A Phase 1, Open-label, Two-part Study to Investigate the Absorption, Metabolism, and Excretion, and the Absolute Bioavailability of [14C]-LOXO-292 in Healthy Male Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol Amendment 2 J2G-OX-JZJT (LOXO-RET-18016) 
A Phase 1, Open-label, Two-part Study to Investigate the Absorption, Metabolism and Excretion and the 
Absolute Bioavailbility of [ l 4C]-LOXO-292 in Healthy Male Subjects 
NCT05630287 
Approval Date: 15-Aug-2018 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 of 6 0 
A P H A S E 1, O P E N- L A B E L, T W O- P A R T S T U D Y T O I N V E S TI G A T E T H E 
A B S O R P TI O N, M E T A B O LI S M, A N D E X C R E TI O N, A N D T H E A B S O L U T E 
BI O A V AI L A BI LI T Y O F [ 1 4C]- L O X O- 2 9 2 I N H E A L T H Y M A L E S U B J E C T S 
Pr ot oc ol A me n d me nt 2 Stat us:  Fi nal  
Pr ot oc ol A me n d me nt 2 Date:  1 5 A u g ust 2 0 1 8 
Pr ot oc ol A me n d me nt 1 Date:  1 2 J ul y 2 0 1 8 
Ori gi nal Pr ot oc ol D ate:  1 5 J u ne 2 0 1 8 
St u d y Dr u g: L O X O- 2 9 2 
S p o ns or Refere n ce N u m ber: L O X O- R E T- 1 8 0 1 6 
C o va nce St u d y N u m ber: 8 3 8 7 0 2 4 
I N D N u m ber: 1 3 3 1 9 3 
f or 
L o x o O nc ol o g y, I nc. 
7 0 1 Gate wa y B o ule var d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
b y 
C o va nce Earl y Cli nical S er vices 
3 4 0 2 Ki ns ma n B o ule var d 
Ma dis o n, Wisc o nsi n 5 3 7 0 4 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 of 6 0 
S T U D Y I D E N TI FI C A TI O N 
S p o ns or
L o x o
 
O nc ol o g y, I nc.
7 0 1
 
Gate wa y
 
B o ule var d, S uite 4 2 0
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
( 6 5 0) 9 8 9- 8 0 5 1 ( Mai n Tele p h o ne N o.)
S p o ns or’s St u d y C o ntact  
L o x o
 
O nc ol o g y, I nc.
 ( M o bile Tele p h o ne N o.) 
 ( Alter nat e C o ntact N o.) 
S p o ns or’s Me dical M o nit or  
C o ns ulti n g t o L o x o O nc ol o g y, I nc. 
 ( M o bile Tele p h o ne N o.) 
S p o ns or C o ntact I nf or mati o n 
f or Seri o us A d verse  
Safet y fa x:  + 1 ( 2 0 3) 6 4 3- 2 0 1 3 
E ve nt Re p orti n g 
Safet y e mail:  safet y @l o x o o nc ol o g y. c o m  
Cli nical Site 
C o va nce Cli nical Researc h U nit, I nc. 
3 4 0 2 Ki ns ma n B o ule var d 
Ma dis o n, Wisc o nsi n 5 3 7 0 4 
( 6 0 8) 4 4 2- 8 2 0 0 ( M ai n Tele p h o ne N o.)
( 6 0 8) 6 6 1- 8 1 6 9 ( M ai n Facsi mile N o.)
Pri nci pal I n v esti gat or 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 of 6 0 
Mai n Cli nical La b orat or y  
Meriter La b orat ories 
3 6 S o ut h Br o o ks Street 
Ma dis o n, Wisc o nsi n 5 3 7 1 5 
( 6 0 8) 4 1 7- 6 5 2 9 ( M ai n Tele p h o ne N o.)
Bi oa nal ytical La b orat or y  
Alt uras A nal ytics, I nc. 
1 3 2 4 Alt uras Dri ve  
M osc o w, I da h o 8 3 8 4 3 
( 2 0 8) 8 8 3- 3 4 0 0 ( Mai n Tele p h o ne N o.)
Ra di oa nal ytical La b orat or y  C o va nce La b orat ories, I n c. 
( Part 1) 
De part me nt of Dr u g Me t a b olis m a n d P har mac o ki netics 
3 3 0 1 Ki ns ma n B o ule var d 
Ma dis o n, Wisc o nsi n 5 3 7 0 4 
( 6 0 8) 2 4 1- 4 4 7 1 ( M ai n Tele p h o ne N o.)
Meta b olite Pr ofili n g La b  
C o va nce La b orat ories, I n c. 
( Part 1) 
De part me nt of Dr u g Met a b olis m a n d P har mac o ki netics 
3 3 0 1 Ki ns ma n B o ule var d 
Ma dis o n, Wisc o nsi n 5 3 7 0 4 
( 6 0 8) 2 4 1- 4 4 7 1 ( M ai n Tele p h o ne N o.)
Ra di oa nal ytical La b orat or y  P har mar o n (f or merl y Xceler o n) 
( Part 2) 
2 0 3 4 0 Se neca M ea d o ws Par k wa y 
Ger ma nt o w n,
 
Mar yla n d 2 0 8 7 6
( 2 4 0) 3 6 1- 1 9 0 0 ( M ai n Tele p h o ne N o.)
P har mar o n St u d y C o ntact 
P P D
P P D
P P D

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 of 6 0 
Ra diati o n Safet y Officer 
Cli nical N uclear P har m acist 
Pr ot oc ol Bi ostatisticia n 
Pr ot oc ol P har mac o ki neti cist 
Pr ot oc ol Me dical Writer 
P P D
P P D
P P D
P P D
P P D

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 of 6 0 
T A B L E O F C O N T E N T S 
TI T L E P A G E .................................................................................................................... ... 1 
S T U D Y I D E N TI FI C A TI O N ............................................................................................... 2  
T A B L E O F C O N T E N T S ..................................................................................................... 5  
A B B R E VI A TI O N S ............................................................................................................. 9  
1  
S Y N O P SI S ............................................................................................................. 1 1  
2  
I N T R O D U C TI O N ................................................................................................. 1 5 
2. 1  
Bac k gr o u n d ................................................................................................ 1 5  
2. 2  
S u m mar y of N o n cli nical St u dies ............................................................... 1 5  
2. 3  
S u m mar y of Cli nical St u dies ..................................................................... 1 7  
2. 4  
St u d y R ati o nale .......................................................................................... 1 7  
2. 5  
D ose Rati o nale ........................................................................................... 1 8  
3  
S T U D Y O BJ E C TI V E S .......................................................................................... 1 9  
4  
I N V E S TI G A TI O N A L P L A N ................................................................................ 2 0 
4. 1  
St u d y Desi g n .............................................................................................. 2 0  
4. 2  
Disc ussi o n of St u d y Desi g n ....................................................................... 2 3  
5  
S U BJ E C T S E L E C TI O N ........................................................................................ 2 4  
5. 1  
I n cl usi o n Criteria ....................................................................................... 2 4 
5. 2  
E x cl usi o n Criteria ...................................................................................... 2 5  
5. 3  
Re m o val of S u bjects fr o m St u d y Partici pati o n .......................................... 2 8  
6  
S T U D Y P R O C E D U R E S ....................................................................................... 2 9  
6. 1  
Sc he d ule of St u d y Pr oce d ures ................................................................... 2 9  
6. 2  
St u d y Treat me nt ......................................................................................... 3 6  
6. 2. 1  Dr u g S u p plies a n d Acc o u nta bilit y ................................................. 3 6  
6. 2. 2  S u bject N u m ber a n d I d e ntificati o n ................................................ 3 7  
6. 2. 3  D ose Pre parati o n a n d A d mi nistrati o n ............................................ 3 7  
6. 2. 4  Bli n di n g.......................................................................................... 3 8  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 6 of 6 0 
6. 3  
St u d y R estricti o ns ...................................................................................... 3 8  
6. 3. 1  Diet, Fl ui d, a n d Acti vit y C o ntr ol ................................................... 3 8  
6. 3. 2  C o nc o mita nt Me dicati o ns .............................................................. 3 9  
6. 3. 3  C o ntrace pti o n ................................................................................. 3 9  
6. 4  
P har mac o ki netic, [ 1 4C] Ra di oacti vit y, a n d Meta b olite Pr oce d ures ........... 4 0  
6. 4. 1  P har mac o ki netic, [ 1 4C] Ra di oacti vit y, a n d Meta b olite Bl o o d Sa m ple 
C ollecti o n ........................................................................... 4 0  
6. 4. 2  P har mac o ki netic, [ 1 4C] Ra di oacti vit y, a n d Meta b olite Uri ne Sa m ple 
C ollecti o n ........................................................................... 4 0  
6. 4. 3  [1 4C] Ra di oacti vit y a n d Meta b olite Fecal Sa m ple C ollecti o n........ 4 1  
6. 4. 4  E mesis Sa m ple C ollecti o n ............................................................. 4 1  
6. 4. 5  A nal ytical Met h o d ol o g y ................................................................ 4 1  
6. 5  
Safet y Pr oce d ures....................................................................................... 4 2  
6. 5. 1  A d verse E v e nts .............................................................................. 4 2  
6. 5. 2  Cli nical La b orat or y E val uati o ns .................................................... 4 3  
6. 5. 3  Vital Si g ns ...................................................................................... 4 3  
6. 5. 4  T wel ve-le a d Electr o car di o gra ms ................................................... 4 3  
6. 5. 5  P h ysical E x a mi nati o ns ................................................................... 4 4  
7  
D A T A A N A L Y S E S A N D S A M P L E SI Z E ........................................................... 4 4  
7. 1  
Sa m ple Siz e ................................................................................................ 4 4  
7. 2  
St u d y P o p ulati o ns ...................................................................................... 4 4  
7. 3  
P har mac o ki netic A n al ysis .......................................................................... 4 4  
7. 4  
Statistical A nal ysis of P har mac o ki netic Data ............................................ 4 7  
7. 5  
Statistical A nal yses of Safet y Data ............................................................ 4 7  
7. 6  
Data Ha n dli n g a n d Rec or d Kee pi n g .......................................................... 4 8  
7. 7  
Q ualit y C o ntr ol a n d Q u alit y Ass ura n ce ..................................................... 4 8  
8  
A D MI NI S T R A TI V E A S P E C T S ........................................................................... 4 9  
8. 1  
C ha n ge i n Pr ot oc ol ..................................................................................... 4 9  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 7 of 6 0 
8. 2  
Site I nitiati o n Visit/I n vesti gat or Meeti n g .................................................. 4 9  
8. 3  
Discl os ure .................................................................................................. 4 9  
8. 4  
M o nit ori n g ................................................................................................. 4 9  
8. 5  
I nstit uti o nal Re vie w B oar d ........................................................................ 5 0 
8. 6  
I nf or me d C o nse nt....................................................................................... 5 0 
8. 7  
Rec or ds ...................................................................................................... 5 0  
8. 8  
Refere n ce t o D eclarati o n of Helsi n ki/ Basic Pri nci ples .............................. 5 1  
8. 9  
Fi na nci n g a n d I ns ura n ce ............................................................................ 5 1  
I N V E S TI G A T O R A G R E E M E N T..................................................................................... 5 2 
S P O N S O R A G R E E M E N T ................................................................................................ 5 3  
R E F E R E N C E S .................................................................................................................. 5 4  
A P P E N DI X A - C LI NI C A L L A B O R A T O R Y E V A L U A TI O N S .................................... 5 5  
A P P E N DI X B - B L O O D S A M P LI N G S U M M A R Y ........................................................ 5 6  
A P P E N DI X C - A D V E R S E E V E N T S .............................................................................. 5 7  
1  
A D V E R S E E V E N T S ............................................................................................. 5 7  
1. 1  
Defi niti o n of A d vers e E v e nts..................................................................... 5 7  
1. 2  
Cate g orizati o n of A d verse E ve nts ............................................................. 5 7  
1. 3  
Pre g n a nc y ................................................................................................... 5 8  
1. 4  
Defi niti o n of Seri o us A d verse E ve nts........................................................ 5 9  
1. 5  
U ne x pecte d A d verse Dr u g E x perie nce ...................................................... 5 9  
1. 6  
Re p orti n g.................................................................................................... 6 0  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 8 of 6 0 
T A B L E O F T A B L E S A N D FI G U R E S 
Ta ble 6- 1  Sc he d ul e of Assess me nts:  Part 1 .................................................................... 3 0  
Ta ble 6- 2  Sc he d ul e of Assess me nts:  Part 2 .................................................................... 3 3  
Ta ble 6- 3  S u p plie d St u d y Dr u gs:  Part 1 ......................................................................... 3 6  
Ta ble 6- 4  S u p plie d St u d y Dr u gs:  Part 2 ......................................................................... 3 6  
Fi g ure  4- 1 St u d y Desi g n Sc he matic:  Part 1 ..................................................................... 2 1 
Fi g ure 4- 2 St u d y Desi g n Sc he matic:  Part 2 ..................................................................... 2 2  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 9 of 6 0 
A B B R E VI A TI O N S 
A D L  
Acti vities of Dail y Li vi n g 
A ef  
a m o u nt e x crete d i n feces per sa m pli n g i nter val 
A e u  
a m o u nt e x crete d i n uri ne per sa m pli n g i nter val 
A E
a d verse
 
e ve nt
A L A R A   
as l o w as (is) reas o na bl y ac hie va bl e 
A L P
al kali ne
 
p h os p hatase
A L T
ala ni ne
 
a mi n otra nsf eras e
A M E   
a bs or pti o n, meta b olis m, a n d e x creti o n 
A M S   
accelerat or mass s pectr o metr y 
A S T
as partate
 
a mi n otra nsferas e
A U C   
area u n d er t he c o nce ntrati o n-ti me c ur ve 
A U C 0- ∞  
area u n d er t he c o nce ntrati o n-ti me c ur ve e xtra p olat e d t o i nfi nit y 
A U C last  
area u n d er t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n 
A V
atri o ve ntric ular
BI D
t wice
 
dail y
B MI   
b o d y mass i n de x 
B P
bl o o d
 
press ure
C F R   
C o de of Fe d eral Re g ul ati o ns 
C L
s yste mic
 
cl eara nce
C last  
last q ua ntifia ble c o nce ntr ati o n 
C L/ F
a p pare nt
 
s yste mic
 
cleara nce
C L R
re nal
 
cleara nce
C ma x   
ma xi m u m o bser ve d c o nce ntrati o n 
C R U   
Cli nical Researc h U nit 
C T C A E   
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
C u m A ef  
c u m ulati ve a m o u nt e x crete d i n feces 
C u m A e u  
c u m ulati ve a m o u nt e x crete d i n uri ne 
C u m % fef  
c u m ulati ve perce nta ge of d ose e x crete d i n feces 
C u m % fe u   
c u m ulati ve perce nta ge of d ose e x crete d i n uri ne   
C Y P
c yt o c hr o me
 
P 4 5 0
D L T
d ose-li miti n g
 
t o xicit y
E C G
electr ocar di o gra m
e C R F  
electr o nic Cas e Re p ort F or m 
E T
Earl y
 
Ter mi nati o n
F
a bs ol ute
 
bi oa vaila bilit y

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 0 of 6 0 
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
%f ef  
perce nt a ge of d os e e x cret e d i n feces per sa m pli n g i nter val 
%f e u  
perce nt a ge of d os e e x cret e d i n uri ne per sa m pli n g i nter val 
GI
gastr oi ntesti nal
G L P
G o o d
 
La b orat or y
 
Practice
H Bc A b  
he patitis B c ore a nti b o d y 
H Bs A g   
he patitis B s urface a nti ge n 
H C V A b   
he patitis C vir us a nti b o d y 
h E R G   
h u ma n et her- a- g o- g o relate d ge ne 
HI V
h u ma n
 
i m m u n o deficie nc y
 
vir us
I B
I n v esti gat or’s Br oc h ure 
I C F
I nf or me d
 
C o nse nt
 
F or m
I R B
I nstit uti o nal
 
Re vie w
 
B oar d
I U D
i ntra uteri ne
 
de vic e
I V
i ntra ve n o us(l y)
Z   
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt 
L F T   
li ver f u ncti o n test 
L S C   
li q ui d sci ntillati o n c o u nti n g 
P K
p har mac o ki netic(s)
R B C   
re d bl o o d cell 
R E T   
rearra n ge d d uri n g tra nsfecti o n 
Q Tc   
Q T i nter val c orrecte d f or heart rate  
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri d erici a’s met h o d 
S A E   
seri o us a d vers e e v e nt 
S A P   
Statistical A nal ysis Pla n 
t1/ 2  
a p pare nt ter mi nal eli mi nati o n half-life 
T E A E   
treat me nt-e mer ge nt a d verse e ve nt 
T F Ls   
ta bles, fi g ures, a n d listi n gs 
T ma x   
ti me t o ma xi m u m o bser ve d c o nce ntrati o n 
T S H
t h yr oi d-sti m ulati n g
 
h or m o ne
U S
U nite d
 
States
V ss  
v ol u me of distri b uti o n at stea d y st ate 
V z  
v ol u me of distri b uti o n d uri n g t he ter mi nal p hase 
V z/ F  
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase 
W B C  
w hite bl o o d cell 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 1 of 6 0 
1  S Y N O P SI S 
Title of St u d y: 
A P hase 1, O pe n-la bel, T w o- p art St u d y t o I n vesti gate t he A bs or pti o n, Meta b olis m, a n d 
E xcreti o n, a n d t he A bs ol ute Bi oa vaila bilit y of [1 4C]- L O X O- 2 9 2 i n Healt h y Male 
S u bj ects  
O bj ecti ves: 
P art 1: 
Pri mar y:  
 
T o deter mi ne mass bala nce a n d r o utes of eli mi nati o n of [ 1 4C]- L O X O- 2 9 2 f oll o wi n g 
oral a d mi nistrati o n of a si n gle 1 6 0- m g ( ~ 4 0 μ Ci) ra di ola bele d d ose of L O X O- 2 9 2 i n 
healt h y male s u bj ects 
 
T o assess t he p har mac o ki netics ( P K) of a si n gle oral d ose of L O X O- 2 9 2 usi n g 
[1 4C]- L O X O- 2 9 2 
 
T o deter mi ne t he w h ole bl o o d a n d plas ma  c o nce ntrati o ns of t otal ra di oacti vit y 
 
T o deter mi ne t he uri nar y a n d fecal rec o ver y of t otal ra di oacti vit y 
 
T o c haracterize a n d i de n tif y meta b olites of [1 4C]- L O X O- 2 9 2 i n plas ma, uri ne, a n d 
feces. 
Sec o n dar y:  
 
T o assess t he safet y a n d t olera bilit y of [ 1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 4 0 μ Ci). 
P art 2:  
Pri mar y:  
 
T o deter mi ne t he a bs ol ute bi oa vaila bilit y of L O X O- 2 9 2 f oll o wi n g a si n gle oral d ose 
of 1 6 0 m g of L O X O- 2 9 2 al o n g wit h a n i ntra ve n o us (I V) d ose of < 1 0 0 μ g of 
[1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci) 
 
T o e val uate t he P K of L O X O- 2 9 2  f oll o wi n g oral a n d I V d osi n g 
 
T o e val uate t he uri nar y e xcreti o n of L O X O- 2 9 2 f oll o wi n g oral d osi n g a n d of 
[1 4C]- L O X O- 2 9 2 f oll o wi n g I V d osi n g 
 
T o e val uate t he fecal rec o ver y of t otal ra di oacti vit y f oll o wi n g I V d osi n g of 
[1 4C]- L O X O- 2 9 2. 
Sec o n dar y:  
 
T o assess t he safet y a n d t olera bilit y of L O X O- 2 9 2. 
Met h o d ol o g y/ St u d y 
Desi g n:  
T his st u d y will be a n o pe n-la bel, 2- part a bs or pti o n, meta b olis m,  e xcreti o n ( A M E) a n d 
a bs ol ute bi oa vaila bilit y st u d y of [ 1 4C]- L O X O- 2 9 2 . S u bj ects i n P art 1 will n ot partici pate 
i n P art 2, n or will s u bj ects i n P art 2 partici pate i n P art 1. P art 1 a n d P art 2 are 
i n de p e n de nt of eac h ot her a n d d o n ot nee d t o be c o n d ucte d i n se q ue ntial or der.  
P art 1 is desi g ne d t o e val uate t he A M E ki netics of L O X O- 2 9 2, t o i de ntif y a n d 
c haracterize meta b olites of L O X O - 2 9 2, a n d t o assess t he safet y a n d t olera bilit y of 
[1 4C]- L O X O- 2 9 2. S u bj ects i n P art 1 will be a d mi nistere d a si n gle oral d ose of 1 6 0 m g of 
[1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 4 0 μ Ci) as a n oral s ol uti o n. I n or der t o c o m plete 
6  s u bj ects, 6 will be e nr olle d ( differe nt s ubj ects fr o m t h ose partici pati n g i n P art 2) , al o n g 
wit h 2  alter nates (t o be d ose d i n t he e ve nt t hat d osi n g is u ns uccessf ul f or a n y of t he 
i nitial 6 s u bj ects). I n t he e ve nt of earl y wit h dra wal of a n y s u bj ects after t he alter nate 
s u bj ects are release d, re place me nt s u bj ects ma y be e nr olle d at t he discreti o n of t he 
S p o ns or.    
P art 2 is desi g ne d t o deter mi ne t he a bs ol ute bi oa vaila bilit y  of L O X O- 2 9 2, t o e val uate t he 
uri n ar y e xcreti o n of L O X O- 2 9 2 a n d [ 1 4C]- L O X O- 2 9 2, t o e val uate t he fecal e xcreti o n of 
[1 4C]- L O X O- 2 9 2, a n d t o assess t he safet y a n d t olera bilit y of L O X O- 2 9 2. S u bj ects i n 
P art  2 will be a d mi nistere d a si n gle oral d ose of 1 6 0 m g of L O X O- 2 9 2 as 2 x 8 0- m g 
ca ps ule s f oll o we d 2 h o urs later b y a si n gle d ose of < 1 0 0 μ g of [ 1 4C]- L O X O- 2 9 2 
(c o ntai ni n g ~ 1 μ Ci) a d mi nistere d as a n I V p us h o ver a p pr o xi matel y 2 mi n utes. I n or der 
t o c o m plete 6 s u bj ects, 6 will be e nr olle d ( differe nt s u bj ects fr o m t h ose partici pati n g i n 
P art 1), al o n g wit h 2 alter nates (t o be d ose d i n t he e ve nt t hat d osi n g is u ns uccessf ul f or 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 2 of 6 0 
a n y of t he i nitial 6 s u bj ects). I n t he e ve nt of earl y wit h dra wal of a n y s u bj ects after t he 
alter nate s u bj ects are release d, re place me nt s u bj ects ma y be e nr olle d at t he discreti o n of 
t he S p o ns or.  
T he star t of t he st u d y is defi ne d as t he earliest date a s u bj ect w h o is e nr olle d i n eit her part 
of t he st u d y  si g ns a n I nf or me d C o nse nt F or m. A s u bj ect w h o c o m pletes s ufficie nt 
L O X O - 2 9 2, [1 4C]- L O X O- 2 9 2 ( P art 2 o nl y), t otal ra di oacti vit y, a n d meta b olite ( P art 1 
o nl y)  sa m pli n g pri or t o Cli nic Disc har ge is c o nsi dere d t o ha ve c o m plete d t he st u d y. T he 
e n d of t he st u d y is defi ne d as t he latest date a s u bj ect recei ves t he Safet y F oll o w- u p Call. 
T he pla n ne d d urati o n of st u d y c o n d uct f or P art  1 is u p t o 5 9 da ys fr o m Scre e ni n g 
t hr o u g h t he Safet y F oll o w- u p Call. T he pla n ne d d urati o n of st u d y c o n d uct f or P art 2 is 
u p t o 4 6 da ys fr o m Scree ni n g t hr o u g h t he Safet y F oll o w- u p Call. 
P art 1:  
After a Scree ni n g peri o d of u p t o 2 8  da ys, s u bj ects will c hec k i n t o t he Cli nical Researc h 
U nit ( C R U) o n Da y - 1 t o c o nfir m eli gi bilit y a n d t o bec o me fa miliar wit h st u d y 
pr oce d ures. O n t he m or ni n g of Da y 1, f oll o wi n g a n o ver ni g ht fast of at least 8  h o urs, 
s u bj ects will recei ve a si n gle oral d ose of 16 0 m g of [ 1 4C]- L O X O- 2 9 2 
(c o ntai ni n g ~ 4 0 μ Ci) a d mi nist ere d as a n oral s ol uti o n. S u bj ects will be c o nfi ne d at t he 
C R U fr o m t he ti me of C hec k -i n u ntil Cli nic Disc har ge ( bet wee n Da ys 8 a n d 2 2). After 
c o m pleti n g disc har ge pr oce d ures, s u bj ects will be disc har ge d fr o m t he C R U as earl y as 
Da y 8 a n d u p t o Da y 2 2 , pr o vi de d rec o ver y of ra di oacti vit y has reac he d t he f oll o wi n g 
t hres h ol d val ues: 
 
≥ 9 0 % of t he ra di oacti ve d ose is rec o vere d, a n d  
 
≤ 1 % of t he ra di oacti ve d ose per da y is rec o vere d i n e xcreta ( uri ne a n d feces) 
f or 3 c o nsec uti ve da ys o n w hi c h a fec al sa m ple is c ollecte d.  
Sa m ple c ollecti o n a n d c o nfi ne me nt will c o nti n ue u ntil disc har ge criteria are met or t he 
ma xi m u m sta y is reac he d, u nl ess ot her wise a g ree d u p o n b y t he S p o ns or a n d I n vesti gat or. 
S u bj ects will recei ve a Safet y F oll o w- u p Call a p pr o xi matel y 7 da ys after Cli nic 
Disc har ge.  
I n t his st u d y, safet y will be m o nit ore d wit h a d verse e ve nt ( A E) i n q uiries, cli nical 
la b orat or y e val uati o ns, vital si g ns meas ure me nts, 1 2-lea d ele ctr ocar di o gra ms ( E C Gs), 
a n d p h ysical e xa mi nati o n s d uri n g t he st u d y.  
Sa m ples f or deter mi nati o n of L O X O -2 9 2 c o nce ntrati o ns i n plas ma, t otal ra di oacti vit y 
c o nce ntrati o ns i n plas ma, w h ole bl o o d, uri ne, a n d feces, a n d f or meta b olite 
pr ofili n g/c haracterizati o n will be o btai ne d t hr o u g h at least 1 6 8 h o urs p ost d ose ( Da y 8), 
a n d p os si bl y u p t o 5 0 4 h o urs p ost d ose ( Da y 2 2). 
P art 2:  
After a Scree ni n g peri o d of u p t o 2 8  da ys, s u bj ects will c hec k i n t o t he C R U o n Da y - 1 t o 
c o nfir m eli gi bilit y a n d t o bec o me fa miliar wit h st u d y pr oce d ures. O n t he m or ni n g of 
Da y  1, f oll o wi n g a n o ver ni g ht fast of at least 8 h o urs, s u bj ects will recei ve a si n gle oral 
d ose of 1 6 0 m g of L O X O- 2 9 2 as 2 x 8 0- m g ca ps ules f oll o we d 2 h o urs later b y a si n gle 
d ose of < 1 0 0 μ g of [ 1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci) a d mi nistere d as a n I V p us h 
o ver a p pr o xi matel y 2  mi n utes. S u bj ects will be c o nfi ne d at t he C R U fr o m t he ti me of 
C hec k -i n u ntil Da y 9 a n d will be disc har ge d fr o m t he C R U after c o m pleti n g all disc har ge 
pr oce d ures. S u bj ects will recei ve a Safet y F oll o w- u p Call a p pr o xi matel y 7 da ys after 
Cli nic Disc har ge.  
As i n P art 1, safet y will be m o nit ore d wit h A E i n q uiries, cli nical la b orat or y e val uati o ns, 
vital si g ns meas ure me nts, 1 2 -l ea d E C Gs, a n d p h ysical e xa mi nati o ns d uri n g t he st u d y.  
Sa m ples f or deter mi nati o n of plas ma a n d uri ne c o nce ntrati o ns of L O X O - 2 9 2 a n d 
[1 4C]- L O X O- 2 9 2 a n d f or deter mi nati o n of t otal ra di oacti vit y c o nce ntrati o ns i n uri ne a n d 
feces will b e o btai ne d t hr o u g h 1 9 2 h o urs p ost d ose ( Da y 9). 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 3 of 6 0 
N u m ber of S u bj ects: 
P art 1:  I n or der t o c o m plete 6 s u bj ects, 6 w ill be e nr olle d ( differe nt s u bj ects fr o m t h ose 
partici pati n g i n P art 2) , al o n g wit h 2 alter nates (t o be d ose d i n t he e ve nt t hat d osi n g is 
u ns uccessf ul f or  a n y of t he i nitial 6 s u bj ects). 
P art 2:  I n or der t o c o m plete 6 s u bj ects, 6 will be e nr olle d ( differe nt s u bj ects fr o m t h ose 
partici pati n g i n P art 1) , al o n g wit h 2 alter nates (t o be d ose d i n t he e ve nt t hat d osi n g is 
u ns uccessf ul f or a n y of t he i nitial 6  s u bj ects). 
I n P arts 1 a n d 2, i n t he e ve nt of earl y wit hdra wal of a n y s u bj ects after t he alter nate 
s u bj ects are release d, re place me nt s u bj ects may be e nr olle d at t he discreti o n of t he 
S p o ns or. 
Dia g n osis a n d Mai n 
Criteria f or I ncl usi o n: 
Healt h y male s u bj ects bet wee n 1 8 a n d 5 5 years of a ge, i ncl usi ve, wit h a b o d y mass i n de x 
of 1 8. 5 t o 3 2. 0 k g/ m 2, i ncl usi ve. 
T est Pr o d uct(s), D ose, 
a n d M o de of 
A d mi nistrati o n:  
P art 1:  S u bj ects will recei ve a si n gle oral d ose of 1 6 0 m g of [ 1 4C]- L O X O- 2 9 2 
(c o ntai ni n g ~ 4 0 μ Ci) as a n oral s ol uti o n after at least a n 8- h o ur fast. 
P art 2:   S u bj ects will recei ve a si n gle oral d ose of 1 6 0 m g of L O X O- 2 9 2 as 2 x 8 0-m g 
ca ps ule s after at least a n 8- h o ur fast f oll o we d 2 h o urs later b y a si n gle d ose of < 1 0 0 μ g 
of [1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci) a d mi nistere d as a n I V p us h o ver a p pr o xi matel y 
2 mi n utes.   
D urati o n of Treat me nt: 
Pla n ne d E nr oll me nt/ Scree ni n g D urati o n:  P art 1; a p pr o xi mat el y 2 8 da ys ( Da ys - 2 9 t o - 2). 
P art 2; a p pr o xi matel y 2 8 da ys ( Da ys - 2 9 t o - 2).   
Le n gt h of C o nfi ne me nt:  Part 1; u p t o 2 3 da ys ( Da ys - 1 t o 2 2). Part 2; 1 0 da ys ( Da ys - 1 
t o 9).   
Pla n ne d St u d y C o n d uct  D urati o n: P art 1; u p t o 5 9 da ys ( Scre e ni n g t o Safet y F oll o w-u p 
Call). P art 2; u p t o 4 6 da ys ( S cr ee ni n g t o Safet y F oll o w- u p Call). 
Criteria f or E val uati o n: 
Safet y 
Safet y will be m o nit ore d wit h A E i n q uiries, cli nical la b orat or y e val uati o ns, vital si g ns 
meas ure me nts, E C Gs, a n d p h ysical e xa mi nati o ns. 
Criteria f or E val uati o n: 
P har mac o ki netics  
P art 1: 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d base d o n t he plas ma 
c o nce ntrati o ns of L O X O- 2 9 2 a n d o n plas ma a n d w h ole bl o o d c o nce ntrati o ns of t otal 
ra di oacti vit y: ma xi m u m o bser ve d c o nce ntrati o n ( Cma x ), ti me t o ma xi m u m o bser ve d 
c o nce ntrati o n ( T ma x ), area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me 0 t o t he 
ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U Cl ast), A U C e xtra p olate d t o i nfi nit y 
( A U C0- ), a p pare nt ter mi nal eli mi nati o n rate c o nsta nt (
z), a p pare nt ter mi nal eli mi nati o n 
half -life (t1/ 2), a p pare nt s yste mic cleara nce ( C L/ F; f or L O X O- 2 9 2 o nl y), a p pare nt v ol u me 
of distri b uti o n  d uri n g t he ter mi nal p hase ( Vz/ F; f or L O X O- 2 9 2 o nl y), A U C0- ∞ of t otal 
ra di oacti vit y i n w h ole bl o o d/ A U C 0- ∞ of t otal ra di oacti vit y i n plas ma ( Bl o o d/ Plas ma A U C 
Rati o) , a n d A U C0- ∞ of L O X O- 2 9 2 i n plas ma/ A U C0- ∞ of t otal ra di oacti vit y i n plas ma 
( Plas ma L O X O- 2 9 2/ T otal Ra di oacti vit y A U C Rati o). 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d base d o n t he uri ne 
c o nce ntrati o ns of  t otal ra di oacti vit y: a m o u nt e xcrete d i n uri ne per sa m pli n g i nter val 
( Ae u), c u m ulati ve a m o u nt e xcr ete d i n uri ne ( C u m Ae u), perce nta ge of d ose e xcrete d i n 
uri ne per sa m pli n g i nte r val ( %fe u), a n d c u m ulati ve perce nta ge of d ose e xcrete d i n uri ne 
( C u m %fe u). 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d base d o n t he fecal 
c o nce ntrati o ns of  t otal ra di oacti vit y: a m o u nt e xcrete d i n feces per sa m pli n g i nter val 
( Aef), c u m ulati ve a m o u nt e xcr ete d i n feces ( C u m Aef), perce nta ge of d ose e xcrete d i n 
feces per sa m pli n g i nter val ( %fef), a n d c u m ulati ve perce nta ge of d ose e xcrete d i n feces 
( C u m %fef). 
P art 2:  
F oll o wi n g oral d osi n g of L O X O - 2 9 2, t he f oll o wi n g P K para meters will be calc ulate d, 
w he ne ver p ossi ble, base d o n t he plas ma c o nce ntrati o ns  of L O X O- 2 9 2:  Cma x , Tma x , 
A U C last, A U C0- , z, t1/ 2, a bs ol ute bi oa vaila bilit y ( F), C L/ F, a n d Vz/ F. 
F oll o wi n g I V d osi n g of [ 1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci), t he f oll o wi n g P K 
para meters will be calc ulate d, w he ne ver p ossi ble,  base d o n t he plas ma c o nce ntrati o ns of 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 4 of 6 0 
[1 4C]- L O X O- 2 9 2:  C ma x , Tma x , A U Clast, A U C0- , z, t1/ 2, s yste mic cleara nce ( C L), v ol u me 
of distri b uti o n d uri n g t he ter mi nal p hase ( V z), a n d v ol u me of distri b uti o n at stea d y state 
( Vss).  
T he f oll o wi n g P K para meters will be calc ulate d, w he ne ver p ossi ble, f or eac h s u bj ect 
base d o n t he uri ne c o nce ntrati o ns of L O X O - 2 9 2, [1 4C]- L O X O- 2 9 2, a n d t otal 
ra di oacti vit y:  Ae u, C u m Ae u, r e nal cleara nce ( C LR ; L O X O- 2 9 2 a n d [1 4C]- L O X O- 2 9 2 
o nl y ), %fe u, a n d C u m %fe u. 
T he f oll o wi n g P K para meters will be calc ulate d, w he ne ver p ossi ble, f or eac h s u bj ect 
base d o n t he fecal c o nce ntrati o ns of t otal ra di oacti vit y:  A ef, C u m Aef, %fef, a n d C u m 
% fef. 
I n P arts 1 a n d 2, t he P K para meters f or rele va nt meta b olites of L O X O- 2 9 2 ma y be 
calc ulate d, as dee me d a p pr o priate, base d o n plas ma, uri ne, a n d fecal c o nce ntrati o n 
le vels. 
Sa m ple Size: 
T he sa m ple sizes c h ose n f or Parts 1 a n d 2 of t his st u d y were base d o n prece de nt set b y 
ot her A M E a n d a bs ol ute bi oa vaila bilit y s t u dies of si milar nat ure a n d were n ot base d o n 
p o wer calc ulati o ns. 
Statistical Met h o ds: 
F or P arts 1 a n d 2, d escri pti ve statistics ( n u m ber of o bser vati o ns, arit h metic mea n, 
sta n dar d de viatio n, me dia n, mi ni m u m, ma xi m u m, ge o metric mea n, a n d ge o metric 
c o efficie nt of variati o n) will be calc ulate d f or t he P K para meters. N o f or mal statistical 
P K  a nal yses are pla n ne d. F or P arts 1 a n d 2, descri pti ve statistics will be calc ulate d o n t he 
safet y para meters. N o f or mal statistical safet y a nal yses are pla n ne d. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 5 of 6 0 
2  I N T R O D U C TI O Na 
Please refer t o t he I n v esti gat or’s Br oc h ure  (I B)1 f or detaile d i nf or mati o n c o ncer ni n g t he a v aila ble 
p har mac ol o g y, t o xic ol o g y, dr u g m eta b olis m, cli ni cal st u dies, a n d a d v erse e ve nt ( A E) pr ofile of 
t he i n vesti gati o nal me dici nal pr o d uct. 
2. 1  B ac k gr o u n d 
L O X O- 2 9 2 is a s mall m olec ule sele cti ve i n hi bit or of t he rearra n ge d d uri n g tra nsfecti o n ( R E T) 
rece pt or t yr osi ne ki nase desi g ne d t o c o m petiti vel y bl oc k t he a de n osi ne tri p h os p hate bi n di n g site 
of t he ki nase. L O X O- 2 9 2 was at least 2 5 0-f ol d m ore selecti ve f or R E T t ha n f or 9 8 % of 3 2 9 ot her 
ki nases teste d i n a lar ge i n vitr o scree n. C o nsiste nt wit h s uc h a hi g h d e gree of selecti vit y, 
L O X O- 2 9 2 ca use d si g nifica nt i n hi biti o n of cell gr o wt h i n h u ma n ca ncer cell li nes t hat har b ore d 
e n d o ge n o us, cli nicall y rele va nt R E T ge ne alterati o ns b ut was m uc h less i n hi bit or y a gai nst h u ma n 
ca ncer cell li nes wit h o ut R E T alterati o ns. P o te nt a n d selecti ve i n hi biti o n of R E T ma y pr o vi d e 
cli nical be nefit t o s u bjects wit h mali g na ncies d u e t o o nc o ge nic alterati o ns i n R E T or wit h ot her 
mec ha nis ms of i ncrease d R E T acti vit y. 
2. 2  S u m m ar y of N o ncli nic al St u dies 
P har mac ol o g y safet y of L O X O- 2 9 2 w as e val u ate d i n a G o o d La b orat or y Practice ( G L P) i n vitr o 
assa y f or h u ma n et her-a- g o- g o relate d ge ne ( h E R G) acti vit y, i n a G L P i n vi v o st u d y i n c o nsci o us 
tele metr y-i nstr u me nte d mi ni pi gs, a n d i n a G L P 2 8- da y re p eat- d os e t o xic ol o g y st u d y ( wit h 
electr ocar di o gra m [ E C G] m o nit ori n g) i n mi ni pi gs. L O X O- 2 9 2 ha d a half m a xi mal i n hi bit or y 
c o nce ntr ati o n val ue (I C 5 0) of 1. 1 μ M i n t he G L P h E R G assa y, w hic h is a p pr o xi matel y 1 7 - a n d 
9-f ol d hi g h er t ha n t he pre dicte d ma xi m u m u n b o u n d c o nce ntr ati o n at t he cli nical d ose of 8 0 m g
a n d 1 6 0 m g, res pecti vel y, t wice dail y ( BI D). T h ere were n o L O X O- 2 9 2-rel ate d c ha n ges i n a n y
car di o vas c ular e n d p oi nts i ncl u di n g Q T i nter val c orrecte d f or heart rat e ( Q T c) at d oses u p t o
1 2 m g/ k g i n t he safet y p h ar mac ol o g y car di o vas c u lar st u d y i n c o nsci o us mi ni pi gs. F urt h er m ore,
t here were n o L O X O- 2 9 2-relate d E C G c ha n ges i n t he 2 8- da y re peat- d os e t o xicit y st u d y i n
mi ni pi gs at t he hi g h d os e of 1 2 m g/ k g. T o get h er, t hese data i n dicate t hat L O X O- 2 9 2 has a l o w
ris k of i n d uci n g d ela ye d ve ntric ular re p olarizati o n, pr ol o n g ati o n of t he Q Tc i nter val, a n d
u nsta ble arr h yt h mias.
A d mi nistrati o n of L O X O- 2 9 2 at si n gle d os es u p t o 4 5 m g/ k g i n male rats h a d n o effect o n 
res pirat or y f u ncti o n. 
a I nf or mati o n s u p plie d b y t he S p o ns or. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 6 of 6 0 
P ote ntial effects of L O X O- 2 9 2 o n t he ce ntral ner v o us s yste m were e v al uate d as part of t he G L P 
2 8- da y re p eat- d os e st u d y i n rats, i n f u ncti o nal o bser vati o nal batter y t ests a n d l oc o m ot or acti vit y
assess me nts. Fi n di n gs w ere li mite d t o a ni mals recei vi n g t he hi g h d ose o n Wee k 4 of t he d osi n g
p hase, a n d w ere attri b ute d t o p o or ge neral b o d y c o n diti o n a n d wei g ht c ha n ges ass ociate d wit h
L O X O- 2 9 2 a d mi nistrati o n rat her t ha n s p ecific n e ur ol o gical effects. A d diti o nall y, n o micr osc o pic
a b n or malities i n ne ur o nal tiss ues were f o u n d.
I n t o xic ol o g y st u dies of L O X O- 2 9 2 t hat were c o n d ucte d i n t he rat a n d mi ni pi g, t he pri mar y 
pat h ol o gic fi n di n gs f or b ot h s pecies were i n t he t o n g ue, p a ncreas, b o n e marr o w, a n d l y m p h oi d 
tiss ues; w hile t he gastr oi ntesti nal ( GI) tract a n d o varies were tar get tiss ues i n mi ni pi g. Ot her 
tar get tiss ues i de ntifie d i n t he rat i ncl u de d: m ulti-tiss ue mi neralizati o n, p h yseal cartila ge, i ncis or 
teet h, l u n g, Br u n ner’s gla n d, a n d p ossi bl y li ver. Assess me nt of d oses ass oci ate d wit h 
m ori b u n dit y/ d eat h r e veal e d a stee p d os e res p o ns e c ur ve f or b ot h s pecies. 
L O X O- 2 9 2 w as n ot m uta ge ni c i n t he G L P b acterial m utati o n assa y. L O X O- 2 9 2 was n ot f o u n d t o 
be p h ot ot o xic w he n e val uate d i n a n i n vitr o ne utr al re d u pta ke p h ot ot o xicit y assa y. 
Base d o n precli nic al p har mac ol o g y e x peri me nts wit h  h u ma n ca ncer cells i n vitr o a n d i n m uri ne 
x e n o graft m o dels, mea ni n gf ul i n hi biti o n of R E T i n t u m ors is e x pecte d t o be ac hie va ble wit h oral 
d osi n g re gi me ns ≥ 4 0 m g/ da y. 
Base d o n t h e n o ncli nical pr ofile, i ncl u di n g res ult s fr o m a ni mal t o xic ol o g y st u dies, t he oretical 
ris ks of h u ma n e x p os ure t o L O X O- 2 9 2 i ncl u de t h e f oll o wi n g: l oss of a p p etite, decrease i n b o d y 
wei g ht, i ncreas e i n t otal w hite bl o o d cells, ne utr o p hils, a n d m o n oc ytes, d ecreas e i n al b u mi n, 
i ncreas e i n gl o b uli n, de crease d al b u mi n: gl o b uli n rati o, decrease i n t otal pr otei n, i ncreas e d b o d y 
te m perat ur e, let har g y, i n creas e i n c h olester ol a n d tri gl yceri des, i ncrease i n p h os p h or us, c ha n ges 
i n taste se nsati o n a n d/ or de vel o p me nt of xer ost omia, GI s y m pt o ms/si g ns: n a usea, v o miti n g, 
l o ose st o ols, a b d o mi nal disc o mf ort, decreases i n r e d cell mass (re d bl o o d cells, he m o gl o bi n, 
he mat ocrit) a n d retic ul oc yt es, decrease i n platel ets, i ncreas es i n li ver f u ncti o n tests (al kali ne 
p h os p hatase [ A L P], as partate a mi n otra nsferas e [ A S T], a n d ala ni ne a mi n otra nsferase [ A L T]). 
L O X O- 2 9 2 has b ee n gi v e n orall y a n d i ntra v e n o usl y (I V) t o mice, rats, d o gs, mi ni pi gs, a n d 
m o n ke y. L O X O- 2 9 2 w as a bs or be d a n d bi o a vaila ble i n all s pecies teste d. S ol u bilit y st u dies a n d 
p har mac o ki netic ( P K) st u dies s u g gest t hat t he P K e x p os ure of L O X O- 2 9 2 ma y b e re d u ce d b y 
pr ot o n p u m p i n hi bit ors a n d ot her a ntaci ds. L O X O - 2 9 2 a p pears t o be meta b olize d pri maril y b y 
c yt o c hr o me P 4 5 0 ( C Y P) 3 A 4, b ut at t hera pe uticall y rele va nt e x p os ures, it is n ot a ntici pate d t o 
i n hi bit or i n d uce dr u g- meta b olizi n g e nz y mes. L O X O-2 9 2 is als o a s u bstrat e f or breast ca ncer 
resista nce pr otei n tra ns p orter. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 7 of 6 0 
 
Refer t o t he I B 1 f or det aile d bac k gr o u n d i nf or mati o n o n L O X O- 2 9 2. 
2. 3  S u m m ar y of Cli nic al St u dies 
L O X O- 2 9 2 is c urre ntl y b ei n g st u die d i n a n o n g oi n g gl o bal P hase 1 first-i n- h u ma n St u d y 
L O X O- R E T- 1 7 0 0 1 i n patie nts wit h a d va nce d s oli d t u m ors i ncl u di n g R E T f usi o n- p ositi ve 
n o n-s mall cell l u n g ca ncer, R E T- m uta nt me d ullar y t h yr oi d ca ncer, a n d ot h er t u m ors wit h 
i ncreas e d R E T acti vit y. T he starti n g d os e of L O X O- 2 9 2 was  
o nce dail y. As of a 
J a n uar y 5, 2 0 1 8 dat a c ut- off date, safet y dat a were a vaila ble fr o m 5 7 patie nts wit h 1 6 0 m g BI D 
as t he hi g h est d ose a d mi nistere d. As of t he J a n uar y 5, 2 0 1 8, n o d ose-li miti n g t o xicities ( D L Ts) 
ha ve bee n re p orte d. Treat me nt-e mer ge nt A Es ( T E A Es) occ urri n g i n ≥ 1 0 % of patie nts were: 
fati g u e ( 1 6 %), diarr h ea ( 1 6 %), a n d d ys p nea ( 1 2 %). T he maj orit y of T E A Es were Gra d es 1 or 2 
a n d n o ≥ Gra d e 3 T E A Es were relate d t o st u d y dr u g. T hree s u bjects ha ve di e d d uri n g t he st u d y, 
a n d n o deat hs ha v e bee n attri b ute d t o st u d y dr u g. 
L o x o O nc ol o g y has als o i nitiate d 3 I nstit uti o nal Re vie w B o ar d (I R B)-a p pr o ve d, F o o d a n d Dr u g 
A d mi nistrati o n ( F D A)-all o we d si n gle patie nt pr ot oc ols ( L O X O- R E T- 1 7 0 0 2, L O X O- R E T-
1 7 0 0 3, a n d L O X O- R E T- 1 7 0 0 4) t o pr o vi de access t o L O X O- 2 9 2 f or patie nts wit h cli nical nee d 
n ot meeti n g eli gi bilit y criteria f or t he o n g oi n g cli nical st u dies. As of J a n uar y 5, 2 0 1 8, n o T E A Es 
ha ve bee n attri b ute d t o st u d y dr u g f or t h ese p atie nts. 
As of Fe br uar y 9, 2 0 1 8, P K data were a vaila bl e fr o m patie nts (fr o m t he L O X O- R E T- 1 7 0 0 1 
st u d y). L O X O- 2 9 2 is a bs or be d aft er oral a d mi nistrati o n wit h a ti me t o ma xi m u m o bser ve d 
c o nce ntr ati o n ( T ma x ) of a p pr o xi matel y 2 h o urs. Alt h o u g h t he P K sa m pli n g of L O X O- 2 9 2 was n ot 
l o n g e n o u g h t o a d e q uatel y c h aracterize area u n d er t he c o nce ntr ati o n-ti me c ur ve ( A U C) fr o m 
ti me 0 t o t he ti me of t he last q ua ntifia ble c o n ce ntr ati o n ( A U C0- ∞), t he half-life was esti mate d t o 
be at least 1 2 h o urs or l o n ger. L o w c o n ce ntr at i o ns of L O X O- 2 9 2 were rec o vere d as u n c ha n ge d 
dr u g i n uri n e i n dicati n g t hat t he ki d ne y c o ntri b utes t o o verall cleara nce.  
Refer t o t he I B 1 f or a d diti o nal detaile d bac k gr o u n d i nf or mati o n o n L O X O- 2 9 2. 
2. 4  St u d y R ati o n ale 
I n n o n cli nical st u dies, t he meta b olic pr ofile of L OX O- 2 9 2 has bee n st u die d i n li ver micr os o mes 
a n d he pat oc yt es fr o m male C D- 1 mice, male S pra g ue- Da wle y rats, male bea gl e d o gs, mal e 
G ötti n ge n mi ni pi gs, a n d h u ma ns. Its e x creti o n ha s bee n st u die d i n mi ni pi gs. H o we ver, e x creti o n 
pat h wa ys i n h u ma ns ha v e n ot bee n f ull y e v al uate d. I n n o n cli nical P K st u dies, L O X O- 2 9 2 w as 
orall y bi oa v aila ble i n t he m o use, rat, d o g, m o n ke y,  a n d mi ni pi g. I n cli nical st u dies, preli mi nar y 
P K data ha ve s h o w n t h at L O X O- 2 9 2 is ra pi dl y a bs or be d aft er oral a d mi nistrati o n. H o we ver, its 
a bs ol ute bi oa vaila bilit y i n h u ma ns has n ot b ee n d eter mi ne d. T he prese nt st u d y will pr o vi de 
C CI

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 8 of 6 0 
 
a d diti o nal data a b o ut t he e x creti o n pr ofile a n d a bs o l ute bi oa vaila bilit y of L O X O- 2 9 2 i n healt h y 
male s u bjects. 
Part 1 is a sta n dar d mass bala nce st u d y t o deter mi ne t he a bs or pti o n, meta b olis m, a n d e x creti o n 
( A M E) ki netics of L O X O- 2 9 2 a n d t o deter mi ne an d c haracterize meta b olit es prese nt i n plas ma, 
uri ne, a n d feces i n healt h y male s u bjects f oll o wi n g a si n gle oral d ose of 1 6 0 m g of 
[1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 4 0 μ Ci) a d mi nistere d as a n oral s ol uti o n. Bl o o d, plas ma, uri ne, 
a n d feces sa m pli n g will be c o n d ucte d u ntil at least Da y 8 a n d p ote ntiall y u ntil Da y 2 2. T h e 
d urati o n of t he st u d y is c o nsi dere d a d e q uate t o ac hie ve st u d y o bjecti ves base d o n t he k n o w n 
cli nical P K of L O X O- 2 9 2. 
Part 2 uses a n I V micr otracer m et h o d t o deter mi ne t he a bs ol ute bi oa vaila bilit y of L O X O- 2 9 2 
f oll o wi n g a si n gle oral d ose of 1 6 0 m g of L O X O- 2 9 2 a n d a n I V micr otracer d ose of < 1 0 0 μ g of 
[1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci). T he I V mi cr otracer met h o d all o ws f or si m ulta ne o us oral 
a n d I V d osi n g i n t he sa m e s u bjects, w hic h is e x pecte d t o res ult i n less varia bilit y i n a bs ol ute 
bi oa vaila bilit y esti mates. A bs ol ute bi oa vaila bilit y will be deter mi ne d b y c o m pari n g t he pl as ma 
e x p os ure of L O X O- 2 9 2 f oll o wi n g oral d osi n g wit h t he plas ma e x p os ure of [ 1 4C]- L O X O- 2 9 2 
f oll o wi n g I V d osi n g. T h e I V d ose of [1 4C]- L O X O- 2 9 2 will be a d mi nistere d s o t hat pea k plas ma 
c o nce ntr ati o ns of [ 1 4C]- L O X O- 2 9 2 occ ur a p pr o xi matel y at t he T ma x  of L O X O- 2 9 2 f oll o wi n g oral 
d osi n g. Beca use it i ncl u des uri ne a n d feces s a m pli n g, Part 2 will als o pr o vi de a d diti o nal data 
a b o ut t he e x creti o n pr ofil e of L O X O- 2 9 2. A nal ysis of uri ne c o n ce ntrati o ns of L O X O- 2 9 2, 
[1 4C]- L O X O- 2 9 2, a n d t otal ra di oacti vit y will all o w f or t he det er mi nati o n of re nal cleara nce 
( C LR ) a n d t he p erce nta ge of L O X O- 2 9 2 e x crete d u nc ha n ge d i n t he uri n e. A nal ysis of t otal 
ra di oacti vit y i n fecal sa m ples f oll o wi n g I V d osi n g will pr o vi de i nf or mati o n a b o ut t he e xte nt of 
fecal e x creti o n of L O X O- 2 9 2. 
Fe male s u bjects will be e x cl u de d t o ali g n wit h re g ulat or y g ui da nce. T h e “as l o w as (is) 
reas o na bl y ac hie v a ble” ( A L A R A) pri nci ple prescri be d b y b ot h t he F D A a n d N uclear R e g ulat or y 
C o m missi o n ( 2 0 0 7) rec o m me n ds t hat ra diati o n e x p os ure t o s u bjects s h o ul d be ke pt A L A R A; 
t heref ore, if n o s pecific reas o n e xists t o i ncl u de fe males (ie, n o a v aila ble data s u g gest 
meta b olis m of t he st u d y dr u g is differe nt i n fe mal es vers us males), t h e n t he ra diati o n e x p os ure t o 
fe male s u bjects s h o ul d be ke pt at zer o p ote ntial b y n ot i ncl u di n g fe mal es i n ra di oacti vit y st u dies 
a n d o nl y e nr olli n g a n d d osi n g male s u bjects. 
2. 5  D ose R ati o n ale 
A n oral d ose has b ee n sel ecte d f or t his st u d y beca use t his is t he i nte n de d cli nical r o ute of 
a d mi nistrati o n. T he n o nra di ola bele d d ose of 1 6 0 m g of L O X O- 2 9 2 was selecte d base d o n st u d y 
o bjecti ves, cli nical st u d y res ults, a n d safet y c o nsi derati o ns. T he 1 6 0- m g d os e is e x pecte d t o 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 1 9 of 6 0 
 
e ns ure s ufficie nt q ua ntifi a ble plas ma c o n ce ntrat i o ns of L O X O- 2 9 2 f or deter mi nati o n of s yste mic 
P K. I n a P hase 1 cli nical st u d y ( L O X O- R E T- 1 7 0 0 1) , 1 6 0 m g of L O X O- 2 9 2 d ose d BI D was well 
t olerate d a n d n o D L Ts w ere det er mi ne d; t heref ore, a si n gle 1 6 0- m g d os e is e x pecte d t o be well 
t olerate d. I n s u m mar y, it is e x pecte d t hat a 1 6 0- m g d ose will all o w f or ac hi e ve me nt of t he st u d y 
o bjecti ves wit h mi ni mal ris k t o s u bjects. 
T he pla n ne d ra di oacti ve d ose of ~ 4 0 μ Ci ( wit h a n all o wa ble ma xi m u m of 4 5 μ Ci) of 
[1 4C]- L O X O- 2 9 2 i n Part 1 is e x pecte d t o pr o vi de a de q uate l e vels of ra di oacti vit y t o ac hie ve t he 
st u d y o bjecti ves w hile mi ni mizi n g t he ris k of e xcessi ve ra diati o n e x p os ure t o healt h y s u bjects. A 
q ua ntitati ve w h ole b o d y a ut ora di o gra p h y st u d y i n male L o n g- E va ns rats i n dicate d t hat 
a d mi nistrati o n of 4 0 μ Ci will res ult i n a n o verall h u ma n male w h ole- b o d y e x p os ure of 
a p pr o xi matel y 3 2 2 mre m, w hic h is well bel o w t he F D A-all o wa ble e x p os ure li mit of 3 0 0 0 mre m 
f or si n gle- d ose is ot o pe st u dies i n h u ma ns, acc or din g t o t he U nite d States ( U S) C o de of Fe deral 
Re g ulati o ns ( C F R) g o v er ni n g Pr otecti o n of H u m a n S u bjects, Ra di oacti ve Dr u gs f or Cert ai n 
Researc h Uses ( 2 1 C F R 3 6 1. 1). It is e x pecte d t h at t he pla n ne d ra di o acti ve d ose will pr o vi de a 
s ufficie nt ra di o acti ve si g nal f or t otal ra di oacti vit y c o u nti n g a n d q u a ntitati ve ra di o pr ofili n g of 
[1 4C]- L O X O- 2 9 2 i n bl o o d, plas ma, a n d e x creta ( uri ne a n d feces) wit h mi ni mal ra diati o n ris k t o 
s u bjects. 
T he ra di oa cti ve d ose of ~ 1 μ Ci of [ 1 4C]- L O X O- 2 9 2 i n Part 2 is o nl y a b o ut 1 % of t he ra di o acti ve 
d ose pla n ne d f or Part 1 a n d will prese nt mi ni mal ra diati o n ris k t o healt h y s u bjects. T he l o w 
le vels of ra di oa cti vit y pla n ne d f or Part 2 will necessitate t he use of accel erat or mass 
s pectr o metr y ( A M S) as a hi g hl y se nsiti ve a nal ytical tec h ni q ue f or q ua ntif yi n g t he ra di oacti vit y i n 
plas ma, uri ne, a n d fecal sa m ples. T he ra di o acti ve d ose of ~ 1 μ Ci t o get her wit h t he use of A M S 
f or a nal ysis of ra di oacti vit y is e x pecte d t o all o w f or c o m pleti o n of st u d y o bjecti ves of Part 2 wit h 
mi ni mal ra diati o n e x p os ure ris k t o healt h y s u bjects. 
3  S T U D Y O B J E C TI V E S 
Part 1: 
T he pri mar y o bje cti ves of Part 1 of t his st u d y are: 
 T o deter mi ne mass bal a n ce a n d r o ut es of eli mi nati o n of [1 4C]- L O X O- 2 9 2 f oll o wi n g oral 
a d mi nistrati o n of a si n gle 1 6 0- m g ( ~ 4 0 μ Ci) ra di ola bele d d ose of L O X O- 2 9 2 i n healt h y 
male s u bjects 
 T o assess t he P K of a si n gle d ose of L O X O- 2 9 2 usi n g [ 1 4C]- L O X O- 2 9 2 
 T o deter mi ne t he w h ol e bl o o d a n d plas ma c o nce ntrati o ns of t otal ra di oacti vit y 
 T o deter mi ne t he uri n ar y a n d fecal rec o ver y of t otal ra di oacti vit y 
 T o c haracteriz e a n d i d e ntif y meta b olites of [ 1 4C]- L O X O- 2 9 2 i n plas ma, uri ne, a n d feces. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 0 of 6 0 
 
T he sec o n d ar y o bjecti ve of Part 1 of t his st u d y is: 
 T o assess t he safet y a n d t olera bilit y of [ 1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 4 0 μ Ci). 
 
Part 2: 
T he pri mar y o bje cti ves of Part 2 of t his st u d y are: 
 T o deter mi ne t he a bs ol ute bi oa vaila bilit y of L O X O- 2 9 2 f oll o wi n g a si n gle oral d ose of 
1 6 0 m g of L O X O- 2 9 2 al o n g wit h a n I V d ose of < 1 0 0 μ g of [ 1 4C]- L O X O- 2 9 2 
(c o ntai ni n g ~ 1 μ Ci) 
 T o e val uate t he P K of L O X O- 2 9 2 f oll o wi n g oral a n d I V d osi n g 
 T o e val uate t he uri nar y e x creti o n of L O X O- 2 9 2 f oll o wi n g oral d osi n g a n d of 
[1 4C]- L O X O- 2 9 2 f oll o wi n g I V d osi n g 
 T o e val uate t he fecal rec o ver y of t otal ra di o acti vit y f oll o wi n g I V d osi n g of 
[1 4C]- L O X O- 2 9 2. 
 
T he sec o n d ar y o bjecti ve of Part 2 of t his st u d y is: 
 T o assess t he safet y a n d t olera bilit y of L O X O- 2 9 2. 
4  I N V E S TI G A TI O N A L P L A N 
4. 1  St u d y Desi g n 
T his st u d y will be a n o pe n-la bel, 2- part A M E a n d a bs ol ute bi oa vaila bilit y st u d y of 
[1 4C]- L O X O- 2 9 2. S u bje cts i n Part 1 will n ot partic i pate i n Part 2, n or will s u bjects i n Part 2 
partici pate i n Part 1. Part 1 a n d Part 2 are i n de pe n d e nt of eac h ot her a n d d o n ot nee d t o be 
c o n d ucte d i n se q ue ntial or der. 
Part 1 is desi g ne d t o e v al uate t he A M E ki netics of L O X O- 2 9 2, t o i de ntif y a n d c haracterize 
meta b olites of L O X O- 2 9 2, a n d t o assess t he safet y a n d t olera bilit y of [1 4C]- L O X O- 2 9 2. S u bjects 
i n Part 1 will be a d mi nistere d a si n gle oral d ose of 1 6 0 m g of [1 4C]- L O X O- 2 9 2 (c o ntai ni n g 
~ 4 0 μ Ci) as a n oral s ol uti o n. I n or der t o c o m plete 6 s u bjects, 6 will be e nr olle d ( differe nt 
s u bjects fr o m t h ose parti ci pati n g i n Part 2), al o n g wit h 2 alter nates (t o be d ose d i n t he e ve nt t hat 
d osi n g is u ns uccessf ul f or a n y of t he i nitial 6 s u bjects). I n t he e ve nt of earl y wit h dra wal of a n y 
s u bjects after t h e alter nate s u bjects are rel eased, re place me nt s u bjects ma y be e nr olle d at t he 
discreti o n of t he S p o ns or. 
Part 2 is desi g ne d t o det er mi ne t he a bs ol ute bi oa v aila bilit y of L O X O- 2 9 2, t o e val uate t he uri n ar y 
e x creti o n of L O X O- 2 9 2 a n d [ 1 4C]- L O X O- 2 9 2, t o e val uate t he fecal e xcreti o n of 
[1 4C]- L O X O- 2 9 2, a n d t o assess t he safet y a n d t olera bilit y of L O X O- 2 9 2. S u bjects i n Part 2 will 
be a d mi nistere d a si n gle oral d ose of 1 6 0 m g  of L O X O- 2 9 2 as 2 x 8 0- m g ca ps ules f oll o we d 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 1 of 6 0 
 
2 h o urs later b y a si n gle d ose of < 1 0 0 μ g of [ 1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci) a d mi nistere d 
as a n I V p us h o v er a p pr o xi matel y 2 mi n utes. I n or der t o c o m plete 6 s u bjec ts, 6 will be e nr olle d 
( differe nt s u bjects fr o m t h ose partici pati n g i n Part 1), al o n g wit h 2 alter nat es (t o be d ose d i n t he 
e ve nt t hat d osi n g is u ns u ccessf ul f or a n y of t h e i nitial 6 s u bjects). I n t he e v e nt of earl y 
wit h dra wal of a n y s u bjects after t he alter nate s u bj ects are release d, re place me nt s u bjects ma y b e 
e nr olle d at t he discreti o n of t he S p o ns or. 
T he start of t he st u d y is d efi ne d as t he earliest d ate  a s u bject w h o is e nr olle d i n eit her part of t he 
st u d y si g ns a n I nf or me d C o nse nt F or m (I C F). A s u bject w h o c o m pletes s ufficie nt L O X O- 2 9 2, 
[1 4C]- L O X O- 2 9 2 ( Part 2 o nl y), t otal ra di oacti vit y, a n d meta b olite ( Part 1 o nl y) sa m pli n g pri or t o 
Cli nic Disc har ge is c o nsi dere d t o ha v e c o m plete d t he st u d y. T he e n d of t he st u d y is defi ne d as 
t he latest date a s u bject recei ves t he Safet y F oll o w- u p Call. T he pla n ne d d urati o n of st u d y 
c o n d uct f or Part 1 is u p t o 5 9 da ys fr o m Scre e ni n g t hr o u g h t he Safet y F oll o w- u p Call. T he 
pla n ne d d urati o n of st u d y c o n d u ct f or Part 2 is u p t o 4 6 da ys fr o m Scree ni n g t hr o u g h t he Safet y 
F oll o w- u p Call. 
A sc he matic of t h e st u d y desi g n of Part 1 is prese nte d i n Fi g ure 4- 1 a n d a sc he matic of t he st u d y 
desi g n of Part 2 is prese nte d i n Fi g ure 4- 2 . 
Fi g ure 4- 1 St u d y Desi g n Sc he m atic:  P art 1 
Scree ni n g 
C hec k -i n 
D osi n g a 
L O X O- 2 9 2 a n d T ot al 
R a di o acti vit y 
C o nce ntr ati o ns , a n d M etI D 
S a m pli n g 
Cli nic 
Disc h ar ge b  
S afet y F oll o w- u p 
C all c 
Da ys -2 9 t o 
- 2 
Da y - 1 
Da y 1 
Da y 1 t o Cli nic Disc har ge 
Da ys 8 t o 2 2 
A p pr o xi matel y 
7  da ys after Cli nic 
Disc har ge  
 
Cli nic C o nfi ne me nt 
 
MetI D = met a b olite pr ofili n g a n d i d e ntificati o n 
a  Si n gle oral d ose of 1 6 0 m g of [1 4C]- L O X O- 2 9 2 ( ~ 4 0 μ Ci) a d mi nistere d as a n oral s ol uti o n f oll o wi n g a n o ver ni g ht fast.  
b  S u bjects will be disc har ge d fr o m t h e Cli nical Researc h U nit ( C R U) starti n g o n Da y 8 if ≥ 9 0 % of t h e ra di oacti ve d ose is 
rec o vere d a n d ≤ 1 % of t h e ra di oacti ve d ose per da y is rec o vere d i n e xcreta ( uri n e a n d feces) f or 3 c o nsec uti ve da ys o n w hi c h a 
fe cal sa m ple is c ollecte d. If t h ese criteria are n ot satisfie d b y t h e m or ni n g of Da y 8, s u bjects will c o nti n ue t o be c o nfi n e d i n t h e 
C R U u ntil t h ese criteria are met, u p t o a ma xi m u m of Da y 2 2. 
c  S u bjects will recei ve a Safet y F oll o w- u p Call a p pr o xi matel y 7 da ys after Cli nic Disc har ge. 
 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 2 of 6 0 
 
Fi g ure 4- 2 St u d y Desi g n Sc he m atic:  P art 2 
Scree ni n g 
C hec k- i n 
D osi n g a 
L O X O- 2 9 2, 
[1 4C]- L O X O- 2 9 2, a n d T ot al 
R a di o acti vit y C o nce ntr ati o ns 
Cli nic 
Disc h ar ge  
S afet y F oll o w- u p 
C all b 
Da ys - 2 9 
t o  - 2 
Da y - 1 
Da y 1 
Da y 1 t o Da y 9 
Da y 9  
A p pr o xi matel y 
7  da ys after Cli nic 
Disc har ge 
 
Cli nic C o nfi ne me nt  
 
a  Si n gle oral d ose of 1 6 0 m g of L O X O- 2 9 2 a d mi nistere d as 2 x 8 0- m g ca ps ules f oll o wi n g a n o ver ni g ht fast. A si n gle i ntra ve n o us 
(I V) d ose of < 1 0 0 μ g of [ 1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci of ra di oacti vit y) will be a d mi nistere d b y I V p us h 2 h o urs after 
t h e oral d ose. 
b  S u bjects will recei ve a Safet y F oll o w- u p Call a p pr o xi matel y 7 da ys after Cli nic Disc har ge. 
 
Part 1: 
After a Scree ni n g p eri o d of u p t o 2 8 da ys, s u bj ects will c hec k i n t o t he Cli nical Researc h U nit 
( C R U) o n Da y - 1 t o c o nfir m eli gi bilit y a n d t o bec o me fa miliar wit h st u d y pr oce d ures. O n t he 
m or ni n g of Da y 1, f oll o wi n g a n o v er ni g ht fast of at least 8 h o urs, s u bjects will recei ve a si n gl e 
oral d ose of 1 6 0 m g of [ 1 4C]- L O X O- 2 9 2 (c o nt ai ni n g ~ 4 0 μ Ci) a d mi nistere d as a n oral s ol uti o n. 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k-i n u ntil Cli nic Disc har ge ( bet wee n 
Da ys 8 a n d 2 2). After c o m pleti n g disc har ge pr oce d ure s, s u bjects will be disc har ge d fr o m t he 
C R U as earl y as D a y 8 a n d u p t o Da y 2 2, pr o vi de d rec o ver y of ra di oacti vit y has reac he d t he 
f oll o wi n g t hres h ol d val u es:  
 ≥ 9 0 % of t he ra di o acti ve d ose is rec o vere d, a n d  
 ≤ 1 % of t he ra di o acti ve d ose per da y is r ec o v ere d i n e x creta ( uri ne a n d feces) f or 
3 c o nsec uti ve da ys o n w hic h a fecal sa m ple is c ollecte d.   
Sa m ple c ollecti o n a n d c o nfi ne me nt will c o nti n ue u ntil disc har ge criteria are met or t he ma xi m u m 
sta y is reac h e d, u nless ot her wise a gree d u p o n b y t he S p o ns or a n d I n vesti gat or ( or desi g nee). 
S u bjects will recei ve a Safet y F oll o w- u p Call  a p pr o xi matel y 7 d a ys after Cli nic Disc har ge. 
Safet y will be m o nit ore d wit h A E i n q uiries, cli nical la b orat or y e val uati o ns ( A p pe n di x A ), vital 
si g ns meas ur e me nts, 1 2-l ea d E C Gs, a n d p h ysic al e xa mi nati o ns d uri n g t he st u d y.  
Sa m ples f or deter mi nati o n of L O X O- 2 9 2 c o nce ntr ati o ns i n plas ma, t otal ra di oacti vit y 
c o nce ntrati o ns i n plas ma, w h ole bl o o d, uri ne, a n d feces, a n d f or m eta b olite 
pr ofili n g/c h aracteriz ati o n will be o btai ne d t hr o u g h at least 1 6 8 h o urs p ost d ose ( Da y 8), a n d 
p ossi bl y u p t o 5 0 4 h o urs p ost d ose ( Da y 2 2). A Sc he d ule of Assess me nts f or Part 1 is prese nte d 
i n Ta ble 6- 1 .  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 3 of 6 0 
 
I n Part 1, f or s u bjects e x perie nci n g e m esis wit hi n 2 h o urs f oll o wi n g d osi n g, v o mit us will be 
c ollecte d. T hat s u bject ma y b e c o nsi dere d n ot e val ua ble a n d t he Me di cal M o nit or ( or desi g nee) 
s h o ul d be c o ntacte d i m m e diatel y f or f urt her i nstr u cti o ns a n d t o deter mi ne if t he s u bject s h o ul d 
c o nti n ue t he st u d y. All v o mit us c ollecte d will be st ore d f or p ossi ble a n al ysis.  
Part 2: 
After a Scree ni n g p eri o d of u p t o 2 8 da ys, s u bj ects will c hec k i n t o t he C R U o n Da y - 1 t o 
c o nfir m eli gi bilit y a n d t o bec o me fa miliar wit h st u d y pr oce d ures. O n t he m or ni n g of Da y 1, 
f oll o wi n g a n o v er ni g ht fast of at least 8 h o urs, s u bjects will recei ve a si n gle oral d ose of 1 6 0 m g 
of L O X O- 2 9 2 as 2 x 8 0- m g ca ps ules f oll o we d 2 h o urs later b y a si n gle d os e of < 1 0 0 μ g of 
[1 4C]- L O X O- 2 9 2 (c o ntai ni n g ~ 1 μ Ci) a d mi nistere d as a n I V p us h o v er a p pr o xi matel y 2 mi n utes. 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k-i n u ntil Da y 9 a n d will be 
disc har ge d fr o m t he C R U after c o m pleti n g all disc har ge pr oce d ures. S u bjects will recei ve a 
Safet y F oll o w- u p Call a p pr o xi matel y 7 d a ys after Cli nic Disc har ge.  
As i n Part 1, safet y will be m o nit ore d wit h A E i n q uiries, cli nical la b orat or y e val uati o ns 
(A p pe n di x A ), vital si g ns meas ure me nts, 1 2-l ea d E C Gs, a n d p h ysic al e xa mi nati o ns d uri n g t he 
st u d y.  
Sa m ples f or deter mi nati o n of plas ma a n d uri ne c o nce ntrati o ns of L O X O- 2 9 2 a n d 
[1 4C]- L O X O- 2 9 2 a n d f or deter mi nati o n of t otal ra di oacti vit y c o n ce ntrati o ns i n uri ne a n d feces 
will be o btai ne d t hr o u g h 1 9 2 h o urs p ost d ose ( Da y  9). A Sc he d ule of Assessme nts f or Part 2 is 
prese nte d i n  Ta bl e 6- 2. 
4. 2  Disc ussi o n of St u d y Desi g n 
Part 1 of t his st u d y is desi g ne d t o c h aracterize t he A M E ki netics of L O X O- 2 9 2 usi n g 
ra di ola bele d dr u g i n healt h y a d ult male s u bjects t o s u p p ort its f urt h er de vel o p me nt a n d 
re gistrati o n. Part 1 will als o all o w f or i de ntificati o n a n d c haracterizatio n of a n y m eta b olites of 
L O X O- 2 9 2 t hat are pr o d uce d f oll o wi n g oral d osi n g.  
Part 2 is desi g ne d t o det er mi ne t he a bs ol ute bi oa v aila bilit y of L O X O- 2 9 2 b y c o m p ari n g its 
plas ma e x p os ure f oll o wi n g oral d osi n g t o t he plas ma e x p os ure of [ 1 4C]- L O X O- 2 9 2 f oll o wi n g I V 
micr otracer a d mi nistrati o n. T he I V micr otr ace r met h o d all o ws f or si m ulta ne o us oral a n d I V 
d osi n g i n t he sa me s u bjects, w hic h is e x pecte d t o res ult i n less varia bilit y i n a bs ol ute 
bi oa vaila bilit y esti mates. T he I V d ose of [ 1 4C]- L O X O- 2 9 2 will be a d mi nistere d s o t hat pea k 
plas ma c o nce ntrati o ns of [ 1 4C]- L O X O- 2 9 2 o cc ur a p pr o xi matel y at t he T ma x  of L O X O- 2 9 2 
f oll o wi n g oral d osi n g. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 4 of 6 0 
 
A nal ysis of uri ne c o n ce ntrati o ns of L O X O- 2 9 2, [ 1 4C]- L O X O- 2 9 2, a n d t otal ra di oacti vit y will 
all o w f or deter mi nati o n of C L R  a n d f or t he perce nt a ge of L O X O- 2 9 2 e x crete d u nc ha n ge d i n 
uri ne. A nal ysis of t otal ra di oacti vit y i n feces will pr o vi de i nf or mati o n a b o ut t he e xte nt of fecal 
e x creti o n of L O X O- 2 9 2. 
I n Part 2, a micr otracer ( ~ 1 μ Ci) of [ 1 4C]- L O X O- 2 9 2 will be use d. T his l o w le vel of ra di oacti vit y 
necessitates t he us e of A M S as a m ore se nsiti ve a nal yti cal met h o d f or detecti n g t he l o w le v els of 
ra di oacti vit y i n plas ma, uri ne, a n d fecal sa m ples. 
T he st u d y will be o p e n la bel beca us e t he st u d y meas ures are o bjecti ve o utc o mes (e g, P K 
para meters, t otal ra di oa cti vit y i n sel ect bi ol o gi cal matrices, meta b olite 
pr ofili n g/c h aracteriz ati o n). C o n d ucti n g t he st u d y i n healt h y s u bjects will all o w t he e val uati o n of 
L O X O- 2 9 2 meta b olis m a n d bi oa vaila bilit y i n t h e a bse nce of c o nc o mita nt m e dicati o ns a n d 
c o m or bi dities. T he d ose, s u bject  p o p ulati o n, st u d y d urati o n, a n d sa m ple c ollecti o n ti mi n g are 
c o nsi dere d a de q uat e t o a c hie ve t he st u d y o bjecti v es. 
5  S U B J E C T S E L E C TI O N 
S u bjects w h o meet all t he i ncl usi o n criteria a n d f or w h o m n o ne of t he e x cl usi o n criteria a p pl y 
will be eli gi ble t o be e nr olle d i nt o t he st u d y. Safet y e v al uati o ns m a y b e re peate d at t he 
I n v esti gat or’s ( or desi g nee’s) discreti o n. 
Eac h s u bject is all o we d t o partici pate i n o nl y o ne part of t he st u d y. I n or der t o c o m plete 
6 s u bjects i n eac h p art of t he st u d y, 6 s u bjects a n d 2 alter nates will be e nr olle d i n Parts 1 a n d 2. 
T he alter nates will be d ose d o nl y i n t he e v e nt t hat d osi n g is u ns uccessf ul f or a n y of t he i nitial 
6 s u bjects. I n t he e ve nt of earl y wit h dr a wal of a n y s u bjects after t h e alter nate s u bjects are 
releas e d, re pla ce me nt s u bjects ma y b e e nr olle d at t he discreti o n of t he S p o ns or. 
T he S p o ns or will re vie w me dical hist or y a n d all scree ni n g e v al uati o ns f or p ote ntial s u bjects pri or 
t o e nr oll me nt. Pri or t o d osi n g, t he S p o ns or will pr o vi de a p pr o val of s u bjects selecte d f or 
e nr oll me nt b y t he I n vesti gat or ( or desi g n ee).  
5. 1  I ncl usi o n Criteri a 
S u bjects w h o meet t he f oll o wi n g criteria at Sc ree ni n g a n d C hec k-i n ma y be i ncl u de d i n t he 
st u d y: 
1.  
Males of a n y race bet wee n 1 8 a n d 5 5 years of a ge, i ncl usi ve, at Scree ni n g 
2.  
B o d y mass i n de x bet wee n 1 8. 5 a n d 3 2. 0 k g/ m 2, i ncl usi ve, at Scree ni n g 
3.  
I n g o o d h ealt h, deter mi ne d b y n o cli nicall y si g nifi ca nt fi n di n gs fr o m me dical 
hist or y, p h ysical e x a mi nati o n, 1 2-lea d E C G, vital si g ns meas ure me nts, or cli nical 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 5 of 6 0 
 
la b orat or y e v al uati o ns (A p pe n di x A ) at Scree ni n g or C hec k-i n as assesse d b y t he 
I n v esti gat or ( or desi g n ee) 
4.  
S u bjects will be s ur gic all y sterile f or at  least 9 0 da ys pri or t o C hec k-i n or, w he n 
se x uall y acti ve wit h f e male part ners of c hil d beari n g p ote ntial, will a gree t o use 
effecti ve c o ntr ace pti o n m et h o ds, as detaile d i n Secti o n 6. 3. 3, or a bstai n fr o m 
se x ual i nterc o urse fr o m t he ti me of first d ose t hr o u g h 6 m o nt hs after st u d y dr u g 
a d mi nistrati o n. S u bjects m ust a gree n ot t o d o nate s per m fr o m C hec k-i n u ntil 
6 m o nt hs after t he last d ose of st u d y dr u g 
5.  
A ble t o c o m pre he n d a n d willi n g t o si g n a n I C F a n d t o a bi de b y t h e st u d y 
restricti o ns 
6.  
Hist or y of ha vi n g a mi ni m u m of 1 b o wel m o ve me nt per da y. 
5. 2  E xcl usi o n Criteri a 
T he f oll o wi n g will e x cl u de p ote n tial s u bjects fr o m t he st u d y: 
1.  
Si g nifica nt hist or y or cli nical ma nifestati o n of a n y meta b olic, aller gic, i nf ecti o us, 
der mat ol o gi cal, he p atic, re nal, he mat ol o gical, p ul m o nar y, car di o vasc ular, GI, 
ne ur ol o gi cal, res pirat or y, e n d ocri ne, or ps yc hiatric dis or der, as det er mi ne d b y t he 
I n v esti gat or ( or d esi g n ee) 
2.  
Hist or y of si g nifica nt h y perse nsiti vit y, i nt olera n ce, or aller g y t o a n y dr u g 
c o m p o u n d, f o o d, or ot her s u bsta nce, u nless a p pr o ve d b y t h e I n vesti gat or ( or 
desi g nee) 
3.  
Hist or y of st o ma c h or i ntesti nal s ur ger y or resecti o n t hat w o ul d p ote ntiall y alter 
a bs or pti o n a n d/ or e x creti o n of orall y a d mi nistere d dr u gs ( u nc o m plicate d 
a p pe n dect o m y a n d her ni a re pair will be all o we d)  
4.  
Hist or y of c o n ge nital n o n he m ol ytic h y per bilir u bi ne mia (e g, Gil bert’ s 
s y n dr o me) 
5.  
Has ha d a c h olec yste ct o m y 
6.  
Hist or y of alc o h olis m or dr u g/c he mical a b us e wit hi n 2 years pri or t o C hec k-i n 
7.  
T y pic al alc o h ol c o ns u m pti o n of > 2 1 u nits per wee k f or males. O ne u nit of 
alc o h ol e q uals 1 2 oz ( 3 6 0 m L) beer, 1 ½ oz ( 4 5 m L) li q u or, or 5 oz ( 1 5 0 m L wi ne) 
8.  
P ositi ve uri ne dr u g scree n (i ncl u di n g c o ti ni ne) at Scree ni n g, or p ositi ve uri ne dr u g 
scree n (i ncl u di n g c oti ni ne) or al c o h ol breat h test at C hec k-i n 
9.  
P ositi ve he patitis pa nel a n d/ or p ositi v e h u ma n i m m u n o deficie nc y vir us ( HI V) test 
(A p pe n di x A ). S u bjects w h ose res ults are c o m pati ble wit h pri or i m m u nizati o n 
a n d n ot i nfecti o n ma y be i ncl u de d at t h e discreti o n of t he I n vesti gat or ( or 
desi g nee) 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 6 of 6 0 
 
1 0.  
Esti mate d creati ni ne cleara nce < 9 0 m L/ m i n at Scree ni n g or C hec k-i n, calc ulate d 
usi n g t he C oc kcr oft- G a ult e q uati o n 
1 1.  
A b n or mal li ver f u ncti o n tests ( L F Ts), as defi ne d b y A S T, A L T, A L P, a n d s er u m 
(t otal a n d direct) bilir u bi n, as well as a mylase a n d li pase a b o ve t he u p per li mit of 
t he n or mal ra n ge at Scree ni n g or C hec k-in, u nless dee me d acce pta ble b y t h e 
I n v esti gat or ( or d esi g n ee) wit h pri or S p o ns or a p pr o val. Rec hec ks of L F Ts will be 
per mitte d u p t o 2 ti mes t o c o nfir m eli gi bilit y f or st u d y partici p ati o n. S u bjects ma y 
be eli gi ble f or partici pati o n i n t he st u d y base d o n rec hec ke d L F T val u es if t he 
I n v esti gat or a n d t he S p o ns or dee m t hat t he res ults are n ot cli nicall y si g nifica nt 
a n d will n ot i m pact st u d y c o n d uct.  
1 2.  
S u pi ne s yst olic bl o o d press ure ( B P) is < 8 9 m m H g or > 1 3 9 m m H g, or s u pi ne 
diast olic B P is < 5 0 m m H g or > 8 9 m m H g, at Scree ni n g, C hec k-i n, or pri or t o 
d osi n g o n Da y 1 of Part 1 or Part 2, u nless dee me d acce pta ble b y t he I n v esti gat or 
( or desi g nee) wit h pri or S p o ns or a p pr o val. Rec h ec ks of B P val u es will be 
per mitte d u p t o 2 ti mes t o c o nfir m eli gi bili t y f or st u d y partici p ati o n. S u bjects ma y 
be eli gi ble f or partici pati o n i n t he st u d y base d o n rec hec ke d B P val ues if t h e 
I n v esti gat or a n d t he S p o ns or dee m t hat t he res ults are n ot cli nicall y si g nifica nt 
a n d will n ot i m pact st u d y c o n d uct. 
1 3.  
S u pi ne heart rat e is < 5 0 b p m or > 9 9 b p m at Scree ni n g or C h ec k-i n, u nless 
dee me d acce pta ble b y t h e I n vesti gat or ( or desi g nee) wit h pri or S p o ns or a p pr o val. 
Rec hec ks of h eart rate will be per mitte d u p t o 2 ti mes t o c o nfir m eli gi bilit y f or 
st u d y partici p ati o n. S u bjects ma y be eli gi ble f or partici pati o n i n t he st u d y b ase d 
o n rec hec ke d h eart rates if t he I n vesti gat or a n d/ or t he S p o ns or dee m t hat t he 
res ults are n ot cli nicall y si g nifica nt a n d will n ot i m pact st u d y c o n d uct. 
1 4.  
Car diac e x cl usi o ns: Hist or y or pres e nce of a n y of t he f oll o wi n g, dee me d cli nicall y 
si g nifica nt b y t he I n vesti gat or ( or desi g n ee) a n d/ or S p o ns or: 
o  hist or y or prese n ce of cli nicall y si g nifica nt car di o vasc ular dise ase:  
 
m y ocar dial i nfarcti o n or cere br o vasc ul ar t hr o m b o e m b olis m wit hi n 
6 m o nt hs pri or t o first d osi n g  
 
s y m pt o matic a n gi na pect oris 
 
Ne w Y or k Heart Ass ociati o n Class ≥ 2 c o n gesti ve heart fail ure 
 
c o n ge nital pr ol o n ge d Q T s y n dr o me  
 
ve ntric ular pre-e x citati o n s y n dr o me ( W olff- Par ki ns o n W hite 
s y n dr o me) 
 
arr h yt h mia (e x cl u di n g b e ni g n si n us arr h yt h mia) or hist or y of 
arr h yt h mia re q uiri n g m e dical i nter ve nti o n  
 
ve ntric ular d ysf u ncti o n or ris k fact ors f or T ors a des de P oi ntes (e g, 
heart fail ure, car di o m y o p at h y, fa mil y hist or y of L o n g Q T S y n dr o me)  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 7 of 6 0 
 
 
si g nifica nt scree ni n g E C G a b n or malities:   
 
Left b u n dle- bra nc h bl oc k  
 
Sec o n d de gree atri o v e ntric ular ( A V) bl oc k, t y pe 2, or t hir d 
de gree A V bl oc k  
 Q T i nter val c orrecte d f or heart rate usi n g Fri d erici a’s met h o d  
( Q Tc F) is > 4 5 0 mse c 
o  E C G fi n di n gs dee me d a b n or mal wit h cli nical si g nifica nce b y t h e 
I n v esti gat or ( or desi g n ee) at Scree ni n g or C hec k-i n 
1 5.  
Partici pati o n i n a n y ot her ra di ola bele d i n vesti gati o nal st u d y dr u g trial wit hi n 
1 2 m o nt hs pri or t o C hec k-i n. A n y pre vi o us  ra di ola bele d st u d y dr u g m ust ha ve 
bee n recei ve d m ore t ha n 1 2 m o nt hs pri or t o C hec k-i n f or t his st u d y 
1 6.  
E x p os ure t o si g nifica nt r a diati o n (e g, seri al x-ra y or c o m p ute d t o m o gra p h y sca ns, 
bari u m meal, c urre nt e m pl o y me nt i n a j o b re q uiri n g ra diati o n e x p os ure 
m o nit ori n g) wit hi n 1 2 m o nt hs pri or t o C hec k-i n 
1 7.  
Partici pati o n i n a n y ot her i n vesti gati o nal st u d y dr u g trial i n v ol vi n g a d mi nistrati o n 
of a n y i n vesti gati o nal dr u g i n t he past 3 0 da ys or 5 half-li ves (if k n o w n), 
w hic he ver is l o n ger, pri or t o C hec k-i n  
1 8.  
Use or i nte nti o n t o use a n y me dicati o ns/ pr o d ucts k n o w n t o alter dr u g A M E 
pr ocesses, i n partic ular str o n g i n d u cer s or i n hi bit ors of C Y P 3 A 4 e nz y mes, 
i ncl u di n g St. J o h n’s w ort, wit hi n 3 0 da ys pri or t o C hec k-i n, u nless dee m e d 
acce pta ble b y t he I n v esti gat or ( or desi g n ee) 
1 9.  
Use or i nte nti o n t o use a n y prescri pti o n me dicati o ns/ pr o d ucts wit hi n 1 4 da ys pri or 
t o C hec k-i n, u nless dee m e d acce pta ble b y t he I n vesti gat or ( or desi g nee) 
2 0.  
Use or i nte nti o n t o use sl o w-release me dicati o ns/ pr o d ucts c o nsi dere d t o still be 
acti ve wit hi n 1 4 da ys pri or t o C hec k-i n, u nless dee me d acce pta ble b y t h e 
I n v esti gat or ( or d esi g n ee) 
2 1.  
Use or i nte nti o n t o use a n y n o n prescri pti o n me dicati o ns/ pr o d ucts i ncl u di n g 
vita mi ns, mi nerals, a n d p h yt ot hera pe utic/ h er bal/ pla nt- deri ve d pre parati o ns wit hi n 
7 da ys pri or t o C hec k-i n, u nless dee me d acce pta bl e b y t h e I n vesti gat or ( or 
desi g nee) 
2 2.  
C o ns u m pti o n of f o o ds a n d be vera ges c o ntai ni n g p o p p y see ds, gra p efr uit, or 
Se ville ora n ges fr o m 7 d a ys pri or t o C hec k-i n  
2 3.  
C o ns u m pti o n of alc o h ol-, caffei ne-, or  xa nt hi ne-c o ntai ni n g f o o ds a n d b e vera ges 
fr o m 7 2 h o urs pri or t o C hec k-i n, u nless dee me d acce pta bl e b y t he I n vesti gat or ( or 
desi g nee) 
2 4.  
Stre n u o us e x ercise wit hi n 4 8 h o urs pri or t o C hec k-i n  
2 5.  
Use of t o bacc o- or ni c oti ne-c o ntai ni n g pr o d u cts wit hi n 3 m o nt hs pri or t o 
C hec k-i n  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 8 of 6 0 
 
2 6.  
Recei pt of bl o o d pr o d ucts wit hi n 2 m o nt hs pri or t o C hec k-i n 
2 7.  
D o nati o n of bl o o d fr o m 5 6 da ys pri or t o Scree ni n g, plas ma fr o m 2 wee ks pri or t o 
Scree ni n g, or plat elets fr o m 6 wee ks pri or t o Scree ni n g  
2 8.  
P o or peri p heral ve n o us access 
2 9.  
Ha ve pre vi o usl y c o m plete d or wit h dra w n fr o m a n y ot her st u d y i n vesti gati n g 
L O X O- 2 9 2, a n d h a ve pre vi o usl y re cei ve d t he i n v esti gati o nal pr o d uct 
3 0.  
S u bjects w h o, i n t he o pi ni o n of t he I n vesti gat or ( or desi g n ee), s h o ul d n ot 
partici pate i n t his st u d y. 
5. 3  Re m o v al of S u bjects fr o m St u d y P artici p ati o n 
S u bjects will be i nf or me d t hat t he y are free t o wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y 
reas o n. T he I n vesti gat or ( or desi g nee) or S p o ns or ma y re m o ve a s u bj ect fr o m t he st u d y if, i n t he 
I n v esti gat or’s ( or desi g nee’s) or S p o ns or’s o pi ni o n, it is n ot i n t he best i nterest of t he s u bject t o 
c o nti n ue t he st u d y. S u bje cts ma y b e wit h dra w n d u e t o t he f oll o wi n g: c ha n ge i n c o m plia nce wit h 
i ncl usi o n/e x cl usi o n criteri o n t hat is cli nicall y rele va nt a n d affects s u bject safet y, o cc urre n ce of 
A Es, i nta ke of n o n per mitte d c o nc o mita nt me dicat i o n t hat mi g ht affect s u bject safet y or st u d y 
assess me nts/ o bjecti ves, etc. N otificati o n of wit h dr a wal will i m me diatel y b e ma de t o t he 
S p o ns or’s St u d y M o nit or. I n case of wit h dra wal of st u d y partici p ati o n, eff orts will be ma de t o 
perf or m all fi n al st u d y da y ass ess me nts ( Ta ble 6- 1 a n d Ta ble 6- 2). T he d ate t he s u bject is 
wit h dra w n fr o m t he st u d y a n d t h e reas o n f or wit h dra wal will be rec or de d o n t he s u bject’s 
electr o nic Cas e Re p ort F or m (e C R F). All wit h dra w n  s u bjects will be f oll o we d u ntil res ol uti o n of 
all t heir A Es or u ntil t he u nres ol ve d A Es are j u d ge d b y t h e I n vesti gat or ( or desi g nee) t o ha ve 
sta bilize d. 
 
T he e ntire st u d y ma y be disc o nti n ue d at t he discreti o n of t he I n v esti gat or ( or desi g n ee) or 
S p o ns or base d o n t he occ urre nce of t he f oll o wi n g: 
 A Es n ot pre vi o usl y o bs er ve d f oll o wi n g a d mi nistrati o n of L O X O- 2 9 2 wit h r es pect t o t heir 
nat ure, se v erit y, a n d/ or d urati o n 
 i ncreas e d fre q ue nc y a n d/ or se verit y a n d/ or d urati o n of k n o w n A Es 
 me dical or et hical reas o ns affecti n g t h e c o nti n ue d perf or ma n ce of t he st u d y 
 diffic ulties i n t he recr uit me nt of s u bjects 
 disc o nti n uati o n of cli nical de vel o p me nt of L O X O- 2 9 2. 
 
 
 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 2 9 of 6 0 
 
6  S T U D Y P R O C E D U R E S 
6. 1  Sc he d ule of St u d y Pr oce d ures 
 
A Sc he d ule of Ass ess me nts f or  Part 1 is prese nte d i n Ta ble 6- 1 . A Sc he d ul e of Assess me nts f or 
Part 2 is prese nte d i n Ta ble 6- 2 . T he t otal bl o o d v ol u me t hat will be ta ke n d uri n g t he st u d y is 
o utli ne d i n A p pe n di x B . 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 0 of 6 0 
 
 
 
T a ble 6- 1  Sc he d ule of Assess me nts:  P a rt 1 
 
Scree ni n g 
C hec k-i n 
Tre at me nt 
C hec k- o ut 
F oll o w- u p 
E ve nts  
D a ys - 2 9 
t o -2 
D a y - 1 
D a y 
1 
D a y 
2 
D a y 
3 
D a y 
4 
D a y 
5 
D a y 
6  
D a y 
7 
Cli nic 
Disc h ar ge a  
( D a ys 8 t o 
2 2)/ E T b  
S af et y F oll o w- u p 
C all 
(a p pr o xi m atel y 
7  d a ys after Cli nic 
Disc h ar ge) 
I nf or me d C o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
Assi g n me nt of Scree ni n g N u m ber 
X 
 
 
 
 
 
 
 
 
 
 
Re vie w of I ncl usi o n/ E xcl usi o n Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
De m o gra p hic Data 
X 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y 
c 
X 
X 
 
 
 
 
 
 
 
 
 
Pri or Me dicati o ns 
X 
X 
 
 
 
 
 
 
 
 
 
Hei g ht, W ei g ht, B MI Calc ulati o n d 
X 
X 
 
 
 
 
 
 
 
 
 
Alc o h ol a n d Dr u g Scree n e 
X 
X 
 
 
 
 
 
 
 
 
 
Ser ol o g y T est ( H B c A b, H Bs A g, H C V A b, HI V) 
X 
 
 
 
 
 
 
 
 
 
 
C o nfi ne me nt t o C R U 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assi g n me nt of S u bj ect N u m b er 
 
 
X 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n f 
X 
X 
 
 
 
 
 
 
 
X 
 
Cli nical La b orat or y Safet y T ests (cli nical 
c he mistr y, T S H [ Scree ni n g o nl y], he mat ol o g y, 
a n d uri nal ysis)  g 
X  
X  
 
 
 
X 
 
 
 
X 
 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 1 of 6 0 
 
 
 
 
Scree ni n g 
C hec k-i n 
Tre at me nt 
C hec k- o ut 
F oll o w- u p 
E ve nts  
D a ys - 2 9 
t o -2 
D a y - 1 
D a y 
1 
D a y 
2 
D a y 
3 
D a y 
4 
D a y 
5 
D a y 
6  
D a y 
7 
Cli nic 
Disc h ar ge a  
( D a ys 8 t o 
2 2)/ E T b  
S af et y F oll o w- u p 
C all 
(a p pr o xi m atel y 
7  d a ys after Cli nic 
Disc h ar ge) 
Vital Si g ns ( oral te m perat ure, B P, heart rate, a n d 
res pirat or y rate) h 
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
 
1 2-lea d E C G i 
X 
X 
X 
 
 
 
 
 
 
X 
 
L O X O- 2 9 2 A d mi nistrati o n 
( L O X O- 2 9 2 1 6 0 m g/ ~ 4 0 μ Ci [ 1 4C]- L O X O- 2 9 2) 
 
 
X 
 
 
 
 
 
 
 
 
A E, S A E, a n d C o nc o mita nt M e dicati o ns a n d 
Pr oce d ures M o nit ori n g a n d R ec or di n g n 
       X--------------------------------------------------- O n g oi n g--------------------------------------------------- X 
A E = a d verse e ve nt; B MI = b o d y mass i n de x; B P = bl o o d press ur e; C R U = Cli nical Rese arc h U nit; E C G = electr ocar di o gra m; E T = ear l y ter mi nati o n; 
H B c A b = he p atitis B c ore a nti b o d y; H Bs A g = he patitis B s urface a n ti ge n; H C V A b = he patitis C vir us a nti b o d y; HI V = h u ma n i m m u n odeficie nc y vir us; 
S A E = seri o us a d verse e ve nt; T S H = t h yr oi d-sti m ulati n g h or m o ne. 
 
C CI

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 2 of 6 0 
 
 
 
a S u bj ects ma y be disc har ge d fr o m t he C R U starti n g o n Da y 8 if ≥ 9 0 % of t he ra di oacti ve d ose is rec o vere d a n d ≤ 1 % of t he ra di oacti ve d ose per da y is rec o vere d 
i n e xcreta ( uri ne a n d feces) f or 3 c o nsec uti ve da ys o n w hi c h a fecal sa m ple is c ollecte d. If t h ese criteria are n ot satisfie d b y t he m or ni n g of Da y 8, s u bj ects will 
c o nti n ue t o be c o nfi ne d i n t he C R U u ntil t hes e criteria are met, u p t o a ma xi m u m of Da y 2 2. 
b S u bj ects w h o wit h dr a w fr o m t he st u d y pri or t o meeti n g disc har ge criteria s h o ul d u n der g o all disc har ge tests a n d assess me nts at E T, a n d will recei ve a Safet y 
F oll o w- u p Call a p pr o xi matel y 7 da ys after E T.  
c A f ull me dical hist or y will b e rec or de d at Scree ni n g. A n i nteri m me dical hist or y u p date will be rec or de d o n Da y - 1. 
d Hei g ht a n d B MI will be meas ure d at Scree ni n g o nl y. 
e Dr u g uri ne scree n ( w hic h i ncl u des c oti ni ne) will be c o n d ucte d at Scree ni n g a n d at C hec k-i n ( Da y - 1). A n alc o h ol breat h test wi ll be c o n d ucte d at C hec k-i n o nl y. 
f A c o m plete p h ysical e xa mi nati o n will be c o n d ucte d at Scre e ni n g a n d at Cli nic Disc har ge/ E T. A n a b bre viate d p h ysical e xa mi nati o n ( ge neral, heart, l u n gs, 
a b d o me n, a n d s ki n) will be c o n d ucte d at C hec k-i n. 
g E ver y atte m pt will be ma de t o e ns ure bl o o d sa m ples f or t he cli nical c he mistr y pa nel are c ollecte d f oll o wi n g a fast fr o m f o o d f or at least 8 h o urs. T est f or T S H 
will b e perf or me d at Scree ni n g o nl y. Ot her cli nical la b orat or y e val uati o ns will be c o n d uct e d at Scree ni n g, C hec k-i n, o n Da y 4, a n d at Cli nic Disc har ge/ E T. 
h S u bj ects are t o re mai n s u pi ne f or at least 5 mi n utes pri or t o vital si g ns meas ure me nts. Vital si g ns will be o btai ne d at S cree ni n g; C hec k-i n; o n Da y 1 pre d ose a n d 
2 h o urs p ost d ose; a n d dail y ( 2 4- h o ur i nter va ls) u p t o a n d i ncl u di n g da y of Cli nic Disc har ge/ E T. W he n sc he d ule d at t he s a me n o minal ti mes, p ost d ose vital si g ns 
meas ure me nts are t o be perf or me d pri or t o p ost d ose P K bl o o d dra ws (see Secti o n 6. 5 ), wit h bl o o d dra ws occ urri n g as cl ose t o t he n o mi nal ti mes as p ossi ble. 
i S u bj ects are t o r e mai n s u pi ne f or at least 5 mi n utes pri or t o E C G assess me nts. T he E C Gs will be  o btai ne d at S cree ni n g a n d C heck-i n, o n Da y 1 pre d ose, 2 h o urs 
p ost d ose, a n d at Cli nic Disc har ge/ E T.  W he n sc he d ule d at t he sa me n o mi nal ti mes, p ost d os e E C Gs are t o be perf or me d pri or t o p ostd ose vital si g ns 
meas ure me nts a n d P K bl o o d dra ws (see Secti o n 6. 5 ), wit h bl o o d dra ws occ urri n g as cl ose as p ossi ble t o t he n o mi nal ti mes.   
j 
 
 
 
 
 
 
 
 
   
n A Es, S A Es, a n d c o nc o mita nt me dicati o ns a n d pr oc e d ures will be m o nit ore d a n d rec or de d t hr o u g h o ut t he st u d y fr o m t he ti me of si g n i n g t he i nf or me d c o nse nt, 
as descri be d i n Secti o n 6. 5. 1 , A p pe n di x C , a n d Secti o n 6. 3. 2 . A “ H o w D o Y o u Feel? ” A E i n q uir y will be perf or me d at Scree ni n g, C hec k-i n, eac h vital si g ns 
meas ure me nt, a n d d uri n g t he Safet y F oll o w- u p Call.
C CI

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 3 of 6 0 
 
 
 
T a ble 6- 2  Sc he d ule of Assess me nts:  P a rt 2 
 
Scree ni n g 
C hec k-i n 
Tre at me nt 
C hec k- o ut 
F oll o w- u p 
E ve nts  
D a ys - 2 9 
t o -2 
D a y - 1 
D a y 
1 
D a y 
2 
D a y 
3 
D a y 
4  
D a y 
5  
D a y 
6  
D a y 
7  
D a y 
8 
Cli nic 
Disc h ar g e  
or E T a 
D a y 9 
S af et y F oll o w- u p 
C all ( a p pr o xi m atel y 
7 d a ys after Cli nic 
Disc h ar ge)  
I nf or me d C o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
Assi g n me nt of Scree ni n g N u m ber 
X 
 
 
 
 
 
 
 
 
 
 
 
Re vie w of I ncl usi o n/ E xcl usi o n Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
De m o gra p hic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y 
b 
X 
X 
 
 
 
 
 
 
 
 
 
 
Pri or Me dicati o ns 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hei g ht, W ei g ht, B MI Calc ulati o n c 
X 
X 
 
 
 
 
 
 
 
 
 
 
Alc o h ol a n d Dr u g Scree n d 
X 
X 
 
 
 
 
 
 
 
 
 
 
Ser ol o g y T est ( H B c A b, H Bs A g, H C V 
A b, HI V)  
X  
 
 
 
 
 
 
 
 
 
 
 
C o nfi ne me nt t o C R U 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assi g n me nt of S u bj ect N u m b er 
 
 
X 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n  e 
X 
X  
 
 
 
 
 
 
 
 
X 
 
Cli nical La b orat or y E val uati o ns 
(cli nical c he mistr y T S H [ Scree ni n g 
o nl y], he mat ol o g y, uri nal ysis)  f 
X  
X  
 
 
 
X 
 
 
 
 
X 
 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 4 of 6 0 
 
 
 
 
Scree ni n g 
C hec k-i n 
Tre at me nt 
C hec k- o ut 
F oll o w- u p 
E ve nts  
D a ys - 2 9 
t o -2 
D a y - 1 
D a y 
1 
D a y 
2 
D a y 
3 
D a y 
4  
D a y 
5  
D a y 
6  
D a y 
7  
D a y 
8 
Cli nic 
Disc h ar g e  
or E T a 
D a y 9 
S af et y F oll o w- u p 
C all ( a p pr o xi m atel y 
7 d a ys after Cli nic 
Disc h ar ge)  
Vital Si g ns ( oral te m perat ure, B P, heart 
rate, a n d res pirat or y rate) g 
X  
X  
X   
X 
X 
X 
X 
X 
X 
X 
X 
 
1 2-lea d E C G h 
X 
X 
X  
 
 
 
 
 
 
 
X 
 
Oral L O X O- 2 9 2 1 6 0 m g 
A d mi nistrati o n i 
 
 
X 
 
 
 
 
 
 
 
 
 
I V [1 4C]- L O X O- 2 9 2, < 1 0 0 μ g 
( ~ 1 μ Ci) A d mi nistrati o n i 
 
 
X 
 
 
 
 
 
 
 
 
 
A E, S A E, a n d C o nc o mita nt 
Me dicati o ns a n d Pr oce d ures 
M o nit ori n g a n d Rec or di n g 
m  
       X-------------------------------------------------------------- O n g oi n g------------------------------------------------------ X 
A E = a d verse e ve nt; B MI = b o d y mass i n de x; B P = bl o o d press ur e; C R U = Cli nical Rese arc h U nit; E C G = electr ocar di o gra m; E T = ear l y ter mi nati o n; 
H B c A b = he p atitis B c ore a nti b o d y; H Bs A g = he patitis B s urface a n ti ge n; H C V A b = he patitis C vir us a nti b o d y; HI V = h u ma n i m m u n odeficie nc y vir us; 
I V = i ntra ve n o us; S A E = seri o us a d verse e ve nt; T S H = t h yr oi d-sti m ulati n g h or m o ne. 
C CI

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 5 of 6 0 
 
 
 
a S u bj ects w h o wit h dr a w fr o m t he st u d y pri or t o Da y 9 s h o ul d u n der g o all disc har ge tests a n d assess me nts at E T, a n d will recei ve  a Safet y F oll o w- u p C all 
a p pr o xi matel y 7 da ys after E T.  
b A f ull me dical hist or y will b e rec or de d at Scree ni n g. A n i nteri m me dical hist or y u p date will be rec or de d o n Da y - 1. 
c Hei g ht a n d B MI will b e meas ure d at Scree ni n g o nl y. 
d Dr u g uri ne scree n ( w hic h i ncl u des c oti ni ne) will be c o n d ucte d at Scree ni n g a n d at C hec k-i n ( Da y - 1). A n alc o h ol breat h test will be c o n d ucte d at C hec k-i n 
o nl y. 
e A c o m plete p h ysical e xa mi nati o n will be c o n d ucte d at Scr ee ni n g a nd at Cli nic Disc har ge/ E T. A n a b bre viate d p h ysical e xa mi nati o n  ( ge neral, heart, l u n gs, 
a b d o me n, a n d s ki n) will be c o n d ucte d at C hec k-i n. 
f E ver y atte m pt will be ma de t o e ns ure bl o o d sa m ples f or t he cli nical c he mistr y pa nel are c ollecte d f oll o wi n g a fast fr o m f o o d f or at least 8 h o urs. T est f or T S H 
will b e perf or me d at Scree ni n g o nl y. Ot her cli nical la b orat or y e val uati o ns will be c o n d uct e d at Scree ni n g, C hec k-i n, o n Da y 4, a n d at Cli nic Disc har ge/ E T.  
g S u bj ects are t o re mai n s u pi ne f or at least 5 mi n utes pri or t o vital si g ns meas ure me nts. Vital si g ns will be o btai ne d at S cree ni n g; C hec k-i n; o n Da y 1 pre d ose, at 
2 h o urs p ost d ose relati ve t o oral d ose a d mi nistrati o n; a n d dail y ( 2 4- h o ur i nter vals) u p t o a n d i ncl u di n g da y of Cli nic Disc har g e/ E T. W he n sc he d ule d at t he sa me 
n o mi nal ti mes, p ost d ose vital si g ns meas ure me nts are t o  be perf or me d pri or t o p ost d ose P K bl o o d dra ws (see Secti o n 6. 5 ), wit h bl o o d dra ws occ urri n g as cl ose 
t o t he n o mi nal ti mes as p ossi ble. 
h S u bj ects are t o re mai n s u pi ne f or at least 5 mi n utes pri or t o E C G assess me nts. T he E C Gs will be o btai ne d at Scree ni n g a n d C hec k-i n, o n Da y 1 pre d ose a n d 
2 h o urs p ost d ose relati ve t o oral d ose a d mi ni strati o n, a n d at Cli nic Disc har ge/ E T. W he n sc he d ule d at t he sa me n o mi nal ti mes, p ost d ose E C Gs are t o be 
perf or me d pri or t o p ost d ose vital si g ns meas ure me nts a n d P K bl o o d dra ws (see Secti o n 6. 5 ), wit h bl o o d dra ws occ urri n g as cl ose t o t he n o mi nal ti mes as 
p ossi ble. 
i See Secti o n 4. 1  f or d osi n g details. 
j 
 
 
 
 
 
 
  
 
 
  
m A Es, S A Es, a n d c o nc o mita nt me dicati o ns a n d pr oc e d ures will be m o nit ore d a n d rec or de d t hr o u g h o ut t he st u d y fr o m t he ti me of si g n i n g t he i nf or me d c o nse nt,   
as descri be d i n Secti o n 6. 5. 1 , A p pe n di x C , a n d Secti o n 6. 3. 2 . A “ H o w D o Y o u Feel? ” A E i n q uir y will be perf or me d at Scree ni n g, C hec k -i n, eac h vital si g ns 
meas ure me nt, a n d d uri n g t he Safet y F oll o w- u p Call. 
 
C CI

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 6 of 6 0 
 
6. 2  St u d y Tre at me nt 
6. 2. 1  Dr u g S u p plies a n d Acc o u nt a bilit y 
T he S p o ns or ( or desi g nee) will pr o vi de t he I n v esti gat or ( or desi g nee) wit h a de q uate q ua ntities of 
t he st u d y dr u gs f or Part 1 (Ta ble 6- 3 ) a n d Part 2 ( Ta ble 6- 4 ). F or Part 1, n o nra di ola bele d 
L O X O- 2 9 2 ( pr o vi de d as a p o w der) a n d [ 1 4C]- L O X O- 2 9 2 ( pr o vi d e d as a s oli d) will be 
f or m ulate d b y C o va nce t o t he desire d c o n ce ntrati o n i n or der t o ac hi e ve t he fi nal oral d ose 
s ol uti o n ( ~ 4 0 μ Ci/ 1 6 0 m g per s u bject). F or t he oral d os e p orti o n of Part 2, n o nra di ola bele d 
L O X O- 2 9 2 will be s u p plie d b y t he S p o ns or as 2 x 8 0- m g ca ps ules. F or t he I V d ose p orti o n of 
Part 2, [ 1 4C]- L O X O- 2 9 2 ( pr o vi de d as a s oli d) will be f or m ulate d b y C o va n ce i n or der t o ac hie ve 
t he fi nal I V d ose s ol uti o n ( ~ 1 μ Ci/ < 1 0 0 μ g per s u bject). 
 
T a ble 6- 3  S u p plie d St u d y Dr u gs:  P a rt 1 
St u d y Dr u g 
[1 4C]- L O X O- 2 9 2 
L O X O- 2 9 2 
F or m a 
S oli d 
P o w der 
Stre n gt h 
N/ A 
N/ A 
S pecific Acti vit y 
~ 1 0 0 μ Ci/ m g  
N/ A 
S u p plier 
L o x o O nc ol o g y, I nc. 
L o x o O nc ol o g y, I nc. 
M a n uf act urer 
Selcia, Lt d. 
A vista P har ma S ol uti o ns, I nc. 
aS pecific i n gre die nts/ p urit y will be i d e ntifie d i n t h e Certificate of A nal ysis ( or e q ui vale nt) t h at is s u p plie d wit h t he st u d y d r u g(s). 
 
T a ble 6- 4  S u p plie d St u d y Dr u gs:  P a rt 2 
St u d y Dr u g 
L O X O- 2 9 2 
[1 4C]- L O X O- 2 9 2  
F or m a 
Oral Ca ps ule 
S oli d 
Stre n gt h 
8 0 m g 
N/ A 
S pecific Acti vit y 
N/ A 
~ 1 0 0 μ Ci/ m g  
S u p plier 
L o x o O nc ol o g y, I nc. 
L o x o O nc ol o g y, I nc. 
M a n uf act urer 
A vista P har ma S ol uti o ns, I nc. 
Selcia, Lt d. 
aS pecific i n gre die nts/ p urit y will be i d e ntifie d i n t h e Certificate of A nal ysis ( or e q ui vale nt) t h at is s u p plie d wit h t he st u d y d r u g(s). 
 
T he l ot n u m bers ( or e q ui vale nt) f or t he st u d y dr u gs will be pr o vi de d t o t he C R U b y t he 
s u p plier/ ma n ufact ur er w he n s u p plies are s hi p pe d. 
N o nra di ola bele d st u d y dr u g ca ps ules will be st ore d at r o o m te m perat ur e ( bet wee n 1 5 C a n d 
3 0 C) u n der sec ure c o n diti o ns. N o nra di ola bele d  st u d y dr u g p o w der will be st ore d at r o o m 
te m perat ur e ( bet w ee n 1 5 C a n d 3 0 C) u n der sec ure c o n diti o ns. Ra di ola bel e d st u d y dr u g will be 
st ore d fr oze n as i n dicat e d o n t he pr o d uct la bel a nd/ or Certificate of A nal ysis ( or e q ui vale nt).  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 7 of 6 0 
 
T he I n vesti gat or ( or desi g nee) will mai ntai n a n acc urate rec or d of t he recei pt of t he cli nical trial 
materials as s hi p pe d b y t he S p o ns or ( or desi g nee), i ncl u di n g t he dat e recei v e d. O ne c o p y of t his 
recei pt will be ret ur ne d t o t he S p o ns or w he n t he c o nte nts of t he s hi p me nt ha ve bee n verifi e d. I n 
a d diti o n, a n acc urate dr u g dis p ositi o n rec or d will be ke pt, s pecif yi n g t he a m o u nt dis pe nse d t o 
eac h s u bject a n d t he dat e of dis pe nsati o n. T his dr u g acc o u nta bilit y rec or d will be a vaila ble f or 
i ns pecti o n at a n y ti me. At t he c o m pleti o n of t he st u d y, t he ori gi nal dr u g acc o u nta bilit y rec or d 
will be a vaila ble f or re vi e w b y t he S p o ns or o n re q uest. 
At t he c o m pleti o n of t he st u d y, all u n use d dr u g s u p plies will be ret ur ne d t o t he S p o ns or ( or 
desi g nee) or dis p os e d of b y t he C R U per t he S p o ns or’s ( or desi g n ee’s) writte n i nstr ucti o ns.  
6. 2. 2  S u bject N u m ber a n d I de ntific ati o n 
After si g ni n g t he I C F, s u bjects will be assi g n e d a u ni q ue scree ni n g n u m b er b y t he st u d y site. 
S u bjects will be assi g ne d a s u bject n u m ber at t he ti me of t he first d osi n g o ccasi o n. Assi g n m e nt 
of n u m bers will be i n asce n di n g or der a n d n o n u m bers will be o mitt e d. S u bject n u m bers will be 
use d o n all st u d y d oc u m e ntati o n. F or s u bjects w h o are wit h dr a w n b y t he I n vesti gat or ( or 
desi g nee) or w h o v ol u ntaril y wit h dra w pre mat urel y fr o m t he st u d y, re place me nt s u bjects will be 
e nr olle d o nl y if dee m e d necessar y b y t he S p o ns or. Re place me nt s u bjects will be assi g ne d a 
s u bject n u m ber b y a d di n g 1 0 0 t o t he n u m ber of t h e s u bject t he y are re placi n g (e g, S u bject 
N o. 1 0 5 re pla ces S u bject N o. 0 0 5). 
6. 2. 3  D ose Pre p ar ati o n a n d A d mi nistr ati o n 
S pecific i nstr ucti o ns re gar di n g d ose pre p arati o n will be m ut uall y a gree d u p o n bet wee n t he 
S p o ns or a n d t he a p pr o pri ate cli nical staff a n d w ill be prese nt e d i n a se parat e d oc u me nt. 
Eac h u nit d ose will be pre pare d b y q u alifie d cl i nical staff. Eac h u nit d ose c o ntai ner will be 
a p pr o priatel y la b ele d. 
A p pr o priate u nit d oses, as descri be d a b o ve, will be a d mi nistere d t o c o nsec uti vel y- n u m bere d 
s u bjects. Alt h o u g h t he ti mi n g of e v e nts re q uir es t hat eac h s u bject will be c o nsiste ntl y 
a d mi nistere d t he a p pr o priate d ose at s pe cific ti mes, t he e x act d ose ti me of c o nsec uti ve s u bjects 
ma y b e sta g gere d t o o b viate t he nee d t o ha ve all s u bjects o n precisel y t he s a me st u d y s c he d ule. 
F or eac h d ose, t h e s u bject’s act ual d ose ti me will be rec or de d i n t he s o urce d oc u me nts a n d 
tra nscri be d i nt o t he e C R Fs. 
Eac h oral d ose will be a d mi nist ere d orall y w it h a p pr o xi matel y 2 4 0 m L r o o m te m perat ure water. 
A ha n d a n d m o ut h c hec k will be perf or me d t o v e rif y t hat t he d os e a d mi nistere d was s wall o we d. 
Oral d oses will be prece d e d b y a n o ver ni g ht f ast (i e, at least 8 h o urs) fr o m f o o d ( n ot i ncl u di n g 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 8 of 6 0 
 
water) a n d will be f oll o w e d b y a fast fr o m f o o d ( n ot i ncl u di n g water) f or at least 4 h o urs 
p ost d ose. E x ce pt as part of d ose a d mi nistrati o n, s u bjects will restrict t heir c o ns u m pti o n of water 
f or 1 h o ur pr e d ose a n d f or 2 h o urs p ost d ose; at all ot her ti mes d uri n g t he st u d y, s u bjects ma y 
c o ns u me water a d li bit u m. 
E x ce pt w he n t he y are usi n g t he t oilet, st u d y s u bj ects will be o bser ve d f or a p pr o xi matel y 4 h o urs 
p ost d ose. S u bjects will n ot la y s u pi ne f or 1 h o ur f oll o wi n g eac h d ose a d mi nistere d, e x ce pt as 
necessitate d b y t he o cc urre nce of a n A E(s) a n d/ or st u d y pr oce d ures. 
6. 2. 4  Bli n di n g 
T his is a n o pe n-la bel st u d y. 
6. 3  St u d y Restricti o ns 
6. 3. 1  Diet, Fl ui d, a n d Acti vit y C o ntr ol 
S u bjects are re q uire d t o r efrai n fr o m use of t o bacc o- or nic oti ne-c o nt ai ni n g pr o d ucts wit hi n 
3 m o nt hs pri or t o C hec k-i n u ntil Cli nic Disc har ge. 
F o o ds a n d be v era ges c o ntai ni n g p o p p y see ds, gra p efr uit, or Se ville ora n ges will n ot be all o we d 
fr o m 7 da ys pri or t o C hec k-i n u ntil Cli nic Disc har ge. 
S u bjects are re q uire d t o a bstai n fr o m c o ns u mi n g alc o h ol-, caffei ne-, or xa nt hi ne-c o ntai ni n g 
f o o ds a n d be vera ges fr o m 7 2 h o urs pri or t o C heck-i n u ntil Cli nic Disc har ge, u nl ess dee me d 
acce pta ble b y t he I n v esti gat or ( or desi g n ee). 
S u bjects will refrai n fr o m stre n u o us e x ercise fr o m 4 8 h o urs pri or t o C hec k-i n a n d d uri n g t he 
peri o d of c o nfi n e me nt at t he C R U a n d will ot her wise mai ntai n t heir n or mal le vel of p h ysical 
acti vit y t hr o u g h o ut t he e ntire st u d y (ie, will n ot be gi n a ne w e x ercise pr o gra m or partici p ate i n 
a n y u n us u all y str e n u o us p h ysical e x erti o n). 
W hile c o nfi ne d at t he C R U, s u bjects will recei v e  a sta n dar dize d hi g h-fi ber diet at sc he d ule d 
ti mes t hat d o n ot c o nflict wit h ot her st u d y-related acti vities. Pitte d pr u nes or pr u ne j uice m a y be 
gi ve n o n a n as- n ee de d b asis t o ai d i n n or mal b o wel f u ncti o n a n d will n ot be c o nsi dere d a 
c o nc o mita nt me dicati o n.  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 3 9 of 6 0 
 
6. 3. 2  C o nc o mit a nt Me dic ati o ns 
S u bjects will refrai n fr o m partici pati o n i n a n y ot her i n vesti gati o nal st u d y dr u g tri al i n w hic h 
recei pt of a n y i n vesti gati o nal dr u g occ urre d wit hi n 3 0 da ys or 5 half-li ves (if k n o w n), w hic h e ver 
is l o n ger, pri or t o C hec k-i n u ntil Cli nic Disc har ge. 
S u bjects will refrai n fr o m t he use of a n y me dicati o ns/ pr o d ucts k n o w n t o alter dr u g A M E 
pr ocesses, i n partic ular str o n g i n d u cers or i n hi bit ors of C Y P 3 A 4 , i ncl u di n g St. J o h n’s w ort, 
wit hi n 3 0 da ys pri or t o C hec k-i n, u nless dee me d acce pta bl e b y t he I n vesti gat or ( or desi g n ee). 
S u bjects will als o refrai n fr o m t he use of a n y pres cri pti o n me dicati o ns/ pr o d ucts d uri n g t he 
i nter val fr o m 1 4 da ys pri or t o C hec k-i n t hr o u g h Cli nic Disc har ge, u nless d ee me d acce pta ble b y 
t he I n v esti gat or ( or d esi g nee). I n a d diti o n, s u bjects will refrai n fr o m t he use of a n y 
o ver-t he- c o u nter n o n pres cri pti o n me dicati o ns  (i ncl u di n g vita mi ns, mi nerals, a n d 
p h yt ot hera pe utic/ her bal/ pla nt- deri ve d pre parati o ns) fr o m 7 da ys pri or t o C hec k-i n t hr o u g h Cli nic 
Disc har ge, u nl ess dee me d acce pta ble b y t he I n v esti gat or ( or desi g nee). 
Pitte d pr u nes or pr u ne j ui ce ma y be us e d t o h el p wit h b o wel m o ve me nts if necessar y. U p t o 
2 gra ms per d a y of aceta mi n o p he n ma y b e a d mi nist ere d if a p pr o ve d b y t he I n v esti gat or ( or 
desi g nee). T h e a d mi nistrati o n of a n y ot her c o nc o mita nt me dicati o ns d uri n g t he st u d y is 
pr o hi bite d wit h o ut pri or a p pr o val of t he I n vesti gat or ( or desi g nee), u nless its use is dee me d 
necessar y i n a me dic al e mer ge nc y. A n y m e dicati o n ta ke n b y a s u bject d uri n g t he st u d y a n d t he 
reas o n f or its use will be d oc u me nte d i n t he s o urce d oc u me nts a n d t he e C R F.  
6. 3. 3  C o ntr ace pti o n 
Males w h o are ca pa ble of fat heri n g a c hil d m ust  a gree t o use o n e of t he f oll o wi n g effecti ve 
met h o ds of c o ntrace pti o n or a bstai n fr o m se x ual i nterc o urse fr o m t he ti me of t he first d ose 
t hr o u g h 6 m o nt hs after st u d y dr u g a d mi nistrati o n: 
 Male steriliz ati o n, wit h d oc u me nte d c o nfir mati o n of s ur gical s uc cess. Male s u bjects will 
be s ur gicall y sterile f or at least 9 0 da ys pri or t o C hec k-i n. If d oc u me ntati o n is n ot 
a vaila ble, male s u bjects m ust f oll o w t he c o ntrace pti o n met h o ds bel o w: 
o  Male c o n d o m wit h s per mici de, a n d 
o  F or fe male part ner of m ale st u d y partici pa nt: 
 i ntra uteri ne de vice (I U D; h or m o nal I U D; e g, Mir e na® ). C o p per I U Ds are 
acce pta ble (e g, Para Gar d ® ); 
 esta blis he d use of oral, i m pla nte d, tra ns der mal, or h or m o nal met h o d of 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n; 
 bilateral t u bal li gati o n; or 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 0 of 6 0 
 
 s p o n ge, cer vi cal ca p, or dia p hra g m ( barrier m et h o d). 
S u bjects w h o practice tr u e a bsti ne nce b eca use of t he s u bject’s lifest yle c h oi ce (ie, t he s u bj ect 
s h o ul d n ot bec o me a bsti ne nt j ust f or t he p ur p ose of st u d y partici pati o n) are e x e m pt fr o m 
c o ntrace pti ve re q uir e me nts. Peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds f or t he fe mal e part ner of a male s u bject) a n d wit h dra wal are n ot 
acce pta ble met h o ds of c o ntrace pti o n. If a s u bject w h o is a bsti ne nt at t he ti me of si g ni n g t he I C F 
bec o mes se x uall y acti ve, t he y m ust a gree t o use c o ntrace pti o n as d escri be d a b o ve.  
F or male s u bjects, se x ual i nterc o urse wit h f e male  part ners w h o are pre g n a nt or breastf ee di n g 
s h o ul d be a v oi de d u nless c o n d o ms wit h s per mici de are us e d fr o m t he ti me of t he first d ose u ntil 
6 m o nt hs after t he last d ose of st u d y dr u g. Male s u bjects are re q uir e d t o refrai n fr o m d o nati o n of 
s per m fr o m C hec k-i n u ntil 6 m o nt hs after t he last d ose of st u d y dr u g. 
F or s u bjects w h o are e x cl usi vel y i n sa me-s e x relati o ns hi ps, c o ntrace pti ve re q uire me nts d o n ot 
a p pl y. 
6. 4  P h ar m a c o ki netic, [ 1 4C] R a di o acti vit y, a n d Met a b olite Pr o ce d ures 
6. 4. 1  P h ar m a c o ki netic, [ 1 4C] R a di o acti vit y, a n d Met a b olite Bl o o d S a m ple C ollecti o n 
Part 1: 
Bl o o d sa m ples f or L O X O- 2 9 2 a nal ysis, t otal ra di oacti vit y, a n d m eta b olite 
pr ofili n g/c h aracteriz ati o n will be c ollecte d v ia direct ve ni p u nct ure. Bl o o d sa m ples will be 
c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 6- 1 . 
Part 2: 
Bl o o d sa m ples f or d eter mi na ti o n of L O X O- 2 9 2 a n d [1 4C]- L O X O- 2 9 2 pl as ma c o nce ntr ati o ns will 
be c ollecte d via direct v e ni p u nct ure. Bl o o d sa m pl es will be c ollecte d at t he ti me p oi nts s pecifie d 
i n Ta ble 6- 2 . 
Pr ocessi n g, st or a ge, a n d s hi p pi n g i nstr ucti o ns f or t hese bl o o d sa m ples will be prese nt e d i n a 
se parat e d oc u me nt. 
6. 4. 2  P h ar m a c o ki netic, [ 1 4C] R a di o acti vit y, a n d Met a b ol ite Uri ne S a m ple C ollecti o n 
Part 1: 
Uri ne sa m ples f or t otal ra di oacti vit y c o n ce ntrat i o ns a n d meta b olite pr ofili n g/c haracterizati o n will 
be c ollecte d at t he ti me i nter vals s pecifi e d i n Ta bl e 6- 1 . 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 1 of 6 0 
 
Part 2: 
Uri ne sa m ples f or deter mi nati o n of L O X O- 2 9 2, [ 1 4C]- L O X O- 2 9 2, a n d t otal ra di oacti vit y 
c o nce ntr ati o ns will be c ollecte d at t he ti me i nter vals s pecifie d i n  Ta ble 6- 2. 
Pr ocessi n g, st or a ge, a n d s hi p pi n g i nstr ucti o ns f or  t hese uri ne sa m ples will be prese nt e d i n a 
se parat e d oc u me nt. 
6. 4. 3   [1 4C] R a di o acti vit y a n d Met a b olite Fec al S a m ple C ollecti o n 
Part 1: 
Fecal sa m ples f or t otal r a di oacti vit y c o n ce ntrat i o ns a n d meta b olite pr ofili n g/c haracterizati o n will 
be c ollecte d at t he ti me i nter vals s pecifi e d i n Ta bl e 6- 1 . If p ossi ble, a si n gl e baseli ne fecal 
sa m ple will be c ollecte d fr o m after C hec k-i n o n D a y - 1 u ntil j ust pri or t o d ose a d mi nistrati o n o n 
Da y 1. 
Part 2: 
Fecal sa m ples f or d eter mi nati o n of t o tal ra di oacti vit y c o nce ntrati o ns will be c ollecte d at t he ti me 
i nter vals s pecifie d i n T a ble 6- 2. If p ossi ble, a si n gl e baseli ne fecal sa m ple will be c ollecte d fr o m 
after C hec k-i n o n Da y - 1 u ntil j ust pri or t o d ose a d mi nistrati o n o n Da y 1. 
Pr ocessi n g, st or a ge, a n d s hi p pi n g i nstr ucti o ns f or  t hese fecal sa m ples will be prese nt e d i n a 
se parat e d oc u me nt. 
6. 4. 4  E mesis S a m ple C ollecti o n 
I n Part 1, f or s u bjects e x perie nci n g e m esis wit hi n 2 h o urs f oll o wi n g d osi n g, v o mit us will be 
c ollecte d. All v o mit us c ollecte d will be st ore d f or p ossi ble a nal ysis. T he ti me a n d date of 
c ollecti o n will be rec or de d o n t he s u bject’s s o urce d oc u me nts a n d e C R F. V o mit us will be 
a nal yze d as dee m e d a p pr o priat e. 
6. 4. 5  A n al ytic al Met h o d ol o g y 
I n Part 1, c o nce ntrati o ns of t otal ra di oacti vit y will be deter mi ne d i n w h ole bl o o d, plas ma, uri ne, 
a n d feces usi n g li q ui d sci ntillati o n c o u nti n g ( L S C).  Plas ma c o nce ntr ati o ns of L O X O- 2 9 2 will be 
deter mi ne d usi n g a vali d ate d bi oa nal ytical met h o d. Pr ofili n g a n d c h aracterizati o n of meta b olites 
i n plas ma, uri ne, a n d feces will be co n d ucte d usi n g sta n dar d la b orat or y pr oce d ures.  
I n Part 2, c o nce ntrati o ns of t otal ra di oacti vit y i n uri ne a n d feces will be d eter mi ne d usi n g A M S 
a n d/ or L S C. Plas ma a n d uri ne c o nce ntrati o ns of [ 1 4C]- L O X O- 2 9 2 will be d eter mi ne d usi n g hi g h 
perf or ma n ce li q ui d c hr o mat o gra p h y fracti o nati o n f oll o we d b y A M S a nal ysis. Plas ma a n d uri ne 
c o nce ntr ati o ns of L O X O- 2 9 2 will be deter mi ne d usi n g a v ali date d bi oa nal ytical met h o d. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 2 of 6 0 
 
S pecifics of t he a n al yti cal met h o ds will be pr o vi de d i n a se parate d oc u me nt.  
6. 5  S afet y Pr oce d ures 
Safet y e val uati o ns ma y b e re peate d at t he I n vesti gat or’s  ( or d esi g n ee’s) discreti o n. 
 
E ver y eff ort will be ma d e t o sc he d ule a n d p e rf or m t he pr oce d ures i n acc or da nce wit h t he 
n o mi nal ti me, gi vi n g c o nsi derati o ns t o a p pr o pri ate p ost ure c o n diti o ns, practical restricti o ns, a n d 
t he ot her pr oce d ures t o b e perf or me d at t he s a me ti me p oi nt. E x ce pt f or at Scree ni n g a n d 
C hec k-i n, t he or der of pri orit y f or s c he d uli n g pr oce d ures ar o u n d a ti me p oi nt is (i n desce n di n g 
or der of pri orit y): 
 D osi n g 
 P ost d ose P K bl o o d sa m pli n g ( w hic h i ncl u d es L O X O- 2 9 2, [ 1 4C]- L O X O- 2 9 2 [ Part 2 o nl y], 
a n d t otal ra di oacti vit y c o nce ntrati o ns, a n d met a b olite pr ofili n g/c haract erizati o n [ Part 1 
o nl y]) 
 Start a n d e n d of uri ne a n d fecal c ollecti o ns (f or dr u g ass a y) 
 Vital si g ns meas ur e me nts 
 E C Gs 
 Bl o o d a n d uri ne s a m ples f or cli nical la b orat ories 
 P h ysical e x a mi nati o ns. 
6. 5. 1  A d verse E ve nts 
A d verse e ve nt defi niti o ns; assi g n me nt of se v e rit y, ca usalit y, acti o n ta ke n, a n d o utc o me; a n d 
pr oce d ures f or re p orti n g seri o us A Es ( S A Es) are d etaile d i n A p pe n di x C . 
T he c o n diti o n of eac h s u bject will be m o nit ore d fr o m ti me of si g ni n g t h e I C F t o Cli nic 
Disc har ge. I n a d diti o n, s u bjects will be o bser ve d f or a n y si g ns or s y m pt o ms a n d as ke d a b o ut 
t heir c o n diti o n b y o pe n q uesti o ni n g, s uc h as “ H o w d o y o u feel? ” or “ H o w h a ve y o u bee n feeli n g 
si nce y o u were last as ke d ? ”, as s pecifie d i n Ta ble 6- 1  a n d Ta ble 6- 2 , t o ass ess f or t he oc c urre nce 
of A Es. S u bjects will als o be e nc o ura ge d t o s p o nt a ne o usl y re p ort A Es occ urri n g at a n y ot her 
ti me d uri n g t he st u d y. 
All A Es, w het her v ol u nteere d, i de ntifie d b y t h e s u bject’s res p o ns es t o H o w D o Y o u Feel? 
i n q uiries, or n ote d o n la b orat or y tests, vit al si g ns meas ure me nts, E C Gs, or p h ysical 
e x a mi nati o ns, will be rec or de d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F u ntil St u d y 
C o m pleti o n), eit her as s u bject me dical hist or y (if t he e ve nt is n o nseri o us a n d re p orte d pri or t o 
d osi n g) or as A Es (if s eri o us or t he e ve nt occ urs  after a d mi nistrati o n of L O X O- 2 9 2). T h e nat ure, 
ti me of o nset, d urati o n, a n d se verit y will be d oc u me nte d, t o get her wit h a n I n v esti gat or’s ( or 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 3 of 6 0 
 
desi g nee’s) o pi ni o n of t h e  relati o ns hi p t o st u d y dr u g. A d verse e ve nts rec or de d d uri n g t he c o urse 
of t he st u d y will be f oll o we d u p, w here p ossi ble, u ntil t he y ha ve res ol ve d or bec o me sta bl e. T his 
will be c o m plete d at t he I n vesti gat or’s ( or desi g n ee’s) discreti o n.  
S u bjects will recei ve a Safet y F oll o w- u p Call a p pr o xi matel y 7 d a ys after t he y are dis c har ge d 
fr o m t he C R U t o deter mi ne if a n y A E h as occ urre d si nce t he last st u d y visit. 
At all ti mes, a s u bject ma y be re q uir e d t o re mai n at t he C R U f or l o n ger at t he discreti o n of t he 
I n v esti gat or ( or desi g n ee). 
Si nce t he safet y pr ofile of L O X O- 2 9 2 i n h u ma ns has n ot bee n f ull y esta blis he d, all S A Es relate d 
t o L O X O- 2 9 2 will be c o nsi dere d u ne x pecte d a n d re p orte d as s us pecte d u ne x pecte d seri o us 
a d verse reacti o ns. 
6. 5. 2  Cli nic al L a b or at or y E v al u ati o ns 
Cli nical la b orat or y e val u ati o ns (i ncl u di n g cli nical c he mistr y p a nel [s h o ul d be faste d at least 
8 h o urs], t h yr oi d-sti m ulati n g h or m o ne [ Scree ni n g o nl y], he m at ol o g y, a n d uri nal ysis; 
A p pe n di x A ) will be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 6- 1  a n d Ta ble 6- 2 .  
Scree ns f or a he p atitis pa nel a n d HI V a nti b o d y will be perf or m e d at Scree ni n g. A dr u g scree n f or 
selecte d dr u gs of a b use, i ncl u di n g c oti ni ne ( n ot i n cl u di n g al c o h ol), will be perf or me d at 
Scree ni n g a n d re peate d (i ncl u di n g al c o h ol) at C hec k-i n.  
6. 5. 3   Vit al Si g ns 
Vital si g ns meas ur e me nts (i ncl u di n g oral te m perat ure, B P, heart rat e, a n d res pirat or y rate) will 
be o btai ne d at t he ti me p oi nts s pecifie d i n Ta ble 6- 1  a n d Ta ble 6- 2 . Vital si g ns will be meas ure d 
after t he s u bje ct has bee n s u pi ne f or at least 5 mi n utes. 
6. 5. 4   T w el ve-le a d Electr oc ar di o gr a ms 
A 1 2-lea d E C G will be o btai ne d at t he ti me p oi nts s pecifie d i n Ta ble 6- 1  a n d Ta ble 6- 2.  S u bjects 
will be s u pi ne f or at least 5 mi n utes pri or t o o btai ni n g a n E C G meas ure m e nt. 
T he E C G para meters (i n cl u di n g heart rate; P R, Q R S, a n d Q T i nter vals; a n d Q Tc F) a n d t he 
I n v esti gat or’s ( or desi g nee’s) o verall i nter pretati o n of t he E C G will be rec or de d i n t he e C R F. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 4 of 6 0 
 
6. 5. 5   P h ysic al E x a mi n ati o ns 
C o m plete p h ysical e x a mi nati o ns a n d a b bre vi ate d p h ysical e x a mi nati o n ( ge neral, heart, l u n gs, 
a b d o me n, a n d s ki n) will be perf or me d at t he ti me p oi nts s pecifie d i n Ta ble 6- 1  a n d Ta ble 6- 2 . 
T he ti me a n d date of t he p h ysical e x a mi nati o n will  be rec or de d i n t he e C R F a n d a n y cli nicall y 
si g nifica nt fi n di n gs will be rec or de d as A Es. 
7   D A T A A N A L Y S E S A N D S A M P L E SI Z E 
7. 1  S a m ple Size 
T he sa m ple siz es c h ose n f or Parts 1 a n d 2 of t h is st u d y were bas e d o n prece de nt set b y ot her 
A M E a n d a bs ol ute bi oa v aila bilit y st u dies of si milar nat ur e a n d were n ot base d o n p o wer 
calc ulati o ns. 
7. 2  St u d y P o p ul ati o ns 
T he P K P o p ulati o ns f or Parts 1 a n d 2 will c o nsist of all s u bjects w h o recei ve d at least 1 d ose of 
st u d y dr u g a n d h a ve e val ua ble P K data. 
T he Safet y P o p ulati o n will c o nsist of all s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g. 
T he All S u bject P o p ulati o n will c o nsist of a n y s u bjects w h o e nr olle d o n t o t he st u d y (si g ne d 
i nf or me d c o nse nt). 
7. 3  P h ar m a c o ki netic A n al ysis 
Part 1: 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d f or eac h s u bject, base d o n 
t he plas ma c o nce ntrati o ns of L O X O- 2 9 2 a n d t he w h ole bl o o d a n d plas ma c o nce ntr ati o ns of t otal 
ra di oacti vit y, acc or di n g t o t he m o del i n de pe n de nt a p pr oac h. 
C ma x  
ma xi m u m o bser ve d c o nce ntrati o n 
T ma x    
ti me t o ma xi m u m o bser ve d c o nce ntrati o n 
A U C last 
A U C fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntr ati o n, 
calc ulate d usi n g t he li near tra pez oi dal r ule f or i ncreasi n g 
c o nce ntr ati o ns a n d t he l o garit h mic r ule f or decreasi n g 
c o nce ntr ati o ns 
A U C 0-   
  
A U C e xtra p olate d t o i nfi nit y, cal c ulate d usi n g t he f or m ula: 
A U C 0-  = A U Clast + ( Clast ÷ 
z)  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 5 of 6 0 
 
w here C last is t he last q ua ntifia ble c o nce ntr ati o n a n d 
z is t he 
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt 
z  
 
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt,  
 
  
w here
 Z  is t he ma g nit u d e of t he sl o pe of t he li near re gressi o n of 
t he l o g c o n ce ntr ati o n vers us-ti me pr ofile d uri n g t he ter mi nal p hase 
t1/ 2  
 
a p pare nt ter mi nal eli mi nati o n half-life ( w he ne v er p ossi ble),  
 
  
w here
 
t
1/ 2 = nat ural l o g ( 2)/ z 
C L/ F   
a p pare nt s yste mic cleara nce (f or L O X O- 2 9 2 o nl y) 
V z/ F   
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase (f or 
L O X O- 2 9 2 o nl y) 
 
Bl o o d/ Plas ma A U C Rati o 
 A U C
0- ∞ of t otal ra di oacti vit y i n w h ole bl o o d/ A U C0- ∞ of t otal 
ra di oacti vit y i n plas ma 
 
Plas ma L O X O- 2 9 2 / T otal Ra di oacti vit y A U C Rati o 
 A U C
0- ∞ of L O X O- 2 9 2 i n plas ma/ A U C0- ∞ of t otal ra di oacti vit y i n 
plas ma. 
 
A d diti o nall y, bl o o d-t o- pl as ma rati os at eac h sa m p li n g ti me p oi nt will be calc ulate d t o deter mi ne 
partiti o ni n g of t otal ra di o acti vit y i nt o re d bl o o d cells.  
I n a d diti o n, f or eac h s u bj ect, t he f oll o wi n g P K para meters will be calc ulate d w he ne ver p ossi ble, 
base d o n t he uri ne c o nce ntrati o ns of t otal ra di oacti vit y: 
A e u  
 
a m o u nt e x crete d i n uri ne per sa m pli n g i nter val 
C u m A e u 
c u m ulati ve a m o u nt e x crete d i n uri ne 
 
%f e u   
perce nt a ge of d os e e x cret e d i n uri ne per sa m pli n g i nter val, w here 
%f e u = 1 0 0 ( Ae u/ d ose) 
C u m %f e u  
c u m ulati ve perce nta ge of d ose e x crete d i n uri ne. 
 
F or eac h s u bject, t he f oll o wi n g P K para meters will be calc ulate d w he ne v er p ossi ble, base d o n 
t he fecal c o nce ntrati o ns of t otal ra di oacti vit y: 
 
Aef 
a m o u nt e x crete d i n feces per sa m pli n g i nter val 
C u m A ef 
c u m ulati ve a m o u nt e x crete d i n feces 
 %f
ef 
perce nt a ge of d os e e x cret e d i n feces per sa m pli n g i nter val, w here 
%f ef = 1 0 0 ( Aef/ d ose) 
C u m %f ef  
c u m ulati ve perce nta ge of d ose e x crete d i n feces. 
  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 6 of 6 0 
 
Part 2: 
Oral d ose P K:  W he ne ver p ossi ble, t he f oll o w i n g P K para meters will be calc ulate d f or eac h 
s u bject, base d o n t he plas ma c o nce ntr ati o ns of L O X O- 2 9 2: 
C ma x  
ma xi m u m o bser ve d c o nce ntrati o n 
T ma x    
ti me t o ma xi m u m o bser ve d c o nce ntrati o n 
A U C last 
A U C fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntr ati o n 
A U C 0-   
  
A U C e xtra p olate d t o i nfi nit y, cal c ulate d as d escri be d a b o ve 
z  
 
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt 
t1/ 2  
 
a p pare nt ter mi nal eli mi nati o n half-life ( w he ne v er p ossi ble),  
 
  
w here
 
t
1/ 2 = nat ural l o g ( 2)/ Z 
F  
 
a bs ol ute bi oa vaila bilit y, calc ulate d usi n g t he f or m ula: 
  
 
F = A U C 0- ∞ ( oral) x D ose (I V) 
  
 
      A U C0- ∞ (I V) x D ose ( oral) 
C L/ F    
a p pare nt  s yste mic  cleara nce  
V z/ F   
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase. 
 
I ntr a ve n o us d ose P K:  F or eac h s u bj ect, t he f oll o wi n g P K para meters will be calc ul ate d 
w he ne ver p ossi ble, base d o n t he plas ma c o nce ntrati o ns of [ 1 4C]- L O X O- 2 9 2: 
C ma x  
ma xi m u m o bser ve d c o nce ntrati o n 
T ma x    
ti me t o ma xi m u m o bser ve d c o nce ntrati o n 
A U C last 
A U C fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntr ati o n 
A U C 0-   
  
A U C e xtra p olate d t o i nfi nit y, cal c ulate d as d escri be d a b o ve 
z  
 
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt 
t1/ 2  
 
a p pare nt ter mi nal eli mi nati o n half-life ( w he ne v er p ossi ble),  
 
  
w here
 
t
1/ 2 = nat ural l o g ( 2)/ Z 
C L
 
  
s yste mic
 
cl eara nce
 
V z  
 
v ol u me of distri b uti o n d uri n g t he ter mi nal p hase 
V ss  
 
v ol u me of distri b uti o n at stea d y st ate. 
 
I n a d diti o n, f or eac h s u bj ect, t he f oll o wi n g P K para meters will be calc ulate d w he ne ver p ossi ble, 
base d o n t he uri ne c o nce ntrati o ns of L O X O- 2 9 2, [ 1 4C]- L O X O- 2 9 2, a n d t otal ra di oacti vit y: 
A e u  
 
a m o u nt e x crete d i n uri ne per sa m pli n g i nter val 
C u m A e u 
c u m ulati ve a m o u nt e x crete d i n uri ne 
C L R  
re nal cleara nce ( L O X O- 2 9 2 a n d [1 4C]- L O X O- 2 9 2 o nl y), w here 
C L R  = Ae u/ A U C 
 
A U C 0- ∞ ma y b e use d, if a p pr o priate  
 
%f e u   
perce nt a ge of d os e e x cret e d i n uri ne per sa m pli n g i nter val, w here 
%f e u = 1 0 0 ( Ae u/ d ose) 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 7 of 6 0 
 
C u m %f e u  
c u m ulati ve perce nta ge of d ose e x crete d i n uri ne. 
 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d f or eac h s u bject, base d o n 
t he fecal c o nce ntrati o ns of t otal ra di oacti vit y: 
 
Aef 
a m o u nt e x crete d i n t he feces per sa m pli n g i nter val 
C u m A ef 
c u m ulati ve a m o u nt e x crete d i n feces 
 %f
ef 
perce nt a ge of d os e e x cret e d i n feces per sa m pli n g i nter val, w here 
%f ef = 1 0 0 ( Aef/ d ose) 
C u m %f ef  
c u m ulati ve perce nta ge of d ose e x crete d i n feces. 
 
P har mac o ki netic calc ulati o ns will be perf or me d, if a p pr o priate, us i n g c o m m ercial s oft ware s u c h 
as P h oe ni x ™ Wi n N o nli n®  Versi o n 6. 4 or hi g h er ( Certara U S A I nc.). 
P har mac o ki netic para met ers f or rele va nt met a b olites  of L O X O- 2 9 2 m a y be calc ulate d i n Part 1 
a n d/ or Part 2, as dee me d a p pr o priate, base d o n plas ma, uri ne, a n d/ or fecal c o nce ntrati o n le vels.  
Ot her para meters m a y be a d de d as a p pr o priate. Fi na l P K para meters re p orte d will be detaile d i n 
t he Statistical A nal ysis Pla n ( S A P). 
P har mac o ki netic a n al ysis will use act ual ti mes  as rec or de d o n t h e e C R F. Ot her data ha n dli n g 
pr oce d ures will be detail e d i n t he S A P. 
7. 4  St atistic al A n al ysis of P h ar m a c o ki netic D at a 
F or Parts 1 a n d 2, d escri pti ve statistics ( n u m ber of o bser vati o ns, arit h metic mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, ma xi m u m, ge o metric m ea n, a n d ge o metric c oeffi cie nt of variati o n) 
will be calc ulate d f or t he P K para meters. N o  f or m al statistical a nal ys es are pla n ne d. 
S pecificati o n of P K para meters f or a nal ysis; pr oce d ures f or acc o u nti n g f or missi n g, u n us e d, or 
s p uri o us data; pr oce d ures f or re p orti n g d e viati o ns fr o m t he ori gi nal statistical pla n; a n d selecti o n 
of s u bjects t o be i ncl u de d i n t he a nal ys es p o p ulati o n(s), as a p plica ble, will be prese nt e d i n t he 
Cli nical St u d y Re p ort a n d/ or S A P as a p pr o priate. 
7. 5  St atistic al A n al yses of S afet y D at a 
F or Parts 1 a n d 2, d escri pti ve statistics will be calc ulate d o n t he safet y p ara meters. N o f or m al 
statistical a nal ys es are pla n ne d. 
All A Es will be c o de d b y t he Me dical Dicti o na r y f or Re g ul at or y Acti vities ( Versi o n 2 0. 0 or 
hi g her). Eac h si g n or s y m pt o m re p orte d will be gra de d o n t he Nati o nal I nstit uti o n of Healt h’s 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 8 of 6 0 
 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts Versi o n 5. 0 ( or hi g her) t o xicit y gra di n g scale 
as refere n ce d i n  A p p e n di x C . T he n u m ber ( %) of s u bjects wit h a n y A E will be s u m marize d b y 
s yste m or ga n class a n d preferre d t er m. Des cri pti ve statistics will be pr o vi de d f or cli nical 
la b orat or y val u es, vital si g ns, a n d E C Gs. C o nc o mita nt me dicati o ns will be liste d a n d c o de d 
acc or di n g t o t he W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y ( Se pte m ber 2 0 1 5 or later). 
A d diti o nal details will be pr o vi de d i n t he S A P. 
7. 6  D at a H a n dli n g a n d Rec or d Kee pi n g 
A n y c ha n ges t o i nf or mati o n i n t he trial pr o gress n otes a n d ot her s o urce d oc u me nts will be 
i nitiale d a n d date d o n t he da y t h e c ha n ge is ma de b y a C R U staff me m ber a ut h orize d t o ma ke t he 
c ha n ge. C ha n ges will be ma de b y stri ki n g a si n gle li ne t hr o u g h err o ne o us d ata a n d cl earl y 
e nteri n g t he c orrect data (e g, wr o n g d ata ri g ht dat a ). If t he reas o n f or t he c ha n ge is n ot a p pare nt, 
a brief e x pla nati o n f or t he c ha n ge will be writ te n a djace nt t o t he c h a n ge b y t he cli nicia n. 
T he Data M a na ge m e nt Pla n will be a p pr o ve d b y t he S p o ns or. 
Data will be vali date d d uri n g dat a e ntr y b y t he C R U a n d verifi e d b y t he St u d y M o nit or. Dat a will 
t he n be re vie we d b y t he data ma na ge me nt gr o u p t o res ol ve a n y o utsta n di n g iss ues. Listi n gs will 
be ge nerate d after t he d at a base is clea ne d b y  Data Ma na ge me nt a n d will be re vie we d b y t h e 
C o va nce scie ntific t ea m. T he e C R F a n d a ncillar y da ta will be c o n verte d i nt o fi nal S A S datasets 
f oll o wi n g St u d y Data Ta b ulati o n M o del or clie nt-pr o vi de d s pecificati o ns. T he fi nal datas ets 
str uct ure will be verifie d usi n g We b S u b missi o n Data Ma na ger® , w hile t he dataset c o nte nt will 
be peer re vie we d b y a n i n de pe n de nt pr o gra m mer. 
T he ta bles, fi g ures, a n d listi n gs ( T F Ls) will be  pr o gra m me d per t h e fi nal S A P. All T F Ls will be 
peer re vie we d b y a n i n de pe n de nt pr o gra m mer. I n a d diti o n, draft T F Ls will be re vie we d b y t he 
C o va nce scie ntific t ea m d uri n g t he dr y r u n a n d d ata re vie w meeti n gs. 
T he peer re vie w will be perf or me d b y i n d e pe n de nt pr o gra m mers f oll o wi n g t he q ualit y c o ntr ol 
pr ocess a n d pr o gra m mi n g c h ec klists. 
7. 7  Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce 
Q ualit y c o ntr ol a n d q ualit y ass ur a nce will be pe rf or me d acc or di n g t o C o va nce sta n dar d o perati n g 
pr oce d ures or per clie nt r e q uest a n d as a p plica ble acc or di n g t o t he c o ntract bet wee n C o va n ce a n d 
t he S p o ns or. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 4 9 of 6 0 
 
8  A D MI NI S T R A TI V E A S P E C T S 
8. 1  C h a n ge i n Pr ot oc ol 
T here will be n o alterati o ns i n t he pr ot oc ol  wit h o ut a gree me nt b et wee n t h e S p o ns or a n d t he 
I n v esti gat or ( or d esi g n ee). 
T here will be n o alterati o ns i n t he pr ot oc ol affecti n g s u bject s afet y wit h o ut t he e x press writte n 
a p pr o val of t he S p o ns or, I n v esti gat or ( or d esi g n ee), a n d t he I R B (see F or m F D A 1 5 7 2). 
8. 2  Site I niti ati o n Visit/I n vesti g at or Meeti n g 
Pri or t o t he start of t he cli nical st u d y, t he re pres e ntati ve(s) of t he S p o ns or will meet wit h t he 
I n v esti gat or ( or d esi g n ee) a n d a p pr o priate cli nical staff t o fa miliarize t he I n vesti gat or ( or 
desi g nee) a n d cli nical staff wit h t he materials n ecessar y f or c o n d ucti n g t he cli nical st u d y. 
8. 3  Discl os ure 
All i nf or mati o n pr o vi de d re gar di n g t he st u d y, as well as all i nf or mati o n c ollecte d/ d oc u me nte d 
d uri n g t he st u d y, will be re gar de d as c o nfi de nti al. T he I n vesti gat or ( or desi g nee) a grees n ot t o 
discl ose s uc h i nf or mati o n i n a n y w a y wit h o ut pri or writte n per missi o n fr o m t he S p o ns or. 
A n y p u blicati o n of t he res ults, i n part or i n t o tal (e g, articles i n j o ur nals or n e ws pa pers, oral 
prese ntati o ns, a bstracts) b y t he I n vesti gat or ( or d esi g nee) or t heir re prese nt ati ve(s), s hall re q uire 
pri or n otificati o n a n d re vie w, wit hi n a reas o n a ble ti mefra me, b y t he S p o ns or, a n d ca n n ot b e 
ma de i n vi olati o n of t he S p o ns or’s c o nfi de ntialit y restricti o ns or t o t he detri me nt of t he 
S p o ns or’s i ntellect ual pr o pert y ri g hts.  
8. 4  M o nit ori n g 
T he S p o ns or will desi g nate a S p o ns or’s St u d y M o nit or w h o will be res p o nsi ble f or m o nit ori n g 
t his cli nical trial. T he S p o ns or’s St u d y M o nit or will m o nit or t he st u d y c o n d uct, pr o per e C R F a n d 
s o urce d oc u m e ntati o n c o m pleti o n an d rete nti o n, a n d acc urate st u d y dr u g acc o u nta bilit y. T o t his 
e n d, t he S p o ns or’s St u d y M o nit or will visit t he C R U at s uita ble i nter vals a n d be i n fre q u e nt 
c o ntact t hr o u g h ve r bal a n d writte n c o m m u nicati o n. It is esse ntial t hat t he S p o ns or’s St u d y 
M o nit or has access t o all d oc u me nts (relat e d t o t he st u d y a n d t he i n di vi d ual partici pa nts) at a n y 
ti me t hese are re q ueste d. I n t ur n, t h e S p o ns or’s St u d y M o nit or will a d here t o all re quire me nts f or 
s u bject c o nfi de ntialit y as o utli ne d i n t he I C F. T h e I n v esti gat or ( or d esi g n ee) a n d I n vesti gat or’s 
staff will be e x pecte d t o c o o perat e wit h t he S p o ns or’s St u d y M o nit or, t o be a vaila ble d uri n g a 
p orti o n of t he m o nit ori n g visit t o a ns wer q uesti o ns, a n d t o pr o vi de a n y missi n g i nf or mati o n. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 0 of 6 0 
 
8. 5  I nstit uti o n al Re vie w B o ar d 
I n acc or da n ce wit h U S Title 2 1 C FR 5 6, t he pr ot oc ol, a d vertise me nt, I C F, a n d ot her i nf or mati o n 
pr o vi de d t o s u bjects will be re vie we d a n d a p pr o ve d b y t he I R B. T he S p o ns or will s u p pl y 
rele va nt material f or t he I n vesti gat or ( or desi g nee) t o s u b mit t o t he I R B f or t he pr ot oc ol’s re vie w 
a n d a p pr o val. Verific ati o n of t he I R B u n c o n diti o n al a p pr o val of t h e pr ot oc ol a n d t he writte n I C F 
state me nt will be tra ns mitte d t o t he I n v esti gat or ( or desi g n ee). 
T he I R B will be i nf or me d b y t he I n vesti gat or  ( or desi g nee) of s u bs e q ue nt pr ot oc ol a me n d me nts 
a n d of seri o us a n d u n e x pecte d A Es. A p pr o val f o r pr ot oc ol a me n d me nts will be tra ns mitte d i n 
writi n g t o t he I n v esti gat or ( or desi g nee). If re q u est e d, t he I n vesti gat or ( or d esi g nee) will per mit 
a u dits b y t he I R B a n d re g ulat or y i ns pe cti o ns b y pr o vi di n g direct access t o s o urce 
data/ d oc u me nts. 
T he I n vesti gat or ( or desi g nee) will pr o vi de t he I R B wit h pr o gress re p orts at a p pr o priate i nter v als 
( n ot t o e xcee d 1 year) a n d a St u d y Pr o gress Re p ort f oll o wi n g t he c o m pleti o n, ter mi nati o n, or 
disc o nti n uati o n of t he I n vesti gat or ’s ( or d esi g n ee’s) partici pati o n i n t he st u d y. 
8. 6  I nf or me d C o nse nt 
Writte n i nf or me d c o nse nt f or t he st u d y will be o btai ne d fr o m all s u bjects b ef ore 
pr ot oc ol-s pecifi c pr oce d ures are carrie d o ut. T h e I C F will be a p pr o ve d (al o n g wit h t he pr ot oc ol) 
b y t he I R B a n d will be acce pta ble t o t he S p o ns or. 
T he I n vesti gat or ( or desi g nee) will e x plai n t he nat ure of t he st u d y a n d t he acti o n of t he test 
pr o d uct. T he s u bjects will be i nf or me d t hat partici p ati o n is v ol u ntar y a n d t h at t he y ca n wit h dr a w 
fr o m t he st u d y at a n y ti me. I n acc or da nce wit h 2 1 C F R 5 0, t he i nf or me d c o nse nt pr ocess s hall be 
d oc u me nte d b y t he use of a writte n I C F a p pr o ve d b y t he I R B a n d si g ne d b y t he s u bject pri or t o 
pr ot oc ol-s pecifi c pr oce d ures bei n g perf or me d. 
T he s u bject will si g n 2 c o pies of t he I C F. O ne c o p y will be gi ve n t o t he s u bject, a n d t he ot her 
will be mai ntai ne d wit h t he s u bject’s rec or ds.  
8. 7  Rec or ds 
T he res ults fr o m dat a c ollecte d at Scree ni n g a n d d uri n g t he st u d y will be rec or de d i n t he 
s u bject’s e C R F. T o mai ntai n c o nfi de ntiali t y, t he s u bjects will be i de ntifie d o nl y b y n u m bers. 
T he c o m plete d e C R Fs will be tra nsferre d t o t he S p o ns or ( or desi g nee). C o pi es of eac h e C R F will 
be retai ne d b y t h e I n vesti gat or ( or desi g n ee). All s o urce d oc u m e nts, rec or ds, a n d re p orts will be 
retai ne d b y t he C R U i n a cc or da n ce wit h 2 1 C F R 3 1 2. 6 2(c). 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 1 of 6 0 
All pri mar y d ata, or c o pies t here of (e g, la b orat or y rec or ds, e C R Fs, data s h eets, c orres p o n d e nce, 
p h ot o gra p hs, a n d c o m p ut er rec or ds), w hic h are a re s ult of t he ori gi n al o bser vati o ns a n d acti vities 
of t he st u d y a n d are necessar y f or t he rec o nstr ucti o n a n d e val uati o n of a n y st u d y re p ort, will be 
retai ne d i n t he C R U arc hi ves. 
8. 8  Refere nce t o Decl ar ati o n of Helsi n ki/ B asic Pri nci ples 
T he st u d y pr oce d ures o utli ne d i n t his pr ot oc ol will be c o n d ucte d i n acc or da nce wit h t he U S C F R 
g o ver ni n g Pr otecti o n of H u ma n S u bjects ( 2 1 C F R 5 0), Fi na ncial Discl os ure b y Cli nical 
I n v esti gat ors ( 2 1 C F R 5 4), I R Bs ( 2 1 C F R 5 6), I n v esti gati o n al N e w Dr u g A p plicati o n 
( 2 1 C F R 3 1 2), A p plicati o ns f or F D A A p pr o val t o Mar ket a Ne w Dr u g ( 2 1 C F R 3 1 4), a n d 
Ra di oacti ve Dr u gs f or Certai n Researc h Us es  ( 2 1 C F R 3 6 1. 1), as a p pr o priate. As s uc h, t hese 
secti o ns of U S Title 2 1 C F R, al o n g wit h t he ap plica ble I nter n ati o nal C o u ncil f or Har m o nisati o n 
G ui deli nes, are c o m m o nl y k n o w n as G o o d Cli nical  Practices, w hic h are c o nsiste nt wit h t he 
Declarati o n of Helsi n ki. 
8. 9  Fi n a nci n g a n d I ns ur a nce 
Fi na nci n g a n d i ns ura nce will be a d dresse d i n a s e parate a gree me nt. 

P P D

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 3 of 6 0 
S P O N S O R A G R E E M E N T 
I h a ve rea d t he f ore g oi n g pr ot oc ol a n d a gree t o t he c o n d uct of t he st u d y as d escri be d h erei n: 
 
Date 
P P D

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 4 of 6 0 
R E F E R E N C E S 
1.
L O X O- 2 9 2 –  I n v esti gat or’s Br oc h ure. ( Versi o n 3.0, 0 5 A pril 2 0 1 8).

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 5 of 6 0 
 
A P P E N DI X A - C LI NI C A L L A B O R A T O R Y E V A L U A TI O N S 
Cli nic al C he mistr y P a nel ( F aste d): 
He m at ol o g y: 
Uri n al ysis: 
Ala ni ne a mi n otra nsferase 
He mat ocrit 
Bilir u bi n 
Al b u mi n 
He m o gl o bi n 
C ol or a n d a p peara nce 
Al kali ne p h os p hatase 
Mea n c or p usc ular he m o gl o bi n 
Gl uc ose 
As partate a mi n otra nsferase 
Bl o o d urea nitr o ge n 
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n 
Ket o nes 
Le u k oc yte esterase 
Calci u m 
Mea n c or p usc ular v ol u me 
Nitrite 
C hl ori de 
Platelet c o u nt 
Occ ult bl o o d 
C h olester ol 
Re d bl o o d cell ( R B C) c o u nt 
p H a n d s pecific gra vit y 
Creati ni ne 
R B C distri b uti o n wi dt h 
Pr otei n 
Gl uc ose 
W hite bl o o d cell ( W B C) c o u nt 
Ur o bili n o ge n 
Ir o n  
P h os p h or us  
P otassi u m  
S o di u m  
T h yr oi d -sti m ulati n g h or m o ne (at 
Scree ni n g o nl y) 
T otal bilir u bi n  
T otal pr otei n 
W B C differe ntial (a bs ol ute a n d 
perce nt ): 
B as o p hils 
E osi n o p hils 
L y m p h oc ytes 
M o n oc ytes 
Ne utr o p hils 
Micr osc o pic e xa m i ncl u di n g 
bacteria, casts, cr ystals, 
e pit helial cells, R B Cs, a n d 
W B Cs (if pr otei n, le u k oc yte 
esterase, nitrite, or bl o o d is 
p ositi ve) 
Tri gl yceri des 
 
 
Uric aci d 
A m ylase  
Li pase 
 
 
 
 
 
 
 
 
Dr u g Scree n: 
Ser ol o g y: 
 
I ncl u di n g b ut n ot li mite d t o t he 
f oll o wi n g: 
He p atitis B s urface a nti ge n 
He p atitis B c ore a nti b o d y  
He p atitis C vir us a nti b o d y 
 
Alc o h ol (et ha n ol, Da y - 1 o nl y, b y 
breat hal yzer ) 
A m p heta mi nes/ met ha m p heta mi nes 
H u ma n i m m u n o deficie nc y vir us 
a nti b o d y 
 
B ar bit urates 
B e nz o diaze pi nes 
 
 
Ca n na bi n oi ds 
 
 
C ocai ne ( meta b olite) 
C oti ni ne ( b y uri nal ysis) 
 
 
Met ha d o ne 
 
 
O piates 
 
 
P he nc ycli di ne 
 
 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 6 of 6 0 
A P P E N DI X B - B L O O D S A M P LI N G S U M M A R Y 
P art 1 
P ur p ose 
Ma xi m u m Bl o o d 
V ol u me per Sa m ple 
( m L) 
Ma xi m u m N u m ber of 
Bl o o d Sa m ples  
Ma xi m u m T otal 
V ol u me ( m L) 
Ser ol o g y 
4 
1 
4 
He mat ol o g y 
4 
4 
1 6 
Cli nical C he mistr y 
4 
4 
1 6 
L O X O- 2 9 2 a n d T otal 
Ra di oacti vit y Sa m pli n g 
6 
2 5 a
1 5 0
Meta b olite Sa m pli n g 
1 0 
1 9 a 
1 9 0 
A p pr o xi m ate T ot al 
Bl o o d V ol u me 
3 7 6
P art 2 
Ser ol o g y 
4 
1 
4 
He mat ol o g y 
4 
4 
1 6 
Cli nical C he mistr y 
4 
4 
1 6 
L O X O- 2 9 2, [ 1 4C]- L O X O- 2 9 2, 
a n d T otal Ra di oacti vit y 
Sa m pli n g 
6 
2 5
1 5 0
A p pr o xi m ate T ot al 
Bl o o d V ol u me  
1 8 6 
a T otal n u m ber of bl o o d sa m pl es c ollecte d i n P art 1 f or L O X O- 2 9 2/t otal ra di oacti vit y a nal ysis a n d f or 
meta b olite pr ofili n g/c haracteri zati o n  is base d o n s u bj ect c o nfi ne me nt u ntil Da y 2 2. If a s u bj ect meets t he 
disc har ge criteria as defi ne d i n T a ble 6- 1  earlier t ha n Da y 2 2, t he t otal n u m ber of bl o o d sa m ples c ollecte d 
a n d t he t otal bl o o d v ol u mes will be less.  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 7 of 6 0 
 
A P P E N DI X C - A D V E R S E E V E N T S 
1  A D V E R S E E V E N T S 
1. 1  Defi niti o n of A d verse E ve nts 
A n a d vers e e ve nt ( A E; or a d verse e x perie nce) is defi ne d as a n y u nt o war d me dical occ urre n ce 
e x perie nce d b y a p atie nt or healt h y s u bject, w h et her or n ot c o nsi dere d dr u g relate d b y t he 
I n v esti gat or ( or desi g n ee). A treat me nt-e mer ge nt A E is a n A E t hat is re p orte d after a d ose of 
st u d y dr u g. 
T he f oll o wi n g are all A Es: 
 U nfa v ora ble c h a n ges i n ge n eral c o n diti o n; 
 S u bjecti ve or o bjecti ve si g ns/s y m pt o ms; 
 C o nc o mita nt diseases or acci de nts; 
 Cli nicall y rele v a nt a d verse c ha n ges i n la b orat or y para meters o bser ve d i n a s u bject d uri n g 
a cli nical st u d y. 
A d verse e ve nts c o m prise all dist ur ba nces of ge ne ral healt h stat us, s u bjecti ve a n d o bjecti ve 
disease s y m pt o ms (i ncl u di n g la b orat or y a b n or m alities), a n d acci de nts o bser ve d i n t he c o nte xt of 
a cli nical trial, irres pecti v e of a p ossi ble ca usal rel ati o ns hi p wit h t he a d mi nistrati o n of t he trial 
s u bsta nce. E ve nts oc c urri n g i n t he fra me w or k of a cli nical trial d uri n g dr u g-free a n d 
p ost-treat me nt peri o ds, u n der place b o, or i n a re fere nce gr o u p recei vi n g dr u g or n o n dr u g t hera p y 
are als o t o be d esi g n ate d as A Es. All A Es, c o m plai nts, or s y m pt o ms t hat occ ur fr o m t he ti me 
i nf or me d c o nse nt is si g n e d u ntil t he Safet y F oll o w- u p Call are t o be rec or de d o n t he a p pr o priate 
electr o nic Cas e Re p ort F or m (e C R F ) (e ve nts t hat occ ur pri or t o c o nse nt are c o nsi der e d me di cal 
hist or y). D o c u me ntati o n m ust be s u p p orte d b y a n e ntr y i n t he p atie nt’s s o urce me dical rec or ds. 
La b orat or y test a b n or malities c o nsi dere d b y t he I n vesti gat or t o b e cli nicall y rele va nt s h o ul d be 
re p orte d i n t he e C R F as a n A E. Eac h A E is t o be e val u ate d f or d urati o n, se v erit y, a n d ca us al 
relati o ns hi p wit h t he i n vesti gati o nal pr o d uct or ot h er fact ors. 
1. 2  C ate g oriz ati o n of A d verse E ve nts 
T he se verit y of A Es will be cate g orize d ba se d o n t he Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E) Versi o n 5. 0 as f oll o ws: 
 Gr a de 1 Mil d : As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d 
 Gr a de 2 M o der ate : Mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge-
a p pr o priate i nstr u me nt al Acti vit ies of Dail y Li vi n g ( A D L) *  

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 8 of 6 0 
 
 Gr a de 3 Se v ere o r me di c all y si g nific a nt b ut n ot i m me di atel y lif e t hre ate ni n g : 
H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self-care 
A D L * *  
 Gr a de 4 Lif e-t hre ate ni n g c o nse q ue nces : Ur ge nt i nter ve nti o n i n dicate d 
 Gr a de 5 D e at h rel ate d t o A E  
N ote: N ot all gra d es are a p pr o priate f or all A Es. T heref ore, s o me A Es are liste d wit hi n t he C T C A E wit h fe wer t ha n 
5 o pti o ns f or gra d e selecti o n. Gra d e 5 ( deat h) is n ot a p pr o priate f or s o me A Es a n d t heref ore is n ot a n o pti o n.  
* I nstr u me ntal A D L refer t o pre pari n g meals, s h o p pi n g f o r gr oceries or cl ot hes, usi n g t he t ele p h o ne, ma na gi n g 
m o ne y, etc.  
* * S elf-care A D L refer t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g me dic ati o ns, a n d n ot 
be dri d de n. 
T he I n vesti gat or ( or desi g nee) will ma ke a dete r mi nati o n of t he relati o ns hi p of t he A E t o t he 
st u d y dr u g usi n g a 2- cate g or y s yste m acc or di n g t o t he f oll o wi n g g ui deli nes: 
 
N O T R E L A T E D  = T he ti me c o urse bet w ee n t he a dmi nistrati o n of i n vesti gati o nal 
pr o d uct a n d t he occ urre n ce or w orse ni n g of t he A E r ules o ut a ca us al relati o ns hi p a n d 
a n ot her ca use (e g, c o nc o mita nt dr u gs, t h era pies, c o m plicati o ns, c o m or bi dities) is 
s us pecte d; 
 
R E L A T E D  = T he ti me c o urse bet wee n a d mi nistrati o n of i n vesti gati o nal pr o d uct a n d t he 
occ urre nce or w ors e ni n g of t he A E is c o nsiste nt wit h a ca usal r elati o ns hi p a n d n o ot her 
ca use (e g, c o n c o mita nt dr u gs, t hera pies, c o m p licati o ns, c o m or bi dities) ca n be i de ntifie d. 
A n A E is ass ociate d wit h t he use of t he dr u g if t h ere is a reas o na ble p ossi bilit y t h at t he 
e x perie nce ma y h a ve bee n ca use d b y t he dr u g. 
T he acti o n ta ke n wit h t he i n vesti gati o nal pr o d u ct i n res p o nse t o t he A E s h o ul d be pr o vi de d at t he 
ti me t he e ve nt is re p orte d. F or t his st u d y, o pti o ns f or acti o n ta ke n i ncl u d e t he f oll o wi n g: 
 D osi n g st o p pe d :  Me dicati o n a d mi nistrati o n was st o p pe d bef ore or d uri n g d osi n g. 
1. 3  Pre g n a nc y 
As i nf or mati o n is a vaila ble, a pre g n a nc y i n a fe male part ner of a male s u bj ect dia g n os e d d uri n g 
t he st u d y a n d f or u p t o 6 m o nt hs after st u d y dru g a d mi nistrati o n s h o ul d be re p orte d b y t he 
I n v esti gat or ( or desi g n ee) via e Fa x t o t he S p o ns or’s C o ntact f or Seri o us A d verse E ve nt 
Re p orti n g liste d i n t he St u d y I d e ntificati o n secti o n wit hi n 2 4 h o urs of bei n g n otifie d. T he 
S p o ns or’s C o ntact f or Seri o us A d verse E v e nt Re p orti n g will t he n f or war d t he Pre g na nc y F or m 
t o t he I n v esti gat or ( or d esi g nee) f or c o m pleti o n. 
e F a x: + 1 ( 2 0 3) 6 4 3- 2 0 1 3 
T he part ner s h o ul d be f oll o we d b y t h e I n vesti gat or ( or desi g nee) u ntil c o m pleti o n of t he 
pre g na nc y. If t he pre g na nc y e n ds f or a n y reas o n bef ore t h e a ntici pate d d ate, t he I n vesti gat or ( or 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 5 9 of 6 0 
 
desi g nee) s h o ul d n otif y t he S p o ns or’s C o ntact f or Seri o us A d verse E v e nt Re p orti n g. At t he 
c o m pleti o n of t he pre g n a nc y, t h e I n vesti gat or ( or desi g nee) will d oc u me nt t he o utc o me of t he 
pre g na nc y. If t he o utc o m e of t he pre g na nc y m eets t he criteria f or i m me diat e classificati o n as a 
seri o us A E ( S A E) (i e, p ost part u m c o m plicati o n, 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), t he I n vesti gat or ( or desi g nee) s h o ul d f oll o w t he pr oce d ures f or re p orti n g 
a n S A E. 
Male s u bjects will be i nstr ucte d t o n otif y t he I n vesti gat or ( or desi g nee) i m me diatel y if t he y 
disc o ver t heir se x ual part ner is pre g na nt. I n t his i nsta nce, t he part ner m ust pr o vi de writte n 
c o nse nt bef ore pre g na nc y i nf or m ati o n ca n be c o llecte d. W he n a site bec o mes a ware t hat t he 
fe male part ner of a male s u bject is pre g na nt, t he y are t o c o ntact t he C o va nce Me dical M o nit or 
i m me diatel y ( wit hi n 2 4 h o urs of t he site staff bec o mi n g a ware of t he e v e nt) i n a d diti o n t o 
n otif yi n g t he S p o ns or’s C o ntact f or Seri o us A d verse E ve nt Re p orti n g via e Fa x. 
1. 4  Defi niti o n of Seri o us A d verse E ve nts 
A n S A E ( b y F o o d a n d Dr u g A d mi nistrati o n [ F D A] defi niti o n) is a n y a d verse dr u g e x perie nce 
occ urri n g at a n y d ose t hat res ults i n a n y of t h e f oll o wi n g o utc o mes: 
 Deat h; 
 A life-t hreate ni n g a d vers e dr u g e x perie nce (ie, o n e t hat places t he s u bj ect, i n t he vie w of 
t he I n v esti gat or [ or desi g nee], at i m me diate ris k of deat h; it d oes n ot mea n a n e ve nt t hat, 
ha d it occ urre d i n a m ore se vere f or m, mi g ht h a ve ca use d deat h); 
 I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
 A persiste nt or si g nifica nt disa bilit y/i nca p acit y; 
 A c o n ge nital a n o mal y/ birt h defect; 
 A n i m p orta nt me dical e v e nt t hat ma y re q uir e me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he a b o v e o utc o m es. 
I m p ort a nt me dical e v e nts t hat ma y n ot r es ult i n deat h, be life t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d S A Es w he n, b ase d o n a p pr o priate me di cal j u d g m e nt, t he y 
ma y je o p ar dize t he patie nt or 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 pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n.  
1. 5  U ne x pecte d A d ve rse Dr u g E x perie nce 
A n u ne x pecte d a d verse dr u g e x perie nce is a n y a d v erse dr u g e x perie nce, t h e s pecificit y or 
se verit y of w hic h is n ot c o nsiste nt wit h t he c urre nt I n v esti gat or’s Br oc h ure (I B) or, if a n I B is n ot 
re q uire d or a vaila ble, t h e s pecificit y or se v erit y of w hic h is n ot c o nsiste nt wit h t he 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 h ere i n t h e c urre nt a p plicati o n, 
as a me n de d. 

Pr ot oc ol A me n d me nt 2 
C o va nce St u d y 8 3 8 7 0 2 4 
C O N FI D E N TI A L 
Pr ot oc ol L O X O- R E T- 1 8 0 1 6 
 
 
Fi nal, 1 5 A u g ust 2 0 1 8 
Pa ge 6 0 of 6 0 
 
1. 6  Re p orti n g 
F o o d a n d Dr u g A d mi nistrati o n-re p orta ble A Es are A Es t hat are ass ociate d wit h t he use of t he 
dr u g a n d are seri o us a n d u ne x pecte d. F o o d a n d Dr u g A d mi nistrati o n-re p ort a ble A Es will be 
re p orte d b y t he Cli nical Researc h U nit t o t he S p o ns or, t he C o va nce M e dical M o nit or, a n d t he 
res p o nsi ble I nstit uti o nal Re vie w B o ar d (I R B). 
Wit hi n 2 4 h o urs of w he n a n A E t hat is p ote ntiall y F D A-re p ort a ble is first rec o g nize d or re p orte d, 
a n d wit hi n 2 4 h o urs of a n y S A E –  eit her e x pe dite d or n o ne x pe dite d –  bei n g first r ec o g nize d or 
re p orte d, t he S p o ns or’s C o ntact f or Seri o us A d verse E ve nt Re p orti n g will be n otifie d b y t h e 
I n v esti gat or ( or desi g n ee) i n writi n g (e g, facsi mile) usi n g t he f oll o wi n g e Fa x n u m ber: 
e F a x: + 1 ( 2 0 3) 6 4 3- 2 0 1 3  
All S A Es occ urri n g fr o m t he ti me of si g ni n g t he I nf or me d C o nse nt F or m t hr o u g h t h e Safet y 
F oll o w- u p Call m ust be re p orte d. T o re p ort t he S A E a n d/ or p ote ntiall y F D A-re p orta ble A E, t he 
c o m plete d S A E Re p ort F or m will be se nt b y e Fa x  wit hi n 2 4 h o urs of first a ware n ess. I nc o mi n g 
re p orts are re vi e we d d uri n g n or mal b usi ness h o urs. A d diti o nal re p orti n g i nstr ucti o ns a n d t he 
S A E Re p ort F or m are pr o vi de d i n t he St u d y Ma n ual.  
T he I n vesti gat or ( or desi g nee) is n ot o bli gate d t o acti vel y see k i nf or mati o n re gar di n g t he 
occ urre nce of ne w S A Es be gi n ni n g after t he Safet y  F oll o w- u p Call. H o we v er, if t he I n v esti gat or 
( or desi g nee) lear ns of s u c h a n S A E, a n d t hat e v e nt is dee m e d rele va nt t o t he use of st u d y dr u g, 
he/s he s h o ul d pr o m ptl y d oc u me nt a n d re p ort t he e ve nt. T he I n vesti gat or ( or desi g nee) will be 
re q ueste d t o s u p pl y detaile d i nf or mati o n as well as f oll o w- u p re gar di n g t he S A E.  
T he I R B will be n otifie d of a n y F D A-re p orta ble A E wit hi n t he ti mefra me re q uire d b y t he I R B. 
T he I R B Seri o us a n d U n e x pecte d A d verse E x perie nce S u b missi o n F or m will be c o m plete d a n d 
s u b mitte d wit h t he c o p y of t he writte n c o nfir mati o n or s u m mar y of t he A E.