Clinical trial NCT05630287
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2018-08-01; Completion date: 2018-09-24
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to compare the amount of selpercatinib that gets into the blood stream and how long it takes the body to get rid of it and also to assess the pharmacokinetics (PK), metabolism, and routes and extent of elimination of selpercatinib in healthy male participants. The study will last up to 59 days (Part 1) or 46 days (Part 2) including screening and 7-day safety follow-up.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 165 milligram (mg) of \[14C\]-Selpercatinib (containing approximately 40 µCi). arm 2: Participants received a single oral dose of 160 mg Selpercatinib followed by single dose of \<100 µg of \[14C\]-Selpercatinib (containing approximately 1 µCi) administered intravenously (IV).
Interventions: intervention 1: [14C]-Selpercatinib intervention 2: Selpercatinib intervention 3: [14C]-Selpercatinib
Intervention descriptions: intervention 1: Administered as an oral solution intervention 2: Administered orally intervention 3: Administered intravenously

Protocol documents:
Prot_000.pdf: 
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. 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 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 [14C]-LOXO-292 in Healthy Male Subjects
NCT05630287
Approval Date: 08-Oct-2018


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