  Gra de 1 Mil d A E  
•  Gra de 2 M o derate A E  
•  Gra de 3 Se vere A E  
•  Gra de 4 Life -t hreate ni n g or disa bli n g A E 
•  Gra de 5 Deat h relate d t o A E  
F or A Es t hat ca n be descri be d b y t he N CI C T C A E g ui deli nes, t he N CI C T C A E Gra de  
(life-t hreate ni n g or disa bli n g A E) is assesse d base d o n u ni q ue cli nical descri pti o ns of se verit y f or 
                                                 
1 A n a d verse e ve nt or s us pecte d a d verse reacti o n is c o nsi dere d " u ne x pecte d" if it is n ot liste d i n t he I n vesti gat or’s Br oc h ur e or is 
n ot liste d at t he s pecificit y or se veri t y t hat has bee n o bser ve d; or, if a n I n vesti gat or’s Br oc h ure is n ot re q uire d or a vaila ble, is n ot 
c o nsiste nt wit h the ris k i nf or mati o n descri be d i n t he ge neral i n vesti gati o nal pla n or else w here i n t he c urre nt a p plicati o n, as 
a me n de d. S o urce: 2 1 C F R 3 1 2. 3 2 (a)  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 3  of 1 1 7  
 
eac h A E, a n d t hese criteria ma y be differe nt fr o m t h ose use d f or t h e assess me nt of A E 
seri o us ness.  A n A E assesse d as Gra de  4 base d o n t he N CI C T C A E gra des ma y or ma y n ot be 
assesse d as seri o us base d o n t he seri o us ness criteria.  
7. 7  
Assess me nt of C a us alit y  
T he I n vesti gat or will pr o vi de t he S p o ns or wit h a n assess me nt of ca usalit y f or a n a d verse e ve nt 
a n d st u d y treat me nt ( A R Q 7 5 1, paclita xel a n d f ul vestra nt) base d o n his/ her cli nical j u d g me nt a n d 
t he defi niti o ns descri be d bel o w. 
7. 7. 1  
Relate d A d verse E ve nts  
•  T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y treat me nt 
a d mi nistrati o n, a n d ca n n ot be reas o na bl y e x plai ne d b y t he s u bject’s cli nical 
state or ot her fact ors (e. g., disease u n der st u d y, c o nc urre nt  diseases, 
c o nc o mita nt me dicati o ns)  
•  T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y dr u g a d mi nistrati o n 
a n d is a k n o w n reacti o n t o t he dr u g(s) u n der  st u d y or its c he mical gr o u p or  is 
pre dicte d b y k n o w n p har mac ol o g y  or  a k n o w n reacti o n t o a ge nt or c he mical 
gr o u p.  
7. 7. 2  
N ot Relate d A d verse E ve nts  
•  T he 
A E d oes n ot f oll o w a reas o na ble se q ue nce fr o m st u d y treat me nt 
a d mi nistrati o n or  ca n be reas o na bl y e x plai ne d b y  t he s u bject’s cli nical state or 
ot her fact ors (e. g., disease u n der st u d y, c o nc urre nt diseases, a n d c o nc o mita nt 
me dicati o ns ). 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 4  of 1 1 7  
 
8  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  
T he st u d y will be i ni tiate d a n d c o n d ucte d u n der t he sp o ns ors hi p of Ar Q ule.  St u d y dr u g s A R Q  7 5 1, 
clinical s u p plies, a n d e C R Fs will be s u p plie d b y t he S p o ns or or its re prese ntati ve.  Re prese ntati ves 
of t he S p o ns or will m o nit or t he st u d y  t o verif y st u d y data, me dical rec or ds, a n d e C R Fs i n 
acc or da nce wit h c urre nt I C H G C P a n d ot her a p plica ble re g ulati o ns a n d  g ui deli nes.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 5  of 1 1 7  
 
9  
P L A N N E D S T A TI S TI C A L M E T H O D S  
T he material prese nte d i n t his secti o n will ser ve as t he basis f or t he statistical a nal ysis pl a n.  T his 
pla n ma y be re vise d d uri n g t he st u d y t o acc o m m o date pr ot oc ol a me n d me nts.  Beca use of t he nat ure 
of t his st u d y, n o f or mal statistical a nal ysis is pla n ne d.  E val uati o n of t he data will c o nsist pri maril y 
of s u m mar y dis pla ys (e. g., descri pti ve statis tics a n d gra p hs). 
9. 1  
Deter mi n ati o n of S a m ple Size  
T he e xact n u m ber of s u bjects esti mate d f or t his st u d y is de pe n de nt o n t he n u m ber of s u bject 
c o h orts i n vesti gate d base d o n t he t o xicit y e nc o u ntere d.  A p pr o xi matel y 9 4 s u bjects will be e nr olle d 
i n t his st u d y at 4 -1 0  sites i n t he U S A; 6 4 s u bjects i n Part 1 ( D ose escalati o n c o h orts a n d Ar m A) 
a n d 3 0 i n Part 2 ( Ar m B a n d Ar m C). T hir t y f o ur s u bjects were e nr olle d i n d ose escalati o n c o h orts. 
It is pla n ne d t hat u p t o 3 0 s u bjects wit h a d va nce d, i n o pera ble, metastatic, or rec urre nt s oli d t u m ors 
will be e nr olle d i n Ar m A, u p t o 1 5 s u bjects wit h PI K 3 C A/ P T E N acti vati n g  m utati o ns a n d u p t o 
1 5  s u bjects wit h A K T ge netic alterati o ns. I n Part 2, a p pr o xi matel y 1 5 s u bjects will be e nr olle d i n 
eac h c o m bi nati o n t hera p y ar m ( Ar m B, A R Q 7 5 1 + paclita xel a n d Ar m C, A R Q 7 5 1 +f ul vestra nt) . 
 . 
9. 2  
A n al ysis V ari a bles  
9. 2. 1  
De m o gra p hics a n d Baseli ne C haracteristics  
S u bjec t de m o gra p hics a n d baseli ne c haracteristics will i ncl u de: 
•  De m o gra p hics (a ge, ge n der, race)  
•  Baseli ne disease c haracteristics (sta ge, date of dia g n osis, t u m or bi o mar ker 
stat us, a n d ot her pr o g n ostic fact ors) 
•  Cli nicall y si g nifica nt me dical hist or y, i ncl u di n g s ur geries  
•  Pri or t hera pies  
•  Baseli ne c o nc o mita nt me dicati o ns a n d treat me nts  
9. 2. 2  
Safet y  
T he safet y a nal ysis will be base d o n t he safet y p o p ulati o n.  T he safet y p o p ulati o n i ncl u des all 
s u bjects w h o recei ve at least o ne d ose of A R Q 7 5 1.  Safet y varia bles i ncl u de t he  re p orte d A Es, 
la b orat or y tests, vital si g ns, E C O G perf or ma nce stat us, a n d p h ysical e xa mi nati o n. 
9. 2. 3  
P har mac o ki netics  
P K para met ers i ncl u de C ma x , A U C , a n d w here p ossi ble  t1/ 2. 
9. 3  
St atistic al Met h o ds  
9. 3. 1  
De m o gra p hic a n d Baseli ne C haracteristics  
All de m o gra p hic a n d bas eli ne c haracteristics will be descri pti vel y s u m marize d. Cate g orical 
varia bles will be s u m ma rize d as t he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 6  of 1 1 7  
 
C o nti n u o us varia bles will be s u m marize d as mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d 
ma xi m u m.  
9. 3. 2  
E xte nt of Treat me nt E x p os ure  
D urati o n of e x p os ure is defi ne d as t he t otal n u m ber of da ys of  st u d y dr u g a d mi nistrati o n, i g n ori n g 
a n y te m p orar y dr u g disc o nti n uati o n. F or i nter mitte nt a n d wee kl y d osi n g sc he d ules, t he d urati o n of 
e x p os ure is defi ne d as t he d ur ati o n fr o m t he date of t he first d ose (i ncl u di n g first d ose date) t o t he 
date of t he last d ose, i g n ori n g a n y te m p orar y dr u g disc o nti n uati o ns a n d pla n ne d dr u g brea ks.  If 
t he date of last a d mi nistrati o n is u n k n o w n, t he date u ntil w hic h t he dis pe nse d dr u g w oul d ha ve 
laste d wit h o ut c o u nti n g t he e xtra dr u g pr o vi de d s h o ul d be use d. 
9. 3. 3  
A nal yses of Safet y  Varia bles  
9. 3. 3. 1  
A d verse E ve nts  
A d verse e ve nts will be e val uate d f or se verit y usi n g N CI C T C A E, versi o n 4. 0 3.  A E s u m maries 
will i ncl u de t he i nci de nce of treat me nt e mer ge nt A Es ( T E A E ).  All T E A Es will be c o de d usi n g 
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A
® ) a n d s u m maries will prese nt data b y 
s yste m or ga n class a n d preferre d ter m.  Se parate T E A E s u m maries will be ge nerate d f or t he 
f oll o wi n g: 
•  All T E A Es  
•  Se vere T E A E s ( Gra de 3 or hi g her) 
•  S A Es  
•  T E A Es relate d t o A R Q 7 5 1  
•  T E A E relate d t o c o m bi nati o n  dr u g s ( paclita xel or  f ul vestra nt) 
•  T E A Es lea di n g t o treat me nt disc o nti n uati o n  
•  T E A Es res ulti n g i n deat h  
•  T E A Es liste d acc or di n g t o ma xi m u m se verit y  
•  T E A Es liste d b y d osi n g sc he d ule /re gi me n 
•  T E A Es relate d t o A R Q 7 5 1  b y treat me nt Ar m 
9. 3. 3. 2  
La b orat or y Tests  
S u m mar y statistics f or baseli ne,  eac h p ost -baseli ne meas ure me nt, a n d c ha n ge fr o m baseli ne f or 
eac h p ost -baseli ne meas ure me nt will be prese nte d f or eac h he mat ol o g y, ser u m c he mistr y, li ver 
fu ncti o n test, electr ol yte, a n d uri nal ysis para meter.  
9. 3. 3. 3  
Vital Si g ns  
S u m mar y statistics f or baseli ne, ea c h p ost -baseli ne meas ure me nt, a n d c ha n ge fr o m baseli ne f or 
eac h p ost -baseli ne meas ure me nt will be prese nte d f or eac h vital si g n para meter.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 7  of 1 1 7  
 
9. 3. 3. 4  
E C O G Perf or ma nce Stat us  
N u m ber a n d perce nt of s u bjects ha vi n g eac h E C O G perf or ma nce stat us le vel will be prese nte d f o r 
baseli ne a n d eac h p ost -baseli ne meas ure me nt.  
9. 3. 3. 5  
P h ysical E xa mi nati o ns  
Data fr o m p h ysical e xa mi nati o ns will be prese nte d i n t he data listi n gs.  
9. 3. 3. 6  
Res p o nse Rate  
A nal yses o n t he O verall Res p o nse Rate ( O R R) will be perf or me d i n t he I nte nt t o Treat (I T T) a n d 
E val ua ble s u bject p o p ulati o ns. T he e val ua ble s u bject p o p ulati o n is defi ne d as t he s u bjects w h o 
ha ve recei ve d at least o ne c ycle of A R Q 7 5 1 a n d ha ve ha d at least o ne disease assess me nt 
f oll o wi n g t he i nitiati o n of t hera p y.  T he 9 5 %  c o nfi de nce i nter val will be esti mate d.   
T he 9 5 % c o nfi de nce i nter val f or perce nt of s u bjects i n eac h R E CI S T res p o nse cate g or y ( e. g., 
c o m plete res p o nse [ C R ], partial res p o nse [ P R ], sta ble disease [S D ], a n d pr o gressi ve disease [ P D ]) 
a n d disease c o ntr ol rate  [ D C R] will als o be esti mate d.  
 
9. 3. 4  
P har mac o ki netics a n d P har mac o d y na mics  
P K  para meters i ncl u de C ma x , A U C, a n d t 1/ 2  ( w here p ossi ble) s u m mar y statistics will be perf or me d. 
S u m mar y st atistics i nc l u di n g mea n, sta n dar d de viati o n, me dia n, c oefficie nt of variati o n, mi ni m u m 
a n d ma xi m u m f or baseli ne, eac h p ost -baseli ne meas ure me nt, a n d c h a n ge fr o m baseli ne will be 
perf or me d o n s pecifie d bi o mar kers.  
T o e x pl ore t he ass ociati o n of bl o o d c o nce ntrati o n wit h cli nical o utc o me, t he a b o ve descri pti ve 
statistics will als o be prese nte d se paratel y f or eac h res p o nse cate g or y ( C R, P R , a n d S D c o m bi ne d 
vs . P D).  L o gistic re gressi o n will als o be utilize d if a p pr o priate.  
9. 3. 5  
I nteri m A nal ysis 
T here will be n o i nteri m a nal ysis  f or t his P hase 1, si n gle ar m, o pe n-la bel st u d y. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 8  of 1 1 7  
 
1 0  C O M P LI A N C E 
WI T H 
G O O D  
C LI NI C A L 
P R A C TI C E 
A N D 
E T HI C A L 
C O N SI D E R A TI O N S  
1 0. 1  
I nstit uti o n al Re vie w B o ar d or I n de pe n de nt Et hics C o m mittee A p pr o v al  
T he pr ot oc ol, a n y pr ot oc ol m o dificati o ns, t he I C F, a n d, if a p plica ble, pe r missi o n t o use pri vate 
healt h i nf or mati o n m ust be a p pr o ve d b y t he I n vesti gat or’s I R B/I E C i n c o m plia nce wit h Fe deral 
re g ulati o ns 2 1 C F R  § 5 6  pri or t o st u d y i nitiati o n.  D oc u me ntati o n of t his a p pr o val m ust be pr o vi de d 
t o t he S p o ns or or its desi g nee a n d  ma de a vaila ble d uri n g a n i ns pecti o n b y t he F D A or ot her 
re g ulat or y a ge nc y i ns pect ors.  T he I n vesti gat or will als o pr o vi de t he S p o ns or wit h t he Ge neral 
Ass ura nce N u m ber d oc u me nti n g t hat t he I R B/I E C is d ul y c o nstit ute d, as well as a list of t he na mes, 
occ u pati o ns , a n d affiliati o ns of t he me m bers of t he I R B/I E C w he n a vaila ble.  
Bef ore i nitiati n g a trial, t he I n vesti gat or/I nstit uti o n s h o ul d 
ha ve 
writt e n a n d 
date d 
a p pr o val/fa v ora ble 
o pi ni o n 
fr o m 
t he 
I R B/I E C 
a n d 
w here 
a p plica ble, 
c o m pete nt 
a ut h orities/re g ulat or y b o die s f or t he trial pr ot oc ol/a me n d me nt(s), writte n I C F s u bject recr uit me nt 
pr oce d ures (e. g., a d vertise me nts) , a n d writte n i nf or mati o n t o be pr o vi de d t o s u bjects.  
1 0. 2  
C o m pli a nce wit h G o o d Cli nic al Pr actice a n d Et hic al C o nsi der ati o ns  
T his st u d y m ust be c o n d ucte d i n c o m plia nce wit h I R B/I E C i nf or me d c o nse nt re g ulati o n a n d t he 
I C H G C P G ui deli nes.  I n a d diti o n, all l ocal re g ulat or y re q uire me nts will be a d here d t o, i n partic ular 
t h ose aff or di n g greater pr otecti o n t o t he safet y of t he trial partici pa nts. 
T his st u d y will al s o be c o n d ucte d acc or di n g t o t he c urre nt re visi o n of t he Declarati o n of Helsi n ki 
Re vise d E di n b ur g h, Sc otla n d, 2 0 0 0, wit h all s u bse q ue nt re v isi o ns, a n d wit h l ocal la ws a n d 
re g ulati o ns rele va nt t o t he use of ne w t hera pe utic a ge nts i n t he c o u ntr y of c o n d uct. 
C ha n ges t o t he pr ot oc ol will re q uire writte n I R B/I E C a n d, w here a p plica ble, c o m pete nt 
a ut h orities/re g ulat or y b o dies a p pr o val/fa v ora ble o pi n i o n pri or t o i m ple me ntati o n, e xce pt w he n t he 
m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o s u bjects.  
1 0. 3  
S u bject I nf or m ati o n a n d C o nse nt  
T he I n vesti gat or, or desi g nee, is res p o nsi ble f or t he c o nte nt of t he I C F, b ut t he ori gi nal a n d a n y 
u p date d versi o ns m ust be a p pr o ve d b y t he S p o ns or pri or t o s u b missi o n t o t he I R B/I E C.  T he I C F 
s h o ul d als o i ncl u de a n y a d diti onal i nf or mati o n re q uire d b y l ocal la ws relati n g t o i nstit uti o nal 
re vie w. 
Bef ore t he start of a n y st u d y -relate d pr oce d ures are u n derta ke n, the I n vesti gat or or a ut h orize d 
desi g nee m ust o btai n writte n, i nf or me d c o nse nt fr o m eac h st u d y partici pa nt ( or his/ her le gal 
re prese ntati ve) i n acc or da nce wit h U S fe deral re g ulati o ns ( 2 1 C F R § 5 0) a n d t he I C H d oc u me nt 
“ G ui da nce f or I n d ustr y –  E 6 G o o d Cli nical  Practice: C o ns oli date d G ui da nce”.  I nf or me d c o nse nt 
will be o btai ne d b y disc ussi n g wit h t he s u bject t he p ur p ose of t he st u d y, t he ris ks a n d be nefits, t he 
st u d y pr oce d ures, a n d a n y ot her i nf or mati o n rele va nt t o t he s u bject.  
T he I n vesti gat or or desi g nee m u st e x plai n t o t he s u bject t hat f or p ur p oses of e val uati n g t he st u d y 
res ults, t he s u bject’s pri vate healt h i nf or mati o n o btai ne d d uri n g t he st u d y ma y be s hare d wit h t he 
st u d y S p o ns or, re g ulat or y a ge ncies, a n d I R Bs/I E Cs, bef ore e nr olli n g t hat s u bject i nt o t he  st u d y.   
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 7 9  of 1 1 7  
 
It is t he I n vesti gat or’s ( or desi g nee’s) res p o nsi bilit y t o o btai n per missi o n t o use pri vate healt h 
i nf or mati o n per t he Healt h I nf or mati o n P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) fr o m eac h 
s u bject, or if a p pr o priate, t he s u bject’s le gal re presentati ve.  
T he s u bject or his/ her le gal re prese ntati ve will d oc u me nt his/ her i nf or me d c o nse nt b y si g ni n g t he 
c urre nt ve rsi o n of t he writte n, I R B-a p pr o ve d I C F. T he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt 
disc ussi o n wit h t he s u bject a n d/ or s u bject’s le gal re prese ntati ve m ust als o si g n t he I C F.  T he 
s u bject is gi ve n a f ull y e xec ute d c o p y of t he I C F beari n g all a p pr o priate si g nat ures, a n d t he ori gi nal 
m ust be mai ntai ne d i n t he cli nical master files at t he site.  
All acti ve s u bjects partici pati n g o n t he pr ot oc ol m ust be re -c o nse nte d eac h ti me t he I C F is u p date d 
a n d re -a p pr o ve d b y t he I R B/I E C.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 0  of 1 1 7  
 
1 1  S T U D Y M A N A G E M E N T A N D  M A T E RI A L S  
1 1. 1  
M o ni t ori n g, Verific ati o n of D at a, A u dit, a n d I ns pecti o n 
A S p o ns or m o nit or or desi g nee will peri o dicall y visit eac h cli nical st u d y site t o disc uss t he pr o gress 
of t he cli nical trial a n d t o re vie w e C R Fs a n d ori gi nal s o urce d oc u me nts f or acc urac y of data 
rec or di ng, st u d y dr u g acc o u nta bilit y, a n d c orres p o n de nce.  W he n re q ueste d, t he I n vesti gat or m ust 
be a vaila ble t o t he st u d y m o nit or f or pers o nal, o ne -t o-o ne c o ns ultati o n.   
Peri o dicall y, s o me or all of t he facilities use d i n t he trial ma y be re vie we d or i ns pecte d b y t he 
I R B/I E C a n d/ or re g ulat or y a ut h orities. A n a u dit or i ns pecti o n ma y i ncl u de, f or e xa m ple, a re vie w 
of all s o urce d oc u me nts, dr u g rec or ds, a n d ori gi nal cli nical me dical n otes.  
T he I n vesti gat or is t o e ns ure t hat t he trial partici pa nts are a ware of a n d c o nse nt t o t he re vie w of 
pers o nal i nf or mati o n d uri n g t he data verificati o n pr ocess, as part of t he m o nit ori n g/a u diti n g 
pr ocess c o n d ucte d b y pr o perl y a ut h orize d a ge nts of t he S p o ns or or  be s u bject t o i ns pecti o n b y 
re g ulat or y a ut h orities.  I n a d diti o n, participati o n a n d pers o nal i nf or mati o n is treate d as strict l y 
c o nfi de ntial t o t he e xte nt of a p plica ble la w a n d is n ot p u blicl y a vaila ble.  
1 1. 2  
D at a Rec or di n g a n d Rete nti o n of St u d y D at a  
I n c o m plia nce wit h G C P, t he me dical rec or ds/ me dical n otes, a n d ot her st u d y-relate d materials 
s h o ul d be clearl y mar ke d a n d per mit eas y i de ntificati o n of partici pati o n b y a n i n di vi d ual i n a 
s pecifie d cli nical trial. 
T he I n vesti gat or is t o rec or d all data wit h res pect t o pr ot oc ol pr oce d ures, dr u g a d mi nistrati o n, 
la b orat or y data, safet y data, a n d efficac y rati n gs o n t he e C R Fs.  
If t he I n vestigat or rel ocates or retires, or ot her wise 
wit h dra ws his/ her res p o nsi bilit y f or 
mai nte na nce a n d rete nti o n of t he master cli nical st u d y rec or ds, t he S p o ns or m ust be n otifie d i n 
writi n g s o t hat a de q uate pr o vi si o n ca n be ma de wit h re gar d t o t he trial d oc u me nts. 
Trial d oc u me nts s h o ul d be retai ne d f or at least t w o years after t he a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or pla n ne d mar keti n g a p plicati o ns i n 
a n I C H re gi o n,  or u ntil at least t w o years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of cli nical 
de vel o p me nt of A R Q  7 5 1 b y t he S p o ns or.  T he d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, 
h o we ver, if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n a gr ee me nt wit h t he 
S p o ns or t hat it will i nf or m t he I n ve sti gat or, i n writi n g, as t o w he n t he rete nti o n of t hese d oc u me nts 
is n o l o n ger necessar y.  
1 1. 3  
Electr o nic C ase Re p ort F or ms  
A n E D C s yste m will be use d t o c ollect t he data i n t his st u d y.  T he E D C s yste m pr o vi de s 
f u ncti o nalit y f or t he cli nical sites t o e nter t he data directl y i nt o t he e C R Fs a n d res p o n d t o data 
discre pa ncies.  O nce t he data are e ntere d, t he i nf or mati o n is e ncr y pte d a n d tra ns mitte d o ver t he 
I nter net t o a cli nical trial ser ver w here it is electr o nicall y re vie we d.  A n y res ulti n g data q ueries are 
i m me diatel y se nt bac k t o t he site f or res ol uti o n.  T he s yste m a ut o maticall y kee ps a f ull a u dit trail 
of all data c ha n ges t hat occ ur.  T he cli nical tea m will u n derta ke a d diti o nal ma n ual re vie w of t he 
data, b ut all res ulti n g data q ueries or clarificati o ns will be  e ntere d i nt o t he E D C s yste m f or 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 1  of 1 1 7  
 
res ol uti o n.  All e C R Fs will be c o m plete d acc or di n g t o i nstr ucti o ns pr o vi de d i n t he e C R F 
C o m pleti o n G ui deli nes a n d I C H/ G C P g ui deli nes.  
1 1. 4  
C o nfi de nti alit y, P u blic ati o n, a n d Dis cl os ure P olic y  
T he I n vesti gat or u n dersta n ds t hat t he  S p o ns or will use t he i nf or mati o n de vel o pe d i n t he cli nical 
st u d y i n c o n necti o n wit h t he de vel o p me nt of A R Q 7 5 1. T his i nf or mati o n ma y be discl ose d t o ot her 
cli nical I n vesti gat ors, t he F D A, a n d ot her g o ver n me nt a ge ncies.  
All i nf or mati o n discl ose d t o t he I n v esti gat or b y t he S p o ns or f or t he p ur p ose of ha vi n g t he 
I n vesti gat or c o n d uct t he cli nical trial descri be d i n t his pr ot oc ol, or i nf or mati o n ge nerate d b y t he 
I n vesti gat or as res ults i n t he cli nical trial s hall be treate d b y t he I n vesti gat or as strictl y c o nfi de ntial.  
T he I n vesti gat or s hall n ot use s uc h i nf or mati o n ot her t ha n f or t he p ur p ose of c o n d ucti n g t he cli nical 
trial a n d ma y n ot discl ose s uc h i nf or mati o n t o ot hers, e xce pt w he n s uc h discl os ure is ma de t o 
c ollea g ues a n d/ or e m pl o yees w h o reas o na bl y re q uire t he i nf or mati o n i n or der t o assist i n carr yi n g 
o ut t he cli nical trial a n d w h o are b o u n d b y li ke -o bli gati o ns of c o nfi de ntialit y.  N ot wit hsta n di n g, 
t he I n vesti gat or ma y use or discl ose t o ot hers a n y i nf or mati o n w hic h: (i) was k n o w n t o t he 
I n vesti gat or pri or t o t he date of its discl os ure; (ii) is n o w, or bec o mes i n t he f ut ure, p u blicl y 
a vaila ble; or (iii) is la wf ull y discl ose d t o t he I n vesti gat or o n a n o n -c o nfi de ntial basis b y a t hir d 
part y w h o is n ot o bli gat e d t o t he S p o ns or or a n y ot her part y t o retai n s uc h i nf or mati o n i n 
c o nfi de nce.  
T he S p o ns or ac k n o wle d ges t hat t he I n vesti gat or has certai n pr ofessi o nal res p o nsi bilities t o re p ort 
t o t he scie ntific c o m m u nit y o n fi n di n gs ma de i n t he cli nical i n vesti gati o ns t he y c o n d uct.  T he 
I n vesti gat or s hall ha ve t he ri g ht to p u blis h t he res ults of researc h perf or me d u n der t his pr ot oc ol, 
pr o vi de d t hat s uc h p u blicati o n d oes n ot discl ose a n y C o nfi de ntial I nf or mati o n or tra de secrets of 
t he S p o ns or ( ot her t ha n t he Data).  If t he st u d y is c o n d ucte d as part of a m ulti -ce nter pr ot o c ol, t he 
I n vesti gat or a grees n ot t o i n de pe n de ntl y p u blis h t he fi n di n gs e xce pt as part of a n o verall m ulti-
ce nter p u blicati o n, u nless s pecificall y a p pr o ve d i n writi n g b y t he S p o ns or  or u nless m ore t ha n 
1 2  m o nt hs ha ve ela pse d si nce t he last s u bject i n t he st u d y has c o m plete d his/ her st u d y desi g ne d 
treat me nt. 
0 7 Y 3 G R

Ar Q ule, I nc. 
5. 3 Pr ot oc ol or A me n d me nt 
A R Q 7 5 1- 1 0 1 
1 6. 1. 1 Pr ot oc ol A me n d me nt 7 
 
0 9 A pril 2 0 1 9  
C o nfi de ntial  
Pa g e 8 2  of 1 1 7  
 
1 2  R E F E R E N C E LI S T 
Alt o mare  D A,  Testa  J R.  Pert ur bati o ns  of  t he  A K T  si g nali n g  pat h w a y  i n  h u ma n  ca ncer. 
O nc o ge ne. 2 0 0 5; 2 4( 5 0): 7 4 5 5- 6 4. 
A n djel k o vic M, Alessi D R, Meier R, et al. R ole of Tra nsl ocati o n  i n t he Acti vati o n a n d F u ncti o n 
of Pr otei n Ki nase B. J Bi ol C he m. 1 9 9 7; 2 7 2: 3 1 5 1 5- 2 4. 
Ba n g YJ, Ka n g Y K, Alsi na M,et al. , (a bstract):  J A G U A R: A ra n d omize d p hase II st u d y of t he 
A K T  i n hi bit or  i pataserti b  ( G D C- 0 0 6 8)  vers us  place b o  i n  c o m bi nat i o n  wit h  m F O L F O X 6 
c he m ot hera p y i n patie nts ( pts) wit h l ocall y a d va nce d or metasta tic H E R 2- ne gati ve gastric ( G) 
or  gastr oes o p ha geal  j u ncti o n  ( G EJ )  a de n ocarci n o ma.  Prese nte d  A SC O  2 0 1 4,  Ma y  3 1,  2 0 1 4, 
C hica g o, I L, U S A 
Bea ver  J A,  G usti n  J P,  Yi  K H,  et  al.  PI K 3 C A  a n d  A K T 1  m utati o ns  h a ve  disti nct  effects  o n 
se nsiti vit y t o tar gete d pat h wa y i n hi bit ors i n a n is o ge nic l u mi nal breast ca ncer m o del s yste m. 
Cli n Ca ncer Res. 2 0 1 3; 1 9( 1 9): 5 4 1 3- 2 2. 
Bellac osa  A,  K u mar  C C,  Di  Crist ofa n o  A,  Testa  J R.  Acti vati o n  of   A K T  Ki nases  i n  Ca ncer: 
I m plicati o ns f or T hera pe utic Tar geti n g. A d v Ca ncer Res. 2 0 0 5; 9 4: 2 9- 8 6. 
Be n der  A,  O pel  D,  Na u ma n n  I,  et  al.,  PI 3 K  i n hi bit ors  pri me  ne ur o blast o ma  cells  f or 
c he m ot hera p y  b y  s hifti n g  t he  bala nce  t o war ds  pr o-a p o pt otic  Bcl- 2  pr otei ns  a n d  e n ha nce d 
mit oc h o n drial a p o pt osis. O nc o ge ne ( 2 0 1 1) 3 0, 4 9 4 – 5 0 3; d oi: 1 0. 1 0 3 8/ o nc. 2 0 1 0. 4 2 9; p u blis he d 
o nli ne 2 0 Se pte m ber 2 0 1 0. 
Blee ker  F E,  Felici o ni  L,  B uttitta  F,  et  al.  A K T 1( E 1 7 K)  i n  h u ma n   s oli d  t u m o urs.  O nc o ge ne. 
2 0 0 8; 2 7( 4 2): 5 6 4 8- 5 0. 
Brazil D P, Ya n g Z, He m mi n gs B A. A d va nces i n pr otei n ki nase B si g nali n g: A K Ti o n o n m ulti ple 
fr o nts. Tre n ds Bi oc he m Sci. 2 0 0 4; 2 9( 5): 2 3 3- 4 2. 
Br u g ge J, H u n g M C, Mills G B. A ne w m utati o nal A K Ti vati o n i n t he  PI 3 K pat h wa y. Ca ncer 
Cell. 2 0 0 7; 1 2( 2): 1 0 4- 7. 
B usai d y  N L,  Far o o ki  A,  D o wlati  A,  et  al.  Ma na ge me nt  of  meta b olic  effects  ass ociate d  wit h 
a ntica ncer a ge nt tar geti n g t he P I 3 K- A kt- m T O R pat h wa y. J Cli n O nc ol. 2 0 1 2; 3 0( 2 3): 2 9 1 9- 2 8. 
B yr o n  S A,  Gartsi de  M G,  Welle ns  C L,  et  al.  I n hi biti o n  of  acti vat e d  fi br o blast  gr o wt h  fact or 
rece pt or 2 i n e n d o metrial ca ncer cells i n d uces cell deat h des pi te P T E N a br o gati o n. Ca ncer Res. 
2 0 0 8; 6 8 ( 1 7): 6 9 0 2- 7. 
Car pte n  J D,  Fa ber  A L,  H or n  C,  et  al.  A  tra nsf or mi n g  m utati o n  i n   t he  plec kstri n  h o m ol o g y 
d o mai n of A K T 1 i n ca ncer . Nat. 2 0 0 7; 4 4 8( 7 1 5 2): 4 3 9- 4 4. 
Die nst ma n n R, R o d o n J, Serra V, Pic ki n g t he P oi nt of I n hi biti o n : A C o m parati ve Re vie w of 
PI 3 K/ A K T/ m T O R  Pat h wa y  I n hi bit ors .  P u blis he d  O nli ne First  A pril  18,  2 0 1 4;  D OI: 
1 0. 1 1 5 8/ 1 5 3 5- 7 1 6 3. M C T- 1 3- 0 6 3 9. 
E n gel ma n J A, L u o J, Ca ntle y L C. T he e v ol uti o n of p h os p hati d yli n osit ol 3- ki nases as re g ulat ors 
of gr o wt h a n d meta b olis m. Nat Re v Ge net. 2 0 0 6; 7 ( 8): 6 0 6- 1 9. 
Frec h M, A n djel k o vic M, I n gle y E, Re d d y K K, Falc k J R, He m mi n gs B A. Hi g h Affi nit y Bi n di n g 
of  I n osit ol  P h os p hates  a n d  P h os p h oi n ositi des  t o  t he  Plec kstri n H o m ol o g y   D o mai n  of 
0 7 Y 3 G R

Ar Q ule, I nc. 
5. 3 Pr ot oc ol or A me n d me nt 
A R Q 7 5 1- 1 0 1 
1 6. 1. 1 Pr ot oc ol A me n d me nt 7 
 
0 9 A pril 2 0 1 9  
C o nfi de ntial  
Pa g e 8 3  of 1 1 7  
 
R A C/ Pr otei n Ki nase B a n d t heir I nfl ue nce o n Ki nase Acti vit y. J Bi ol C he m. 1 9 9 7; 2 7 2: 8 4 7 4-
8 1. 
F o kas E, I m J H, Hill S, at el,  D ual I n hi biti o n of t he PI 3 K/ m T O R Pat h wa y I ncreases T u m or 
Ra di ose nsiti vit y b y N or malizi n g T u m or Vasc ulat ure. Ca ncer Res 7 2 2 9 3- 2 4 8, 2 0 1 2. 
Fr u ma n D, R o m mel C, 2 0 1 4 PI 3 K a n d Ca ncer: Less o ns, C halle n ges a n d O p p ort u nities. Nat Re v 
Dr u g Disc o v 1 3 1 4 0- 1 5 6, 2 0 1 4. 
H ussai n  K,  C hallis  B,  R oc ha  N,  et  al.  A n  acti vati n g  m utati o n  of   A K T 2  a n d  h u ma n 
h y p o gl yce mia. Sci. 2 0 1 1; 3 3 4( 6 0 5 5): 4 7 4. 
Kilic- Ere n M, B o yl u T, Ta b or V. Tar geti n g PI 3 K/ A kt re presses H y p o xia i n d uci ble fact or- 1 α 
acti vati o n a n d se nsitizes R ha b d o m y osarc o ma a n d E wi n g's sarc o ma cells f or a p o pt osis. 
Ca ncer Cell I nt. 2 0 1 3 A pr 1 6; 1 3: 3 6  
K o n o ple va M Y, Walter R B, Fa derl S H, et al. Precli nical a n d Earl y Cli nical E val uati o n of t he 
Oral A K T I n hi bit or, M K- 2 2 0 6, f or t he Treat me nt of Ac ute M yel o ge n o us Le u ke mia. Cli n Ca ncer 
Res. 2 0 1 4; 2 0( 8): 2 2 2 6- 3 5. 
L o R uss o P M, 2 0 1 6 I n hi biti o n of t he PI 3 K/ A K T/ m T O R Pat h wa y i n S ol i d T u m ors. J Cli n O nc ol 
3 4: 3 8 0 3- 3 8 1 5. © 2 0 1 6 b y A merica n S ociet y of Cli nical O nc ol o g y. 
Lee J H, H u y n h M, Sil ha v y J L, Ki m S, Di x o n- Salazar T, Hei ber g A.  De n o v o s o matic m utati o ns 
i n  c o m p o ne nts  of  t he  PI 3 K- A K T 3- m T O R  pat h wa y  ca use  he mi me gale ncep hal y.  Nat  Ge net. 
2 0 1 2; 4 4: 9 4 1- 4 5. 
Li X, Dai D, C he n B, 2 0 1 8 Efficac y of PI 3 K/ A K T/ m T O R pat h wa y i n h i bit ors f or t he treat me nt 
of  a d va nce d  s oli d  ca ncers:  A  literat ure- base d  meta-a nal ysis  of 4 6  ra n d o mise d  c o ntr ol  trials. 
htt ps:// d oi. or g/ 1 0. 1 3 7 1/j o ur nal . 0 1 9 2 4 6 4 P u blis he d: Fe br uar y 6, 2 0 1 8. 
Miller T W, Re xer B N, Garrett J T. M utati o ns i n t he p h os p hati d yli n osit ol 3- ki nase pat h wa y: 
r ole i n t u m or pr o gressi o n a n d t hera pe utic i m plicati o ns i n breast ca ncer. Breast Ca ncer Res. 
2 0 1 1; 1 3( 6): 2 2 4 
Nit ulesc u G M, Mar gi na D, J uze nas P, et al. A kt i n hi bit ors i n ca ncer treat me nt: T he l o n g j o ur ne y 
fr o m  dr u g  disc o ver y  t o  cli nical  use  ( Re vie w).  I nt  J  O nc ol.  2 0 1 6  Mar;  4 8( 3):  8 6 9 – 8 8 5  D OI: 
1 0. 3 8 9 2/ij o. 2 0 1 5. 3 3 0 6. 
Sa h m  F,  Bissel  J,  K oelsc he  C,  et  al.  A K T 1 E 1 7 K  m utati o ns  cl uster   wit h  me ni n g ot helial  a n d 
tra nsiti o nal  me ni n gi o mas  a n d  ca n  be  detecte d  b y  S F R P 1  i m m u n o hist oc he mistr y.  Acta 
Ne ur o pat h ol. 2 0 1 3; 1 2 6( 5): 7 5 7- 6 2. 
S he  Q- B,  C ha n darla pat y  S,  Ye  Q,  et  al.  Breast  T u m or  Cells  wit h PI 3 K  M utati o n  or  H E R 2 
A m plificati o n Are Selecti vel y A d dicte d t o A kt Si g nali n g. P L o S O ne. 2 0 0 8; 3( 8):e 3 0 6 5. 
S h oji K, O da K, Na ka ga wa S, et al. T he o nc o ge nic m utati o n i n t h e plec kstri n h o m ol o g y d o mai n 
of A K T 1 i n e n d o metrial carci n o mas. Br J Ca ncer. 2 0 0 9; 1 0 1( 1): 1 4 5 - 8. 
S oria  J C,  A djei  A A,  Ba hle da  R,  et  al.  A  p hase  I B  d ose-escalati o n  st u d y  of  t he  safet y  a n d 
p har mac o ki netics  of pictilisi b i n  c o m bi nati o n  wit h  eit her  pacli ta xel  a n d  car b o plati n  ( wit h  or 
wit h o ut be vaciz u ma b) or pe metre x e d a n d cis plati n ( wit h or wit h o ut be vaciz u ma b) i n patie nts 
wit h  a d va nce d  n o n-s mall  cell  l u n g  ca ncer.  E ur  J  Ca ncer. 2 0 1 7  N o v; 8 6: 1 8 6- 1 9 6.  d oi: 
1 0. 1 0 1 6/j.ejca. 2 0 1 7. 0 8. 0 2 7. E p u b 2 0 1 7 Oct 6. 
0 7 Y 3 G R

Ar Q ule, I nc. 
5. 3 Pr ot oc ol or A me n d me nt 
A R Q 7 5 1- 1 0 1 
1 6. 1. 1 Pr ot oc ol A me n d me nt 7 
 
0 9 A pril 2 0 1 9  
C o nfi de ntial  
Pa g e 8 4  of 1 1 7  
 
Ste m ke- Hale K, G o nzalez- A n g ul o A M, Ll uc h A, et, al., A n i nte grati ve ge n o mic a n d pr ote o mic 
a nal ysis of PI K 3 C A, P T E N, a n d A K T m utati o ns i n breast ca ncer. C a ncer Res. 2 0 0 8 A u g 
1; 6 8( 1 5): 6 0 8 4- 9 1 
Ta n S, N g Y, Ja mes D E. Ne xt- ge nerati o n A kt i n hi bit ors pr o vi de g reater s pecificit y: effects o n 
gl uc ose meta b olis m i n a di p oc ytes. Bi oc he m J. 2 0 1 1; 4 3 5( 2): 5 3 9- 4 4 . 
Ya p T A, Ya n L, Pat nai k A, et al. First-i n- ma n cli nical trial of  t he oral pa n- A K T i n hi bit or M K-
2 2 0 6 i n patie nts wit h a d va nce d s ol i d t u m ors. J Cli n O nc ol. 2 0 1 1; 2 9( 3 5): 4 6 8 8- 9 5. 
Y u Y, Sa va ge R, S u d hars ha n E, et al., Tar geti n g A K T 1- E 1 7 K a n d t he PI 3 K/ A K T Pat h wa y wit h 
a n All osteric A K T I n hi bit or , A R Q 0 9 2. d oi: 1 0. 1 3 7 1/j o ur nal. p o ne.0 1 4 0 4 7 9, P u blis he d: Oct o ber 
1 5, 2 0 1 5. 
Z ha n g X, Z ha n g S, Ya ma ne H, et al. Ki netic Mec ha nis m of A K T/ P K B  E nz y me Fa mil y. J Bi ol 
C he m. 2 0 0 6; 2 8 1: 1 3 9 4 9- 5 6. 
Z ha n g Y, Xia o J, Wa n g H, et al. Rest ori n g de presse d H E R G K +  c ha n nel f u ncti o n as a mec ha nis m 
f or  i ns uli n  treat me nt  of  a b n or mal  Q T  pr ol o n gati o n  a n d  ass ociated  arr h yt h mias  i n  dia betic 
ra b bits. A m J P h ysi ol Heart Circ P h ysi ol. 2 0 0 6; 2 9 1( 3): H 1 4 4 6- 5 5. 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 5  of 1 1 7  
 
A p pe n di x 1  
Sc he d ule of Assess me nts  
Tests & Pr oce d ures  
 Scree ni n g  
Tre at me nt Visits  
E n d of 
Tre at me nt  
3 0 -d a y 
S afet y 
F oll o w -u p  
C ycle  
B aseli ne  
1  
2 +  
 
Wit hi n 7 da ys of 
decisi o n t o 
per ma ne ntl y 
disc o nti n ue  
3 0 + da ys 
after t he last 
d ose of 
A R Q  7 5 1  
D a y  
0  
1  
2  
8 1 
1 5  
1  
2  
8 1 
1 5 2 
 
 
Wi n d o w  (i n d a ys) 
-1 4 - 0  
-1  
0  
± 2   
± 3 3 
± 3 3 
0  
± 2  
± 3 3 
 
 
Writte n I nf or me d C o nse nt 4 
X  
 
 
 
 
 
 
 
 
 
 
Me dic a l Hist or y 
X  
 
 
 
 
 
 
 
 
 
 
P h ysic al E x a mi n ati o n (i ncl u di n g 
s ki n) 
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
E C O G P S  
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
Vit al Si g ns 5   
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
F asti n g Cli nic al Bl o o d Tests 6 
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
Uri n al ysis  
X  
 
 
 
 
 
 
 
 
X  
 
Ser u m Pre g n a nc y Test, if 
a p plic a ble  
X  
 
 
 
 
 
 
 
 
X  
 
C Y P 2 D 6 S a m ple  
 
X  
 
 
 
 
 
 
 
 
 
ct D N A S a m ple  
 
X  
 
 
 
 
 
 
 
 
 
Gl uc ose Met a b olis m Bl o o d 
S a m ples 7 
 
X  
X  
 
X  
X  
X  
 
 
 
 
P K Bl o o d S a m ples 7 
 
X  
X  
 
X  
X  
X  
 
 
 
 
H o me Bl o o d Gl uc ose M o nit ori n g 8 
 
 
X  
X  
X  
 
 
 
 
 
 
Bl o o d T u m or M ar kers, (if 
a p plic a ble )9 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
1 2 -Le a d E C G 1 0 
X  
X  
 
 
X  
X  
 
 
 
X  
 
B o ne Sc a n  
X  
 
 
 
 
 
 
 
 
 
 
Ec h oc ar di o gr a p h y/ M U G A  (if 
a p plic a ble )1 1 
X  
 
 
 
 
 
 
 
 
 
 
T u m or Assess me nt a n d 
Re -st a gi n g1 2  
X  
 
 
 
 
X  
 
 
 
X  
 
C o nc o mit a nt Me dic ati o ns  
X  
X  
 
X  
X  
X  
 
X  
X  
X  
X  
A d verse E ve nts Assess me nt  
 
X  
 
X  
X  
X  
 
X  
X  
X  
X  
A R Q 7 5 1  Dis pe ns ati o n  
 
X  
 
 
 
X  
 
 
 
 
 
1 
Da y 8 visits are o nl y re q uire d f or Ar m B ( A R Q 7 5 1 + paclita xel)  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 6  of 1 1 7  
 
2 
C y cle 2 Da y 1 5 visit is o nl y re q u ire d f or Ar m B ( A R Q  7 5 1 + paclita xel) a n d Ar m C ( A R Q 7 5 1 +f ul vestra nt).  Da y 1 5 visits i n c ycle 3 are hi g her are re q uire d o nl y f or Ar m B 
( A R Q 7 5 1 + paclitaxel)  
3 
Wi n d o w of ± 3 da ys is all o we d f or Ar ms A ( A R Q 7 5 1 si n gle a ge nt) a n d Ar m  C  ( A R Q 7 5 1 +f ul vestra nt), b ut wi n d o w of ± 2 da ys is re q uire d f or Ar m  B  ( A R Q 7 5 1 +paclita xel ). 
4 
I C F ca n be si g ne d greater t ha n 1 4 da ys pri or t o first d ose.  
5 
Te m perat u re, B P, H R a n d R R  at e very visit.  Hei g ht o nl y at Scree ni n g.  Wei g ht at Scree ni n g, Da y 1 of eac h c ycle a n d at E n d of Treat me nt visit.  
6 
Refer t o  Secti o n 5. 4  f or detaile d descri pti o n of cli nical la b orat or y tests  
7 
Refer  t o Secti o n 5. 5  a n d A p pe n di x 3 f or details o n P K a n d Gl uc ose Meta b olis m (i ns uli n a n d gl uc ose) ti me p oi nts . 
8 
Refer t o  Secti o n 5. 6 . H o me bl o o d gl uc ose m o nit ori n g s h o ul d b e perf or me d b y t he s u bjects at least once per da y ( bef ore brea kfast) f or t he first 4  wee ks .  N ot necessar y o n da ys 
w here gl uc ose will be teste d at t he st u d y site.  After t he f irst f o ur wee ks of treat me nt, t he I n vesti gat or will deter mi ne if a s u bject s h o ul d c o nti n ue h ome gl uc ose testi n g a n d t he 
testi n g fre q uenc y.  
9 
T u m or mar kers testi n g  (if a p plica ble) will be d o ne at t he st u d y site . T u m or mar kers will be teste d at Scree ni n g a n d fre q ue nc y of testi n g w hile o n treat me nt will be  as per 
F D A/ N C C N g ui del i nes, or i ns tit uti o nal sta n dar ds. 
1 0 
Refer t o Secti o n  5. 3 .  Si n gle 1 2 -lea d E C G t o be perf or me d at Scree ni n g a n d at E n d of Treat me nt visit.  Re peat t ri plicate E C Gs t o be perf or me d  at C 1 D 1, C 1 D 1 5, C 2 D 1, C 3 D 1 
a n d C 4 D 1.    See A p p e n di x 3 f or details f or sc he d uled visits .  A d diti o nal E C Gs ma y  be c o n d ucte d if cli nicall y i n dicate d. 
1 1 
Ec h o/ M U G A o nl y re q uire d f or s u bjects w h o recei ve d pri or t hera p y wit h a nt hrac ycli nes 
1 2 
Re fer t o Secti o n  5. 7 . T u m or assess me nt ( C T a n d/ or M RI) at Scree ni n g ca n be d o ne u p t o 2 8 da ys pri or t o t he 1st d ose of A R Q  7 5 1).  P ost treat me nt, t u m or assess me nt m ust be 
d o ne at t he b e gi n ni n g of e ver y ot her c ycl e, starti n g at C ycle 3 Da y 1.   T u m or assess me nt re q uire d at t he E n d of  Treat me nt  ( E O T) visit  u nless disease pr o gressi o n was see n o n 
t he pri or sca n.
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 7  of 1 1 7  
 
 
A p pe n di x 2  
 
Perf or m a nce St at us  
E C O G Perf or m a nce St at us Sc ale  
Gr a de  
Descri pti o ns  
0  
N or mal acti vit y.  F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n.  
1  
S y m pt o ms, b ut a m b ulat or y.  Restricte d i n p h ysicall y stre n u o us acti vit y, b ut a m b ulat or y a n d a ble 
t o carr y o ut w or k of a li g ht or se de ntar y nat ure (e. g., li g ht h o use w or k, office w or k). 
2  
I n be d <  5 0 % of t he ti me.  A m b ulat or y a n d ca pa ble of all self -care, b ut u na ble t o carr y o ut a n y 
w or k acti vities.  U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.  
3  
I n be d > 5 0 % of t he ti me.  Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 
5 0 % of wa ki n g h o urs.  
4  
1 0 0 % be dri d de n.  C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d or 
c hair. 
5  
Dea d.  
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 8  of 1 1 7  
 
A p pe n di x 3  
P h ar m ac o ki netic, P h ar m ac o d y n a mic, Gl uc ose Met a b olis m  ( G M) 
S a m pli n g a n d E C G Sc he d ule  
A.  
Bl o o d C ollecti o n Sc he d ule f or P K a n d G M  (i ns uli n & gl uc ose) a n d E C G sc he d ule 
D a y  
Bl o o d S a m ples  
Desire d Ti me  
E C G  
(wit hi n 3 0 mi n utes pri or t o ti me-
matc he d P K c ollecti o n)  
S C R E E NI N G  
1 4 - -1  
N A  
N A  
 1 2 -lea d  si n gle E C G,  
a n y ti me  
C Y C L E 1 D A Y 1  
C 1 D 1  
P K  
G M  
0 h o ur ( pri or t o t he 1 st d ose 
of A R Q  7 5 1)  
Tri plicate 1 2 -lea d E C G 
 
C 1 D 1  
P K  
G M  
1 h o ur ( ± 1 5 mi n utes)  
 
C 1 D 1  
P K  
G M  
2 h o ur ( ± 2 0 mi n utes)  
Tri plicate 1 2 -lea d E C G 
 
C 1 D 1  
P K  
G M  
4  h o urs ( ± 3 0 mi n utes)  
Tri plicate 1 2 -lea d E C G 
 
C 1 D 1  
P K  
G M  
6 h o urs ( ± 3 0 mi n utes)  
 
C 1 D 1  
P K  
G M  
8 h o urs ( ± 3 0 mi n utes)  
 
C Y C L E 1 D A Y 2  
C 1 D 2  
P K  
G M  
2 4 h o urs ( ± 2 h o urs)  
( pri or t o t he m or ni n g d ose) 
 
C Y C L E 1 D A Y 1 5  
C 1 D 1 5  
P K  
G M  
0 h o ur ( pri or t o t he m or ni n g 
d ose)  
Tri plicate 1 2 -lea d E C G 
 
C 1 D 1 5  
P K  
G M  
1 h o ur ( ± 1 5 mi n utes)  
  
C 1 D 1 5  
P K  
G M  
2 h o ur ( ± 2 0 mi n utes)  
Tri plicate 1 2 -lea d E C G 
  
C Y C L E 2 D A Y 1  
C 2 D 1  
P K  
G M  
0 h o ur ( pri or t o t he m or ni n g 
d ose)  
 
C 2 D 1  
P K  
G M  
1 h o ur ( ± 1 5 mi n utes)  
 
C 2 D 1  
P K  
G M  
2 h o ur ( ± 2 0 mi n utes)  
Tri plicate  1 2 -lea d E C G 
 
C 2 D 1  
P K  
G M  
4  h o urs ( ± 3 0 mi n utes)  
Tri plicate  1 2 -lea d E C G 
 
C 2 D 1  
P K  
G M  
6 h o urs ( ± 3 0 mi n utes)  
 
C 2 D 1  
P K  
G M  
8 h o urs ( ± 3 0 mi n utes)  
 
C Y C L E 2 D A Y 2  
C 2 D 2  
P K  
G M  
2 4 h o urs ( ± 2 h o urs)  
( pri or t o t he m or ni n g d ose) 
 
C Y C L E 3  D A Y 1  
C 3 D 1  
P K  
G M  
0 h o ur ( pri or t o t he m or ni n g 
d ose)  
Tri plicate  1 2 -lea d E C G 
 
C 3 D 1  
P K  
 
1 h o ur ( ± 1 5 mi n utes)  
 
C 3 D 1  
P K  
 
2 h o ur ( ± 2 0 mi n utes)  
Tri plicate  1 2 -lea d E C G 
 
C Y C L E 4 D A Y 1  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 8 9  of 1 1 7  
 
C 4 D 1  
P K  
G M  
0 h o ur ( pri or t o t he m or ni n g 
d ose)  
Tri plicate  1 2 -lea d E C G 
 
C 4 D 1  
P K  
 
1 h o ur ( ± 1 5 mi n utes)  
 
C 4 D 1  
P K  
 
2 h o ur ( ± 2 0 mi n utes)  
Tri plicate  1 2 -lea d E C G 
 
E n d of Tre at me nt  
E O T  
N A  
N A  
N A  
1 2 -lea d  si n gle E C G,  
a n y ti me  
* T he e xact ti me of c o -dr u g a d mi n istrati o n, i ncl u di n g start/st o p ti me of i nf usi o n if a p plica ble, has t o be rec or de d i n e C R F a n d 
sa m ple c ollecti o n/re q uisiti o n f or m. 
 
 
 
B . 
Bl o o d Sa m ple C ollecti o n f or C Y P 2 D 6  a n d ct D N A  
D A Y  
 
P R O C E D U R E  
S A M P L E  
D E SI R E D TI M E  
 
C Y C L E 1 D A Y 1  
 
 
C 1 D 1  
Dra w bl o o d sa m p le 
C Y P 2 D 6  
0 h o ur  
( pri or t o t he d ose of A R Q 7 5 1)  
C 1 D 1  
Dra w bl o o d sa m ple  
ct D N A 
0 h o ur  
( pri or t o t he d ose of A R Q 7 5 1) 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 0  of 1 1 7  
 
A p pe n di x 4  
E x a m ples of I n Viv o S u bstr ates, I n hi bit ors, a n d I n d ucers f or 
S pecific C Y P E nz y mes a n d P -gl yc o pr otei ns  
E x a m ples of I n Viv o S u bstr ates, I n hi bit ors, a n d I n d ucers f or S pecific C Y P E nz y mes 1 
C Y P  
S u bstr ate  
I n hi bit or 
I n d ucer 
2 D 6  
at o m o xeti ne, desi pra mi ne, 
de xtr o met h or p ha n , eli gl ustat, 
ne bi v ol ol, n ortri pt yli ne, 
per p he nazi ne, t olter o di ne, 
ve nlafa xi ne  
 b u pr o pi o n, fl u o xeti ne, 
par o xeti ne, q ui ni di ne, 
terbi nafi ne  
n o ne i de ntifie d  
2 C 1 9  
S -me p he n yt oi n, o me praz ole  
fl uc o naz ole, fl u o xeti ne, 
fl u v o xa mi ne, ticl o pi di ne 
Rif a m pi n , rit o na vir 
3 A 4/ 3 A 5  
alfe nta nil, a va nafil, b us pir o ne, 
c o ni va pta n, darife naci n, 
dar u na vir, e basti ne, e ver oli m us, 
i br uti ni b, l o mita pi de, l o vastati n, 
mi daz ola m, nal o xe g ol, 
nis ol di pi ne, sa q ui na vir, 
si m vastati n, sir oli m us, 
tacr oli m us, ti pra na vir, 
triaz ola m, var de nafil 
b oce pre vir, c o bicistat, 
c o ni va pta n, da n o pre vir a n d 
rit o na vir, el vite gra vir a n d 
rit o na vir, gra pefr uit j uice, 
i n di na vir a n d rit o na vir, 
itrac o naz ole, ket oc o naz ole, 
l o pi na vir a n d rit o na vir, 
parita pre vir a n d rit o na vir a n d 
( o m bitas vir a n d/ or dasa b u vir, 
p osac o naz ole, rit o na vir, 
sa q ui na vir a n d rit o na vir, 
tela pre vir, ti pra na vir a n d 
rit o na vir, tr olea n d o m yci n, 
v oric o naz ole  
car ba maze pi ne, 
e nzal uta mi de, mit ota ne, 
p he n yt oi n, rifa m pi n, St. 
J o h n’s w ort 
S o urce: w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ uc m 0 9 3 6 6 4. ht m  (e xtracte d 
o n 4/ 3/ 2 0 1 9)  
1 
T his is n ot a n e x ha usti ve list  
 
S u bstrates f or a n y partic ular C Y P  e nz y me liste d i n t his t a ble are t h ose wit h plas ma A U C val ues 
i ncrease d b y 2-f ol d or hi g her w he n c o-a d mi nistere d wit h i n hi bit ors of t hat C Y P e nz y me ; f or 
C Y P 3 A, o nl y t h ose wit h plas ma A U C i ncrease d b y 5 -f ol d or hi g her are liste d. 
I n hi bit ors liste d are t h ose t hat i ncrease plas ma A UC val ues of s u bstrates f or t hat C Y P e nz y me b y 
2 -f ol d or hi g her. F or C Y P 3 A i n hi bit ors, o nl y t h ose t hat i ncrease A U C of C Y P 3 A s u bstrates b y 5-
f ol d or hi g her are liste d.  
I n d ucers liste d are t h ose t hat decrease plas ma A U C val ues of s u bstrates f or t hat C Y P e nzy me b y 
3 0 % or hi g her.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 1  of 1 1 7  
 
E x a m ples of I n Viv o S u bstr ates, I n hi bit ors, a n d I n d ucers of P-gl yc o pr otei n 1 
Tr a ns p or ter 
S u bstr ates  
I n hi bit ors2 
I n d ucers3 
P -g p  
(Ge ne A B C B 1 ) 
da bi gatra n , di g o xi n , 
fe x ofe na di ne 
C ycl os p ori n e 
Elacri dar ( G F 1 2 0 9 1 8)  
Ket oc o naz ole  
Q ui ni di ne  
Reser pi ne  
Rit o na vir  
Tacr oli m us  
Vals p o dar ( P S C 8 3 3)  
Vera pa mil  
Z os u q ui dar ( L Y 3 3 5 9 7 9)  
A vasi mi be 4 
C ar ba maze pi ne  
p he n yt oi n  
rifa mpi n  
St J o h n’s w ort 5 
ti pra na vir/rit ona vir  
S o urce: G ui da nce f or I n d ustr y: Dr u g I nteracti o n St u dies –  St u d y D esi g n, Data A nal ysis, I m plicati o ns f or D osi n g, a n d 
La beli n g Rec o m me n dati o ns.  
1 
N ot a n e x ha usti v e list. F or a n u p date d list, see t he f oll o wi n g li n k: 
ht t ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/uc m 0 9 3 6 6 4  
2 
I n hi bit ors liste d f or P-g p are t h os e t hat s h o we d ( 1) A U C f ol d-i ncrease of di g o xi n ≥2 wit h  c o-a d mi nistrati o n a n d ( 2) i n 
vitr o i n hi bit or.  
3 
I n d ucers listed f or P -g p are t h ose  t hat s h o we d > 2 0 % decrease i n di g o xi n A U C or ot her wise i n dicate d if s u bstrate is ot her 
t ha n di g o xin.  
4 
N ot a mar k ete d dr u g 
5 
Her bal pr o d uct  
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 2  of 1 1 7  
 
A p pe n di x 5  
Assess me nt of A nti -tu m or Acti vit y  
Assess me nt of t u m or res p o nse s h o ul d be perf or me d f oll o wi n g t he re vise d R E CI S T g ui deli nes, 
v ersi o n 1. 1. S o me of t hese defi niti o ns a n d criteria are hi g hli g hte d bel o w.  
T u m or e val uati o ns will be perf or me d at t he Scree ni n g Visit ( Baseli ne ), e ver y 2 c yc les d uri n g first 
1 2 m o nt hs of treat me nt . F or s u bjects w h o d o n ot e x perie nce disease pr o gressi o n a n d c o nti n ue t o 
be nefit fr o m t he treat me nt after 1 2 m o nt hs of treat me nt , t u m or e val uati o n ma y be perf or me d e ver y 
3 c ycles u p o n a gre e me nt bet wee n t he I n vesti gat o r a n d t he Me dical M o nit or.  T u m or e val uati o n 
will als o be perf or me d at t he E n d of Treat me nt visit if ra di o gra p hic disease pr o gressi o n was n ot 
see n o n t he pri or sca n. 
Scree ni n g  
O n -tre at me nt 
≤1 2 m o nt hs  of t x  
O n -tre at me nt    
> 1 2 
m o nt hs  of t x  
E O T  
wit hi n 2 8 da ys pri or t he 1 st 
d ose of A R Q 7 5 1  
C 3 D 1,  
C 5 D 1,  
C 7 D 1, 
C 9 D 1 , C 1 1 D 1 
C 1 3 D 1  
C 1 6 D 1, C 1 9 D 1, etc.  
If n o P D see n at pri or sca n 
 
Me as ur a bilit y of T u m or B aseli ne  
C T wit h i ntra ve n o us (I V) c o ntrast a n d M RI are t he best c urre ntl y a vaila ble a n d re pr o d uci ble 
met h o ds t o meas ure tar get lesi o ns selecte d f or res p o nse assess me nt.  C o n ve nti o nal C T a n d M RI 
s h o ul d be perf or me d wit h c uts of 1 0 m m or less i n slice t hic k ness c o nti g u o usl y.  S piral C T s h o u l d 
be perf or me d usi n g a 5 m m c o nti g u o us rec o nstr ucti o n al g orit h m.  
All i ma gi n g met h o ds s h o ul d be perf or me d acc or di n g t o i nstit uti o nal sta n dar ds wit h eac h s u bject 
ha vi n g c o nsiste nc y of met h o ds be gi n ni n g fr o m baseli ne t hr o u g h t he c o urse of t he st u d y.  
Defi niti o ns  
At baseli ne, t u m or lesi o ns/l y m p h n o des will be ca te g orize d meas ura ble or n o n-meas ura ble as 
f oll o ws: 
Meas ura ble  
T u m or lesi o ns:  M ust be acc uratel y meas ure d i n at least o ne di me nsi o n (l o n gest dia meter i n t he 
pla ne of meas ure me nt is t o be rec or de d ) wit h a mi ni m u m size of: 
•  1 0 m m b y C T sca n ( C T sca n slice t hi c k ness n o greater t ha n 5 m m)  
•  1 0 m m cali per meas ure me nt b y cli nical e xa mi nati o n (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h cali pers s h o ul d be rec or de d as n o n -meas ur a ble) 
•  2 0 m m b y c hest X -ra y 
Me as ur a ble m ali g n a nt ly m p h n o des:  T o be c o nsi dere d pat h ol o g icall y e nlar ge d a n d meas ura ble, a 
l y m p h n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice t hic k ness 
rec o m me n de d t o be n o greater t ha n 5 m m). At baseli ne a n d i n f oll o w-u p , o nl y t he s h ort a xis will 
be meas ure d a n d f oll o we d. See als o n otes bel o w o n ‘ Baseli ne d oc u me ntati o n of tar get a n d n o n -
tar get lesi o ns’ f or i nf or mati o n o n l y m p h n o de meas ure me nt. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 3  of 1 1 7  
 
N o n -Meas ura ble  
All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0  m m or pat h ol o gical l y m p h n o des 
wit h ≥ 1 0 t o <  1 5 m m s h ort a xis) as well as tr ul y n o n -meas ura ble lesi o ns. Lesi o ns c o nsi dere d tr ul y 
n o n -meas ura ble i ncl u de: le pt o me ni n geal disease, ascites, ple ural or pericar dial eff usi o n, 
i nfla m mat or y breast disease, l y m pha n gitic i n v ol ve me nt of s ki n ( ne vi) or l u n g, a n d a b d o mi nal 
mas ses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysical e xa m t hat is n ot 
meas ura ble b y 
re pr o d uci ble i ma gi n g tec h ni q ues. 
S peci al C o nsi der ati o ns Re g ar di n g Lesi o n Me as ur a bilit y  
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y treate d wit h l ocal t hera p y re q uire partic ular 
c o m me nt:  
B o ne lesi o ns  
B o ne sca n, P E T sca n, or plai n fil ms are n ot c o nsi dere d a de q uate i ma gi n g tec h ni q ues t o meas ure 
b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m t he prese nce or disa p peara nce of 
b o ne lesi o ns.  
L ytic b o ne lesi o ns or mi xe d l ytic -blastic lesi o ns, wit h i de ntifia ble s oft tiss ue c o m p o ne nts, t hat ca n 
be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T or M RI ca n be c o nsi dere d as 
meas ura ble lesi o ns if  t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of meas ura bilit y descri be d 
a b o ve.  
Blastic b o ne lesi o ns are n o n -meas ura ble.  
C ystic lesi o ns  
Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be c o nsi dere d 
as mali g na nt lesi o ns ( neit her meas ura ble n or n o n -meas ura ble) si nce t he y are, b y de fi niti o n, si m ple 
c ysts. 
‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble lesi o ns, if 
t he y meet t he defi niti o n of meas ura bilit y descri be d ab o ve. H o we ver, if n o nc ystic lesi o ns are 
prese nt i n t he sa me s u bject, t hese are preferre d f or selecti o n as tar get lesi o ns.  
Lesi o ns wit h pri or l ocal treat me nt  
T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her l oc o -re gi onal 
t hera p y, are n ot c o nsi dere d meas ura ble u nless t here has bee n de m o nstrate d pr o gressi o n i n t he 
lesi o n.  
S pecific ati o ns b y Met h o ds of Me as ure me nts  
Meas ure me nt of Lesi o ns  
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y assesse d. All 
baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d N E V E R 
m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt.  
Met h o d of Assess me nt  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 4  of 1 1 7  
 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll ow -u p. I ma gi n g -base d e val uati o n s h o ul d 
al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot be 
i ma ge d b ut are assessa ble b y cli nical e xa m.  
Cli nic al lesi o ns:  Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are s u perficial a n d 
≥ 1 0  m m dia meter as asse sse d usi n g cali pers (e. g., s ki n [ne vi ] n o d ules). F or t he case of s ki n ( ne vi) 
lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y incl u di n g a r uler t o esti mate t he size of t he lesi o n is 
s u g geste d. As n ote d a b o ve, w he n lesi o ns ca n be e val uate d b y b ot h cli nical e xa m a n d i ma gi n g, 
i ma gi n g e val uati o n s h o ul d be u n derta ke n si nce it is m ore o bjecti ve a n d ma y als o be re vie we d at 
t he e n d of t he st u d y. 
C hest X -r ay: C hest C T is preferre d o ver c hest X -ra y, partic ularl y w he n pr o gressi o n is a n i m p orta nt 
e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X -ra y, partic ularl y i n i de ntif yi n g ne w lesi o ns. H o we ver, 
lesi o ns o n c hest X-ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y defi ne d a n d s urr o u n de d 
b y aerate d l u n g.  
C T, M RI:  C T is t he best c urr e ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns selecte d 
f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n base d o n 
the ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve a slice t hic k nes s 
greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. 
M RI is als o acce pta ble i n certai n sit uati o ns (e. g. , f or b o d y sca ns).  
T u m or Res p o nse E v al u ati o n  
Assess me nt of O verall T u m or B ur de n a n d Meas ura ble Disease  
T o assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mate t he o verall t u m or 
b ur de n at baseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure m e nts. I n t his st u d y, o nl y 
s u bjects wit h meas ura ble disease at baseli ne s h o ul d be i ncl u de d i n t he st u d y.  
Baseli ne D oc u me ntati o n of ‘ Tar get’ a n d ‘ N o n -Tar get’ Lesi o ns  
W he n m ore t ha n o ne meas ura ble lesi o n is prese nt at baseli ne, all lesi o ns u p t o a ma xi m u m of  fi ve 
lesi o ns t otal (a n d a m axi m u m  of t w o lesi o ns per or ga n) re prese ntati ve of all i n v ol ve d or ga ns s h o ul d 
be i de ntifie d as tar get lesi o ns a n d will be rec or de d a n d meas ure d at baseli ne (t his mea ns i n 
i nsta nces w here s u bjects ha ve o nl y o ne or t w o or ga n sites i n v ol ve d, a ma xi m u m of t w o a n d f o ur 
lesi o ns res pecti vel y will be rec or de d).  
Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re prese ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o 
re pr o d uci ble re peate d meas ure me nts. It ma y be t he case t hat, o n occasi o n, t he lar gest lesi o n d oes 
n ot le n d itself t o re pr o d uci ble meas ure me nt i n w hic h circ u msta nce t he ne xt lar gest lesi o n w hic h 
ca n be meas ure d re pr o d uci bl y s h o ul d be selec te d.  
Ly m p h n o des  merit s pecial me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h ma y be 
visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or. As n ote d a b o ve, pat h ol o gical n o des w hic h are 
defi ne d as meas ura ble a n d ma y be i de ntifie d as tar get lesi o ns m u st meet t he criteri o n of a s h ort 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 5  of 1 1 7  
 
a xis of ≥ 1 5  m m b y C T sca n. O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne s u m. 
T he s h ort a xis of t he n o de is t he dia meter n or mall y use d b y ra di ol o gists t o j u d ge if a n o de is 
i n v ol ve d b y s oli d t u m or. N o dal size is n or mall y re p orte d as t w o di me nsi o ns i n t he pla ne i n w hic h 
t he i ma ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; f or M RI t he pla ne of 
ac q uisiti o n ma y be a xial, sa gittal, or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. F or 
e xa m ple, a n a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m x 3 0 m m has a s h ort a xis of 2 0 
m m a n d q ualifies as a mali g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s h o ul d be rec or de d as 
t he n o de meas ure me nt. All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥ 1 0 m m b ut < 1 5 m m) 
s h o ul d be c o nsi dere d n o n-tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n-
pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.  
A s u m of t he di a meters  (l o n gest f or n o n-n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m of t he dia meters. If l y m p h n o des are t o 
be i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. T he baseli ne 
s u m of t he dia meters will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve t u m or 
re gressi o n i n t he meas ura ble di me nsi o n of t he disease. 
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l y m p h n o des s h o ul d be i de ntifie d as 
n o n -tar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne. Meas ure me nts are n ot re q uire d, a n d 
t hese lesi o ns s h o ul d be f oll o we d as ‘ prese nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n’ 
( m ore details t o f oll o w). I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n-tar get lesi o ns i n v ol vi n g 
t he sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e. g. ‘ m ulti ple e nlar ge d pel vic l y m p h 
n o des’ or ‘ m ulti ple li ver metastases’).  
Res p o nse Criteri a  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne o bjecti ve t u m or res p o nse f o r 
tar get lesi o ns. 
E val uati o n of Tar get Lesi o ns  
C o m plete Res p o nse ( C R):  Disa p peara nce of all tar get lesi o ns. A n y pat h ol o gical l y m p h n o des 
( w het her tar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
P arti al Res p o nse ( P R):  At least a 3 0 % decr ease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g 
as refere nce t he baseli ne s u m dia meters.  
Pr o gressive Dise ase ( P D):  At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g 
as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he ba seli ne s u m if t hat is t he s mallest o n 
st u d y). I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute 
i ncrease of at least 5 m m. ( N ote: t he a p peara nce of o ne or m ore ne w lesi o ns is als o c o nsi dere d 
pr o gressi o n).  
St a ble Dise ase  ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o 
q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u d y. I n t his st u d y, t he 
mi ni m u m d urati o n f or S D is defi ne d as 8 wee ks ( ± 3 da ys).  
S pecial N otes o n t h e Assess me nt of Tar get Lesi o ns  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 6  of 1 1 7  
 
Ly m p h n o des.  L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e xa mi nati o n), e ve n 
if t he n o des re gress t o bel o w 1 0 m m  o n st u d y. T his mea ns t hat w he n l y m p h n o des are i ncl u de d as 
tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot be zer o e ve n if c o m plete res p o nse criteria are met, 
si nce a n or mal l y m p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. F or P R, S D, a n d P D, t he 
actual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n t he s u m of tar get lesi o ns.  
T ar get lesi o ns  t h at bec o me ‘t o o s m all t o me as ure’. W hile o n st u d y, all lesi o ns ( n o dal a n d n o n-
n o dal) rec or de d at baseli ne s h o ul d ha ve t heir act ual meas ure me n ts rec or de d at eac h Res p o nse 
Criteria s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e. g. 2 m m). H o we ver, s o meti mes lesi o ns or 
l y m p h n o des w hic h are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat t he 
ra di ol o gist ma y n ot feel c o mf orta ble assi g ni ng a n e xact meas ure a n d ma y re p ort t he m as bei n g 
‘t o o s mall t o meas ure’. W he n t his occ urs, it is i m p orta nt t hat a val ue be rec or de d o n t he case re p ort 
f or m. If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, t he meas ure me nt 
s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall 
t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d ( N ote: It is less li kel y t hat t his r ule will be 
use d f or l y m p h n o des si nce t he y us uall y ha ve  a defi na bl e size w he n n or mal a n d are fre q ue ntl y 
s urr o u n de d b y fat s uc h as i n t he retr o perit o ne u m; h o we ver, if a l y m p h n o de is belie ve d t o be 
prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d i n 
t his circ u mstance as well ). T his defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut 
s h o ul d n ot be c ha n ge d wit h var yi n g C T slice t hic k ness). T he meas ure me nt of t hese lesi o ns is 
p ote ntiall y n o n -re pr o d uci ble, t heref ore pr o vi di n g t his defa ult val ue will pre ve nt false res p onses or 
pr o gressi o ns base d u p o n meas ure me nt err or. T o reiterate, h o we ver, if t he ra di ol o gist is a ble t o 
pr o vi de a n act ual meas ure, t hat s h o ul d be rec or de d, e ve n if it is bel o w 5 m m.  
Lesi o ns t h at s plit or c o alesce o n tre at me nt.  W he n n o n -n o dal les i o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m. 
Si milarl y, as lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat w o ul d ai d i n o btai ni n g 
ma xi mal dia meter meas ure me nts of eac h i n d i vi d ual lesi o n. If t he lesi o ns ha ve tr ul y c oalesce d s uc h 
t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n t his i nsta nce s h o ul d be t he 
ma xi mal l o n gest dia meter f or t he ‘c oalesce d lesi o n’.  
E val uati o n of N o n -Tar get Lesi o ns  
T his secti o n  pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne t he t u m or res p o nse f or t he 
gr o u p of n o n -tar get lesi o ns. W hile s o me n o n-tar get lesi o ns ma y act uall y be meas ura ble, t he y nee d 
n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q ualitati vel y at t he  ti me p oi nts s pecifie d i n 
t he pr ot oc ol.  
C o m plete Res p o nse ( C R):  Disa p peara nce of all n o n -tar get lesi o ns a n d n or malizati o n of t u m or 
mar ker le vel. All l y m p h n o des m ust be n o n -pat h ol o gical i n size ( < 1 0 m m s h ort a xis).  
N o n -C R/ N o n -P D:  Pers iste nce of o ne or m ore n o n-tar get lesi o n(s) a n d/ or mai nte na nce of t u m or 
mar ker le vel a b o ve t he n or mal li mits.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 7  of 1 1 7  
 
Pr o gressive Dise ase ( P D):  U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n -tar get 
lesi o ns. ( N ote: t he a p peara nce of o ne or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).  
S pecial N otes o n t he Assess me nt of Pr o gressi o n of N o n -tar get Disease 
T he c o nce pt of pr o gressi o n of n o n -tar get disease re q uires a d diti o nal e x pla nati o n as f oll o ws: 
W he n t he s u bject als o h as me as ur a ble dise ase. I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal pr o gressi o n’ 
o n t he basis of t he n o n -tar get disease, t here m ust be a n o verall le vel of s u bsta ntial w orse ni n g i n 
n o n -tar get disease s uc h t hat, e ve n i n t he prese nce of S D or P R i n tar get disease, t he o verall t u m or 
b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y (see f urt her details bel o w). A 
m o dest ‘i ncrease’ i n t he size of o ne or m ore n o n -tar get lesi o ns is us uall y n ot s ufficie nt t o q ualit y 
f or u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall pr ogressi o n s olel y o n t he basis of 
c ha n ge i n n o n -tar get disease i n t he face of S D or P R of tar get disease will t heref ore be e xtre mel y 
rare.  
E val uati o n of Ne w Lesi o ns  
T he a p peara nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me c o m me nt s 
o n detecti o n of ne w lesi o ns are i m p orta nt. T here are n o s pecific criteria f or t he i de ntificati o n of 
ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal: e. g., n ot 
attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g m o dalit y or fi n di n gs t h o u g ht 
t o re prese nt s o met hi n g ot her t ha n t u m or (f or e xa m ple, s o me ‘ ne w’ b o ne lesi o ns ma y be si m pl y 
heali n g or flare of pre -e xisti n g lesi o ns). T his is partic ularl y i m p orta nt w he n t he s u bject’s baseli ne 
lesi o ns s h o w partial or c o m plete res p o nse. F or e xa m ple, necr osis of a li ver lesi o n ma y be re p orte d 
o n a C T sca n re p ort as a ‘ ne w’ c ystic lesi o n, w hic h it is n ot.  
A lesi o n i de ntifie d o n a f oll o w -u p st u d y i n a n a nat o mical l ocati o n t hat was n ot sca n ne d at baseli ne 
is c o nsi dere d a ne w lesi o n a n d will i n dicate disease pr o gressi o n. A n e xa m ple of t his is t he s u bject 
w h o has visceral disease at B aseli ne a n d w hile o n st u d y has a C T or M RI of t he brai n or dere d 
w hic h re veals metastases. T he s u bject’s brai n metastases are c o nsi dere d t o be e vi de nce of P D e ve n 
if he/s he di d n ot ha ve brai n i ma gi n g at baseli ne.  
If a ne w lesi o n is e q ui v ocal, f or e xa m ple beca use of its s mall size, c o nti n ue d t hera p y a n d f oll o w-
u p e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m t here is 
defi nitel y a  ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n.  
E val uati o n of Best O verall Res p o nse  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y treat me nt u ntil 
t he e n d of treat me nt. N o c o nfir mat or y meas ure me nt f or C R or P R is re q uire d i n t his st u d y.  
T he s u bject’s best o verall res p o nse assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d n o n -
tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns.  
Ti me P oi nt Res p o nse  
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a res p o nse assess me nt occ urs. T he ta ble 
bel o w pr o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at eac h ti me p oi nt f or s u bjects 
w h o ha ve meas ura ble disease at bas eli ne. 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 8  of 1 1 7  
 
Ti me P oi nt Re s p o nse: S u bjects wit h T ar get (±  n o n -t ar get) Dise ase 
T ar get Lesi o ns  
N o n -T ar get Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -P D or n ot all e val uate d  
N o  
P R  
S D  
N o n -P D or n ot all e val uate d  
N o  
S D  
N o t all e val uate d 
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
C R  =  c o m plete  res p o nse, P R  =  partial  res p o nse, S D  =  sta ble disease,  P D  =  pr o gressi ve  disease,  a n d N E  =  n ot  e val ua ble .  
 
Missi n g Assess me nts a n d I ne val ua ble Desi g nati o n  
W he n n o i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me  p oi nt, t he s u bject is n ot e val ua ble 
( N E) at t hat ti me p oi nt. If o nl y a s u bset of lesi o n meas ure me nts are ma de at a n assess me nt, us uall y 
t he case is als o c o nsi dere d N E at t hat ti me p oi nt, u nless a c o n vi nci n g ar g u me nt ca n be ma de t hat 
t he c o ntri b uti o n of t he i n di vi d ual missi n g lesi o n(s) w o ul d n ot c ha n ge t he assi g ne d ti me p oi nt 
res p o nse. T his w o ul d be m ost li kel y t o ha p pe n i n t he case of P D. F or e xa m ple, if a s u bject ha d a 
baseli ne s u m of 5 0 m m w it h t hree meas ure d lesi o ns a n d at f oll o w-u p o nl y t w o lesi o ns wer e 
assesse d, b ut t h ose ga ve a s u m of 8 0 m m, t he s u bject will ha ve ac hie ve d P D stat us, re gar dless of 
t he c o ntri b uti o n of t he missi n g lesi o n.  
Best O verall Res p o nse: All Ti me P oi nts  
T he best o ver all res p o nse is deter mi ne d o nce all t he data f or t he s u bject is k n o w n.  
Best res p o nse deter mi n ati o n i n tri als w here c o nfir m ati o n of c o m plete or p arti al res p o nse I S N O T 
re q uire d: Best res p o nse i n t hese trials is defi ne d as t he best res p o nse acr oss all ti me poi nts (f or 
e xa m ple, a s u bject w h o has S D at first assess me nt, P R  at sec o n d assess me nt, a n d P D o n last 
assess me nt has a best o verall res p o nse of P R). W he n S D is belie ve d t o be t he best res p o nse, it 
m ust als o meet t he pr ot oc ol s pecifie d mi ni m u m ti me fr o m B aseli ne of 8 wee ks. If t he mi ni m u m 
ti me is n ot met w he n S D is ot her wise t he best ti me p oi nt res p o nse, t he s u bject’s best res p o nse 
de pe n ds o n t he s u bse q ue nt assess me nts. F or e xa m ple, a s u bject w h o has S D at t he first assess me nt, 
P D at sec o n d t he assess me nt,  an d d oes n ot meet t he mi ni m u m d urati o n f or S D, t he s u bject will 
ha ve a best res p o nse of P D. T he sa me s u bject l ost t o f oll o w -u p after t he first S D assess me nt w o ul d 
be c o nsi dere d i ne val ua ble.  
S pecial N otes o n Res p o nse Assess me nt  
W he n n o dal disease is i ncl u d e d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o ‘ n or mal’ 
size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns. T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstate pr o gressi o n s h o ul d it be 
ba se d o n i ncrease i n t he size of t he n o des. As n ote d earlier, t his mea ns t hat s u bjects wit h C R ma y 
n ot ha ve a t otal s u m of ‘zer o’ o n t he e C R F.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 9 9  of 1 1 7  
 
S u bjects wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt wit h o ut 
o bjecti ve e v i de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as ‘s y m pt o matic 
deteri orati o n’. E ver y eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n e ve n after 
disc o nti n uati o n of treat me nt. S y m pt o matic deteri orati o n is n ot a descri pt or of a n o bjecti ve  
res p o nse: it is a reas o n f or st o p pi n g st u d y t hera p y. T he o bjecti ve res p o nse stat us of s uc h s u bjects 
is t o be deter mi ne d b y e val uati o n of tar get a n d n o n-tar get disease. 
F or e q ui v ocal fi n di n gs of pr o gressi o n (e. g. , ver y s mall a n d u ncertai n ne w lesi o ns; c y stic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at 
t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he 
earlier date w he n pr o gressi o n was s us pecte d.  
Fre q u e nc y of T u m or Re -e val uati o n 
I n t his st u d y, t u m or meas ure me nt will be c o n d ucte d at t he Baseli ne  visit , a n d t he n i n 8-wee k 
i nter vals (e ver y t w o c ycles) d uri n g t he first 3 2 wee ks ( 8 c ycles) a n d t he n i n 1 2-wee k i nter vals 
(e ver y 3 c ycles) w hile t he s u bject is  o n treat me nt or as cli nicall y i n dicate d u ntil pr o gressi o n of 
disease, wit h dra wal of c o nse nt, deat h, or l oss t o f oll o w -u p. T u m or meas ure me nt will als o be 
perf or me d d uri n g t he E n d  of  Treat me nt visit if it is n ot d o ne wit hi n 2 8 da ys of t he visit date.  
Baseli ne  t u m or assess me nts m ust be perf or me d wit hi n f o ur wee ks ( 2 8 da ys) of t he first d ose of 
treat me nt.  
All eff orts s h o ul d be ma de t o e ns ure c o nsiste nc y bet wee n t he baseli ne meas ure me nts a n d all 
s u bse q ue nt meas ure me nts i n refere nce t o utilizati o n of sca n ni n g meth o ds, e q ui p me nt, tec h ni q ue 
(i ncl u di n g slice t hic k ness a n d fiel d of vie w), a n d t he ra di o gra p hic i nter preter. 
T he ra di ol o gical e val uati o n m ust i ncl u de C T or M RI sca n ni n g of t he c hest, a b d o me n, a n d pel vis.  
A n y a d diti o nal s us pecte d sites of disease s h o ul d a lso be i ma ge d. All e val uati o ns s h o ul d meet t he 
sta n dar d of care f or i ma gi n g of lesi o ns i n t he res pecti ve or ga n(s).  
All tar get a n d n o n -tar get sites are e val uate d at eac h ti me p oi nt of t u m or assess me nt.  
C o nfir m at or y Me as ure me nt/ D ur ati o n of Res p o nse  
C o nfir m ati o n 
C o nfir mati o n of P R a n d C R is N O T re q uire d i n t his st u d y.  
D urati o n of O verall Res p o nse  
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or 
C R/ P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec ur re nt or pr o gressi ve disease is 
o bjecti vel y d oc u me nte d (ta ki n g as refere nce f or pr o gressi ve disease t he s mallest meas ure me nts 
rec or de d o n st u d y). 
T he d urati o n of o verall c o m plete res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria t hat are 
first met for  C R u ntil t he first date t hat rec urre nt disease is o bjecti vel y d oc u me nte d.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 0  of 1 1 7  
 
D urati o n of Sta ble Disease  
Sta ble disease is meas ure d fr o m t he start of t he treat me nt u ntil t he criteria f or pr o gressi o n are met, 
ta ki n g as refere nce t he s mallest s u m o n st u d y (if the baseli ne s u m is t he s mallest, t his is t he 
refere nce f or calc ulati o n of P D). I n t his st u d y, t he mi ni m u m d urati o n f or S D is defi ne d as 8  wee ks 
( ± 3 da ys). 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 1  of 1 1 7  
 
 
 
 
 
A N N E X 1  
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 2  of 1 1 7  
E LI GI BI LI T Y F O R P A R T 1 S U B J E C T S E N R O L L E D U N D E R A M E N D M E N T 5
A d ult s u bj ects wit h a d va nce d s oli d t u m ors  wit h k n o w n/ d oc u me nte d  A K T 1,  2, 3 ge netic 
alterati o ns, acti vati n g PI 3 K  m utati o ns,  P T E N - n ull, or  ot her  k n o w n acti o na ble  P T E N  m utati o ns 
w h ose ca ncer has pr o gresse d  f oll o wi n g sta n dar d t hera p y, or f or w h o m sta n dar d t hera p y is n ot 
a vaila ble or is n ot  t olera ble will be e nr olle d. 
S u bject accr ual will occ ur o ver a peri o d of tim e de pe n de nt u p o n t he n u m ber of c o h orts e nr olle d. 
I ncl usi o n Criteri a 
Eac h pr os pecti ve s u bject m ust meet A L L of t he f ollo wi n g i ncl usio n criteria i n or der t o be eligi ble 
f or t his st u d y: 
1.
Si g ne d writte n i nf or m e d c o nse nt gra nte d pri or t o i nitiati o n of a n y st u d y -s pecific pr oce d ures
2.
1 8 years of a ge  a n d ol der
3.
Hist ol o gicall y or c yt ol o gicall y d oc u me nte d l ocall y a d va nce d, i n o pera ble or metastatic
s oli d t u m ors wit h d oc u me nte d A K T 1,  2,  3 ge netic alterati o n s, acti vati n g PI 3 K m utati o ns,
P T E N -n ull , or ot her k n o w n acti o na ble P T E N m utati o ns
4.
Fail ure t o res p o n d t o sta n dar d t hera p y, or f or w h o m sta n dar d or c urati ve t hera p y d oes n ot
e xist, or is not t olera ble.
a.
S u bjects e nr ol le d i n t he E x pa n de d C o h or t s h o ul d ha ve n o m ore t ha n 3 pri or
s yste mic re gi me ns wit h c o nfir me d disease pr o gressi o n. If t he s u bject is refract or y
or has disea se pr o gressi o n wit hi n 6 m o nt hs of t he a dj u va nt treat me nt, t he n t he
pre vi o us tr eat me nt s h o ul d be c o nsi d ere d as t he li ne of treat me nt rat her t ha n a n
a dj u va nt t hera p y.
5.
Meas ura ble diseas e
6.
Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G) perf or m a nce stat us  ( P S) ≤ 2
7.
Arc hi val tiss ue sa m ples a n d/ or fres h t u m or bi o ps y sa m ples:
a.
S u bjects s h o ul d a gr ee t o pr o vi de arc hi val a n d/ or fres h t u m or bi o ps y  sa m ples
b.
Arc hi val t u m or sa m ples s h o ul d be c ollecte d f or all e nr olle d s u bjects ; if arc hi val
tiss ue sa m ples are n ot a vaila ble, a rece nt c ore nee dle bi o ps y sh o ul d be c ollecte d
c.
Paire d, pre - an d p ost -treat me nt, t u m or bi o ps y is o pti o nal f or s u bjects e nr olle d i n
t he D ose Escalati o n a n d F o o d-effect c o h orts
d.
Paire d t u m or bi o ps y is ma n dat or y f or all s u bjects e nr olle d i n t he E x pa n de d c o h ort;
s u bjects s h oul d a gree t o a n d be eli gi ble f or paire d  t u m or bi o ps y
8.
A de q uate or ga n f u ncti o n as i n dicate d b y t he f oll o wi n g la b orator y val ues. All la b orat or y
tests m ust be o btai ne d wit hi n 7 da ys pri or t o t he first d ose of A R Q 7 5 1 :
a.
He mat ol o gi cal
i. A bs ol ute ne utr o p hi l c o u nt ( A N C) ≥ 1. 5 x 1 09/ L
ii. Platelet c o u nt ( Plt) ≥ 1 0 0  x 1 0 9/ L
iii. He m o gl o bi n ( H b) ≥ 9 g/ d L
i v. I nter nati o nal n or malize d rati o ( I N R) 0. 8 t o u p per li m it of n or mal (U L N ) or
≤ 3 f or s u bjects recei vi n g a ntic oa g ula nt t hera p y s uc h as C o u ma di n or
he pari n
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 3  of 1 1 7  
 
b.  Re nal  
i. Ser u m creati ni ne ≤ 1. 5 x 
U L N  or c alc ulate d creati ni ne cleara nce 
≥ 6 0  m L/ mi n/ 1. 7 3 
m 2 f or s u bjects wit h ser u m 
creati ni ne le vels 
>  1. 5  x  instit uti o nal U L N  
c. He patic  
i. T otal bilir u bi n ≤ 1. 5 x U L N  
ii. As partate ami n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T ) ≤ 3 
x U L N or ≤ 5 x U L N f or s u bjects wit h k n o w n li ver metastases  
d.  Meta b olic  
i. Gl ycate d he m o gl o bi n ( H b A 1c ) ≤ 8 %  
9.  If a s u bject is c urre ntl y recei vi n g bis p h os p h o nates, t he s u bject m ust ha ve recei ve d t he 
bis p h os p h o nates f or at least f o ur wee ks pri or t o t he first d ose of A R Q 7 5 1.  
a. I nitiati o n of bis p h os p h o nates d uri n g t he st u d y ma y be all o we d pr o vi de d t he s u bject 
c o m pletes t he first c ycle of trea t me nt wit h o ut a n y d ose li miti n g t o xicit y ( D L T) a n d 
t he I n vesti gator r ules o ut t u m or pr o gressi o n.  
1 0.  Male or fe male s u bjects of c hil d -pr o d uci n g p ote ntial m ust a gree t o use d o u ble -barrie r 
c o ntrace pti ve meas ures, oral c o ntrace pti o n, or a v oi da nce of i nterc o urse d ur i n g t he st u d y 
a n d f or 9 0 da ys after t he last d ose of A R Q 7 5 1.  
1 1.  W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na nc y test d uri n g 
t he 
Scree ni n g Peri o d a n d wit hi n 4 8 h o urs of t he first d ose of A R Q 7 5 1. “ W o me n of 
c hil d beari n g p ote ntial” is def i ne d as se x uall y mat ure w o me n w h o ha ve n ot u n der g o ne a 
h ysterect o m y or w h o ha ve n ot bee n nat urall y p ost me n o pa usal f or at least 1 2 c o nsec uti ve 
m o nt hs pri or t o t he first d ose of A R Q 7 5 1.  
E xcl usi o n Criteri a  
 
P ote ntial s u bjects w h o meet A N Y of t he f oll o wi n g e xc lusi o n criteria are n ot eli gi ble f or e nr oll me nt 
i nt o t his st u d y: 
1.  A nti -ca ncer 
t hera p y, 
s uc h 
as 
c he m ot hera p y, 
i m m u n ot hera p y, 
tar gete d, 
a n d 
h or m o nal/e n d ocri ne t hera p y, or i n vesti gati o nal a ge nts wit hi n fi ve half-li ves or f o ur wee ks, 
w hic he ver is s h orter, pri or  t o a d mi nistrati o n of t he first d ose of st u d y dr u g (fi ve half-li ves 
or t w o wee ks, w hic he ver is s h orter, f or orall y a d mi nistere d dr u gs a n d si x wee ks f or 
nitr os o ureas, mit o m yci n C, or be vaciz u ma b)  
a. T o be eli gi ble f or st u d y treat me nt, t o xicit y fr o m pri or treat m e nt m ust rec o ver t o 
Gra de ≤ 1, e xce pt f or al o pecia  
b.  C o nc urre nt s yste mic hi g h -d ose c ortic oster oi ds w he n use d i nter mitte ntl y i n a n 
a ntie metic re gi me n, f or ce ntral ner v o us s yste m ( C N S ) metastases ma na ge me nt , or 
as a part of t he pre me dicati o n re gi me n are all o w e d 
c. C o nc urre nt sta n dar d l o n g -ter m a ntica ncer h or m o nal t hera p y with dr u gs i ncl u di n g , 
b ut n ot li mite d  t o, selecti ve estr o ge n rece pt or 
m o d ulat ors or G o na d otr o pi n -
releasi n g h or m o ne (G n R H ) a nal o gs if starte d at least si x m o nt hs bef ore t he first 
d ose of A R Q 7 5 1  is all o we d 
2.  Ra diati o n t hera p y wit hi n f o ur wee ks pri or t o a d mi nistr ati o n of t he first d ose of A R Q 7 5 1  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 4  of 1 1 7  
 
a. T o be eli gi ble f or st u d y treat me nt, ra diati o n t hera p y -relate d t o xicit y m ust rec o ver 
t o Gra de ≤ 1 pri or t o a d mi nistrati o n of t he first d ose of A R Q 7 5 1 .  
b.  C o nc urre nt palliati ve ra di ot hera p y f or l o cal pai n-c o ntr ol ma y be all o we d pr o vi de d 
t he s u bject c o m pletes t he first c ycle of treat me nt, d oes n ot meet criteria of 
pr o gressi ve disease , a n d treate d lesi o ns will n ot be i ncl u de d i n t he tar get/ n o n -tar get 
lesi o n assess me nt. 
3.  Maj or s ur gical pr oce d ure wit hi n f o ur wee ks pri or t o a d m i nistrati o n of t he first d ose of A R Q 
7 5 1  
a. T o be eli gi ble f or t he st u d y treat me nt, all s ur gical w o u n ds m ust be f ull y heale d a n d 
a n y s ur ger y -relate d a d verse e ve nts m ust rec o ver t o Gra de ≤ 1. 
4.  Pre vi o us treat me nt wit h A K T i n hi bit ors (e. g., A R Q 0 9 2, 
M K -2 2 0 6, G S K 2 1 4 1 7 9 5, 
A Z D 5 3 6 3)  
5.  U na ble or u n willi n g t o s wall o w t he c o m plete dail y d ose of A R Q 7 5 1   
6.  A Q Tc i nter val ≥ 4 8 0 msec usi n g  t he Fri dericia's f or m ula Q Tc F  
7.  Hist or y of T y pe 1 or 2 dia betes mellit us re q uiri n g re g ular me dicati o n ( ot her t ha n oral 
h y p o gl yce mic a ge nts) o r fasti n g gl uc ose ≥ 16 0 m g/ d L at t he Pre -St u d y visit  
8.  Si g nifica nt gastr oi ntesti n al ( GI) dis or der(s)  t hat c o ul d, i n t he o pi ni o n of t he I n vesti gat or, 
i nterfere wit h t he a bs or pti o n, meta b olis m, or e xcreti o n of A R Q 7 5 1 (e. g., Cr o h n’s disease, 
ulcerati ve c olitis , e xte nsi ve gastric resecti o n) 
9.  K n o w n acti ve C N S met astases a n d/ or carci n o mat o us me ni n gitis   
a. T o be eli gi ble f or t he st u d y treat me nt, s u bj ects m ust ha ve sta ble disease ≥ 1  m o nt h, 
c o nfir me d b y ma g netic res o na nce i ma gi n g ( M RI) or c o m p ute d t o m o gra p h y ( C T) 
sca n, a n d ha ve C N S 
metastases well c o ntr olle d b y l o w-d ose ster oi ds, a nti -
e pile ptics, or ot her s y m pt o m -relie vi n g me dicati o ns. 
1 0.  Hist or y of m y oca r dial i nfarcti o n ( MI) or Ne w Y or k Heart Ass ociati o n ( N Y H A ) Class II -
I V c o n gesti ve heart fail ure wit hi n 6 m o nt hs of t he a d mi nistrati o n of t he first d ose of 
A R Q  7 5 1 ( MI occ urri n g > 6 m o nt hs of t he first d ose of A R Q 7 5 1 will be per mitte d); Gra de 
2 or w orse c o n d ucti o n defect (e. g., ri g ht or left b u n dle bra nc h bl oc k ) 
1 1.  C o nc urre nt se vere u nc o ntr olle d ill ness n ot relate d t o ca n cer a n d s ocial sit uati o n t hat w o ul d 
li mit c o m plia nce wit h st u d y re q uire me nts, i ncl u di n g b ut n ot li mite d t o: 
a. Ps yc hiatric ill ness, s u bsta nce a b use  
b.  O n g oi n g or acti ve k n o w n i nfecti o n, i ncl u di n g h u ma n i m m u n o deficie nc y vir us 
( HI V) i nfecti o n  
1 2.  Acti ve or hist or y of ot her mali g na nc y ot her t ha n t he c urre nt ca ncer wit hi n 2 years of t he 
first d ose of A R Q 7 5 1, wit h t he e xce pti o n of carci n o ma i n-sit u of t he cer vix, basal cell 
carci n o ma, a n d s u perficial bla d der t u m ors c urati vel y treate d  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 5  of 1 1 7  
 
1 3.  Bl o o d tra nsf usi o n or a d mi nistrati o n of gr o wt h fact ors  wit hi n 5 da ys pri or t o a bl o o d dra w 
bei n g use d t o c o nfir m eli gi bilit y  
1 4.  Pre g na nt or breastfee di n g  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 6  of 1 1 7  
 
S C H E D U L E O F E V E N T S F O R P A R T 1  S U B J E C T S E N R O L L E D U N D E R A M E N D M E N T 5  
Tests & Pr oce d ures  
Pre -
S t u d y 
Tre at me nt Visits  
E n d of Tre at me nt  
3 0 -d a y S afet y 
F oll o w -u p  
C ycle  
B aseli ne  
C ycle 1  
C ycle 2 +  
7 d a ys after t he l ast 
d ose of A R Q  7 5 1  
3 0 d a ys after t he l ast 
d ose of  A R Q  7 5 1  
Wee k  
 
1  
2  
3  
4  
1  
3  
 
 
D a y  
0  
1  
2  
8  
1 5  
2 2  
2 3  
1  
1 5  
 
 
Wi n d o w  
-1 4 - 0  
-1  
0  
± 3 d a ys  
0  
± 3 d a ys  
+ 3 d a ys  
± 3  d a ys  
Writte n I nf o r me d C o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
Me dic al Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
P h ysic al E x a mi n ati o n 
(i ncl u di n g s ki n) 
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
E C O G P S  
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
Vit al Si g ns ( T°, B P, R R, H R)  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
•  hei g ht  
X  
 
 
 
 
 
 
 
 
 
 
•  wei g ht  
X  
X  
 
 
 
 
 
X  
 
X  
 
F asti n g Cli nic al Bl o o d 
Test s0 
X  
X  
 
X  
X  
X  
 
X  
X  
X  
 
Uri n al ysi s0 
X  
X  
 
X  
X  
X  
 
X  
 
X  
 
Ser u m Pre g n a nc y Test, if 
a p plic a ble 0 
X  
 
 
 
 
 
 
 
 
X  
 
C Y P 2 D 6 S a m ple  
 
X  
 
 
 
 
 
 
 
 
 
Gl uc ose Met a b olis m Bl o o d 
S a m ple s7 
 
X 1 0 
X  
X  
X  
X  
X  
X  
X  
 
 
P K Bl o o d S a m ples 7 
 
X 1 0 
X  
X  
X  
X  
X  
X  
X  
 
 
P D Bl o o d S a m ples Err or! 
Refere nce s o urce n ot f o u n d.   
 
X 1 0 
 
 
 
 
 
X  
 
X  
 
H o me Bl o o d Gl uc ose 
M o nit ori n g
8 
 
X  
X  
X  
X  
X  
 
X  
X  
 
 
T u m or M ar kers Bl o o d 
S a m ples, if a p plic a ble 9 
X  
X  
 
 
 
 
 
X  
 
X  
 
1 2 -Le a d E C G 1 0 
X  
X  
 
 
 
 
 
X  
 
X  
 
•  i n tri plic ate, pre- a n d 
p ost -d ose  
 
X  
 
 
 
 
 
X  
 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 7  of 1 1 7  
 
Tests & Pr oce d ures  
Pre -
S t u d y 
Tre at me nt Visits  
E n d of Tre at me nt  
3 0 -d a y S afet y 
F oll o w -u p  
C ycle  
B aseli ne  
C ycle 1  
C ycle 2 +  
7 d a ys after t he l ast 
d ose of A R Q  7 5 1  
3 0 d a ys after t he l ast 
d ose of  A R Q  7 5 1  
Wee k  
 
1  
2  
3  
4  
1  
3  
 
 
D a y  
0  
1  
2  
8  
1 5  
2 2  
2 3  
1  
1 5  
 
 
Wi n d o w  
-1 4 - 0  
-1  
0  
± 3 d a ys  
0  
± 3 d a ys  
+ 3 d a ys  
± 3  d a ys  
Ec h oc ar di o gr a p h y/ M U G A, 
if a p plic a ble1 0 
X  
 
 
 
 
 
 
X  
 
X  
 
Arc hi v al a n d/ or Fres h 
T u m or Bi o ps y 7 
X  
 
 
 
X  
 
 
 
 
 
 
T u m o r Assess me nt a n d 
Re -st a gi n g 1 1  
X  
 
 
 
 
 
 
X  
 
X  
 
C o nc o mit a nt Me dic ati o n s 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse E ve nts Ass ess me nt9 
 
X 1 0 
X  
X  
X  
X  
X  
X  
X  
X  
X  
A R Q 7 5 1 Dis pe ns ati o n  
 
X 1 0 
X  
X  
X  
X  
X  
X  
X  
 
 
1  
D etaile d descri pti o n of cli nical la b orat or y tests rec or de d i n Pr ot oc ol Secti o n 5. 4  
2  
Refer t o A n ne x 1 f or ti me p oi nts. Da y 2 2 a n d Da y 2 3 P K a n d g l uc ose meta bolis m bl o o d sa m ples s h o ul d be c ollecte d o n Da y 2 1 a n d Da y 2 2 f or s u bjects 
recei vi n g A R Q 7 5 1 Q O D.  
3  
P D bl o o d sa m ples s h o ul d be c ollecte d o n Da y 1 of C ycle 1 , 2, 3 a n d E n d of treat me nt visit. 
4  
Refer t o A n ne x 1 f or ti mep oi nts . H o me bl o o d gl uc ose m o nit ori n g s h o ul d be perf or me d at least o nce per da y ( be f ore brea kfast) f or t he first 4  wee ks e xc e pt 
f or P K da ys ( C ycle 1 Da ys 1, 2, 8, 1 5, 2 2  [ Da y 2 1 for s u bjects recei vi n g A R Q 7 5 1 Q O D] , a n d 2 3  [ Da y 2 2 f or s u bjects recei vi n g A R Q 7 5 1 Q O D]). After 
t he first f o ur wee ks of treat me nt, t he I n vesti gat or will deter mi ne if a s u bject s h o ul d c o nti n ue h o me gl uc ose test i n g a n d t he testi ng fre q ue nc y.  
5  
T u m or mar ker s testi n g will be d o ne at t he st u d y site 
6  
1 2 -lead E C G s h o ul d be perf or me d at Baseli ne a n d o n Da y 1 of t he first si x c ycles; a n d i n tri plicate pre - a n d p ost-d os e o n Da y 1 of C y cle 1 a n d C ycle 2. 
If a p plica ble (pre vi o us treat me nt wit h a nt hrac ycli nes), ec h ocar di o gra p h y or M U G A sca n  s h o ul d be d o ne at Baseli ne, e ver y  ei g ht wee ks f or t he first 2 4 
wee k s (si x c ycles) of treat me nt a n d e ver y 1 2 wee ks t hereafter. 
7  
Arc hi val t u m or sa m ples s h o ul d be c ollecte d f or all e nr olle d s u bjects; paire d, pre - a n d p ost-treat me nt bi o psy is o pti o nal f or s u bj ects e nr olled i n t he D ose  
Escalati o n  a n d F o o d-effect c o h orts a n d ma n dat or y f or s u bjects e nr olle d i n t he E x pa n de d c o h ort. P ost -treat me nt bi o ps y ca n be perf or me d Da y 1 5 of C ycle 
1 a n d Da y 1 of C ycle 2.  
8  
T u m or assess me nt s h o ul d be d o ne at Baseli ne (if d o ne wit hi n 2 8 da ys  pri or t o t he 1 st d ose of A R Q 7 5 1), e ver y ei g ht wee ks d uri n g treat me nt, a n d at E n d 
of Treat me nt  ( E O T) u nless it w as d o ne wit hi n 2 8 da ys pri or t o t he E O T visit.  
9  
O nl y A Es t hat o cc urr e d after t he a d mi nistrati o n of t he first d ose of A R Q 7 5 1 a n d wit h i n 3 0 da ys of t he Safet y F oll o w -u p peri o d s h o ul d be re p orte d as a n 
A E, a n y A E t hat occ urre d pri or t o t he a d mi nistrati o n of t he first d ose of A R Q 7 5 1 s h o ul d be re p orte d as Me dical hist or y.  
1 0  T he se tests a n d pr oced ures m ust be perf or me d o n C 1 D 1 .  A R Q 7 5 1 m ust be dis pe nse d o n C 1 D 1.  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 8  of 1 1 7  
 
S T U D Y VI SI T S F O R P A R T 1  S U B J E C T S E N R O L L E D U N D E R A M E N D M E N T 5  
 
Pre -St u d y Visit  
 
After writte n i nf or me d c o nse nt is o btai ne d, s u bject’s eli gi bilit y f or t he st u d y a n d baseli ne disease 
stat us will be assesse d.  
T he f oll o wi n g will be e val ua te d a n d d oc u me nte d wit hin 1 4 da ys pri or t o first d ose of A R Q  7 5 1:  
•  Me dical hist or y  
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns ( hei g ht, wei g ht, te m perat ure, bl o o d press ure, res pi rati o n rate, a n d heart rate) 
•  Fasti n g cli nical bl o o d tests  
•  Uri nal ys is  
•  Ser u m pre g na nc y test , if a p plica ble 
•  1 2 -lea d electr ocar di o gra m ( E C G) 
•  Ec h ocar di o gra p h y or M ulti ple Gate d Ac q uisiti o n ( M U G A) sca n, if a p plica ble  
•  Arc hi val a n d/ or fres h t u m or sa m ples s h o ul d be c ollecte d a n d a vaila ble t o be s hi p pe d t o t he 
S p o ns or or desi g ne e 
o  T u m or bi o ps y is o pti o n al f or s u bjects e nr olle d i n t he D ose Escalati o n a n d F o o d -
effect c o h orts a n d is ma n dat or y f or s u bjects e nr olle d i n t he E x pa n de d c o h ort  
•  Bl o o d sa m ple f or t u m or mar kers, if a p plica ble (t o be teste d at t he st u d y site) 
•  Rec or d pri or a n d c o nc o mita nt me dicati o ns ( me dicati o ns use d wit hi n 3 0 da ys pri or t o t he 
first d ose of A R Q 7 5 1) 
•  T u m or meas ure me nt a n d sta gi n g  
N ote: C T, M RI , a n d P E T sca ns ca n be use d as Baseli ne assess me nt if the y were perf or me d wit hi n 
f o ur wee ks ( 2 8 da ys) pri or t o t he first d ose of A R Q  7 5 1. F or s u bjects wit h k n o w n or s us pecte d 
b o ne metastases, a b o ne sca n s h o ul d be perf or me d wit hi n f o ur wee ks ( 2 8 da ys) pri or t o t he first 
d ose of A R Q 7 5 1.  
S u bjects w h o satisf y al l i ncl usi o n a n d e xcl usi o n criteria ma y be e nr olle d i n t he st u d y. 
C ycle 1, We e kl y E v al u ati o ns  
 
C ycle 1, D a y 1 ( - 1 D a y)  
 
T he f oll o wi n g assess me nts will be ma de d uri n g t his visit:  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 0 9  of 1 1 7  
 
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns ( wei g ht, te m perat ure, bl o o d press ure, res pirati o n rate, a n d heart rate)  
•  C Y P 2 D 6 sa m ples   
•  Fasti n g cli nical bl o o d tests  
•  Uri nal ysis  
•  Bl o o d sa m ple f or t u m or mar kers, if a p plica ble (t o be teste d at t he st u d y site)  
•  Bl o o d sa m ples f or P K a n d gl uc ose meta b olis m; m ust be perf or me d o n C 1 D 1  
•  Bl o o d sa m ples f or p har mac o d y na mics (cell -free ct D N A a n d C T Cs); m ust be perf or me d o n 
C 1 D 1   
•  1 2 -lea d E C G i n tri plicate at pre-d ose a n d p ost -d ose  
•  Rec or d c o nc o mita nt me dicati o n  
•  Dis pe nse a n d a d mi nister t he first d ose of A R Q 7 5 1 after all assess me nts liste d a b o ve are 
c o m plete d ( ot her t ha n p ost -d ose P K a n d p ost -d ose gl uc o se/i ns uli n bl o o d sa m ples a n d p ost-
d ose E C G); m ust be perf or me d o n C 1 D 1  
•  Assess a d verse e ve nts ( A E) (after a d mi nistrati o n of t he first d ose); m ust be perf or me d o n 
C 1 D 1  
N ote: Bl o o d sa m ples f or P K  will be c ollecte d i m me diatel y pri or t o t he first d ose of A R Q  7 5 1 a n d 
will c o nti n ue t hr o u g h 2 4 h o urs after a d mi nistrati o n of t he first d ose of A R Q 7 5 1.  
C ycle 1, D a y 2  
 
T he f oll o wi n g assess me nts will be ma de d uri n g t his visit:  
•  Vital si g ns (te m perat ure, bl o o d  press ure, res pirati o n rate, a n d heart rate)  
•  Bl o o d  sa m ples f or P K a n d gl uc ose meta b olis m, pri or t o a d mi nistrati o n of t he dail y d ose of 
A R Q 7 5 1  
•  Rec or d c o nc o mita nt me dicati o n  
•  Assess A Es  
•  Dis pe nse A R Q 7 5 1  
C ycle 1, D a y 8 ( ± 3 d a ys)  
 
T he f oll o wi n g assess me nts wi ll be ma de d uri n g t his visit: 
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n 
•  E C O G P S  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 0  of 1 1 7  
 
•  Vital si g ns (te m perat ure, bl o o d press ure, res pirati o n rate, a n d heart rate)  
•  Fasti n g cli nical bl o o d tests  
•  Uri nal ysis  
•  Bl o o d sa m ples f or P K a n d gl uc ose meta b olis m, pri or t o a d mi nist rati o n of t he dail y d ose of 
A R Q 7 5 1  
•  Re c or d c o nc o mita nt me dica ti o n 
•  Assess A Es  
•  Dis pe nse A R Q 7 5 1  
 
C ycle 1, D a y 1 5 ( ± 3 d a ys)  
 
T he f oll o wi n g assess me nts will be ma de d uri n g t his visit:  
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns (te m perat ure, bl o o d press ure, res pirati o n rate, a n d hear t rate) 
•  Fasti n g cli ni cal bl o o d tests  
•  Uri nal ysis  
•  Bl o o d sa m ples f or P K a n d gl uc ose meta b olis m, pri or t o a d mi nistrati o n of t he dail y d ose of 
A R Q 7 5 1  
•  T u m or bi o ps y, if a p plica ble  
•  Rec or d c o nc o mita nt me dicati o n  
•  Assess A Es  
•  D is pe nse A R Q 7 5 1 
C ycle 1, D a y 2 2 ( ± 3 d a ys)  
 
T he f oll o wi n g as sess me nts will be ma de d uri n g t his visit: 
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns (te m perat ure, bl o o d press ure, res pirati o n rate, a n d heart rate)  
•  Fasti n g cli nical bl o o d tests  
•  Uri na l ysis  
•  Bl o o d sa m ples f or P K a n d gl uc ose meta b olis m ( Da y 2 1 f or s u bjects recei vi n g A R Q 7 5 1 
Q O D ) 
•  Rec or d c o nc o mita nt me dicati o n  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 1  of 1 1 7  
 
•  Assess A Es  
•  Dis pe nse A R Q 7 5 1  
C ycle 1, D a y 2 3  
 
T he f oll o wi n g assess me nts will be ma de d uri n g t his visit:  
•  Vital si g ns (te m perat ure, bl o o d pres s ure, res pirati o n rate, a n d heart rate) 
•  Bl o o d sa m pl es f or P K a n d gl uc ose meta b olis m, pri or t o a d mi nistrati o n of t he dail y d ose of 
A R Q 7 5 1  ( Da y 22  f or s u bjects recei vi n g A R Q 7 5 1 Q O D )  
•  Rec or d c o nc o mita nt me dicati o n  
•  Assess A Es  
•  Dis pe nse A R Q 7 5 1  
N ote: H o me bl o o d gl uc ose m o nit ori n g s h o ul d be perf or me d at least once per da y ( be f ore brea kfast) 
f or t he first 4 wee ks e xce pt f or P K da ys ( C ycle 1 Da ys 1, 2, 8, 1 5, 2 2  ( Da y 2 1 f or s u bjects recei vi n g 
A R Q 7 5 1 Q O D) , a n d 2 3  ( Da y 2 2 f or s u bjects recei vi n g A R Q 7 5 1 Q O D), a n d C y cle 2 Da y 1 a n d 
Da y 1 5 ). If t he fasti n g gl uc ose le vel is > 1 6 0 m g/ d L b ut ≤ 2 5 0 m g/ d L, s u bjects are t o test a gai n 
bef ore di n ner.  If t he fasti n g gl uc ose le vel is > 2 5 0 m g/ d L, s u bjects are t o call t heir I n vesti gat or. 
After t he first 4 wee ks, t he I n ves ti gat or will deter mi ne if a s u bject s h o ul d c o nti n ue h o me g l uc ose 
testi n g a n d t he testi n g fre q ue nc y. 
C ycle 2 a n d All S u bse q ue nt C ycles, Bi -Wee kl y E v al u ati o ns  
 
C ycle 2 a n d All S u bse q ue nt C ycles, Da y 1 ( ± 3 da ys)  
 
T he f oll o wi n g assess me nts will be ma de d uri n g t his visit:  
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns ( wei g ht, te m perat ure, bl o o d press ure, res pirati o n rate, a n d heart rate)  
•  Fasti n g cli nical bl o o d tests  
•  Uri nal ysis, C ycles 2 - 6 a n d if cli nicall y i n dicate d  
•  Bl o o d sa m ple f or t u m or mar kers, i f a p plica ble (t o be teste d at t he st u d y site) 
•  Bl o o d sa m p les f or P K a n d gl uc ose meta b olis m, pri or t o a d mi nistrati o n of t he dail y d ose of 
A R Q 7 5 1; o nl y o n C ycle 2 Da y 1   
•  Bl o o d sa m ples f or p har mac o d y na mics (cell -free ct D N A a n d C T Cs), pri or t o a d mi nistrati o n 
o f t he dail y d ose of A R Q 7 5 1; o nl y o n C ycle 2 Da y 1 a n d Cycle 3 Da y 1  
•  1 2 -lea d E C G m o nt hl y f or t he first 6 m o nt hs o n st u d y a n d t hereafter o nce e ver y 3  m o nt hs . 
E C G s h o ul d be d o ne  i n tri plicate at pre-d ose a n d p ost -d ose  o n C ycle 2 Da y 1.  D uri n g 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 2  of 1 1 7  
 
s u bse q ue nt m ont hl y visits, it s h o ul d be d o ne o nce at pre -d ose . If clinicall y i n dicate d , 
1 2 -lea d E C G will c o nti n ue t o be d o ne m o nt hl y .  
•  Ec h ocar di o gra p h y or M U G A sca n, if a p plica ble  
•  T u m or assess me nt a n d sta gi n g  
•  Rec or d c o nc o mita nt me dicati o n  
•  Assess A Es  
•  Dis pe ns e A R Q 7 5 1  
C ycle 2 a n d all S u bse q ue nt C ycles, D a y 1 5 ( ± 3 d a ys)  
 
T h e f oll o wi n g assess me nts will be ma de d uri n g t his visit:  
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns (te m perat ure, bl o o d press ure, res pirati o n rate, a n d heart rate)  
•  Fasti n g cli n ical bl o o d tests  
•  Bl o o d sa m ples f or P K a n d gl uc ose meta b olis m, pr i or t o a d mi nistrati o n of t he dail y d ose of 
A R Q 7 5 1; o nl y o n C ycle 2 Da y 1 5  
•  Rec or d c o nc o mita nt me dicati o n  
•  Assess A Es  
•  Dis pe nse A R Q 7 5 1  
N otes:  
1) S u bjects w h o d o n ot e x perie nce Gra de  3/ 4 t o xicit y after 4 m o nt hs/c ycles ( 1 6 wee ks) at t he sa me 
d ose le vel ca n b e e val uate d e ver y 4 wee ks (a n d s ki p t he mi d -m o nt h/c ycle visits) u p o n a gree me nt 
bet wee n t he I n vesti gat or a n d t he Me dical M o nit or.  
2) F or s u bje cts w h o d o n ot e x perie nce disease pr o gressi o n a n d c o nti n ue t o be nefit fr o m t he 
treat me nt after 1 1 c ycles, t u m or e val uati o n ma y be perf or me d e ver y 3 m o nt hs u p o n a gree me nt 
bet wee n t he I n vesti gat or a n d t he Me dical M o nit or.  
E n d of Tre at me nt Visit  
 
If p ossi ble, t he E n d of Treat me nt visit s h o ul d be perf or me d 7 ( + 3) da ys after t he decisi o n t o 
per ma ne ntl y disc o nti n ue A R Q 7 5 1 is ma de.  T he f oll o wi n g assess me nts will be ma de d uri n g t he 
E n d of Treat me nt visit:  
•  P h ysical e xa mi nati o n, i ncl u di n g s ki n  
•  E C O G P S  
•  Vital si g ns ( wei g ht, te m perat ure, bl o o d press ure, res pirati o n rate, a n d heart rate)  
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 3  of 1 1 7  
 
•  Fasti n g cli nical bl o o d tests  
•  Uri nal ysis  
•  Ser u m pre g na nc y test, if a p plica ble  
•  Bl o o d sa m ple f or t u m or mar kers, if a p plica ble (t o be teste d at t he st u d y site)  
•  Bl o o d sa m ples f or p h ar mac o d y na mics (cell -free ct D N A a n d C T Cs)  
•  1 2 -lea d E C G  
•  Ec h ocar di o gra p h y or M U G A sca n, if a p plica ble  
•  T u m or assess me nt a n d sta gi n g, if n ot d o ne wit hi n f o ur wee ks ( 2 8 da ys) pri or t o t he E n d of 
Treat me nt visit  
•  Rec or d c o nc o mita nt me dicati o n  
•  Assess A Es  
3 0 -D a y  S afet y F oll o w -u p Visit ( ± 3 d a ys)  
 
All s u bjects will be f oll o we d f or a mi ni m u m of 3 0 da ys after t he last d ose of A R Q 75 1.  If a s u bject 
is re m o ve d fr o m t he st u d y treat me nt d ue t o dr u g-relate d A Es, t he s u bject will be f oll o we d u ntil 
dr u g -relate d A Es, occ urri n g d uri n g t he st u d y or wit hi n 3 0 da ys after t he last d ose of A R Q 7 5 1, 
ha ve res ol ve d t o baseli ne, N CI C T C A E Gra de 1, a re sta bilize d, or dee me d irre versi ble.  If a s u bject 
recei ves ot her a ntica ncer t hera p y wit hi n t he 3 0-da y f oll o w -u p peri o d, t he f oll o w -u p f or A Es will 
cease, be gi n ni n g o n t he first da y of t he ne w t hera p y.   
N ote: T he visit ca n occ ur eit her as a n office visit  or b y tele p h o ne.  
 
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or  A me n d me nt 
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol  A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 4  of 1 1 7  
 
P K , PD , A N D G L U C O S E M E T A B OLI S M S A M P LI N G S C H E D U L E S F O R P A R T 1  
S U B J E C T S E N R O L L E D U N D E R A M E N D M E N T 5  
A.  
Bl o o d C ollecti o n Sc he d ule f or P K a n d G M 1 ,2 
D a y  
Pr oce d ure  
 
Desire d Ti me  
C Y C L E 1 D A Y 1  
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
0 h o ur  ( pri or t o t he 1st d ose of A R Q  7 5 1)  
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
1 h o ur ( ± 1 0 m i n utes) 
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
2 h o urs ( ± 1 0 mi n ut es)  
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
4 h o urs ( ± 1 0 mi n ut es)  
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
6 h o urs ( ± 1 0 m i n utes) 
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
8 h o urs ( ± 1 0 m i n utes) 
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
1 0 h o urs ( ± 1 0 m i n utes) 
C 1 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
1 2 h o urs ( ± 1 0 m i n utes) 
C Y C L E 1 D A Y 2  
C 1 D 2  
Dra w bl o o d sa m ple  
P K  
G M  
2 4 h o urs ( ± 2 h o urs)  
( pri or t o the m or ni n g d ose)  
C Y C L E 1 D A Y 8  
C 1 D 8  
Dra w bl o o d sa m ple  
P K  
G M  
0 h o ur  ( pri or t o t he m or ni n g d ose) 
C Y C L E 1 D A Y 1 5  
C 1 D 1 5  
Dra w bl o o d sa m ple  
P K  
G M  
0 h o ur  ( pri or t o t he m or ni n g d ose)  
C Y C L E 1 D A Y 2 2 3 
C 1 D 2 2  
Dra w  bl o o d sa m ple  
P K  
G M  
0 h o ur  ( pri or t o t he m or ni n g d ose) 
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
1 h o ur ( ± 1 0 m i n utes) 
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
2 h o urs ( ± 1 0 m i n utes) 
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
4 h o urs ( ±  1 0 mi n ut es)  
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
6 h o urs ( ± 1 0 mi n ut es)  
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
8 h o urs ( ± 1 0 m i n utes) 
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
1 0 h o urs ( ± 1 0 m i n utes) 
C 1 D 2 2  
Dra w bl o o d sa m ple  
P K  
G M  
1 2 h o urs ( ± 1 0 m i n utes) 
C Y C L E 1 D A Y 2 3 4 
C 1 D 2 3  
D ra w bl o o d sa m ple 
P K  
G M  
2 4 h o urs ( ± 2 h o urs)  
( pri or t o t he m or nin g d ose)  
C Y C L E 2 D A Y 1  
C 2 D 1  
Dra w bl o o d sa m ple  
P K  
G M  
0 h o ur  ( pri or t o t he m or ni n g d ose) 
C Y C L E 2 D A Y 1 5  
C 2 D 1 5  
Dra w bl o o d sa m ple  
P K  
G M  
0 h o ur  ( pri or t o t he m or ni n g d ose) 
1 
Base d o n P K m o deli n g data a n d/ or t he d osi n g  re gi me n, t he P K Bl o o d C ollectio n Sc he d ule ma y b e 
m o difie d, as a p pr o priate.  C ha n ge will be i nc or p orate d i nt o t he la b orat or y ma n ual.  
2 
Gl uc ose meta b olis m i ncl u des plas ma gl uc ose a n d i ns uli n meta b olis m  
3 
C y cle 1 Da y  2 1 f or s u bjects treate d wit h  A R Q 7 5 1 Q O D  
4 
C y cle 1 Da y  2 2 f or s u bjects treate d wit h A R Q 7 5 1 Q O D  
 
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 5  of 1 1 7  
 
B.  
T u m or Tiss ue Bi o ps y Sc he d ule f or P har mac o d y na mic Assess me nt  
D A Y  
P R O C E D U R E  
D E SI R E D TI M E  
B A S E LI N E ( Re q uire d)  
-1 4 –  0 da ys  
T u m or bi o ps y (if arc hi val tiss ue is n ot or 
paire d bi o ps y i s pla n ne d)  
0  
( pri or t o t he 1st d ose of A R Q  7 5 1 ) 
O N S T U D Y: p ost -tre at me nt bi o ps y 
A n y da y bet wee n 
C 1 D 1 5 a n d C 2 D 1  
D ose Escalati o n c o h orts: o pti o nal  
E x pa n de d C o h ort: re q uire d  
pri or t o t he d ose  
 
C.  
Bl o o d Sa m ple C ollecti o n Sc he d ule f or P har mac o d y na mic Assess me nt  
D A Y  
P R O C E D U R E  
S A M P L E  
D E SI R E D TI M E  
C Y C L E 1 D A Y  1  
C 1 D 1  
Dra w bl o o d sa m ple  
P D  
0 h o ur  
( pri or t o t he d ose of A R Q  7 5 1 ) 
C 1 D 1  
Dra w bl o o d sa m ple  
C Y P 2 D 6  
0 h o ur  
( pri or t o t he d ose of A R Q  7 5 1 ) 
C Y C L E 2  D A Y 1  
C 2 D 1  
Dra w bl o o d sa m ple  
P D  
0 h o ur  
(pri or t o t he d ose of A R Q  7 5 1 ) 
C Y C L E 3  D A Y 1  
C 3 D 1  
Dra w bl o o d sa m ple  
P D  
0 h o ur  
(pri or t o t he d ose of A R Q  7 5 1 ) 
E N D O F T R E A T M E N T  
E O T  
Dra w bl o o d sa m ple  
P D  
-- 
 
 
0 7 Y 3 G R

Ar Q ule, I nc.
5. 3 Pr ot oc ol or A me n d me nt
A R Q 7 5 1- 1 0 1
1 6. 1. 1 Pr ot oc ol A me n d me nt 7
0 9  A pril 2 0 1 9
C o nfi de ntial
Pa ge 1 1 6 of 1 1 7
S p o ns or ’s Si g n at ure
St u d y Title:
A P hase 1 b St u d y of A R Q 7 5 1 as a Si n gle A ge nt or i n C o m bi nati o n 
wit h Ot her A nti -ca ncer A ge nts i n A d ult S u bjects wit h A d va nce d S oli d 
T u m ors wit h PI K 3 C A/ A K T/ P T E N M utati o ns
St u d y  N u m ber:
A R Q 7 5 1- 1 0 1
T his cli nical st u d y pr ot oc ol was s u bject t o critical re vie w a n d has bee n a p pr o ve d b y t he S p o ns or. 
Si g ne d:  
Date:
C hief Me dical Officer
Ar Q ule, I nc.
0 9 A pril 2 0 1 9
P P D
P P D
0 7 Y 3 G R

Ar Q ule, I nc.  
5. 3 Pr ot oc ol or A me n d me nt  
A R Q 7 5 1 -1 0 1  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 1 1 7  of 1 1 7  
 
I n vesti g at or’s Si g n at ure 
St u d y Title:  
A P hase 1 b St u d y of A R Q 7 5 1 as a Si n gle A ge nt or i n C o m bi nati o n 
wit h Ot her A nti -ca ncer A ge nts i n A d ult S u bjects wit h A d va nce d 
S oli d T u m ors wit h PI K 3 C A/ A K T/ P T E N M utati o ns  
St u d y N u m ber:  
A R Q 7 5 1 -1 0 1   
I ha ve recei ve d a n d rea d   t he pr ot oc ol descri be d a b o ve. I a gree t o c o m pl y wit h all a p plica ble 
re g ulati o ns a n d t o c o n d uct t he st u d y as descri be d i n t he pr ot oc ol. I a gree to mai ntai n t he 
c o nfi de ntialit y of all i nf or mati o n rec ei ve d or de vel o pe d i n c o n necti o n wit h t his pr ot oc ol.  
 
Pri n te d Na me: 
 
 
 
 
 
 
 
Si g ne d:  
 
 
Date:   
 
0 7 Y 3 G R