Conditions: Healthy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to assess the safety and tolerability of pirtobrutinib and to look at the amount of the study drug, pirtobrutinib, that gets into the blood stream and how long it takes the body to get rid of it when given in healthy adult participants. For each participant, the total duration of the study will be 46 days, including screening.

Detailed description:

Arms:
arm 1: Participants received a single dose of Pirtobrutinib 300 milligram (mg) administered orally on Day 1. arm 2: Participants received a single dose of Pirtobrutinib 600 mg administered orally on Day 1. arm 3: Participants received a single dose of Pirtobrutinib 800 mg administered orally on Day 1. arm 4: Participants received a single dose of Pirtobrutinib 900 mg administered orally on Day 1.

Interventions: intervention 1: Pirtobrutinib
Intervention descriptions: intervention 1: Administered orally.

Protocol document:
Prot_000.pdf: 
Protocol J2N-OX-JZNS Version 1.0
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LOXO-305 
in Healthy Adult Subjects
NCT06181006
Approval Date: 04-Aug-2020


 
 
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A P h ase I, Si n gle -Asce n di n g D ose St u d y t o E v al u ate t he S afet y, T oler a bilit y, a n d 
P h ar m ac o ki netics of L O X O -3 0 5 i n He alt h y A d ult S u bjects  
Pr ot oc ol Stat us: Fi nal 
Pr ot oc ol Date: 0 4 A u g ust 2 0 2 0  
Pr ot oc ol Versi o n: 1. 0 
I n vesti gati o nal Me dici nal Pr o d uct: L O X O-3 0 5  
 
Pr ot oc ol Refere nce N u m ber: L O X O -B T K -2 0 0 1 7 
C o va nce St u d y N u m ber: 8 4 2 6 6 6 5  
I N D N u m ber: 1 3 9 8 7 6 
 
 
 
S p o ns or:  
L o x o O nc ol o g y, I nc.  
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d 
C o m pa n y  
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  
St u d y Site:  
C o va nce Cli nical Researc h U nit I nc. 
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, F L 3 2 1 1 7  
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S p o ns or Si g nat or y: 
Pri nci pal I n vesti gat or: 
 
 
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d ma y be discl ose d o nl y wit h t he e x press 
writte n per missi o n of t he S p o ns or.  
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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. 
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d C o m pa n y 
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 
U S A  
Tel ( mai n): 
 
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.  
Tel ( m o bile): 
 
Tel (alter nati ve c o ntact): 
 
E mail : 
 
S p o ns or’s  Me dical  C o ntact  
 
C o ns ulti n g t o L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
E mail : 
 
Seri o us A d verse E ve nt ( S A E) 
Re p orti n g  
E mail : S A EI nta ke @c o va nce.c o m 
 
 
St u d y  Site  
C o va nce Cli nical Researc h U nit ( C R U),  I nc. 
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, Fl ori da 3 2 1 1 7 
U S A  
Pri nci pal  I n vesti gat or 
 
 
C o va nce Cli nical Researc h U nit I nc. 
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, Fl ori da 3 2 1 1 7  
U S A  
Tel: 
 
Fa x: 
 
S u b -i n vesti gat or(s) 
O btai n i nf or mati o n fr o m F or m F D A  1 5 7 2  
 
Cli nical  La b orat or y  
La b C or p - H oll y w o o d 
4 2 0 0 N ort h 2 9 t h A ve n ue 
H oll y w o o d, Fl ori da 3 3 0 2 0 
U S A  
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  
Tel ( mai n): 
 
E mail : 
 
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Statisticia n  
 
C o va nce  
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C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
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S Y N O P SI S  
 
St u d y Title  
 
A P hase I, Si n gle -Asce n di n g D ose St u d y t o E val uate t he Safet y, T olera bilit y, a n d 
P har mac o ki netics of L O X O -3 0 5 i n Healt h y A d ult S u bjects  
 
O bjecti ves  
 
T he pri mar y o bjecti ve of t he st u d y is:  
 
•  T o assess t he safet y a n d t olera bilit y of si n gle oral d oses of L O X O -3 0 5 w he n 
a d mi nistere d t o healt h y a d ult  s u bjects. 
 
T he sec o n dar y o bjecti ve of t he st u d y is:  
 
•  T o assess t he p har mac o ki netics ( P K) of si n gle oral d oses of L O X O -3 0 5 w he n 
a d mi nistere d t o healt h y a d ult  s u bjects. 
 
St u d y Desi g n  
 
T his is a n o pe n -la bel, si n gle-asce n di n g d ose st u d y t o e val uate t he safet y, t olera bilit y, a n d P K 
of L O X O -3 0 5.  
 
U p t o 4 c o h orts are pla n ne d f or e val uati o n. I n eac h c o h ort, 6 healt h y a d ult s u bjects are 
pla n ne d f or e val uati o n. S u bjects will partici pate i n o nl y 1 c o h ort. I n eac h c o h ort, s u bjects will 
recei ve a si n gle oral d ose of L O X O-3 0 5 o n Da y 1. I n eac h c o h ort, a se nti nel gr o u p of  
2 s u bjects will be d ose d at least 4 8 h o urs bef ore t he re mai ni n g 4 s u bjects i n t he c o h ort 
(f oll o wi n g re vie w of a vaila ble safet y data). Bl o o d sa m ples will be c ollecte d f or t he P K 
assess me nt of L O X O -3 0 5 i n plas ma f or 1 6 8 h o urs p ost d ose.  
 
A si n gle oral d ose of L O X O -3 0 5 will be a d mi nistere d o n Da y 1 f or eac h c o h ort as f oll o ws:  
 
•  C o h ort 1 ( Treat me nt A): 3 0 0  m g  
•  C o h ort 2 ( Treat me nt B): u p t o 6 0 0  m g  
•  C o h ort 3 ( Treat me nt C): u p t o 9 0 0  m g  
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he ma xi m u m o bser ve d  
plas ma c o nce ntrati o n ( C ma x ) w o ul d e xcee d  
 n g/ m L. 
 
D ose escalati o n t o a hi g her d ose le vel (ie, ne xt c o h ort) will n ot ta ke place u ntil t he 
I n vesti gat or ( or desi g nee) a n d t he S p o ns or ha ve re vie we d all perti ne nt safet y/t olera bilit y data 
(ie, p h ysical e xa mi nati o ns, electr ocar di o gra ms [ E C Gs], vital si g n meas ure me nts, cli nical 
la b orat or y e val uati o ns, a n d a d verse e ve nts [ A Es]) t hr o u g h a mi ni m u m of 1 6 8 h o urs ( Da y 8) 
a n d ha ve deter mi ne d t hat a de q uate safet y a n d t olera bilit y fr o m t he pre vi o us l o wer d ose  
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 7  of 5 8  
 
 
c o h ort has bee n de m o nstrate d t o per mit pr ocee di n g t o t he ne xt c o h ort. P har mac o ki netic data 
t hr o u g h at least 7 2 h o urs (a p pr o xi matel y 3 half-li ves) will be re vie we d t o g ui de t he 
d ose -escalati o n decisi o n. Data fr o m a mi ni m u m of 4 s u bjects will be re vie we d i n or der t o 
ma ke a d ose escalati o n decisi o n.  
 
\T o assess t heir eli gi bilit y t o e nter t he st u d y, p ote ntial s u bjects will be scree ne d wit hi n 
2 8 da ys ( Da ys -2 9 t o -2) a n d be a d mitte d t o t he Cli nical Researc h U nit ( C R U) o n Da y  -1  
( C hec k-i 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 ( Da y -1) u ntil 
E n d of Treat me nt ( E O T) o n Da y 8 u p o n c o m pleti o n of all P K a n d safet y assess me nts or Earl y 
Ter mi nati o n ( E T) if t he s u bject disc o nti n ues. A f oll o w -u p p h o ne call will occ ur f or all 
s u bjects w h o recei ve d 1 d ose of st u d y dr u g (i ncl u di n g s u bjects w h o are ter mi nate d earl y)  
7 da ys ( ± 2 da ys) after E O T or E T.  
 
Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d necessar y b y t he S p o ns or.  
 
T he start of t he st u d y is defi ne d as t he date t he first s u bject w h o is e nr olle d i n 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). N ote t hat e nr olle d s u bjects are defi ne d as t h ose s u bjects 
w h o are assi g ne d a d ose of st u d y dr u g; t his defi niti o n e xcl u des scree n fail ure s u bjects. St u d y 
c o m pleti o n is defi ne d as t he ti me of t he last s u bject’s f oll o w -u p.  
 
I n t his st u d y, p h ysical e xa mi nati o ns, 1 2-lea d E C Gs, vital si g n meas ure me nts, P K sa m pli n g, 
H o w D o Y o u Feel? i n q uiries, cli nical c he mistr y pa nel, c oa g ulati o n para meters, he mat ol o g y 
pa nel, uri nal ysis ( A p pe n di x 2 ) a n d rec or di n g of c o nc o mita nt me dicati o ns will be perf or me d 
at s pecifie d ti mes d uri n g t he st u d y (f or s pecific ti me p oi nts a n d details o n eac h st u d y varia ble, 
refer t o A p pe n di x 4 ). 
 
A d verse e ve nts a n d seri o us A Es ( S A Es) will be c ollecte d be gi n ni n g at i nf or me d c o nse nt. 
A d verse e ve nts will be re p orte 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 E n d of 
St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w-u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g 
pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as n ot relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee]) or as A Es 
(if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee], or if t he e ve nt 
occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p 
t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g b y 
t he I n vesti gat or ( or desi g nee) are t o be re p orte d. All S A Es t hat de vel o p fr o m t he ti me of I C F 
si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w-u p p h o ne call) are t o be re p orte d.  
 
N u m ber of S u bjects  
 
T he st u d y is pla n ne d t o e nr oll u p t o 2 4 healt h y a d ult male a n d fe male s u bjects ( w o me n of 
n o n -c hil d beari n g p ote ntial o nl y). Si x s u bjects will partici pate i n eac h c o h ort.  
 
T he sa m ple size c h ose n f or t his st u d y was selecte d wit h o ut statistical c o nsi derati o ns. It has 
bee n deter mi ne d a de q uate t o meet t he st u d y o bjecti ves.  
 
E ver y atte m pt will be ma de t o e nr oll at least 1 s u bject of eac h se x i n eac h c o h ort i n t he st u d y.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 8  of 5 8  
 
 
M ai n Criteri a f or I ncl usi o n  
 
Male s u bjects a n d fe male s u bjects of n o n -c hil d beari n g p ote ntial, bet wee n 1 8 a n d 5 5 years of 
a ge, i ncl usi ve, at Scree ni n g, a n d wit hi n b o d y mass i n de x ra n ge 1 8. 0 t o 3 2. 0 k g/ m 2, i ncl usi ve. 
S u bjects will be i n g o o d ge neral healt h, base d o n me dical hist or y, p h ysical e xa mi nati o n 
fi n di n gs, vital si g n meas ure me nts, 1 2-lea d E C G, or cli nical la b orat or y e val uati o ns at 
Scree ni n g a n d/ or C hec k -i n ( Da y -1), as deter mi ne d b y t he I n vesti gat or ( or desi g nee).  
 
I n vesti g ati o n al Me dici n al Pr o d ucts, D ose, a n d M o de of A d mi nistr ati o n 
 
L O X O -3 0 5 will be s u p plie d b y t he S p o ns or as 2 5 -m g ta blets. Li g ht bl ue o pa q ue size 0 
ca ps ules will be s u p plie d b y C o va nce. L O X O -3 0 5 ta blets will be o ver -e nca ps ulate d i nt o li g ht 
bl ue o pa q ue size 0 ca ps ules ( 4 ta blets per ca ps ule) b y C o va nce f or oral a d mi nistrati o n.  
 
C o h ort 1 ( Treat me nt A):  
•  A si n gle oral d ose of 3 0 0 m g L O X O -3 0 5 ( 1 2 × 2 5 -m g ta blets, o ver -e nca ps ulate d 
[ 3 ca ps ules]) f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 2 ( Treat me nt B):  
•  A si n gle oral d ose of u p t o 6 0 0 m g L O X O -3 0 5 ( 2 4 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 6 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 3 ( Treat me nt C):  
•  A si n gle oral d ose of u p t o 9 0 0 m g L O X O -3 0 5 ( 3 6 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 9 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
 
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he C ma x w o ul d e xcee d  
 n g/ m L. 
 
All st u d y dr u gs will be a d mi nistere d wit h a p pr o xi matel y 2 4 0 m L of water. A n a d diti o nal 
2 4 0 m L of water ma y be a d mi nistere d if nee de d.  
 
D ur ati o n of S u bject P artici p ati o n i n t he St u d y:  
 
Pla n ne d E nr oll me nt/ Scree ni n g D urati o n: 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: U p t o 9 da ys ( Da ys -1 t o 8).  
Pla n ne d St u d y C o n d uct D urati o n: U p t o 4 6 da ys ( Scree ni n g t hr o u g h f oll o w -u p call).  
 
Criteri a f or E v al u ati o n: 
P h ar m ac o ki netics:  
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 9  of 5 8  
 
 
Serial P K bl o o d sa m ples f or t he a nal ysis of plas ma c o nce ntrati o ns of L O X O -3 0 5 will be 
c ollecte d fr o m pre d ose t hr o u g h 1 6 8 h o urs p ost -L O X O -3 0 5 a d mi nistrati o n f or eac h treat me nt.  
 
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 -3 0 5 (as a p pr o priate): area u n der t he c o nce ntrati o n -ti me c ur ve fr o m 
h o ur 0 t o 2 4 h o urs p ost d ose, as calc ulate d b y t he li near tra pez oi dal met h o d ( A U C 0 -2 4), area 
u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o t he last meas ura ble c o nce ntrati o n 
( A U C0 -t), area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y 
( A U C0 -i nf), perce nta ge e xtra p olati o n f or A U C0 -i nf ( % A U Ce xtra p), Cma x , ti me t o ma xi m u m 
o bser ve d c o nce ntrati o n (t ma x ), a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λZ ), a p pare nt 
s yste mic cleara nce ( C L/ F), a p pare nt v ol u me of distri b uti o n at ter mi nal p hase ( V z/ F), a n d 
a p pare nt plas ma ter mi nal eli mi nati o n half -life (t½ ). T he λZ a n d t ½ will be calc ulate d b y li near 
least s q uares re gressi o n a nal ysis usi n g t he ma xi m u m n u m ber of p oi nts i n t he ter mi nal l o g 
li near p hase (e g, 3 or m ore n o n-zer o plas ma c o nce ntrati o ns).  
 
I n di vi d ual a n d mea n plas ma c o nce ntrati o n-ti me c ur ves ( b ot h li near a n d l o g li near) will be 
i ncl u de d i n t he fi nal re p ort. 
 
S afet 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 n 
meas ure me nts, E C Gs, c o nc o mita nt me dicati o ns, a n d p h ysical e xa mi nati o ns.  
 
St atistic al Met h o ds:  
 
P har mac o ki netics:  
 
Plas ma c o nce ntrati o ns a n d P K para meters will be s u m marize d wit h descri pti ve statistics 
( n u m ber, arit h metic mea n, sta n dar d de viati o n, c oefficie nt of variati o n [ C V %], ge o metric 
mea n, ge o metric C V %, me dia n, mi ni m u m, a n d ma xi m u m).  
 
P har mac o ki netic d ose pr o p orti o nalit y will be assesse d f or C o h ort 1, 2, a n d 3. Nat ural  
l o g-tra nsf or me d A U C0 -2 4, A U C 0 -t, A U C0 -i nf, a n d Cma x of L O X O -3 0 5 will be e val uate d usi n g a 
p o wer m o del of t he f or m: l n( p ar a meter) = i nterce pt + sl o pe × l n( d ose) + r a n d o m err or 
 
F or eac h P K para meter se paratel y, a p o ole d esti mate (acr oss all d oses) of sl o pe, 
c orres p o n di n g 9 5 % c o nfi de nce i nter val, a n d bet wee n -s u bject C V % will be calc ulate d. 
 
Safet y:  
 
All safet y assess me nts, i ncl u di n g A Es a n d S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
e val uati o ns, p h ysical e xa mi nati o n res ults, c o nc o mita nt me dicati o ns, a n d 1 2 -lea d E C Gs, will 
be ta b ulate d a n d s u m marize d, w here p ossi ble, usi n g descri pti ve met h o d ol o g y, as nee de d, b y 
ti me p oi nt. U nless ot her wise s pecifie d, baseli ne val ue is defi ne d as t he last n o n-missi n g 
meas ure me nt bef ore a d mi nistrati o n of L O X O -3 0 5. N o f or mal statistical a nal yses are pla n ne d 
f or t he safet y data. All safet y data will be liste d b y s u bject. 
 
A d diti o nal details o n t he a nal yses will be i ncl u de d i n t he Statistical A nal ysis Pla n.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 0  of 5 8  
 
 
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 P O N S O R  A P P R O V A L  .......................................................................................................... 2  
I N V E S TI G A T O R A G R E E M E N T  ............................................................................................ 3  
S T U D Y  I D E N TI FI C A TI O N .................................................................................................... 4  
S Y N O P SI S  ................................................................................................................................ 6  
T A B L E O F C O N T E N T S  ........................................................................................................ 1 0  
LI S T  O F  T A B L E S  .................................................................................................................. 1 2  
LI S T  O F  A B B R E VI A TI O N S  ................................................................................................. 1 3  
1.  
I N T R O D U C TI O N .......................................................................................................... 1 5  
1. 1.  Bac k gr o u n d  ............................................................................................................... 1 5  
1. 2.  N o n -cli nical P har mac o ki netics  ................................................................................. 1 5  
1. 3.  S u m mar y of  Cli nical E x perie nce  .............................................................................. 1 7  
1. 3. 1.  
Safet y  .......................................................................................................... 1 7  
1. 3. 2.  
P har mac o ki netics  ........................................................................................ 1 8  
1. 4.  St u d y  Rati o nale  ......................................................................................................... 2 1  
1. 5.  Ris k  Assess me nt  ....................................................................................................... 2 1  
2.  
O BJ E C TI V E S  A N D  E N D P OI N T S  ................................................................................ 2 2  
2. 1.  O bjecti ves  ................................................................................................................. 2 2  
2. 1. 1.  
Pri mar y  O bjecti ve  ....................................................................................... 2 2  
2. 1. 2.  
Sec o n dar y  O bjecti ve  ................................................................................... 2 2  
2. 2.  E n d p oi nts  .................................................................................................................. 2 2  
2. 2. 1.  
Pri mar y  E n d p oi nts  ...................................................................................... 2 2  
2. 2. 2.  
Sec o n dar y  E n d p oi nts  .................................................................................. 2 2  
3.  
I N V E S TI G A TI O N A L P L A N ......................................................................................... 2 4  
3. 1.  O verall St u d y Desi g n  a n d Pla n  ................................................................................. 2 4  
3. 2.  Disc ussi o n of  St u d y Desi g n  ...................................................................................... 2 5  
3. 3.  Selecti o n of D oses i n  t he St u d y  ................................................................................ 2 5  
4.  
S E L E C TI O N O F  S T U D Y  P O P U L A TI O N  .................................................................... 2 6  
4. 1.  Scree ni n g  Pr oce d ures  ................................................................................................ 2 6  
4. 2.  C hec k -i n Pr oce d ures ( Da y -1)  .................................................................................. 2 7  
4. 3.  I ncl usi o n Criteria  ...................................................................................................... 2 7  
4. 4.  E xcl usi o n  Criteria  ..................................................................................................... 2 9  
4. 5.  S u bject N u m ber  a n d I de ntificati o n ........................................................................... 3 2  
4. 6.  Re m o val of S u bjects fr o m  St u d y Partici pati o n  ......................................................... 3 2  
5.  
S T U D Y  T R E A T M E N T S  .................................................................................................3 4  
5. 1.  Descri pti o n, St ora ge, Pac ka gi n g,  a n d La beli n g  ........................................................ 3 4  
5. 2.  St u d y  Treat me nt A d mi nistrati o n  .............................................................................. 3 4  
5. 3.  Ra n d o mizati o n  .......................................................................................................... 3 5  
5. 4.  Bli n di n g  .................................................................................................................... 3 5  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 1  of 5 8  
 
 
5. 5.  D ose Escalati o n Criteria a n d  St o p pi n g R ules  ........................................................... 3 5  
5. 6.  Treat me nt  C o m plia nce  .............................................................................................. 3 6  
5. 7.  Dr u g  Acc o u nta bilit y  ................................................................................................. 3 7  
6.  
C O N C O MI T A N T T H E R A PI E S A N D  O T H E R  R E S T RI C TI O N S  ............................... 3 8  
6. 1.  C o nc o mita nt  T hera pies  ............................................................................................. 3 8  
6. 2.  Diet, Fl ui d, a n d  Acti vit y  C o ntr ol  .............................................................................. 3 8  
7.  
S T U D Y A S S E S S M E N T S  A N D  P R O C E D U R E S  .......................................................... 3 9  
7. 1.  P har mac o ki netic  Assess me nts  .................................................................................. 3 9  
7. 1. 1.  
P har mac o ki netic Bl o o d Sa m ple C ollecti o n  a n d Pr ocessi n g  ....................... 3 9  
7. 1. 2.  
A nal ytical  Met h o d ol o g y  ............................................................................. 3 9  
7. 2.  Safet y a n d  T olera bilit y  Assess me nts  ........................................................................ 3 9  
7. 2. 1.  
A d verse  E ve nts  ........................................................................................... 3 9  
7. 2. 2.  
Cli nical  La b orat or y E val uati o ns  ................................................................. 4 0  
7. 2. 3.  
Vital  Si g ns  ................................................................................................... 4 1  
7. 2. 4.  
1 2 -lea d Electr ocar di o gra m  ...........................................................................4 1  
7. 2. 5.  
P h ysical  E xa mi nati o n  .................................................................................. 4 1  
8.  
S A M P L E SI Z E A N D  D A T A  A N A L Y SI S  ..................................................................... 4 2  
8. 1.  Deter mi nati o n of  Sa m ple Size  .................................................................................. 4 2  
8. 2.  A nal ysis  P o p ulati o ns  ................................................................................................ 4 2  
8. 2. 1.  
St u d y  P o p ulati o ns  ....................................................................................... 4 2  
8. 3.  P har mac o ki netic  A nal ysis ......................................................................................... 4 2  
8. 3. 1.  
Descri pti ve  A nal ysis  ................................................................................... 4 3  
8. 3. 2.  
Statistical  Met h o d ol o g y  .............................................................................. 4 3  
8. 4.  Safet y  A nal ysis  ......................................................................................................... 4 3  
8. 5.  Data Ha n dli n g a n d  Rec or d Kee pi n g  ......................................................................... 4 4  
8. 6.  Q ualit y C o ntr ol a n d  Q ualit y Ass ura nce  .................................................................... 4 4  
9.  
A D MI NI S T R A TI V E A S P E C T S  .................................................................................... 4 5  
9. 1.  C ha n ge  i n Pr ot oc ol ................................................................................................... 4 5  
9. 2.  Site I nitiati o n  Visit/I n vesti gat or Meeti n g  ................................................................. 4 5  
9. 3.  Discl os ure  ................................................................................................................. 4 5  
9. 4.  M o nit ori n g  ................................................................................................................ 4 5  
9. 5.  I nstit uti o nal Re vie w  B oar d  ....................................................................................... 4 5  
9. 6.  I nf or me d C o nse nt  ..................................................................................................... 4 6  
9. 7.  Rec or ds  ..................................................................................................................... 4 6  
9. 8.  Refere nce t o Declarati o n of  Helsi n ki/ Basic  Pri nci ples  ............................................. 4 6  
9. 9.  Fi na nci n g  a n d I ns ura nce  ........................................................................................... 4 7  
1 0.  R E F E R E N C E S  ................................................................................................................4 8  
1 1.  A P P E N DI C E S  ................................................................................................................ 4 9  
A p pe n di x 1: A d verse  E ve nt Re p orti n g  .............................................................................. 5 0  
A p pe n di x 2: Cli nical  La b orat or y E val uati o ns  .................................................................... 5 4  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 2  of 5 8  
 
 
A p pe n di x 3: T otal  Bl o o d  V ol u me  ...................................................................................... 5 5  
A p pe n di x 4: Sc he d ule  of  Assess me nts  .............................................................................. 5 6  
 
 
LI S T O F T A B L E S  
Ta ble 1 P har mac o ki netic Para meters of L O X O -3 0 5 i n Ca ncer Patie nts  
( St u d y L O X O-B T K -1 8 0 0 1) at Stea d y State ( C ycle 1  Da y  8)  ............................ 1 8  
Ta ble 2 P har mac o ki netic of L O X O -3 0 5 F oll o wi n g a Si n gle 2 0 0 -m g D ose of 
L O X O -3 0 5 i n Ca ncer Patie nts ( St u d y L O X O -B T K -1 8 0 0 1, C ycle 1 Da y 1)  
a n d Healt h y S u bjects  ( St u d y L O X O -B T K -2 0 0 1 4)  ............................................. 2 0  
Ta ble 3  St u d y Dr u gs  ........................................................................................................ 3 4  
 C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 3  of 5 8  
 
 
LI S T O F A B B R E VI A TI O N S  
 
A b bre vi ati o n  
Defi niti o n  
% A U C
e xtra p 
perce nta ge e xtra p olati o n f or area u n der t he c o nce ntrati o n -ti me c ur ve 
fr o m ti me 0 e xtra p olate d t o i nfi nit y 
A D L  
Acti vities of Dail y  Li vi n g  
A E  
a d verse  e ve nt 
A U C 0 -2 4  
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o 2 4 h o urs p ost d ose 
A U C 0 -i nf 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit y 
A U C 0 -t 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o t he last 
meas ura 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  
B T K  
Br ut o n’s t yr osi ne  ki nase  
C F R  
C o de of Fe deral  Re g ulati o ns  
C K  
creati ne  ki nase  
C L/ F  
a p pare nt s yste mic  cleara nce  
C L L  
c hr o nic l y m p h oc ytic  le u ke mia 
C ma x  
ma xi m u m o bser ve d plas ma  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 V %  
c oefficie nt of  variati o n  
C Y P  
c yt oc hr o me  P 4 5 0  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic Case Re p ort  F or m  
E O S  
E n d of  St u d y  
E O T  
E n d of  Treat me nt  
E T  
Earl y  Ter mi nati o n  
F D A  
F o o d a n d Dr u g  A d mi nistrati o n  
F S H  
f ollicle-sti m ulati n g h or m o ne  
H b A 1c  
he m o gl o bi n  A 1c  
H Bs A g  
he patitis B s urface  a nti ge n 
H B V  
he patitis B  vir us  
H C V  
he patitis C  vir us  
H D Y F?  
H o w D o Y o u  Feel?  
h E R G  
h u ma n  et her-à-g o -g o -relate d 
HI V  
h u ma n i m m u n o deficie nc y  vir us  
H R T  
h or m o ne -re place me nt t hera p y 
I B 
I n vesti gat or’s Br oc h ure  
I C9 0  
c o nce ntrati o n re q uire d f or 9 0 %  i n hi biti o n 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 4  of 5 8  
 
 
I C F 
I nf or me d C o nse nt F or m  
I C H 
I nter nati o nal C o u ncil f or/ C o nfere nce o n Har m o nisati o n 
I M P 
i n vesti gati o nal me dici nal pr o d uct  
I R B 
I nstit uti o nal Re vie w B oar d  
I U D 
i ntra uteri ne de vice  
I V 
i ntra ve n o us 
L F T  
li ver f u ncti o n test 
L n  
nat ural l o g  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
N H L  
n o n -H o d g ki n  l y m p h o ma 
N O E L  
n o o bser ve d effect  le vel 
P C R  
p ol y merase c hai n  reacti o n 
P -g p  
P -gl yc o pr otei n  
P K  
p har mac o ki netic(s)  
Q D  
o nce dail y  
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s met h o d 
R B C  
re d bl o o d cell(s) 
S A E  
seri o us a d verse e ve nt(s) 
S A P  
Statistical A nal ysis  Pla n  
S D D  
s pra y-drie d  dis persi o n  
S O C  
s yste m or ga n class 
S O P 
S U S A R  
Sta n dar d O perati n g Pr oce d ure  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
t1/ 2  
a p pare nt plas ma 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 
tma x  
ti me t o ma xi m u m o bser ve d plas ma 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 A  
uri nal ysis  
V z/ F 
a p pare nt v ol u me of  distri b uti o n  
W B C  
w hite bl o o d  cell(s) 
W H O  
W orl d Healt h  Or ga nizati o n  
λ Z  
a p pare nt ter mi nal eli mi nati o n rate  c o nsta nt 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 5  of 5 8  
 
 
1.  I N T R O D U C TI O N 
 
Refer t o t he I n vesti gat or’s Br oc h ure (I B) f or detaile d i nf or mati o n c o ncer ni n g t he a vaila ble 
p har mac ol o g y, t o xic ol o g y, dr u g meta b olis m, cli nical st u dies, a n d a d verse e ve nt ( A E) pr ofile 
of t he i n vesti gati o nal me dici nal pr o d uct (I M P), L O X O -3 0 5. 1  
1. 1.  
B ac k gr o u n d  
L O X O -3 0 5 (als o k n o w n as L Y 3 5 2 7 7 2 7) is a selecti ve i n hi bit or of t he Br ut o n’s t yr osi ne 
ki nase ( B T K) bei n g de vel o pe d b y L o x o O nc ol o g y. L O X O -3 0 5 is disti nct fr o m t he a p pr o ve d 
B T K i n hi bit ors (i br uti ni b, acala br uti ni b, a n d za n u br uti ni b) i n se veral i m p orta nt wa ys 
i ncl u di n g o n t he basis of its selecti vit y, fa v ora ble a bs or pti o n, distri b uti o n, meta b olis m, a n d 
e xcreti o n pr o perties, a n d n o n -c o vale nt bi n di n g m o de. 2  T he n o n -c o vale nt bi n di n g m o de of 
L O X O -3 0 5 is u naffecte d b y B T K C 4 8 1 s u bstit uti o ns, a c o m m o n mec ha nis m of dr u g 
resista nce descri be d f or all a vaila ble c o vale nt i n hi bit ors.3 ,4 ,5 ,6 ,7  T hese feat ures e na ble  
L O X O -3 0 5 d ose d orall y at 1 0 0 m g a n d hi g her o nce dail y ( Q D) t o ac hie ve p har mac o ki netic 
( P K) e x p os ures t hat e xcee d t he c o nce ntrati o n re q uire d f or 9 0 % i n hi biti o n (I C9 0) of B T K-wt 
a n d B T K C 4 8 1 at tr o u g h a n d t h us deli ver t o nic B T K tar get i n hi biti o n t hr o u g h o ut t he d osi n g 
peri o d, re gar dless of t he i ntri nsic rate of B T K t ur n o ver. L O X O -3 0 5 is als o a hi g hl y selecti ve 
m olec ule, wit h m ore t ha n 3 0 0 -f ol d m ore selecti vit y f or B T K vers us 3 7 0 ot her ki nases teste d 
a n d n o si g nifica nt i n hi biti o n of n o n -ki nase off -tar gets at 1 μ M, t h us li miti n g t he p ote ntial f or 
off -tar get me diate d t o xicities. C ollecti vel y, t hese u ni q ue pr o perties of L O X O-3 0 5 are 
e x pecte d t o deli ver m ore p ote nt, c o nti n u o us, a n d selecti ve i n hi biti o n of B T K i n a variet y of 
setti n gs, p ote ntiall y res ulti n g i n i ncrease d efficac y. Of n ote, t he acti vit y of L O X O-3 0 5 i n 
di verse precli nical m o del s yste ms s u p p orts t his u n derl yi n g h y p ot hesis. 2  
L O X O -3 0 5 is a s mall m olec ule t hat was desi g ne d t o 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 B T K c o m petiti vel y, wit h n o e vi de nce of irre versi ble bi n di n g.  
 
1. 2.  
N o n -cli nic al  P h ar m ac o ki netics  
 
L O X O -3 0 5 ha d hi g h per mea bilit y i n vitr o, b ut l o w a q ue o us s ol u bilit y. T o re d uce t he 
varia bilit y i n oral a bs or pti o n, a s pra y -drie d dis persi o n ( S D D) ta blet f or m ulati o n was 
de vel o pe d t hat s h o we d c o nsiste nt oral bi oa vaila bilit y of a p pr o xi matel y 5 0 % i n rats a n d 8 0 % 
i n d o gs. T he bi oa vaila bilit y of t he S D D f or m ulati o n was als o n ot de pe n de nt o n fee di n g state 
i n d o gs. 
 
As is c o m m o n i n r o de nts, oral e x p os ure of L O X O -3 0 5 was c o nsiste ntl y m uc h hi g her i n 
fe male rats t ha n i n males gi ve n t he sa me d ose of L O X O-3 0 5. T he se x differe nce was als o 
a p pare nt after i ntra ve n o us (I V) a d mi nistrati o n of L O X O -3 0 5. T here was n o differe nce i n t he 
P K of L O X O -3 0 5 bet wee n se xes of d o g, a n d n o ne is e x pecte d i n ot her n o n -r o de nt s pecies, 
i ncl u di n g h u ma ns. 
T he v ol u me of distri b uti o n of L O X O -3 0 5 ra n ge d fr o m a p pr o xi matel y 2 L/ k g i n t he d o g t o 
5 L/ k g i n t he male rat, w hic h i n dicates t hat L O X O -3 0 5 distri b utes i nt o tiss ues. L O X O -3 0 5 
ha d pr otei n bi n di n g of a p pr o xi matel y 9 5 % i n h u ma n plas ma. A s o me w hat l o wer e xte nt of 
bi n di n g (a p pr o xi matel y 8 2 % t o 9 2 %) was o bser ve d acr oss m o use, rat, ra b bit, a n d d o g.  
L O X O -3 0 5 was meta b olize d sl o wl y b y h u ma n micr os o mal fracti o ns a n d he pat oc ytes. T he 
l o w rates of meta b olis m i n b ot h t hese h u ma n i n vitr o s yste ms s u g gest t hat L O X O-3 0 5 will 
ha ve l o w cleara nce i n h u ma ns. I n vitr o data wit h cl o ne d e x presse d c yt oc hr o me P 4 5 0 ( C Y P)  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 6  of 5 8  
 
 
e nz y mes a n d h u ma n li ver micr os o mes i n dicate t hat C Y P 3 A 4 is t he pri mar y C Y P e nz y me t hat 
meta b olizes L O X O -3 0 5. It is als o a s u bstrate f or direct gl uc ur o ni dati o n.  
 
I n l o n g-ter m he pat oc yte i nc u bati o ns, L O X O-3 0 5 was meta b olize d b y b ot h o xi dati o n a n d 
gl uc ur o ni dati o n. I n hi biti o n of o xi dati ve meta b olis m b y a d diti o n of t he P 4 5 0 i n hi bit or  
1 -a mi n o be nz otriaz ole s h o we d t hat o xi dati ve meta b olis m is C Y P de pe n de nt. All meta b olites 
f or me d b y h u ma n he pat oc ytes were als o f or me d i n rat a n d/ or d o g he pat oc ytes s u p p orti n g t he 
use of rat a n d d o g f or n o ncli nical safet y assess me nt.  
 
Re nal cleara nce of L O X O -3 0 5 i n male a n d fe male rats was ne gli gi ble. N o data o n re nal 
cleara nce are a vaila ble i n ot her s pecies; h o we ver, t he re nal e xcreti o n pat h wa y is ofte n 
c o nser ve d acr oss s pecies, a n d t heref ore n o re nal cleara nce w o ul d be e x pecte d i n h u ma ns.  
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-à-g o -g o -relate d ge ne 
( h E R G) acti vit y, t he c o nce ntrati o n res ulti n g i n 5 0 % i n hi biti o n f or t he i n hi bit or y effects of 
L O X O -3 0 5 o n h E R G p otassi u m c urre nts was 
 μ M, w hic h is a p pr o xi matel y 
 hi g her 
t ha n t he ma xi m u m u n b o u n d c o nce ntrati o n of L O X O-3 0 5 i n patie nts treate d wit h t he d ose of 
2 0 0 m g Q D. T here were n o L O X O -3 0 5 -relate d c ha n ges i n a n y car di o vasc ular e n d p oi nts 
i ncl u di n g Q Tc at si n gle d oses u p t o 6 0 m g/ k g i n t he G L P car di o vasc ular st u d y i n t he 
c o nsci o us tele metr y -i nstr u me nte d d o g. T he ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ) 
f or t his d ose was  
 n g/ m L, w hic h is a p pr o xi matel y 
 a b o ve t he pre dicte d Cma x 
plas ma L O X O -3 0 5 c o nce ntrati o n ( 
 n g/ m L) at t he pr o p ose d cli nical t hera pe utic d ose of 
2 0 0 m g Q D. F urt her m ore, t here were n o L O X O -3 0 5 -relate d a b n or malities i n r h yt h m or 
wa vef or m m or p h ol o g y i n t he G L P 2 8 -da y re peate d -d ose t o xicit y st u d y i n d o gs at t he l o w - 
a n d mi d-d ose gr o u ps base d o n c o m paris o n of pre d ose a n d p ost d ose electr ocar di o gra m ( E C G) 
rec or di n gs. T he hi g h d ose ( 9 0/ 6 0 m g/ k g/ d ose t wice dail y [ BI D]) was n ot e val uate d as 
a ni mals i n t his gr o u p were m ori b u n d/ de bilitate d a n d were ter mi nate d o n Da y 1 3. Mea n Q Tc 
i nter val was statisticall y si g nifica ntl y pr ol o n ge d ( + 6 %; + 1 5 msec) o n Da y 2 6 of t he d osi n g 
p hase i n males a d mi nistere d 3 0/ 1 0 m g/ k g/ d ose BI D c o m pare d wit h c o ntr ols. T he 
pr ol o n gati o n i n Q Tc f or males was bel o w t he 1 0 % i ncrease or t he t hres h ol d re p orte d f or 
ca ni nes e x p ose d t o t hera pe utic c o nce ntrati o ns of dr u gs k n o w n t o ca use Q T pr ol o n gati o n i n 
h u ma ns. 8  T heref ore, t he Q Tc c ha n ges were c o nsi dere d p h ysi ol o gicall y u ni m p orta nt, a n d t h us 
n ot dee me d t o be a d verse. T o get her, t hese data i n dicate t hat L O X O -3 0 5 has a l o w ris k of 
i n d uci n g dela ye d ve ntric ular re p olarizati o n, pr ol o n gati o n of t he Q Tc i nter val, a n d u nsta ble 
arr h yt h mias i n  patie nts.  
T here were n o L O X O -3 0 5 -relate d fi n di n gs o n t he ce ntral ner v o us s yste m w he n e val uate d i n 
rat f u ncti o nal o bser vati o nal batter y tests a n d l oc o m ot or acti vit y assess me nts after 4 wee ks of 
d osi n g or d uri n g rec o ver y at d oses of u p t o 5 0 0 m g/ k g/ d ose BI D i n male rats a n d  
1 7 5 m g/ k g/ d ose BI D i n fe male rats as part of t he G L P 2 8 -da y re peat -d ose st u d y.  
 
L O X O -3 0 5 ha d n o effect o n res pirati o n rate i n t he d o g at d oses u p t o 1 0 m g/ k g/ d ose BI D.  
 
Tar gets of t o xicit y were c haracterize d i n re peate d d ose st u dies c o n d ucte d i n 2 rele va nt 
t o xicit y s pecies. Certai n tar gets (t he he mat o p oietic a n d l y m p h oi d s yste ms) were f o u n d i n 
b ot h t he rat a n d t he d o g. Rat s pecific c ha n ges i n t he pa ncreas are s pecies s pecific a n d see n 
wit h ot her B T K i n hi bit ors. D o g s pecific c ha n ges i n l u n g a n d lar ge i ntesti ne were lesi o ns 
c o ntri b uti n g t o m ori b u n dit y i n hi g h d ose a ni mals i n t he 2 8 -da y st u d y. D oses e val uate d i n 
t he 2 8-da y d o g st u d y de m o nstrate d a stee p d ose res p o nse c ur ve f or t o xicit y a n d pr o n o u nce d 
c ha n ges i n he mat ol o gic para meters at hi g h e x p os ures.  
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 7  of 5 8  
 
 
L O X O -3 0 5 was n ot m uta ge nic i n 2 bacterial re verse m utati o n assa ys a n d was ne gati ve i n a 
n o n -G L P micr o n ucle us assa y usi n g C hi nese ha mster o var y cells. L O X O -3 0 5 was p ositi ve f or 
t he i n d ucti o n of micr o n uclei via a n a ne u ge nic mec ha nis m i n t he a bse nce a n d prese nce of t he 
e x o ge n o us meta b olic acti vati o n s yste m i n a G L P i n vitr o micr o n ucle us assa y i n h u ma n 
peri p heral bl o o d l y m p h oc ytes. H o we ver, L O X O -3 0 5 was ne gati ve i n a G L P i n vi v o 
micr o n ucle us assa y i n rat at d oses u p t o a n d i ncl u di n g a d ose of  
 m g/ k g. T he C
ma x at t he 
n o o bser ve d effect le vel ( N O E L) of  
 m g/ k g was  
 n g/ m L f or males a n d  
 n g/ m L f or fe males. 
 
L O X O -3 0 5 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 utral re d u pta ke 
p h ot ot o xicit y assa y.  
 
1. 3.  
S u m m ar y of Cli nic al  E x perie nce  
 
L O X O -3 0 5 is c urre ntl y bei n g st u die d i n a n o n g oi n g gl o bal P hase 1/ 2 first -i n-h u ma n st u d y, 
L O X O -B T K -1 8 0 0 1 (t he B R UI N St u d y), i n patie nts wit h pre vi o usl y treate d c hr o nic 
l y m p h oc ytic le u ke mia ( C L L)/ s mall l y m p h oc ytic l y m p h o ma or n o n-H o d g ki n l y m p h o ma 
( N H L). T he starti n g d ose of L O X O-3 0 5 was 2 5 m g Q D.  
 
As of 0 9 A pril 2 0 2 0, safet y data were a vaila ble fr o m 1 7 2 treate d patie nts, wit h 3 0 0 m g Q D as 
t he hi g hest d ose a d mi nistere d (Secti o n 1. 3. 1 ). As of 3 0 Marc h 2 0 2 0 ( data c ut off date), P K 
data were a vaila ble fr o m 1 0 7 patie nts ( Secti o n 1. 3. 2 ). L O X O-3 0 5 was rece ntl y i n vesti gate d 
i n 1 st u d y i n healt h y v ol u nteers ( L O X O-B T K -2 0 0 1 4). L O X O -B T K -2 0 0 1 4 is a  pil ot  
f o o d-effect cr oss -o ver st u d y e val uati n g t he effects of f o o d a n d a pr ot o n -p u m p i n hi bit or 
( o me praz ole) o n t he P K of L O X O-3 0 5 w here 1 0 healt h y v ol u nteers were gi ve n 2 0 0 m g of 
L O X O -3 0 5 o n 3 se parate da ys, eac h f oll o we d b y a was h o ut peri o d. A sec o n d st u d y is 
o n g oi n g i n healt h y v ol u nteers ( L O X O -B T K -2 0 0 0 6), w hic h is a dr u g -dr u g i nteracti o n st u d y 
e val uati n g t he effects of a str o n g C Y P 3 A 4 i n hi bit or (itrac o naz ole) a n d a str o n g C Y P 3 A 4 
i n d ucer (rifa m pi n) o n t he P K of L O X O-3 0 5 w here, at t he ti me of pr ot oc ol de vel o p me nt, 3 
healt h y v ol u nteers were gi ve n 2 0 0 m g of L O X O -3 0 5 o n 3 se parate da ys ( o ne of w hic h was 
c o-a d mi nistere d wit h itrac o naz ole), eac h f oll o we d b y a was h o ut peri o d.  
 
1. 3. 1.  
S afet y  
 
As of 0 9 A pril 2 0 2 0, 1 7 2 patie nts were treate d i n t he first -i n-h u ma n st u d y  
( L O X O-B T K -1 8 0 0 1) a n d recei ve d L O X O -3 0 5 at d oses ra n gi n g fr o m 2 5 m g Q D t o 3 0 0 m g 
Q D. A f ull s u m mar y of treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) f or patie nts i n t his st u d y 
is pr o vi de d i n t he L O X O-3 0 5 I B a n d t he I n vesti gat or is directe d t o t he safet y i nf or mati o n 
descri be d i n t hat d oc u me nt. 1  
O verall, T E A Es were re p orte d i n 1 2 3 of 1 7 2 treate d patie nts i n t he safet y p o p ulati o n a n d 
were mil d or m o derate se verit y ( Gra de 1 or 2) i n 8 9 of 1 2 3 ( 5 1. 7 %) patie nts a n d were 
Gra de 3 or 4 i n se verit y i n 3 3 of 1 2 3 ( 1 9. 2 %) patie nts. T he m ost fre q ue ntl y re p orte d T E A Es 
occ urri n g i n ≥ 1 0 % of patie nts were fati g ue ( 1 2. 8 % t otal, 7. 0 % relate d) a n d diarr hea ( 1 0. 5 % 
t otal, 6. 4 % relate d). T he m ost fre q ue ntl y re p orte d dr u g-relate d T E A Es (t h ose i n > 5 % of 
patie nts) were fati g ue ( 7. 0 %), diarr hea ( 6. 4 %), a n d c o nt usi o n ( 5. 2 %). All ot her dr u g -relate d 
T E A Es occ urre d i n < 5 % of patie nts eac h. T he m ost fre q ue ntl y re p orte d Gra de ≥ 3  T E A Es  
i ncl u de d ne utr o pe nia ( 4. 1 % t otal; 2. 9 % relate d), ne utr o p hil c o u nt decrease d ( 2. 3 % t otal; 1. 2 % 
relate d), a ne mia ( 1. 7 % t otal; 0. 6 % relate d), fati g ue a n d platelet c o u nt decrease d (eac h 1. 2 % 
t otal; eac h 0. 6 % relate d), a n d h y p o kale mia ( 1. 2 % t otal; n o ne relate d). 
C CI
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 8  of 5 8  
 
 
Fi ve patie nts ( 2. 9 % of all 1 7 2 patie nts treate d) disc o nti n ue d L O X O -3 0 5 beca use of T E A Es; 
2 of t he 5 patie nts ( 1. 2 % of all patie nts treate d) disc o nti n ue d L O X O -3 0 5 beca use of a 
treat me nt-relate d e ve nt. O ne of t hese patie nts wit h ma ntle cell l y m p h o ma treate d i n t he 
1 0 0 m g Q D gr o u p disc o nti n ue d d ue t o Gra de 3 le u k oc yt osis c o nsi dere d relate d t o st u d y dr u g. 
St u d y t hera p y was hel d f or res ol uti o n of le u k oc yt osis a n d t he patie nt s u bse q ue ntl y pr o gresse d 
a n d st u d y t hera p y was n ot res u me d; t he e ve nt of le u k oc yt osis was rec or de d as 
rec o vere d/res ol ve d. T he sec o n d patie nt treate d i n t he 1 5 0 m g Q D gr o u p disc o nti n ue d d ue t o 
Gra de 2 m yal gia; t he m yal gia was o n g oi n g. T he patie nt ha d pre vi o usl y recei ve d i br uti ni b 
w hic h was disc o nti n ue d after 3 m o nt hs of treat me nt f or A Es.  
 
A t otal of 5 deat hs ha ve bee n re p orte d f or patie nts treate d i n t his st u d y, L O X O -B T K -1 8 0 0 1. 
N o deat hs were c o nsi dere d relate d t o L O X O -3 0 5.  
 
Fr o m preli mi nar y A E data re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n i n healt h y 
v ol u nteers i n t he L O X O -B T K -2 0 0 1 4 st u d y, all T E A Es ( hea dac he, na usea, a n d v o miti n g) 
were Gra de 1 i n se verit y a n d c o nsi dere d relate d t o L O X O -3 0 5. All 3 e ve nts were re p orte d b y 
1 s u bject a n d res ol ve d pri or t o E n d of Treat me nt ( E O T; data o n file at t he ti me of pr ot oc ol 
de vel o p me nt). T here were n o A Es re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n i n 3 healt h y 
v ol u nteers i n t he L O X O -B T K -2 0 0 0 6 st u d y fr o m preli mi nar y data a vaila ble ( data o n file at 
t he ti me of pr ot oc ol de vel o p me nt). 
 
1. 3. 2.  
P h ar m ac o ki netics  
 
As of Marc h 3 0, 2 0 2 0, P K data were a vaila ble fr o m 1 0 7 patie nts e nr olle d i n  
L O X O -B T K -1 8 0 0 1. Stea d y -state P K para meters of L O X O-3 0 5 i n t hese ca ncer patie nts c o ul d 
be deri ve d fr o m data c ollecte d o n C ycle 1 Da y 8 a n d are s h o w n i n Ta ble 1 . T hese data s h o w 
t hat L O X O-3 0 5 is a bs or be d after oral a d mi nistrati o n wit h a me dia n ti me t o ma xi m u m 
o bser ve d plas ma c o nce ntrati o n (t ma x ) of a p pr o xi matel y 2 h o urs a n d l o w cleara nce (Ta ble 1 ). 
D ue t o t he li mite d sa m pli n g i nter val ( 0 -8 h o urs), i m p utati o n f or t he 2 4 -h o ur sa m ple was 
ma de fr o m C ycle 1 Da y 8 pre d ose sa m ple, lea di n g t o a n esti mate d plas ma half -life of 
a p pr o xi matel y 2 0 h o urs. F oll o wi n g a d mi nistrati o n of d oses of 1 0 0 m g Q D or hi g her, mea n 
tr o u g h plas ma le vels of L O X O-3 0 5 e xcee de d t he 
 of B T K i n vitr o  
(Fi g ure 1 ). 
 
T a ble 1 P h ar m ac o ki netic P ar a meters of L O X O -3 0 5 i n C a ncer P atie nts 
( St u d y L O X O-B T K -1 8 0 0 1) at Ste a d y St ate ( C ycle 1 D a y 8)  
 
 
 
 
D ose Le vel  
 
 
 
N  
C m a x 
( n g/ m L) 
Ge o me a n 
( % C V) 
 
T m a x  ( h) 
Me di a n 
( mi n, m a x) 
A U C 0 -2 4  
( n g * h/ m L) 
Ge o me a n 
( % C V) 
C L/ F  
( L/ h) 
Ge o me a n 
( % C V) 
t1/ 2 
( h) 
Ge o me a n 
( % C V) 
2 5 m g Q D  
5 0 m g Q D  
1 0 0 m g Q D  
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 9  of 5 8  
 
 
 
 
 
 
D ose Le vel  
 
 
 
N  
C m a x 
( n g/ m L) 
Ge o me a n 
( % C V) 
 
T m a x  ( h) 
Me di a n 
( mi n, m a x) 
A U C 0 -2 4  
( n g * h/ m L) 
Ge o me a n 
( % C V) 
C L/ F  
( L/ h) 
Ge o me a n 
( % C V) 
t1/ 2 
( h) 
Ge o me a n 
( % C V) 
1 5 0 m g Q D  
2 0 0 m g Q D  
2 5 0 m g Q D  
3 0 0 m g Q D  
A b bre viati o ns: A U C 0 -2 4 =  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; C L/ F = a p pare nt oral 
cleara nce; C ma x  = ma xi m u m dr u g c o nce ntrati o n, Ge o mea n = ge o metrical mea n, N = n u m ber of s u bjects;  
P K = p har mac o ki netic; Q D = o nce dail y; % C V = c oefficie nt of variati o n i n perce nt; t 1/ 2 =  half -life; tma x  = ti me of 
ma xi mal plas ma c o nce ntrati o n.  
a N = 5; b N = 8; c N = 1 8; d N = 1 6; e N = 2 0; f N = 1 6; g N = 1 5  
Data c ut off date: Marc h 3 0, 2 0 2 0.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0  
2 5 m g  ( N = 5) 
5 0 m g  ( N = 6) 
1 0 0 m g  ( N = 1 0) 
1 5 0 m g  ( N = 2 0) 
2 0 0 m g  ( N = 2 9) 
2 5 0 m g  ( N = 2 4) 
             3 0 0 m g  ( N = 1 8) 
 
 
0  
2  
4  
6  
8  
Ti m e ( h)  
M e a n C o n c e ntr ati o n  ( n g/ m L) 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 0  of 5 8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0  
0  
2  
4  
6  
8  
Ti m e ( h)  
 
Data c ut off date: Marc h 3 0, 2 0 2 0  
 
Si n gle d oses of 2 0 0 m g L O X O -3 0 5 were i n vesti gate d i n a st u d y i n healt h y v ol u nteers 
( L O X O-B T K -2 0 0 1 4, Pil ot F o o d Effect st u d y) i n w hic h t he P K was deter mi ne d. F oll o wi n g a 
si n gle d ose of 2 0 0 m g L O X O-3 0 5 t o patie nts or healt h y s u bjects, A U C fr o m 0 t o 8 h o urs was 
si milar bet wee n t he t w o gr o u ps a n d C ma x was a p pr o xi matel y 
% hi g her i n healt h y s u bjects, 
as s h o w n i n t he ta ble bel o w ( data o n file at t he ti me of pr ot oc ol de vel o p me nt).  
 
T a ble 2 P h ar m ac o ki netic of L O X O -3 0 5 F oll o wi n g a Si n gle 2 0 0 -m g D ose of L O X O -3 0 5 
i n C a ncer P atie nts ( St u d y L O X O-B T K -1 8 0 0 1, C ycle 1 D a y 1) a n d He alt h y 
S u bjects ( St u d y L O X O -B T K -2 0 0 1 4)  
He alt h y  V ol u nteers a  
C a ncer P atie nts b  
P ar a meter  
 
Ge o metric  Me a n  
C V  
n  
Ge o metric  Me a n  
C V  
n  
A b bre viati o ns: A U C 0 -8 = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m 0 t o 8 h o urs; C V =c oefficie nt of variati o n; 
C ma x = ma xi m u m c o nce ntrati o n; n = n u m ber of s u bjects.  
a L O X O-B T X -2 0 0 1 4, 2 0 0 m g si n gle d ose, faste d 
b L O X O -B T K -1 8 0 0 1, 2 0 0 m g si n gle d ose, faste d  
 
I n healt h y v ol u nteers, t he ge o metric mea n si n gle-d ose C ma x of a p pr o xi matel y  
 n g/ m L 
f oll o wi n g a 2 0 0-m g si n gle d ose is 
 bel o w t he N O E L (i n rat, Cma x 
 n g/ m L) f or 
micr o n uclei i n d ucti o n.  
2 5 m g  ( N = 5) 
5 0 m g  ( N = 6) 
1 0 0 m g ( N = 9)  
1 5 0 m g  ( N = 2 0) 
2 0 0 m g  ( N = 2 4) 
2 5 0 m g  ( N = 2 5) 
3 0 0 m g  ( N = 1 6) 
M e a n  C o n c e nt ati o n  ( n g/ m L) 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 1  of 5 8  
 
 
1. 4.  
St u d y  R ati o n ale  
 
W he n de vel o pi n g ne w dr u gs f or cli nical i n dicati o ns, it is necessar y t o c ollect data o n t he 
safet y, t olera bilit y, a n d P K i n or der t o s u p p ort f urt her de vel o p me nt of t he c o m p o u n d as a 
usef ul cli nical ca n di date a n d deter mi ne d ose le vels a n d d ose i nter vals f or s u bse q ue nt st u dies. 
T his st u d y will assess t he safet y, t olera bilit y, a n d P K of L O X O -3 0 5 i n healt h y s u bjects at 
hi g her d ose le vels t ha n pre vi o usl y a d mi nistere d i n t his p o p ulati o n t o deter mi ne t he si n gle 
d ose of L O X O -3 0 5 nee de d t o reac h t hera pe utic a n d s u prat hera pe utic e x p os ures of  
L O X O -3 0 5 t o desi g n a p ote ntial cli nical st u d y t o deter mi ne t he effect of L O X O -3 0 5 i n t he 
Q T i nter val.  
 
1. 5.  
Ris k  Assess me nt  
S u bjects i n t he c urre nt st u d y will n ot recei ve a n y healt h be nefit ( be y o n d t hat of a n assess me nt 
of t heir me dical stat us) fr o m partici pati n g i n t he st u d y. T he ris ks of partici pati o n are 
pri maril y t h ose ass ociate d wit h a d verse reacti o ns t o t he st u d y treat me nts, alt h o u g h t here ma y 
als o be s o me disc o mf ort fr o m c ollecti o n of bl o o d sa m ples a n d ot her st u d y  pr oce d ures.  
 
D oses of L O X O -3 0 5 u p t o 3 0 0 m g Q D are c urre ntl y bei n g i n vesti gate d i n t he o n g oi n g gl o bal 
P hase 1/ 2 st u d y i n ca ncer patie nts, L O X O -B T K -1 8 0 0 1. Si n gle d oses of 2 0 0 m g L O X O -3 0 5 
were i n vesti gate d i n a st u d y c o n d ucte d i n healt h y v ol u nteers ( L O X O -B T K -2 0 0 1 4).  
L O X O -B T K -2 0 0 1 4 is a pil ot f o o d effect st u d y e val uati n g t he effects of f o o d a n d of a 
pr ot o n -p u m p i n hi bit or ( o me praz ole) o n t he P K of L O X O -3 0 5. Si n gle d oses of 2 0 0 m g 
L O X O -3 0 5 are c urre ntl y bei n g i n vesti gate d i n a st u d y c o n d ucte d i n healt h y v ol u nteers 
( L O X O-B T K -2 0 0 0 6). L O X O -B T K -2 0 0 0 6 is a dr u g -dr u g i nteracti o n st u d y e val uati n g t he  
effects of a str o n g C Y P 3 A 4 i n hi bit or (itrac o naz ole) a n d a str o n g C Y P 3 A 4 i n d ucer (rifa m pi n) 
o n t he P K of L O X O -3 0 5.  
 
Fr o m A E data re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n i n 1 0 healt h y v ol u nteers i n t he 
L O X O -B T K -2 0 0 1 4 st u d y, all T E A Es ( hea dac he, na usea, a n d v o miti n g) were Gra de 1 i n 
se verit y a n d c o nsi dere d relate d t o L O X O-3 0 5. All 3 e ve nts occ urre d were re p orte d b y  
1 s u bject a n d res ol ve d b y E O T ( data o n file at t he ti me of pr ot oc ol de vel o p me nt). T here were 
n o A Es re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n i n 3 healt h y v ol u nteers i n t he  
L O X O -B T K -2 0 0 0 6 st u d y fr o m preli mi nar y data a vaila ble ( data o n file at t he ti me of pr ot oc ol 
de vel o p me nt).  
 
T he d oses of L O X O -3 0 5 a d mi nistere d i n t his st u d y are n ot a ntici pate d t o i n d uce a n y p ote ntial 
ris k t o s u bjects partici pati n g i n t his st u d y. 
 
M ore i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, a n d reas o na bl y a ntici pate d 
A Es ass ociate d wit h L O X O -3 0 5 ma y be f o u n d i n t he I B. 1  
T he d ose -escalati o n pr oce d ures a n d safet y m o nit ori n g practices e m pl o ye d b y t his pr ot oc ol 
(ie, re vie wi n g A E re p orti n g, c o n d ucti n g p h ysical e xa mi nati o ns a n d cli nical la b orat or y 
e val uati o ns, meas uri n g vital si g ns, a n d perf or mi n g 1 2 -lea d E C Gs) are c o nsi dere d a de q uate t o 
pr otect t he s u bjects’ safet y.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 2  of 5 8  
 
 
2.  O B J E C TI V E S A N D  E N D P OI N T S  
2. 1.  
O bjecti ves  
2. 1. 1.  
Pri m ar y  O bjecti ve  
 
T he pri mar y o bjecti ve of t he st u d y is:  
 
•  T o assess t he safet y a n d t olera bilit y of si n gle oral d oses of L O X O -3 0 5 w he n 
a d mi nistere d t o healt h y a d ult  s u bjects. 
2. 1. 2.  
Sec o n d ar y  O bjecti ve  
 
T he sec o n dar y o bjecti ve of t he st u d y is:  
 
•  T o assess t he P K of si n gle oral d oses of L O X O -3 0 5 w he n a d mi nistere d t o healt h y 
a d ult  s u bjects. 
 
2. 2.  
E n d p oi nts  
2. 2. 1.  
Pri m ar y E n d p oi nts 
S afet y  
T he pri mar y e n d p oi nt 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 -3 0 5 at 
si n gle d oses ≥ 3 0 0 m g. T his st u d y will i n vesti gate t he safet y a n d t olera bilit y of si n gle d oses 
(ie, p ote ntial t hera pe utic a n d s u prat hera pe utic e x p os ures) of L O X O-3 0 5 w he n a d mi nistere d 
t o healt h y s u bjects. Asce n di n g d oses u p t o a n d p ossi bl y i ncl u di n g 9 0 0 m g will be 
i n vesti gate d. 
 
Safet y a n d t olera bilit y will be assesse d b y m o nit ori n g A Es a n d c o nc o mita nt me dicati o ns, 
perf or mi n g p h ysical e xa mi nati o ns a n d cli nical la b orat or y e val uati o ns, meas uri n g vital si g ns, 
a n d perf or mi n g 1 2 -lea d E C Gs. T hese safet y a n d t olera bilit y e n d p oi nts are dee me d a de q uate 
t o detect a n y safet y si g nals w he n t he pla n ne d d ose ra n ge of L O X O-3 0 5 is a d mi nistere d t o 
healt h y s u bjects.  
 
2. 2. 2.  
Sec o n d ar y E n d p oi nts 
P h ar m ac o ki netic  
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 -3 0 5 (as a p pr o priate):  
 
•  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o 2 4 h o urs p ost d ose ( A U C0 -2 4) 
•  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o t he last meas ura ble 
c o nce ntrati o n  ( A U C0 -t) 
•  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y 
( A U C0 -i nf) 
•  perce nta ge e xtra p olati o n f or A U C 0 -i nf ( % A U Ce xtra p) 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 3  of 5 8  
 
 
•  C ma x  
•  ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n (tma x ) 
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  ( λZ ) 
•  a p pare nt s yste mic cleara nce  ( C L/ F) 
•  a p pare nt v ol u me of distri b uti o n at ter mi nal p hase  ( Vz/F)  
•  a p pare nt plas ma ter mi nal eli mi nati o n half -life (t½ ). 
I n di vi d ual a n d mea n plas ma c o nce ntrati o n ti me c ur ves ( b ot h li near a n d l o g-li near) will be 
i ncl u de d i n t he fi nal Cli nical St u d y Re p ort. 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 4  of 5 8  
 
 
3.  I N V E S TI G A TI O N A L P L A N  
3. 1.  
O ver all St u d y Desi g n a n d  Pl a n  
T his is a n o pe n -la bel, si n gle-asce n di n g d ose st u d y t o e val uate t he safet y, t olera bilit y, a n d P K 
of L O X O -3 0 5.  
 
U p t o 4 c o h orts are pla n ne d f or e val uati o n. I n eac h c o h ort, 6 healt h y a d ult s u bjects are 
pla n ne d f or e val uati o n. S u bjects will partici pate i n o nl y 1 c o h ort. I n eac h c o h ort, s u bjects will 
recei ve a si n gle oral d ose of L O X O-3 0 5 o n Da y 1. Eac h c o h ort will i ncl u de a se nti nel gr o u p 
of 2 s u bjects will be d ose d at least 4 8 h o urs bef ore t he re mai ni n g 4 s u bjects (f oll o wi n g 
re vie w of all a vaila ble safet y data).  
 
A si n gle oral d ose of L O X O -3 0 5 will be a d mi nistere d o n Da y 1 f or eac h c o h ort as f oll o ws:  
 
•  C o h ort 1 ( Treat me nt A): 3 0 0  m g  
•  C o h ort 2 ( Treat me nt B): u p t o 6 0 0  m g  
•  C o h ort 3 ( Treat me nt C): u p t o 9 0 0  m g.  
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he C ma x w o ul d e xcee d  
 n g/ m L. 
 
D ose escalati o n t o a hi g her d ose le vel (ie, ne xt c o h ort) will n ot ta ke place u ntil t he 
I n vesti gat or ( or desi g nee) a n d t he S p o ns or ha ve re vie we d all perti ne nt safet y/t olera bilit y data 
(ie, p h ysical e xa mi nati o ns, E C Gs, vital si g n meas ure me nts, cli nical la b orat or y e val uati o ns, 
a n d a d verse e ve nts [ A Es]) t hr o u g h a mi ni m u m of 1 6 8 h o urs ( Da y 8) a n d ha ve deter mi ne d 
t hat a de q uate safet y a n d t olera bilit y fr o m t he pre vi o us, l o wer d ose, c o h ort has bee n 
de m o nstrate d t o per mit pr ocee di n g t o t he ne xt c o h ort. P har mac o ki netic data t hr o u g h at least 
7 2 h o urs (a p pr o xi matel y 3 half -li ves) after d osi n g will be re vie we d t o g ui de t he 
d ose -escalati o n decisi o n. Data fr o m a mi ni m u m of 4 s u bjects will be re vie we d i n or der t o 
ma ke a d ose escalati o n decisi o n. D ose -escalati o n criteria a n d st o p pi n g r ules are descri be d i n 
Secti o n 5. 5 . 
 
Eac h treat me nt ( A, B, a n d C) will be a d mi nistere d orall y i n t he m or ni n g f oll o wi n g a fast of at 
least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g. 
 
T he P K sa m pli n g will be o btai ne d f or 1 6 8 h o urs after a d mi nistrati o n of eac h d ose of 
L O X O -3 0 5.  
 
T o assess t heir eli gi bilit y t o e nter t he st u d y, p ote ntial s u bjects will be scree ne d wit hi n 2 8 da ys 
( Da ys 2 9 t o -2) a n d be a d mitte d t o t he Cli nical Researc h U nit ( C R U) o n Da y -1 ( C hec k -i 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 ( Da y -1) u ntil E O T o n Da y 8 
u p o n c o m pleti o n of all P K a n d safet y assess me nts or Earl y Ter mi nati o n ( E T) if t he s u bject 
disc o nti n ues. A f oll o w u p p h o ne call will occ ur f or all s u bjects w h o recei ve d 1 d ose of st u d y 
dr u g (i ncl u di n g s u bjects w h o are ter mi nate d earl y) 7 da ys ( ± 2 da ys) after E O T or E T. T he  
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 5  of 5 8  
 
 
d urati o n of partici pati o n is e x pecte d t o be a p pr o xi matel y 4 6 da ys ( Scree ni n g t hr o u g h 
f oll o w-u p p h o ne call).  
 
Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d necessar y b y t he S p o ns or.  
 
T he start of t he st u d y is defi ne d as t he date t he first s u bject w h o is e nr olle d i n 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). N ote t hat e nr olle d s u bjects are defi ne d as t h ose s u bjects 
w h o are assi g ne d a d ose of st u d y dr u g; t his defi niti o n e xcl u des scree n fail ure s u bjects.  
 
I n t his st u d y, p h ysical e xa mi nati o ns, 1 2-lea d E C Gs, vital si g n meas ure me nts, H o w D o Y o u 
Feel? ( H D Y F?) i n q uiries, cli nical c he mistr y pa nel, c oa g ulati o n para meters, he mat ol o g y 
pa nel, uri nal ysis ( U A; A p pe n di x 2 ) a n d rec or di n g of c o nc o mita nt me dicati o ns will be 
perf or me d at s pecifie d ti mes d uri n g t he st u d y (f or s pecific ti me p oi nts a n d details o n eac h 
st u d y varia ble, refer t o A p pe n di x 4 . 
 
A d verse e ve nts a n d seri o us A Es ( S A Es) will be c ollecte d be gi n ni n g at i nf or me d c o nse nt. 
A d verse e ve nts will be re p orte 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 E n d of 
St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w-u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g 
pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as n ot relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee]) or as A Es 
(if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee], or if t he e ve nt 
occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p 
t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g b y 
t he I n vesti gat or ( or desi g nee) are t o be re p orte d. All S A Es t hat de vel o p fr o m t he ti me of I C F 
si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w-u p p h o ne call) are t o be re p orte d.  
 
A Sc he d ule of Assess me nts is prese nte d i n A p pe n di x 4 . St u d y c o m pleti o n is defi ne d as t he 
ti me of t he last s u bject’s f oll o w-u p.  
 
3. 2.  
Disc ussi o n of St u d y  Desi g n  
 
W he n de vel o pi n g ne w dr u gs f or cli nical i n dicati o ns, it is necessar y t o c ollect data o n t he 
safet y, t olera bilit y, a n d P K t o s u p p ort f urt her de vel o p me nt of t he c o m p o u n d as a usef ul 
cli nical ca n di date a n d deter mi ne d ose le vels a n d d ose i nter vals f or s u bse q ue nt st u dies. T his 
st u d y will assess t he safet y, t olera bilit y, a n d P K of L O X O-3 0 5 i n healt h y s u bjects at hi g her 
d ose le vels t ha n pre vi o usl y a d mi nistrate d i n t his p o p ulati o n s o as t o deter mi ne t he si n gle d ose 
of L O X O -3 0 5 nee de d t o reac h t hera pe utic a n d s u prat hera pe utic e x p os ures of L O X O -3 0 5 t o 
desi g n a p ote ntial cli nical st u d y t o deter mi ne t he effect of L O X O -3 0 5 o n t he Q T i nter val.  
 
C o n d ucti n g t he st u d y i n healt h y a d ult s u bjects miti gates t he p ote ntial c o nf o u n di n g effects of 
t he disease state a n d c o nc o mita nt me dicati o ns. 
 
3. 3.  
Selecti o n of D oses i n t he  St u d y  
 
T he t hree pla n ne d si n gle d oses of 3 0 0 m g, 6 0 0 m g, a n d 9 0 0 m g i n t his st u d y are desi g ne d t o 
yiel d a C ma x of L O X O -3 0 5 u p t o 
 hi g her t ha n t he t hera pe utic Cma x  ( 
 n g/ m L, 
Ta ble 1 ) at t he rec o m me n de d P hase 2 d ose of 2 0 0 m g Q D t hat ma y arise fr o m i ntri nsic or  
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 6  of 5 8  
 
 
e xtri nsic fact ors t hat lea d t o hi g her e x p os ures i n ca ncer patie nts. A f o urt h o pti o nal d ose le vel, 
n ot t o e xcee d 9 0 0 m g, ma y be use d if necessar y, t o f urt her defi ne t he d ose -e x p os ure 
relati o ns hi p. 
 
T he starti n g si n gle d ose of 3 0 0 m g i n t his st u d y is e x pecte d t o pr o d uce a C ma x t hat is 
a p pr o xi matel y  
 n g/ m L (
 t hera pe utic). As L O X O-3 0 5 s h o ws ge nerall y li near P K 
i n ca ncer patie nts (Ta ble 1 ), if e x p os ure als o i ncreases li nearl y wit h d ose i n healt h y s u bjects, 
t he pr o p ose d si n gle d oses of 6 0 0 m g a n d 9 0 0 m g w o ul d pr o d uce Cma x val ues of  
 a n d 
, res pecti vel y. As t he P K li nearit y of 
d oses greater t ha n 3 0 0 m g is n ot k n o w n, t he P K of L O X O -3 0 5 f oll o wi n g eac h d ose will be 
e val uate d pri or t o a d mi nisteri n g hi g her d oses, a n d n o d ose will be gi ve n f or w hic h t he 
ge o metric mea n C ma x is pre dicte d t o e xcee d 
 
base d o n t he P K o bser ve d at l o wer d oses.  
 
4.  S E L E C TI O N O F S T U D Y  P O P U L A TI O N  
4. 1.  
Scree ni n g  Pr oce d ures  
 
T he f oll o wi n g scree ni n g pr oce d ures will be perf or me d f or all p ote ntial s u bjects at a visit 
c o n d ucte d wit hi n 2 8 da ys of st u d y e ntr y (ie, pri or t o C hec k -i n [ Da y -1]):  
 
I ncl usi o n/e xcl usi o n criteria 
I nf or me d c o nse nt 
De m o gra p hic data  
Me dical hist or y (i ncl u di n g re vie w of me dicati o n[s]) 
Hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI)  
1 2 -lea d E C G meas ure d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 1 0 mi n utes (Secti o n 7. 2. 4 ) 
Vital si g n meas ure me nts (i ncl u di n g o x y ge n sat urati o n, oral te m perat ure, res pirat or y 
rate, a n d s u pi ne bl o o d press ure [ B P] a n d p ulse rate [ meas ure d after t he s u bject has 
bee n s u pi ne f or at least 5 mi n utes]; Secti o n 7. 2. 3 ) 
H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me dicati o n e val uati o ns ( Secti o n 7. 2. 1 ) 
Cli nical la b orat or y e val uati o ns ( Secti o n 7. 2. 2 ; cli nical c he mistr y pa nel [faste d at least 
8 h o urs], c oa g ulati o n para meters, he mat ol o g y pa nel, a n d U A; A p pe n di x 2 ) 
Scree ns f or he patitis C vir us ( H C V) a nti b o d y, he patitis B s urface a nti ge n ( H Bs A g), 
he patitis B vir us ( H B V) c ore a nti b o d y, h u ma n i m m u n o deficie nc y vir us ( HI V) 
a nti b o d y, a n d S A R S -C o V -2 ( C O VI D -1 9) via p ol y merase c hai n reacti o n testi n g 
([ P C R] or e q ui vale nt (A p pe n di x 2 ) 
He m o gl o bi n A 1c ( H b A 1c) test ( A p pe n di x 2 ) 
Scree n f or selecte d dr u gs of a b use, i ncl u di n g c oti ni ne a n d alc o h ol ( A p pe n di x 2 ) 
Esti mate d gl o mer ular filtrati o n rate ( A p pe n di x 2 ) 
Ser u m pre g na nc y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 7  of 5 8  
 
 
F ollicle -sti m ulati n g h or m o ne ( F S H) test (f or p ost-me n o pa usal fe male s u bjects o nl y; 
A p pe n di x 2 ) 
T h yr oi d -sti m ulati n g h or m o ne ( T S H) test (A p pe n di x 2 ) 
4. 2.  
C hec k -i n Pr oce d ures ( D a y -1)  
At C hec k -i n ( Da y -1), s u bjects will re p ort t o t he C R U a n d t he f oll o wi n g pr oce d ures will be 
perf or me d:  
 
Re vie w of i ncl usi o n/e xcl usi o n criteria  
I nteri m me dical hist or y, i ncl u di n g c o nc o mita nt me dicati o n(s) 
Wei g ht a n d B MI  
C o m plete p h ysical e xa mi nati o n ( Secti o n 7. 2. 5 ) 
1 2 -lea d E C G meas ure d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 1 0 mi n utes (Secti o n 7. 2. 4 ) 
Vital si g n meas ure me nts (i ncl u di n g o x y ge n sat urati o n, oral te m perat ure, res pirat or y 
rate, a n d s u pi ne B P a n d p ulse rate [ meas ure d after t he s u bject has bee n s u pi ne f or at 
least 5 mi n utes]; Secti o n 7. 2. 3 ) 
H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me dicati o n e val uati o ns ( Secti o n 7. 2. 1 ) 
Cli nical la b orat or y e val uati o ns ( Secti o n 7. 2. 2 ; cli nical c he mistr y pa nel [faste d at least 
8 h o urs], c oa g ulati o n para meters, he mat ol o g y pa nel, a n d U A; A p pe n di x 2 ) 
Scree n f or C O VI D -1 9 via P C R or e q ui vale nt  
Scree n f or selecte d dr u gs of a b use, i ncl u di n g c oti ni ne a n d alc o h ol ( A p pe n di x 2 ) 
Esti mate d gl o mer ular filtrati o n rate ( A p pe n di x 2 ) 
Ser u m pre g na nc y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
C o m plia nce wit h c o nc o mita nt me dicati o ns a n d e xcl usi o nar y restricti o ns ( Secti o n 6 ) 
 
F or s u bjects t o c o nti n ue t heir partici pati o n i n t he st u d y, t he i ncl usi o n/e xcl usi o n criteria m ust 
c o nti n ue t o be met at C hec k -i n ( Da y -1 [as a p pr o priate; # 1 , Secti o n 4. 2 ]). I n a d diti o n, 
c o nti n ue d c o m plia nce wit h c o nc o mita nt me dicati o n a n d ot her restricti o ns will be verifie d.  
 
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 val 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 nee).  
 
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 xcl 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 val uati o ns ma y be re peate d at t he 
discreti o n of t he I n vesti gat or ( or desi g nee) or S p o ns or.  
 
4. 3.  
I ncl usi o n Criteri a  
 
S u bjects w h o meet t he f oll o wi n g criteria at Scree ni n g a n d C hec k -i n ( Da y -1), u nless 
ot her wise s pecifie d, ma y be i ncl u de d i n t he st u d y:  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 8  of 5 8  
 
 
Males, a n d fe males of n o n -c hil d beari n g p ote ntial, bet wee n 1 8 a n d 5 5 years of a ge, 
i ncl usi ve, at Scree ni n g. 
Wit hi n B MI ra n ge 1 8. 0 t o 3 2. 0 k g/ m
2, i ncl usi ve. 
I n g o o d healt h, deter mi ne d b y n o cli nicall y si g nifica nt fi n di n gs fr o m me dical hist or y, 
p h ysical e xa mi nati o n, 1 2 -lea d E C G, vital si g n meas ure me nts, or cli nical la b orat or y 
e val uati o ns ( A p pe n di x 4 ) at Scree ni n g a n d/ or C hec k-i n ( Da y -1) as assesse d b y t he 
I n vesti gat or ( or desi g nee). 
Fe male s u bjects of n o n -c hil d beari n g p ote ntial, defi ne d as bei n g per ma ne ntl y sterile 
(ie, d ue t o h ysterect o m y, bilateral t u bal li gati o n, bilateral sal pi n gect o m y, bilateral 
o o p h orect o m y, or c o nfir me d t u bal occl usi o n m ore t ha n 6 m o nt hs pri or t o st u d y dr u g 
a d mi nistrati o n) or p ost -me n o pa usal ( defi ne d as at least 1 2 m o nt hs p ost -cessati o n of 
me nses wit h o ut a n alter nati ve me dical ca use). P ost -me n o pa usal stat us will be 
c o nfir me d wit h a scree ni n g ser u m F S H le vel ≥ 4 0 mI U/ m L. All fe male s u bjects m ust 
ha ve a ne gati ve q ualitati ve ser u m pre g na nc y test (ser u m h u ma n c h ori o nic 
g o na d otr o pi n; ser u m q ua ntitati ve h u ma n c h ori o nic g o na d otr o pi n tests ma y be use d f or 
c o nfir mati o n as nee de d) at Scree ni n g a n d C hec k -i n ( Da y -1). Fe male s u bjects are 
re q uire d t o refrai n fr o m d o nati o n of o va fr o m C hec k-i n ( Da y -1) u ntil 6 m o nt hs after 
a d mi nistrati o n of st u d y dr u g.  
Male s u bjects w h o are ca pa ble of fat heri n g a c hil d m ust a gree t o use 1 of t he 
f oll o wi n g met h o ds of c o ntrace pti o n fr o m t he ti me of t he d ose a d mi nistrati o n t hr o u g h 
6 m o nt hs after t he last d ose of L O X O -3 0 5 a d mi nistrati o n:  
a. Male sterilizati o n, wit h d oc u me nte d c o nfir mati o n of s ur gical s uccess. 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 
( Da y -1). If d oc u me ntati o n is n ot a vaila ble, male s u bjects m ust f oll o w 1 of t he 
c o ntrace pti o n met h o ds bel o w:  
i. Male c o n d o m wit h s per mici de,  or  
ii. A male s u bject m ust e ns ure t hat t heir fe male part ner meets 1 of t he 
f oll o wi n g criteria: 
1.  i ntra uteri ne de vice (I U D) ( h or m o nal I U D; e g, Mire na® ). 
C o p per I U Ds are acce pta ble (e g,  Para Gar d ® ); 
2.  esta blis he d use of oral, i m pla nte d, i njecte d, tra ns der mal, 
i ntra va gi nal, 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;  or  
3.  n o n -c hil d beari n g p ote ntial, defi ne d as bei n g per ma ne ntl y sterile 
(ie, d ue t o h ysterect o m y, bilateral t u bal li gati o n, bilateral 
sal pi n gect o m y, bilateral o o p h orect o m y, or c o nfir me d t u bal 
occl usi o n m ore t ha n 6 m o nt hs pri or t o male part ner’s st u d y 
dr u g a d mi nistrati o n);  or  
4.  be p ost -me n o pa usal wit h a me n orr hea f or at least 1 year pri or t o 
d osi n g a n d F S H ser u m le vels c o nsiste nt wit h p ost -me n o pa usal 
stat us. 
Male s u bjects w h o practice tr ue a bsti ne nce beca use of a lifest yle c h oice (ie, d o 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 xe m pt fr o m  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 9  of 5 8  
 
 
c o ntrace pti ve re q uire me nts. Peri o dic a bsti ne nce b y a fe male part ner (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) 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 male s u bject is a bsti ne nt at t he ti me of si g ni n g t he I C F 
b ut bec o mes se x uall y acti ve 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, he 
m ust a gree t o use c o ntrace pti o n as descri be d a b o ve.  
F or male s u bjects, se x ual i nterc o urse wit h fe male part ners w h o are pre g na nt, or 
breastfee di n g s h o ul d be a v oi de d. Male s u bjects are re q uire 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 ( Da y -1) u ntil 6 m o nt hs after a d mi nistrati o n of st u d y dr u g.  
F or s u bjects w h o are e xcl usi vel y i n sa me -se x relati o ns hi ps, c o ntrace pti ve 
re q uire me nts d o n ot a p pl y. 
A ble t o s wall o w m ulti ple ca ps ules.  
A ble t o u n dersta n d a n d pr o vi de writte n i nf or me d c o nse nt.  
A ble t o c o m pl y wit h all st u d y pr oce d ures, i ncl u di n g t he 8 -ni g ht sta y at t he C R U a n d 
f oll o w-u p p h o ne call.  
4. 4.  
E xcl usi o n  Criteri a  
T he f oll o wi n g will e xcl u de p ote ntial s u bjects fr o m t he st u d y:  
 
Hist or y or prese 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 nee) a n d/ or S p o ns or: 
a. li ver disease  
b.  pa ncreatitis  
c. pe ptic ulcer  disease  
d.  i ntesti nal mala bs or pti o n  
e. c h olec ystect o m y  
f. gastric re d ucti o n  s ur ger y 
g.  hist or y or prese nce of cli nicall y si g nifica nt car di o vasc ular  disease:  
i. M y ocar dial i nfarcti o n or cere br o vasc ular t hr o m b oe m b olis m wit hi n 
6 m o nt hs pri or t o t he first d ose a d mi nistrati o n ( Da y  1)  
ii. S y m pt o matic a n gi na pect oris wit hi n 6 m o nt hs pri or t o t he first d ose 
a d mi nistrati o n ( Da y  1)  
iii. Ne w Y or k Heart Ass ociati o n Class ≥ 2 c o n gesti ve heart fail ure wit hi n 
6 m o nt hs pri or t o t he first d ose a d mi nistrati o n ( Da y  1)  
i v. C o n ge nital pr ol o n ge d Q T s y n dr o me  
v.  Ve ntric ular pre -e xcitati o n s y n dr o me ( W olff -Par ki ns o n W hite 
s y n dr o me) 
vi.  Arr h yt h mia (e xcl u di n g be 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 me dical  i nter ve nti o n 
vii.  Ve ntric ular d ysf u ncti o n or ris k fact ors f or T orsa des de P oi ntes (e g, 
heart fail ure, car di o m y o pat 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  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 0  of 5 8  
 
 
viii.  Si g nifica nt scree ni n g E C G  a b n or malities:  
1.  left b u n dle bra nc h bl oc k  
2.  sec o n d de gree atri o ve ntric ular ( A V) bl oc k, t y pe 2, or 
t hir d-de gree A V  bl oc k  
3.  Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s met h o d 
( Q Tc F) is > 4 5 0 msec  
4.  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 he I n vesti gat or ( or desi g nee) at Scree ni n g, C hec k-i n ( Da y -1), 
or pri or t o d osi n g o n Da y  1.  
S u bjects wit h o ut -of -ra n ge, at-rest (ie, s u pi ne f or at least 5 mi n utes) vital si g n 
meas ure me nts at Scree ni n g, C hec k -i n ( Da y -1), or pri or t o d osi n g o n Da y 1, 
i ncl u di n g: 
a. oral b o d y te m perat ure >  3 7. 5° C;  
b.  p ulse rate < 5 0 or > 9 9 beats per mi n ute  ( b p m); 
c. s yst olic B P < 8 9 or > 1 3 9 m m H g;  
d.  diast olic B P < 5 0 or > 8 9  m m H g;  
e. o x y ge n sat urati o n < 9 5 % (r o o m  air) 
F or t hese para meters, o ut -of -ra n ge val ues t hat are n ot cli nicall y si g nifica nt (as 
deter mi ne d b y t he I n vesti gat or [ or desi g nee]) ma y be re peate d t wice d uri n g 
Scree ni n g, C hec k -i n ( Da y -1), a n d pre d ose o n Da y 1. N ote: Rec hec ks of p ulse rate 
a n d B P val ues 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 pati 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 p ulse rate a n d/ or B P val ues if t he val ues fall wit hi n t he ra n ges state d a b o ve. 
A b n or mal la b orat or y val ues ( he mat ol o g y pa nel, U A, cli nical c he mistr y pa nel [faste d 
at least 8 h o urs], e xcl u di n g t h ose f urt her defi ne d i n e xcl usi o n criteria # 5 , # 6 , # 7 , a n d 
# 8  bel o w) deter mi ne d t o be cli nicall y si g nifica nt b y t he I n vesti gat or ( or desi g nee), 
a n d S p o ns or at Scree ni n g a n d/ or C hec k -i n ( Da y -1) as c o nfir me d b y re peat 
assess me nt. 
Cli nicall y si g nifica nt a b n or malit y, as deter mi ne d b y t he I n vesti gat or ( or desi g nee), 
fr o m p h ysical e xa mi nati o n at C hec k-i n ( Da y -1).  
A b n or mal li ver f u ncti o n tests ( L F Ts), as defi ne d b y as partate a mi n otra nsferase, 
ala ni ne a mi n otra nsferase, a n d ser u m (t otal a n d direct) bilir u bi n, as well as a m ylase 
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 -i n 
( Da y -1). Rec hec ks of L F Ts, a m ylase, a n d li pase 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 pati o n if t he val ues fall wit hi n n or mal  ra n ges. 
A n y cli nicall y si g nifica nt de viati o ns fr o m n or mal ra n ges i n creati ne ki nase ( C K) 
u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. Rec hec ks of C K 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 pati o n if t he  
o ut -of -ra n ge val ues are sta ble or tre n di n g d o w n a n d t he I n vesti gat or ( or desi g nee) 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. 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 1  of 5 8  
 
 
Esti mate d gl o mer ular filtrati o n rate ≤ 9 0 m L/ mi n ute/ 1. 7 3 m 2 at Scree ni n g or C hec k -i n 
( Da y -1) calc ulate d usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
e q uati o n. 
He m o gl o bi n, w hite bl o o d cell c o u nt, a n d platelet c o u nts bel o w t he l o wer li mit of 
n or mal ra n ge at Scree ni n g or C hec k -i n ( Da y -1). Rec hec ks of he m o gl o bi n, w hite 
bl o o d cell c o u nt, a n d platelet c o u nts 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 pati o n if t he val ues fall wit hi n n or mal ra n ges.  
P ositi ve ser ol o gic test f or H Bs A g, H B V c ore a nti b o d y, H C V, or HI V a nti b o d y at 
Scree ni n g. S u bjects w h o are p ositi ve f or H C V b y a nti b o d y will re q uire c o nfir mati o n 
b y P C R bef ore e nr oll me nt t o detect prese nce of acti ve vir us. S u bjects w h o are H C V 
P C R p ositi ve or f or w h o m a P C R is u na ble t o be o btai ne d will n ot be eli gi ble.  
P ositi ve P C R test ( or e q ui vale nt) f or C O VI D -1 9 at Scree ni n g or C hec k -i n ( Da y -1). 
F urt her details re gar di n g C O VI D -1 9 testi n g (i ncl u di n g pr oce d ures w h o test p ositi ve at 
a n y ti me t hr o u g h o ut C R U c o nfi ne me nt) are s pecifie d i n se parate d oc u me nts.  
S u bjects wit h k n o w n o n g oi n g alc o h ol a n d/ or dr u g a b use wit hi n 2 years pri or t o 
Scree ni n g, or e vi de nce of s uc h a b use as i n dicate d b y t he la b orat or y assa ys f or dr u gs 
of a b use (i ncl u di n g c oti ni ne a n d alc o h ol) c o n d ucte d d uri n g Scree ni n g a n d/ or at 
C hec k -i n ( Da y -1). Tests f or dr u gs of a b use m ust be ne gati ve at b ot h Scree ni n g a n d 
C hec k -i n ( Da y -1).  
C o ns u m pti o n of gra pefr uit/ gra pefr uit j uice or Se ville ora n ges or its j uice wit hi n 
7 da ys pri or t o C hec k -i n ( Da y -1) a n d t hr o u g h E O T or E T.  
C o ns u m pti o n of alc o h ol - or caffei ne -c o ntai ni n g f o o ds or be vera ges wit hi n 7 2 h o urs 
pri or t o C hec k -i n ( Da y -1) a n d t hr o u g h E O T or E T, u nless dee me d acce pta ble b y t he 
I n vesti gat or ( or desi g nee) a n d S p o ns or. 
Stre n u o us e xercise wit hi n 5 da ys pri or t o C hec k -i n ( Da y -1) a n d t hr o u g h E O T or E T.  
Hist or y of si g nifica nt h y perse nsiti vit y, i nt olera nce, 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 he I n vesti gat or ( or desi g nee). 
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 t he first d ose a d mi nistrati o n ( Da y 1). 
Use or i nte nti o n t o use a n y prescri pti o n or o ver -t he-c o u nter me dicati o ns (i ncl u di n g, 
b ut n ot li mite d t o, a n y m o derate or str o n g C Y P 3 A 4 a n d/ or C Y P 3 A 5 i n hi bit ors or 
i n d ucers (i ncl u di n g her bal pr o d ucts s uc h as St. J o h n’s w ort), str o n g P-gl yc o pr otei n  
( P-g p) i n hi bit ors, pr ot o n p u m p i n hi bit ors, a ntaci ds, H 2-rece pt or a nta g o nists, a n d dr u gs 
t hat pr ol o n g Q T/ Q Tc i nter val, her bal pr o d ucts, nat ural or her bal s u p ple me nts, a n d 
h or m o ne -re place me nt t hera p y [ H R T]) wit hi n 1 4 da ys pri or t o t he first d ose 
a d mi nistrati o n ( Da y 1) a n d t hr o u g h E O T or E T, u nless dee me d acce pta ble b y t he 
I n vesti gat or ( or desi g nee) a n d S p o ns or. 
Hist or y of a maj or s ur gical pr oce d ure wit hi n 3 0 da ys pri or t o Scree ni n g.  
Hist or y or prese nce, u p o n cli nical e val uati o n, of a n y ill ness t hat, i n t he o pi ni o n of t he 
I n vesti gat or ( or desi g nee), w o ul d i nterfere wit h t he a bilit y t o pr o vi de i nf or me d 
c o nse nt or c o m pl y wit h st u d y i nstr ucti o ns, or t hat mi g ht c o nf o u n d t he i nter pretati o n 
of t he st u d y res ults, or p ut t he s u bject at u n d ue ris k.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 2  of 5 8  
 
 
P o or peri p heral ve n o us access.  
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 or platelets fr o m 4 wee ks 
pri or t o Scree ni n g.  
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 ( Da y -1).  
Use of t o bacc o, s m o ki n g cessati o n pr o d ucts, or pr o d ucts c o ntai ni n g nic oti ne wit hi n 
3 m o nt hs pri or t o Scree ni n g a n d t hr o u g h E O T or E T.  
Si g nifica nt hist or y or cli nical ma nifestati o n of a n y aller gic, der mat ol o gical, biliar y, 
he patic, gastr oi ntesti nal, re nal, meta b olic, he mat ol o gical, p ul m o nar y, car di o vasc ular 
(i ncl u di n g a n y pri or hist or y of car di o m y o pat h y or car diac fail ure), ne ur ol o gical, or 
ps yc hiatric dis or der (as deter mi ne d b y t he I n vesti gat or [ or desi g nee]), or ca ncer 
wit hi n t he past 5 years (e xce pt l ocalize d basal cell, s q ua m o us, or i n sit u ca ncer of t he 
s ki n). N ote: s u bjects wit h a hist or y of a p pe n dect o m y a n d/ or her nia re pairs will be 
acce pta ble. 
Hist or y of dia betes mellit us; H b A 1c ≥ 6. 5 %.  
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).  
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 -3 0 5 a n d ha ve pre vi o usl y recei ve d t he i n vesti gati o nal pr o d uct.  
Has bee n o n a diet i nc o m pati ble wit h t he o n -st u d y diet, i n t he o pi ni o n of t he 
I n vesti gat or ( or desi g nee), a n d as c o nfir me d b y t he S p o ns or, wit hi n t he 3 0 da ys pri or 
t o t he first d osi n g a n d t hr o u g h E O T or E T. 
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 nee), s h o ul d n ot partici pate 
i n t his st u d y. 
4. 5.  
S u bject N u m ber a n d  I de ntific ati o n 
S u bject n u m bers will c o nsist of 6 di gits i n w hic h t he first set of 3 di gits will i de ntif y t he site 
a n d t he sec o n d set of 3 di gits will i de ntif y t he s u bject (e g, 0 0 1 -1 0 1). If s u bjects are 
wit h dra w n b y t he I n vesti gat or ( or desi g nee) or 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 me d necessar y b y t he S p o ns or. If 
necessar y, as deter mi ne d b y t he S p o ns or, s u bjects w h o fail t o c o m plete t he treat me nt or ha ve 
i ns ufficie nt P K data ma y be re place d. 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 5 0 t o t he last 3 di gits of t he s u bject n u m ber f or t he s u bject t he y are 
re placi n g (e g, S u bject N u m ber 0 0 1-1 5 1 re places S u bject N u m ber 0 0 1 -1 0 1).  
 
4. 6.  
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) ma y re m o ve a s u bject fr o m t he st u d y if, i n t he 
I n vesti gat or’s ( or desi g nee’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 bjects ma y be wit h dra w n beca use of 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 xcl usi o n criteri o n t hat is cli nicall y rele va nt a n d 
affects s u bject  safet y 
•  occ urre nce of  A Es  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 3  of 5 8  
 
 
•  occ urre nce of  pre g na nc y  
•  i nta ke of n o n-per mitte d c o nc o mita nt me dicati 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 dra wal will i m me diatel y be ma de t o t he S p o ns or. I n case of wit h dra wal, 
eff orts will be ma de t o perf or m all fi nal st u d y da y assess me nts ( A p pe n di x 4 ). T he date t he 
s u bject is wit h dra w n fr o m t he st u d y a n d t he 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 Case Re p ort F or m (e C R F). All wit h dra w n s u bjects wit h A Es t hat are 
assesse d as relate d t o st u d y dr u g a n d w hic h are o n g oi n g at E T ma y c o nti n ue t o be f oll o we d 
u ntil t he s y m pt o ms or val ue(s) ret ur n t o n or mal, or acce pta ble le vels, as j u d ge d b y t he 
I n vesti gat or ( or desi g nee) a n d c o nfir me d b y t he S p o ns or. 
 
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 vesti gat or ( or desi g nee) 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 u n k n o w n t o date wit h res pect t o t heir nat ure, se verit y, a n d/ or  d urati o n;  
•  i ncrease 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 he c o nti n ue d perf or ma nce of t he  st u d y; 
•  diffic ulties i n t he recr uit me nt of  s u bjects; 
•  ca ncellati o n of dr u g  de vel o p me nt.  
I n t he e ve nt t hat t he st u d y is ter mi nate d earl y, t he S p o ns or or its desi g nee will pr o vi de 
s pecific g ui da nce t o t he C R U re gar di n g t he E O S pr oce d ures. 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 4  of 5 8  
 
 
5.  S T U D Y  T R E A T M E N T S  
5. 1.  
Descri pti o n, St or a ge, P ac k a gi n g, a n d  L a beli n g  
 
T he S p o ns or ( or desi g nee) will pr o vi de t he I n vesti gat or ( or desi g nee) wit h a de q uate 
q ua ntities of t he L O X O -3 0 5.  
 
T a ble 3 St u d y Dr u gs  
 
St u d y Dr u g  
L O X O -3 0 5  
F or m a  
Ta blet  
Stre n gt h  
2 5 m g  
S u p plier  
L o x o O nc ol o g y, I nc.  
M a n uf act urer  
Be n d Researc h, I nc.  
a S pecific i n gre die nts/ p urit y will be i de ntifie d i n t he Certificate of A nal ysis ( or e q ui vale nt) t hat is s u p plie d wit h 
t he st u d y dr u g(s). 
 
T he ta blets c o ntai ni n g 2 5 m g L O X O -3 0 5 will be s u p plie d b y t he S p o ns or ( or desi g nee), 
al o n g wit h t he batc h/l ot n u m bers a n d Certificate of A nal ysis. It will be pr o vi de d i n  
hi g h -de nsit y p ol yet h yle ne b ottles a n d st ore d acc or di n g t o t he i nstr ucti o ns o n t he la bel.  
 
Size 0 li g ht bl ue o pa q ue ca ps ules t o o ver -e nca ps ulate L O X O -3 0 5 ta blets will be s u p plie d b y 
C o va nce. L O X O -3 0 5 ta blets will be o ver -e nca ps ulate d ( wit h 4 ta blets of L O X O -3 0 5 bei n g 
place d i n eac h ca ps ule) acc or di n g t o C o va nce C R Us Sta n dar d O perati n g Pr oce d ures ( S O Ps) 
a n d rele va nt pr ocesses.  
 
St u d y dr u gs will be st ore d at t he C R U i n a l ocati o n t hat is l oc ke d wit h restricte d access.  
 
T he b ul k dr u g c o ntai ner a n d u nit d ose c o ntai ners will be la bele d i n acc or da nce wit h nati o nal 
la ws a n d re g ulati o ns. T he st u d y dr u g will be tra nsferre d fr o m b ul k s u p plies i nt o t he s u bject’s 
d ose c o ntai ner b y q ualifie d C R U e m pl o yees. Eac h u nit d ose c o ntai ner will be a p pr o priatel y 
la bele d. 
 
5. 2.  
St u d y Tre at me nt  A d mi nistr ati o n  
C o h ort 1 ( Treat me nt A):  
•  A si n gle oral d ose of 3 0 0 m g L O X O -3 0 5 ( 1 2 × 2 5 -m g ta blets, o ver -e nca ps ulate d 
[ 3 ca ps ules]) f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 2 ( Treat me nt B):  
•  A si n gle oral d ose of u p t o 6 0 0 m g L O X O -3 0 5 ( 2 4 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 6 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 3 ( Treat me nt C):  
•  A si n gle oral d ose of u p t o 9 0 0 m g L O X O -3 0 5 ( 3 6 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 9 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 5  of 5 8  
 
 
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he C ma x w o ul d e xcee d  
 n g/ m L. 
 
All st u d y dr u gs will be a d mi nistere d wit h a p pr o xi matel y 2 4 0 m L of water. A n a d diti o nal 
2 4 0 m L of water ma y be a d mi nistere d if nee de d.  
 
Eac h u nit d ose will be pre pare d b y q ualifie d C R U staff. Eac h u nit d ose c o ntai ner will be 
a p pr o priatel y la belle d.  
 
A p pr o priate u nit d ose(s), as descri be d a b o ve, will be a d mi nistere d t o s u bjects. Alt h o u g h t he 
ti mi n g of e ve nts re q uires 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 a s pecific ti me, t he e xact d ose ti me of s u bjects ma y be 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 sa me st u d y sc he d ule. F or eac h d ose, t he 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 F.  
 
S u bjects will be i nstr ucte d n ot t o cr us h, s plit, or c he w t he st u d y dr u gs.  
 
S u bjects will n ot la y s u pi ne f or 4 h o urs f oll o wi n g L O X O -3 0 5 d ose a d mi nistrati o n, e xce pt as 
necessitate d b y t he occ urre nce of a n A E(s) a n d/ or st u d y pr oce d ure(s).  
 
5. 3.  
R a n d o miz ati o n  
 
T his is a n o nra n d o mize d st u d y.  
 
5. 4.  
Bli n di n g  
 
T his is a n o pe n -la bel st u d y. 
 
5. 5.  
D ose Esc al ati o n Criteri a a n d St o p pi n g  R ules  
 
D ose escalati o n t o t he ne xt d ose le vel (ie, ne xt c o h ort) will n ot ta ke place u ntil t he 
I n vesti gat or ( or desi g nee) a n d t he S p o ns or ha ve deter mi ne d t hat a de q uate safet y a n d 
t olera bilit y data (ie, p h ysical e xa mi nati o ns, E C Gs, vital si g n meas ure me nts, cli nical 
la b orat or y e val uati o ns, a n d A Es t hr o u g h 1 6 8 h o urs [ Da y 8] f oll o wi n g d osi n g o n Da y 1) fr o m 
t he pre vi o us, l o wer d ose, c o h ort has bee n de m o nstrate d t o per mit pr ocee di n g t o t he ne xt 
c o h ort. A s ufficie nt peri o d of ti me will be all o we d bet wee n d osi n g ( 1 6 8 h o urs [ Da y 8], 
f oll o wi n g d osi n g o n Da y 1) of t he pri or c o h ort a n d t he d osi n g of t he ne xt c o h ort i n or der f or 
t he I n vesti gat or ( or Desi g nee) a n d t he S p o ns or t o a de q uatel y re vie w t he safet y a n d 
t olera bilit y data fr o m t he pri or c o h ort. P har mac o ki netic data t hr o u g h at least 7 2 h o urs 
(a p pr o xi matel y 3 half-li ves) will be re vie we d t o g ui de d ose-escalati o n decisi o ns or f or 
selecti o n of a n alter nate d ose f or e val uati o n, a n d/ or t o c o nfir m t he sa m pli n g sc he d ule. Data 
fr o m a mi ni m u m of 4 s u bjects will be re vie we d i n or der t o ma ke a d ose escalati o n decisi o n. 
 
T he I n vesti gat or ( or desi g nee) a n d t he S p o ns or will ma ke 1 of t he f oll o wi n g deter mi nati o ns: 
T o c o nti n ue wit h t he st u d y as pla n ne d.  
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 6  of 5 8  
 
 
T o c o nti n ue wit h t he st u d y a n d a d d a d diti o nal safet y e val uati o ns t o s u bse q ue nt 
c o h orts. 
I n t he e ve nt of t he f oll o wi n g occ urre nce: 
a. O ne s u bject at a gi ve n d ose le vel e x perie nces a dr u g -relate d C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) gra de ≥ 3 t o xicit y ( w hic h 
is n ot a n S A E), w hic h is dee me d cli nicall y si g nifica nt b y t he I n vesti gat or ( or 
desi g nee), wit h a gree me nt fr o m t he S p o ns or, a decisi o n will be ma de as 
f oll o ws: 
o  A dj ust t o a n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he ne xt 
pla n ne d  d ose;  
o  A dj ust t o a n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he pre vi o us 
l o wer d ose;  
o  D ose a d mi nistrati o n ma y be per mitte d t o c o nti n ue as dee me d b y t he 
I n vesti gat or ( or desi g nee), wit h a gree me nt fr o m t he S p o ns or, w here t he 
safet y para meter assesse d d oes n ot p ose a s u bject safet y ris k base d o n 
safet y k n o wle d ge fr o m pri or L O X O-3 0 5  st u dies. 
b.  T w o or m ore s u bjects i n a d ose le vel e x perie nce a dr u g -relate d C T C A E gra de  
≥ 3 t o xicit y ( w hic h is n ot a n S A E), w hic h are dee me d cli nicall y si g nifica nt b y 
t he I n vesti gat or ( or desi g nee), wit h a gree me nt fr o m t he S p o ns or, a decisi o n 
will be ma de as f oll o ws:  
o  D ose a d mi nistrati o n ma y be per mitte d t o c o nti n ue as pla n ne d if dee me d 
acce pta ble b y t he I n vesti gat or ( or desi g nee), wit h a gree me nt fr o m t he 
S p o ns or, w here t he safet y para meter assesse d d oes n ot p ose a s u bject 
safet y ris k base d o n safet y k n o wle d ge fr o m pri or L O X O-3 0 5  st u dies; 
o  E val uate a n alter nati ve d ose  le vel; 
o  T he st u d y ma y be ter mi nate d wit h n o a d diti o nal d ose a d mi nistrati o n t o a n y 
s u bjects. 
c. O ne or m ore s u bject(s) i n a d ose le vel has a C ma x of >  
 n g/ m L or a 
pre dicte d C ma x of ≥  
 n g/ m L i n a s u bse q ue nt d ose le vel, a decisi o n will  
be ma de as  f oll o ws: 
o  A dj ust t o a n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he pre vi o us 
l o wer d ose;  
o  T he st u d y ma y be ter mi nate d wit h n o a d diti o nal d ose a d mi nistrati o n t o a n y 
s u bjects. 
5. 6.  
Tre at me nt  C o m pli a nce  
 
T he f oll o wi n g meas ures will be e m pl o ye d t o e ns ure treat me nt c o m plia nce:  
 
•  All d oses will be a d mi nistere d u n der t he s u per visi o n of s uita bl y q ualifie d C R U  staff. 
•  I m me diatel y after oral d ose a d mi nistrati o n, a vis ual i ns pecti o n of t he m o ut h a n d 
ha n ds will be perf or me d f or eac h  s u bject. 
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 7  of 5 8  
 
 
•  At eac h d ose pre parati o n occasi o n, a pre d ose a n d p ost d ose i n ve nt or y of L O X O -3 0 5 
will be perf or me d, as  a p pr o priate. 
5. 7.  
Dr u g  Acc o u nt a bilit y  
 
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 st u d y 
s u p plies (i ncl u di n g L O X O-3 0 5 ta blets a n d ca ps ules t o o ver -e nca ps ulate L O X O -3 0 5) recei ve d 
or pr oc ure d b y C o va nce. 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 date of dis pe nsi n g. 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 vie w b y t he S p o ns or 
u p o n re q uest.  
 
F or eac h batc h of u nit d oses, t he e m pt y use d u nit d ose c o ntai ners will be discar de d u p o n 
satisfact or y c o m pleti o n of t he c o m plia nce a n d acc o u nta bilit y pr oce d ures. A n y u n use d 
asse m ble d u nit d oses will be retai ne d u ntil c o m pleti o n of t he st u d y.  
 
At t he c o m pleti o n of t he st u d y, all u n use d s u p plies (i ncl u di n g all I M P) will be dis p ose d of b y 
t he C R U, per t he S p o ns or’s writte n i nstr ucti o ns a n d/ or i n acc or da nce wit h l ocal/state/fe deral 
g ui deli nes g o ver ni n g waste dis p osal of i n vesti gati o nal dr u gs a n d t he C R Us S O Ps.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 8  of 5 8  
 
 
6.  C O N C O MI T A N T T H E R A PI E S A N D O T H E R  R E S T RI C TI O N S  
6. 1.  
C o nc o mit a nt  T her a pies  
 
Paraceta m ol/aceta mi n o p he n ( ma xi m u m of 2 g/ da y f or u p t o 3 c o nsec uti ve da ys) is a n 
acce pta ble c o nc o mita nt me dicati o n.  
 
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 trial i n w hic h 
recei pt of a n y i n vesti gati o nal dr u g occ urs wit hi n 5 half-li ves (if k n o w n) or 3 0 da ys, 
w hic he ver is l o n ger, pri or t o d ose a d mi nistrati o n ( Da y 1).  
 
All prescri pti o n/ n o n prescri pti o n me dicati o ns a n d o ver -t he-c o u nter me dicati o ns (i ncl u di n g 
H R T, her bal pr o d ucts, nat ural or her bal s u p ple me nts, e xce pt f or paraceta m ol/aceta mi n o p he n 
as refere nce d a b o ve) are pr o hi bite d f or 1 4 da ys pri or t o d ose a d mi nistrati o n ( Da y 1) a n d 
t hr o u g h E O T or E T, u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
T his i ncl u des, b ut is n ot li mite d t o: m o derate or str o n g C Y P 3 A 4 a n d/ or C Y P 3 A 5 i n hi bit ors or 
i n d ucers (i ncl u di n g her bal pr o d ucts s uc h as St. J o h n’s w ort), str o n g P-g p i n hi bit ors, pr ot o n 
p u m p i n hi bit ors, a ntaci ds, H 2-rece pt or a nta g o nists, a n d dr u gs t hat pr ol o n g Q T/ Q Tc i nter val. 
 
A n y me dicati o n ta ke n b y a s u bject d uri n g t he c o urse of t he st u d y, i ncl u di n g details of its 
d osa ge, a d mi nistrati o n, a n d t he reas o n f or its use, will be d oc u me nte d i n t he e C R F.  
 
T he a d mi nistrati o n of a n y c o nc o mita nt me dicati o n 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) a n d S p o ns or, u nless its use is dee me d 
necessar y i n a me dical e mer ge nc y. I n t his case, t he use of t he c o nc o mita nt me dicati o n will be 
re p orte d as s o o n as is practical. 
 
6. 2.  
Diet, Fl ui d, a n d Acti vit y  C o ntr ol  
 
S u bjects are re q uire d t o refrai n fr o m use of t o bacc o, s m o ki n g cessati o n pr o d ucts, a n d 
nic oti ne -c o ntai ni n g pr o d ucts wit hi n 3 m o nt hs pri or t o Scree ni n g t hr o u g h E O T or E T.  
 
C o ns u m pti o n of f o o ds or be vera ges c o ntai ni n g gra pefr uit/ gra pefr uit j uice or Se ville ora n ges 
or its j uice wit hi n 7 da ys pri or t o C hec k -i n ( Da y -1) a n d t hr o u g h E O T or E T will n ot be 
all o we d u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or.  
 
C o ns u m pti o n of alc o h ol - or caffei ne -c o ntai ni n g f o o ds or be vera ges wit hi n 7 2 h o urs pri or t o 
C hec k -i n ( Da y -1) a n d t hr o u g h E O T or E T will n ot be all o we d u nless dee me d acce pta ble b y 
t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
 
S u bjects will refrai n fr o m stre n u o us e xercise fr o m 5 da ys pri or t o C hec k -i n ( Da y -1) a n d 
d uri n g t he peri o d of c o nfi ne 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 E O T or E T (ie, s h o ul d n ot be gi n a ne w e xercise pr o gra m or 
partici pate i n a n y u n us uall y stre n u o us p h ysical e xerti o n).  
 
W hile c o nfi ne d at t he C R U, s u bjects will recei ve a sta n dar d 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 -relate d acti vities. 
 
Fasti n g re q uire me nt i n relati o n t o d osi n g are descri be d i n Secti o n 3. 1  a n d Secti o n 5. 2 . 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 9  of 5 8  
 
 
7.  S T U D Y A S S E S S M E N T S A N D  P R O C E D U R E S  
7. 1.  
P h ar m ac o ki netic  Assess me nts  
7. 1. 1.  
P h ar m ac o ki netic Bl o o d S a m ple C ollecti o n a n d  Pr ocessi n g  
 
Bl o o d sa m ples f or P K a nal ysis of L O X O -3 0 5 plas ma le vels will be c ollecte d at t he 
ti me p oi nts s pecifie d i n A p pe n di x 4 . T he e xact ti me of t he st u d y dr u g a d mi nistrati o n a n d t he 
act ual ti me of bl o o d sa m pli n g f or P K a nal ysis will be rec or de d o n t he e C R F.  
 
Pr ocessi n g, st ora ge, a n d s hi p pi n g i nstr ucti o ns f or t hese P K bl o o d sa m ples will be pr o vi de d i n 
a se parate La b orat or y Ma n ual. T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d 
f or P K testi n g is prese nte d i n A p pe n di x 3 . 
 
7. 1. 2.  
A n al ytic al  Met h o d ol o g y  
 
C o nce ntrati o ns of L O X O -3 0 5 i n plas ma will be deter mi ne d usi n g a vali date d bi oa nal ytical 
met h o d. S pecifics of t he bi oa nal ytical met h o ds will be pr o vi de d i n a se parate d oc u me nt.  
 
7. 2.  
S afet y a n d T oler a bilit y  Assess me nts  
 
Safet y e val uati o ns ma y be re peate d at t he discreti o n of t he I n vesti gat or ( or desi g nee) or 
S p o ns or.  
 
E ver y eff ort will be ma de t o sc he d ule a n d perf 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 priate p ost ure c o n diti o ns, practical restricti o ns, 
a n d a n y ot her pr oce d ures t o be perf or me d at t he sa me ti me p oi nt. T he or der of pri orit y f or 
sc 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 K bl o o d  sa m pli n g 
•  1 2 -lea d E C Gs  
•  vital si g n  meas ure me nts  
•  bl o o d a n d uri ne sa m ples f or cli nical la b orat or y  e val uati o ns 
•  p h ysical  e xa mi nati o n. 
7. 2. 1.  
A d verse  E ve nts  
 
A d verse e ve nt defi niti o ns; assi g n me nt of se verit 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 S A Es are detaile d i n A p pe n di x 1 . 
 
S u bjects will be as ke d a n o n -lea di n g H D Y F? q uesti o n s uc h as “ Ha ve t here bee n a n y c ha n ges 
i n y o ur healt h stat us si nce Scree ni n g/si nce y o u were last as ke d?” at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4  (ie, at Scree ni n g [after t he I C F is si g ne d], at C hec k-i n [ Da y -1], at eac h 
p ost d ose vital si g n meas ure me nt, a n d at a n a p pr o priate ti me f or all ot her da ys). S u bjects will 
als o be e nc o ura ge d t o v ol u ntaril y re p ort A Es occ urri n g at a n y ot her ti me t hr o u g h t he E O S.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 0  of 5 8  
 
 
A d verse e ve nts, w het her v ol u nteere d, i de ntifie d b y t he s u bject’s res p o nses t o H D Y F? 
i n q uiries, or n ote d o n p h ysical e xa mi nati o n, E C G, vital si g n meas ure me nts, or cli nical 
la b orat or y e val uati 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 E O S [ or E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a  
f oll o w-u p p h o ne call]), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g 
pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as n ot relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee]) or as A Es 
(if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee], or if t he e ve nt 
occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p 
t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g b y 
t he I n vesti gat or ( or desi g nee) are t o be re p orte d. All S A Es t hat de vel o p fr o m t he ti me of I C F 
si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w-u p p h o ne call) are t o be re p orte d.  
 
U nless a s u bject wit h dra ws c o nse nt or is wit h dra w n fr o m t he st u d y a n d d oes n ot c o m plete t he 
f oll o w-u p p h o ne call, all s u bjects m ust be f oll o we d u ntil E O S. S u bjects wit h A Es t hat are 
assesse d as relate d t o st u d y dr u g b y t he I n vesti gat or ( or desi g nee) w hic h are o n g oi n g at E O S 
ma y c o nti n ue t o be f oll o we d u ntil t he s y m pt o ms or val ue(s) ret ur n t o n or mal, or acce pta ble 
le vels, as j u d ge d b y t he I n vesti gat or ( or desi g nee) a n d c o nfir me d b y t he S p o ns or. T he 
I n vesti gat or ( or desi g nee) s h o ul d use a p pr o priate j u d g me nt i n or deri n g a d diti o nal tests as 
necessar y t o m o nit or t he res ol uti o n of e ve nts. T he S p o ns or ma y re q uest t hat a d diti o nal safet y 
tests be perf or me d. 
 
S u bjects will recei ve a f oll o w -u p p h o ne call 7 da ys ( ± 2 da ys) after E O T or E T t o deter mi ne 
if a n y S A E or dr u g-relate d A E has occ urre d si nce t he E O T or E T visit. 
 
At all ti mes, a s u bject ma y be re q uire 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 vesti gat or ( or desi g nee). 
 
A n y e ve nt t hat meets t he criteria of a s us pecte d u ne x pecte d seri o us a d verse reacti o n 
( S U S A R) will be re p orte d t o t he I nstit uti o nal Re vie w B oar d (I R B) acc or di n g t o C R U p olic y 
b y t he I n vesti gat or ( or desi g nee) a n d t o re g ulat or y a ut h orities b y t he S p o ns or ( or S p o ns or 
desi g nee) acc or di n g t o re g ulat or y a ut h orit y re q uire me nts. Refer t o Refere nce Safet y 
I nf or mati o n i n t he c urre nt I B1  f or L O X O-3 0 5 f or e x pecte d a d verse reacti o ns.  
7. 2. 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 uati o ns (cli nical c he mistr y pa nel [faste d at least 8 h o urs; at E O T or 
E T, s u bjects are n ot re q uire d t o be faste d pri or t o cli nical la b orat or y e val uati o ns], c oa g ulati o n 
para meters, he mat ol o g y pa nel, T S H [ Scree ni n g o nl y], H b A 1c [ Scree ni n g o nl y], esti mate d 
gl o mer ular filtrati o n rate [ Scree ni n g a n d C hec k -i n/ Da y -1], a n d U A) will be c ollecte d at t he 
ti me p oi nts s pecifie d i n A p pe n di x 4 . 
 
Scree ns f or H C V a nti b o d y, H B V c ore a nti b o d y, H Bs A g, a n d HI V a nti b o d y will be perf or me d 
at Scree ni n g.  
 
Testi n g f or C O VI D -1 9 via P C R ( or e q ui vale nt) will be perf or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . Testi n g f or C O VI D -1 9 ma y als o be c o n d ucte d peri o dicall y d uri n g t he 
s u bject’s C R U c o nfi ne me nt, at t he discreti o n of t he I n vesti gat or ( or desi g nee). F urt her details  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 1  of 5 8  
 
 
re gar di n g C O VI D-1 9 testi n g (i ncl u di n g pr oce d ures w h o test p ositi ve at a n y ti me t hr o u g h o ut 
C R U c o nfi ne me nt) are s pecifie d i n se parate d oc u me nts.  
 
A uri ne 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 a n d alc o h ol) will be 
perf or me d at Scree ni n g a n d re peate d at C hec k -i n ( Da y -1) f or all s u bjects.  
 
A ser u m q ualitati ve pre g na nc y test (fe male s u bjects o nl y [ser u m q ua ntitati ve ma y be use d f or 
c o nfir mati o n if nee de d]) a n d a n F S H test ( p ost -me n o pa usal fe male s u bjects o nl y) will be 
perf or me d at t he ti me p oi nts s pecifie d i n A p pe n di x 4 . 
 
T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d f or cli nical la b orat or y 
e val uati o ns are prese nte d i n A p pe n di x 3 . A list of t he s pecific e val uati o ns is i n A p pe n di x 2 . 
 
7. 2. 3.  
Vit al  Si g ns  
 
Vital si g n meas ure me nts (i ncl u di n g o x y ge n sat urati o n, oral te m perat ure, res pirat or y rate, a n d 
s u pi ne B P, a n d p ulse rate) will be o btai ne d at t he ti me p oi nts s pecifie d i n A p pe n di x 4 . 
 
Bl o o d press ure a n d p ulse rate meas ure me nts s h o ul d be perf or me d usi n g t he sa me ar m f or 
eac h rea di n g a n d meas ure me nts s h o ul d be ta ke n after t he s u bject has bee n resti n g i n t he 
s u pi ne p ositi o n f or at least 5 mi n utes. 
 
W he n vital si g n meas ure me nts are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he bl o o d 
dra ws will be o btai ne d at t he sc he d ule d ti me p oi nt, a n d t he vital si g n meas ure me nts will be 
o btai ne d pri or t o a n d as cl ose as p ossi ble t o t he sc he d ule d bl o o d dra w.  
 
7. 2. 4.  
1 2 -le a d Electr oc ar di o gr a m  
 
A 1 2 -lea d E C G (i ncl u di n g P R, R R, Q R S, a n d Q T i nter val para meters) will be o btai ne d after 
t he s u bject has bee n resti n g f or at least 1 0 mi n utes i n t he s u pi ne p ositi o n at t he ti me p oi nts 
s pecifie d i n A p pe n di x 4 . T he Q T i nter val will be c orrecte d f or heart rate b y Fri dericia’s 
( Q Tc F = Q T/[ R R]1/ 3) f or m ula. 
W he n 1 2 -lea d E C Gs are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he bl o o d dra ws will be 
o btai ne d at t he sc he d ule d ti me p oi nt, a n d t he 1 2 -lea d E C Gs will be o btai ne d pri or t o a n d as 
cl ose as p ossi ble t o t he sc he d ule d bl o o d dra w.  
 
7. 2. 5.  
P h ysic al  E x a mi n ati o n  
 
A c o m plete or a b bre viate d p h ysical e xa mi nati o n will be perf or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . C o m plete p h ysical e xa mi nati o ns will e val uate ge neral a p peara nce a n d t he 
f oll o wi n g b o d y s yste ms/ or ga ns: der mat ol o gical; hea d a n d e yes; ears, n ose, m o ut h, a n d t hr oat; 
p ul m o nar y; car di o vasc ular; a b d o mi nal; l y m p hatic; m usc ul os keletal/e xtre mities; a n d 
ne ur ol o gical. Wei g ht a n d hei g ht will be re p orte d ( hei g ht o nl y re p orte d d uri n g Scree ni n g).  
A b bre viate d p h ysical e xa mi nati o ns will e val uate ge neral a p peara nce a n d t he f oll o wi n g b o d y 
s yste ms/ or ga ns: der mat ol o gical; p ul m o nar y; car di o vasc ular; a b d o mi nal; a n d ne ur ol o gical.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 2  of 5 8  
 
 
8.  S A M P L E SI Z E A N D D A T A  A N A L Y SI S  
8. 1.  
Deter mi n ati o n of S a m ple  Size  
 
T his st u d y is pla n ne d t o e nr oll u p t o 2 4 healt h y a d ult male a n d fe male s u bjects ( w o me n of 
n o n -c hil d beari n g p ote ntial o nl y). Si x s u bjects will partici pate i n eac h c o h ort.  
 
Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d necessar y b y t he S p o ns or. 
E ver y atte m pt will be ma de t o e nr oll at least 1 s u bject of eac h se x i n eac h c o h ort.  
N o f or mal statistical assess me nt of sa m ple size has bee n c o n d ucte d. T he sa m ple size c h ose n 
f or t his st u d y is c o m m o n i n si n gle-asce n di n g d ose st u dies a n d is c o nsi dere d s ufficie nt t o 
ac hie ve t he o bjecti ves of t he st u d y.  
 
8. 2.  
A n al ysis  P o p ul ati o ns  
8. 2. 1.  
St u d y  P o p ul ati o ns  
 
T he P K p o p ul ati o n will c o nsist of all s u bjects w h o recei ve d at least 1 d ose of L O X O -3 0 5, 
ha ve at least 1 q ua ntifia ble P K c o nce ntrati o n, a n d f or w h o m at least 1 P K para meter ca n be 
c o m p ute d. A s u bject ma y be e xcl u de d fr o m t he P K s u m mar y statistics a n d statistical a nal ysis 
if t he s u bject has a n A E of v o miti n g t hat occ urs at or bef ore 2 ti mes t he me dia n tma x . T he 
i m pact of pr ot oc ol de viati o ns o n t he P K p o p ulati o n will be e val uate d case-b y -case basis. 
 
T he s afet y p o p ul ati o n will c o nsist of all s u bjects w h o recei ve d 1 d ose of L O X O -3 0 5. 
S u bjects will be classifie d i nt o gr o u ps base d o n act ual treat me nt recei ve d.  
 
8. 3.  
P h ar m ac o ki netic  A n al ysis  
Serial P K bl o o d sa m ples f or t he a nal ysis of plas ma c o nce ntrati o ns of L O X O -3 0 5 will be 
c ollecte d fr o m pre d ose t hr o u g h 1 6 8 h o urs p ost -L O X O -3 0 5 d ose f or Treat me nts A, B, a n d C.  
 
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-3 0 5 (as  a p pr o priate): 
 
A U C 0 -2 4  
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o 2 4 h o urs p ost d ose, as 
calc ulate d b y t he li near tra pez oi dal  met h o d  
A U C 0 -t 
area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m h o ur 0 t o t he last 
meas ura ble c o nce ntrati o n, calc ulate d usi n g t he li near tra pez oi dal r ule f or 
i ncreasi n g a n d decreasi n g c o nce ntrati o ns  
A U C 0 -i nf 
A U C fr o m ti me 0 e xtra p olate d t o i nfi nit y, calc ulate d usi n g t he  f or m ula: 
C t 
A U C 0 -i nf = A U C 0 -t +  
z 
w here C t is t he last meas ura ble c o nce ntrati o n a n d λZ is t he a p pare nt ter mi nal 
eli mi nati o n rate c o nsta nt  
% A U C
e xtra p  
perce nta ge e xtra p olati o n f or A U C 0 -i nf 
C ma x  
ma xi m u m o bser ve d plas ma  c o nce ntrati o n  
tma x  
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n  
λ  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 3  of 5 8  
 
 
λ 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 de of t he 
sl o pe of t he li near re gressi o n of t he l o g c o nce ntrati o n vers us ti me pr ofile 
d uri n g t he ter mi nal  p hase  
C L/ F  
a p pare nt s yste mic  cleara nce  
t½  
a p pare nt plas ma ter mi nal eli mi nati o n half -life ( w he ne ver p ossi ble), w here 
t½ =  l n( 2)/ λZ  
V z/ F 
a p pare nt v ol u me of distri b uti o n at ter mi nal  p hase  
 
P har mac o ki netic calc ulati o ns will be perf or me d usi n g c o m mercial s oft ware s uc h as P h oe ni x ™ 
Wi n N o nli n
® Versi o n 8. 1 or hi g her ( Certara U S A I nc.).  
T he λ Z a n d t ½ will be calc ulate d b y li near least s q uares re gressi o n a nal ysis usi n g t he 
ma xi m u m n u m ber of p oi nts i n t he ter mi nal l o g li near p hase (e g, 3 or m ore n o n -zer o plas ma 
c o nce ntrati o ns). Ot her para meters ma y be a d de d as a p pr o priate. Fi nal 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 nal ysis will use act ual ti mes as rec or de d o n t he e C R F. All statistical 
a nal ysis will be perf or me d usi n g S A S  Versi o n 9. 4 or greater. M ore details o n t he a nal yses 
will be i ncl u de d i n t he S A P.  
 
8. 3. 1.  
Descri pti ve  A n al ysis  
 
Plas ma c o nce ntrati o ns a n d P K para meters will be s u m marize d wit h descri pti ve statistics 
( n u m ber, arit h metic mea n, sta n dar d de viati o n, c oefficie nt of variati o n [ C V %], ge o metric 
mea n, ge o metric C V %, me dia n, mi ni m u m, a n d ma xi m u m).  
 
I n di vi d ual a n d mea n plas ma c o nce ntrati o n-ti me c ur ves ( b ot h li near a n d l o g li near) will be 
i ncl u de d i n t he fi nal re p ort. 
 
8. 3. 2.  
St atistic al  Met h o d ol o g y  
 
P har mac o ki netic d ose pr o p orti o nalit y will be assesse d f or C o h orts 1, 2, a n d 3. Nat ural  
l o g-tra nsf or me d A U C0 -2 4, A U C 0 -t, A U C0 -i nf, a n d Cma x of L O X O -3 0 5 will be e val uate d usi n g a 
p o wer m o del of t he f or m:  
 
l n( p ar a meter) = i nterce pt + sl o pe × l n( d ose) + r a n d o m err or 
 
F or eac h P K para meter se paratel y, a p o ole d esti mate (acr oss all d oses) of sl o pe, 
c orres p o n di n g 9 5 % c o nfi de nce i nter val, a n d bet wee n -s u bject C V % will be calc ulate d. 
 
8. 4.  
S afet y  A n al ysis  
 
All safet y assess me nts, i ncl u di n g A Es a n d S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
e val uati o ns, p h ysical e xa mi nati o n res ults, c o nc o mita nt me dicati o ns, a n d 1 2 -lea d E C Gs, will 
be ta b ulate d a n d s u m marize d w here p ossi ble, usi n g descri pti ve met h o d ol o g y, as nee de d, b y 
ti me p oi nt. U nless ot her wise s pecifie d, baseli ne val ue is defi ne d as t he last n o n-missi n g 
meas ure me nt bef ore a d mi nistrati o n of L O X O -3 0 5. N o f or mal statistical a nal yses are pla n ne d 
f or t he safet y data. All safet y data will be liste d b y s u bject. 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 4  of 5 8  
 
 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he W H O Dr u g Dicti o nar y ( W H O Dr u g Gl o bal 
B 3, Se pte m ber 2 0 1 9) a n d A Es will be c o de d usi n g Me d D R A Versi o n 2 2. 1 ( or hi g her). T he 
i nci de nce of A Es will be prese nte d b y se verit y a n d b y relati o ns hi p t o st u d y dr u g as 
deter mi ne d b y t he I n vesti gat or ([ or desi g nee], A p pe n di x 1  f or A E re p orti n g). All T E A Es will 
be s u m marize d b y s yste m or ga n class a n d preferre d ter m.  
 
8. 5.  
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 he 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 data a n d clearl y 
e nteri n g t he c orrect data (e g, wr o n g data  ri g ht data). 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 writte n a djace nt t o t he c ha n ge b y t he 
cli nicia n. 
 
T he Data Ma na ge me 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 data e ntr y b y t he C R U a n d verifie d b y t he St u d y M o nit or. Data 
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 data 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 he C o va nce scie ntific tea m. T he e C R F a n d a ncillar y data 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 datasets 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 he 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 tea m d uri n g t he dr y r u n a n d data re vie w meeti n gs. 
 
T he peer re vie w will be perf or me d b y i n de 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 hec klists.  
 
8. 6.  
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 ura nce will be perf 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 re 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 nce a n d t he S p o ns or.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 5  of 5 8  
 
 
9.  A D MI NI S T R A TI V E  A S P E C T S  
9. 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 bet wee n t he S p o ns or a n d t he 
I n vesti gat or ( or desi g nee). 
 
T here will be n o alterati o ns i n t he pr ot oc ol affecti n g s u bject safet 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 vesti gat or ( or desi g nee), a n d t he I R B (see F or m 
F D A 1 5 7 2).  
 
9. 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 prese ntati ve(s) of t he S p o ns or will meet wit h t he 
I n vesti gat or ( or desi g nee) a n d a p pr o priate C R U staff t o fa miliarize t he I n vesti gat or ( or 
desi g nee) a n d C R U staff wit h t he materials necessar y f or c o n d ucti n g t he cli nical st u d y.  
 
9. 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 ntial. 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 wa 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 otal (e g, articles i n j o ur nals or ne ws pa pers, oral 
prese ntati o ns, a bstracts) b y t he I n vesti gat or ( or desi g nee) or t heir re prese ntati 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 na ble ti mefra me, b y t he S p o ns or, a n d 
ca n n ot be 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. 
 
9. 4.  
M o nit ori n g  
 
T he S p o ns or will desi g nate a 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 me ntati o n c o m pleti o n a n 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 ue nt c o ntact t hr o u g h ver 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 (relate 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 he S p o ns or’s St u d y M o nit or will a d here 
t o all re q uire 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 he I n vesti gat or ( or 
desi g nee) a n d I n vesti gat or’s staff will be e x pecte d t o c o o perate 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.  
 
9. 5.  
I nstit uti o n al Re vie w B o ar d  
 
I n acc or da nce wit h U S Title 2 1 C o de of Fe deral Re g ulati o ns ( C F R) 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. Verificati o n of t he  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 6  of 5 8  
 
 
I R B u nc o n diti o nal a p pr o val of t he 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 vesti gat or ( or desi g nee). 
 
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 bse q ue nt pr ot oc ol 
a me n d me nts a n d of seri o us a n d u ne x pecte d A Es. A p pr o val f or 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 vesti gat or ( or desi g nee). If re q ueste d, t he I n vesti gat or ( or 
desi 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 pecti 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 vals ( 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 desi g nee’s) partici pati o n i n t he st u d y. 
 
9. 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 bef ore 
pr ot oc ol -s pecific pr oce d ures are carrie d o ut. T he 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 pati o n is v ol u ntar y a n d t hat t he y ca n 
wit h dra 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 pecific 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.  
 
9. 7.  
Rec or ds  
 
T he res ults fr o m data 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 ntialit 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 pies of eac h e C R F 
will be retai ne d b y t he I n vesti gat or ( or desi g nee). All s o urce d oc u me nts, rec or ds, a n d re p orts 
will be retai ne d b y t he C R U i n acc or da nce wit h 2 1 C F R 3 1 2. 6 2(c).  
 
All pri mar y data, or c o pies t here of (e g, la b orat or y rec or ds, e C R Fs, data s heets, 
c orres p o n de nce, p h ot o gra p hs, a n d c o m p uter rec or ds), w hic h are a res ult of t he ori gi nal 
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.  
 
9. 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 vesti gat ors ( 2 1 C F R 5 4), I R Bs ( 2 1 C F R 5 6), I n vesti gati o nal Ne 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 Uses ( 2 1 C F R 3 6 1. 1), as a p pr o priate. As s uc h, t hese  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 7  of 5 8  
 
 
secti o ns of U S Title 2 1 C F R, al o n g wit h t he a p plica ble I C H 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.  
 
9. 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 se parate a gree me nt.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 8  of 5 8  
 
 
1 0.  R E F E R E N C E S  
1.  L o x o O nc ol o g y, I nc. L O X O -3 0 5 - I n vesti gat or’s Br oc h ure ( Versi o n 3. 1). 2 0 2 0.  
 
2.  Bra n d h u ber B, G o mez E, S mit h S, Ear y T, S pe ncer S, R ot he n ber g S M, et al. A ne xt 
ge nerati o n re versi ble B T K I n hi bit or, f or o verc o mi n g ac q uire d resista nce t o irre versi ble 
B T K i n hi bit ors. Cli n L y m p h o ma M yel o ma Le u k.  2 0 1 8; 1 8.  
 
3.  B yr d J C, F ur ma n R R, C o utre S E, Fli n n I W, B ur ger J A, Bl u m K A, et al. Tar geti n g B T K 
wit h i br uti ni b i n rela pse d c hr o nic l y m p h oc ytic le u ke mia. N E n gl J Me d. 2 0 1 3 J ul 
4; 3 6 9( 1): 3 2 – 4 2.  
 
4.  W o yac h J A, R u p pert A S, G ui n n D, Le h ma n A, Blac hl y J S, L oza ns ki A, et al. 
B T K C 4 8 1 S -Me diate d Resista nce t o I br uti ni b i n C hr o nic L y m p h oc ytic Le u ke mia. J Cli n 
O nc ol. 2 0 1 7 Ma y  1; 3 5( 1 3): 1 4 3 7 – 4 3.  
 
5.  W o yac h J, H ua n g Y, R o gers K, B hat S A, Gre ver M R, L oza ns ki A, et al. Resista nce t o 
acala br uti ni b i n C L L is me diate d pri maril y b y B T K m utati o ns.  2 0 1 9; 1 3 4( S u p ple me nt _ 1).  
 
6.  C hir o n D, Di Li bert o M, Marti n P, H ua n g X, S har ma n J, Blec ua P, et al. Cell -c ycle 
re pr o gra m mi n g f or PI 3 K i n hi biti o n o verri des a rela pse-s pecific C 4 8 1 S B T K m utati o n 
re veale d b y l o n git u di nal f u ncti o nal ge n o mics i n ma ntle cell l y m p h o ma. Ca ncer Disc o v. 
2 0 1 4  Se p; 4( 9): 1 0 2 2 – 3 5.  
 
7.  X u L, Tsa k ma klis N, Ya n g G, C he n J G, Li u X, De m os M, et al. Ac q uire d m utati o ns 
ass ociate d wit h i br uti ni b resista nce i n Wal de nstr ö m macr o gl o b uli ne mia. Bl o o d. 2 0 1 7 
0 4; 1 2 9( 1 8): 2 5 1 9 – 2 5.  
 
8.  T o y os hi ma S, Ka n n o A, Kita ya ma T, Se ki ya K, Na kai K, Har u na M, et al. Q T 
P R O D A C T: I n Vi v o Q T Assa y i n t he C o nsci o us D o g f or Assessi n g t he P ote ntial f or Q T 
I nter val Pr ol o n gati o n b y H u ma n P har mace uticals [I nter net]. J o ur nal of p har mac ol o gical 
scie nces. 2 0 0 5 [cite d 2 0 2 0 J u n 1 0]. A vaila ble fr o m: 
htt ps:// p u b me d. nc bi. nl m. ni h. g o v/ 1 6 4 9 3 1 8 7/  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 9  of 5 8  
 
 
1 1.  A P P E N DI C E S  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 0  of 5 8  
 
 
A p pe n di x 1: A d verse E ve nt Re p orti n g 
A d verse E ve nts  
Defi niti o n of A d verse E ve nts  
 
A n a d verse 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 nce 
e x perie nce d b y a patie nt or healt h y a d ult s u bject, w het her or n ot c o nsi dere d dr u g -relate d b y 
t he I n vesti gat or ( or desi g nee). A treat me nt-e mer ge nt a d verse e ve nt ( T E A E) is a n A E t hat 
starts o n or after t he first a d mi nistrati o n 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 ha n ges i n ge neral  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 va 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 neral 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 malities t hat are dee me d cli nicall y si g nifica nt 
b y t he I n vesti gat or [ or desi g nee]), 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 ve of a p ossi ble ca usal relati o ns hi p wit h t he a d mi nistrati o n of t he trial s u bsta nce. 
 
Cate g orizati o n of A d verse E ve nts  
 
T he se verit y of A Es will be cate g orize d base d o n t he Nati o nal Ca ncer I nstit ute 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 ntal Acti vities of Dail y Li vi n g  ( A D L) * 
•  
Gr a de 3 Se vere or me dic all y si g nific a nt b ut n ot i m me di atel y life -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 Life -t hre ate ni n g c o nse q ue nces: A n e ve nt t hat p uts t he s u bject at 
i m me diate ris k of deat h  
•  
Gr a de 5: Deat h relate d t o  A E.  
N ote: N ot all gra des 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 de selecti o n. Gra de 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 or gr oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g m o ne y, etc. 
* * Self -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 dicati o ns, a n d n ot 
be dri d de n.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 1  of 5 8  
 
 
T he I n vesti gat or ( or desi g nee) will ma ke a deter 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 wee n t he 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 orse ni n g of t he A E r ules o ut a ca usal 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 hera 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 orse ni n g of t he A E is c o nsiste nt wit h a ca usal relati o ns hi p 
a n d n o ot her ca use (e g, c o nc o mita nt dr u gs, t hera pies, c o m plicati 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 here is a reas o na ble p ossi bilit y t hat t he 
e x perie nce ma y ha ve bee n ca use d b y t he dr u g.  
 
Pre g na nc y  
 
As i nf or mati o n is a vaila ble, a pre g na nc y (i ncl u di n g pre g na nc y i n fe male part ners of male 
s u bjects) dia g n ose d t hr o u g h E n d of St u d y ( E O S) or Earl y Ter mi nati o n ( E T; if t he s u bject 
disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w -u p p h o ne call) a n d f or u p t o  
9 0 da ys after st u d y dr u g a d mi nistrati o n s h o ul d be re p orte d b y t he I n vesti gat or ( or desi g nee) 
via e mail t o C o va nce or t he S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4 h o urs of 
bei n g n otifie d. C o va nce or t he S p o ns or’s Cli nical Safet y Re prese ntati ve will t he n f or war d t he 
Pre g na nc y F or m t o t he I n vesti gat or ( or desi g nee) f or  c o m pleti o n. 
 
e m ail: S A EI nt a ke @ C o v a nce.c o m  
 
A s u bject bec o mi n g pre g na nt w hile o n st u d y dr u g will i m me diatel y be wit h dra w n fr o m t he 
st u d y a n d E T st u d y pr oce d ures will be perf or me d. T he s u bject or part ner s h o ul d be f oll o we d 
b y t he 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 he a ntici pate d date, t he I n vesti gat or ( or desi g nee) s h o ul d n otif y C o va nce 
or t he S p o ns or’s Cli nical Safet y Re prese ntati ve. At t he c o m pleti o n of t he pre g na nc y, t he 
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 me of t he 
pre g na nc y meets t he criteria f or i m me diate classificati o n as a n S A E (ie, 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 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 mati o n ca n be c ollecte d. W he n a C R U 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 I n vesti gat or ( or desi g nee) i m me diatel y 
( wit hi n 2 4 h o urs of t he C R U staff bec o mi n g a ware of t he e ve nt) i n a d diti o n t o n otif yi n g 
C o va nce or t he S p o ns or’s Cli nical Safet y Re prese ntati ve via e mail.  
 
All pre g na ncies s h o ul d be rec or de d o n t he A E e C R F (as a p pr o priate), i n a d diti o n t o 
c o m pleti o n of t he re q uire d pre g na nc y f or ms. If t he I n vesti gat or ( or desi g nee) s us pects t hat a 
pre g na nc y was t he res ult of a n i nteracti o n bet wee n t he st u d y treat me nt a n d t he c o ntrace pti ve 
met h o d, i n a d diti o n t o t he pre g na nc y t he dr u g i nteracti o n s h o ul d als o be ca pt ure d as a 
se parate A E. 


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 2  of 5 8  
 
 
Defi niti o n of Seri o us A d verse E ve nts  
 
A n S A E ( b y 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 he f oll o wi n g o utc o mes: 
 
•  
Deat h;  
•  
A life -t hreate ni n g a d verse dr u g e x perie nce (ie, o ne t hat places t he s u bject, i n t he 
vie w of t he I n vesti gat or [ or desi g nee], at i m me diate ris k of  deat h);  
•  
I n patie 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 pacit 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 ve nt t hat ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he a b o ve  o utc o mes.  
 
I m p orta nt me dical e ve nts t hat ma y n ot res 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, base d o n a p pr o priate me dical j u d g me nt, t he y 
ma y je o par dize t he 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 1 of t he o utc o mes liste d i n t his defi niti o n.  
 
U ne x pecte d A d verse Dr u g Reacti o n  
 
A n A E or s us pecte d a d verse dr u g reacti o n is c o nsi dere d ‘ u ne x pecte d’ if t he e ve nt is n ot liste d 
i n t he Refere nce Safet y I nf or mati o n secti o n of t he I n vesti gat or’s Br oc h ure or if it is n ot liste d 
at t he s pecificit y or se verit y t hat has bee n o bser ve d f or a n u na p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct.  
 
Re p orti n g  
 
T he F D A -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 re prese nt 
e ve nts t hat are assesse d as seri o us, relate d, a n d u ne x pecte d. T he F D A -re p orta ble A Es will be 
re p orte d b y t he C R U t o t he S p o ns or a n d t he res p o nsi ble I nstit uti o nal Re vie w B oar d. Fi nal 
deter mi nati o n of w het her a n e ve nt re prese nts a s us pecte d u ne x pecte d seri o us a d verse reacti o n 
will be t he res p o nsi bilit y of t he S p o ns or.  
 
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 orta 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 (re gar dless of w het her t he e ve nt is assesse d as 
relate d or u nrelate d t o st u d y dr u g) bei n g first rec o g nize d or re p orte d, C o va nce or t he 
S p o ns or’s Cli nical Safet y Re prese ntati ve will be n otifie d b y t he I n vesti gat or ( or desi g nee) i n 
writi n g usi n g t he f oll o wi n g e mail a d dress:  
 
e m ail: S A EI nt a ke @ C o v a nce.c o m 
 
T o re p ort t he S A E, t he c o m plete d re p ort f or m s h o ul d be se nt b y e mail t o C o va nce or t he 
S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4 h o urs of a ware ness. I nc o mi n g re p orts are 
re vie 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.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 3  of 5 8  
 
 
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 ne 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.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 4  of 5 8  
 
 
A p pe n di x 2: Cli nic al L a b or at or y E v al u ati o ns  
 
Cli nic al C he mistr y P a nel 
( F aste d): 
He m at ol o g y P a nel:  
Ot her Tests:  
Ala ni ne a mi n otra nsferase ( A L T) 
Al b u mi n  
Al kali ne p h os p hatase ( A L P) 
A m ylase  
As partate a mi n otra nsferase 
( A S T) 
Bilir u bi n ( direct a n d t otal) 
Bl o o d urea nitr o ge n 
Calci u m  
C hl ori de 
C h olester ol 
Creati ne  ki nase 
Creati ni ne 
Gl uc ose  
Ir o n 
Li pase  
Ma g nesi u m 
P h os p h or us 
P otassi u m 
S o di u m 
T otal pr otei n 
Tri gl yceri des 
Uric  aci d  
He mat ocrit 
He m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n 
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n  
Mea n c or p usc ular v ol u me 
Platelet  c o u nt  
Re d bl o o d cell ( R B C) c o u nt 
R B C distri b uti o n wi dt h  
W hite bl o o d cell ( W B C) c o u nt 
W B C differe ntial ( perce nt a n d 
a bs ol ute):  
Bas 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  
He m o gl o bi n A 1c ( H b A 1c) b 
T h yr oi d -sti m ulati n g h or m o ne 
( T S H)b 
Esti mate d gl o mer ular filtrati o n 
ratea 
S A R S -C o V -2 ( C O VI D -1 9)  
Testi n g  
C o a g ul ati o n P ar a meters:  
Partial t hr o m b o plasti n ti me 
Pr ot hr o m bi n ti me 
I nter nati o nal n or malize d rati o 
Ser ol o g y: b  
H u ma n i m m u n o deficie nc y vir us 
( HI V) a nti b o d y 
He patitis B s urface a nti ge n 
( H Bs A g) 
He patitis B vir us ( H B V)  c ore 
a nti b o d y 
He patitis C vir us  ( H C V) 
a nti b o d y 
F or Fe m ale S u bjects o nl y:  
Pre g na nc y test (ser u m 
q ualitati ve, ser u m q ua ntitati ve 
ma y be use d f or c o nfir mati o n if 
nee de d) c 
F ollicle -sti m ulati n g h or m o ne 
( p ost-me n o pa usal fe male 
s u bjects o nl y) b 
Uri n al ysis:  
Bilir u bi n  
C ol or a n d a p peara nce 
Gl uc ose  
Ket o nes 
Le u k oc yte  esterase 
Nitrite  
Occ ult bl o o d  
p H a n d s pecific gra vit y 
Pr otei n  
Ur o bili n o ge n 
Micr osc o pic e xa mi nati o n 
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)  
Uri ne Dr u g Scree n: a  
I ncl u di n g, b ut n ot li mite d t o, t he 
f oll o wi n g: 
Alc o h ol (et ha n ol) 
A m p heta mi nes 
Bar bit urates 
Be nz o diaze pi nes 
Ca n na bi n oi ds 
C ocai ne ( meta b olite) 
Met ha d o ne  
O piates 
P he nc ycli di ne 
C oti ni ne  
a. Perf or me d at Scree ni n g a n d C hec k -i n ( Da y -1)  o nl y.  
b.  Perf or me d at Scree ni n g  o nl y.  
c. Perf or me d at Scree ni n g, C hec k -i n ( Da y -1), a n d E n d of Treat me nt ( E O T) or Earl y Ter mi nati o n ( E T)  o nl y.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 5  of 5 8  
 
 
A p pe n di x 3: T ot al Bl o o d V ol u me  
T he f oll o wi n g bl o o d v ol u mes will be wit h dra w n f or eac h s u bject:  
 
 
Assess me nt  
A p pr o xi m ate Bl o o d 
V ol u me per S a m ple 
( m L) 
M a xi m u m 
N u m ber of Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al V ol u me 
( m L) 
Ser ol o g y  
8. 0  
1  
8. 0  
He m o gl o bi n A 1c ( H b A 1c)  
4. 0  
1  
4. 0  
L O X O -3 0 5 p har mac o ki netic sa m pli n g  
4. 0  
2 0  
8 0. 0  
Cli nical la b orat or y e val uati o ns: 
He mat ol o g y  
Cli nical c he mistr y 
C oa g ulati o n para meters  
 
4. 0  
4. 0  
3. 0  
 
4  
 
4 4. 0  
Ser u m pre g na nc y test (fe male s u bjects 
o nl y)  
4. 0  
3  
1 2. 0  
Ser u m f ollicle -sti m ulati n g h or m o ne ( F S H; 
p ost -me n o pa usal fe male s u bjects o nl y) 
a n d t h yr oi d -sti m ulati n g h or m o ne ( T S H) 
 
4. 0  
 
1  
 
4. 0  
T ot al:  
1 5 2. 0 m L  
 
If e xtra bl o o d sa m ples are re q uire d, t he ma xi m u m bl o o d v ol u me t o be wit h dra w n per s u bject 
will n ot e xcee d 2 0 0 m L.  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 6  of 5 8  
 
 
A p pe n di x 4: Sc he d ule of Assess me nts  


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 7  of 5 8  
 
 
 
 
 
 
 
St u d y Pr oce d ures a  
 
 
Scree ni n g 
( D a ys -2 9  
t o -2)  
 
 
 
C hec k -i n 
( D a y -1)  
St u d y C o n d uct  
Cli nic Disc h ar ge/ 
E O T/ E T t 
F oll o w -u p P h o ne 
C all ( E O S)  
1  
2  
3  
4  
5  
6  
7  
8  
7 ( ± 2) d a ys p ost 
E O T/ E T v  
C o nfi ne d t o t he C R U  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
I ncl usi o n/ E xcl usi o n Criteria 
X  
X  
 
 
 
 
 
 
 
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X  
X b  
 
 
 
 
 
 
 
 
 
Hei g ht/ Wei g ht/ B MI  
X c 
X c 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n d  
 
X  
 
 
 
 
 
 
 
X  
 
1 2 -lea d E C Ge 
X  
X  
X  
X  
 
X  
 
 
 
X  
 
Vital Si g ns f 
X g, h  
X g, h  
X h  
X  
X  
X  
X  
X  
X  
X g, h  
 
H D Y F? I n q uir y i 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A Es/ S A Es j 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
L O X O -3 0 5 A d mi nistrati o n  
 
 
X k  
 
 
 
 
 
 
 
 
Cli nical La b orat or y E val uati o ns n  
X  
X  
 
 
 
X  
 
 
X u  
X u  
 
Esti mate d Gl o mer ular Filtrati o n Rate  
X  
X  
 
 
 
 
 
 
 
 
 
He patitis a n d HI V Scree n  
X  
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 Testi n g o  
X  
X  
 
 
 
 
 
 
 
 
 
H b A 1c Test  
X  
 
 
 
 
 
 
 
 
 
 
Dr u g Scree n p  
X  
X  
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt Me dicati o ns q  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ser u m Pre g na nc y Test r 
X  
X  
 
 
 
 
 
 
X u  
X u  
 
F S H Test s 
X  
 
 
 
 
 
 
 
 
 
 
T S H Test  
X  
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: 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 ure; C O VI D -1 9 = S A Rs C or o na vir us 1 9; C R U = Cli nical Researc h U nit; E C G = electr ocar di o gra m; E O S = E n d 
of St u d y; E O T = E n d of Treat me nt; E T = Earl y Ter mi nati o n; F S H = f ollicle -sti m ulati n g h or m o ne; H b A 1c = he m o gl o bi n A 1c; H D Y F? = H o w D o Y o u Feel?; HI V = h u ma n i m m u n o deficie nc y 
vir us; I C F = I nf or me d C o nse nt F or m; P K = p har mac o ki netic; 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; U A = uri nal ysis. 
a. F or details o n st u d y pr oce d ures, see Secti o n  7 . 
b.  I nteri m me dical hist or y o nl y.  
c. Hei g ht c ollecte d at Scree ni n g o nl y, b o d y mass i n de x base d o n Scree ni n g  hei g ht.  
d.  A  c o m plete  p h ysical  e xa mi nati o n will  be  perf or me d  at C hec k -i n ( Da y -1).  A n  a b bre viate d  p h ysical  e xa mi nati o n  will  be  perf or me d  o n  Da y  8  ( E n d of  Treat me nt  [ E O T]) or  Earl y  Ter mi nati o n 
( E T). 
e. 1 2 -lea d electr ocar di o gra ms ( E C Gs) will be o btai ne d pri or t o a n d as cl ose as p ossi ble t o t he sc he d ule d bl o o d dra ws at Scree ni n g an d C hec k -i n ( Da y -1), a n d at t he f oll o wi n g ti mes relate d t o 
a d mi nistrati o n of eac h Treat me nt: Da y 1 ( pre d ose a n d 2 a n d 4 h o urs after L O X O -3 0 5 d osi n g), Da y 2, Da y 4, a n d Da y 8 ( E O T) or E T. 1 2 -lea d E C Gs will be c ollecte d after t he s u bject has 
reste d i n t he s u pi ne p ositi o n f or at least 1 0 mi n utes.  
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 8  of 5 8  
 
 
 
f. Vital si g n meas ure me nts (s u pi ne bl o o d press ure [ B P] a n d p ulse rate) will be o btai ne d at Scree ni n g a n d C hec k -i n ( Da y -1), at t he f oll o wi n g ti mes relate d t o a d mi nistrati o n of eac h Treat me nt: 
pre d ose ( wit hi n 4 5 mi n utes pri or t o d osi n g), 4 5 mi n utes p ost d ose, a n d 2, 4, 2 4, 4 8, 7 2, 9 6, 1 2 0, 1 4 4, a n d 1 6 8 h o urs p ost d ose ( Da y 8 [ E O T]) or E T. Vital si g n meas ure me nts s h o ul d be carrie d 
o ut  pri or  t o a n d as cl ose as p ossi ble  t o t he sc he d ule d bl o o d  dra w.  B P  a n d p ulse  rate will be meas ure d usi n g  t he sa me ar m f or eac h rea di n g after t he s u bject has  bee n  s u pi ne f or at least 
5  mi n utes.  
g.  Oral te m perat ure a n d res pirat or y rate will be o btai ne d at Scree ni n g a n d C hec k -i n ( Da y -1) a n d o n Da y 8 ( E O T) or  E T.  
h.  O x y ge n sat urati o n will be meas ure d via p ulse o xi metr y o nce at Scree ni n g, C hec k -i n ( Da y -1), pre d ose o n Da y 1, a n d Da y 8 ( E O T) or  E T.  
i. A H o w D o Y o u Feel? i n q uir y will be perf or me d at Scree ni n g (after t he I C F is si g ne d), at C hec k -i n ( Da y -1), at eac h p ost d ose vital si g n meas ure me nt, a n d at a n a p pr o priate ti me f or all ot her 
da ys.  
j. A d verse e ve nts ( A Es) a n d seri o us A Es ( S A Es) will be c ollecte d be gi n ni n g at i nf or me d c o nse nt. A d verse e ve nts 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 nf or me d 
C o nse nt F or m [I C F] u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w -u p p h o ne call), eit her as s u bject me dical hist or y (if t he 
e ve nt is re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1  a n d is assesse d as n ot relate d t o st u d y pr oce d ures b y t he 
I n vesti gat or [ or desi g nee]) or as A Es (if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d b y t he I n vesti gat or [ or desi g nee]) as relate d 
t o st u d y pr oce d ures, or if t he e ve nt occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es 
assesse d as relate d t o st u d y dr u g are t o be rec or de d. All S A Es t hat de vel o p fr o m t he ti me of I C F si g ni n g u ntil E O S ( or E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w-u p p h o ne call) are t o be  re p orte d. 
k.  S u bjects will be assi g ne d t o 1 c o h ort o nl y, C o h ort 1 ( Treat me nt A/ 3 0 0 m g L O X O -3 0 5), C o h ort 2 ( Treat me nt B/ 6 0 0 m g L O X O -3 0 5), or C o h ort 3 ( Treat me nt C/ 9 0 0 m g  L O X O -3 0 5)  
n.  Cli nical c he mistr y pa nel (faste d f or at least 8 h o urs), c oa g ulati o n para meters, he mat ol o g y pa nel, a n d uri nal ysis ( U A) will be  perf or me d.  
o.  Testi n g f or C O VI D -1 9 will be c o n d ucte d at a mi ni m u m at Scree ni n g a n d C hec k -i n ( Da y -1). Testi n g f or C O VI D -1 9 ma y als o be c o n d ucte d peri o dicall y d uri n g t he s u bject’s C R U 
c o nfi ne me nt, at t he discreti o n of t he I n vesti gat or ( or desi g nee). Tests will be perf or me d b y ra pi d p ol y merase c hai n reacti o n or  e q ui vale nt.  
p.  Dr u gs of a b use uri ne test, i ncl u di n g c oti ni ne a n d alc o h ol. Res ults fr o m t he dr u gs of a b use tests will be use d t o deter mi ne s u bject eli gi bilit y per t he i ncl usi o n/e xcl usi o n  criteria. 
q.  Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de d be gi n ni n g at i nf or me d c o nse nt. I n a d diti o n, all I n vesti gat or -a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 1 4 da ys pri or t o 
st u d y dr u g a d mi nistrati o n ( Da y 1) f or prescri pti o n me dicati o ns a n d n o n -prescri pti o n me dicati o n, will be rec or de d o n t he s u bject’s electr o nic Case Re p ort  F or m.  
r. Fe male s u bjects  o nl y.  
s. P ost -me n o pa usal fe male s u bjects  o nl y.  
t. E O T is defi ne d as w he n t he s u bject is release d fr o m t he C R U f oll o wi n g c o m pleti o n of all assess me nts t hr o u g h Da y 8. E T is defi ne d as w he n t he s u bject is release d fr o m t he C R U if t he 
s u bject ter mi nates t he st u d y earl y. Vital  si g n meas ure me nts,  E C G,  a n d a b bre viate d p h ysical  e xa mi nati o n  res ults are t o be  a vaila ble f or re vie w b y  t he I n vesti gat or ( or desi g nee)  pri or  t o s u bject 
release fr o m t he C R U at t he E O T visit. Cli nical la b orat or y e val uati o ns f or cli nical c he mistr y, he mat ol o g y, c oa g ulati o n, a n d UA a n d pre g na nc y test res ults (fe male s u bjects o nl y) are t o be 
a vaila ble f or  re vie w b y  t he I n vesti gat or ( or desi g nee)  pri or  t o s u bject release fr o m t he C R U  at t he E O T  visit a n d  pri or  t o s u bject release fr o m t he C R U  at t he E T  visit,  if a vaila ble. 
u.  Cli nical la b orat or y e val uati o ns a n d pre g na nc y test (fe male s u bjects o nl y) will be perf or me d o n t he da y pri or t o s u bject relea se fr o m t he C R U ( Da y 7) if t he s u bject c o m pletes t he st u d y 
( E O T). Cli nical  la b orat or y e val uati o ns  a n d pre g na nc y  test (fe male s u bjects o nl y)  will  be  perf or me d  o n  t he da y  of  s u bject release fr o m t he C R U if t he s u bject ter mi nates earl y ( E T). 
v.  T o be c o n d ucte d 7 da ys ( ± 2 da ys) f oll o wi n g E O T or E T. E O S is defi ne d as w he n t he s u bject atte n ds t he C R U f or a f oll o w -u p p h o ne call 7 da ys ( ± 2 da ys) after t he E O T visit or E T visit t o 
deter mi ne if a n y S A E or st u d y dr u g -relate d A E has occ urre d si nce t he E O T or E T visit. All s u bjects w h o recei ve d L O X O-3 0 5 (i ncl u di n g s u bjects w h o are ter mi nate d earl y) will recei ve a 
f oll o w-u p p h o ne  call. 
C CI

SAP_001.pdf: 
Statistical Analysis Plan J2N-OX-JZNS Version 1.0
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LOXO-305
in Healthy Adult Subjects
NCT06181006
Approval date: 16-Nov-2020


Statistical Analysis Plan 
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LOXO-305 in Healthy Adult 
Subjects 
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 16NOV2020 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20017 
Covance Study: 8426665 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Principal Investigator: 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
PPD


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objectives .......................................................................................................... 6 
2.2. Secondary Objectives ...................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN ................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 9 
6. STUDY TREATMENTS ....................................................................................................... 9 
7. DEFINITIONS OF POPULATIONS .................................................................................. 10 
7.1. All Subjects Population ................................................................................................. 10 
7.2. Safety Population .......................................................................................................... 10 
7.3. Pharmacokinetic Population .......................................................................................... 10 
8. STATISTICAL METHODOLOGY .................................................................................... 10 
8.1. General .......................................................................................................................... 10 
8.1.1. Calculation of the Summary Statistics ................................................................... 11 
8.1.2. Repeat and Unscheduled Assessments ................................................................... 11 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 12 
8.2. Subject Disposition and Population Assignment .......................................................... 12 
8.3. Demographics and Baseline Characteristics ................................................................. 12 
8.4. Prior and Concomitant Medication ............................................................................... 12 
8.5. Pharmacokinetic Assessments ...................................................................................... 13 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 15 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ............................................................................. 17 
8.6.1. Adverse Events ....................................................................................................... 17 
8.6.2. Clinical Laboratory Parameters .............................................................................. 19 


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8.6.3. Vital Signs Results ................................................................................................. 19 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 19 
8.6.5. Other Assessments ................................................................................................. 19 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
9. INTERIM ANALYSES ....................................................................................................... 20 
10. CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES .................................. 20 
11. REFERENCES .................................................................................................................. 20 
12. APPENDICES ................................................................................................................... 21 


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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]). 
 
ADaM 
analysis data model 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from hour 0 to 24 hours 
postdose 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
extrapolated to infinity 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
Geom CV 
Geometric CV 
GLSM 
Geometric least square mean 
Geom Mean 
Geometric mean 
GMR 
Geometric mean ratio 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
λZ 
apparent terminal elimination rate constant 
ln 
natural log 
LSM 
Least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 


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NC 
not calculated 
NR 
No result 
PK 
pharmacokinetic(s) 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
apparent plasma terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time to maximum observed plasma concentration 
Vz/F 
apparent volume of distribution at terminal phase 
WHODrug 
World Health Organization Drug Dictionary 


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1. INTRODUCTION 
 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 04 August 2020) and electronic case report form. 
 
This SAP describes the planned analysis of the pharmacokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document. 
 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR. 
 
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR. 
 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2 
The document history is presented in Appendix 1. 
 
2. STUDY OBJECTIVES 
 
2.1. Primary Objectives 
 
The primary objective of the study is: 
 
● To assess the safety and tolerability of single oral doses of LOXO-305 when 
administered to healthy adult subjects. 
 
2.2. Secondary Objectives 
 
The secondary objective of the study is: 
 
● To assess the PK of single oral doses of LOXO-305 when administered to healthy adult 
subjects. 
 
3. STUDY ENDPOINTS 
 
3.1. Primary Endpoints 
 
Safety 


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The primary endpoint of this study is to assess the safety and tolerability of LOXO-305 at 
single doses ≥ 300 mg. This study will investigate the safety and tolerability of single doses 
(ie, potential therapeutic and supratherapeutic exposures) of LOXO-305 when administered 
to healthy subjects. Ascending doses up to and possibly including 900 mg will be 
investigated. 
 
Safety and tolerability will be assessed by monitoring adverse events (AEs) and concomitant 
medications, performing physical examinations and clinical laboratory evaluations, 
measuring vital signs, and performing 12-lead electrocardiograms (ECGs). These safety and 
tolerability endpoints are deemed adequate to detect any safety signals when the planned dose 
range of LOXO-305 is administered to healthy subjects. 
 
3.2. Secondary Endpoints 
 
PK 
 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): 
 
● area under the concentration-time curve from hour 0 to 24 hours postdose (AUC0-24) 
 
● area under the concentration-time curve from hour 0 to the last measurable 
concentration (AUC0-t) 
 
● area under the concentration-time curve from hour 0 extrapolated to infinity (AUC0-inf) 
 
● percentage extrapolation for AUC0-inf (%AUCextrap) 
 
● maximum observed plasma concentration (Cmax) 
 
● time to maximum observed plasma concentration (tmax) 
 
● apparent terminal elimination rate constant (λZ) 
 
● apparent systemic clearance (CL/F) 
 
● apparent volume of distribution at terminal phase (VZ/F) 
 
● apparent plasma terminal elimination half-life (t1/2). 
 
4. STUDY DESIGN 
 
This is an open-label, single-ascending dose study to evaluate the safety, tolerability, and PK 
of LOXO-305. 
 
Up to 4 cohorts are planned for evaluation. In each cohort, 6 healthy adult subjects are 
planned for evaluation. Subjects will participate in only 1 cohort. In each cohort, subjects will 
receive a single oral dose of LOXO-305 on Day 1. Each cohort will include a sentinel group 


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of 2 subjects which will be dosed at least 48 hours before the remaining 4 subjects (following 
review of available safety data). 
 
A single oral dose of LOXO-305 will be administered on Day 1 for each cohort as follows: 
 
● Cohort 1 (Treatment A): 300 mg 
 
● Cohort 2 (Treatment B): up to 600 mg 
 
● Cohort 3 (Treatment C): up to 900 mg 
 
One additional cohort (6 subjects) may be enrolled if it is deemed appropriate to repeat any 
dose level, or to add an interim dose level or levels (equal to or lower than 900 mg), as 
determined by the Sponsor in consultation with the Investigator (or designee), depending on 
the safety, tolerability, and PK results from the prior cohort(s). Dosing will not exceed 
900 mg in any subject, nor will any subject be given a dose for which the Cmax would exceed 
26,000 ng/mL. 
 
Dose escalation to a higher dose level (ie, next cohort) will not take place until the 
Investigator (or designee) and the Sponsor have reviewed all pertinent safety/tolerability data 
(ie, physical examinations, 12-lead ECGs, vital sign measurements, clinical laboratory 
evaluations, and AEs) through a minimum of 168 hours (Day 8) and have determined that 
adequate safety and tolerability from the previous lower dose cohort has been demonstrated 
to permit proceeding to the next cohort. PK data through at least 72 hours (approximately 3 
half-lives) after dosing will be reviewed to guide the dose-escalation decision. Data from a 
minimum of 4 subjects will be reviewed in order to make a dose escalation decision. Each 
cohort will include a sentinel group of 2 subjects will be dosed at least 48 hours before the 
remaining 4 subjects (following review of all available safety data). 
 
Each treatment (A, B, and C) will be administered orally in the morning following a fast of at 
least 10 hours prior to and 4 hours after dosing. 
 
The PK sampling will be obtained for 168 hours after administration of each dose of 
LOXO-305. 
 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 8 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. A follow-up phone call will occur for all 
subjects who received 1 dose of study drug (including subjects who are terminated early) 
7 days (± 2 days) after EOT or ET. The duration of participation is expected to be 
approximately 46 days (Screening through follow-up phone call). 
 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
 
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 


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who are assigned a dose of study drug; this definition excludes screen failure subjects. Study 
completion is defined as the time of the last subject’s follow-up phone call. 
 
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistry panel, coagulation parameters, hematology panel, 
urinalysis and recording of concomitant medications will be performed at specified times 
during the study. 
 
AEs and serious AEs (SAEs) will be collected beginning at informed consent. AEs will be 
reported throughout the study (ie, from signing of the ICF until End of Study [EOS], or until 
ET if the subject discontinues from the study and does not complete a follow-up phone call), 
either as subject medical history (if the event is reported as beginning prior to signing of the 
ICF or if the event occurs prior to study drug administration on Day 1 and is assessed as not 
related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs 
after signing of the ICF but prior to study drug administration on Day 1 and is assessed as 
related to study procedures by the Investigator [or designee], or if the event occurs after study 
drug administration on Day 1 through EOT or ET regardless of relationship to study drug). 
From EOT or ET through EOS, only AEs assessed as related to study drug by the 
Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be reported. 
 
5. SAMPLE SIZE JUSTIFICATION 
 
This study is planned to enroll up to 24 healthy adult male and female subjects (women of 
non-childbearing potential only). Six subjects will participate in each cohort. 
 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
Every attempt will be made to enroll at least 1 subject of each sex in each cohort. 
No formal statistical assessment of sample size has been conducted. The sample size chosen 
for this study is common in single-ascending dose studies and is considered sufficient to 
achieve the objectives of the study. 
 
6. STUDY TREATMENTS 
 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 1. 
 
Table 1: 
Presentation of Study Treatments in TFLs 
 
Study Treatment 
Order in TFLs 
300 mg LOXO-305 
1 
600 mg LOXO-305 
2 
800 mg LOXO-305 
3 
900 mg LOXO-305 
4 


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All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received, and dose levels will be displayed in increasing order. 
 
7. DEFINITIONS OF POPULATIONS 
 
Any protocol deviations, including those related to COVID-19, will be considered prior to 
database lock for their importance and taken into consideration when assigning subjects to 
populations. 
 
7.1. All Subjects Population 
 
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol. 
 
7.2. Safety Population 
 
The safety population will include all subjects who received one dose of LOXO-305. 
Subjects will be classified into groups based on actual treatment received. 
 
7.3. Pharmacokinetic Population 
 
The PK population will include all subjects who received one dose of LOXO-305, have at 
least 1 quantifiable PK concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times the median tmax. The 
impact of protocol deviations on the PK population will be evaluated case-by-case basis. 
 
8. STATISTICAL METHODOLOGY 
 
8.1. General 
 
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the EOT visit. Any 
subject who discontinued the study will be identified accordingly in the listings. Summaries 
and statistical analyses will include the subjects assigned to the relevant population based on 
data type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study). 
 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards. 


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Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
 
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, and any parameter 
derivations. 
 
8.1.1. Calculation of the Summary Statistics 
 
For continuous data the following rules will be applied: 
 
● Missing values will not be imputed, unless specifically stated otherwise. 
 
● Unrounded data will be used in the calculation of summary statistics. 
 
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum. 
 
● As ET data is not associated with any scheduled timepoint, it will be excluded from all 
calculations of summary statistics. 
 
● Postdose repeats and unscheduled assessments will not be included in calculations of 
summary statistics. 
 
For categorical data the following rules will be applied: 
 
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included. 
 
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is missing. 
This will ensure that the population size totals are consistent across different 
parameters. 
 
All protocol deviations and data issues (eg missing data, out of protocol window) that occur 
during the study, including those related to COVID-19, will be considered prior to database 
lock for their severity/impact on how the data will be displayed. 
 
8.1.2. Repeat and Unscheduled Assessments 
 
For vital sign measurements and 12-lead ECG data only, any predose value recorded in 
addition to the original value or a postdose value recorded within 15 minutes of the original 
value will be defined as a repeat value; any postdose value recorded more than 15 minutes 
after the original value will be defined as an unscheduled value. For all other data types (eg, 
clinical laboratory values), any value recorded in addition to the original value will be 
defined as an unscheduled value. 


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The original scheduled value will be used in all calculations postdose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value. 
 
Postdose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations with the exception of the baseline derivation (see Section 8.1.3). 
 
8.1.3. Definitions of Baseline and Change from Baseline 
 
Baseline value is defined as the last non-missing measurement before administration of 
LOXO-305. 
 
If the date/time of the value is incomplete or missing, it will be excluded from the baseline 
calculation, unless the incomplete date/time indicates the value was recorded prior to dosing. 
 
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects. 
 
See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations. 
 
8.2. Subject Disposition and Population Assignment 
 
Subject disposition and population assignment will be listed. 
 
A summary table by treatment will be provided, based on the all subjects population. 
 
8.3. Demographics and Baseline Characteristics 
 
The demographics and baseline characteristics including age, sex, race, ethnicity, height, 
body weight, and body mass index will be listed. 
 
A summary table by treatment will be provided, based on the safety population. 
 
8.4. Prior and Concomitant Medication 
 
Prior medication will be defined as medication that ends prior to the dose of LOXO-305. 
Concomitant medication will be defined as medication that starts during or after dosing 
LOXO-305 or starts but does not end prior to dosing LOXO-305. 
 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2020. Prior and concomitant 
medications will be listed. 


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8.5. Pharmacokinetic Assessments 
 
8.5.1. Pharmacokinetic Analysis 
 
The following PK parameters will be determined where possible from the plasma 
concentrations of LOXO-305 using noncompartmental methods in validated software 
program Phoenix WinNonlin (Certara, Version 8.1 or higher): 
 
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mL 
area under the concentration-time curve from hour 0 to the last 
measurable concentration (tlast)b 
AUC0-inf 
h*ng/mL 
area under the concentration-time curve from hour 0 extrapolated 
to infinityc 
AUC0-24 
h*ng/mL 
area under the concentration-time curve from hour 0 to 24 hours 
postdose 
%AUCextrap 
% 
percentage extrapolation for AUC0-inf 
Cmax 
ng/mL 
maximum observed plasma concentration 
tmax 
h 
time to maximum observed plasma concentration 
λZ 
1/h 
apparent terminal elimination rate constant 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent systemic clearance 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
d 
DAUC0-t 
h*ng/mL/mg AUC0-t normalized by dose administered 
d 
DAUC0-inf 
h*ng/mL/mg AUC0-inf normalized by dose administered 
AUC0-24d 
h*ng/mL/mg AUC0-24 normalized by dose administered 
d 
DCmax 
ng/mL/mg 
Cmax normalized by dose administered 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing and decreasing 
concentrations 
c Based on the last observed quantifiable concentration 
d Calculated by dividing the parameter by the dose (mg) 
 
Additional PK parameters may be determined where appropriate. 
 
PK analysis will be carried out where possible using actual blood sampling times postdose. If 
an actual time is missing, the sample concentration result will be treated as missing unless 
there is scientific justification to include the result using the nominal time. 
 
The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax. 


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8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
 
The apparent terminal elimination rate constant (λZ) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-inf, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
 
Parameter 
Units 
Definition 
λZ 
1/h 
apparent terminal elimination rate constant 
λZ Upper 
h 
end of exponential fit 
λZ Lower 
h 
start of exponential fit 
λZ N 
NA 
number of data points included in the log-linear regression 
λZ Span Ratio 
NA 
time period over which λZ was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
 
Where possible, the span of time used in the determination of λZ (ie, the difference between 
λZ Upper and λZ Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of 
the t1/2 values will be discussed in the CSR. 
 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
 
The minimum requirement for the calculation of area under the concentration-time curve 
(AUC) will be the inclusion of at least 3 consecutive concentrations above the lower limit of 
quantification. If there are only 3 consecutive concentrations, at least 1 should follow Cmax. 
 
If the extrapolated area is >30%, AUC0-inf (and derived parameters) may be excluded from 
the summary statistics and statistical analysis at the discretion of the sponsor or 
pharmacokineticist. 
 
If AUC0-inf cannot be determined reliably for all subjects and/or treatments, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUC0-t, may be used in the statistical 
analysis of dose proportionality. 


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8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rules apply with special situations defined below: 
 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
 
● If a predose plasma concentration is missing, it may be set to zero by default within 
Phoenix WinNonlin. 
 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
 
Any quantifiable predose concentration value will be considered anomalous and set to 
missing for the PK analysis. 
 
8.5.2. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the concentration will be flagged and excluded from the summary statistics. Individual 
concentrations deemed to be anomalous will be flagged in the listings and excluded from the 
summary statistics. 
 
For PK concentration data the following rules will apply: 
 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
 
● If any BLQ results (treated as 0) are in a series of summarized data, geometric mean 
and coefficient of variation (CV) of geometric mean will be reported as not calculated 
(NC). 
 
For PK parameters the following rule will apply: 
 
● Geometric mean and coefficient of variation will not be calculated for tmax. 
PK analysis will use actual times as recorded on the electronic case report form. 


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8.5.2.1. Presentation Pharmacokinetic Parameters 
 
For the calculation of summary statistics of PK parameters, all not reported (NR) and Not 
Calculated (NC) values in a data series will be set to missing. 
 
The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
 
8.5.3. Pharmacokinetic Statistical Methodology 
 
All PK concentrations and parameters will be listed. 
 
Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment and time postdose will be provided for plasma PK 
concentrations. All PK concentration figures will be produced on both linear and semi- 
logarithmic scales. The +SD bars will only be displayed on the linear scale. 
 
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV, 
minimum, median, maximum, geometric mean [Geom Mean] and geometric CV [Geom CV]) 
will be calculated for plasma LOXO-305 PK parameters. Excluded subjects will be listed in 
the PK parameter tables, but will be excluded from the statistical analysis and summary 
statistics and noted as such in the tables. 
 
Individual and mean plasma concentration time curves (both linear and log-linear) will be 
included in the final CSR 
 
8.5.3.1. Statistical Analysis 
 
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-24, 
AUC0-t, AUC0-inf, and Cmax. 
 
The natural log (ln) transformed LOXO-305 PK parameters will be analyzed using a power 
model3, 4 that can be expressed as a linear regression equation with ln-transformed dose as a 
covariate: 
 
ln(parameter) = intercept + slope × ln(dose) + random error 
 
For dose proportionality, the slope of the regression line is equal to 1; for dose independence, 
it is equal to 0. 
 
At first, a statistical linear relationship between the ln-transformed PK parameters and the ln- 
transformed dose will be verified by including a quadratic (ln-transformed dose)2 term in the 
model as indicated above. A 5% level of significance will be used for testing of the quadratic 
effect. If the quadratic term is not suggested from the model, the slope of ln(dose) around 1 
suggests dose-proportionality from the linear regression model of ln-transformed PK 
parameters versus ln(dose). 


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For each PK parameter separately, an estimate of slope, corresponding 90% confidence 
interval (CI), and between-subject coefficient of variation (CV) will be calculated from the 
power model. Figures (on the logarithmic scale) containing individual values, power model 
line (90% CI), and dose proportionality line (defined as the power model line with slope of 1) 
will be created for each PK parameter; figures (on the semi-logarithmic scale) containing 
individual values and geometric means will be created for each corresponding PK parameter 
normalized by dose administered. 
 
The lack of fit test will be conducted for the statistical assessment of linearity assumption, 
and thus appropriateness of a power model. The lack of fit model will be the same as the 
power model fitted, but with dose included as additional fixed effect. The statistical 
assessment will rule the linearity assumption acceptable if the diagnostic plots appear 
reasonable and the lack of fit p-value >0.05 (dose effect is not significant at the 0.05 level of 
significance). The assessment of linearity assumption may also occur via visual examination 
of the figures by the pharmacokineticist. This assessment may override the statistical 
assessment; where this occurs, it will be detailed in the CSR. 
 
It will be concluded that PK parameter is dose proportional for the dose range studied if the 
assumption of linearity is ruled acceptable and the 90% CI for the slope spans 1. 
 
If the assumption of linearity is ruled unacceptable for any PK parameter, its corresponding 
PK parameter normalized by dose administered will be ln-transformed and analyzed using an 
analysis of variance (ANOVA) model.5 The model will include dose as a factor. For each PK 
parameter separately, the geometric least squares mean (GLSM) for each dose, p-values for 
the overall, and pairwise dose comparisons will be calculated. 
 
Residual plots will be produced to assess the adequacy of the model(s) fitted. 
 
8.6. Safety and Tolerability Assessments 
 
8.6.1. Adverse Events 
 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0. All AEs will be assigned severity grade using Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0. 
 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after LOXO-305 dosing, or starts prior to dosing and increases in severity after LOXO-305 
dosing. 
 
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator. 
 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of 
dosing for TEAEs only. 


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The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories: 
 
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment 
 
● TEAEs by severity and treatment 
 
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment 
 
● Treatment-related TEAEs by severity and treatment 
 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following: 
 
● System organ class, preferred term, and treatment 
 
● Preferred term and treatment 
 
● System organ class, preferred term, day of onset, and treatment 
For the AE data the following rules will apply: 
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to dosing. 
 
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE. 
 
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, the 
minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of dosing is 01MAY2019/08:00 and recorded start date/time 
of an AE is 03MAY2019, then the minimum possible onset time will be calculated by 
assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing). 
 
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing). 
 
● For the calculation of summary statistics: If the severity of a TEAE is missing, a 
TEAE will be counted under the maximum severity possible, up to Grade 4 in the 
absence of a fatal outcome. 


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● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded. 
 
8.6.2. Clinical Laboratory Parameters 
 
All clinical laboratory evaluations, with changes from baseline, will be listed; any value 
outside the clinical reference range will be flagged, and whether the out of range value was 
deemed clinically significant or not clinically significant will be indicated. Separate listings 
will be provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range. 
 
The observed results and change from baseline for clinical chemistry, hematology, and 
coagulation parameters will be summarized descriptively by treatment and timepoint. 
 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to 0, whereas >x and ≥x values will be set to x. 
 
8.6.3. Vital Signs Results 
 
All vital sign results with changes from baseline will be listed; any value outside the clinical 
reference range will be flagged, and whether the out of range value was deemed clinically 
significant or not clinically significant will be indicated. 
 
The observed results and change from baseline for all vital signs results will be summarized 
descriptively by treatment and timepoint. 
 
8.6.4. 12-lead Electrocardiogram Parameters 
 
All 12-lead ECG parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. 
 
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by treatment and timepoint. QTcF values that are > 450 msec and 
increase from baseline > 30 msec will be flagged in the data listing. 
 
8.6.5. Other Assessments 
 
Medical history and physical examination will be listed. Any physical examination 
abnormalities reported will also be flagged as clinically significant or not clinically 
significant as indicated. 
 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 


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8.6.6. Safety and Tolerability Statistical Methodology 
 
No inferential statistical analyses are planned. 
 
9. INTERIM ANALYSES 
 
No interim analyses are planned. 
 
10. CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
 
Since the finalization of the protocol the dose levels of each cohort have been confirmed as 
300 mg, 600 mg, 800 mg, and 900 mg, therefore these values have been included in Section 6 
Study Treatments and within the TFL shells. 
 
11. REFERENCES 
 
1. ICH.  ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9).  
5 February 1998. 
 
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995. 
 
3. Gough K, Hutchinson M, Keene O, et al. Assessment of dose proportionality: report from 
the statisticians in the pharmaceutical industry/Pharmacokinetics UK Joint Working 
Party. Drug Inf J. 1995;29(3):1039-1048. 
 
4. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
 
5. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999 


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12. APPENDICES 
 
Appendix 1: 
Document History 
 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
NA = not applicable 


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