Clinical trial NCT02761694
Conditions: Cancer Solid Tumors
Keywords: AKT1 AKT2 AKT3 PI3K solid tumors cancer ARQ 751 PTEN
Sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Start date: 2016-06-26; Completion date: 2021-03-10
Enrollment: 78 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are: Part 1 - Vevorisertib as single agent: To assess the safety and tolerability of vevorisertib in participants with advanced solid tumors with v-Akt murine thymoma viral oncogene homolog (AKT) 1, 2, 3 genetic alterations, activating phosphatidylinositol-3-kinase (PI3K) mutations, phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null, or other known actionable PTEN mutations; Part 2 - Vevorisertib in combination with other anti-cancer agents: To assess the safety and tolerability of vevorisertib in combination with paclitaxel or fulvestrant in participants with advanced, inoperable, metastatic and/or recurrent solid tumors with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) / PTEN actionable mutations and/or AKT genetic alterations.

Detailed description:
This study was terminated due to business reasons, and pharmacokinetic (PK) testing was prioritized.

Arms: arm 1: Participants will receive vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. arm 2: Participants will receive vevorisertib 10 mg orally QD until discontinuation or toxicity. arm 3: Participants will receive vevorisertib 20 mg orally QD until discontinuation or toxicity. arm 4: Participants will receive vevorisertib 25 mg orally QD until discontinuation or toxicity. arm 5: Participants will receive vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. arm 6: Participants will receive vevorisertib 50 mg orally QD until discontinuation or toxicity. arm 7: Participants will receive vevorisertib 75 mg orally QD until discontinuation or toxicity. arm 8: Participants will receive vevorisertib 100 mg orally QD until discontinuation or toxicity. arm 9: Participants will receive vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m\^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. arm 10: Participants will receive vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m\^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. arm 11: Participants will receive vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. arm 12: Participants will receive vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
Interventions: intervention 1: Vevorisertib intervention 2: Fulvestrant intervention 3: Paclitaxel
Intervention descriptions: intervention 1: Administered as an oral dose every day or every other day. intervention 2: Administered as an intramuscular (IM) injection. intervention 3: Administered as an intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
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
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Ar Q ule, I nc.  
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C o nfi de ntial  
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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
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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 g e 3  of 1 1 7  
 
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  
 
0 9  A pril  2 0 1 9  
C o nfi de ntial  
Pa ge 4  of 1 1 7  
 
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). 
 
 
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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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0 9  A pril  2 0 1 9  
C o nfi de ntial  
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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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C o nfi de ntial  
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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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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). 
 
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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 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.  
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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 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.  
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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 ).   
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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  
1 6. 1. 1 Pr ot oc ol A me n d me nt 7  
 
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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
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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)  
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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 ). 
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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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C o nfi de ntial  
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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.  
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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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C o nfi de ntial  
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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.  
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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  
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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.  
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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 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. 
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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 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.  
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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 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. 
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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 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  
 
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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 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  
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-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  
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( 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  
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P D  
0 h o ur  
(pri or t o t he d ose of A R Q  7 5 1 ) 
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C 3 D 1  
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(pri or t o t he d ose of A R Q  7 5 1 ) 
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-- 
 
 
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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 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
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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 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:   
 
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
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
10 March 2021
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Statistical Analysis Plan, Protocol MK-4440-001
10 MAR 2021, Version 1.0
CONFIDENTIAL
1
STATISTICAL ANALYSIS PLAN
PROTOCOL MK-4440-001/ARQ 751-101
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
Protocol Number:
MK-4440-001/ARQ 751-101
Protocol Version and Date:
Original Protocol: 10 November 2015
Protocol Amendment 1: 12 January 2016
Protocol Amendment 2: 29 March 2017
Protocol Amendment 3: 28 June 2017
Protocol Amendment 4: 05 January 2018
Protocol Amendment 5: 16 May 2018
Protocol Amendment 6: 18 December 2018
Protocol Amendment 7: 09 April 2019
Name of Testing Drug:
MK-4440/ARQ 751
Phase:
Phase 1b
Methodology:
Open-Label, Multi-Arm, Dose Escalation, Dose Expansion
Sponsor:
Merck & Co.
Tel: 
Fax: 
Sponsor Representative:
Danny Chih Hsun Liaw, M.D.
Senior Principal Scientist, Clinical Research
Mo Huang, Ph.D.
Senior Scientist, Biostatistics
Analysis Plan Date:
10 March 2021
Analysis Plan Version:
Version 1.0
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Merck 
& Co. and any unauthorized use or disclosure of such information without the prior 
written authorization of Merck & Co. is expressly prohibited.
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APPROVAL SIGNATURE PAGE
Protocol Title:
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
Sponsor:
Merck & Co.
Tel: 
Fax: 
Protocol Number:
MK-4440-001
Document Date / Version:
10 March 2021 / Version 1.0
Veristat, Inc. Author:
Approval Signature
Job Title
Sponsor Approval
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines.
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author.
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments. All changes to the 
planned analyses will be described in the clinical study report.
	





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Sponsor Signatory:
Approval Signature
Job Title
	

	





	
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TABLE OF CONTENTS
1.
Information From the Study Protocol.........................................................................9 
1.1. 
Introduction and Objectives ............................................................................9 
1.1.1. 
Introduction ..........................................................................................9 
1.1.2. 
Study Objectives ..................................................................................9 
1.1.3. 
Purpose of this Document ..................................................................10 
1.2. 
Study Design ....................................................................................................11 
1.2.1. 
Synopsis of Study Design ..................................................................11 
1.2.1.1. Part 1 – MK-4440 as Single Agent ........................................11 
1.2.1.1.1. Dose Escalation ...................................................... 11 
1.2.1.1.2. Dose Expansion ...................................................... 12 
1.2.1.2. Part 2 – MK-4440 in Combination with Other Anti-Cancer 
Agents ....................................................................................12 
1.2.1.2.1. Dose Escalation ...................................................... 12 
1.2.1.2.2. Dose Expansion ...................................................... 13 
1.2.1.3. Dose Limiting Toxicity ..........................................................13 
1.2.1.4. Dosing Details ........................................................................14 
1.2.2. 
Randomization Methodology .............................................................16 
1.2.3. 
Stopping Rules and Unblinding .........................................................16 
1.2.4. 
Study Procedures ...............................................................................16 
1.2.5. 
Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Parameters
 ............................................................................................................23 
1.2.5.1. Safety Parameters ...................................................................23 
1.2.5.2. Efficacy Parameters ...............................................................23 
1.2.5.3. Pharmacokinetic and Pharmacodynamic Parameters ............23 
2.
Subject Population ......................................................................................................24 
2.1. 
Population Definitions ....................................................................................24 
2.2. 
Protocol Deviations .........................................................................................24 
3.
General Statistical Methods .......................................................................................25 
3.1. 
Sample Size Justification ................................................................................25 
3.2. 
General Methods .............................................................................................25 
3.3. 
Computing Environment ................................................................................26 
3.4. 
Baseline Definitions .........................................................................................26 
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3.5. 
Methods of Pooling Data ................................................................................26 
3.6. 
Adjustments for Covariates ...........................................................................26 
3.7. 
Multiple Comparisons/Multiplicity ...............................................................26 
3.8. 
Subpopulations ................................................................................................26 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................26 
3.10. Missing, Unused, and Spurious Data ............................................................26 
3.11. Visit Windows ..................................................................................................27 
3.12. Interim Analyses .............................................................................................27 
4. 
Study Analyses .............................................................................................................28 
4.1. 
Subject Disposition ..........................................................................................28 
4.2. 
Demographics, Baseline Characteristics and Medical History ...................28 
4.3. 
Safety Analyses ................................................................................................29 
4.3.1. 
Study Drug Exposure .........................................................................29 
4.3.2. 
Adverse Events ..................................................................................30 
4.3.3. 
Laboratory Data .................................................................................36 
4.3.4. 
Vital Signs and Physical Examination ...............................................38 
4.3.5. 
ECOG Performance Status ................................................................38 
4.3.6. 
12-lead ECG and MUGA/Echocardiogram .......................................38 
4.3.7. 
Concomitant Medications ..................................................................39 
4.4. 
Efficacy Evaluation .........................................................................................40 
4.5. 
Pharmacokinetics and Pharmacodynamics Evaluations .............................41 
5. 
Changes to Planned Analyses .....................................................................................42 
6. 
References ....................................................................................................................43 
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TABLES INCLUDED IN THE TEXT
Table 1  
Dosing Scheme for Dose Escalation and Dose Expansion for MK-4440-001................15 
Table 2    
Schedule of Assessment for MK-4440-001 .................................................................... 17 
Table 3    
Schedule of Assessment for Part 1 Subjects Enrolled under Amendment 5 
for MK-4440-001 ............................................................................................................ 19 
Table 4    
Study Visits for Arm B (MK-4440 + Paclitaxel) ............................................................ 21 
Table 5  
Study Visits for Arm C (MK-4440 + Fulvestrant) .......................................................... 22 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
Adverse event
AKT
v-Akt murine thymoma viral oncogene homolog
ALT (SGPT)
Alanine aminotransferase (serum glutamic pyruvic transaminase)
ASaT
All-Subjects-as-Treated
AST (SGOT)
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
BOR
Best overall response
CI
Confidence interval
CR
Complete response 
CRF
Case report form
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DLT
Dose-limiting toxicity
ECOG
Eastern Cooperative Oncology Group
ECG
Electrocardiogram
EE
Efficacy-evaluable
ER
Estrogen receptor
IM
Intramuscular
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MUGA
Multiple gated acquisition
NCI
National Cancer Institute
ORR
Objective response rate
PD
Pharmacodynamic
PI3K
Phosphatidylinositol 3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PK
Pharmacokinetic
PR
Partial response 
PT
Preferred term
PTEN
Phosphatase and tensin homolog deleted on chromosome ten
QD
Daily
QOD
Every other day
QW
Weekly
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Abbreviation
Definition
RECIST
Response evaluation Criteria in Solid Tumors
RP2D
Recommended phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease 
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WHO
World Health Organization
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1.
INFORMATION FROM THE STUDY PROTOCOL
1.1.
Introduction and Objectives
1.1.1.
Introduction 
The phosphatidylino-3-kinase (PI3K) / v-Akt murine thymoma viral oncogene homolog (AKT) /
mammalian target of rapamycin (mTOR) signaling pathway (PI3K pathway) plays a major role 
in physiological processes regulating cellular growth, proliferation, angiogenesis, survival, and 
metabolism [1, 2, 4]. The PI3K pathway is frequently altered in solid malignancies, promoting 
tumor growth, proliferation and survival. The pathway’s three critical nodes, PI3K, AKT and 
mTOR, have been recognized as important therapeutic targets.
MK-4440 (ARQ 751) is a potent allosteric pan-AKT inhibitor with biochemical IC50 values of 
0.55, 0.81, and 1.31 nM against AKT1, AKT2, and AKT3, respectively and is highly selective 
among the kinome. Out of 245 kinases screened, MK-4440 did not inhibit any kinase other than 
AKT1 by more than 50% at a concentration of 5 μM.
The anti-tumor in vivo activity of MK-4440 was tested in an athymic mouse xenograft model 
explanted with the AN3CA cells. Tumor growth inhibition (TGI) of MK-4440 after ten days 
oral treatment at 120 mg/kg daily to 5 mg/kg ranged from 92% to 29%. Furthermore, 
combination of MK-4440 at defined concentrations with estrogen receptor (ER) antagonist, 
fulvestrant (10 μM), or aromatase inhibitor, anastrozole (200 μ M), showed significant 
enhancement in anti-proliferative activity in MFE-280 (ER+, PIK3CAH1047R), HEC-1B (ER+, 
PIK3CAG1049R), and Ishkawa (ER+, PIK3R1T319fs*1&V290fs*1), compared to single 
agents (data on file). These studies suggest MK-4440 is a promising anticancer agent by itself 
and/or in combination with other anti-cancer agents.   
This study (MK-4440-001/ARQ 751-101) was initiated in August 2016 as an open-label, phase 
1, first-in-human, dose escalation study, and has been amended to a phase 1b trial exploring two 
treatment routes for MK-4440: 
Part 1: MK-4440 as a single agent (dose escalation and expansion) 
Part 2: MK-4440 in combination with paclitaxel and with fulvestrant (dose escalation and 
expansion)
As of November 2018 the dose escalation study of MK-4440 as a single agent was completed. 
Seven dose levels of MK-4440 (from 5 mg daily [QD] to 100 mg QD) were evaluated and the 
recommended phase 2 dose (RP2D) was determined to be 75 mg QD. As of August 2020, 
enrollment for the study (both Part 1 expansion and Part 2) has been discontinued.   
1.1.2.
Study Objectives
The primary objectives of this study are: 
Part 1 – MK-4440 as single agent:
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To assess the safety and tolerability of MK-4440 in subjects with advanced solid tumors 
with AKT1, 2, 3 genetic alterations, activating PI3K mutations, phosphatase and tensin 
homolog deleted on chromosome ten (PTEN)-null, or other known actionable PTEN 
mutations.
Part 2 – MK-4440 in combination with other anti-cancer agents:
To assess the safety and tolerability of MK-4440 in combination with paclitaxel or 
fulvestrant in subjects with advanced, inoperable, metastatic and/or recurrent solid tumors 
with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) /
PTEN actionable mutations and/or AKT genetic alterations.
The secondary objectives of this study are:
Part 1 – MK-4440 as single agent:
x
To assess the pharmacokinetic (PK) profile of MK-4440
x
To assess the pharmacodynamic (PD) activity of MK-4440 in blood specimens obtained 
from subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating 
PI3K mutations, PTEN-null, or other known actionable PTEN mutations
x
To determine the maximum tolerated dose (MTD) and/or RP2D of MK-4440 as single 
agent
x
To generate preliminary evidence of anti-tumor activity
Part 2 – MK-4440 in combination with other anti-cancer agents:
x
To determine MTD/RP2D dose of MK-4440 in combination with paclitaxel or 
fulvestrant
x
To assess the PK profile of MK-4440 in combination with paclitaxel or fulvestrant
x
To generate preliminary evidence of anti-tumor activity of MK-4440 in combination 
with paclitaxel or fulvestrant in subjects with advanced, inoperable, metastatic and/or 
recurrent solid tumors with PIK3CA/PTEN actionable mutations and/or AKT genetic 
alterations
1.1.3.
Purpose of this Document
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objectives. Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial.
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol.
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1.2.
Study Design
1.2.1.
Synopsis of Study Design
MK-4440-001 is a Phase 1b, multi-center, open label study of a second-generation pan-AKT 
inhibitor MK-4440 administered orally as a single agent or in combination with paclitaxel or 
fulvestrant in subjects with advanced, inoperable, metastatic and/or recurrent solid tumors with 
PIK3CA/AKT/PTEN mutations.  
The study has two parts and explores 3 treatment arms (Arm A, Arm B, Arm C) according to 
combination of anti-tumor agents as summarized in Section 1.2.1.4, Table 1. Part 1, MK-4440 
as a single agent which includes a dose escalation portion and an expansion portion (Arm A).
Part 2, MK-4440 in combination with other anti-cancer agents (Arm B and Arm C), with each 
arm having a dose escalation and dose expansion portion.  
1.2.1.1.
Part 1 – MK-4440 as Single Agent 
Part 1 of this study was open to subjects with advanced solid tumors with AKT1, 2, 3 genetic 
alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations.
Eligibility for Part 1 subjects enrolled under Amendment 5 includes adult subjects with any of 
the above mutations whose cancer has progressed following standard therapy, or for whom 
standard therapy is not available or is not tolerable. 
1.2.1.1.1.
Dose Escalation
The dose escalation followed a 3 + 3 dose escalation design with the initial dose of 5 mg QD 
and the highest dose of 100 mg QD, continuously. 
Treatment dosing was administered orally in 28-day treatment cycles. The dose limiting toxicity 
(DLT) evaluation period was 1 cycle of treatment (i.e., 28 days). See Section 1.2.1.3 for the 
definition of a DLT. Enrollment at the next dose level and/or additional subjects into the 
ongoing cohort occurred according to the following:
x
If 0 of 3 initially treated subjects experience a treatment-related DLT by Day 29, then 
dose escalation to the next dose level will occur.
x
If 1 of 3 initially treated subjects experience a treatment-related DLT by Day 29, then an 
additional 3 subjects will be enrolled for a total of 6 subjects treated at the same dose 
level. Escalation will occur if no additional DLTs are seen in that cohort (DLT in 1 of 6 
subjects).
x
If 2 or more treated subjects at a dose level experience a treatment-related DLT by 
Day 29 of continuous dosing, dose escalation will stop and the prior dose level and/or a 
less frequent drug administration schedule will be considered the MTD for that schedule. 
If the first dose level results in DLTs in 2 or more subjects, subsequent subjects will be 
enrolled at a less frequent drug administration schedule (e.g., 5 mg every other day 
[QOD])
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Dose escalation continued until the MTD and/or RP2D and dosing schedule was reached. The 
MTD is defined as the dose level at which no more than 1 out of 6 subjects have an observable 
DLT.
Additional details on dose escalation included the following:
x
If a subject withdraws from the study treatment for any reason other than a DLT during 
the first cycle (28 days), that subject is replaced. 
x
During the dose escalation period, intra-subject dose escalation is only permitted if the 
following criteria are met:
o
The next higher dose for this regimen has demonstrated to be safe by at least 3 
subjects and the last subject completed one cycle without exceeding a DLT.  
o
The subject in question has not experienced a DLT.  
x
Once MTD is determined, intra-subject dose escalation to the MTD can be considered 
for subjects enrolled at lower dose levels. 
As of November 2018, 34 subjects are enrolled in the Part 1 dose escalation portion.  
1.2.1.1.2.
Dose Expansion 
To further evaluate safety and tolerability, and to assess preliminary efficacy of MK-4440 as a 
single agent, up to 30 subjects will be enrolled and treated with MK-4440 at the RP2D in
expansion cohort (Arm A). It is planned to enroll up to 15 subjects with solid tumors with 
PIK3CA or PTEN actionable mutations and up to 15 subjects with AKT genetic alterations. 
Subjects enrolled in Arm A will receive MK-4440 at 75 mg QD, continuously. 
1.2.1.2.
Part 2 – MK-4440 in Combination with Other Anti-Cancer Agents 
Part 2 of this study is open to subjects with advanced, inoperable, metastatic, and/or recurrent 
solid tumors with PIK3CA/PTEN actionable mutations and/or AKT genetic alterations. Subjects 
may be assigned to one of the combination treatment arms (Arm B: MK-4440 + paclitaxel or 
Arm C: MK-4440 + fulvestrant) based on Investigator discretion, if such therapy choice is 
deemed appropriate for the subject’s disease. 
1.2.1.2.1.
Dose Escalation
Dose escalation follows the standard 3 + 3 escalation design with two MK-4440 dose levels of 
50 mg QD and 75 mg QD (RP2D of MK-4440 as a single agent). The dose levels for paclitaxel 
(Arm B) and fulvestrant (Arm C) will not change in dose escalation phase (Table 1):
x
Arm B: paclitaxel 80 mg/m2 weekly (QW) (intravenous [IV]) on days 1, 8, 15 followed 
by a week of rest. 
x
Arm C: fulvestrant 500 mg (intramuscular [IM]) on days 1 and 15 of Cycle 1, and on 
day 1 of all subsequent cycles. 
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Dose escalation criteria for MK-4440 enrollment at the next dose level and/or additional 
subjects into the ongoing cohort is the same as Part 1 as described in Section 1.2.1.1.1, with the 
exception of dose modification in case the initial dose of 50 mg MK-4440 results in 2 or more 
subjects experiencing a DLT: 
x
If the first dose level of study treatment (50 mg QD) results in 2 or more subjects 
experiencing a DLT, subsequent subjects will be enrolled at 25 mg QD (Cohort -1 in 
Table 1) 
DLT for dose escalation portion in Part 2 will be determined during the first cycle (28 days) of 
combination therapy. DLT is defined identically to Part 1 as described in Section 1.2.1.3 with an 
additional criterium below:
x
The Investigator is to assess alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) changes to determine if these changes may be a DLT:
o
t Grade 3 ALT or AST elevation for subjects with ALT/AST ≤ 3x upper limit of 
normal (ULN) at baseline
o
ALT/AST levels for subjects with known liver metastases and ALT/AST ≤ 5x
ULN at baseline
o
Grade 2 ALT/AST elevation accompanied by t Grade 2 elevation in bilirubin 
1.2.1.2.2.
Dose Expansion 
Following the determination of the RP2D in dose escalation phase, 6 – 9  subjects will be 
enrolled in each of the combination therapy arms for the dose expansion portion: 
x
Arm B: MK-4440 at RP2D and paclitaxel 80 mg/m2 QW (IV) on days 1, 8, 15 followed 
by a week of rest. 
x
Arm C: MK-4440 at RP2D and fulvestrant 500 mg (IM) on days 1 and 15 of Cycle 1,
and on day 1 of all subsequent cycles. 
1.2.1.3.
Dose Limiting Toxicity
A DLT is defined by the occurrence of any of the following toxicities related, probably related, 
or possibly related to MK-4440, when administered either as a single agent (Part 1) or in 
combination with another anti-cancer agent (Part 2), within the first cycle (28 days) of treatment 
and graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03:
x
Grade 4 anemia 
x
Grade 4 neutropenia 
x
Grade 4 thrombocytopenia 
x
Grade 3 neutropenia lasting longer than 7 days despite optimal treatment 
x
Grade 3 thrombocytopenia in the presence of bleeding 
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x
t Grade 3 hyperglycemia (fasting blood glucose > 250 mg/dL or non-fasting > 500 
mg/dL) requiring insulin (uncontrolled with oral hypoglycemic agents) 
x
t Grade 3 non-hematological toxicity of any duration, except for the following: 
o
Nausea, vomiting, or diarrhea responding to optimal medical management within 
48 hours  
o
Alopecia 
x
Any other toxicity that in the view of the Investigator represents a clinically significant 
hazard to the subject
1.2.1.4.
Dosing Details
The investigational drug MK-4440 is supplied as capsules for oral administration. MK-4440 is 
packaged in strength of 25 mg and is supplied to the pharmacy at the clinical site. MK-4440 
should be administered by mouth under fasted condition (one hour prior to or two hours after 
the meal) and should be taken at approximately the same time each day. Paclitaxel and 
fulvestrant will be obtained by the subject from commercial sources, and administration of them 
should follow the Food and Drug Administration (FDA) approved label, National 
Comprehensive Cancer Network (NCCN) guidelines, or institutional practice. The dosing 
scheme is described in Table 1.  
For an individual subject, treatment with MK-4440 as a single agent or in combination with 
paclitaxel or fulvestrant will continue until unacceptable toxicity, documented disease 
progression (clinical or radiological), or another discontinuation criterion is met. It is expected 
that most subjects will receive between one (4 weeks) and six cycles (24 weeks) of treatment 
with MK-4440 as a single agent or in combination with other anti-cancer agents. A treatment 
cycle is defined as 28 days.    
Based on review of the preliminary safety, PD and anti-tumor data from 34 subjects enrolled in 
the dose escalation portion of Part 1 of this study, the RP2D was selected as 75 mg QD and all 
subjects enrolled in Part 1 expansion cohort were dosed with MK-4440 at 75 mg QD.  
When a MK-4440-related toxicity (any toxicity considered to be related, probably related, or 
possibly related to MK-4440) is observed, dose delays and/or reductions in MK-4440 
administration are allowed. If dose reduction is indicated, the subject should be assigned to the 
previous (lower) cohort dose and schedule (dose re-escalation is not permitted) or to a dose and 
schedule agreed upon by the Sponsor and the Investigator. In the event of a dose modification, 
the dose change(s) must be captured in the electronic data capture (EDC) system. In general, 
once the dose of MK-4440 has been modified for a subject, all subsequent doses should be 
administered to that subject at the modified dose level and dose administration schedule. 
In case of non-MK-4440-related toxicity and if treatment with paclitaxel or fulvestrant is 
interrupted, the subject may continue taking MK-4440 upon agreement between the Investigator 
and the Sponsor’s Medical Monitor. In case of MK-4440-related toxicity that required MK-
4440-treatment interruption, the subject may continue treatment with paclitaxel or fulvestrant 
upon agreement between the Investigator and the Sponsor’s Medical Monitor. 
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Table 1
Dosing Scheme for Dose Escalation and Dose Expansion for MK-4440-001
Study 
Part
Study Cohorts
MK-4440
Anti-tumor 
Agents
to be Combined 
with MK-4440
Number of 
Subjects
Part 1
Dose 
Escalation
1
5 mg QD
None
34 enrolled
2
10 mg QD
3
25 mg 
QOD
4
25 mg QD
5
50 mg QD
6
100 mg QD
7*
75 mg QD
Expansion
(Arm A)
Expansion
(MTD/RP2D)
75 mg QD
30 planned
Part 2 
(Arm B)
Dose 
Escalation
-1
25 mg QD
Paclitaxel
80 mg/m2 (IV) on 
days 1, 8, 15 
followed by a week 
of rest 
6 – 9 planned
1
50 mg QD
2
75 mg QD
Expansion
Expansion
(MTD/RP2D)
RP2D
6 – 9 planned
Part 2
(Arm C)
Dose 
Escalation
-1
25 mg QD
Fulvestrant 
500 mg (IM) on 
days 1 and 15 of 
Cycle 1, and day 1 
of all subsequent 
cycles
6 – 9 planned
1
50 mg QD
2
75 mg QD
Expansion
Expansion
(MTD/RP2D)
RP2D
6 – 9 planned
Abbreviations: IM = intramuscularly; IV = intravenously; MTD = maximum tolerated dose; QD = once daily; RP2D = 
recommended phase 2 dose. 
* Based on drug-related AEs observed in cohort 6 of Part 1 dose escalation (100 mg QD), the intermediate dose of 
75 mg QD was introduced
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1.2.2.
Randomization Methodology 
Randomization is not applicable for this Phase 1b, open-label study, as all subjects will receive 
active treatment with MK-4440. Concurrent enrollment into expansion Arms A, B, or C will be 
based on Investigator assessment. 
1.2.3.
Stopping Rules and Unblinding 
Unblinding is not applicable to this open-label study. 
Subjects will be removed from the treatment at any time if they meet any of the following
criteria:
x
Documented radiographic or clinical progression of disease – subjects may remain on 
study treatment if, in the opinion of the Investigator and with the agreement of the 
Sponsor’s Medical Monitor, they continue to derive benefit from MK-4440 
x
Clinically unacceptable toxicities despite optimal treatment or dose reduction.
x
Noncompliance with any part of the study, as evaluated by the Investigator and Medical 
Monitor. 
x
Withdrawal of consent.
x
Investigator decision (in agreement with the Sponsor/Medical Monitor or designee).
x
Death
Subjects will be removed from the study at any time if they meet any of the following criteria:
x
Safety follow-up visit is completed per the protocol and drug-related adverse events 
(AEs) have resolved to baseline, National Cancer Insttitute (NCI) CTCAE (Common 
Terminology Criteria for Adverse Events) Grade 1, stabilized, or are deemed 
irreversible.
x
Withdrawal of consent.
x
Lost to follow-up. 
x
Death.
1.2.4.
Study Procedures 
The schedule of assessment, as outlined in the study protocol, is provided in Table 2 and Table 
3. Study visits will consist of a Screening Visit, during which the subject’s eligibility for the 
study and baseline disease state will be evaluated, weekly visits for the first 3 weeks of each 
cycle of treatment during which the subject will be evaluated throughout the treatment period, 
the End of Treatment Visit, and a 30-Day Safety Follow-up. Study visits for Arm B and Arm C 
are presented in Table 4 and Table 5 to show paclitaxel and fulvestrant administration visits.
Imaging scans will be performed during screening, every cycle throughout the treatment period, 
and during End of Treatment Visit. 
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Table 2
Schedule of Assessment for MK-4440-001
Tests & Procedures
Screening
Treatment Visits
End of 
Treatment
30-day
Safety
Follow-
  Cycle
Baseline
Cycle 1
Cycle 2+
Within 7 days of
decision to 
permanently
discontinue
30+ days 
after the
last dose of 
MK-4440
Day
0
1
2
81
15
1
2
81
152
Window (in days)
-14 - 0
-1
0
±2
±33
±33
0
±2
±33
Written Informed Consent4
X
Medical History
X
Physical Examination (including skin)
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
Vital Signs5
X
X
X
X
X
X
X
X
Fasting Clinical Blood Tests6
X
X
X
X
X
X
X
X
Urinalysis
X
X
Serum Pregnancy Test (if applicable)
X
X
CYP2D6 Sample
X
ctDNA Sample
X
Glucose Metabolism Blood Samples7
X
X
X
X
X
PK Blood Samples7
X
X
X
X
X
Home Blood Glucose Monitoring8
X
X
X
Blood Tumor Markers (if applicable)9
X
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X
X
X
X
X
Bone Scan
X
Electrocardiography/MUGA (if 
applicable)
X
Tumor Assessment and Re-
staging12
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
X
X
MK-4440 Dispensation
X
X
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1
Day 8 visits are only required for Arm B (MK-4440+paclitaxel)
2
Cycle 2 Day 15 visit is only required for Arm B (MK-4440+paclitaxel) and Arm C (MK-4440+fulvestrant). Day 15 visits in Cycle 3 are higher are required only for Arm
B (MK-4440+paclitaxel)
3
Window of ±3 days is allowed for Arms A (MK-4440 single agent) and Arm C (MK-4440+fulvestrant), but window of ±2 days is required for Arm B (MK-4440+paclitaxel).
4
ICF can be signed greater than 14 days prior to first dose.
5
Temperature, BP, HR and RR at every visit. Height only at Screening. Weight at Screening, Day 1 of each cycle and at End of Treatment visit.
6
Refer to Protocol Section 5.4 for detailed description of clinical laboratory tests
7
Refer to Protocol Section 5.5 and Appendix 3 of the study protocol for details on PK and glucose metabolism (insulin and glucose) timepoints.
8    Refer to Protocol Section 5.6. Home blood glucose monitoring should be performed by the subjects at least once per day (before breakfast) for the first 4 weeks. Not necessary
on days where glucose will be tested at the study site. After the first four weeks of treatment, the Investigator will determine if a subject should continue home glucose testing
and the testing frequency.
9
Tumor markers testing (if applicable) will be done at the study site. Tumor markers will be tested at Screening and frequency of testing while on treatment will be as
per FDA/NCCN guidelines, or institutional standards.
10
Refer to Protocol Section 5.3. Single 12-lead ECG to be performed at Screening and at End of Treatment visit. Repeat triplicate ECGs to be performed at C1D1, C1D15, 
C2D1, C3D1 and C4D1. See Appendix 3 for details for scheduled visits. Additional ECGs may be conducted if clinically indicated.
11
Echo/MUGA only required for subjects who received prior therapy with anthracyclines
12
Refer to Protocol Section 5.7. Tumor assessment (CT and/or MRI) at Screening can be done up to 28 days prior to the 1st dose of MK-4440). Post treatment, tumor
assessment must be done at the beginning of every other cycle, starting at Cycle 3 Day 1. Tumor assessment required at the End of Treatment (EOT) visit unless disease
progression was seen on the prior scan.
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Table 3
Schedule of Assessment for Part 1 Subjects Enrolled under Amendment 5 for MK-4440-001
Tests & Procedures
Pre-
Study
Treatment Visits
End of 
Treatment
30-day
Safety
Follow-up
  Cycle
Baseline
Cycle 1
Cycle 2+
7 days after the 
last dose of MK-
4440
30 days after
the last dose 
of MK-4440
Week
1
2
3
4
1
3
Day
0
1
2
8
15
22
23
1
15
Window (in days)
-14 - 0
-1
0
±3
0
±3
±3
±3
Written Informed Consent
X
Medical History
X
Physical Examination (including skin)
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
Vital Signs (To, BP, RR, HR)
X
X
X
X
X
X
X
X
X
X
x
Height
X
x
Weight
X
X
X
X
Fasting Clinical Blood Tests
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Serum Pregnancy Test (if applicable)
X
X
CYP2D6 Sample
X
Glucose Metabolism Blood Samples7
X
X
X
X
X
X
X
X
PK Blood Samples7
X
X
X
Home Blood Glucose Monitoring8
X
X
X
X
X
X
X
Tumor Markers Blood Sample, if
applicable9
X
X
X
X
12-Lead ECG10
X
X
X
X
x
In triplicate, pre- and post-dose
X
X
Electrocardiography/MUGA (if 
applicable)10
X
X
X
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Tests & Procedures
Pre-
Study
Treatment Visits
End of 
Treatment
30-day
Safety
Follow-up
  Cycle
Baseline
Cycle 1
Cycle 2+
7 days after the 
last dose of MK-
4440
30 days after
the last dose 
of MK-4440
Week
1
2
3
4
1
3
Day
0
1
2
8
15
22
23
1
15
Window (in days)
-14 - 0
-1
0
±3
0
±3
±3
±3
Archival and/pr Fresh Tumor Biopsy7
X
X
Tumor Assessment and Re-staging11
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events Assessment9
X
X
X
X
X
X
X
X
X
X
MK-4440 Dispensation
X
X
X
X
X
X
X
X
1
Detailed description of clinical laboratory tests recorded in Protocol Section 5.4 
2
Refer to Annex 1 of the study protocol for timepoints. Day 22 and Day 23 PK and glucose metabolism blood samples should be collected on Day 21 and Day 22 for subjects 
receiving MK-4440 QOD. 
3
PD blood samples should be collected on Day 1 of Cycle 1, 2, 3 and End of treatment visit. 
4
Refer to Annex 1 of the study protocol for timepoints. Home blood glucose monitoring should be performed at least once per day (before breakfast) for the first 4 weeks except 
for PK days (Cycle 1 Days 1, 2, 8, 15, 22 [Day 21 for subjects receiving MK-4440 QOD], and 23 [Day 22 for subjects receiving MK-4440 QOD]). After the first four weeks of 
treatment, the Investigator will determine if a subject should continue home glucose testing and the testing frequency. 
5
Tumor markers testing will be done at the study site 
6
12-lead ECG should be performed at Baseline and on Day 1 of the first six cycles; and in triplicate pre- and post-dose on Day 1 of Cycle 1 and Cycle 2. If applicable (previous 
treatment with anthracyclines), echocardiography or MUGA scan should be done at Baseline, every eight weeks for the first 24 weeks (six cycles) of treatment and every 12 
weeks thereafter. 
7
Archival tumor samples should be collected for all enrolled subjects; paired, pre- and post-treatment biopsy is optional for subjects enrolled in the Dose Escalation and Food-
effect cohorts and mandatory for subjects enrolled in the Expanded cohort. Post-treatment biopsy can be performed Day 15 of Cycle 1 and Day 1 of Cycle 2. 
8
Tumor assessment should be done at Baseline (if done within 28 days prior to the 1st dose of MK-4440), every eight weeks during treatment, and at End of Treatment (EOT) 
unless it was done within 28 days prior to the EOT visit. 
9
Only AEs that occurred after the administration of the first dose of MK-4440 and within 30 days of the Safety Follow-up period should be reported as an AE, any AE that 
occurred prior to the administration of the first dose of MK-4440 should be reported as Medical history. 
10 These tests and procedures must be performed on C1D1. MK-4440 must be dispensed on C1D1.
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Table 4
Study Visits for Arm B (MK-4440 + Paclitaxel)
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Table 5
Study Visits for Arm C (MK-4440 + Fulvestrant)
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1.2.5.
Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Parameters
1.2.5.1.
Safety Parameters
The safety profile of MK-4440 is one of the primary endpoints of the study. Safety parameters 
include AEs, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, 
electrocardiogram (ECG), echocardiograms/Multiple gated acquisition (MUGA) scan, physical 
examination, and clinical laboratory tests including hematology, coagulation, chemistry, and 
urinalysis.  
1.2.5.2.
Efficacy Parameters
Efficacy is a secondary objective in Protocol Amendment 7 of the study. The efficacy endpoint 
is preliminary evidence of anti-tumor activity of MK-4440 as a single agent and in combination 
with other anti-cancer agents as assessed by Response Evaluation Criteria in Solid Tumor  
(RECIST) version 1.1 [3].  
The efficacy parameters are as follows: 
x
Best overall response (BOR), defined as the best response recorded from the start of the 
study treatment until the end of treatment: complete response (CR), partial response 
(PR), stable disease (SD), or progressive disease.  
x
Objective response rate (ORR), defined as the proportion of subjects with a best overall 
response of CR or PR. 
x
Disease control rate (DCR), defined as the proportion of subjects with a best overall 
response of CR, PR, or SD; when SD is believed to be the best response, it must also 
meet the protocol specified minimum time from start of treatment of 8 weeks for 
inclusion in DCR.   
1.2.5.3.
Pharmacokinetic and Pharmacodynamic Parameters
Pharmacodynamic activity will be evaluated by changes in serum glucose and insulin levels, 
and by changes in cell-free circulating tumor deoxyribonucleic acid (ctDNA).  
Pharmacokinetic parameters include measurement of maximum plasma drug concentration 
(Cmax), area under the curve (AUC), and when possible, elimination half-life (t1/2). 
PD and PK analysis will be performed independently from this SAP. A separate report will be 
generated. 
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2.
SUBJECT POPULATION
2.1.
Population Definitions
The following subject populations will be evaluated and used for presentation and analysis of 
the data:
x
All-Subjects-as-Treated (ASaT) Population: All subjects who received at least 1 dose of 
study drug. 
x
Efficacy-Evaluable (EE) Population: All subjects who have received at least one cycle of 
MK-4440 and have had at least one disease assessment following the initiation of therapy. 
The ASaT population is the primary population for the analysis of efficacy and safety endpoints.
Efficacy parameters will also be evaluated for the EE population (see Section 4.4).
2.2.
Protocol Deviations 
Major protocol deviations will be determined by a review of the data. The Sponsor or designee 
will be responsible for producing the final determination in collaboration with Veristat, prior to 
hard database lock. 
All protocol violations will be presented in a data listing.
Relevant Output 
Table 14.1.7A 
Important Protocol Deviations Summary – Part 1 (MK-4440) (All 
Subjects Enrolled)
Table 14.1.7B 
Important Protocol Deviations Summary – Part 2 (Combination Therapy) 
(All Subjects Enrolled)
Listing 16.2.2.2   
Protocol Deviations (ASaT Population) 
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3.
GENERAL STATISTICAL METHODS
3.1.
Sample Size Justification
It is expected that approximately 94 subjects will be enrolled in this study; 64 subjects in Part 1 
(dose escalation cohorts and Arm A) and 30 subjects in Part 2.  
The exact number of subjects estimated for the dose escalation portion in both Part 1 and Part 2 
is dependent on the number of subject cohorts investigated based on the toxicity encountered. A 
standard 3+3 design is used. As of November 2018, the dose escalation portion of Part 1 was 
completed and 34 subjects were enrolled in this portion of the study. 
The dose expansion portion in both Part 1 and Part 2 is designed to examine preliminary 
evidence of anti-tumor activity of MK-4440, not as a formal efficacy study. The sample sizes 
were determined to be clinically reasonable to evaluate the study objectives, and consistent with 
standard sample sizes used in early phase, exploratory studies.
In Part 1, it is planned that up to 30 subjects with advanced, inoperable, metastatic, or recurrent 
solid tumors will be enrolled in expansion Arm A, up to 15 subjects with PIK3CA/PTEN 
activating mutations and up to 15 subjects with AKT genetic alterations. In Part 2, 
approximately 15 subjects (6 – 9 in escalation and 6 – 9 in expansion) will be enrolled in each 
combination therapy arm (Arm B, MK-4440+paclitaxel and Arm C, MK-4440+fulvestrant).
3.2.
General Methods
All data listings that contain an evaluation date will contain a relative study day (Rel Day). Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication which is designated as Day 1. The preceding day is Day -1, the day before that is 
Day -2, etc.
All output will be incorporated into Microsoft Word or Excel files, or Adobe Acrobat PDF files,
sorted and labeled according to the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) recommendations, and formatted to
the appropriate page size(s).
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented. For continuous variables, the number of subjects, mean, median, standard deviation, 
minimum, and maximum values will be presented.
The study is primarily descriptive in nature; therefore, no formal statistical hypothesis tests are 
planned. Data will be presented by subject and summarized by treatment arm and dose level.
Evaluation of the data will consist primarily of summary displays (e.g., descriptive statistics and 
graphs). All tabulation of dose levels will be based on initial dose level received. 
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3.3.
Computing Environment
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4,
unless otherwise noted. Medical history and adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 22.0 and CTCAE Version 4.03 will be 
used for the description of AE terms and toxicity grade. Concomitant medications will be coded 
using the World Health Organization (WHO) Drug Dictionary Global B3 March 2019.
3.4.
Baseline Definitions
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug (MK-4440).
3.5.
Methods of Pooling Data
Data will be pooled across sites within each arm/cohort. No additional pooling of data is 
planned.
3.6.
Adjustments for Covariates
No formal statistical analyses that adjust for possible covariate effects are planned.
3.7.
Multiple Comparisons/Multiplicity
Multiplicity is not of concern for this study with a descriptive interpretation and a primary 
objective to assess safety and tolerability.
3.8.
Subpopulations
A subgroup analysis will be performed on efficacy endpoints based on mutation types.
3.9.
Withdrawals, Dropouts, Loss to Follow-up
In the dose escalation portion of the study, if a subject withdraws from the study treatment for 
any reason other than a DLT during the first cycle (28 days), that subject will be replaced.
3.10.
Missing, Unused, and Spurious Data
In general, there will be no substitutions made to accommodate missing data points, other than 
as described in this section for the determination of treatment-emergence in AE and the 
determination of concomitancy (vs. prior) in concomitant medication. All data recorded on the 
case report form (CRF) will be included in data listings that will accompany the CSR.
When tabulating adverse event data, partial dates will be handled as follows. If the day of the 
month is missing, the onset day will be set to the first day of the month unless it is the same 
month and year as study treatment. In this case, in order to conservatively report the event as
treatment-emergent, the onset date will be assumed to be the date of treatment. If the onset day 
and month are both missing, the day and month will be assumed to be January 1, unless the 
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event occurred in the same year as the study treatment.  In this case, the event onset will be 
coded to the day of treatment in order to conservatively report the event as treatment-emergent.  
A missing onset date will be coded as the day of treatment. If an imputed start date is after a 
reported end date, the start date will be coded to the end date. Partial dates are imputed only to 
determine treatment emergence; by-subject listings will display the partial date as recorded.
When tabulating concomitant medication data, if an end date is missing or the medication is 
ongoing, the medication will be included as a concomitant medication.
3.11.
Visit Windows
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the CRF even if the assessment is outside of the 
visit window. In data listings, the relative day of all dates will be presented.
3.12.
Interim Analyses
No interim analyses are planned for this study.
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4.
STUDY ANALYSES
4.1.
Subject Disposition
Subject disposition will be tabulated, including number of subjects screened and enrolled, the 
number of subjects treated in each treatment arm, dose level, and study portion, and the number
and percentage of subjects in each analysis population. The number and percentage of subjects
who prematurely withdrew from the treatment or from the study, along with the primary reasons
for withdrawal, will also be summarized. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented.
Relevant Output
Table 14.1.1A
Subject Disposition by Treatment and Initial Dose Level – Part 1 (MK-
4440)
Table 14.1.1B
Subject Disposition by Treatment and Initial Dose Level – Part 2 
(Combination Therapy)
Listing 16.2.1.1
Treatment Completion
Listing 16.2.1.2  
Study Completion
Listing 16.2.1.3  
Informed Consent and Re-Consent
Listing 16.2.2.1  
Inclusion/Exclusion Criteria Not Met
Listing 16.2.3.1  
Study Populations
4.2.
Demographics, Baseline Characteristics and Medical History
All demographic and baseline characteristics will be descriptively summarized for the ASaT
Population. Categorical variables will be summarized by the number and percentage of subjects 
in each category. Continuous variables will be summarized by mean, standard deviation, 
median, minimum, and maximum.
Demographic characteristics include age, gender, race, ethnicity, baseline characteristics include 
ECOG performance status, height, weight, and body mass index (BMI).
Baseline disease characteristics including current cancer type, tumor grade and staging at initial 
diagnosis, grade and staging at study entry, histology, ER (estrogen receptor), progesterone 
receptor, and human epidermal growth factor receptor 2 (HER2) status, gene mutation, and 
specific PTEN gene mutation will be presented. Frequency and percentage of subjects with any 
prior radiotherapy, surgery, and systemic cancer therapy will be summarized by therapy type. 
Medical history will be tabulated by system organ class (SOC) and preferred term (PT). 
Baseline concomitant medication will also be summarized. 
Demographic, baseline characteristic, disease history, prior surgeries, cancer therapies and 
medical history data for each subject will be provided in data listings.
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Relevant Output
Table 14.1.2A  
Demographics and Baseline Characteristics by Treatment and Initial Dose 
Level – Part 1 (MK-4440) (ASaT Population)
Table 14.1.2B
Demographics and Baseline Characteristics by Treatment and Initial Dose 
Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.1.3A  
Baseline Disease Characteristics by Treatment and Initial Dose Level –
Part 1 (MK-4440) (ASaT Population)
Table 14.1.3B
Baseline Disease Characteristics by Treatment and Initial Dose Level –
Part 2 (Combination Therapy) (ASaT Population)
Table 14.1.4A  
Prior Therapy by Treatment Arm and Initial Dose Level – Part 1 (MK-
4440) (ASaT Population)
Table 14.1.4B
Prior Therapy by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.1.5A  
Medical History by Treatment Arm and Initial Dose Level – Part 1 (MK-
4440) (ASaT Population)
Table 14.1.5B
Medical History by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.1.6A  
Prior Medications by Treatment Arm and Initial Dose Level – Part 1 
(MK-4440) (ASaT Population)
Table 14.1.6B
Prior Medications by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Listing 16.2.4.1  
Demographics and Baseline Characteristics
Listing 16.2.4.2  
Medical History
Listing 16.2.4.3.1  
Current Cancer History: Histology
Listing 16.2.4.3.2  
Current Cancer History: Initial Diagnosis and Study Entry
Listing 16.2.4.3.3  
Current Cancer History: Receptor Status
Listing 16.2.4.3.4  
Current Cancer History: Molecular Profile
Listing 16.2.4.3.5  
Current Cancer History: Mutation
Listing 16.2.4.4  
Current Cancer Radiotherapy History
Listing 16.2.4.5  
Current Cancer Surgical History
Listing 16.2.4.6  
Current Cancer Systemic Therapy History
Listing 16.2.4.7
Bone Scan
4.3.
Safety Analyses
The safety analyses will be based on the ASaT Population.
4.3.1.
Study Drug Exposure
Study drug exposure will be summarized for MK-4440, including number of treatment cycles
and duration of exposure (days). Cumulative dose (mg), dose intensity (mg/day), and overall 
treatment compliance (%) for MK-4440 will be summarized. 
Duration of exposure is defined as the total number of days of study drug administration, 
ignoring any temporary drug discontinuation. If the date of last administration is unknown, the
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date until which the dispensed drug would have lasted without counting the extra drug provided 
will be used. Duration of exposure will be calculated by the formula:
Duration of exposure (days) = (date of last dose) – (date of first dose) + 1
Cumulative dose (mg) is defined as the total number of milligrams of MK-4440 that have been 
ingested. Cumulative dose (mg) is calculated as below:
Cumulative dose (mg) = (Number of tablets*mg concentration dispensed) –
(Number of tablets*mg concentration returned)
Dose intensity (mg/day) is defined as the dose administered per unit time. Dose intensity is 
calculated as:
Dose intensity = Cumulative dose / Duration of exposure
Overall treatment compliance by subjects with study drug MK-4440 will be summarized and 
calculated as:
ܲ݁ݎܿ݁݊ݐ᩸ܥ݋݉݌݈݅ܽ݊ܿ݁=
(ܰݑܾ݉݁ݎ ݋݂ ݐܾ݈ܽ݁ݐݏ ݀݅ݏ݌݁݊ݏ݁݀െܰݑܾ݉݁ݎ ݋݂ ݐܾ݈ܽ݁ݐݏ ݎ݁ݐݑݎ݊݁݀)
(ܰݑܾ݉݁ݎ ݋݂ ݐܾ݈ܽ݁ݐݏ ݀݅ݏ݌݁݊ݏ݁݀)
× 100
Treatment exposure and subject compliance with study drug will be presented in a data listing,
including exposure data for combination therapies (paclitaxel and fulvestrant). 
Relevant Output
Table 14.3.5.1.1  
MK-4440 Study Drug Exposure in Part 1 by Initial Dose Level (ASaT
Population)
Table 14.3.5.1.2  
MK-4440 Study Drug Exposure in Part 2 by Initial Dose Level (ASaT
Population)
Listing 16.2.5.1.1  
MK-4440 Administration
Listing 16.2.5.1.2  
Paclitaxel Administration (Arm B)
Listing 16.2.5.1.3  
Fulvestrant Administration (Arm C)
Listing 16.2.5.1.4  
Study Drug Accountability
Listing 16.2.5.2.1  
MK-4440 Overall Study Drug Exposure
Listing 16.2.5.2.2  
Combination Drug Overall Study Drug Exposure
4.3.2.
Adverse Events
All AEs will be coded using the MedDRA coding system and displayed in tables and data 
listings using SOC and PT.
Analyses of adverse events will be performed on those events that are considered treatment-
emergent, where treatment-emergent is defined as any adverse event with onset after the 
administration of study treatment through the end of the study (30 days after the last dose), or 
any event that was present at baseline but worsened in intensity or was subsequently considered 
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drug-related to MK-4440 (for Part 1) or drug-related to MK-4440 or combination drug (for Part 
2) by the Investigator through the end of the study.
A Summary of treatment-emergent AEs (TEAEs) will be presented by initial dose level received 
and include the number of and percentage of subjects with any of the following:
x
All TEAEs
x
TEAEs related to MK-4440 (for Part 1)
x
TEAEs related to MK-4440 or combination drugs (for Part 2)
x
Severe and treatment related severe TEAEs (Grade 3 or higher)
x
Serious and treatment related serious Adverse Events (SAEs)
x
TEAEs and treatment related TEAEs leading to treatment discontinuation
x
TEAEs and treatment related TEAEs leading to dose interruption or reduction
x
TEAEs and treatment related TEAEs resulting in death
x
TEAEs listed according to maximum severity
x
Dose limiting toxicity TEAEs 
x
Common (> 10% in one or more treatment group) TEAE 
In addition to the overall summary, separate summaries of each of the above categories will also 
be presented by SOC and PT. In these tabulations, each subject will contribute only once to the 
count for a given adverse event (SOC or PT), regardless of the number of episodes (i.e., adverse 
events are summarized by subject incidence rates).
For tabulations that include classification by maximum severity grade or TEAE >= Grade 3 
(Severe TEAE), AEs with missing severity will be included in a missing severity category, and 
each participant will contribute only once (e.g., the most intense occurrence) to each of the 
incidence rates in the descriptive analysis, regardless of the number of episodes. For tabulations 
that include classification by relationship to study treatment, AEs with missing relationship will 
be considered related to treatment drug.
In addition to the summary tabulations, the following by-subject data listings will be provided:
x
All AEs, with a flag indicating TEAEs
x
All SAEs
x
All AEs leading to Death
x
All TEAEs characterized as a DLT (if any)
x
All AEs leading to discontinuation of study treatment
Relevant Output
Table 14.3.1.1.1  
Treatment-Emergent Adverse Events Summary by Initial Dose Level –
Part 1 (MK-4440) (ASaT Population)
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Table 14.3.1.1.2  
Treatment-Emergent Adverse Events Summary by Treatment Arm and 
Initial Dose Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.1.2.1A
Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 1 (MK-
4440) (ASaT Population)
Table 14.3.1.2.1B
Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.2.2A
MK-4440 Related Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, Treatment Arm and Initial Dose 
Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.2.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class, Preferred Term, Treatment 
Arm and Initial Dose Level – Part 2 (Combination Therapy) (ASaT
Population)
Table 14.3.1.2.3A
MK-4440 Related Treatment-Emergent Adverse Events by Decreasing 
Incidence, MedDRA Preferred Term, Treatment Arm and Initial Dose 
Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.2.3B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events by Decreasing Incidence, MedDRA Preferred Term, Treatment 
Arm and Initial Dose Level – Part 2 Arm B (MK-4440 + Paclitaxel)
(ASaT Population)
Table 14.3.1.2.3C
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events by Decreasing Incidence, MedDRA Preferred Term, Treatment 
Arm and Initial Dose Level – Part 2 Arm C (MK-4440 + Fulvestrant)
(ASaT Population)
Table 14.3.1.3.1A
Treatment-Emergent Adverse Events with CTCAE Grade >= 3 by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.3.1B
Treatment-Emergent Adverse Events with CTCAE Grade >= 3 by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.1.3.2A
MK-4440 Related Treatment-Emergent Adverse Events with CTCAE 
Grade >= 3 by MedDRA System Organ Class, Preferred Term, Treatment 
Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.3.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events with CTCAE Grade >= 3 by MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.3.3A
Treatment-Emergent Adverse Events with CTCAE Grade >= 3 by
Decreasing Incidence, MedDRA Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.3.3B
Treatment-Emergent Adverse Events with CTCAE Grade >= 3 by
Decreasing Incidence, MedDRA Preferred Term, Treatment Arm and 
Initial Dose Level – Part 2 Arm B (MK-4440 + Paclitaxel) (ASaT
Population)
Table 14.3.1.3.3C
Treatment-Emergent Adverse Events with CTCAE Grade >= 3 by
Decreasing Incidence, MedDRA Preferred Term, Treatment Arm and 
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Initial Dose Level – Part 2 Arm C (MK-4440 + Fulvestrant) (ASaT
Population)
Table 14.3.1.3.4A
MK-4440 Related Treatment-Emergent Adverse Events with CTCAE 
Grade >= 3 by Decreasing Incidence, MedDRA Preferred Term,
Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.1.3.4B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events with CTCAE Grade >= 3 by Decreasing Incidence, MedDRA 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 Arm B 
(MK-4440 + Paclitaxel) (ASaT Population)
Table 14.3.1.3.4C
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events with CTCAE Grade >= 3 by Decreasing Incidence, MedDRA 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 Arm C 
(MK-4440 + Fulvestrant) (ASaT Population)
Table 14.3.1.4.1A
Treatment-Emergent Serious Adverse Events by MedDRA System Organ 
Class, Preferred Term, Treatment Arm and Initial Dose Level – Part 1 
(MK-4440) (ASaT Population)
Table 14.3.1.4.1B
Treatment-Emergent Serious Adverse Events by MedDRA System Organ 
Class, Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.4.2A
MK-4440 Related Treatment-Emergent Serious Adverse Events by
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.4.2B
MK-4440 or Combination Drug Related Treatment-Emergent Serious 
Adverse Events by MedDRA System Organ Class, Preferred Term, 
Treatment Arm and Initial Dose Level – Part 2 (Combination Therapy)
(ASaT Population)
Table 14.3.1.4.3A
Treatment-Emergent Serious Adverse Events by Decreasing Incidence, 
MedDRA Preferred Term, Treatment Arm and Initial Dose Level – Part 1 
(MK-4440) (ASaT Population)
Table 14.3.1.4.3B
Treatment-Emergent Serious Adverse Events by Decreasing Incidence, 
MedDRA Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
Arm B (MK-4440 + Paclitaxel) (ASaT Population)
Table 14.3.1.4.3C
Treatment-Emergent Serious Adverse Events by Decreasing Incidence, 
MedDRA Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
Arm C (MK-4440 + Fulvestrant) (ASaT Population)
Table 14.3.1.4.4A
MK-4440 Related Treatment-Emergent Serious Adverse Events by 
Decreasing Incidence, MedDRA Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.4.4B
MK-4440 or Combination Drug Related Treatment-Emergent Serious 
Adverse Events by Decreasing Incidence, MedDRA Preferred Term, 
Treatment Arm and Initial Dose Level – Part 2 Arm B (MK-4440 + 
Paclitaxel) (ASaT Population)
Table 14.3.1.4.4C
MK-4440 or Combination Drug Related Treatment-Emergent Serious 
Adverse Events by Decreasing Incidence, MedDRA Preferred Term, 
Treatment Arm and Initial Dose Level – Part 2 Arm C (MK-4440 + 
Fulvestrant) (ASaT Population)
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Table 14.3.1.5.1A
Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation by MedDRA System Organ Class, Preferred Term, 
Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.1.5.1B
Treatment-Emergent Adverse Events Leading to Treatment (MK-4440 or 
Combination Drug) Discontinuation by MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.5.2A
MK-4440 Related Treatment-Emergent Adverse Events Leading to 
Treatment Discontinuation by MedDRA System Organ Class, Preferred 
Term, Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.1.5.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events Leading to Treatment (MK-4440 or Combination Drug) 
Discontinuation by MedDRA System Organ Class, Preferred Term, 
Treatment Arm and Initial Dose Level – Part 2 (Combination Therapy)
(ASaT Population)
Table 14.3.1.6.1A
Treatment-Emergent Adverse Events Leading to Dose Reduction by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.6.1B
Treatment-Emergent Adverse Events Leading to Dose (MK-4440 or 
Combination Drug) Reduction by MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.6.2A
MK-4440 Related Treatment-Emergent Adverse Events Leading to Dose 
Reduction by MedDRA System Organ Class, Preferred Term, Treatment 
Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.6.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events Leading to Dose (MK-4440 or Combination Drug) Reduction by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.1.7.1A
Treatment-Emergent Adverse Events Leading to Dose Interruption by
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.7.1B
Treatment-Emergent Adverse Events Leading to Dose (MK-4440 or 
Combination Drug) Interruption by MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.7.2A
MK-4440 Related Treatment-Emergent Adverse Events Leading to Dose 
Interruption by MedDRA System Organ Class, Preferred Term, 
Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.1.7.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events Leading to Dose (MK-4440 or Combination Drug) Interruption by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 2 (Combination Therapy) (ASaT Population)
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Table 14.3.1.8.1A
Treatment-Emergent Adverse Events Leading to Death by MedDRA 
System Organ Class, Preferred Term, Treatment Arm and Initial Dose 
Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.8.1B
Treatment-Emergent Adverse Events Leading to Death by MedDRA 
System Organ Class, Preferred Term, Treatment Arm and Initial Dose 
Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.1.8.2A
MK-4440 Related Treatment-Emergent Adverse Events Leading to Death 
by MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.8.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events Leading to Death by MedDRA System Organ Class, Preferred 
Term, Treatment Arm and Initial Dose Level – Part 2 (Combination 
Therapy) (ASaT Population)
Table 14.3.1.9A
Dose Limiting Toxicity Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.9B
Dose Limiting Toxicity Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.1.10.1A
Treatment-Emergent Adverse Events by Maximum CTCAE Grade, 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.1.10.1B
Treatment-Emergent Adverse Events by Maximum CTCAE Grade, 
MedDRA System Organ Class, Preferred Term, Treatment Arm and 
Initial Dose Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.1.10.2A
MK-4440 Related Treatment-Emergent Adverse Events by Maximum 
CTCAE Grade, MedDRA System Organ Class, Preferred Term, 
Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.1.10.2B
MK-4440 or Combination Drug Related Treatment-Emergent Adverse 
Events by Maximum CTCAE Grade, MedDRA System Organ Class, 
Preferred Term, Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.1.11A
Common (>10% in One or More Treatment Group) Treatment-Emergent 
Adverse Events by Decreasing Incidence, MedDRA Preferred Term, 
Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.1.11B
Common (>10% in One or More Treatment Group) Treatment-Emergent 
Adverse Events by Decreasing Incidence, MedDRA Preferred Term, 
Treatment Arm and Initial Dose Level – Part 2 Arm B (MK-4440 + 
Paclitaxel) (ASaT Population)
Table 14.3.1.11C
Common (>10% in One or More Treatment Group) Treatment-Emergent 
Adverse Events by Decreasing Incidence, MedDRA Preferred Term, 
Treatment Arm and Initial Dose Level – Part 2 Arm B (MK-4440 + 
Fulvestrant) (ASaT Population)
Table 14.3.2.1A  
Listing of Serious Adverse Events by Subject and System Organ Class / 
Preferred Term – Part 1 (MK-4440) (ASaT Population)
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Table 14.3.2.1B  
Listing of Serious Adverse Events by Subject and System Organ Class / 
Preferred Term – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.2.2A  
Listing of Adverse Events Leading to Death by Subject and System 
Organ Class / Preferred Term – Part 1 (MK-4440) (ASaT Population)
Table 14.3.2.2B  
Listing of Adverse Events Leading to Death by Subject and System 
Organ Class / Preferred Term – Part 2 (Combination Therapy) (ASaT
Population)
Table 14.3.2.3A  
Listing of Dose Limiting Toxicity Adverse Events by Subject and System 
Organ Class / Preferred Term – Part 1 (MK-4440) (ASaT Population)
Table 14.3.2.3B  
Listing of Dose Limiting Toxicity Adverse Events by Subject and System 
Organ Class / Preferred Term – Part 2 (Combination Therapy) (ASaT
Population)
Table 14.3.2.4A  
Listing of Adverse Events Leading to Treatment Discontinuation by 
Subject and System Organ Class / Preferred Term – Part 1 (MK-4440)
Table 14.3.2.4B  
Listing of Adverse Events Leading to Treatment Discontinuation by 
Subject and System Organ Class / Preferred Term – Part 2 (Combination 
Therapy)
Listing 16.2.7.1  
Listing of Adverse Events by Subject and System Organ Class / Preferred 
Term – Part 1 (MK-4440)
Listing 16.2.7.2
Listing of Adverse Events by Subject and System Organ Class / Preferred 
Term – Part 2 (Combination Therapy)
Listing 16.2.9.8  
Safety Follow-Up
Listing 16.2.9.9  
Death Details
4.3.3.
Laboratory Data
Clinical laboratory values will be expressed in International System of Units (SI units).
The actual value and change from baseline to each on-study evaluation will be summarized for 
each clinical laboratory parameter, including hematology, clinical chemistry, coagulation, liver 
function tests, electrolytes, and urinalysis. All lab tests for the corresponding category as 
identified on the CRF will be included in the analysis. In the event of repeat values, the last non-
missing value per study day/time will be used.
Toxicities will be graded according to the NCI CTCAE v4.03. Shift table of changes in toxicity 
grade from baseline to worst value and from baseline to last value on study will be presented for 
NCI CTCAE specified laboratory tests. Laboratory values collected from both scheduled and 
unscheduled visits will be included in these summaries.
All laboratory data will be provided in data listings.
Relevant Output
Table 14.3.5.2.1A
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Hematology by Treatment Arm and Initial Dose Level – Part 1 
(MK-4440) (ASaT Population)
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Table 14.3.5.2.1B
Descriptive Statistics and Change from Baseline for Clinical Laboratory
Data: Hematology by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.5.2.2A
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Chemistry by Treatment Arm and Initial Dose Level – Part 1 (MK-
4440) (ASaT Population)
Table 14.3.5.2.2B
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Chemistry by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.5.2.3A
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Coagulation by Treatment Arm and Initial Dose Level – Part 1 
(MK-4440) (ASaT Population)
Table 14.3.5.2.3B
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Coagulation by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.5.2.4A
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Glucose/Insulin by Treatment Arm and Initial Dose Level – Part 1 
(MK-4440) (ASaT Population)
Table 14.3.5.2.4B
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Glucose/Insulin by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.5.2.5A
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Urinalysis by Treatment Arm and Initial Dose Level – Part 1 (MK-
4440) (ASaT Population)
Table 14.3.5.2.5B
Descriptive Statistics and Change from Baseline for Clinical Laboratory 
Data: Urinalysis by Treatment Arm and Initial Dose Level – Part 2 
(Combination Therapy) (ASaT Population)
Table 14.3.5.3.1  
Clinical Laboratory Shifts from Baseline to Worst On-Study and Last On-
Study Values by CTCAE Grade: Hematology by Treatment Arm and 
Initial Dose Level (ASaT Population)
Table 14.3.5.3.2  
Clinical Laboratory Shifts from Baseline to Worst On-Study and Last On-
Study Values by CTCAE Grade: Chemistry by Treatment Arm and Initial 
Dose Level (ASaT Population)
Table 14.3.5.3.3  
Clinical Laboratory Shifts from Baseline to Worst On-Study and Last On-
Study Values by CTCAE Grade: Coagulation by Treatment Arm and 
Initial Dose Level (ASaT Population)
Table 14.3.5.3.4 
Clinical Laboratory Shifts from Baseline to Worst On-Study and Last On-
Study Values by CTCAE Grade: Glucose/Insulin by Treatment Arm and 
Initial Dose Level (ASaT Population)
Listing 16.2.8.1  
Clinical Laboratory Results: Hematology
Listing 16.2.8.2  
Clinical Laboratory Results: Chemistry
Listing 16.2.8.3  
Clinical Laboratory Results: Coagulation
Listing 16.2.8.4  
Serial Glucose/Insulin
Listing 16.2.8.5  
Home Glucose Monitoring
Listing 16.2.8.6  
Clinical Laboratory Results: Urinalysis
Listing 16.2.8.7  
Tumor Markers
Listing 16.2.8.8  
Pregnancy Test Results
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Listing 16.2.8.9  
Pharmacodynamic Archival Tissue Collection
Listing 16.2.8.10
Pharmacodynamic Biopsy Tissue Collection
4.3.4.
Vital Signs and Physical Examination
Summary statistics for baseline, each post-baseline measurement, and change from baseline for 
each post-baseline measurement will be presented for each vital sign parameter including 
temperature, diastolic/systolic blood pressure, respiration rate, heart rate, and weight.
Vital sign measurements and all physical examination findings will be presented for each 
subject in data listings.
Relevant Output
Table 14.3.5.4A
Descriptive Statistics and Change from Baseline for Vital Signs Data by 
Treatment Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT
Population)
Table 14.3.5.4B
Descriptive Statistics and Change from Baseline for Vital Signs Data by 
Treatment Arm and Initial Dose Level – Part 2 (Combination Therapy)
(ASaT Population)
Listing 16.2.9.1  
Vital Sign Results
Listing 16.2.9.2  
Physical Examination Results
4.3.5.
ECOG Performance Status
Number and percentage of subjects within each ECOG performance status level will be 
presented for baseline and each on-study evaluation. In addition, a summary of shift from 
baseline status to the worst and last post treatment status will be presented by treatment arm and 
cohort.
ECOG performance data will be provided in a data listing.
Relevant Output
Table 14.3.5.7.1A
ECOG Performance Status Over Time by Treatment Arm and Initial 
Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.5.7.1B
ECOG Performance Status Over Time by Treatment Arm and Initial 
Dose Level – Part 2 (Combination Therapy) (ASaT Population)
Table 14.3.5.7.2  
ECOG Shifts from Baseline to Worst On-Study and Last On-Study 
Values by Treatment Arm and Initial Dose Level (ASaT Population)
Listing 16.2.9.3  
ECOG Performance Status Results
4.3.6.
12-lead ECG and MUGA/Echocardiogram
Descriptive statistics will be provided for heart rate (HR), PR, QRS, QT and QTcF at baseline 
and each study visit. Change from baseline will also be summarized. The number and 
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percentage of subjects within each cardiac rhythm category will be summarized for baseline and 
each on study visit. Number and percentage of subjects with normal, abnormal, and clinically 
significant abnormal results at baseline and each study visit for overall ECG interpretation will 
be provided. 
Similarly, descriptive statistics will be summarized for left ventricular ejection fraction (LVEF) 
from MUGA/echocardiogram performed at Screening. Any post-baseline 
MUGA/echocardiogram assessments will be included in data listings, but will not be tabulated.
An echocardiogram/MUGA will be conducted at the screening visit only for subjects who 
received prior therapy with anthracyclines. 12-lead ECGs will be conducted at time points 
specified in the protocol. 
All ECG and MUGA/echocardiogram measurements will be presented in data listings.
Relevant Output
Table 14.3.5.5.1A
Descriptive Statistics and Change from Baseline for Electrocardiogram 
Data by Treatment Arm and Initial Dose Level – Part 1 (MK-4440)
(ASaT Population)
Table 14.3.5.5.1B
Descriptive Statistics and Change from Baseline for Electrocardiogram 
Data by Treatment Arm and Initial Dose Level – Part 2 (Combination 
Therapy) (ASaT Population)
Table 14.3.5.5.2A
Electrocardiogram Interpretations Over Time by Initial Dose Level – Part
1 (MK-4440) (ASaT Population)
Table 14.3.5.5.2B
Electrocardiogram Interpretations Over Time by Initial Dose Level – Part 
2 (Combination Therapy) (ASaT Population)
Table 14.3.5.6A
Descriptive Statistics for Left Ventricular Ejection Fraction by Treatment 
Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT Population)
Table 14.3.5.6B
Descriptive Statistics for Left Ventricular Ejection Fraction by Treatment 
Arm and Initial Dose Level – Part 2 (Combination Therapy) (ASaT
Population)
Listing 16.2.9.4  
12-Lead Electrocardiogram Results
Listing 16.2.9.5  
Echocardiogram/MUGA Results
4.3.7.
Concomitant Medications
Concomitant medications will be coded using the WHO Drug Dictionary. Results will be 
tabulated by anatomic therapeutic class (ATC) level 3 and preferred term per treatment arm and 
cohort. Any medications that did not end prior to first dose or any medication taken between 
first and last dose of MK-4440 will be included.
The use of prior and concomitant medications will be included in a by-subject data listing.
Relevant Output
Table 14.3.5.8A
Concomitant Medications by Treatment Arm and Initial Dose Level –
Part 1 (MK-4440) (ASaT Population)
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Table 14.3.5.8B   
Concomitant Medications by Treatment Arm and Initial Dose Level – 
Part 2 (Combination Therapy) (ASaT Population) 
Listing 16.2.9.6   
Prior and Concomitant Medications 
4.4.
Efficacy Evaluation
Efficacy analyses will be performed on the ASaT population and EE population. The efficacy 
endpoints defined in Section 1.2.5.2 will be summarized overall for dose escalation cohorts, 
each expansion cohort, and by mutation type. All tumor response assessment will be performed 
by following RECIST version 1.1.  
x
BOR will be presented, with a two-sided exact 95% confidence intervals (CIs) for the 
percentage of subjects in each RECIST response category (i.e., CR, PR, SD, and 
Progressive Disease).   
x
ORR, defined as the proportion of subjects with best overall response of CR or PR, will 
be presented with a two-sided exact 95% CI.  
x
Disease control rate, defined as the proportion of subjects with an overall response of 
CR, PR, or SD (for at least 8 weeks), will be presented with a two-sided exact 95% CI.  
All efficacy data will be provided in data listings, including scan results and associated 
parameters for assessment of response.
Relevant Output 
Table 14.2.1.1A   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Initial Dose Level – Part 1 (MK-4440) (ASaT Population) 
Table 14.2.1.1B   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Initial Dose Level – Part 2 (Combination Therapy) (ASaT
Population) 
Table 14.2.1.2A   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Initial Dose Level – Part 1 (MK-4440) (Efficacy-Evaluable 
Population) 
Table 14.2.1.2B   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Initial Dose Level – Part 2 (Combination Therapy) (Efficacy-
Evaluable Population) 
Table 14.2.1.3A   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Mutation Type – Part 1 (MK-4440) (ASaT Population) 
Table 14.2.1.3B   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Mutation Type ̢ Part 2 Arm B (MK-4440 + Paclitaxel) (ASaT
Population) 
Table 14.2.1.3C   
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Mutation Type ̢ Part 2 Arm C (MK-4440 + Fulvestrant)
(ASaT Population) 
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Table 14.2.1.4A  
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Mutation Type – Part 1 (MK-4440) (Efficacy-Evaluable 
Population)
Table 14.2.1.4B  
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Mutation Type ̢ Part 2 Arm B (MK-4440 + Paclitaxel)
(Efficacy-Evaluable Population)
Table 14.2.1.4C
Summary of Best Overall Response and Response Rates by Treatment 
Arm and Mutation Type ̢ Part 2 Arm C (MK-4440 + Fulvestrant)
(Efficacy-Evaluable Population)
Listing 16.2.6.1A
RECIST 1.1 Response Assessment
Listing 16.2.6.1B
Best Overall Response
Listing 16.2.6.2  
Target Lesions
Listing 16.2.6.3  
Non-Target Lesions
Listing 16.2.6.4  
New Lesions
4.5.
Pharmacokinetics and Pharmacodynamics Evaluations
All PK and PD analyses will be described in a separate analysis plan. 
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5.
CHANGES TO PLANNED ANALYSES
There are no changes between the protocol-defined statistical analyses and those presented in 
this SAP. Study drug name is changed from ARQ 751 (per protocol) to MK-4440 per Sponsor 
request. The Safety Population (per protocol) is renamed to All-Subjects-as-Treated (ASaT)
Population per Sponsor’s internal standard for early oncology trials.  
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6.
REFERENCES
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2. Brazil DP, Yang Z, Hemmings BA. Advances in protein kinase B signaling: AKTion on 
multiple fronts. Trends Biochem Sci. 2004; 29(5):233-42.
3. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 
Verweij J. New response criteria in solid tumours: Revised RECIST guideline (version 1.1). 
European Journal of Cancer 2009; 45:228-247.
4. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as 
regulators of growth and metabolism. Nat Rev Genet. 2006; 7(8):606-19.
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