A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way Crossover Study to Evaluate the Effect of LOXO-292 on the QTc Interval in Healthy Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol: J2G-OX-JZJG 
 
 
A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way Crossover 
Study to Evaluate the Effect of LOXO-292 on the QTc Interval in Healthy Adult Subjects 
 
 
NCT05630274 
 
 
Approval Date: 25-Apr-2019 
 
 

 
16. 
Appendices 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
1

--celer ·on 
Translating Science ta 
Medicine 
Protocol Clarification Letter for Study No.: CA25494 
Loxo Oncology Study No.: LOXO-RET-18032 
Date of Final Protocol: 03-Apr-2019 
Date of Protocol Clarification Letter: 18-Apr-2019 
A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way 
Crossover Study to Evaluate the Effect of LOX0-292 on the QTc Interval in Healthy Adult 
Subjects 
Tiris protocol clarification letter is being written to address discrepancies in the positioning of 
subjects during cardiodynamic ECG and vital sign measurements, as follows: 
1. The first paragraph in Section 12.4.3 Activity states that the subjects will be seated or 
ambulatory for the first 12 hours postdose, while the second paragraph in the same 
section states that subjects will be lying down or sitting for the first 7 hours postdose. In 
order to clarify that subject will remain lying down or sitting for the first 7 hours 
following study drug administration, Section 12.4.3 Activity should be updated to read as 
follows (deleted text is in skikethf:eagh and added text in bold): 
"Section 12.4.3 Activity 
Subjects must be awakened at least 1 hour prior to the start of the cardiodynamic ECGs 
on Day 1 and before the ECG recording scheduled at the 24-hour (Day 2) postdose time 
point. Following dosing (Day 1), subject will remain seatea or amhalatery lying down or 
sitting and awake for the first 7 hours postdose, ete0fJt ·.vh:en a supiae fl0sitien is 
Gietatea ey Stady flreeedUfes, t8reugli of the 12-hour postdose cardiodynamic ECGs 
monitoring period, as the QT-RR relationship is different during sleep. There will be no 
significant stimuli such as TV, loud radio, interactions with other subjects. Subjects must 
lie down for at least 10 minutes prior to all safety ECG recordings to aveid Sflj' physical 
aetivity. 
will feHl:atft lyieg Elewa or sitt:iag fer the H:rst 7 hears pesttiese, eteept vlhee. 
they are seated, supifte, er semi Feeliaea fer 
pEesed-ares. 
sfl:eala In the 
event that an AE(s) occur at any time, subjects may be placed in an appropriate position 
or will be permitted to lie down on their right side." 
2. During the study, all vital signs measurements will be performed after subjects are in the 
supine position for 5 minutes. Section 14.2.2 Vital Signs erroneously states that vital 
signs will be measured in a semi-supine position. Section 14.2.2 Vital Signs should be 
updated to read as follows (deleted text is in stfiketftreagh. and added text in bold): 
"Section 14.2.2 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, 
will be measured as outlined in the Study Events Flow Chart (Section 7) using calibrated 
100 Alexis-Nihon Blvd, Suite 360 •Montreal, QC H4M 2N8 Canada 
Tel: 514-744-9090 •Fax: 514-744-8700 
Page I of2 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
2

c el e ri o n 
T r a n sl ati n g S ci e n c e t: o 
M e di ci n e 
di git al B P e q ui p m e nt wit h t h e s u bj e ct i n t h e s e mi S HJlifl e s u pi n e p ositi o n. A d diti o n al vit al 
si g ns m a y b e t a k e n at a n y ot h er ti m es, if d e e m e d n e c ess ar y. 
Bl o o d pr ess ur e, h e art r at e, a n d r es pir at or y r at e m e as ur e m e nts will b e p erf or m e d wit h 
s u bj e cts i n a se mi S HfJi Be s u pi n e p ositi o n, u nl ess a n ot h er p ositi o n is r e q uir e d d u e t o A Es 
(e. g. n a us e a, di z zi n ess) or if d e e m e d n e c ess ar y b y t h e PI or d esi g n e e." 
T h e fi nal pr ot o c ol, d at e d 0 3- A pr- 2 0 1 9 w as n ot a m e n d e d t o i n c or p or at e t h es e c h a n g es; t h er ef or e, 
t his pr ot o c ol cl arifi c ati o n l ett er is b ei n g writt e n. 
 Pr ot o c ol D esi g n & D e v el o p m e nt 
C el eri o n 
 M D C PI 
Pri n ci p al I n v esti g at or 
C el eri o n 
Cli ni c al St u d y M a n a g e m e nt 
C el eri o n 
4 
i 
-
": > 
ff 2 ' 2 O l 
' 1 
D at e 
D at e 
2 5- A pr- 1 9 I 0 8: 0 5: 4 5 P D T 
M D, P h D 
D at e 
 t o L o x o O n c ol o g y, I nc. 
L o x o O n c ol o g y, I nc. 
1 0 0 Ale xis- Ni h o n Bl v d, S uite 3 6 0 • M o ntreal, Q C H 4 M 2 N 8 Ca na da 
Pa ge 2 of 2 
Tel: 5 1 4- 7 4 4- 9 0 9 0• Fa x: 5 1 4- 7 4 4- 8 7 0 0 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

 
Page 1 
 
 
 
 
 
Clinical Protocol 
 
 
A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way 
Crossover Study to Evaluate the Effect of LOXO-292 on the QTc Interval in Healthy 
Adult Subjects 
 
Celerion Project No.: CA25494 
 
Sponsor Project No.: LOXO-RET-18032 
 
US IND No.: 133193 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Loxo Oncology, Inc. 
and/or Celerion. Any viewing or disclosure of such information that is not authorized in 
writing by Loxo Oncology, Inc. and/or Celerion is strictly prohibited. Such information may 
be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
4

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal , 0 3 A pr 2 0 1 9 
 
Pa ge 2 
1  
P R O T O C O L R E VI SI O N HI S T O R Y  
D ate/ N a me  
Descri pti o n  
0 3 A p r 2 0 1 9  
b y 
 
Fi nal  Pr ot oc ol 
 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
5
P P D

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal , 0 3 A pr 2 0 1 9 
 
Pa ge 3 
2  
S P O N S O R – SI G N A T O RI E S  
A Si n gle - D ose, R a n d o mize d, D o u ble -Bli n d , Pl ace b o - a n d P ositi ve- C o ntr olle d, 4- W a y 
Cr oss o ver St u d y t o E v al u ate t he Effect of L O X O- 2 9 2 o n t he Q Tc I nter v al i n He alt h y 
A d ult S u bjects  
S P O N S O R:  
L o x o O nc ol o g y, I nc. 
7 0 1 Gate wa y B o ule v ar d , S uite 4 2 0 
S o ut h Sa n Fra ncisc o, C alif or nia 9 4 0 8 0, U S A 
 
S P O N S O R’ S 
R E P R E S E N T A TI V E:  
 
 M D, P h D 
 t o L o x o O nc ol o g y, I nc. 
M o bile: 
 
E- mail: 
 
 
 
 
 
Si g nat ure 
 Date  
 
 
ＰＴＭａｰｲＭＱＹ＠ｼ＠ＱＰＺＰＶＺＰＵ＠ｐｄｔ
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6
P P D
P P D
P P D
P P D
P P D

C O N FI D E N TI A L 
C A 2 5 4 9 4 ( L O X O- R E T- 1 8 0 3 2), Fi n al , 0 3 A pr 2 0 1 9 
3 
P RI N CI P A L I N V E S TI G A T O R A N D C LI NI C A L SI T E- SI G N A T O R Y 
A Si n gle- D ose, R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- a n d P ositi v e- C o ntr oll e d, 4- W a y 
Cr oss o v er St u d y t o E v al u at e t h e Eff e ct of L O X 0- 2 9 2 o n t h e Q T c I nt er v al i n H e alt h y 
A d ult S u bj e cts 
C E L E RI O N P RI N CI P A L I N V E S TI G A T O R A N D C LI NI C A L SI T E: 
 
 
Tel.: 
 
F a x:
Si g n at ur e 
Pri nt e d N a m e 
P a g e 4 
o s f\ P:' <- 2 0 11 
D at e 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7
P P D
P P D
P P D
P P D
P P D

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal , 0 3 A pr 2 0 1 9 
 
Pa ge 5 
4  
A D DI TI O N A L K E Y C O N T A C T S F O R T H E S T U D Y  
S p o ns or C o nt act I nf or m ati o n 
f or Seri o us A d verse E ve nt 
Re p orti n g  
efa x : + 1 2 0 3 6 4 3- 2 0 1 3 
E- mail: safet y @l o x o o nc ol o g y.c o m 
 
 
Me dic al M o nit or  
 M D, P h D 
t o L o x o O nc ol o g y, I nc. 
M o bile: 
 
E- mail: 
 
 
 
A d diti o n al S p o ns or C o nt act  
  
Cli nical Trial Ma na ger, Cli nical O perati o ns  
L o x o O nc ol o g y, I nc. 
Tel.: 
 
E -mail: 
 
 
 
Pr ot oc ol A ut h or  
 P h D 
 Pr ot oc ol D esi g n a n d D e vel o p me nt 
 
 Ca na da  
T el.: 
 
Fa x: 
 
E- mail: 
 
 
 
Certifie d Cli nic al L a b or at or y 
Celeri o n  
2 4 2 0 West Baseli ne R oa d 
Te m pe, Ariz o na 8 5 2 8 3 , U S A 
C o n tact: 
 
Tel.: 
 
Fa x: 
 
 
 
Bi o a n al ytic al L a b or at or y f or 
L O X O - 2 9 2 a n d M o xifl o x aci n 
Alt uras A nal ytics, I nc.  
Alt uras Tec h n ol o g y Par k  
1 3 2 4 Alt uras Dri ve  
M osc o w, I da h o 8 3 8 4 3, U S A 
Tel.: + 1 2 0 8 8 8 3- 3 4 0 0 
 
 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
8
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal , 0 3 A pr 2 0 1 9 
 
Pa ge 6 
P h ar m a c o ki netic A n al ysis 
Celeri o n  
1 0 0 Ale xis- Ni h o n B o ule var d, S uite 3 6 0 
M o ntreal, Q ue b ec H 4 M 2 N 8, C a na da  
Tel.: + 1 5 1 4 7 4 4- 9 0 9 0 
Fa x: + 1 5 1 4 7 4 4- 8 7 0 0 
 
a n d/ or 
 
Celeri o n  
6 2 1 R ose Street 
Li nc ol n, N e bras k a 6 8 5 0 2, U S A  
Tel.: + 1 4 0 2 4 7 6- 2 8 1 1 
Fa x: + 1 4 0 2 9 3 9- 0 4 2 8 
 
C ar di o d y n a mic A n al ysis 
E R T  
1 5 0 Alle ns Cree k R oa d ,  
R oc hester, Ne w  Y or k 1 4 6 1 8, US A 
C o ntact: 
 
Tel.: 
  
E- mail: 
 
 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
9
P P D
P P D
P P D

CONFIDENTIAL 
CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 7 
5 
TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY ............................................................................. 2 
2 SPONSOR – SIGNATORIES .......................................................................................... 3 
3 PRINCIPAL INVESTIGATOR AND CLINICAL SITE – SIGNATORY ................. 4 
4 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................ 5 
5 TABLE OF CONTENTS ................................................................................................. 7 
6 SYNOPSIS ....................................................................................................................... 10 
7 STUDY EVENTS FLOW CHART ............................................................................... 13 
8 ABBREVIATIONS ......................................................................................................... 19 
9 INTRODUCTION........................................................................................................... 22 
9.1 
Background ............................................................................................................. 22 
9.1.1 
LOXO-292 ................................................................................................ 22 
9.1.2 
Moxifloxacin ............................................................................................. 24 
9.2 
Rationale .................................................................................................................. 25 
9.2.1 
Rationale for this Study and Study Design ............................................... 25 
9.2.2 
Rationale for the Dose Selection............................................................... 26 
9.3 
Risks and/or Benefits to Subjects ............................................................................ 26 
10 OBJECTIVES AND ENDPOINTS ............................................................................... 28 
10.1 Objectives ................................................................................................................ 28 
10.2 Endpoints ................................................................................................................. 28 
11 STUDY DESIGN ............................................................................................................. 30 
11.1 Overall Study Design and Plan ............................................................................... 30 
11.1.1 
Confinement, Return Visits, and Follow-Up ............................................ 30 
11.1.2 
End of Study Definition ............................................................................ 31 
12 STUDY POPULATION ................................................................................................. 32 
12.1 Inclusion Criteria ..................................................................................................... 32 
12.2 Exclusion Criteria .................................................................................................... 33 
12.3 Early Termination of Subjects from the Study ........................................................ 37 
12.4 Study Restrictions ................................................................................................... 37 
12.4.1 
Prohibitions and Concomitant Medication ............................................... 37 
12.4.2 
Meals ......................................................................................................... 38 
12.4.3 
Activity ..................................................................................................... 39 
13 TREATMENTS............................................................................................................... 40 
13.1 Treatments Administered ........................................................................................ 40 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
10

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 8 
1 3. 2 
D ose M o dificati o n ................................................................................................... 4 0 
1 3. 3 
Met h o d of Treat me nt Assi g n me nt ........................................................................... 4 0  
1 3. 4 Bli n di n g ................................................................................................................... 4 1  
1 4 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  ......................................................... 4 3 
1 4. 1 Scree ni n g  ................................................................................................................. 4 3 
1 4. 2 Safet y  Assess me nts ................................................................................................. 4 4 
1 4. 2. 1 
P h ysical E x a mi nati o n ................................................................................ 4 4  
1 4. 2. 2 
Vital Si g ns  ................................................................................................. 4 4 
1 4. 2. 3 
E C Gs  ......................................................................................................... 4 4 
1 4. 2. 3. 1 
Sta n dar d 1 2- Le a d E CGs ( Safet y E C Gs)  .................................. 4 4 
1 4. 2. 3. 2 
Car di o d y n a mic E C Gs ............................................................... 4 5  
1 4. 2. 4 
B o d y Wei g ht ............................................................................................. 4 5  
1 4. 2. 5 
C li nical La b or at or y Tests .......................................................................... 4 5 
1 4. 2. 6 
A d verse E v e nts  ......................................................................................... 4 6 
1 4. 2. 6. 1 
A d verse E v e nt D efi niti o n ......................................................... 4 6 
1 4. 2. 6. 2 
M o nit ori n g ............................................................................... 4 7  
1 4. 2. 6. 3 
Re p ort i n g .................................................................................. 4 7 
1 4. 2. 6. 4 
Seri o us A d verse E v e nt ............................................................. 4 8  
1 4. 3 P ha r mac o ki netic Assess me nts ................................................................................. 4 9 
1 4. 3. 1 
Bl o o d Sa m pli n g a n d Pr o c essi n g ............................................................... 4 9  
1 4. 3. 2 
P har mac o ki netic Para meters  ..................................................................... 5 0 
1 4. 3. 3 
A nal ytical Met h o d  .................................................................................... 5 0 
1 4. 3. 4 
F ut ure Res ear c h  ........................................................................................ 5 1 
1 4. 4 Bl o o d V ol u me Dr a w n f or St u d y Assess me nts ........................................................ 5 1  
1 5 S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................... 5 2 
1 5. 1 Sa m ple Size Deter mi n ati o n ..................................................................................... 5 2 
1 5. 2 P o p ulati o n f or A nal ys e s .......................................................................................... 5 2 
1 5. 3 Car di o d y n a mic A nal yses  ......................................................................................... 5 2 
1 5. 3. 1 
Baseli ne A dj ust me nt  ................................................................................. 5 3 
1 5. 3. 2 
C o nce ntrati o n- Q T Rela ti o ns hi p A nal ysis ................................................. 5 3 
1 5. 3. 3 
Assa y Se nsiti vit y  ....................................................................................... 5 5 
1 5. 3. 4 
Cate g orical A n al ysi s ................................................................................. 5 5 
 
 
1 5. 3. 6 
P har mac o ki netic A n al ys es ........................................................................ 5 6 
1 5. 3. 6. 1 
Descri pti ve Statistics  ................................................................ 5 6  
1 5. 3. 7 
Safet y A nal yses  ......................................................................................... 5 6 
1 6 S T U D Y A D MI NI S T R A TI O N  ....................................................................................... 5 7  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 1
C CI

CONFIDENTIAL 
CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 9 
16.1 Ethics ....................................................................................................................... 57 
16.1.1 
Institutional Review Board ....................................................................... 57 
16.1.2 
Ethical Conduct of the Study .................................................................... 57 
16.1.3 
Subject Information and Consent.............................................................. 57 
16.2 Termination of the Study ......................................................................................... 58 
16.3 Data Quality Assurance ........................................................................................... 58 
16.4 Direct Access to Source Data/Documents .............................................................. 58 
16.5 Drug Supplies, Packaging and Labeling ................................................................. 58 
16.6 Data Handling and Record Keeping ........................................................................ 59 
16.7 Report Format ......................................................................................................... 59 
16.8 Publication Policy ................................................................................................... 59 
17 REFERENCES ................................................................................................................ 60 
 
LIST OF TABLES 
Table 1: 
Blood Volume during the Study .................................................................... 51 
 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
12

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 1 0 
6  
S Y N O P SI S  
C o m p o u n d: 
L O X O - 2 9 2 
Cli nical I n dicati o n:  
Ca ncer  
St u d y P has e a n d T y p e:  
P hase 1 – Car diac El ectr o car di o gra p hic E ffect st u d y 
St u d y O bjecti ve s: 
Pri m ar y:  
T o e val uate t h e effects of t hera pe utic a n d s u prat hera pe utic 
e x p os ure of L O X O - 2 9 2 o n t he heart rate -c orrecte d Q T ( Q Tc) 
i nter val b y assessi n g c o n ce ntrati o n-Q T ( C - Q T) rel ati o ns hi p 
usi n g e x p os ure-res p o nse m o delli n g. 
Sec o n d ar y:  
T o assess t he effect of t hera pe utic a n d s u prat h era pe utic e x p os ure 
of L O X O - 2 9 2 o n ot h er el ectr ocar di o gra m ( E C G) p ara meters . 
T o de m o nstrate se nsiti vit y of t his Q T c assa y usi n g m o xifl o x aci n 
as a p ositi ve c o ntr ol i n healt h y a d ult s u bjects. 
T o e val uate t he p h ar mac o ki netics ( P K) of t hera pe utic a n d 
s u prat hera p e utic d oses of L O X O - 2 9 2 i n healt h y a d ult s u bjects. 
T o e val uate t he s afet y a n d t olera bilit y of t hera pe utic a n d 
s u prat hera p e utic d oses of L O X O - 2 9 2 d ose i n h ealt h y a d ult 
s u bjects. 
 
 
 
 
S u m mar y of St u d y 
Desi g n:  
T his is a si n gle -d ose, ra n d o mize d, d o u ble- bli n d ( e x ce pt f or t he 
use of m o xifl o x aci n ), place b o - a n d p ositi ve-c o ntr olle d, 4-wa y 
cr oss o ver st u d y. 
O n Da y  1 of eac h p eri o d, s u bject will recei v e o ne of t w o si n gle 
oral d ose le vels of L O X O - 2 9 2, a si n gle oral d ose of 
m o xifl o x aci n, or a si n gle oral d ose of L O X O - 2 9 2 matc hi n g 
place b o o n o ne o ccasi o n, acc or di n g t o a ra n d o mizati o n sc he me.  
C ar di o d y n a mic sa m ples will be c ollecte d pre d ose a n d f or u p t o 
2 4 h o urs p ost d ose. P K  sa m ples will be c ollecte d pre d ose a n d f or 
u p t o 2 4 h o urs p ost d ose f or m o xifl o x aci n a n d u p t o 2 4 0 h o urs 
p ost d ose f or L O X O-2 9 2, as per treat me nt recei ve d . 
T here will be a was h o ut peri o d of 1 0 da ys  b et wee n d osi n g i n 
eac h p eri o d . 
T he cli nical res earc h u nit ( C R U) will c o ntact all s u bjects w h o 
recei v e d at least o ne d ose of st u d y dr u g (i ncl u di n g s u bjects w h o 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 3
C CI

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 1 1 
ter mi nate fr om t he st u d y earl y) at t he E n d of St u d y ( E O S, as 
defi ne d i n t he St u d y E v e nts Fl o wc hart, Secti o n  7 ) b y  a f oll o w- u p 
( F U) p h o n e call. T he E O S/ F U p h o ne call will be perf or me d 
7 da ys (± 2 da ys) after t h e E n d of Treat me nt ( E O T) or Earl y 
Ter mi nati o n ( E T) (as defi ne d i n t he St u d y E ve nts Fl o wc hart, 
Secti o n  7) t o deter mi ne if a n y s eri o us a d v erse e ve nt ( S A E) or 
st u d y dr u g relate d a d v ers e e ve nt ( A E) has o cc urre d si nce E O T 
or E T.  
N u m ber of S u bjects: 
T hirt y -t w o ( 3 2), healt h y, a d ult male a n d fe m ale ( w o me n of 
n o n-c hil d beari n g p ote nti al o nl y) s u bjects will be e nr olle d.  
D osa ge, D osa ge F or m, 
R o ute, a n d D ose 
Re gi me n:  
Treat me n t A: 
m g L O X O - 2 9 2 ( 
 
m g  
)  a n d 
L O X O - 2 9 2 matc hi n g place b o (
 m g 
matc hi n g place b o  
) a d mi nistere d at 
H o ur 0 o n Da y 1. 
Treat me nt B:   
 m g L O X O - 2 9 2 ( 
 
 m g  
) 
a d mi nistere d at H o ur 0 o n Da y 1. 
Treat me nt C:  
 m g m o xifl o x aci n ( 1 x 
m g  
) 
a d mi nistere d at H o ur 0 o n Da y 1. 
Treat me nt D: 
L O X O - 2 9 2 matc hi n g place b o (
  m g 
matc hi n g place b o  
) a d mi nistere d at 
H o ur 0 o n Da y 1. 
Eac h treat me nt  will be a d mi nistere d orall y  after a fast of at least 
1 0 h o urs fr o m f o o d ( n ot i ncl u di n g w ater), wit h a p pr o xi matel y 
2 4 0 m L of w ater . S u bjects will re mai n 
 ( n ot 
i ncl u di n g wat er) f or at least 4 h o urs p ost d ose. 
Ke y Assess me nts : 
C ar di o d y n a mics: 
C o nce ntr ati o n- Q T c relati o ns hi p: 
T he p ote ntial relati o ns hi p bet wee n Q T c i nter v al c ha n ge fr o m 
baseli ne ( ∆Q T c) ( usi n g t he m ost a p pr o priate h eart rate 
c orrecti o n fact or)  a n d plas ma L O X O- 2 9 2 c o nce ntrati o ns ( C-Q T 
relati o ns hi p) will be assesse d. P ote ntial f or h ysteresis will be 
e val uate d pri or t o perf or mi n g li near mi x e d -effect m o deli n g.  
Assa y s e nsiti vit y:  
T he relati o ns hi p bet wee n ∆Q Tc a n d m o xifl o x aci n plas ma 
c o nce ntrati o ns ( C- Q T rel ati o ns hi p) will be assesse d usi n g a 
li near mi x e d-effect m o del si milar t o t he o ne o utli ne d f or 
L O X O - 2 9 2. 
T h or o u g h Q T/c orrecte d Q T ( Q Tc; T Q T): 
 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 4
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 1 2 
 
  
P h ar m a c o ki netics:  
T h e f oll o wi n g P K p ara m eters will be calc ulate d f or L O X O - 2 9 2 
a n d m o xifl o x aci n i n plas ma, as a p pr o priate: A U C 0 -t, A U C 0-i nf, 
A U C %e xtra p, C ma x, T ma x,  Kel , a n d t ½. 
S af et 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 res ults, p h ysical e x a mi nati o n 
res ults, c o nc o mita nt me dicati o ns, a n d E C G i nter pretati o ns, will 
be ta b ulate d a n d s u m marize d w here p ossi ble, usi n g des cri pti ve 
met h o d ol o g y b y treat me nt a n d b y ti me  p oi nt. 
 
 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 5
C CI

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CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 13 
7 
STUDY EVENTS FLOW CHART 
Study Procedures a 
Scr b 
Study Days in Period 1 c 
Study Days → 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 g 
Period Days → 
-1  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 g 
Hours → 
C-I d -0.75 -0.5 -0.25 0 0.25 0.5 0.75 1.5 2 2.5 3 4 7 9 12 24 36 48 72 96 120 144 168 192 216 
240 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical Examination e 
 
 
X f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Safety ECG h 
X 
 
X f 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X g 
Vital Signs (HR, R, and BP) i 
X 
X 
X f 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X g 
Vital Signs (T) 
X 
X 
X f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Hem, Serum Chem j, Coag, and UA  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Thyroid Stimulating Hormone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Preg Test (♀ only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (PMP ♀s only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug, Cotinine, and Alcohol 
Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring k 
X 
X 
Conmeds Monitoring 
X 
X 
Study Drug Administration / 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOXO-292/Placebo Administration 
(Treatments A, B, and D) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Moxifloxacin Administration 
(Treatment C)  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Cardiodynamic Sampling 
 
 
X 
X 
X 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
Blood for LOXO-292 l 
(Treatments A, B, and D) 
 
 
 
 
X m 
 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g, m 
Blood for Moxifloxacin l 
(Treatment C) 
 
 
 
 
X m 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
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Study Procedures a 
Scr b 
Study Days in Period 1 c 
Study Days → 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 g 
Period Days → 
-1  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 g 
Hours → 
C-I d -0.75 -0.5 -0.25 0 0.25 0.5 0.75 1.5 2 2.5 3 4 7 9 12 24 36 48 72 96 120 144 168 192 216 
240 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU n 
 
X 
Visit  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Procedures a 
Study Days in Period 2 c 
Study Days → 
11 g 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21g 
Period Days → 
1 g 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 g 
Hours → -0.75 -0.5 -0.25 
0 
0.25 0.5 0.75 1.5 2 2.5 3 4 7 9 12 24 36 
48 
72 
96 
120 
144 
168 192 
216 
240 
Safety Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical Examination e 
X g, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
12-Lead Safety ECG h 
X g, f 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X g 
Vital Signs (HR, R, and BP) i 
X g, f 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X g 
Vital Signs (T) 
X g, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Hem, Serum Chem j, Coag, and UA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
AE Monitoring k 
X 
Conmeds Monitoring 
X 
Study Drug Administration / 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOXO-292/Placebo Administration 
(Treatments A, B, and D) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g  
Moxifloxacin Administration (Treatment C)  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
 
Cardiodynamic Sampling 
X 
X 
X 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
Blood for LOXO-292 l 
(Treatments A, B, and D) 
 
 
X g, m 
 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g, m 
Blood for Moxifloxacin l 
(Treatment C) 
 
 
X g, m 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU n 
X 
 
 
 
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Study Procedures a 
Study Days in Period 3 c 
Study Days → 
21 g 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 g 
Period Days → 
1 g 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 g 
Hours → -0.75 -0.5 -0.25 
0 
0.25 0.5 0.75 1.5 2 2.5 3 4 7 9 12 24 36 
48 
72 
96 
120 
144 
168 192 
216 
240 
Safety Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical Examination e 
X g, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
12-Lead Safety ECG h 
X g, f 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X g 
Vital Signs (HR, R, and BP) i 
X g, f 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X g 
Vital Signs (T) 
X g, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Hem, Serum Chem j, Coag, and UA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
AE Monitoring k 
X 
Conmeds Monitoring 
X 
Study Drug Administration / 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOXO-292/Placebo Administration 
(Treatments A, B, and D) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Moxifloxacin Administration (Treatment C)  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cardiodynamic Sampling 
X 
X 
X 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
Blood for LOXO-292 l 
(Treatments A, B, and D) 
 
 
X g, m 
 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g, m 
Blood for Moxifloxacin l 
(Treatment C) 
 
 
X g, m 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU n 
X 
 
 
 
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Page 16 
 
 
Study Procedures a 
Study Days in Period 4 c 
41 
Clinic 
Discharge/ 
EOT / ET o 
FU/ 
EOS p 
Study Days → 
31 g 
32 
33 34 35 
36 
37 
38 
39 
40 
41 
Period Days → 
1 g 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Hours → -0.75 -0.5 -0.25 
0 
0.25 0.5 0.75 1.5 2 2.5 3 4 7 9 12 24 36 48 72 96 120 144 168 192 216 240 
 
 
Safety Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Physical  
Examination e 
X g, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Safety ECG h 
X g, f 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Vital Signs (HR, R, and BP) i 
X g, f 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Vital Signs (T) 
X g, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Hem, Serum Chem j, Coag, and 
UA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Serum Preg Test (♀ only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring k 
X 
Conmeds Monitoring 
X 
Study Drug Administration / 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOXO-292/Placebo 
Administration (Treatments A, B, 
and D) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moxifloxacin Administration 
(Treatment C)  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiodynamic Sampling 
X 
X 
X 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for LOXO-292 l 
(Treatments A, B, and D) 
 
 
X g, m 
 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood for Moxifloxacin l 
(Treatment C) 
 
 
X g, m 
 
X 
X 
X 
X X X X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU n 
X 
 
 
 
 
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Page 17 
a: 
For details on Procedures, refer to Section 14. 
b: Within 28 days prior to the first study drug administration. 
c: 
There will be a washout period of 10 days between dosing in each period. 
d: Subjects will be admitted to the CRU on C-I (Day -1) of Period 1, at the time indicated by the CRU. 
e: 
Symptom-driven physical examination may be performed at other times, at the PI’s or designee’s discretion. Scheduled abbreviated physical examinations 
will include, at a minimum, examination of respiratory, cardiovascular, and gastrointestinal systems, with the option for further examination of additional 
systems as necessary based on reported symptoms/AEs. 
f: 
To be performed within 2 hours prior to dosing. 
g: Study Day 11 is the last day of Period 1 and the first day of Period 2. Period Day 11 in Period 1 is the same as Period Day 1 in Period 2. Study Day 21 is the 
last day of Period 2 and the first day of Period 3. Period Day 11 in Period 2 is the same as Period Day 1 in Period 3. Study Day 31 is the last day of Period 3 
and the first day of Period 4. Period Day 11 in Period 3 is the same as Period Day 1 in Period 4. These study procedures will only be performed once. 
h: Subjects are to be supine for 10 minutes prior to safety ECG assessment without any potentially interfering stimuli – TV, loud radio, interactions with other 
participants, etc. Safety ECGs will be measured within 2 hours prior to Day 1 dosing in each period for the predose time point. When scheduled postdose, 
safety ECGs will be performed within approximately 20 minutes of the scheduled time point. 
i: 
Vital signs (HR, BP, and R) will be obtained at Screening and C-I (Day -1), predose, at 0.75 hours (± 10 minutes), 2 hours (± 10 minutes) and 4 hours 
(± 10 minutes) postdose on Day 1, on Day 2, and Day 3, Day 4, Day 5, Day 6, and Day 11 in each period and at EOT (or ET). BP and HR will be measured 
using the same arm for each reading. Subjects are to be supine for 5 minutes prior to vital signs assessments.  
j: 
Samples for serum chemistry will be obtained following a fast of at least 12 hours at Screening and at Check-in; at other scheduled times, serum chemistry 
tests will be performed after at least an 8-hour fast. However, in case of dropouts or rechecks, subjects may not have fasted for 12 or 8 hours prior to the time 
that the serum chemistry sample is taken. 
k: AEs and SAEs will be recorded beginning at informed consent. All AEs will be recorded throughout the study (i.e., from signing of the ICF until EOS or ET 
if the subject discontinues from the study and does not complete a follow up 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 of Period 1 and is assessed as not related to study procedures by 
the PI [or designee]) or as AEs (if the event occurs after signing of the ICF but prior to study drug administration on Day 1 of Period 1 through EOT or ET 
and is assessed as related to study procedures by the PI (or designee), or if the event occurs after study drug administration on Day 1 of Period 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 PI (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 call) are to be reported. 
l:  The sampling windows for PK blood samples will be as follows: within 30 minutes prior to dosing for the predose sample time point; ± 5 minutes for 
sampling time points within the first 12 hours; ± 30 minutes for sampling time points > 12 hours ≤ 36 hours; and ± 60 minutes for the sampling time points 
from ≥ 48 to ≤ 240 hours. PK samples will always be drawn just after the ECG acquisition windows. 
m: To be performed prior to dosing and/or following completion of the last of the baseline triplicate ECGs. 
n.  Subjects will be confined to the CRU from Day -1 of Period 1 until completion of study procedures on Day 11 of Period 4 (Study Day 41). 
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o: To be performed at EOT or at ET. EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 11 of 
Period 4. ET is defined as when the subject is released from the CRU if the subject terminates the study early. Vital sign, ECG, and safety laboratory results 
for serum chemistry, hematology, coagulation, and urinalysis are to be available for review by the PI or designee prior to subject release from the CRU at the 
EOT or ET visit. 
p: To be performed 7 days (± 2 days) following EOT or ET. End of Study (EOS) is defined as when the CRU contacts the subject by phone call 7 days 
(± 2 days) after EOT or ET to determine if any SAE or study drug related AE has occurred since EOT or ET. All subjects who received at least one dose of 
study drug (including subjects who terminate the study early) will be contacted. 
 
Abbreviations: ♀ = Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, Coag = Coagulation, Conmeds = Concomitant 
medications, CRU = Clinical research unit, ECG = Electrocardiogram, EOS = End of Study, EOT = End of Treatment, ET = Early termination, 
FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart rate, PI = Principal Investigator, 
PK = Pharmacokinetic(s), PMP = Postmenopausal, Preg = Pregnancy, R = Respiratory rate, Scr = Screening, T = Temperature, UA = Urinalysis.  
 
 
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Page 19 
8 
ABBREVIATIONS 
~ 
Approximately  
μM 
Micromolar 
AIC  
Akaike Information Criterion 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC%extrap 
Percent of AUC0-inf extrapolated  
AUC0-t 
Area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration (t) 
AUC0-inf 
Area under the concentration-time curve, from time 0 
extrapolated to infinity 
AV 
Atrioventricular 
BID 
Twice daily 
BMI 
Body mass index 
bpm 
Beats per minute 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cm 
Centimeter 
Cmax 
Maximum observed concentration  
CRF 
Case report form 
CRU 
Clinical Research Unit 
CYP 
Cytochrome p450 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
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Page 20 
g 
Gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GoF 
Goodness-of-fit 
HBsAg 
Hepatitis B surface antigen 
HCl 
Hydrochloride 
HCV 
Hepatitis C virus 
hERG 
Human ether-a-go-go related gene 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Inhibitory concentration at 50% 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
Kel 
Apparent terminal elimination rate constant 
kg 
Kilogram 
LSMs 
Least-squares means 
m2 
Meters squared 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
mRNA 
Messenger ribonucleic acid 
msec 
Millisecond 
No. 
Number 
oz 
Ounces 
P-gp 
P-glycoprotein 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
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QTc 
Corrected value of the interval between the Q and T waves on the 
electrocardiogram tracing 
RET 
Rearranged during transfection 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
SUSAR 
Statistical analysis plan 
Suspected Unexpected Serious Adverse Reaction  
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to reach maximum observed concentration 
t½ 
Apparent terminal elimination half-life 
US 
United States 
USA 
United States of America 
Vz/F 
Apparent volume of distribution during the terminal elimination 
phase after oral (extravascular) administration 
WHO 
World Health Organization 
 
 
 
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Page 22 
9 
INTRODUCTION 
9.1 
Background 
9.1.1 
LOXO-292 
LOXO-292 is a small molecule and a selective inhibitor of the rearranged during transfection 
(RET) receptor tyrosine kinase designed to competitively block the adenosine triphosphate 
binding site of the kinase. LOXO-292 was at least 250-fold more selective for RET than for 
98% of 329 other kinases tested in a large in vitro screen. Consistent with such a high degree 
of selectivity, LOXO-292 caused significant cytotoxicity in human cancer cell lines that 
harbored endogenous, clinically relevant RET gene alterations but was much less cytotoxic 
against human cancer cell lines without RET alterations. Potent and selective inhibition of 
RET may provide clinical benefit to subjects with malignancies due to oncogenic alterations 
in RET or with other mechanisms of increased RET activity. 
Nonclinical 
Cardiac safety of LOXO-292 was evaluated in a Good Laboratory Practice (GLP) in vitro 
assay for human ether-a-go-go related gene (hERG) activity, in a GLP in vivo study in 
conscious telemetry-instrumented minipigs, and in a GLP 28-day repeat-dose toxicology 
study (with ECG monitoring) in minipigs. LOXO-292 had a 50% inhibitory concentration 
(IC50) value of 1.1 μM in the GLP hERG assay, which is approximately 14- and 6-fold higher 
than the predicted maximum unbound concentration at the dose of 80 mg and 160 mg 
respectively twice daily (BID). There were no LOXO-292-related changes in any 
cardiovascular endpoints including QT interval corrected for heart rate (QTc) at doses up to 
12 mg/kg in the safety pharmacology cardiovascular study in conscious minipigs. 
Furthermore, there were no LOXO-292-related ECG changes in the 28-day repeat-dose 
toxicity study in minipigs at the high dose of 12 mg/kg. Together, these data indicate that 
LOXO-292 has a low risk of inducing delayed ventricular repolarization, prolongation of the 
QTc interval, and unstable arrhythmias. 
Administration of LOXO-292 at single doses up to 45 mg/kg in male rats had no effect on 
respiratory function. 
Potential effects of LOXO-292 on the central nervous system were evaluated as part of the 
GLP 28-day repeat-dose study in rats, in functional observational battery tests and locomotor 
activity assessments. Findings were limited to animals receiving the high dose on week 4 of 
the dosing phase, and were attributed to poor general body condition and weight changes 
associated with LOXO-292 administration rather than specific neurological effects. 
Additionally, no microscopic abnormalities in neuronal tissues were found. 
In toxicology studies of LOXO-292 that were conducted in the rat and minipig, the primary 
pathologic findings for both species were in the tongue, pancreas, bone marrow and 
lymphoid tissues; while the gastrointestinal tract and ovaries were target tissues in minipig. 
Other target tissues identified in the rat included: multi-tissue mineralization, physeal 
cartilage, incisor teeth, lung, Brunner’s gland, and possibly liver. Assessment of doses 
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associated with moribundity/death revealed a steep dose response curve for both species. 
LOXO-292 was not mutagenic in the GLP bacterial mutation assay. When evaluated in two 
in vitro assays, LOXO-292 was not genotoxic. LOXO-292 was not found to be phototoxic 
when evaluated in an in vitro neutral red uptake phototoxicity assay. 
Based on preclinical pharmacology experiments with human cancer cells in vitro and in 
murine xenograft models, meaningful inhibition of RET in tumors is expected to be 
achievable with oral dosing regimens ≥ 40 mg/day. 
Based on the nonclinical profile, including results from animal toxicology studies, theoretical 
risks of human exposure to LOXO-292 include the following: loss of appetite, decrease in 
body weight, increase in total white blood cells, neutrophils, and monocytes, decrease in 
albumin, increase in globulin, decreased albumin:globulin ratio, decrease in total protein, 
increased body temperature, lethargy, increase in cholesterol and triglycerides, increase in 
phosphorus, changes in taste sensation and/or development of xerostomia, gastrointestinal 
symptoms/signs: nausea, vomiting, loose stools, abdominal discomfort, decreases in red cell 
mass (red blood cell [RBC], hemoglobin, hematocrit) and reticulocytes, decrease in platelets, 
increases in liver function tests (alkaline phosphatase, aspartate aminotransferase, and alanine 
aminotransferase) and possible pancreas injury. 
LOXO-292 has been given orally and intravenously to mice, rats, dogs, minipigs, and 
monkey. LOXO-292 was absorbed and bioavailable in all species tested. Solubility studies 
and pharmacokinetic (PK) studies suggest that the PK exposure of LOXO-292 may be 
reduced by proton pump inhibitors and other antacids. LOXO-292 appears to be metabolized 
primarily by cytochrome p450 (CYP)3A4, but at therapeutically relevant exposures, it is not 
anticipated to inhibit or induce drug-metabolizing enzymes. LOXO-292 is also a substrate for 
breast cancer resistance protein (BCRP). 
Refer to the current Investigator’s Brochure (IB) for detailed background information on 
LOXO-292 (Investigator’s Brochure, Version 4, October 2018). 
Clinical 
LOXO-292 is currently being studied in an ongoing global Phase 1/2 (Study 
LOXO-RET-17001) in patients with advanced solid tumors including RET fusion-positive 
NSCLC, RET-mutant medullary thyroid carcinoma, and other tumors with increased 
RET activity. The starting dose of LOXO-292 was 20 mg once daily.  
As of a July 19, 2018 data cut-off date, safety data was available from 153 patients with 
240 mg BID as the highest dose administered. As of this date, two dose-limiting toxicities 
(DLTs) of tumor lysis syndrome and Grade 3 thrombocytopenia at the 240 mg BID dose 
level have been reported. The most frequently reported treatment-emergent adverse events 
(TEAEs; [> 10% of patients]), were dry mouth (20.3%; 14.4% related), diarrhea (15.7%; 
7.2% related), fatigue (15.7%; 11.8% related), constipation (12.4%; 2.6% related), headache 
(11.1%; 3.3% related), and hypertension (10.5%; 3.9% related). Regarding TEAEs, 8 patients 
experienced ≥ Grade 3 TEAEs that were judged by the Investigator as related to study drug. 
Three (3) patients have died within 28 days of their last dose of study drug and no deaths 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
26

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 2 4 
ha ve bee n attri b ute d t o st u d y dr u g. A s mall n u m ber of pat ie nts ha ve e x perie nce d Gra de 3 or 
hi g her li ver f u ncti o n test a b n or malities, c o nsi dere d relate d t o t he st u d y dr u g, occ urri n g 
bet wee n 2 0  - 5 6 da ys after starti n g L O X O - 2 9 2. T hese c ha n ges were as y m pt o matic a n d 
res olve d wit h d ose i nterr u pti o n. L O X O - 2 9 2 was res u me d at a l o wer d ose f oll o wi n g 
n or malizati o n of t he L F Ts. Please refer t o t he I B f or a d diti o nal safet y i nf or mati o n  
(I n vesti gat or’s Br o c h ure, Versi o n 4, Oct o ber 2 0 1 8).  
As of A u g ust 2 4, 2 0 1 8, P K data were  a v aila ble fr o m 1 4 1 patie nts (fr o m t he gl o bal P hase 1/ 2 
st u d y). L O X O-2 9 2 is a bs or be d aft er oral a d mi nistrati o n wit h a me dia n ti me t o ma xi m u m 
c o nce ntr ati o n ( T ma x ) of a p pr o xi matel y 2 h o urs. Alt h o u g h t he P K sa m pli n g of L O X O- 2 9 2 
was n ot l o n g e n o u g h t o a de q uatel y c h aracterize A U C 0-i nf, t h e half-life a p p ears t o be 
2 0 h o urs. L o w c o nce ntrati o ns of L O X O- 2 9 2 w ere rec o vere d as u nc ha n ge d dr u g i n uri n e 
i n dicati n g t hat t he ki d ne y c o ntri b utes t o o verall cleara nce. 
As of Se pte m ber 1 4, 2 0 1 8, L o x o O nc ol o g y has i nitiate d 1 6 si n gle patie nt pr ot oc ols, S pe cial 
Access Sc h e me, or T e m p orar y A ut h orizati o n Use cases t o pr o vi de access t o L O X O - 2 9 2 f or 
patie nts wit h cli nical nee d n ot meeti n g eli gi bilit y criteria f or t he o n g oi n g gl o bal P hase 1/ 2  
st u d y. As of Se pte m b er 1 4, 2 0 1 8, n o T E A Es ha ve bee n attri b ute d t o st u d y dr u g f or t hese 
patie nts.  
P K data a vaila ble fr o m st u dies ( St u d y L O X O -R E T - 1 8 0 1 4 a n d St u d y L O X O -R E T - 1 8 0 1 5) 
c o n d ucte d i n healt h y s u bjects i n dicate t hat L O X O- 2 9 2 has a ter mi nal t ½ of a p pr o xi matel y 
2 4 h o urs after a si n gle d ose.   
9. 1. 2  M o xifl o x aci n 
M o xifl o x aci n h y dr oc hl ori de ( H Cl) is a s y nt hetic C - 8- met h o x y-fl u or oq ui n ol o ne a nti micr o bial 
a ge nt. It has diff ere nt pr o perties t ha n ot her q ui n ol o ne a ge nts. W hile still acti ve a gai nst 
gr a m - ne gati ve pat h o ge ns, it is als o hi g hl y acti ve a gai nst gra m- p ositi ve c occi, aer o bic, 
a naer o bi c, i ntracell ular b acteria a n d “at y pi cal’ or ga nis ms s uc h as M yc o plas ma a n d 
C hla m y dia. He n ce it is effecti ve f or t he treat me nt of res pirat or y tract i nfecti o ns, i ncl u di n g 
ac ute e x acer bati o ns of c hr o nic br o nc hitis, c o m m u nit y-ac q uire d p n e u m o nia, a n d ac ute 
bacterial si n usitis. It is als o i n dicate d f or t he treat me nt of c o m plicate d a n d u nc o m plicate d 
s ki n a n d s ki n str uct ure i nfecti o ns, a n d c o m plicate d i ntra-a b d o mi nal i nfecti o ns. T he 
rec o m me n de d oral d ose is  
 m g o nce dail y f or 5 t o 2 1 da ys, d e pe n di n g o n t he s pecific 
i nfecti o n (A vel o x ®  2 0 1 6).  
F oll o wi n g a d mi nistrati o n of t he us ual t hera p e utic d ose ( 
 m g), pea k plas ma le vels occ ur at 
a p pr o xi matel y 1. 5 h o urs a n d t he eli mi nati o n half-life of m o xifl o x aci n is a b o ut 1 3 h o urs. 
M o xifl o x aci n ca n be gi ve n c o nc urre ntl y wit h f o o d, b ut n ot wit h a ntaci ds c o ntai ni n g 
ma g n esi u m or al u mi n u m or pre parati o ns c o ntai ni n g s ucralfat e or metal cati o ns, s uc h as ir o n 
or zi nc ( A vel o x ®  2 0 1 6; Stass  1 9 9 8).  
M o xifl o x aci n pr ol o n gs Q T  i nter val d urati o n a n d is use d as a p ositi ve c o ntr ol i n m ost T Q T 
st u dies t o deter mi ne st u d y se nsiti vit y. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
2 7
C CI
C CI

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 2 5 
T he m ost c o m m o n a d verse e ve nts ( A Es) see n wit h m o xifl o x aci n are na usea, diarr h ea, 
hea dac he, a n d dizzi ness. M o xifl o x aci n is i n t he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) 
pre g na nc y cate g or y C  (A vel o x ®  2 0 1 6).  
9. 2  
R ati o n ale 
9. 2. 1  R ati o n ale f or t his St u d y a n d St u d y Desi g n  
Car diac safet y is a maj or fact or i n cli nical d e vel o p me nt gi ve n t hat t he effect of ne w dr u gs i n 
dela yi n g car di ac r e p olari zati o n are a c o m m o n ca use f or dr u g wit h dra wal fr o m t he mar ket a n d 
dela ys i n, or de nial of, re g ulat or y a p pr o val f or mar keti n g. T h e p ote ntial effect of a dr u g o n 
car diac re p ol arizati o n ca n be meas ure d as pr ol o n gati o n of t he Q T i nter val o n 
electr ocar di o gr a p hic rec or di n gs.  
Rece nt disc ussi o ns bet wee n re g ulat or y a ge n cies a n d p har mace utical i n d ustries t o i m pr o ve t he 
efficie n c y of T h or o u g h Q T ( T Q T) st u dies h a ve l e d t o t he searc h f or alter n ati ves t o t he 
c o n ve nti o nal T Q T st u dies ( Dar p o 2 0 1 5 ; F er b er 2 0 1 5 ).  A n alter nat i ve a p pr o ac h b y c ollecti n g 
q ualit y tri plicate E C G d uri n g t he si n gle- a n d/ or m ulti ple-asce n di n g d oses st u dies, w hic h 
pr o vi des data o ver a wi d e ra n ge of d oses w as  a p pr o ve d b y t he T hir d I C H E 1 4 Q uesti o ns a n d 
A ns wers d oc u m e nt ( I C H E 1 4 2 0 1 5). M o delli n g t h e C- Q T rel ati o ns hi p o bser ve d d uri n g t hese 
st u dies will c haracterize t he Q T pr ol o n gati o n effect o ver t he o bser v e d ra n ge of dr u g 
c o nce ntr ati o ns t o assess t he dr u g car diac effect. 
T he st u d y d esi g n i ncl u d es t he use of a place b o, t w o L O X O- 2 9 2 d oses, a t hera pe utic o n e a n d 
o ne i n e x cess of t he pr o p ose d t hera p e utic d ose t o mi mic t he e x p os ure i n healt h y s u bjects t hat 
ma y o cc ur i n t he tar get p o p ulati o n  un der t he m ost e xtre me circ u msta nces a n d t o assess t he 
effect o n car diac re -p olarizati o n , as well as a p ositi ve c o ntr ol , m o xifl o x aci n. It will be a 
d o u ble- bli n d st u d y wit h r es pect t o L O X O- 2 9 2 a n d place b o d oses. Res ults of t his cli nical 
st u d y will be use d t o assess t he p ote ntial of L O X O - 2 9 2 t o dela y car diac re p olarizati o n. 
T he st u d y will be c o n d ucte d i n healt h y s u bjects t o eli mi nate varia bles k n o w n t o c ha n ge E C G 
para meters i n patie nts ( e. g., c o n c o mita nt me dicati o ns a n d diseases) . A ra n d o mize d cr oss o ver 
desi g n has b ee n s electe d  t o mi ni mize assi g n me nt bias  a n d t o all o w eac h s u bject t o ser ve as 
his or her o w n c o ntr ol, w hic h i m pr o ves t he precisi o n of t he esti mate d treat me nt differe n ces 
as well as decreasi n g t h e o verall n u m ber of s u bj ects nee de d f or t h e st u d y.  
M o xifl o x aci n as a si n gle 
m g d ose is a sta n dar d p ositi ve c o ntr ol t o be use d i n Q T st u dies. 
T his pr o d uct has bee n s h o w n t o pr o d uce a pea k Q Tc pr ol o n gati o n ra n gi n g fr o m 
1 0 t o 1 5 ms ec i n cr oss o v er desi g n st u dies (Bl o o mfiel d 2 0 0 8 ; Ta u bel 2 0 1 4 ), wit h a mea n QTc 
pr ol o n gati o n of a b o ut 5 ms ec w hic h is t he t hres h ol d of re g ulat or y c o n cer n. He nce, 
m o xifl o x aci n -i n d uce d c h a n ges i n ve ntric ular re p ol arizati o n, w he n c o m pare d t o t he place b o 
treat me nt i n healt h y s u bjects, will be use d t o e val uate assa y se nsiti vit y. 
T he sa m pli n g sc h e me is e x pecte d t o a de q uatel y c haract erize L O X O - 2 9 2 e x p os ure i ncl u di n g 
h yster esis a n d late eff ects a n d di ur nal varia bilit y, a n d t he was h o ut peri o d of 1 0 da ys bet wee n 
eac h L O X O - 2 9 2 a n d m o xifl o x aci n d osi n g is c o nsi dere d s uffi cie nt t o pre ve nt carr y o v er 
effects . 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
2 8
C CI

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 2 6 
9. 2. 2  R ati o n ale f or t he D ose Selecti o n  
L O X O - 2 9 2: A si n gle d ose of  
 m g L O X O -2 9 2 was select e d beca use it is a d ose t hat is 
e x pecte d t o pr o vi de a C ma x of a p pr o xi matel y 3 3 0 0 n g/ m L si milar t o t hat of t he 
rec o m me n de d P has e 2 d ose ( R P 2 D) a n d p ote ntial mar kete d d ose of 1 6 0 m g BI D at stea d y 
state i n ca ncer patie nts.  
A si n gle d ose of  
 m g L O X O -2 9 2 w as select e d as t he s u prat hera pe utic d ose t o pr o vi de a 
C ma x  a p pro xi matel y 2 -f ol d greater t h a n t hat of t h e R P 2 D. T he pr o p ose d s u prat hera pe utic 
d ose ta kes i nt o acc o u nt t he a p pr o xi mate 2- f ol d i ncreas e i n pre dict e d L O X O - 2 9 2 stea d y state 
C ma x  d uri n g c o nc o mita nt a d mi nistrati o n  wit h a str o n g C Y P 3 A 4 i n hi bit or, s uc h as 
itrac o naz ole ( bas e d o n St u d y L O X O -R E T - 1 8 0 1 4). As C Y P 3 A 4 is t he mai n cleara nce 
pat h wa y of L O X O- 2 9 2, t he ma g nit u de of t he i ncrease i n L O X O- 2 9 2 e x p os ure wit h 
itrac o naz ole was c o nsi dere d t he ma xi m u m li kel y i ncreas e i n L O X O- 2 9 2 e x p os ure. 
Si n gle d oses of  
 m g,  
m g, a n d 7 2 0 m g ha v e bee n a d mi nistere d t o healt h y v ol u nteers i n 
t he o n g oi n g St u d y L O X O -R E T - 1 8 0 5 7. I nteri m safet y a n d t olera bilit y a n al ysis s h o we d t hat 
all d ose le vels wer e well -t olerate d a n d t here w ere n o Gra de ≥ 3 t o xicities u p t o t he ma xi m u m 
d ose le vel teste d ( 7 2 0 m g ). I nteri m P K  assess me nt s h o we d t hat C ma x a p peare d t o i ncrease i n 
a less-t ha n- pr o p orti o nal ma n ner bet w ee n 3 2 0 m g a n d  
 m g. T h e mea n C ma x o btai ne d 
f oll o wi n g t he 3 2 0 m g d ose was si milar t o t hat of t he stea d y state C ma x at t he R P 2 D i n 
patie nts, c o nfir mi n g t his d ose as s uita ble t o assess t he t hera pe utic e x p os ure i n t he c urre nt 
st u d y. T he d os e of  
 m g r es ulte d i n a n a v era ge C ma x of sli g htl y less t ha n 2-f ol d hi g h er 
t ha n 3 2 0 m g, h o w e ver, 2 of 6 s u bjects gi ve n  
 m g ha d a C ma x a p pr o xi matel y t wice t he 
C ma x of t he R P 2 D c o nfir mi n g t he s uita bilit y of  
 m g as t he s u prat hera p e utic d ose i n t he 
c urre nt st u d y. T he a ver a ge C ma x f oll o wi n g t he d ose of 7 2 0 m g was o nl y m ar gi nall y hi g h er 
t ha n t hat of t he  
 m g d ose a n d, s o as n ot t o e x p ose s u bjects t o a d diti o nal a m o u nts of st u d y 
dr u g t hat are n ot li kel y t o res ult i n si g nifica ntl y hi g her C ma x val ues,  
m g will be t he d ose 
use d t o o btai n s u prat her a pe utic e x p os ure.   
M o xifl o x aci n:  A si n gle  
m g d ose is a sta n d ar d p ositi ve c o ntr ol t o be use d i n T Q T st u dies. 
T his pr o d uct has bee n s h o w n t o pr o d uce a pea k Q Tc pr ol o n gati o n ra n gi n g fr o m 1 0 - 1 5 msec 
i n cr oss o ver desi g n st u di es, wit h a mea n Q T c pr ol o n gati o n of a p pr o xi matel y 5 msec w hic h is 
t he t hres h ol d of re g ul at or y c o n cer n. He nce, m o xifl o x aci n-i n d uce d c ha n ges i n ve ntric ular 
re p olarizati o n, w he n c o m pare d t o t he place b o treat me nt i n healt h y s u bjects, will be use d t o 
e val uate assa y se nsiti vit y  (A vel o x ®  2 0 1 6; Stass 1 9 9 8 ; Ta u bel 2 0 1 4 ). T he test f or assa y 
se nsiti vit y is t o e x clu de a l o wer b o u n d of t he 9 0 % c o nfi de nce i nter val ( CI) of 5 msec. T he 
d osi n g re gi me n f or m o xifl o x aci n i n t his st u d y is wit hi n t he F D A -a p pr o ve d d osi n g re gi me n. 
9. 3  
Ris ks a n d/ or Be nefits t o S u bjects  
L O X O - 2 9 2: T he t hera p e utic (
 m g ) a n d s u prat hera pe utic (
 m g ) d oses of L O X O - 2 9 2 
a d mi nistere d i n t his st u d y are n ot a ntici pat e d t o i n d uce a n y p ote ntial ris k or be nefit t o 
s u bjects partici pati n g i n t his st u d y. As of J ul y 1 9, 2 0 1 8 data c ut-off date, s afet y d ata w ere 
a vaila ble fr o m 1 5 3 ca n cer patie nts wit h d oses u p t o 2 4 0 m g BI D ( 4 8 0 m g/ d a y). As of t his 
date, 2 D L Ts of gra de 3 t u m or l ysis s y n dr o me a n d gra de 3 t hr o m b oc yt o p e nia at t he 2 4 0 m g 
BI D d os e le vel ha v e bee n re p orte d. T h e s u prat hera p e utic (  
m g) d ose of L O X O- 2 9 2 w as  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
2 9
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

CONFIDENTIAL 
CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 27 
administered to healthy adult subjects in a placebo-controlled single ascending dose study 
(Study LOXO-RET-18057) that was conducted prior to the current study. There were no 
Grade ≥3 toxicities observed, and there were no AEs that would preclude administering 
single oral doses up to 720 mg in this study.   
Moxifloxacin: The moxifloxacin dosing regimen for this study is within the FDA-approved 
dosing regimen. It has been marketed in the US since 1999 as Avelox® and the risk of 
moxifloxacin-induced Torsade de Pointes is expected to be minimal when the drug is 
administered at the recommended dose (Avelox® 2016). 
The safety monitoring practices employed by this protocol (i.e., 12-lead ECG, vital signs, 
clinical laboratory tests, AE questioning, and physical examination) are adequate to protect 
the subjects’ safety. 
There will be no direct health benefit for study participants from receipt of study drug. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at Screening and during the study.
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
30

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 2 8 
1 0  O B J E C TI V E S A N D E N D P O I NT S 
1 0. 1  O bjecti ve s 
Pri m ar y:  
T o e val uate t he eff ects of t hera pe utic a n d s u prat hera pe utic e x p os ure of L O X O- 2 9 2 o n t he Q T c 
i nter val b y assessi n g C- Q T relati o ns hi p usi n g e x p os ure-res p o nse m o delli n g. 
Sec o n d ar y:  
T o assess t he effect of t hera pe utic a n d s u prat h era pe uti c e x p os ure of L O X O - 2 9 2 o n ot her E C G 
para meters . 
T o de m o nstrate se nsiti vit y of t his Q T c assa y usi n g m o xifl o x aci n as a p ositi ve c o ntr ol i n 
healt h y a d ult s u bjects . 
T o e val uate t he P K  of t hera pe utic a n d s u prat h era pe utic d oses of L O X O - 2 9 2 i n healt h y a d ult 
s u bjects. 
T o e val uate t he s afet y a n d t olera bilit y of t hera pe utic a n d s u prat hera pe utic d oses of L O X O - 2 9 2 
d ose i n healt h y a d ult s u bjects. 
 
 
1 0. 2  E n d p oi nt s 
C ar di o d y n a mics: 
T he pri mar y e n d p oi nt is: 
•  T he eff ect of L O X O - 2 9 2 plas ma c o nce ntrati o ns o n t he Q Tc i nter v al usi n g li near 
mi x e d -effect e x p os ure -r es p o nse m o deli n g, i ncl u di n g t he pre dicte d ∆∆Q Tc at C ma x 
val ues c orr es p o n di n g t o e x p os ure le vels of i nterest. 
T he sec o n d ar y e n d p oi nts are: 
•  T he c ha n ge i n  ot her E C G para meters s uc h as s u c h as Q T, P R, a n d R R i nter vals, Q R S 
d urati o n, a n d H R. 
•  M or p h ol o gical c ha n ges of E C G wa vef or m (e . g., T wa ve m or p h ol o g y a n d pre se nce of 
pat h ol o gic U wa ve).  
•  Deter mi nati o n  of ass a y se nsiti vit y usi n g e x p os ure-res p o nse m o deli n g of t h e ∆∆Q Tc 
f oll o wi n g m o xifl o x aci n a d mi nistrati o n.  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 1
C CI

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 2 9 
 
 
  
P h ar m a c o ki netics:  
T he f oll o wi n g P K p ara m eters will be calc ulate d f or L O X O - 2 9 2 i n plas ma, as a p pr o priat e: 
A U C 0 -t, A U C 0 -i nf, A U C %e xtra p , C ma x, T ma x, Kel , a n d t ½. 
S af et y: 
Safet y e n d p oi nts will i ncl u de 1 2- lea d E C Gs, p h ysical e x a mi nati o ns, vital si g ns, cli nical 
la b orat or y tests, a n d A Es . 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 2
C CI

CONFIDENTIAL 
CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 30 
11 STUDY DESIGN 
11.1 Overall Study Design and Plan 
This is a single-dose, randomized, double-blind (except for the use of moxifloxacin), 
placebo- and positive-controlled, 4-way crossover study. 
Thirty-two (32), healthy, adult male and female (women of non-childbearing potential only) 
subjects will be enrolled. 
Screening of subjects will occur within 28 days prior to the first dosing. 
On Day 1, subjects will be randomized to 1 of 4 treatment sequences.  
On Day 1 of each period, subject will receive one of two single oral dose levels of LOXO-292, 
a single oral dose of moxifloxacin, or a single oral dose of LOXO-292 matching placebo on 
one occasion, according to a randomization scheme. Cardiodynamic samples will be collected 
predose and for up to 24 hours postdose as outlined in the Study Events Flow Chart 
(Section 7). PK samples will be collected predose and for up to 24 hours postdose for 
moxifloxacin and up to 240 hours postdose for LOXO-292, as per treatment received and as 
outlined in the Study Events Flow Chart (Section 7).  
There will be a washout period of 10 days between dosing in each period. 
Safety and tolerability will be assessed through End of Treatment (EOT) or Early Termination 
(ET) by monitoring AEs, performing physical examinations and clinical laboratory tests, 
measuring vital signs, and recording ECGs.  
Timing of all study procedures are indicated in the Study Events Flow Chart (Section 7). 
11.1.1 Confinement, Return Visits, and Follow-Up 
Subjects will be housed throughout the study beginning in Period 1, Day -1, at the time 
indicated by the CRU, until after completion of study procedures in Period 4, on Day 11 (EOT) 
or ET study procedures. EOT is defined as the day on which the subject is released from the 
CRU, following all study procedures (see Study Events Flow Chart, Section 7). Vital signs, 
ECG, clinical safety laboratory results, and adverse events are to be available for review by the 
Principal Investigator (PI) or designee prior to release from the clinic on Day 11 of Period 4. 
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
PI or designee.  
The CRU will contact all subjects who received at least one dose of study drug (including 
subjects who terminate from the study early) at the EOS (as defined in the Study Events 
Flowchart, Section 7) by a follow-up phone call (FU). The EOS/FU phone call will be 
performed 7 days (± 2 days) after the EOT or ET (as defined in the Study Events Flowchart, 
Section 7) to determine if any SAE or study drug related AE has occurred since EOT or ET. 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
33

CONFIDENTIAL 
CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 31 
11.1.2 End of Study Definition 
End of Study (EOS) is defined as the day on which the subject completes the follow up phone 
call (Study Events Flow Chart, Section 7). 
Study completion applies to the clinical conduct of the study overall (i.e., last subject’s 
Follow-up phone call). 
 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
34

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 2 
1 2  S T U D Y P O P U L A TI O N  
T he I n vesti gat or ( or desi g nee), Celeri o n Me dical M o nit or, a n d 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. T he S p o ns or 
will pr o vi de a p pr o val of s u bjects f or e nr oll me nt pri or t o d osi n g. 
1 2. 1  I ncl usi o n Criteri a 
S u bjects m ust f ulfill all of t he f oll o wi n g i n cl usi o n criteria t o be eli gi ble f or partici pati o n i n t he 
st u d y: 
1.  Healt h y, a d ult, male or fe male  ( of n o n-c hil d beari n g p ote ntial o nl y), 1 8- 5 5 years of a ge, 
i ncl usi ve, at S cree ni n g. 
2.  C o nti n u o us n o n-s m o ker w h o has n ot use d t o bacc o- a n d/ or nic oti ne-c o ntai ni n g pr o d u cts f or 
at least 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 a n d h a d n o hea v y s m o ki n g 
hist or y (i.e., h ea v y s m o ki n g det er mi ne d as 2 0 or m ore ci garettes per da y, or 2 0 or m or e 
pac k -years) . 
3.  B o d y m ass i n de x ( B MI) ≥ 1 8. 0 a n d ≤ 3 2. 0 k g/ m 2 at S cree ni n g a n d h a ve a mi ni m u m wei g ht 
of at least 5 0  k g at S cr ee ni n g.  
4.  Me dicall y h ealt h y wit h n o cli nicall y si g nifica nt  m e dical hist or y, p h ysi cal e x a mi nati o n, 
la b orat or y pr ofiles, vital si g ns or E C G  a b n or malities , as dee me d b y t h e PI or desi g n ee , a n d 
as c o nfir me d b y t he S p o ns or. Li ver f u n cti o n tests (ala ni ne a mi n otra nsferas e [ A L T], 
as partate a mi n otra nsferas e [ A S T]), ser u m (t otal a n d direct) bilir u bi n, a n d a m ylase a n d 
li pase, m ust be wit hi n t he u pper li mit of n or mal f or t he la b orat or y us e d b y t he cli nical site 
at Scree ni n g a n d C h ec k -i n ( Da y - 1). Rec hec ks of t he li ver f u ncti o n tests ( A L T a n d A S T), 
ser u m (t otal a n d direct) bilir u bi n, a n d a m ylas e a n d li pase will be per mitte d u p t o t w o ti mes 
t o c o nfir m s u bject eli gi bilit y. S u bjects ma y b e eli gi ble f or partici pati o n i n t he st u d y b ase d 
o n rec hec ke d v al ues if t h e PI ( or desi g nee), wit h a gree me nt fr o m t he S p o ns or, feels 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 u ct. 
5.  A female of n o n -c hil d beari n g p ot e ntial: m ust ha ve u n der g o ne o ne of t he f oll o wi n g 
sterilizati o n pr oce d ures at least 6 m o nt hs pri or t o t he Scree ni n g : 
•  h yster os c o pic sterilizati o n;  
•  bilateral t u bal li gati o n or bilateral sal pi n gect o m y;  
•  h yster ect o m y;  
•  bilateral o o p h or ect o m y;  
or 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 t he first d osi n g a n d 
f ollicle-sti m ulati n g h or m o ne ( F S H) s er u m le vels c o nsiste nt wit h p ost me n o pa usal stat us. 
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 val ue wit hi n 
t he C R U’s la b orat or y’s e x pecte d ra n ge f or p ost- me n o pa usal stat us. All fe m ales m ust ha ve a 
ne gati ve q ualitati ve ser u m pre g n a nc y test (s er u m h u ma n c h ori o nic g o na d otr o pi n) at 
Scree ni n g a n d C hec k -i n ( Da y - 1).  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 5

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 3 
6.  Males w h o ar e ca p a ble of fat heri n g a c hil d m ust a gree t o use o n e of t he f oll o wi n g 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 l ast 
d ose: 
Male sterilizati o n, wit h d oc u me nte d c o n fir 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 o c u me ntati o n is n ot 
a vaila ble, male s u bjects m ust f oll o w o ne of t he c o ntrace pti o n met h o ds bel o w: 
•  Male c o n d o m wit h s per mici de, a n d  
•  F or a fe male p art ner of male st u d y partici pa nt:  
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, tra ns der mal, or h or m o nal met h o d of 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n; or 
3.  b ilateral t u bal li gati o n. 
Males w h o practice tr u e a bsti ne nce beca us e of a lifest yl e c h oice (i .e., 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 p artici pati o n ) are e x e m pt fr o m c o ntrace pti ve 
re q uire me nts. Peri o dic a bsti ne nce b y a fe male p art ner  (e. g., cale n d ar, 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 mal e 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 d uri n g t h e st u d y, h e m ust a gree t o use c o ntrace pti o n as des cri be d a b o ve.  
M ale s u bjects  s h o ul d e ns ure t hat c o n d o ms wit h s per mici de are use d fr o m t he ti me of t he 
st u d y dr u g a d mi nistrati o n u ntil 6 m o nt hs after t he last d ose w he n ha vi n g i nterc o urse wit h 
fe male part ners w h o are pre g na nt or breastfee di n g. 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 ( D a y - 1) u ntil  6 m o nt hs after t he last d ose of st u d y 
dr u g. 
F or s u bjects w h o are e x cl usi vel y i n sa me -s e x relati o ns hi ps, c o ntrace pti ve re q uire me nts d o 
n ot a p pl y.  
7.  A ble t o s wall o w m ulti ple ca ps ules.  
8.  U n dersta n ds t he st u d y pr oce d ures i n t he i nf or me d c o nse nt f or m (I C F), a n d be willi n g a n d 
a ble t o c o m pl y wit h t he pr ot oc ol. 
1 2. 2  E xcl usi o n Criteri a  
S u bjects m ust n ot be e nr olle d i n t he st u d y if t he y meet a n y of t he f oll o wi n g criteria:  
1.  Is me nt all y or l e gall y i nca pacitate d or has si g nifica nt e m oti o nal pr o ble ms at t he ti me of t he 
S cree ni n g visit or e x pecte d d uri n g t he c o n d uct of t he st u d y. 
2.  Hist or y or prese n ce of cli nicall y si g nifica nt me dical or ps yc hiatric c o n diti o n or disease i n 
t he o pi ni o n of t he PI or d esi g nee, a n d as c o nfir m e d b y t he S p o ns or. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 6

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 4 
3.  Hist or y of a n y i ll ness t hat, i n t he o pi ni o n of t he PI or desi g n ee, a n d as c o nfir me d b y t h e 
S p o ns or, mi g ht c o nf o u n d t he res ults of t he st u d y or p oses a n a d diti o nal ris k t o t he s u bject 
b y t heir p artici pati o n i n t he st u d y.  
4.  H ist or y of gastritis, gastr oi ntesti nal tract, or he pati c dis or der or ot h er cli nical c o n diti o n t hat 
mi g ht, i n t he o pi ni o n of t he PI or desi g nee, a n d as c o nfir me d b y t he S p o ns or, affect t he 
a bs or pti o n, distri b uti o n, bi otra nsf or mati o n, or e x creti o n of L O X O- 2 9 2, m o xifl o x aci n , or 
L O X O - 2 9 2 matc hi n g place b o .  
5.  Hist or y or prese n ce of al c o h olis m or dr u g a b use wit hi n t he past 2 years pri or t o Scree ni n g 
or C hec k -I n ( Da y - 1).  
6.  Hist or y or prese n ce of h y perse nsiti vit y or i di os y ncratic reacti o n t o t he st u d y dr u gs or 
relate d c o m p o u n ds, or i n acti ve i n gre die nts. 
7.  Hist or y or prese n ce  of: 
•  aller g y t o ba n d ai ds, a d h esi ve dressi n g or me dical ta pe 
•  li ver disease 
•  dia betes  
•  pa ncreatitis  
•  pe ptic ulcer disease  
•  i ntesti nal mala bs or pti o n 
•  gastri c re d u cti o n s ur ger y  
•  seiz ure(s)  
•  hist or y or pr ese n ce of cli nicall y si g nifica nt car di o vasc ular disease:  
o  car diac s ur ger y re v asc ularizati o n (c or o nar y arter y b y pass grafti n g or p erc ut a ne o us 
tra nsl u mi nal c or o nar y a n gi o plast y) 
o  u nsta ble a n gi na, m y ocar dial i nfarcti o n, cere br o vasc ular acci de nt or str o k e or 
tra nsie nt isc he mic attack, pace ma k er  
o  atrial fi brillati o n, fl utter, or n o n-s ustai ne d or s ustai ne d ve ntric ular tac h ycar dia  , or 
ve ntric ular fi brillati o n  
o  c o n gesti ve heart fail ure or car di o m y o pat h y 
o  pers o nal or f a mil y hist or y of s u d d e n deat h or l o n g Q T s y n dr o me: u ne x plai ne d 
s y nc o p e or s y nc o p e wit hi n t he last 3 years re gar dl ess of eti ol o g y; or hist or y of 
T orsa des de P oi ntes 
o  ve ntric ular pr e- e x citati o n s y n dr o me ( W olff - Par ki ns o n W hite s y n dr o me) 
o  si g nifica nt S cr ee ni n g E C G a b n or malities:  
 left b u n dle- bra n c h bl oc k or ri g ht b u n dle bra nc h bl oc k or i ntra ve ntri c ular 
c o n d ucti o n dela y wit h Q R S > 1 1 0 msec 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 7

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 5 
 sec o n d de gr ee atrio ve ntri c ular ( A V) bl oc k, t y pe 2, or t hir d de gree A V bl oc k 
 Q Tc F i nter val is > 4 4 0 msec  
 Q R S i nter val > 1 1 0 msec ; res ult will be c o nfir me d b y ma n u al o ver rea d 
 P R i nter val > 2 2 0 msec 
 electr o gr a p hicall y si g nifica nt a b n or malities t hat mi g ht i nterfere wit h E C G 
a nal ysis i ncl u di n g e vi d e n ce of a pre vi o us m y ocar dial i nfarcti o n , left 
ve ntric ular h y p ertr o p h y, flat T wa ves ( partic ularl y i n t he i nferi or lea ds) or 
m ore t ha n mi n or n o n- s pecific S T-T wa v e c h a n ges . 
8.  Fe male s u bjects of c hil d beari n g p ote ntial.   
9.  Fe male s u bjects wit h a p ositi ve pre g n a nc y test or w h o are lactati n g. 
1 0.  P ositi ve uri ne dr u g or alc o h ol res ults at S cree ni n g or C hec k -i n. 
1 1.  P ositi ve res ults at S cree ni n g f or h u m a n i m m u n o deficie nc y vir us (HI V), h e p atitis B s urface 
a nti ge n ( H Bs A g) or h e patitis C vir us ( H C V)  a nti b o d y. S u bjects w h o are p ositi ve f or 
he patitis B vir us , H C V, or HI V b y a nti b o d y will re q uire c o nfir mati o n b y p ol y merase c h ai n 
reacti o n ( P C R) bef ore e nr oll me nt t o detect prese n ce of acti ve vir us. S u bjects w h o are P C R 
p ositi ve will n ot be eli gi ble . 
1 2.  S u bjects wit h at -rest (i.e., s u pi ne f or at least 5 mi n utes) diast olic bl o o d press ure of < 5 0 or 
> 8 9 m m H g a n d/ or s u pi ne s yst olic B P of < 8 9 or > 1 3 9 m m H g at Scree ni n g, C hec k- i n ( Da y -
1), a n d pri or t o d osi n g o n Da y 1 of Peri o d 1. Rec h ec ks of bl o o d press ure val ues will be 
per mitte d u p t o t w o 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 b e 
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 v al ues if t he PI ( or desi g n ee), 
wit h a gr ee me nt fr o m t he S p o ns or, feels t hat t he res ults are n ot cli nicall y si g nifica nt, a n d 
will n ot i m pact st u d y c o n d uct.  
1 3.  S u pi ne heart rat e is l o wer t ha n 5 0 b p m or hi g her t h a n 9 5 b p m at Scree ni n g, C hec k -i n 
( Da y - 1), a n d pri or t o d osi n g o n Da y 1 of Peri o d 1. Rec hec ks of heart rate v al ues will be 
per mitte d u p t o t w o 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 b e 
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 v al ues if t he PI ( or desi g n ee), 
wit h a gr ee me nt fr o m t he S p o ns or, fe els t hat t he res ults are n ot cli nicall y si g nifica nt, a n d 
will n ot i m pact st u d y c o n d uct.  
1 4.  Esti mate d creati ni ne cleara nce < 9 0 m L/ mi n at S cree ni n g or C hec k -i n ( Da y -1; rec h ec ks 
will be per mitte d u p t o t w o ti mes t o c o nfir m s u bject eli gi bilit y f or st u d y p artici pati o n) . 
1 5.  Has ser u m p otassi u m le v els < 3. 8 m E q/ L at S cree nin g or C hec k -i n (D a y  - 1; rec hec ks will 
be per mitte d u p t o t w o ti mes t o c o nfir m s u bject eli gi bilit y  f or st u d y partici pati o n). 
1 6.  Has ser u m calci u m  le vels < 8. 5 m g/ dL at S cree ni n g or C hec k-i n ( D a y  -1; rec hec ks will be 
per mitte d u p t o t w o ti mes t o c o nfir m s u bject eli gi bilit y  f or st u d y p artici pati o n). 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 8

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 6 
1 7.  Has ser u m ma g n esi u m le vels <2. 0 m E q/ L at Scree ni n g or C hec k -i n (D a y  -1; rec hec ks will 
be per mitte d u p t o t w o ti mes t o c o nfir m s u bject eli gi bilit y  f or st u d y partici pati o n).  
1 8.  Has he m o gl o bi n le vels < 1 2. 0 g/ d L at S cree ni n g or C hec k -i n (Da y  - 1; rec hec ks will be 
per mitte d u p t o t w o ti mes t o c o nfir m s u bject eli gi bilit y  f or st u d y p artici pati o n). 
1 9.  U na ble t o refrai n fr o m or a ntici pates t he use of a n y dr u g, i n cl u di n g prescri pti o n a n d 
n o n- prescri pti o n me dicati o ns, her bal re me di es, or vita mi n s u p ple me nts f or 1 4 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, u nless all o we d b y t he PI ( or d esi g nee), wit h 
a gree m e nt fr o m t he S p o ns or. After first d osi n g, aceta mi n o p he n ( u p t o 2 g p er 2 4  h o urs) 
ma y b e a d mi nistere d at t he discreti o n of t he PI or desi g nee. 
2 0.  U na ble t o refrai n fr o m or a ntici pates t he use of a n y dr u gs k n o w n t o b e a n i n hi bit or or 
i n d ucer of C Y P 3 A 4/ 5, or P- g p (i ncl u di n g St. J o h n’s W ort) f or 2 8 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. A p pr o pri ate s o urces (e. g., Fl oc k hart Ta ble T M ) will be 
c o ns ulte d t o c o nfir m lac k of P K i nteracti o n wit h st u d y dr u g. 
2 1.  U na ble t o refrai n fr o m or a ntici pates t he use of a n y pr ot o n p u m p i n hi bit ors , a ntaci ds, or 
H 2 -rece pt or a nt a g o nists fr o m 1 4 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. 
2 2.  U na ble t o refrai n fr o m or a ntici pates t he use of a n y  dr u g t h at pr ol o n gs t he Q T/ Q Tc i nter val 
f or 1 4 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. 
2 3.  S u bject is u n willi n g t o a bsta i n fr o m i n gesti o n of caffei ne or x a nt hi ne-c o ntai ni n g pr o d u cts 
(e. g. tea, c off ee, c h o c olat e, c ola, et c.) be gi n ni n g 9 6 h o urs ( 5 da ys) pri or first d osi n g a n d 
t hr o u g h E O T or E T. 
2 4.  S u bject is u n willi n g t o a bstai n fr o m alc o h ol be gi n ni n g 4 8 h o urs pri or t o first d osi n g a n d 
t hr o u g h E O T or E T. 
2 5.  E n ga ge me nt i n stre n u o us p h ysical e x ercise wit hi n 2 wee ks pri or t o d osi n g (e. g. m arat h o n 
r u n ners, l o n g dista nce c yclists, wei g ht lifters). 
2 6.  S u bject has a hist or y of hi g h alc o h ol c o ns u m pti o n wit hi n 6 m o nt hs pri or t o Scree ni n g, 
defi n e d as a n a vera ge wee kl y i nta k e of > 1 4 u nits f or males or > 1 0 u nits f or fe males. O n e 
u nit is e q ui vale nt t o 8 g of alc o h ol: a half- pi nt ( ~ 2 4 0 m L) of beer, 1 glass ( 1 2 5 m L) of 
wi ne, or 1 meas ure ( 2 5 m L) of s pirits. 
2 7.  S u bject has a hea v y s m o ki n g hist or y (i.e., hea v y s m o ki n g deter mi ne d as 2 0 or m ore 
ci garettes p er da y, or 2 0 or m ore pac k- years)  or h as use d t o bacc o -c o ntai ni n g pr o d u cts (e. g., 
ci garettes, ci gars, c h e wi n g t o bacc o, s n uff, etc.) wit hi n 3 m o nt hs pri or t o Scree ni n g or has a 
p ositi ve c oti ni ne at Scree ni n g or C hec k-i n ( D a y -1)  a n d is u n willi n g t o a bst ai n fr o m 
t o bacc o c o nt ai ni n g pr o d u cts u ntil E O T or E T . 
2 8.  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 PI or d esi g n ee, 
a n d as c o nfir m e 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 . 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
3 9

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 7 
2 9.  D o nati o n of bl o o d or si g nifi ca nt bl o o d l oss wit hi n 5 6 da ys pri or t o t he first d osi n g. 
3 0.  Plas ma d o nati o n wit hi n 7 da ys pri or t o t he first d osi n g. 
3 1.  Partici pati o n i n pre vi o us i n vesti gati o nal trial wit h L O X O - 2 9 2. 
3 2.  D osi n g i n a n y ot her i n vesti gati o nal st u d y dr u g tri al 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 h e past 3 0 da ys or 5 h alf -li ves (if k n o w n), w hi c he ver is l o n ger, 
pri or t o t he first d osi n g. 
3 3.  S u bject is u n willi n g t o refrai n fr o m stre n u o us e x ercise fr o m 7 d a ys pri or t o C hec k -i n a n d 
t hr o u g h E O T or E T . 
3 4.  S u bject is c o nsi deri n g or sc he d ule d t o u n der g o a n y s ur gical pr oce d ure d uri n g t he st u d y. 
1 2. 3  E arl y Ter mi n ati o n of S u bjects fr o m t he St u d y  
S u bjects are free t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n.  
I n ad diti o n, s u bjects ma y be wit h dra w n fr o m t he st u d y ( h o w e ver all pla n ne d assess me nts o n 
t he st u d y da y will still be c o m plete d, if feasi ble) b y t he PI or d esi g nee  f or t he f oll o wi n g 
reas o ns: 
•  A Es.  
•  Diffic ulties i n bl o o d c ollecti o n.  
•  P ositi ve pre g na n c y test.  
•  P ositi ve uri ne dr u g a n d alc o h ol test. 
•  Q Tc F i nter val >  5 0 0 msec, a n d  o n rec hec k wit hi n 3 0 mi n utes  a n d c o nfir me d b y t he 
c ore E C G la b or at or y, o n a n y s c he d ule d safet y E C G or at a n y ti me a n u nsc he d ule d E C G 
f or saf et y was dee me d necessar y b y t he PI, or a n i ncreas e > 7 5 msec fr o m baseli ne.  
A s u bject ma y be wit h dr a w n b y t he PI, desi g nee, or t he S p o ns or if eit her c o nsi ders e nr oll me nt 
of t he s u bject i nt o t he st u d y is i na p pr o priate, t he st u d y pla n is vi olate d, or f or a d mi nistrati ve 
a n d/ or ot her safet y reas o ns. Pr o m pt n otificati o n t o t he S p o ns or of wit h dra w al of a n y s u bject 
s h o ul d be pr o vi de d. 
S u bjects w h o wit h dra w fr o m t he st u d y will u n der g o earl y ter mi nati o n fr o m t he st u d y 
pr oce d ur es as o utli ne d i n t he St u d y E ve nts Fl o w C hart ( Secti o n  7).  
1 2. 4  St u d y Restricti o ns  
1 2. 4. 1  Pr o hi biti o ns a n d C o nc o mit a nt Me dic ati o n  
C o ns u m pti o n of f o o ds a n d be vera ges c o ntai ni n g t he f oll o wi n g s u bsta n ces will be pr o hi bite d as 
i n dicate d: 
•  Xa nt hi nes/ Caffei n e: 9 6 h o urs ( 5 da ys) pri or t o  first d osi n g a n d t hr o u g h E O T or E T; 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
4 0

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 3 8 
•  Alc o h ol: 4 8 h o urs pri or t o first d osi n g a n d t hr o u g h E O T or E T; 
•  Gra pefr uit/ Se ville ora n ge  a n d t heir j uices : 1 4 da ys pri or t o  first d osi n g a n d t hr o u g h 
E O T or E T ; 
•  Ot her Fr uit J uice: 7 2  h o urs pri or t o first d osi n g a n d t hr o u g h E O T or E T; 
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 v esti gati o nal 
dr u g o cc urs wit hi n 5 half -li ves (if k n o w n) or 3 0 d a ys, w hic he ver is l o n ger, pri or t o first d ose 
a d mi nistrati o n ( Da y 1 , Peri o d 1) is pr o hi bite d. 
A n y prescri pti o n or o ver-t he-c o u nter m e dicati o ns (i ncl u di n g her b al pr o d ucts, nat ural or her bal 
s u p ple me nts) will be pr o hi bite d f or at least 1 4 da ys pri or t o t he first d osi n g t hr o u g h E O T or 
E T , u nless all o we d b y t h e PI ( or desi g nee), wit h a gree me nt fr o m t he S p o ns or, as descri be d 
bel o w.  
All prescri pti o n or n o n- prescri pti o n me dicati o ns t hat are i n hi bit ors or i n d u cers of C Y P 3 A 4/ 5, 
or P - g p (i ncl u di n g St. J o h n’s W ort) f or 2 8 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.  
A n y pr ot o n p u m p i n hi bit ors, a ntaci ds a n d H 2-rece pt or a nta g o nists fr o m 1 4 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. 
A n y dr u g t hat pr ol o n gs t he Q T/ Q Tc i nter v al f or 1 4  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.  
Fr o m Da y - 1 t hr o u g h E O T or E T, a n y c o n c urre nt me dicati o n i ncl u di n g b ot h prescri pti o n a n d 
n o n- prescri pti o n dr u gs m ust be disc usse d wit h t he PI ( or desi g nee), a n d/ or S p o ns or pri or t o 
use, u nless a p pr o pri ate me dical care n ecessitates t hat t hera p y s h o ul d be gi n bef ore t h e PI ( or 
desi g nee) a n d/ or S p o ns or ca n be c o ns ulte d. F oll o wi n g st u d y dr u g a d mi nistrati o n o n Da y 1, 
aceta mi n o p he n ( u p t o 2 g per 2 4 h o urs) ma y b e a d mi nistere d at t he discreti o n of t he PI ( or 
desi g nee ).  
If de viati o ns occ ur, t he PI or desi g nee i n c o ns ultati o n wit h t he S p o ns or if nee de d will deci de o n 
a case -b y -case b asis w het her t he s u bject ma y c o nti n ue partici pati o n i n t he st u d y. 
All me dicati o ns (i ncl u di n g vita mi ns a n d her bal s u p ple me nts) ta ke n b y s u bj ects d uri n g t he 
c o urse of t he st u d y will b e rec or de d. 
Use of a n y t o bacc o - a n d/ or nic oti ne-c o ntai ni n g pr o d ucts will be pr o hi bite d t hr o u g h E O T or 
E T . 
1 2. 4. 2  Me als  
Water (e x ce pt water pr o vi de d wit h eac h d osi n g ) will be restricte d 1  h o ur pri or t o a n d 1 h o ur 
after eac h st u d y dr u g  a d mi nistrati o n,  b ut will be all o we d a d li bit u m at all ot her ti mes.  Ot her 
fl ui ds ma y be gi v e n as part of meals a n d s nac ks b ut will be restricte d at all ot her ti mes 
t hr o u g h o ut t he c o nfi ne m e nt peri o d. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
4 1

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On Day 1 of each period, subjects will fast overnight for at least 10 hours prior to study drug 
administration and will continue to fast for at least 4 hours postdose. A snack will be provided 
at approximately 4.25 and a standard meal at approximately 9.25 hours postdose, and a snack 
at appropriate times thereafter, but never within 2 hours of an ECG acquisition time point. The 
above snacks/meals should be scheduled to be completed at least 120 minutes before any 
scheduled ECG time point (i.e., standard safety 12-lead ECG or cardiodynamic ECG). Subjects 
will be required to fast from all food and drink except water between meals and snacks. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all 
food and drink except water between meals and snacks. 
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each period. 
12.4.3 Activity 
Subjects must be awakened at least 1 hour prior to the start of the cardiodynamic ECGs on 
Day 1 and before the ECG recording scheduled at the 24-hour (Day 2) postdose time point. 
Following dosing, subject will remain seated or ambulatory and awake, except when a supine 
position is dictated by study procedures, through the 12-hour postdose cardiodynamic ECGs, 
as the QT-RR relationship is different during sleep. There will be no significant stimuli such as 
TV, loud radio, interactions with other subjects. Subjects must lie down for at least 10 minutes 
prior to ECG recordings to avoid any physical activity.  
Subjects will remain lying down or sitting for the first 7 hours postdose, except when they are 
seated, supine, or semi-reclined for study procedures. However, should AEs occur at any time, 
subjects may be placed in an appropriate position or will be permitted to lie down on their right 
side. 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from 7 days prior to Check-in 
(Day -1) through EOT or ET. No significant physical activity other than walking is permitted 
on study days. 
 
 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
42

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 4 0 
1 3  T R E A T M E N T S  
1 3. 1  Tre at me nts A d mi nistere d  
L O X O - 2 9 2 will be s u p plie d as 
 m g  
. 
L O X O - 2 9 2 matc hi n g place b o will be s u p plie d as  
. 
M o xifl o x aci n will be s u p plie d as 
m g A v el o x ®  ( m o xifl o x aci n h y dr oc hl ori de) or ge n eric 
e q ui vale nt ta blets. 
Treat me nts are des cri be d as f oll o ws:  
Treat me nt A:   
 m g L O X O - 2 9 2 ( 
 
 m g  
)  a n d L O X O - 2 9 2 matc hi n g place b o 
(
  m g matc hi n g place b o  
) a d mi nistere d at H o ur 0 o n Da y 1. 
Treat me nt B:   
 m g L O X O - 2 9 2 ( 
 
 m g  
) a d mi nistere d at H o ur  0 o n Da y 1. 
Treat me nt C:   
 m g m o xifl o x aci n ( 1 x  
 m g  
) a d mi nistere d at H o ur  0 o n Da y 1. 
Treat me nt D:  
L O X O - 2 9 2 matc hi n g place b o (
  m g matc hi n g place b o  
) 
a d mi nistere d at H o ur 0 o n Da y 1. 
Eac h treat me nt will be a d mi nistere d orall y f oll o wi n g a fast of at least 1 0  h o urs fr o m f o o d ( n ot 
i ncl u di n g wat er), wit h a p pr o xi matel y 2 4 0 m L of water.  S u bjects will re mai n 
 
( n ot i ncl u di n g wat er) f or at least 4 h o urs p ost d ose. 
S u bjects will be i nstr ucte d n ot t o cr us h, s plit, or c he w t he 
 or t he  
. 
T he p har mac y at t he C R U will pr o vi de eac h d os e i n i n di vi d ual u nit d ose c o ntai ners f or eac h 
s u bject a n d f or eac h st u d y peri o d.  
T he e x act cl oc k ti me of d osi n g will be rec or de d.  
1 3. 2  D ose M o dific ati o n 
T he d ose a n d a d mi nistrati o n of t he st u d y dr u gs t o a n y s u bject ma y n ot be m o difie d. If 
necessar y a s u bject m ust be disc o nti n ue d f or t he reas o ns descri be d i n Secti o n 1 2. 3 . 
1 3. 3  Met h o d of Tre at me nt A ssi g nme nt  
Eac h s u bject will be assi g ne d a u ni q ue i de ntificati o n n u m ber u p o n scree ni n g. S u bjects w h o 
c o m plete t he st u d y s cree ni n g assess me nts a n d meet all t he eli gi bilit y criteri a will be assi g n e d a 
u ni q ue ra n d o mizati o n i de ntificati o n n u m ber at t he ti me of t he first d osi n g, differe nt fr o m t he 
scree ni n g n u m ber, a n d will recei ve t he c orres p o n di n g pr o d u ct, acc or di n g t o a ra n d o mizati o n 
sc he me ge n erat e d at Celeri o n.  
S u bjects will recei ve eac h treat me nt o n o ne occasi o n. T he se q ue n ces t o be use d i n t he 
ra n d o mizati o n will be fr o m a selecte d Lati n s q u are: A B C D, B D A C, C A D B, a n d D C B A. 
S u bjects w h o d o n ot c o m plete t he st u d y treat me nts will n ot be re place d.  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
4 3
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

CONFIDENTIAL 
CA25494 (LOXO-RET-18032), Final, 03Apr2019 
 
Page 41 
13.4 Blinding 
This is a double-blind study with respect to LOXO-292 and placebo. Moxifloxacin treatment 
(positive control) will be administered in an open-label fashion because of a different dose 
format.  
13.4.1 
Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion statistician and shall be 
considered blinded.  
The randomization will be available only to the CRU pharmacy staff that is preparing the drug 
who will not be involved in any other aspect of the study including administration of the drug. 
The randomization will also be available to the bioanalytical laboratory as sample analyses will 
be treatment-dependent (i.e., different method and dilutions depending on the treatment and 
dose level). It will not be made available to the Sponsor, subjects, members of the staff 
responsible for the monitoring and evaluation of safety assessments, and the ECG reader. 
13.4.2 
Procedures for Breaking the Blind Prior to Study Completion 
One set of sealed envelopes containing the randomization code will be supplied to the PI or 
designee at the start of the study. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency where 
the identity of the drug must be known in order to properly treat the subject or in the event of 
an interim analysis.  
In the event of a medical emergency, it is requested that the PI or designee make every effort to 
contact the Study Monitor or designee prior to breaking the blind. If breaking the blind is 
required because of a medical emergency, the treatment identity would be revealed by the PI or 
designee, for that subject only. In the event that the emergency is one, in which it appears that 
the other subjects may be at imminent risk, the blind may be broken for all subjects dosed at 
that dose level. The unblinding will be properly documented in the study file. 
In all cases where the code is broken, the PI or designee should record the date and reason for 
code breaking. 
At the end of the study, envelopes will be retained or destroyed according to site procedures 
unless specified otherwise by the Sponsor. 
13.4.3 
Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered in the database, edits checks are performed, queries closed, 
and the database is officially locked.  
Preliminary data and any data received from the bioanalytical laboratory prior to the clinical 
database lock will be blinded (using dummy IDs). 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
44

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Page 42 
13.5 Treatment Compliance  
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the subjects 
have swallowed the study drug. Once a subject has finished the dosing water, the qualified 
designee will use a flashlight and a tongue depressor to check the subject’s mouth. Subjects’ 
hands will also be verified to ensure that the study drug was ingested. 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
45

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 4 3 
1 4  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 
T he St u d y E ve nts Fl o w C hart ( Secti o n  7) s u m marizes t he cli nical pr oce d ures t o be perf or me d 
at eac h visit. I n di vi d ual  cli nical pr oce d ures are des cri be d i n detail bel o w. A d diti o nal 
e val uati o ns/testi n g ma y b e dee me d n ecessar y b y t h e PI or desi g nee a n d/ or t he S p o ns or f or 
reas o ns r elate d t o s u bject safet y. 
F or t his st u d y, t he car di o d y na mic s a m pli n g via E C G e xtracti o ns fr o m t he H olter m o nit or a n d 
t he P K bl o o d sa m ples are t he critical para meters. Car di o d y n a mic rec or di n g via E C G 
e xtracti o n s will be c o m plete d pri or t o t he P K bl o o d sa m ples c ollecte d as cl ose t o t he e x act ti me 
p oi nt as p ossi ble. T he P K sa m pli n g ti me p oi nts will be rec or d e d. All ot her pr oce d ures s h o ul d 
be c o m plete d as cl ose t o t he  prescri b e d/sc he d ule d ti me as p ossi ble, b ut ca n be perf or me d pri or 
t o or after t he prescri be d/sc he d ule d ti me  a n d i n acc or da nce t o t he ti me wi n d o ws pr o vi de d i n 
t he St u d y E ve nts Fl o w c h art (Secti o n  7). 
S t u d y pr oce d ures, e x cl u di n g scree ni n g pr oce d ures, will be perf or me d i n t he f oll o wi n g or der 
( bel o w) wit h r e gar d t o t h e prescri be d ti me.  
a. Safet y E C Gs ; 
b.  Car di o d y n a mic  E C G rec or di n g e xtracti o n peri o d; 
c. Bl o o d sa m ple c ollecti o n; 
d.  He mat ol o g y , c oa g ulati o n, a n d ser u m c h e mis tr y sa m ple c ollecti o n as re q uire d; 
e. Sta n dar dize d meals ( meal m ust be c o ns u me d after or at least 1 2 0 mi n utes pri or t o a n y 
H olter rec or di n g e xtracti o ns or safet y E C G traci n gs).  
Vital si g ns ca n b e perf or me d eit her bef ore s afet y 1 2 -lea d E C Gs or after bl o o d sa mple 
c ollecti o n(s).  
A n y n o nsc h e d ule d pr o ce d ures re q uire d f or ur ge nt e val uati o n of safet y c o ncer ns ta ke 
prece d e nce o ver all r o uti ne sc he d ule d pr oce d ures.  
1 4. 1  Scree ni n g  
Wit hi n 2 8 da ys pri or t o t he first d osi n g o n D a y 1 of Peri o d 1, me dical hist or y a n d de m o gra p hic 
data, i ncl u di n g n a me, se x, a ge, race, et h nicit y, b o d y w ei g ht ( k g), hei g ht (c m), B MI ( k g/ m2), 
a n d hist or y of t o bacc o us e will be rec or de d. E ac h s u bject will ha ve a p h ysi cal e x a mi nati o n, 
vital si g n meas ur e me nts ( heart r ate, bl o o d press ure, te m perat ure, a n d res pirat or y rate), 1 2- lea d 
E C G, a n d t he la b orat or y tests of ser u m c he mistr y, ser ol o g y, t h yr oi d sti m ulati n g h or m o ne, 
pre g na nc y (fe m ales), F S H ( p ost me n o pa usal fe males), he mat ol o g y, a m ylas e, li pase, he patic a n d 
re nal f u n cti o n a n d a d diti o nal tests as n ote d i n Secti o n  1 4. 2. 5. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
4 6

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14.2 Safety Assessments 
14.2.1 Physical Examination 
Full physical examination and abbreviated physical examination will be performed as outlined 
in the Study Events Flow Chart (Section 7). 
An abbreviated physical examination will include at the minimum, examination of respiratory, 
cardiovascular, and gastrointestinal systems, with the option for further examination of 
additional systems as necessary based on reported symptoms/AEs. 
Symptom-driven physical examinations may be performed at other times, if deemed necessary 
by the PI or designee.  
14.2.2 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, will 
be measured as outlined in the Study Events Flow Chart (Section 7) using calibrated digital BP 
equipment with the subject in the semi-supine position. Additional vital signs may be taken at 
any other times, if deemed necessary. 
Blood pressure, heart rate, and respiratory rate measurements will be performed with subjects 
in a semi-supine position, unless another position is required due to AEs (e.g. nausea, 
dizziness) or if deemed necessary by the PI or designee. 
Vital signs (HR, BP, and R) will be obtained at Screening, Check-in (Day -1), predose, and at 
0.75 hour (± 10 minutes), 2 hours (± 10 minutes) and 4 hours (± 10 minutes) postdose on 
Day 1, and on Day 2, Day 3, Day 4, Day 5, Day 6, and Day 11 in each period and at EOT (or 
ET). Blood pressure and HR will be measured using the same arm for each reading. Subjects 
are to be supine for 5 minutes prior to vital signs assessments. 
14.2.3 ECGs 
For study conduct, ECGs will be classified as Safety ECGs or Cardiodynamic ECGs, and will 
be performed as outlined in the Study Events Flow Chart (Section 7). 
14.2.3.1 Standard 12-Lead ECGs (Safety ECGs) 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Section 7). 
Additional ECGs may be taken at any other times, if deemed necessary by the PI or designee. 
All safety single 12-lead ECGs will be performed using a standard ECG machine. For safety 
single 12-lead ECGs scheduled during the 24-hour cardiodynamic recording period, the 
priority of lead placement will be for 12-lead Holter recording device.  
ECGs will be taken following resting in the supine position in a quiet environment. All ECG 
tracings will be reviewed by the PI or designee. 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
47

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 4 5 
Safet y E C Gs will be  meas ure d wit hi n 2 h o urs pri or t o Da y 1 d osi n g i n eac h peri o d f or t he 
pre d ose ti me p oi nt. W he n sc he d ule d p ost d ose, s afet y E C Gs will be perf or me d wit hi n 
a p pr o xi matel y 2 0 mi n utes of t he sc he d ule d ti me p oi nt.  
1 4. 2. 3. 2  C ar di o d y n a mic E C Gs  
H olter m o nit ors will be use d t o c ollect c o nti n u o us 1 2- lea d E C G data f or t he p ur p ose of 
c ollecti n g car di o d y n a mic E C Gs f or a p pr o xi matel y 2 6 h o urs. Rec or di n g will be starte d a n d 
st o p pe d at l o gisticall y o pti mal ti mes t o e ns ure t hat all sc he d ule d ti me p oi nts are c ollecte d. At 
least t hree 1 2-l ea d E C G r ec or din gs will be e xtract e d fr o m t he H olter m o nit or data o n Da y 1 of 
eac h p eri o d wit hi n a 5 - mi n ute ti me wi n d o w ar o u n d t he sc he d ule d ti me p oi nts as o utli ne d i n t he 
St u d y E ve nts Fl o w C hart ( Secti o n  7), b ut pri or t o t he P K bl o o d sa m ple c ollecti o n.  
T i mi n g a n d r ec or di n g tec h ni q ue f or E C Gs will be sta n dar dize d f or all s u bjects. S u bjects will be 
re q uire d t o lie q uietl y i n a s u pi ne p ositi o n wit h mi ni mal m o ve me nt a n d mi ni mal e x p os ure t o 
n oise a n d ot her e n vir o n m e ntal sti m uli (e. g., T V, l o u d ra di o, i nteracti o ns wit h ot her 
partici pa nts, etc.)  f or at l east 1 0 mi n utes bef ore a n d 5 mi n utes d uri n g t he E C G e xtracti o n t o 
all o w f or q ualit y E C G e xtracti o n.  All E C G e xtracti o n s h o ul d occ ur i n a 5-mi n ute ti me wi n d o w 
ar o u n d t he sc h e d ule d/ n o mi nal ti me. If tar gete d E C G ti me p oi nts are artefact ual  or of p o or 
q ualit y, a n al yza ble 1 0 -sec o n d E C Gs will be e xtracte d as cl ose as p ossi ble t o t he tar gete d ti me 
p oi nts. 
N o mi nal ti me of t he E C G rec or di n g will be use d f or t he car di o d y na mic a n al yses.  
1 4. 2. 4  B o d y Wei g ht 
B o d y wei g ht ( k g) will be re p orte d as o utli ne d i n t he St u d y E ve nts Fl o w C hart ( Secti o n  7).  
1 4. 2. 5  Cli nic al L a b or at or y Tests  
All tests liste d bel o w will be perf or me d as o utli ne d i n t he St u d y E v e nts Fl o w C hart ( Secti o n  7). 
In a d diti o n, la b orat or y safet y t ests ma y b e perf or m e d at vari o us u nsc h e d ule d ti me p oi nts, if 
dee me d necessar y b y t he PI or d esi g n ee .  
He m at ol o g y  
 
Ser u m C he mistr y *  
•  
He m o gl o bi n  
•  
Mea n c or p usc ular h e m o gl o bi n 
c o n ce ntrati o n 
•  
Mea n c or p usc ular v ol u me  
•  
He mat o crit  
•  
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  
•  
Platelet c o u nt  
•  
W hite bl o o d cell/le u k o c yte ( W B C) 
c o u nt 
•  
W B C/le u k o c yte differe ntial (a bs ol ute 
a n d p erce nt): 
 
Bas o p hils  
 
E osi n o p hils  
 
L y m p h o c ytes  
 
M o n o c ytes  
 
Ne utr o p hils  
 
 
•  
Bl o o d Urea Nitr o ge n  
•  
Bilir u bi n (t otal a n d direct)  
•  
Al kali n e p h os p h atase  
•  
A S T  
•  
A L T  
•  
Uric aci d  
•  
Al b u mi n  
•  
T otal pr otei n  
•  
Ir o n 
•  
Calci u m  
•  
S o di u m  
•  
P otassi u m  
•  
Ma g n esi u m  
•  
C hl ori d e  
•  
Gl u c ose (fasti n g)  
•  
Creati ni n e * *  
•  
C h olester ol  
•  
Tri gl yceri d es  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
4 8

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 4 6 
 
C o a g ul ati o n  
•  
Pr ot hr o m bi n Ti me/I nter n ati o n al 
n or malize d rati o  
•  
Acti vate d p artial t hr o m b o plasti n ti me  
•  
P h os p h or us  
•  
Creati n e ki n ase  
•  
A m ylas e  
•  
Li p ase  
 
Uri n al ysis  
 
A d diti o n al Tests  
•  
p H  
•  
C ol or a n d a p p eara n ce  
•  
S p ecific gra vit y  
•  
Pr o tei n * * * 
•  
Gl u c ose  
•  
Ket o n es  
•  
Bilir u bi n  
•  
Bl o o d * * *  
•  
Nitrite * * *  
•  
Ur o bili n o ge n  
•  
Le u k o c yt e esteras e * * *  
 
•  
HI V test * * * *  
•  
H Bs A g * * * *  
•  
H C V * * * *  
•  
Uri n e dr u g s cree n 
 
O piates  
 
O pi oi ds  
( met h a d o n e,  
o x yc o d o n e,  
a n d 
fe nta n yl) 
 
A m p h eta mi n es   
 
Bar bit urat es  
 
Be n z o diaze pi n es   
 
C o cai n e meta b olite  
 
Ca n n a bi n oi ds   
 
P h e n c ycli di n e  
•  
Uri n e alc o h ol scree n  
•  
C oti ni n e  
•  
Ser u m pre g n a n c y test  
(f or fe males o nl y) 
•  
F S H (f or p ost me n o p a usal fe mal es o nl y) * * * *  
•  
T h yr oi d sti m ulati n g h or m o n e * * * *  
 
* 
Sa m ples f or ser u m c h e mistr y will b e o btai n e d f oll o wi n g a fast of at least 1 2 h o urs at Scree ni n g a n d at 
C h ec k -i n ( Da y -1); at ot h er sc h e d ule d ti mes, ser u m c h e mistr y tests will b e p erf or me d  after at least a n 
8 h o ur fast. H o we ver, i n case of dr o p o uts or rec h ec ks, s u bjects ma y n ot h a ve faste d f or 1 2 or 8 h o urs 
pri or t o t h e ti me t h at t h e ser u m c h e mistr y sa m ple is b ei n g ta ke n.  
* *  At Scree ni n g  a n d pri or t o d osi n g ( Da y -1 of P eri o d 1), creati ni n e cleara n ce will b e calc ulate d usi n g t h e 
C o c kcr oft -Ga ult f or m ula.  
* * *  If uri n al ysis is p ositi ve f or pr otei n, bl o o d, nitrite a n d/ or le u k o c yte esterase, a mi cr osc o pic e xa mi n ati o n 
(f or re d bl o o d cells, w hite bl o o d cells, b acteria, casts, a n d e pit h elial cells) will b e p erf or me d.  
* * * * P erf or me d at Scree ni n g o nl y.  
1 4. 2. 6  A d verse E ve nts  
1 4. 2. 6. 1  A d verse E ve nt D efi niti o n  
A n A E  mea ns a n y u nt o w ar d me dical o cc urre nce ass ociate d wit h t he use of a dr u g i n h u ma ns, 
w het her or n ot c o nsi dere d dr u g relate d. 
A s us pecte d a d v erse reacti o n mea n s a n y A E f or w hic h t here is a reas o n a ble p ossi bilit y t hat t he 
dr u g ca use d t h e A E. Reas o na ble p ossi bilit y mea ns t here is e vi de nce t o s u g gest a ca us al 
relati o ns hi p bet wee n t h e dr u g a n d t he A E.  
A n A E ca n t h eref ore b e a n y u nf a v ora bl e a n d u ni nt e n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociat e d wit h t he use of a me dici n al 
(i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
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14.2.6.2 Monitoring 
Subjects will be monitored from Screening (signing of informed consent) until EOS (or ET if 
the subject discontinues and does not complete a follow up call) for adverse reactions to the 
study drugs and/or study procedures. At the EOT (or ET), subjects will be asked how they are 
feeling prior to check out from the CRU. During the EOS/follow-up phone call, subjects will 
be queried with an open-ended question such as: ‘How have you been feeling since your last 
visit?’  
AEs (whether serious or non-serious), including abnormal laboratory test value(s), abnormal 
vital signs, and ECG abnormalities deemed clinically significant by the PI or designee will be 
evaluated by the PI or designee and treated and/or followed through EOS (or ET). AEs which 
are ongoing at the EOT or ET which are assessed as related to study drug by the PI (or 
designee) will be followed through the EOS. AEs which are ongoing at the EOS which are 
assessed as related to study drug may be continued to be followed until the symptoms or 
value(s) return to normal, or acceptable levels, as judged by the PI or designee and confirmed 
by the Sponsor. 
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby hospital 
emergency room. Where appropriate, medical test(s) and/or examination(s) will be performed 
to document resolution of event(s). Outcome may be classified as death related to AE, not 
recovered or not resolved, recovered or resolved, recovered or resolved with sequalae, 
recovering or resolving, or unknown. 
14.2.6.3 Reporting 
AEs and SAEs will be collected beginning at informed consent. AEs will be recorded 
throughout the study (i.e., from signing of the ICF until EOS or ET if the subject discontinues 
and does not complete a follow up call), either as subject medical history (if the event is 
reported as occurring prior to signing of the ICF or if the event occurs prior to study drug 
administration on Day 1 of Period 1 and is assessed as not related to study procedures by the PI 
[or designee]) or as AEs (if the event occurs after signing of the ICF but prior to study drug 
administration on Day 1 of Period 1 and is assessed as related to study procedures by the PI [or 
designee], or if the event occurs after study drug administration on Day 1 of Period 1 through 
EOT or ET regardless of relationship to study drug). From EOT through EOS or ET, only AEs 
assessed as related to study drug are to be reported. All SAEs that develop from the time of 
ICF signing until EOS (or ET, if subject discontinues from the study and does not complete a 
follow up call) are to be reported. 
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow up call, all subjects must be followed until EOS. AEs ongoing at the time of the EOS 
which are assessed as related to study drug by the PI (or designee) may be followed until the 
symptoms or value(s) return to normal or acceptable levels, as judged by the PI or designee and 
confirmed by the Sponsor. The PI (or designee) should use appropriate judgment in ordering 
additional tests as necessary to monitor the resolution of events. The Sponsor may request that 
additional safety tests be performed  
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The PI or designee will review each AE and assess its relationship to drug treatment (yes 
[related] or no [unrelated]).  
Unrelated The time course between the administration of study drug and the 
occurrence or worsening of the AE rules out a causal relationship and 
another cause is suspected 
Related 
The time course between administration of study drug and the occurrence or 
worsening of the AE is consistent with a causal relationship and no other 
cause can be identified 
Each sign or symptom reported will be graded on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicity grading scale. Only 
abnormal clinical laboratory results deemed to be clinically significant by the PI or designee 
will be recorded in the AE database and will be graded utilizing CTCAE. 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on the following general guideline (NCI 
CTCAE 27 Nov 2017): 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A Semi-colon indicates ‘or’ within the description of the grade. 
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 5 options 
for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option.  
ADL=Activities of Daily Living  
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
14.2.6.4 Serious Adverse Event 
If any AEs are serious, as defined by the FDA Code of Federal Regulations (CFR), Title 21, 
special procedures will be followed. All SAEs will be reported to the Sponsor or designee via 
fax or e-mail within 24 hours of first awareness of the event, whether or not the serious 
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event(s) are deemed drug-related. All serious event reporting will adhere to 21 CFR 312.32 for 
Investigational New Drugs (IND) and to the Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE, dated December 2012. Any event that meets the 
criteria of a Suspected Unexpected Serious Adverse Reaction (SUSAR) will be reported to the 
IRB/IEC according to site/CRU policy by the Investigator (or designee) and to regulatory 
authorities by the Sponsor (or Sponsor designee) according to regulatory authority 
requirements. Refer to Reference Safety Information (RSI) in the current IB for expected 
adverse reactions. 
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes: Death, a life-threatening AE, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity 
or disability, or a congenital anomaly/birth defect. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI (or 
designee) or Sponsor, places the patient or subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
All SAEs must be reported on a SAE Report Form provided by Loxo Oncology and sent by fax 
or e-mail to the Sponsor listed in Section 4 within 24 hours of first awareness of the event.  
When using the SAE efax (+ 1 203 643-2013) a cover page including study identification 
number and study drug product (i.e., LOXO-292) is required. Alternatively, an email can be 
sent to safety@loxooncology.com. 
The PI is not obligated to actively seek information regarding the occurrence of new SAEs 
beginning after EOS. However, if the PI learns of such an SAE, and that event is deemed 
associated with the use of study drug, he/she should promptly document and report the event. 
The PI will be requested to supply detailed information as well as follow-up regarding the 
SAE. Although not considered an AE per se, the Sponsor must be notified of any subject or 
subject’s partner who becomes pregnant during the study at any time between Screening until 
90 days after the last administration of study drug. 
14.3 Pharmacokinetic Assessments 
14.3.1 Blood Sampling and Processing 
For Treatments A, B and D, blood samples for the determination of LOXO-292 will be 
collected at scheduled time points as delineated in the Study Events Flow Chart (Section 7).  
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For Treatment C, blood samples for the determination of moxifloxacin will be collected at 
scheduled time points as delineated in the Study Events Flow Chart (Section 7).  
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately. 
14.3.2 Pharmacokinetic Parameters 
PK parameters for plasma LOXO-292 and moxifloxacin will be calculated as follows, as 
appropriate: 
 
AUC0-t: 
 
The area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method. 
AUC0-inf: 
The area under the concentration-time curve from time 0 extrapolated to 
infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of 
the last measurable plasma concentration to the elimination rate 
constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated, represented as 
(1 - AUC0-t/AUC0-inf)*100. 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than one 
time point, Tmax is defined as the first time point with this value. 
Kel: 
Apparent first-order terminal elimination rate constant calculated from a 
semi-log plot of the plasma concentration versus time curve. The 
parameter will be calculated by linear least-squares regression analysis 
using the maximum number of points in the terminal log-linear phase 
(e.g., three or more non-zero plasma concentrations). 
t½: 
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations. 
Individual and mean plasma concentration time curves (both linear and log-linear) will be 
included in the final report. 
14.3.3 Analytical Method 
For Treatments A, B and D, all plasma samples will be analyzed for LOXO-292 concentrations 
using a validated bioanalytical method. 
For Treatment C, all plasma samples will be analyzed for moxifloxacin concentrations using a 
validated bioanalytical method. 
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14.3.4 Future Research 
No additional analysis is planned to be performed on the PK blood samples for possible future 
research. Any additional research on these samples unspecified by this protocol will require 
approval from the subjects. 
14.4 Blood Volume Drawn for Study Assessments 
Table 1: Blood Volume during the Study 
Sample Type 
Number of 
Time Points 
Approximate Volume per 
Time Point * (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Screening laboratory safety tests (including hematology, 
serum chemistry, coagulation, serology, thyroid stimulating 
hormone, FSH (for postmenopausal female subjects only) 
and serum pregnancy (for female subjects only) 
1 
16 
16 
On-study hematology, serum chemistry, and coagulation 
and serum pregnancy (for female subjects only) 
13 
16 
208 
Blood for LOXO-292 
Up to 68 
4 
272 
Blood for Moxifloxacin 
13 
4 
52 
Total Blood Volume (mL)→ 
Up to 548 ** 
* 
Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** 
If additional safety or PK analysis is necessary or if larger collection tubes are required to obtain sufficient 
plasma/serum for analysis, additional blood may be obtained (up to a maximum of 50 mL).  
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C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 5 2 
1 5  S T A TI S TI C A L  C O N SI D E R A T I O N S 
Detaile d met h o d ol o g y f or s u m mar y a n d statistical a nal ys es of t he d ata c oll ecte d i n t his st u d y 
will be d oc u me nte d i n a Statistical A nal ysis Pla n ( S A P). Bel o w is a n o v er vie w of t he statistical 
a p pr oac h. A d diti o nal or mil dl y a dj uste d statistical a nal ys es ot her t ha n t h os e descri b e d i n t his 
secti o n ma y b e perf or me d if dee me d a p pr o priate.  
1 5. 1  S a m ple Size D eter mi n ati o n  
T he sa m ple size deter mi nati o n is base d o n testi n g t o s u p p ort a n o n-i nferi orit y h y p ot hesis, wit h 
a n o n-i nferi orit y mar gi n of 1 0 msec f or t his deter mi nati o n. Usi n g n o n-i nferi orit y mar gi n of 
1 0 msec, ass u mi n g a 1 -si de d 0. 0 5 si g nifica nce le v el a n d a c o m m o n wit hi n-s u bject S D of 
8 msec f or Q T c,  
 a sa m ple size of 3 0 (all o wi n g f or 2 dr o p o uts) e v al ua ble s u bjects w o ul d be e x pecte d t o pr o vi de 
at least 
% p o wer t o det ect a n e x pecte d mea n differe n ce of 3 ms ec i n Δ QTc bet wee n 
L O X O - 2 9 2 a n d pl ace b o.  
T he pr o p ose d 4- wa y cr oss o ver desi g n i n t his st u d y, usi n g 3 2 s u bjects ra n d o mize d t o 1 of 
4 treat me nt se q ue n ces will res ult i n u p t o 3 2 sets of o bser vati o ns f or eac h of m o xifl o x aci n a n d 
place b o. Gi ve n w hat was re p orte d i n t he literat ure, t his sa m ple size is dee me d a p pr o pri ate t o 
detect a dr u g -i n d uce d Q Tc pr ol o n gati o n b y m o xifl o x aci n of greater t ha n 5 msec.   
1 5. 2  P o p ul ati o n f or A n al yses 
Car di o d y n a mic  P o p ulati o n: All s u bjects w h o recei ve d at least o ne d ose of st u d y dr u g a n d h a d 
at least o ne pr e d ose a n d o ne p ost d ose vali d Da y 1 Q T/ Q Tc i nter val meas ure me nts . 
P K P o p ulati o n: All s u bjects w h o c o m pl y s ufficie ntl y wit h t he pr ot o c ol a n d dis pla y a n 
e val ua ble P K pr ofile (e. g., e x p os ure t o treat me nt, a vaila bilit y of meas ure m e nts a n d a bse n ce of 
maj or pr ot oc ol vi olati o ns) will be i ncl u de d i n t he statistical a nal ys es.  
Safet y P o p ulati o n : All s u bjects w h o recei ve d at least o ne d ose of st u d y dr u g will be i ncl u de d i n 
t he safet y e v al uati o ns. 
C- Q T P o p ulati o n : All s u bjects w h o recei ve d at least o ne d ose of st u d y dr u g (acti ve or pl ace b o), 
ha ve at least o ne vali d D a y 1 Q T/ Q Tc i nter v al meas ure me nt  at pre d ose a n d p ost d ose a n d are 
i ncl u de d i n t he P K P o p ulatio n wit h a ti me -matc he d Q Tc/ P K assess me nt  will be i ncl u de d i n t he 
C- Q T relati o ns hi p a nal ysis. 
1 5. 3  C ar di o d y n a mic A n al yses 
T he  E C G met h o d ol o g y will b e f urt her det aile d i n t he S A P. T he E C G c ore la b orat or y will 
utilize c o m p uter -assiste d vali date d met h o d ol o gies i n  a f ull y bli n de d ma n n er i n c o m plia nce 
wit h t heir S O P’s t o deter mi ne t he d urati o n of t he E C G i nter vals. A mi ni m u m of 3 E C Gs 
e xtracte d fr o m t he H olter rec or di n gs at t he d efi ne d ti me p oi nts will be assesse d.  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
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QT Interval Correction 
The detailed statistical approach to analyzing the effects of LOXO-292 on electrocardiographic 
parameters will be documented in the SAP. Briefly, the QTcF will be used for the primary 
heart rate correction methodology unless another correction method is judged more appropriate 
in the setting of a significant heart rate increase of > 10 bpm, compared to the placebo. In this 
scenario, the primary heart rate correction method will be selected using a prospective 
procedure, modified from (Tornøe, 2011).  
The regression lines will be evaluated for all correction methods evaluated: 
QTc =
γ +
δ ∗RR +
ε  (Equation 1) 
The RR coefficient, δ, is used to calculate the average sum of the squared slopes (SSS) for each 
of the different QT-RR correction methods γ is the intercept and ε is normally distributed with 
mean zero and variance σ2. The correction method that results in the average on-treatment 
slope closest to zero (the smallest average SSS) is deemed the most appropriate heart rate 
correction method. 
The Bazett corrected QT interval (QTcB) and the population based corrected QT interval 
(QTcP) will also be computed in addition to QTcF. Correction to the QT interval will be 
computed, and is applied as follow: 
Fridericia: QTcF = QT/(RR)⅓ 
Bazett:  
QTcB = QT/(RR)1/2 
Population: QTcP = QT/(RR)p 
Where RR interval is measured in seconds. QTcP will be estimated using linear-mixed effect 
model. 
15.3.1 Baseline Adjustment 
Baseline is defined in each period as the average of predose measurements, i.e., measurements 
taken at -0.75, -0.5, and -0.25 hour in each period.  
For each individual subject, each baseline-adjusted QTc interval (∆QTc) will be calculated as 
the average of the ECG measurements at each scheduled postdose time point minus the 
baseline value obtained from the same treatment (which itself is an average of three predose 
time point measurements). 
15.3.2 Concentration-QT Relationship Analysis 
The relationship between LOXO-292 plasma concentrations and ∆QTc will be assessed using 
linear mixed-effect model by evaluating the ∆QTc on time-matched LOXO-292 concentrations 
using data across all dose levels. After confirming the most adequate method of QT interval 
correction, the following steps will be performed for the C-QT analysis: 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
56

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 5 4 
1.  H ysteresis wi ll be assess e d base d o n j oi nt gra p hical dis pla ys of t he l east-s q uares mea n 
differe n ce b et wee n Δ Q T c i nter val wit h  L O X O - 2 9 2 a n d place b o ( Δ Δ Q Tc) f or eac h 
p ost d ose ti me p oi nt a n d t he mea n c o n ce ntrati o ns of L O X O- 2 9 2 at t he sa me ti me  p oi nts. I n 
a d diti o n, h yster esis pl ots will be gi ve n f or mea n Δ Δ Q Tc i nter v al a n d t he m ea n 
c o nce ntr ati o ns. If a Q T effect ( ∆Δ Q T c) > 1 0 msec ca n n ot be e x cl u de d fr o m t he b y- ti me 
p oi nt a nal ysis a n d if a dela y b et wee n p ea k ∆∆Q Tc i nter val a n d pea k plas ma c o nce ntrati o n 
i n t he pl ot ( ∆∆Q Tc vs. L O X O- 2 9 2) of m ore t ha n 1 h o ur is prese nt , it will be c o ncl u de d t h at 
h yster esis e xists. I n s uc h a case, ot h er m o dels, s uc h as a P K m o del wit h a n a d diti o nal effect 
c o m part me nt ma y be e x pl ore d.  
2.  T he a p pr o pri ate ness of a li near m o del will be e val uate d c o nsiste nt wit h t he a p pr oac h 
descri be d b y G ar n ett, et. al.  (Gar n ett, 2 0 1 7 ), i ncl u di n g assessi n g t he a de q u ac y of u si n g a 
li near m o del b y e val u ati n g t he c o nce ntrati o n - ΔQ T c  pl ot i nc or p orati n g a tre n d li ne (e. g., 
L O E S S (l ocall y w ei g ht e d scatter pl ot s m o ot hi n g)  s m o ot hi n g or li near re gressi o n). If t he 
m o del s u g gests t her e mi g ht be dr u g i n d uce d pr ol o n gati o n of t he Q T i nter val, t he n ot her 
m o dels will be teste d. Ot her m o dels ca n b e  b ut are n ot li mite d t o: E- ma x m o del, a d diti o n of 
a c u bic a n d q u a dratic t er m relate d t o c o nce ntrati o n, or e val uati o n of a l o g- li near 
relati o ns hi p. Selecti o n of t he best m o del will be base d o n t he s mallest A kai ke I nf or mati o n 
Criteri o n ( AI C) val ue f oll o wi n g t he r ules of parsi m o n y i.e. t he si m plest m o del w hic h 
e x plai ns t he data a n d o n t he G o o d ness- of- fit pl ot descri be d i n t he n e xt ste p. 
3.  G o o d ness- of-fit ( G o F) pl ots will be pr o d uce d f or t he pre- s p ecifie d m o d el a n d t he best 
m o del ( base d o n l o west AI C a n d if differe nt t ha n t he pre- s pecifie d m o del). Pl ots will 
i ncl u de: Q Q pl ot t o c o nfir m t he ass u m pti o n of n or malit y; Pre dicte d vs. o bs er ve d res p o nse 
varia ble; St u de ntize d resi d uals vs. ti me; St u de ntize d resi d uals vs. c o n ce ntrati o ns. T he pl ot 
of t he o bser ve d me dia n- q ua n tile L O X O- 2 9 2 c o nce ntrati o ns a n d ass ociate d mea n Δ Δ Q Tc 
( 9 0 % CI), t o get her wit h t he mea n ( 9 0 % CI) pre dicte d Δ Δ Q T c (as d escri be d b y T or n ø e, 
2 0 1 1 ), ma y be use d t o e v al uate t he a d e q uac y of t h e m o del fit t o t he ass u m pti o n of li nearit y 
a n d t he i m pact o n q ua ntif yi n g t he e x p os ure-res p o nse relati o ns hi p. 
4.  I n t he e ve nt t he G o F pl ots s u p p ort a n a p pr o pri ate li near m o del fit, t he mea n a n d u p per 
b o u n d of t he 9 0 % CI of t he mea n pre dicte d ∆∆Q T c i nter val pr ol o n gati o n will be calc ulate d 
at t he ge o metric mea n t h era pe utic CI at t he ge o m etric mea n C ma x c o nce ntrati o n 
s u prat hera p e utic C ma x c o nce ntrati o ns 
5.  I n di vi d ual ti me-matc h e d ∆∆Q Tc a n d pl as ma L O X O - 2 9 2 c o nce ntrati o ns will be dis pla ye d 
i n a scatter pl ot. T he gra p h will dis pla y a n esti mate d re gressi o n li ne a n d 9 0 % CI. T h e 
esti mate d para met ers of t he li near re gressi o n (i nterce pt a n d sl o pe) a n d t heir 9 0 % CIs will 
be i ncl u de d. 
6.  If t he u p per b o u n d of t he 2-si de d 9 0 % CI of t he ∆∆Q Tc at t he o bs er ve d C ma x ass ociate d 
wit h a d ose of i nterest e x cee ds 2 0 msec, t ha n a p ositi ve Q T effect will be c o ncl u de d.  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
5 7

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 5 5 
1 5. 3. 3  Ass a y Se nsiti vit y  
T he relati o ns hi p bet wee n ∆Q Tc a n d m o xifl o x aci n plas ma c o nce ntrati o ns ( C- Q T relati o ns hi p) 
will be assesse d usi n g a li near mi x e d -effect m o del si milar t o t he o ne o utli ne d f or L O X O - 2 9 2 
a b o ve. Assa y s e nsiti vit y will be dee me d t o be met if t he sl o pe of t he c o n ce ntrati o n-Q Tc 
relati o ns hi p is statisticall y si g nifica nt at t he 1 0 % l e vel of si g nifica n ce i n a 2-si de d test a n d t he 
l o wer b o u n d of t he 2-si de d 9 0 % CI) of t h e effect o n ∆∆Q Tc is a b o v e 5  ms ec at t he o bs er ve d 
ge o m etric mea n C ma x of  
m g m o xifl o x aci n.  
1 5. 3. 4  C ate g oric al A n al ysis  
Treat me nt -e mer ge nt co u nts will be pr o vi de d b y treat me nt a n d ti me p oi nt f or Q T a n d Q T c, 
falli n g i n t he f oll o wi n g r a n ges:  ≤ 4 5 0, > 4 5 0, > 4 8 0 a n d > 5 0 0 msec. C o u nts will als o be 
pr o vi de d b y treat me nt a n d ti me p oi nt f or Q Tc c ha n ge fr o m baseli ne v al ues falli n g i n t he 
f oll o wi n g r a n ges:  < 3 0, ≥ 3 0- 6 0 msec, a n d > 6 0 msec.  Eac h s u bject meeti n g a cate g orical 
t hres h ol d will be c o u nte d o nce, usi n g t he lar gest val ue 
C o u nts will als o be pr o vi de d b y tr eat me nt a n d ti m e p oi nt f or t he f oll o wi n g para meters: 
•  I n crease i n P R i nter val fr o m pre d ose bas eli ne > 2 5 % t o a P R > 2 0 0 msec; 
•  I n crease i n Q R S i nter val fr o m pre d ose b aseli ne > 2 5 % t o a Q R S > 1 2 0 msec ; 
•  Decr ease i n H R fr o m pre d ose baseli ne > 2 5 % t o a H R  < 5 0  b p m;  
•  I n crease i n H R fr o m pre d ose baseli ne > 2 5 % t o a H R > 1 0 0 b p m will be deter mi ne d.  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
5 8
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15.3.6 Pharmacokinetic Analyses 
15.3.6.1 Descriptive Statistics 
Values will be calculated for the plasma concentrations and the PK parameters listed in 
Section 14.3.1 for LOXO-292 and moxifloxacin using appropriate summary statistics to be 
fully outlined in the SAP.  
No formal PK analysis will be conducted for placebo samples. Plasma concentrations will be 
reported. 
15.3.7 Safety Analyses 
All safety data will be populated in the individual CRFs. All safety data will be listed by 
subjects. 
Dosing dates and times will be listed by subject. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) and 
summarized by treatment for the number of subjects reporting the TEAE. A by-subject AE data 
listing including verbatim term, coded term, treatment, severity, and relationship to treatment 
will be provided.  
Safety data including ECGs, physical examinations, vital signs assessments, clinical laboratory 
results, will be summarized by treatment and point of time of collection. 
Descriptive statistics using appropriate summary statistics will be calculated for quantitative 
safety data as well as for the difference to baseline, when appropriate.  
Concomitant medications will be coded using the WHO drug dictionary and listed by subject. 
Medical history will be listed by subject. 
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16 STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by the Advarra IRB, and the study will not start until the IRB 
has approved the protocol or a modification thereof. The IRB is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The IRB is compliant to International Council for 
Harmonisation (ICH) guidelines, and may be reached at: 
Advarra IRB  
6940 Columbia Gateway Drive, Suite 110 
Columbia, Maryland 21046, USA 
Tel.: +1 410 884-2900 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration of 
Helsinki, GCP, and the ICH harmonized tripartite guideline regarding GCP (E6[R2] Good 
Clinical Practice: Integrated Addendum to E6 [R1], March 1st 2018). 
16.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date 
an ICF summarizing the discussion prior to Screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
16.1.4 Confidentiality 
All members of the PI’s staff have signed confidentiality agreements. By signing this protocol, 
the PI and investigational staff will regard all information provided by the Sponsor and all 
information obtained during the course of the study as confidential.  
The PI must guarantee the privacy of the subjects taking part in the study. Subjects will be 
identified throughout documentation and evaluation by a unique subject study number. 
Throughout the study, a subject’s source data will only be linked to the Sponsor’s clinical 
study database or documentation via a unique identification number. If subject name appears 
on any study document, it must be redacted before the copy of the documents is supplied to the 
Sponsor. Any information concerning the subjects (clinical notes, identification numbers, etc.) 
must be kept on file by the PI who will ensure that it is revealed only to the Sponsor, IRB, or 
regulatory authorities for the purposes of trial monitoring, auditing or official inspections. As 
required, in the case of an event where medical expenses are the responsibility of the Sponsor, 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
60

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 5 8 
pers o nal i nf or mati o n i.e., f ull na me, s ocial sec urit y det ails etc. , ma y be release d t o  t he 
S p o ns or. A p pr o priate pr eca uti o ns will be ta ke n t o mai ntai n c o nfi de ntialit y of me dical rec or ds 
a n d pers o nal i nf or mati o n i n strictest c o nfi de nce a n d i n acc or d a nce wit h l ocal data.  
1 6. 2  Ter mi n ati o n of t he St u d y  
Celeri o n reser ves t he ri g ht t o ter mi nate t he st u d y in t he i nterest of s u bject welfare.  
S p o ns or reser v es t he ri g ht t o s us pe n d or ter mi nate t he st u d y at a n y ti me. 
1 6. 3  D at a Q u alit y Ass ur a nce 
Sta n dar d o per ati n g pr o ce d ures ar e a vaila bl e f or all acti vities perf or m e d at Celeri o n rel e va nt t o 
t he q ualit y of t his st u d y. Desi g n ate d pers o n nel of Celeri o n will be res p o nsi ble f or 
i m ple me nti n g a n d mai ntai ni n g q ualit y ass ura n ce ( Q A) a n d q u alit y c o ntr ol s yste ms t o e ns ure 
t hat t he st u d y is c o n d uct e d, a n d t hat data are ge n erate d, d oc u me nte d a n d re p orte d i n 
c o m plia nce wit h t he st u d y pr ot oc ol, G C P a n d G L P  re q uire me nts as w ell as a p plica ble 
re g ulat or y r e q uire me nts a n d l ocal la ws, r ul es a n d re g ulati o ns relati n g t o t he c o n d uct of t he 
cli nical st u d y.  
T he Cli nical St u d y Re p ort will be a u dite d b y t h e Q A de part me nt a n d t he Q A a u dit certifi cate 
will be i ncl u de d i n t he st u d y r e p ort. 
All cli nical data will u n der g o a 1 0 0 %  q u alit y c o ntr ol c hec k pri or t o cli nical data base l oc k. E dit 
c hec ks are t he n p erf or me d f or a p pr o priate dat a bas es as a vali dati o n r o uti ne usi n g S A S ®  or 
c o m para ble st atistical pr o gr a m t o c hec k f or missi n g dat a, data i nc o nsiste n cies, data ra n ges , et c. 
C orrecti o ns ar e ma de pri or t o data base l o c k.  
1 6. 4  Direct Access t o S o urce D at a/ D oc u me nts  
Celeri o n will e ns ure t hat t he S p o ns or, I R B, a n d i ns pecti o n b y d o mestic a n d f orei g n re g ul at or y 
a ut h orities will ha ve direct access t o all st u d y-relate d sites, s o urce dat a/ d oc u me nts, a n d re p orts 
f or t he p ur p ose of m o nit ori n g a n d a u diti n g (I C H[ E 6] 5. 1. 2 & 6. 1 0). I n t he e ve nt t hat ot her 
st u d y-r elate d m o nit ori n g s h o ul d be d o ne b y ot her parties, t he y will be re q uire d t o si g n a 
c o nfi de ntialit y a gree me nt pri or t o a n y m o nit ori n g a n d a u diti n g.  
1 6. 5  Dr u g S u p plies, P ac k a gi n g a n d L a beli n g  
T he S p o ns or will s u p pl y s ufficie nt q ua ntities of t h e L O X O - 2 9 2 
t o all o w c o m pleti o n 
of t his st u d y. C eleri o n will pr o vi de s ufficie nt q ua ntities of m o xifl o x aci n  (as A vel o x ®  ta blets, or 
ge n eric e q ui vale nt ) a n d matc hi n g place b o 
 t o all o w c o m pleti o n of t he st u d y. T he l ot 
n u m bers a n d e x pirati o n dates ( w here a v aila ble) of t he st u d y dr u g s s u p plie d will be rec or d e d i n 
t he fi nal Cli nical St u d y R e p ort. 
Rec or ds will be ma de of t he recei pt a n d dis pe nsi n g of t he st u d y dr u gs  s u p plie d. At t he 
c o ncl usi o n of t he st u d y, a n y u n us e d st u d y dr u g s will be retai ne d b y Celeri o n, ret ur ne d t o t he 
S p o ns or or desi g n ee, or d estr o ye d, as p er S p o ns or i nstr ucti o ns. A n y re mai ni n g s u p plies t hat 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 1
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were purchased by Celerion will be destroyed. If no supplies remain, this fact will be 
documented in the pharmacy product accountability records. 
16.6 Data Handling and Record Keeping 
Celerion standard CRFs will be supplied. CRFs are printed off directly from the database. Each 
CRF is reviewed and signed by the PI. 
All raw data generated in connection with this study, together with the original copy of the 
final Clinical Study Report, will be retained by Celerion and the ECG Core Lab until at least 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 5 years have 
elapsed since the formal discontinuation of clinical development of the investigational product. 
These documents should be retained for a longer period however if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. It is the responsibility of the 
Sponsor to inform the PI/Institution as to when these documents no longer need to be retained. 
16.7 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final Clinical Study Report will be written according to 
the ICH E3 Guideline (Structure and Content of Clinical Study Reports).  
16.8 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
62

C O N FI D E N TI A L  
C A 2 5 4 9 4 ( L O X O- R E T - 1 8 0 3 2), Fi nal, 0 3 A pr 2 0 1 9 
 
Pa ge 6 0 
1 7  R E F E R E N C E S  
A vel o x ®  ( m o xifl o x aci n h y dr o c hl ori de) ta bl ets a n d i ntra ve n o us i njecti o n, f ull prescri bin g 
i nf or mati o n (electr o nic m o n o gra p h) p u blis he d o n t he F D A w e bsite ( d oc u me nt re vise d: 
Se p - 2 0 1 6). A vaila ble at: htt p:// w w w.access dat a.f d a. g o v/ dr u gs atf da _ d o cs/la bel/ 2 0 1 6/ 
0 2 1 0 8 5s 0 6 1s 0 6 2, 0 2 1 2 7 7s 0 5 7s 0 5 8l bl. p df. 
Bl o o mfiel d D M, K ost J T, G h os h K, Hre ni u k D, Hic ke y L A, G uitierrez MJ, G ottes die ner K,  
Wa g ner J A. T he effect of m o xifl o x aci n o n Q Tc a n d i m plicati o ns f or t he desi g n of t h or o u g h Q T 
st u dies. Cli n P har mac ol T her. 2 0 0 8; 8 4( 4): 4 7 5- 8 0. 
Dar p o et al. Res ults Fr o m t he I Q- C S R C Pr os pecti ve St u d y S u p p ort Re place me nt of t he 
T h or o u g h Q T St u d y b y Q T Assess me nt i n t he Earl y Cli nical P hase. Cli n P har mac ol T her. 
2 0 1 5; 9 7( 4): 3 2 6- 3 3 5. 
E 1 4 I m ple me ntati o n W or ki n g Gr o u p: I C H E 1 4 G ui deli ne. T he Cli nical E v al uati o n of Q T/ Q T c 
I nter val Pr ol o n gati o n a n d Pr oarr h yt h mic P ote ntial f or N o n-A ntiarr h yt h mi c Dr u gs Q uesti o ns & 
A ns wers ( R 3) ( 1 0 Dece m ber 2 0 1 5). 
Fer b er G, L orc h U, a n d Tä u bel J. T he P o wer of P hase I St u dies t o Detect Cli nical Rele va nt 
Q Tc Pr ol o n gati o n: A Res a m pli n g Si m ulati o n St u d y. Bi o me d Res I nt. 2 0 1 5; 2 0 1 5: 1- 8. 
Gar nett C, B o n ate P L, D a n g Q, Fer ber G, H ua n g D, Li u J, Me hr otra D, Ril e y S, Sa ger P, 
T or n oe C, Wa n g Y. Scie ntific w hite pa per o n c o n ce ntrati o n - Q T m o d eli n g. J P har mac o ki net 
a n d P har mac o d y n 2 0 1 8; 4 5: 3 8 3 – 3 9 7 
L O X O - 2 9 2. I n v esti gat or’s Br oc h ure. L o x o O nc ol o g y, I n c. Versi o n 4. 0, Oct o ber 2 0 1 8. 
Nati o nal Ca ncer I nstit ute, C o m m o n Ter mi n ol o g y Criteria f or A d v erse E v e nts ( C T C A E), 
Re vise d: N o v - 2 0 1 7 ( v5. 0 ). A vaila ble at: 
htt ps://cte p.ca ncer. g o v/ pr ot oc ol de vel o p me nt/electr o nic _a p plicati o ns/ d ocs/ C T C A E _ v 5 _ Q uic k _
Refere n ce _ 8. 5 x 1 1. p df. 
S ha h R R, Mais o n- Bla n c he P, D u va u c helle  T, a n d R o bert P. Esta blis hi n g assa y s e nsiti vit y i n 
Q T st u dies: e x perie nce wit h t he use of m o xifl o xaci n i n a n earl y p h ase cli nical p har mac ol o g y 
st u d y a n d c o m paris o n wit h its effect i n a T Q T st u d y. E ur J Cli n P har mac ol. 2 0 1 5; 7 1( 1 2): 1 4 5 1-
1 4 5 9. 
Stass H, Dal h o ff A, K u bitza D, a n d Sc h u hl y U. P h ar mac o ki netics, s afet y, a n d t olera bilit y of 
asce n di n g si n gle d oses of m o xifl o x aci n, a ne w 8 - met h o x y q ui n ol o ne, a d mi nistere d t o healt h y 
s u bjects. A nti micr o b A ge nts C he m ot her. 1 9 9 8; 4 2( 8): 2 0 6 0- 2 0 6 5. 
Ta u bel J, Fer ber G, L or c h U, Batc h var o v V, Sa v elie va I, Ca m m AJ. T h or o u g h Q T st u d y of t h e 
effect of or al m o xifl o x aci n o n Q Tc i nter val i n t he fe d a n d faste d state i n healt h y J a pa nese a n d 
Ca ucasia n s u bjects. Br J Cli n P har mac ol. 2 0 1 4; 7 7( 1): 1 7 0- 9. 
T or n øe C W, et al. Creati o n of a k n o wle d ge ma na ge m e nt s yste m f or Q T a n al yses. J Cli n 
P har mac ol.  2 0 1 1; 5 1( 7): 1 0 3 5- 1 0 4 2. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 3

m y c e l eri o nf gb V e c r/Ll st sf E C R N o t e t o Fll e/ Di sp C u s t o m. as p x? I D= 1 8 4 0 & C o nt e n t T yp el d = O x 0 10 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
1/ 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 4
C CI

m y c el eri o n / gb V e cr/ Ll s t s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ? I D= 1 8 4 0 & C o nt e n t Ty p el d = O x 0 1 0 0 2 0 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
2 1 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 5
C CI

P er s o n I n C h ar g e 
( Si g n at ur e/ D at e) 
P er s o n I n C h ar g e 
{ N a m e a n d Titl e) 
Pri n ci p al I n v e sti g at or 
Pri n ci p al I n v e sti g at or { Si g n at ur e 
/ D at e) If A p pli c a bl e 
Pri n ci p al I n v e sti g at or ( N a m e) 
If A p pli c a bl e 
 ( Cli ni c al St u d y M a n a g er I) 
I c o nfir m t hi s N T F h a s b e e n e v al u at e d a n d I a gr e e wi t h t h e d e s cri pti o n of 
t h e N T F , a n y a cti o n s t a k e n a n d s af et y a s s e s s m e nt (if n e c e s s ar y). 
c J-
()'f At dclrf 
m y c el eri o n /g b V e cr/ L lst s/ E C R N o l e t o F il e/ Di s p C u st o m. a s px ? I D =1 8 4 0 & C o nt e nt T y p el d = O x 0 1 0 0 2 0 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 0 1 F 8 2 C 6 4 8 
3/ 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 6
P P D
P P D
P P D
C CI

8/ 8/ 2 0 1 9 
M a n a g e m e nt 
M a n a g e m e nt ( Si g n at ur e 
/ D at e) 
M a n a g e m e nt ( N a m e a n d 
Titl e) 
A p pr o v al · S p o n s or 
S p o n s or Si g n at ur e/ D at e 
S p o n s or ( N a m e a n d Titl e) 
If A p pli c a bl e 
I m p a ct t o St u d y 
Cr e at e d at 6/ 5/ 2 0 1 9 5:2 3 P M b y · ' Price, J essi c a 
E C R N ot e t o Fil e - C A 2 5 4 9 4- P H X- 0 1 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e wit h t h e d e s cri pti o n of 
t h e N T F a n d a n y a cti o n s t a k e n. 
 { A s s o ci at e Dir e ct or, Cli ni c al O p er ati o n s) 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e t o t h e d e s cri pti o n of t h e 
N T F i n pr o vi di n g cl arifi c ati o n f or t h e a b o v e- m e nti o n e d pr ot o c ol. 
1 4- A u g- 1 9 I 2 3: 2 0: 0 4 P D T 
M o nit or) 
L
Si g ni n g R e a s o n : I a p pr a v et h 1 s d o c u m e nt 
Si g ni n g Ti m e: 1 4- A u g- 1 9 1 2 3 :1 9 :3 5 P D T 
0 1 A 6 C 8 3 0 E C 5 1 4 5 B 4 8 D E 6 0 B 7 9 B A D 6 9 C B A 
N/ A 
Last m o difi e d at 8/ 8/ 2 0 1 9 1 1 :5 0 A M b y Cl Price, J essi c a 
m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ? I D = 1 8 4 0 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
4/ 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 7
P P D
P P D
P P D
P P D

m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 4 9 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
1/ 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 8
C CI

m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 4 9 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
2 1 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
6 9
C CI

P er s o n I n C h ar g e 
P er s o n I n C h ar g e 
( Si g n at ur e/ D at e) 
P er s o n I n C h ar g e 
( N a m e a n d Titl e) 
Pri n ci p al I n v e sti g at or 
Pri n ci p al I n v e sti g at or ( Si g n at ur e 
/ D at e) If A p pli c a bl e 
Pri n ci p al I n v e sti g at or ( N a m e) 
If A p pli c a bl e 
M a n a g e m e nt 
M a n a g e m e nt ( Si g n at ur e 
/ D at e) 
M a n a g e m e nt ( N a m e a n d 
Titl e) 
A p pr o v al - S p o n s or 
I c o nfir m t hi s N T F h a s b e e n d o c u m e nt e d a c c or di n g t o a p pli c a bl e i nt er n al 
pr o c e d ur e s a n d a p pr o pri at e p arti e s h a v e b e e n n otifi e d of t h e N T F . 
 ( Cli ni c al St u d y M a n a g er I) 
I c o nfir m t hi s N T F h a s b e e n e v al u at e d a n d I a gr e e wit h t h e d e s cri pti o n of 
t h e N T F, a n y a cti o n s t a k e n a n d s af et y a s s e s s m e nt (if n e c e s s ar y). 
 M D 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e wit h t h e d e s cri pti o n of 
t h e N T F a n d a n y a cti o n s t a k e n. 
li ni c al O p er ati o n s) 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e t o t h e d e s cri pti o n of t h e 
m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 4 9 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
3/ 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 0
C CI
P P D
P P D
P P D
P P D
P P D
P P D

8/ 1 3/ 2 0 1 9 
S p o n s or Si g n at ur e/ D at e 
S p o n s or ( N a m e a n d Titl e) 
If A p pli c a bl e 
I m p a ct t o St u d y 
E C R N ot e t o Fil e - C A 2 5 4 9 4- P H X- 0 2 
N T F i n pr o vi di n g cl arifi c ati o n f or t h e a b o v e- m e nti o n e d pr ot o c ol. 
1 4- A u g- 1 9 I 2 3: 2 0: 0 4 P D T 
Si g ni n g Ti m e : 1 4- A u g- 1 9 1 2 3 :1 9 : 21 P D T 
0 1 A 6 C 8 3 0 E C 5 1 4 5 B 4 8 D E 6 0 B 7 9 B A D 6 9 C B A 
I m p a ct u n k n o w n at t hi s ti m e. 
Cr e at e d at 6/ 1 2/ 2 0 1 9 1: 5 6 P M b y 
P a nt oj a, D esir e e 
Last m o difi e d at 8/ 1 3/ 2 0 1 9 1 0: 0 7 A M b y 
Price, J essi c a 
m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 4 9 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
4 1 4 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 1
P P D

1 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 2
C CI

L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 3
C CI

L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 4
C CI

R e p ort E v e nt I D: 1 0 3 3 0 7 8 
P a g e 1 of 1 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 5
C CI

m y c el eri o n /g bl/ e cr/ Li st s /E C R N ot e t o Fi l e/Di s p C u st o m. a s p x ?, D = 1 8 6 7 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 6
C CI

m y c el er io n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e /Di s p C u st o m .a s p x ?I D = 1 8 6 7 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 B D 1 F 8 2 C 6 4 8 
2 1 6 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 7
C CI

m y c e! eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m .a s p x ?I D = 1 8 6 7 & C o nt e n! T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 B D 1 F 8 2 C 6 4 8 
3/ 6 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 8
C CI

m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 6 7 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
4/ 6 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
7 9
C CI

P er s o n I n C h ar g e 
P er s o n I n C h ar g e 
( Si g n at ur e/ D at e) 
P er s o n I n C h ar g e 
( N a m e a n d Titl e) 
I c o nfir m t hi s N T F h a s b e e n d o c u m e nt e d a c c or di n g t o a p pli c a bl e i nt er n al pr o c e d ur e s a n d a p pr o pri at e 
p arti e s h a v e b e e n n otifi e d of t h e N T F . 
 ( Cli ni c al St u d y M a n a g er I) 
m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e /Di s p C u st o m .a s p x ?I D = 1 8 6 7 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
5/ 6 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
8 0
C CI
P P D
P P D

8/ 1 3/ 2 0 1 9 
Pri n ci p al I n v e sti g at or 
Pri n ci p al I n v e sti g at or ( Si g n at ur e 
/ D at e) If A p pli c a bl e 
Pri n ci p al I n v e sti g at or ( N a m e) 
If A p pli c a bl e 
M a n a g e m e nt 
M a n a g e m e nt ( Si g n at ur e 
/ D at e) 
M a n a g e m e nt ( N a m e a n d 
Titl e) 
A p pr o v al - S p o n s or 
S p o n s or Si g n at ur e/ D at e 
S p o n s or ( N a m e a n d Titl e) 
If A p pli c a bl e 
I m p a ct t o St u d y 
E C R N ot e t o Fil e - C A 2 5 4 9 4- P H X- 0 4 
I c o nfir m t hi s N T F h a s b e e n e v al u at e d a n d I a gr e e wit h t h e d e s cri pti o n of t h e N T F, a n y a cti o n s t a k e n 
a n d s af et y a s s e s s m e nt (if n e c e s s ar y). 
 M D 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e wit h t h e d e s cri pti o n of t h e N T F a n d a n y a cti o n s 
t a k e n. 
1. ? 7 2 0 1 1 
 ( A s s o ci at e Dir e ct or, Cli ni c al O p er ati o n s) 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e t o t h e d e s cri pti o n of t h e N T F i n pr o vi di n g 
cl arifi c ati o n f or t h e a b o v e- m e nti o n e d pr ot o c ol. 
1 4- A u g- 1 9 I 2 3: 2 0: 0 4 P D T 
L
Si g ni n g R e a s o n: I a p pr o v e t hi s d o c u m e nt 
Si g ni n g Ti m e : 1 4- A u g- 1 9 1 2 3 :1 9 :0 6 P D T 
0 1 A 6 C 8 3 0 E C 5 1 4 5 B 4 8 D E 6 0 B 7 9 B A D 6 9 C B A 
N/ A 
Cr e at e d at 6/ 2 6/ 2 0 1 9 1 2: 5 6 P M b y 
P a nt oj a, D esir e e 
Last m o difi e d at 8/ 1 3/ 2 0 1 9 1 0: 0 6 A M b y 
Price, Jessica 
m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 6 7 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
6/ 6 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
8 1
P P D
P P D
P P D
P P D
P P D

m y c el e rio n/ g b V e cr /Li st s/ E C R N ot e t o Fi l e/ Di s p C u st om. a s p x ?I D = 1 8 7 3 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 0 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 0 1 F 8 2 C 6 4 8 
1/ 3 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
8 2
C CI

P er s o n I n C h ar g e 
P er s o n I n C h ar g e 
( Si g n at ur e/ D at e) 
P er s o n I n C h ar g e 
( N a m e a n d Titl e) 
Pri n ci p al I n v e sti g at or 
I c o nfir m t hi s N T F h a s b e e n d o c u m e nt e d a c c or di n g t o a p pli c a bl e i nt er n al 
pr o c e d ur e s a n d a p pr o pri at e p arti e s h a v e b e e n n otifi e d of t h e N T F. 
D' 1 Ait 1ltl" 1 
a ( Cli ni c al St u d y M a n a g er I} 
I c o nfir m t hi s N T F h a s b e e n e v al u at e d a n d I a gr e e wit h t h e d e s cri pti o n of 
t h e N T F, a n y a cti o n s t a k e n a n d s af et y a s s e s s m e nt (if n e c e s s ar y). 
Pri n ci p al I n v e sti g at or ( Si g n at ur e 
/ D at e) If A p pli c a bl e 
 
t1'1 At:/ , k/ 1 
Pri n ci p al I n v e sti g at or ( N a m e) 
If A p pli c a bl e 
M a n a g e m e nt 
M a n a g e m e nt ( Si g n at ur e 
/ D at e) 
M a n a g e m e nt ( N a m e a n d 
Titl e) 
A p pr o v al - S p o n s or 
S p o n s or Si g n at ur e/ D at e 
S p o n s or ( N a m e a n d Titl e) 
If A p pli c a bl e 
 M D 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e wit h t h e d e s cri pti o n of 
t h e N T F a n d a n y a cti o n s t a k e n. 
0 7 #y; ?/J I J 
 ( A s s o ci at e Dir e ct or, Cli ni c al O p er ati o n s) 
I c o nfir m t hi s N T F h a s b e e n r e vi e w e d a n d I a gr e e t o t h e d e s cri pti o n of t h e 
N T F i n pr o vi di n g cl arifi c ati o n f or t h e a b o v e- m e nti o n e d pr ot o c ol. 
1 4- A u g- 1 9 I 2 3: 2 0: 0 4 P D T 
M o nit or) 
0 1 A 6 C 8 3 0 E C 5 1 4 5 B 4 8 D E 6 0 B 7 9 B A D 6 9 C B A 
m y c el eri o n/ g bl/ e cr/ Li st s/ E C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 7 3 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
2 1 3 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
8 3
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

8/ 8/ 2 0 1 9 
I m p a ct t o St u d y 
N/ A 
Cr e at e d at 6/ 2 7 / 2 0 1 9 3: 4 7 P M b y L . 
 
Last m o difi e d at 8/ 8/ 2 0 1 9 1 1: 5 3 A M b y r· 
 
E C R N ot e t o Fil e - C A 2 5 4 9 4- P H X- 0 5 
m y c el eri o n/ g b V e cr/ Li st s fE C R N ot e t o Fil e/ Di s p C u st o m. a s p x ?I D = 1 8 7 3 & C o nt e nt T y p el d = O x 0 1 0 0 2 D 3 5 D 2 8 2 9 F B F B 3 4 2 9 F 2 9 4 1 8 D 1 F 8 2 C 6 4 8 
3/ 3 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
8 4
P P D
P P D

 
 
 
INVESTIGATOR’S BROCHURE 
LOXO-292 
 
 
LOXO ONCOLOGY 
281 Tresser Boulevard 
9th Floor 
Stamford, Connecticut 06901 
 
 
 
Current Version 5.0: 
06 June 2019 
Previous Version 4.0: 
01 October 2018 
Previous Version 3.0: 
05 April 2018 
Previous Version 2.0: 
27 March 2017 
Previous Version 1.0: 
28 February 2017 
 
 
This document contains confidential information that is the property of Loxo Oncology, Inc. 
(Loxo) and may not be disclosed to anyone other than the recipient clinical investigator and 
respective members of the Institutional Review Board/Independent Ethics Committee. This 
information cannot be used for any purpose other than the evaluation of the development 
program without the prior written consent of Loxo. 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
85

Loxo Oncology, Inc. 
 
Investigator’s Brochure 
LOXO-292  
 
06 June 2019  
 
Version 5.0 
Confidential & Proprietary 
Page 2 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF TABLES .....................................................................................................................4 
LIST OF FIGURES ...................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................5 
1 
SUMMARY .............................................................................................................9 
2 
INTRODUCTION .................................................................................................13 
2.1 
RET ..................................................................................................................13 
2.2 
RET Activation in Human Cancers .................................................................13 
2.3 
Multi-kinase Inhibitors with RET Activity ......................................................14 
2.4 
LOXO-292 .......................................................................................................15 
3 
PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND 
FORMULATION ..................................................................................................16 
3.1 
Drug Substance ................................................................................................16 
3.2 
Drug Product ....................................................................................................16 
3.2.1 
How Supplied.......................................................................................16 
3.2.2 
LOXO-292 Powder for Oral Suspension .............................................16 
3.2.3 
Storage Conditions, Handling, and Stability........................................17 
3.2.4 
Administration .....................................................................................17 
4 
NONCLINICAL STUDIES ...................................................................................18 
4.1 
Nonclinical Pharmacology ...............................................................................18 
4.1.1 
Overview and Summary ......................................................................18 
4.1.2 
Primary Pharmacodynamics ................................................................18 
4.1.2.1 
In Vitro Studies ...........................................................................18 
4.1.2.2 
In Vivo Studies ...........................................................................20 
4.1.3 
Secondary Pharmacodynamics ............................................................22 
4.1.3.1 
In Vitro Studies ...........................................................................22 
4.2 
Safety Pharmacology .......................................................................................22 
4.3 
Nonclinical Pharmacokinetics .........................................................................26 
4.3.1 
Methods of Analysis ............................................................................26 
4.3.2 
Absorption............................................................................................26 
4.3.3 
Distribution ..........................................................................................26 
4.3.4 
Plasma Protein Binding and Blood Distribution ..................................26 
4.3.5 
Metabolism ..........................................................................................27 
4.3.6 
Metabolites ...........................................................................................27 
4.3.7 
Excretion ..............................................................................................27 
4.3.8 
Exposure in Toxicity Studies Compared to Human Exposure ............27 
4.4 
Toxicology .......................................................................................................29 
LOXO-RET-18032; CA25494; 16.1.1 Protocol and Protocol Amendments
86

Loxo Oncology, Inc. 
 
Investigator’s Brochure 
LOXO-292  
 
06 June 2019  
 
Version 5.0 
Confidential & Proprietary 
Page 3 
 
4.4.1 
Repeat-dose Toxicity in Sprague-Dawley Rats ...................................29 
4.4.2 
Repeated-Dose Toxicity in the Göttingen Minipig ..............................31 
4.4.3 
Genotoxicity .........................................................................................32 
4.4.4 
Carcinogenicity ....................................................................................32 
4.4.5 
Reproductive and Developmental Toxicology ....................................32 
5 
EFFECTS IN HUMANS .......................................................................................38 
5.1 
Rationale for Selection of Human Dose ..........................................................38 
5.2 
Pharmacokinetics and Product Metabolism in Humans ..................................38 
5.2.1 
Clinical Pharmacology .........................................................................38 
5.2.1.1 
Absorption and Bioavailability ...................................................38 
5.2.1.2 
Effect of Food .............................................................................38 
5.2.1.3 
Effect of Omeprazole ..................................................................39 
5.2.1.4 
Effect of CYP3A4 Inhibitors and Inducers on the PK of 
LOXO-292 ..................................................................................39 
5.2.1.5 
Effect of Drug Transporters on the PK of LOXO-292 ...............39 
5.2.1.6 
Effect of LOXO-292 on the PK of other Drugs ..........................40 
5.2.2 
Pharmacokinetics from Patients Treated in Study 
LOXO-RET-17001 ..............................................................................41 
5.3 
Efficacy ............................................................................................................42 
5.4 
Safety ...............................................................................................................42 
5.4.1 
Study LOXO-RET-17001 ....................................................................42 
5.4.1.1 
Demographics and Baseline Characteristics ...............................43 
5.4.1.2 
Dose-Limiting Toxicities ............................................................44 
5.4.1.3 
Common Treatment-Emergent Adverse Events .........................44 
5.4.1.4 
Serious Adverse Events ..............................................................48 
5.4.1.5 
Deaths .........................................................................................50 
5.4.1.6 
Adverse Events Leading to Study Drug Discontinuation ...........50 
5.5 
Single-Patient Protocols ...................................................................................50 
5.6 
Marketing Experience ......................................................................................51 
5.7 
Clinical Experience with Related Molecules ...................................................51 
6 
SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR .........52 
6.1 
Known and Anticipated Risks .........................................................................52 
6.1.1 
Risks Based on Animal Toxicology Studies ........................................52 
6.1.2 
Risks Based on Clinical Studies ..........................................................52 
6.2 
Guidance for Investigator on Specific Adverse Events ...................................53 
6.2.1 
Hypersensitivity Reactions to LOXO-292 ...........................................53 
6.2.2 
Liver Function Test Abnormalities with LOXO-292 ..........................54 
6.2.3 
Thrombocytopenia with LOXO-292....................................................55 
6.2.4 
Hypertension with LOXO-292 ............................................................55 
6.3 
Contraindications, Warnings, and Precautions ................................................55 
6.4 
Pharmacokinetics and Potential for Drug Interactions ....................................56 
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6.5 
Reproductive Risks and Use in Pregnancy and Breast Feeding ......................57 
6.6 
Special Populations ..........................................................................................57 
6.7 
Overdose ..........................................................................................................57 
6.8 
Reference Safety Information ..........................................................................58 
7 
REFERENCES ......................................................................................................59 
 
LIST OF TABLES 
Table 3-1 
Capsule Component Overview of LOXO-292 Capsule Formulations ......16 
Table 3-2 
LOXO-292 20 mg/mL Suspension ............................................................17 
Table 4-1 
GLP Safety Pharmacology Studies ............................................................24 
Table 4-2 
Steady-State Human Pharmacokinetic Parameters of LOXO-292 at 
Doses of 80 mg BID and 160 mg BID, Compared to Exposure at 
Steady State in Toxicity Studies Conducted in Rats and Minipigs ...........28 
Table 4-3 
Summary of LOXO-292 Toxicology Program – Repeat-Dose Studies .....34 
Table 4-4 
Summary of LOXO-292 Toxicology Program – Genotoxicity and 
Other Studies ..............................................................................................36 
Table 5-1 
Preliminary Pharmacokinetic Parameters of LOXO-292 in Cancer 
Patients (Study LOXO-RET-17001)..........................................................41 
Table 5-2 
Demographics and Baseline Characteristics: Study LOXO-RET-17001 
(Safety Analysis Set)..................................................................................43 
Table 5-3 
Overall Incidence of TEAEs in ≥ 5% of Patients in Decreasing Order 
of Frequency, and the Corresponding Events of Severity Grade 3/ 4/ 5 
and Related Events: LOXO-RET-17001 (Safety Analysis Set) ................45 
Table 5-4 
Overall Incidence of SAEs in ≥ 1 Patient in Decreasing Order of 
Frequency, and the Corresponding Related Events: Study LOXO-
RET-17001 (Safety Analysis Set) ..............................................................48 
Table 5-5 
Single Patient Protocols, Special Access Schemes, Compassionate 
Use, and Temporary Authorization Use (ATU) cases with LOXO-292 ...51 
Table 6-1 
Serious Adverse Reactions Considered Expected for Safety Reporting 
Purposes .....................................................................................................58 
 
LIST OF FIGURES 
Figure 4-1 
Preclinical Characterization of RET Inhibitor Potency and Selectivity 
in Cells .......................................................................................................19 
Figure 4-2 
Inhibition of RET Phosphorylation in KIF5B-RET Tumors in Mice ........20 
Figure 4-3 
Preclinical Characterization of RET Inhibitor Anti-Tumor Activity .........21 
Figure 4-4 
Inhibition Tumor Growth in a RET Fusion-Dependent Patient Derived 
Xenograft Implanted into the Brain in Mice ..............................................22 
Figure 5-1 
Preliminary Pharmacokinetics of LOXO-292 on Day 8 (Steady-State) 
in Cancer Patients ......................................................................................42 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or term 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-PD-1 
anti-programmed cell death protein-1 
AST 
aspartate aminotransferase 
ATA 
American Thyroid Association 
ATP 
adenosine triphosphate 
ATU 
Temporary Authorization Use 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-inf 
area under the concentration-time curve from time 0 to infinity 
AUC0-t 
area under the concentration-time curve from time 0 the time of the last 
measurable concentration 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BSA 
body surface area 
CI 
confidence interval 
CL/F 
apparent oral clearance 
Cmax 
maximum plasma concentration 
Cmax(unbound) 
maximum unbound concentration 
Cmin 
predose trough concentration 
CNS 
central nervous system 
CYP 
cytochrome P-450 
DG 
Day of Gestation  
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DRF 
dose range finding 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FOB 
functional observational battery 
GDNF 
glial cell-line derived neurotropic factor 
GFL 
glial cell-line derived neurotropic factor family ligands  
GFR 
glial cell-line derived neurotropic factor family receptor 
GI 
gastrointestinal  
GLP 
Good Laboratory Practices 
HEK 
human embryonic kidney 
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Abbreviation or term 
Definition 
hERG 
human ether-à-go-go related gene 
HNSTD 
highest non-severely toxic dose 
HPBL 
human peripheral blood lymphocytes 
IASLC 
International Association for the Study of Lung Cancer  
IC50 
concentration at which 50% inhibition is achieved 
IC90 
concentration at which 90% inhibition is achieved 
ICF 
Informed Consent Form 
ICIs 
immune checkpoint inhibitors 
IV 
intravenous(ly) 
JAK-STAT 
Janus Kinase-Signal Transducer and Activator of Transcription 
LC-MS 
liquid chromatography–mass spectrometry 
LFTs 
liver function tests 
LMA 
locomotor activity assessments 
MAP(K) 
mitogen-activated protein (kinase) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC-I 
major histocompatibility complex class I 
MKI 
multi-kinase inhibitor 
mRNA 
messenger ribonucleic acid 
MRSD 
maximum recommended starting dose 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NCEs 
normochromatic erythrocytes 
NGS 
next generation sequencing 
NOAEL 
no-observable-adverse-effect-level 
NOEL 
no-observable-effect-level 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
PCEs 
polychromatic erythrocytes  
PDX 
patient derived xenograft 
P-gp 
P-glycoprotein 
PI3K 
phosphatidylinositol-3-kinase  
PK 
pharmacokinetics 
PKA 
protein kinase A 
PKC 
protein kinase C 
PO 
oral(ly) 
PTC 
papillary thyroid cancer 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
RBC 
red blood cell(s) 
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Abbreviation or term 
Definition 
RET 
rearranged during transfection 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
S9 
a fraction of liver homogenate 
SAE 
serious adverse event 
SARs 
serious adverse reactions 
SD 
stable disease; standard deviation; Sprague-Dawley 
SEM 
standard error of the mean 
SOC 
system organ class 
SPP 
single patient protocol 
SRC 
Safety Review Committee 
STD 10 
dose at which 10% of animals have severe toxicity 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
treatment-emergent-adverse event 
TK 
toxicokinetic 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum concentration 
WCLC 
World Conference on Lung Cancer 
 
 
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L o x o O nc ol o g y, I nc.
I n vesti gat or’s Br oc h ure
L O X O- 2 9 2
0 6 J u ne 2 0 1 9 
Versi o n 5. 0
C o nfi de ntial & Pr o prietar y
P a ge 8
I n vesti g at or’s Br oc h ure Si g n at ure P a ge
I n vesti g ati o n al Pr o d uct:
L O X O- 2 9 2
C urre nt I B Versi o n 5. 0:
0 6 J u ne 2 0 1 9
T he c urr e nt versi o n of t h e I n vesti g at or’s Br o c h ure has bee n re vie w e d a n d a p pr o ve d.
           
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                _ _ _ _ _ _ _ _ _ _ _ _ _
 M D, P h D
Date 
 Researc h a n d  De vel o p me nt  
I h a ve r ecei ve d a n d r ea d t he c urre nt versi o n of t he I n v esti gat or’s Br oc h ure.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _              _ _ _ _ _ _ _ _ _ _ _ _ _
Pri nci pal I n v esti gat or's Si g nat ur e
Date 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Pri nt Pri nci pal I n vesti g at or's N a m e
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
9 2
P P D
P P D
P P D

L o x o O nc ol o g y, I nc.  
 
I n vesti gat or’s Br oc h ure 
L O X O -2 9 2  
 
0 6 J u ne 2 0 1 9  
 
Versi o n 5. 0  
C o nfi de ntial & Pr o prietar y  
P a ge 9 
 
1  
S U M M A R Y  
L O X O - 2 9 2 is a sel ecti ve i n hi bit or of t he rearra n ge d d uri n g tra nsfecti o n (R E T ) rece pt or 
t yr osi ne ki nas e ( R T K) b ei n g de v el o pe d b y L o x o O nc ol o g y. I n cell ular assa ys, L O X O- 2 9 2 
i n hi bite d t he KI F 5 B- R E T f usi o n pr otei n wit h a c o nce ntrati o n  at w hic h 5 0 % i n hi biti o n is 
ac hie ve d  (I C5 0) of 4  n M a n d dis pla ye d mi ni mal l oss of i n hi bit or y acti vit y a gai nst  p ote ntial 
ac q uire d resista nt m utati o ns (i.e., V 8 0 4 L/ M “ gate kee per” s u bstit uti o ns) i n KI F 5 B-R E T , or 
a gai nst t he f ull-le n gt h R E T rece pt or har b ori n g acti vati n g m utati o ns  (e. g., M 9 1 8 T) f o u n d i n 
me d ullar y t h yr oi d  ca n cer  (R E T -m uta nt M T C) . L O X O - 2 9 2 was at least 2 5 0 -f ol d m ore 
selecti ve f or R E T t h a n f or 9 8 % of 3 2 9 ot her ki n as es teste d i n a lar ge i n vitr o scree n. 
C o nsiste nt wit h s uc h a hi g h de gree of selecti vit y, L O X O- 2 9 2 ca used si g nifica nt c yt ot o xicity 
i n h u ma n ca ncer  cell li nes t hat har b or e d e n d o ge n o us, cli nicall y rele va nt R E T  ge ne  alterati o ns 
(I C5 0 1 – 1 0 n M) a n d was m uc h less c yt ot o xic a gai nst h u ma n ca ncer cell li nes wit h o ut R E T 
alterati o ns  (I C5 0 1 0 0- 1 0, 0 0 0 n M). 
O nc o ge nic R E T  ge n e f usi o ns ha ve bee n i de ntifi e d i n u p t o ~ 1 0 % t o 2 0 % of pa pillar y t h yr o i d 
ca ncer ( P T C)  (Ca n cer Ge n o me Atlas Researc h 2 0 1 4 ), ~ 1- 2 % of n o n- s mall cell l u n g ca ncers 
( N S C L C, pri maril y a d e n ocarci n o mas) (K o h n o, Ic hi ka wa et al. 2 0 1 2 ) a n d l ess c o m m o nl y i n 
ot her t u m or t y p es (Stra ns k y, Cer a mi et al. 2 0 1 4 ), w hile o nc o ge nic R E T  m uta ti o ns occ ur i n 
t he maj orit y of M T Cs (Ji, o h et al. 2 0 1 5). I n a d diti o n, R E T  m utati o n -i n de pe n de nt 
mec ha nis ms o f i ncr ease d R E T acti vit y ha v e bee n descri be d f or M T C a n d estr o ge n-rece pt or 
( E R) p ositi ve breast ca ncer , a n d i ncreas e d R E T acti vit y ma y n e gati vel y re g ulate t he 
a nti-t u m or i m m u ne res p o nse. T heref ore, pot e n t a n d selecti ve i n hi biti o n of R E T ma y pr o vi d e 
cli nical be nefit t o patie nts wit h mali g na ncies d u e t o o nc o ge nic alterati o ns i n R E T  or wit h 
ot her mec ha nis ms of i ncr ease d R E T acti vit y.  
L O X O - 2 9 2 is a s mall m olec ule t hat was d esi g n e d t o bl oc k t he a de n osi ne tri p h os p hate ( A T P) 
bi n di n g site of t he R E T R T K c o m petiti ve l y. L O X O- 2 9 2 has a m olec ular wei g ht of 
a p pr o xi matel y 5 0 0 g/ m ol. L O X O - 2 9 2 will be s u p plie d  as a si m ple ble n d wit h e x ci pie nts i n 
a har d gel ati n 
 c o ntai ni n g   m g ,   m g ,   m g, a n d   m g of dr u g s u bsta nce a n d a 
li q ui d s us pe nsi o n. 
T he p har mac ol o g y, p ha r mac o ki netic ( P K), a n d t o xic ol o g y pr o gra ms descri be d i n t his 
d oc u me nt wer e desi g ne d t o c haracterize t he n o ncli nical effi cac y, dis p ositi o n, a n d safet y 
of L O X O - 2 9 2. 
P har mac ol o g y st u dies de m o nstrate d t hat L O X O- 2 9 2 i n hi bite d t u m or gr o wt h i n m ulti ple 
R E T - de pe n de nt t u m or m o dels. I n mice i m pla nte d wit h cells t hat e x press a c o nstit uti vel y 
acti ve KI F 5 B - R E T f usi o n pr otei n, si n gle oral d os es of L O X O- 2 9 2 de m o nstrate d d ose-
de pe n de nt s u p pr essi o n of p h os p h o- R E T a n d t wice dail y ( BI D) d osi n g ca us e d si g nifica nt 
i n hi biti o n of t u m or gr o wt h. T wice - d ail y oral d oses of L O X O - 2 9 2 als o i n hi bite d t he gr o wt h 
of t u m ors ge ner ate d fr o m cells e x pressi n g  KI F 5 B -R E T wit h  t he p ote ntial ac q uire d resista nce 
“ gate kee per ” m utati o n  V 8 0 4 M. L O X O - 2 9 2 i n hi bite d t he gr o wt h of t u m ors ge n erat e d fr o m 
h u ma n ca ncer cell li nes har b ori n g e n d o ge n o us R E T  alterati o ns (e. g., C C D C 6 -R E T  f usi o n-
p ositi ve N S C L C,  R E T  C 6 3 4 W M T C ) as well as t w o patie nt - deri v e d x e n o grafts ( P D Xs), eac h 
har b ori n g a C C D C 6- R E T f usi o n, o ne wit h o ut a n d o ne wit h a n ac quire d V 8 0 4 M s u bstit uti o n 
t hat ca use d r esista nce t o m ulti - ki nase i n hi bit ors ( M KIs) wit h a nti-R E T acti vit y.  L O X O - 2 9 2 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
9 3
C CI
C CI
C CI
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demonstrated little potential for off-target pharmacological activity based on receptor 
screening assays. 
LOXO-292 has been given orally and intravenously (IV) to mice, rats, dogs, and minipigs. 
Oral PK has also been determined in the monkey. LOXO-292 was absorbed and bioavailable 
in all species tested.  
Stand-alone safety pharmacology studies evaluated the effects of LOXO-292 on vital organ 
functions (cardiovascular and respiratory systems).  
Cardiac safety was evaluated in a Good Laboratory Practices (GLP) in vitro study assessing 
human ether-à-go-go–related gene (hERG) activity, in a GLP in vivo study in conscious 
telemetry-instrumented minipigs, and in a GLP 28-day repeat-dose toxicology study (with 
electrocardiogram (ECG) monitoring) in minipigs. LOXO-292 had an IC50 value of 1.1 μM 
in the GLP hERG assay, which is approximately 14- and 6-fold higher than the maximum 
unbound concentration at the clinical doses of 80 mg BID and 160 mg BID, respectively. 
There were no LOXO-292-related changes in any cardiovascular endpoints including QT 
interval corrected for heart rate (QTc) at doses up to 12 mg/kg in the safety pharmacology 
cardiovascular study in conscious minipigs. Furthermore, there were no LOXO-292-related 
ECG changes in the 28-day repeated-dose toxicity study in minipigs at the high dose of 
12 mg/kg/day. In the 3-month repeated-dose study, an increase in QTc interval was noted 
in female minipigs administered 5 mg/kg/day of LOXO-292, but the degree of increase was 
small (approximately 7-12%; Section 4.2). These low magnitude QTc changes were 
potentially LOXO-292-related but were not considered adverse. 
Administration of LOXO-292 at single doses up to 45 mg/kg in male rats had no effect on 
respiratory function.  
Potential effects of LOXO-292 on the central nervous system (CNS) were evaluated as part 
of the GLP 28-day repeat-dose study in rats in functional observational battery tests and 
locomotor activity assessments. Findings were limited to animals receiving the high dose on 
Week 4 of the dosing phase and were attributed to poor general body condition and weight 
changes associated with LOXO-292 administration rather than specific neurological effects. 
Additionally, no microscopic abnormalities in neuronal tissues were found. 
In toxicology studies of LOXO-292 that were conducted in the rat and minipig for up to 
3 months in duration, the primary pathologic findings for both species were in the tongue, 
pancreas, bone marrow, lymphoid tissues, physis in femur (thickening or physeal dysplasia), 
testes and epididymis. Other targets identified in the minipig included the gastrointestinal 
(GI) tract and ovaries and other target tissues identified in the rat included multi-tissue 
mineralization, incisor teeth, lung, Brunner’s gland, vagina and possibly liver. Assessment of 
doses associated with moribundity/death revealed a steep dose-response curve for both 
species. LOXO-292 was not genotoxic in a GLP in vitro bacterial reverse mutation assay 
or in the GLP in vitro micronucleus assay in human peripheral blood lymphocytes (HPBL). 
LOXO-292 was embryolethal in a dose range finding (DRF) embryo-fetal development study 
in rat. LOXO-292 was not found to be phototoxic when evaluated in an in vitro neutral red 
uptake phototoxicity assay. 
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Based on preclinical pharmacology experiments with human cancer cells in vitro and in 
murine xenograft models, meaningful inhibition of RET in tumors is expected to be 
achievable with oral dosing regimens ≥ 40 mg/day. 
LOXO-292 is currently being studied in an ongoing global Phase 1/2 first in human Study 
LOXO-RET-17001 in patients with advanced solid tumors including RET fusion-positive 
NSCLC, RET-mutant MTC, and other tumors with increased RET activity. The starting dose 
of LOXO-292 was 20 mg once daily (QD). 
As of a March 30, 2019 data cut-off date, safety data was available from 422 patients with 
240 mg BID as the highest dose administered.  
During dose escalation, 2 dose-limiting toxicities (DLTs) were reported, both at the 240 mg 
BID dose level: 1 DLT of Grade 3 tumor lysis syndrome and 1 DLT of Grade 3 
thrombocytopenia. The remaining 4 patients treated at this dose level cleared the 28-day 
DLT window and continued on study. The dosage of 160 mg BID was selected as the 
recommended Phase 2 dose (RP2D) based on safety data (N = 82) and preliminary efficacy 
data in 64 evaluable patients treated at doses from 20 mg QD through 240 mg BID 
(Drilon et al. 2018).  
Across 9 dose levels ranging from 20 mg QD to 240 mg BID in these 422 patients, TEAEs 
occurring in ≥ 15% patients (Table 5-3) were: dry mouth (30.8% total; 25.1% related), 
diarrhea (27.7% total; 12.8% related), hypertension (27.3% total; 16.8% related), fatigue 
(22.3% total; 14.5% related), constipation (21.8% total; 10.0% related), AST increased 
(21.6% total; 15.6% related), ALT increased (20.4% total; 15.4% related), headache (18.7% 
total; 6.9% related), nausea (18.0% total; 6.6% related), edema peripheral (17.3% total; 
9.5% related), and blood creatinine increased (14.9% total; 7.3% related). 
A total of 205 (48.6%) patients across all dose levels experienced ≥ Grade 3 TEAEs 
(Table 5-3). TEAEs of ≥ Grade 3 that were considered to be related to study drug were 
reported in 95 (22.5%) patients across all dose levels. The most common Grade ≥ 3 TEAEs 
included hypertension (12.3%; 7.1% related), ALT increased (6.2%; 4.7% related), AST 
increased (4.7%; 3.1% related), hyponatremia (4.3%; 0.2% related), ECG QT prolonged 
(2.8%; 2.1% related), dyspnea and lymphopenia (each 2.6%; 0% and 0.9% related, 
respectively), diarrhea and thrombocytopenia (each 2.1%; 0.7% and 1.7% related, 
respectively). All other Grade ≥ 3 TEAEs occurred in less than 2% of patients overall.  
Sixteen (16 patients) have died within 28 days of the last dose of study drug, and no deaths 
have been attributed to study drug (Section 5.4.1.5). 
Efficacy data for LOXO-292 are summarized in Section 5.3. As presented at World 
Conference on Lung Cancer (WCLC) 2018 and American Thyroid Association (ATA) 2018, 
with a data cutoff of July 19, 2018, the overall response rate (ORR) was 68% (95% 
confidence interval [CI] 51–83%, n = 26/38) in NSCLC, 78% (95% CI 40–97%, n = 7/9) in 
thyroid, 50% (n = 1/2) in pancreatic, 59% (95% CI 39–77%, n = 17/29) in MTC and 0% 
(n = 0/4) in patients without a known activating RET alteration in their cancers among the 
first 82 patients enrolled in Study LOXO-RET-17001.  
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As of April 15, 2019, PK data were available from 335 patients. LOXO-292 is absorbed after 
oral administration with a median time to maximum concentration (Tmax) of approximately 
2 hours.  
As of March 30, 2019, Loxo Oncology initiated 40 single patient protocols (SPPs), Special 
Access Scheme, Compassionate Use, or Temporary Authorization Use (ATU) cases 
(Table 5-5) to provide access to LOXO-292 for patients with clinical need not meeting 
eligibility criteria for the ongoing clinical study. For the SPPs, Special Access Scheme, 
Compassionate Use, or ATU cases, only SAEs are required to be reported. To date, there 
have been 39 SAEs reported in 15 of the patients participating in SPPs, of which 3 have been 
reported as serious adverse reactions (SARs) which were submitted as Suspected Unexpected 
Serious Adverse Reactions (SUSARs) (Section 5.5). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 
INTRODUCTION 
2.1 
RET 
RET is a receptor tyrosine kinase (RTK) with critical roles in normal kidney and enteric 
nervous system development and in the maintenance of several adult tissue types, including 
neural, neuroendocrine, hematopoietic, and male germ cell tissues (Mulligan et al. 2014). 
The RET receptors are transmembrane glycoproteins. Normal RET activation is initiated by 
the binding of one of four glial cell-line derived neurotropic factor (GDNF) family ligands 
(GFLs). In contrast to other RTKs, RET does not bind directly to its ligands, but instead 
depends on the activity of the GDNF family receptor-α (GFRα) RET co-receptors. 
GFL-bound, GFRα-mediated RET dimerization leads to RET kinase-mediated 
auto-phosphorylation of tyrosine residues in the RET intracellular domain, the recruitment of 
key signaling adaptors and the activation of several signal transduction pathways involved in 
cellular proliferation, including Mitogen-Activated Protein Kinase (MAPK), 
Phosphatidylinositol-3-Kinase (PI3K), Janus Kinase-Signal Transducer and Activator of 
Transcription (JAK-STAT), Protein Kinase A (PKA) and Protein Kinase C (PKC). 
2.2 
RET Activation in Human Cancers 
Genetic alterations in the RET gene are implicated in the pathogenesis of several human 
cancers. RET can be oncogenically activated by two primary mechanisms: (1) chromosomal 
rearrangements that fuse the RET kinase domain with a partner protein dimerization domain 
(e.g., CCDC6/PTC1, KIF5B, NCOA4/PTC3) producing hybrid proteins that endow the 
kinase with ligand-independent, constitutive activity; and (2) point mutations that directly or 
indirectly activate the kinase. 
The oncogenic potential of RET was first identified as a result of its ability to transform 
NIH-3T3 cells through deoxyribonucleic acid (DNA) rearrangement (Takahashi et al. 1985). 
Since its oncogenic potential was first discovered, the identification of additional, activating 
RET gene alterations in several different tumor types clearly implicates RET in the 
pathogenesis of human cancers. RET gene fusions have been identified in ~6% of sporadic 
PTCs (Fusco et al. 1987, Cancer Genome Atlas Research 2014) and at even higher 
frequencies in radiation-induced PTCs (Ito et al. 1994, Fugazzola et al. 1995, 
Bounacer et al. 1997, Nikiforov et al. 1997). In PTC patients, RET gene fusions are 
associated with unfavorable prognostic features (Prasad et al. 2016, Su et al. 2016). 
In addition, activating RET gene mutations occur at high frequency in human MTC 
(> 90% hereditary, ~50-60% sporadic) (Donis-Keller et al. 1993, Mulligan et al. 1993, 
Carlson et al. 1994, Eng et al. 1994, Hofstra et al. 1994, Agrawal et al. 2013, Ji et al. 2015). 
The application of next-generation sequencing (NGS) approaches to a large collection of 
human tumors has led to the identification of RET fusions in a small fraction (1%–2%) of 
NSCLCs (adenocarcinomas) and in an even smaller fraction of other tumor types, including 
colorectal cancer, breast cancer, and chronic myeloproliferative neoplasms (Ballerini et al. 
2012, Ju et al. 2012, Kohno et al. 2012, Lipson et al. 2012, Takeuchi et al. 2012, Bossi et al. 
2014, Stransky et al. 2014).  
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In addition to direct, mutation-mediated activation of RET, increased RET expression in 
the absence of RET mutations may contribute to the growth and survival of some human 
cancers. For example, RET has been shown to be a direct transcriptional target of the ER 
(Boulay et al. 2008, Wang et al. 2012), a finding that is consistent with 1) possible 
ER-mediated increased RET expression in tumors from rare families with MTC 
(Smith et al. 2016), 2) increased RET expression in some ER-positive breast cancers that 
have acquired resistance to anti-estrogens (Plaza-Menacho et al. 2010, Spanheimer et al. 
2014), and 3) re-sensitization to anti-estrogen treatment through RET inhibition (Plaza-
Menacho et al. 2010, Morandi 2013, Spanheimer 2014). Finally, the results of a recent study 
identified RET as a strong negative regulator of Major Histocompatibility Complex class I 
(MHC-I) expression in several human cancer cell lines of diverse histologies (Brea et al. 
2016). This finding suggests a possible role for RET inhibition in upregulating the 
anti-cancer immune response. 
The combination of low-frequency alterations in a highly prevalent cancer like NSCLC, 
high-frequency alterations in a less-prevalent cancer like MTC, and potential additional roles 
for RET in other contexts indicates that a significant number of patients with advanced, RET 
fusion-positive NSCLC, RET-mutant MTC, and other cancers with increased RET activity 
could benefit from potent and selective RET kinase inhibition.  
2.3 
Multi-kinase Inhibitors with RET Activity 
Highly selective RET tyrosine kinase inhibitors (TKIs) have not yet been evaluated in 
clinical trials, but several MKIs with some degree of anti-RET activity are commercially 
available or are undergoing clinic trials. Examples of Food and Drug Administration 
(FDA)-approved MKIs that inhibit several kinases, including RET, are sorafenib, sunitinib, 
cabozantinib, and vandetanib. In general, the efficacy of MKIs is independent of tumor 
genotype and is attributed to multi-kinase inhibition or to the inhibition of a specific subset of 
targets (e.g., KDR/VEGFR2, EGFR, MET). In RET-dependent tumors, the efficacy of these 
MKIs is limited by incomplete inhibition of RET signaling due to dose limitations imposed 
by off-target toxicity (e.g., VEGFR2, EGFR, MET inhibition) and/or an undesirable PK 
profile (e.g., drug accumulation and long half-life contributing to toxicity, but not efficacy). 
Most patients treated with these agents experience significant toxicities requiring dose 
interruptions, reductions, and/or treatment cessation. 
Two MKIs, cabozantinib and vandetanib, have received regulatory approval for advanced 
MTC (irrespective of the presence or absence of a RET mutation), with tumor response rates 
of 28% and 45%, respectively, and progression-free survival improvements (over placebo) of 
7.2 and 11.2 months, respectively (Wells et al. 2012, Elisei et al. 2013). The different degree 
of benefit observed in each study was most likely due to the different patient populations 
enrolled, because there was an eligibility requirement for recent tumor progression in the 
cabozantinib study, but not in the vandetanib study. In subset analyses of both studies, 
patients whose tumors harbored RET activating mutations derived greater benefit than RET 
mutation–negative patients (Wells et al. 2012, Sherman et al. 2016). Preliminary data 
suggests similar, moderate activity for investigational MKIs with anti-RET activity in RET 
fusion–positive lung cancer, with response rates of 16%–53% (depending on the specific 
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MKI and patient population), but progression-free survival of only 3.6–7.3 months, in several 
ongoing Phase 2 studies (Drilon et al. 2016, Lee 2016, Velcheti 2016, Yoh et al. 2016). 
Patients with RET fusion-positive cancers (e.g., NSCLC, PTC, colon, others) and 
RET-mutated cancers (e.g., MTC) represent populations with high unmet need. Combination 
chemotherapy has short-term palliative potential in advanced NSCLC, while anti-
programmed cell death protein 1 (anti-PD-1) monoclonal antibodies (e.g., nivolumab, 
pembrolizumab), which have recently been approved for NSCLC patients, may be less 
effective in tumors marked by single-gene driver oncogenic kinase alterations (including 
kinase fusions) with otherwise low mutational burdens and low neo-antigen production 
(Borghaei et al. 2015, Rizvi et al. 2015, Gainor et al. 2016, Herbst et al. 2016). 
Chemotherapy is ineffective for MTC and PTC. Therefore, there is an urgent need to identify 
new targeted therapies that potently inhibit RET in tumors, while sparing other kinase and 
non-kinase off-targets that contribute to significant toxicity.  
2.4 
LOXO-292 
LOXO-292 is a small molecule competitive inhibitor of the human RET RTK.  
LOXO-292 has demonstrated potent in vitro and in vivo activity as a selective inhibitor of 
both wild-type and oncogenically activated RET, including RET fusions, “founder” 
mutations, and anticipated acquired resistant mutations. 
Loxo Oncology is initiating the clinical development of LOXO-292 for the treatment of 
patients with an advanced solid tumor, including RET fusion-positive NSCLC, RET-mutant 
MTC, and other tumors with increased RET activity (e.g., RET gene fusions and mutations or 
other evidence of increased RET activity). The following sections summarize the chemistry, 
manufacturing, pharmacology, PKs, toxicology, and proposed development plan for 
LOXO-292. 
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L o x o O nc ol o g y, I nc.  
 
I n vesti gat or’s Br oc h ure 
L O X O -2 9 2  
 
0 6 J u ne 2 0 1 9  
 
Versi o n 5. 0  
C o nfi de ntial & Pr o prietar y  
P a ge 1 6  
 
3  
P H Y SI C A L, C H E MI C A L, A N D P H A R M A C E U TI C A L  PR O P E R TI E S 
A N D F O R M U L A TI O N   
3. 1  
Dr u g S u bst a nce  
T he s y nt h esis  of L O X O - 2 9 2 uses t hree starti n g m aterials a n d c o nsists of f o ur ste ps t o 
pr o d uce t he cr ystalli ne fr ee base f or m of L O X O - 2 9 2 t hat will be use d f or h u ma n d osi n g. 
L O X O - 2 9 2 has a m olec ular wei g ht of a p pr o xi matel y 5 0 0 g/ m ol. 
3. 2  
Dr u g Pr o d uct  
3. 2. 1  
H o w S u p plie d 
 
L O X O - 2 9 2 is pr ovi de d f or cli nical i n vesti gati o n as 
 as i n dicat e d i n Ta ble 3 - 1. 
T a ble 3- 1  
C a ps ule C o m p o ne nt O ver vie w of L O X O- 2 9 2 C a ps ule F or m ul ati o ns 
H o w S u p plie d  
C ol or of C a ps ule a 
E xci pie nts  
D os a ge Stre n gt h of 
L O X O -2 9 2 ( per  
) 
L O X O - 2 9 2 2 0 % Si m ple Ble n d 
 m g  
 
S we dis h ora n ge  
Yes  
 m g 
L O X O - 2 9 2 3 0 % Si m ple Ble n d 
 m g  
 
Dar k gree n  
Yes  
 m g 
L O X O - 2 9 2 3 0 % Si m ple Ble n d 
 m g  
 
Gra y wit h i n k bars 
Yes  
 m g 
L O X O - 2 9 2 3 0 % Si m ple Ble n d 
 m g  
 
Li g ht b l ueb 
Yes  
 m g 
a   All har d gelati n ca ps ules are o pa q ue.   
b   De pe n di n g o n t he batc h, t he a p peara nce of t he L O X O -2 9 2 3 0 % Si m ple Ble n d 
m g  
 ma y or ma y 
n ot ha ve a n i n k bar . 
3. 2. 2  
L O X O - 2 9 2 P o w der f or Or al S us pe nsi o n 
L O X O - 2 9 2 p o w d er f or oral s us pe nsi o n c o nsists of t he dr u g s u bst a nce fille d i nt o a 3 0 0 m L 
K yli x B ottle ma de of A m ber T y pe III Glass wit h a P P 2 8 Nec k a n d ca p p e d wit h a 2 8 m m 
W hite Ta m per E vi de nt a n d C hil d- Resista nt Scre w Ca p Tri Seal ®  Wa d . L O X O - 2 9 2 p o w der 
f or oral s us pe nsi o n r e q uires f or m ulati o n i nt o a li q ui d s us pe nsi o n pri or t o oral or e nteral 
a d mi nistrati o n.  
L O X O - 2 9 2 p o w d er f or oral s us pe nsi o n is pr o vi de d t o t he p har mac y w h ere it will be 
c o m p o u n de d i nt o a 2 0 m g/ m L s us pe nsi o n wit h t he a d diti o n of 1: 1 Ora- S w eet ®  S F a n d 
Ora - Pl us® . T h e c o m p o ne nts of t he s us pe nsi o n are s h o w n i n Ta ble 3- 2 . 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 0 0
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

L o x o O nc ol o g y, I nc.  
 
I n vesti gat or’s Br oc h ure 
L O X O -2 9 2  
 
0 6 J u ne 2 0 1 9  
 
Versi o n 5. 0  
C o nfi de ntial & Pr o prietar y  
P a ge 1 7  
 
T a ble 3- 2 
L O X O - 2 9 2   m g/ m L S us pe nsi o n  
C o m p o ne nt  
Q u a ntit y f or Rec o nstit uti o n  
L O X O - 2 9 2 
g 
Ora -S weet ®  S F a 
 m L 
Ora -Pl us ®a 
 m L 
a  T o be  s u p plie d b y t he p har ma c y. 
 
3. 2. 3  
St or a ge C o n diti o ns, H a n dli n g, a n d St a bility  
L O X O - 2 9 2 gel ati n 
a n d p o w der f or oral s us pe nsi o n are t o be st ore d at c o ntr olle d 
r o o m te m perat ur e 2 0° C t o 2 5° C wit h e x c ursi o ns per mitte d bet wee n 1 5° C a n d 3 0° C.  
will  be s u p plie d t o t he cli nical sites  i n hi g h - de nsit y p ol yet h yle n e b ottles cl ose d wit h 
chil d -resista nt plastic ca ps wit h a n i n d ucti o n seal. 
T he c o m p o u n de d s us pe nsi o n of L O X O- 2 9 2 s h o ul d be st ore d refri gerate d b et wee n 2º  C a n d 
8º C. D o n ot freeze t he s us pe nsi o n. If st ore d c orrectl y, t he s us pe nsi o n ma y be ke pt f or a 
ma xi m u m of 4 2 da ys ( 6 wee ks). 
3. 2. 4  
A d mi nistr ati o n  
A d ult d osi n g is i nte n de d t o be i n fi x e d m g q ua ntities  (i.e., n ot wei g ht-bas e d or b o d y s urface 
area [ B S A]-bas e d).  Pe diatric d osi n g is a dj uste d b y B S A . Detai le d i nf or mati o n o n d osi n g of 
L O X O - 2 9 2 is pr o vi de d i n t he cli nical pr ot oc ols.  
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 0 1
C CI
C CI
C CI
C CI
C CI
C CI

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4 
NONCLINICAL STUDIES 
4.1 
Nonclinical Pharmacology 
LOXO-292 is a specific inhibitor of the RET kinase encoded by the RET gene. The effects of 
LOXO-292 on RET fusion proteins and RET mutant proteins have been extensively 
characterized in nonclinical models (Brandhuber, Haas et al. 2016). 
4.1.1 
Overview and Summary 
LOXO-292 inhibited the human RET kinase in vitro with an IC50 of 0.4 nM at Km ATP 
concentration and 17.3 nM at a high, physiologically relevant (i.e., 1 mM) ATP 
concentration. In cellular assays, LOXO-292 inhibited a constitutively active KIF5B-RET 
fusion protein with an IC50 value of 4 nM. LOXO-292 demonstrated significant inhibitory 
activity against diverse RET mutant proteins found in human MTCs, including initial 
“founder” mutations (e.g., M918T, C634W) and anticipated acquired resistance mutations 
(e.g., V804L and V804M “gatekeeper” mutations). In mice implanted subcutaneously with 
NIH-3T3 cells engineered to express a constitutively active KIF5B-RET fusion protein, 
single oral doses of LOXO-292 caused dose-dependent suppression of RET phosphorylation 
in tumors. In multiple RET-dependent tumor models, twice-daily oral dosing of LOXO-292 
caused significant inhibition of tumor growth. LOXO-292 treatment resulted in significant 
cytotoxicity only in human cancer cell lines that harbor endogenous RET gene alterations 
(e.g., fusions and mutations), with minimal cytotoxicity in human cancer cell lines without an 
endogenous RET gene alteration, as expected for a highly specific inhibitor of RET. 
LOXO-292 was more than 250-fold selective for RET than for 98% of 329 non-RET kinases 
tested in a large in vitro screen. This high degree of selectivity was maintained against both 
kinase and non-kinase off-targets when validated in additional enzyme, cell-based, radio-
ligand binding and in vivo assays. 
4.1.2 
Primary Pharmacodynamics  
4.1.2.1 
In Vitro Studies 
4.1.2.1.1 
Binding Affinity 
The inhibitory activity of LOXO-292 for recombinant RET kinases was determined using a 
commercial assay. At a low concentration of ATP, the IC50 value for wild-type RET kinase 
was 0.4 nM. At a higher, physiologic concentration of ATP (1 mM), the IC50 value was 
17.3 nM. Notably, LOXO-292 retained significant inhibitory activity against RET kinases 
containing mutations found in MTC, with IC50 values within 4-fold of the wild-type RET 
kinase. The dissociation constant of LOXO-292, determined by surface plasmon resonance 
was 0.047 nM for RET and LOXO-292 showed a slow off-rate (off-rate half-life 
49.1 minutes). 
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4.1.2.1.2 
Inhibition of RET fusions and mutations in cells  
Human Embryonic Kidney (HEK-293) cells were stably transfected with a RET gene variant 
encoding KIF5B-RET (oncogenic fusion kinase), with or without V804L or V804M 
substitutions (anticipated acquired resistance mutations), or a full-length RET gene variant 
encoding RET-M918T (the most common activating mutation in MTC). The cells were 
treated with a range of LOXO-292 concentrations. The phosphorylated RET protein was 
quantified by an immunofluorescence assay (“in-cell Western”) and inhibition of 
phosphorylation was determined relative to a non-treated control. LOXO-292 inhibited 
KIF5B-RET with an IC50 value of < 5 nM and with IC50 values for KIF5B-RET V804L/M 
and RET M918T within 10-fold of wild-type KIF5B-RET (Figure 4-1, left) (Subbiah et al. 
2018). Of note, the MKIs cabozantinib and vandetanib had less inhibitory activity against 
KIF5B-RET and even less against KIF5B-RET-V804L and KIF5B-RET-V804M. 
Figure 4-1 
Preclinical Characterization of RET Inhibitor Potency and Selectivity 
in Cells 
 
Abbreviations: EC50-half-maximal effective concentration; IC50-half maximal inhibitory concentration; 
Cabo-cabozantinib; Vande-vandetanib; MTC-medullary thyroid cancer; NSCLC-non-small cell lung cancer; 
RET-rearranged in transfection. 
 
4.1.2.1.3 
 Effects on Non-Target Cells 
A panel of 87 human cancer cell lines was treated with a range of concentrations of 
LOXO-292, cabozantinib, or vandetanib for 72 hours in triplicate, followed by cell counting. 
LOXO-292 strongly inhibited the in vitro growth of 4 cell lines harboring endogenous RET 
gene alterations (LC-2/ad-NSCLC KIF5B-RET fusion, TPC-1-PTC CCDC6-RET fusion, 
TT-MTC RET C634W substitution, and MZ-CRC1-MTC RET M918T substitution), with 
half-maximal effective concentration (EC50) values less than 10 nM (Figure 4-1, left). In 
contrast, LOXO-292 had 60- to 1300-fold less inhibitory anti-proliferative activity against 
83 human cancer cell lines that lacked alterations in the endogenous RET gene (Figure 4-1, 
right). These results demonstrate that LOXO-292 is selectively cytotoxic to cancer cells with 
RET gene alterations. 
LOXO-292
Cabo
Vande
LOXO-292
Cabo
Vande
0.1
1
10
100
1000
10000
EC50/IC50 (normalized)
 <-- Less Potent             More potent -->
Cell Lines
Engineered Cells
RET M918T (MZ-CRC-1 MTC)
CCDC6-RET (LC-2/Ad NSCLC)
RET C634W (TT MTC)
CCDC6-RET (TPC1 Thyroid)
non-RET (n=83)
Tumor Cells
KIF5B-RET
KIF5B-RET V804L
KIF5B-RET V804M
RET M918T
KDR/VEGFR2
FGFR1
AURORA
hERG
HEK-293 Engineered Cells
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4.1.2.2 
In Vivo Studies 
NIH-3T3 cells expressing a human KIF5B-RET fusion gene were implanted subcutaneously 
into the flanks of nude mice and tumors were allowed to grow to approximately 500 mm3 in 
size. Mice were then given a single oral dose of LOXO-292 (10 or 30 mg/kg), cabozantinib 
(60 mg/kg), or vehicle control. Tumor and blood samples were collected serially and levels 
of phosphorylated RET in tumors and LOXO-292 in plasma were measured. LOXO-292 
caused dose-dependent inhibition of RET phosphorylation in these transfected tumors, to a 
greater degree and at a lower dose than cabozantinib (Figure 4-2). Thus, LOXO-292 inhibits 
the mechanistic activity of KIF5B-RET in a RET-dependent tumor model in vivo. 
Figure 4-2 
Inhibition of RET Phosphorylation in KIF5B-RET Tumors in Mice 
 
Abbreviations: Cabo-cabozantinib; h-hour; kg-kilograms; mg-milligrams; mL-milliliter; 
ng-nanograms; pRET-phosphorylated; RET-rearranged in transfection; Veh-vehicle. 
Note: pRET % of control and drug plasma concentration values are displayed as mean ± standard error 
of the mean.  
 
The anti-tumor activity of LOXO-292 was compared with the MKI cabozantinib in 
engineered and patient-derived RET fusion-positive and RET-mutant mouse tumor models, 
including two RET fusion-positive models harboring the V804M acquired resistance 
gatekeeper mutation (Yang et al. 2015). At the maximum tolerated dose (MTD), 
cabozantinib caused only mild regression or tumor growth inhibition and was inactive against 
models harboring RET V804M (Figure 4-3). By contrast, LOXO-292 caused significant 
regression in all models, including those harboring RET V804M, and was well-tolerated 
(Subbiah et al. 2018). 
0
25
50
75
100
1000
10000
Drug Plasma Concentration (ng/mL)
pRET in Tumor
(% of Control)
0
3000
30000
Cabo KIF5B-RET
60 mg/kg (12 h)
Veh
10 mg/kg (8 h)
30 mg/kg (8 h)
LOXO-292 KIF5B-RET
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Figure 4-3 
Preclinical Characterization of RET Inhibitor Anti-Tumor Activity 
Vehicle
Cabo
LOXO-292
-100
-50
0
50
100
500
1000
Treatment
Tumor response (%)
KIF5B-RET  (NIH-3T3)
CCDC6-RET(PDX-CRCA)
CCDC6-RET-V804M (PDX-CRCA)
KIF5B-RET(PDX-NSCLC)
KIF5B-RET-V804M (NIH-3T3)
RET C634W (TT cell line-MTC)
CCDC6-RET (LC-2/ad cell line-NSCLC)
Tumor Models
Abbreviations: Cabo-cabozantinib; PDX-patient-derived xenograft; CRCA-colorectal cancer; MTC-medullary 
thyroid cancer; NSCLC-non-small cell lung cancer; RET-rearranged in transfection.  
 
To determine whether LOXO-292 could have inhibitory activity against RET-dependent 
tumors that have spread to the brain, tumor suspensions of the CR2518 CCDC6-RET fusion 
PDX were orthotopically injected into the brains of immune-deficient mice. Seven days after 
implantation, mice were dosed orally with LOXO-292 (30 mg/kg BID), ponatinib (20 mg/kg 
QD, as a reference compound), or vehicle. Animals were evaluated daily for clinical status 
and sacrificed if they exhibited CNS toxicity (e.g., unsteady gait, ataxia), discomfort, 20% or 
more body weight loss, or if their clinical condition otherwise deteriorated. All vehicle-
treated animals had to be sacrificed between Day 16 and Day 47 (median survival equal to 
21 days). In contrast, both LOXO-292 and ponatinib significantly prolonged survival up to 
51 days after treatment initiation (median survival equal to 100% for each) (Figure 4-4). 
To determine whether survival could be maintained with lower doses, the doses of each agent 
were lowered by the same fraction of the starting dose on Day 52 (e.g., LOXO-292 from 
30 mg/kg BID to 3 mg/kg BID, ponatinib from 20 mg/kg QD to 2 mg/kg QD). Following 
these dose adjustments, all but 1 ponatinib-treated animal had to be sacrificed by Day 84 
(median survival equal to 19 additional days after the dose reduction). In contrast, 9 of the 
10 LOXO-292–treated animals survived to the end of the experiment on Day 84 (Figure 4-4). 
These data demonstrate that LOXO-292 inhibited the tumor growth of a RET fusion-
dependent PDX implanted directly into the brain in mice (Subbiah et al. 2018). 
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Figure 4-4 
Inhibition Tumor Growth in a RET Fusion-Dependent Patient 
Derived Xenograft Implanted into the Brain in Mice 
 
Abbreviations: PDX-patient-derived xenograft; RET-rearranged in transfection. 
 
4.1.3 
Secondary Pharmacodynamics 
4.1.3.1 
In Vitro Studies 
The inhibitory effects of LOXO-292 were tested on 329 non-RET kinases for which an 
inhibition assay was available commercially. At a concentration of 0.1 µM, which is 
approximately 250-fold greater than its IC50 against the human wild-type RET enzyme, 
LOXO-292 was at least 250-fold more selective for RET than for 98% of other kinases 
tested. This high degree of selectivity was maintained against select kinase off-targets when 
validated in additional enzyme and cell-based assays (Figure 4-1). 
LOXO-292 was evaluated at a concentration of 1 µM against 54 targets in a broad screen 
of receptors, enzymes, and nuclear targets. Significant inhibition (≥ 50%) was observed for 
two targets: the 5-HT transporter (70.2% inhibition of antagonist radioligand) and a2c(h) 
(51.7% inhibition of antagonist radioligand). There were no other findings. The concentration 
of 1 μM is approximately 13- to 5-fold higher than the maximum unbound plasma 
concentration at the clinical doses of 80 mg BID and 160 mg BID, respectively. 
4.2 
Safety Pharmacology 
As part of the development program for LOXO-292, three stand-alone safety pharmacology 
studies were conducted. Additionally, individual safety pharmacology endpoints 
(cardiovascular and CNS) were included in the study designs of the GLP repeated-dose 
toxicity studies in the rat and minipig. 
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A tabular summary of the LOXO-292 GLP safety pharmacology program is provided in 
Table 4-1. 
LOXO-292 demonstrated a low risk for inducing delayed ventricular repolarization, QTc 
prolongation, and unstable arrhythmias. In a GLP in vitro hERG assay, LOXO-292 had an 
IC50 value of 1.1 µM, which is approximately 14- to 6-fold higher than the maximum 
unbound concentration (Cmax(unbound) = 80 nM and 190 nM) at the clinical dose of 80 mg BID 
and 160 mg BID, respectively (refer to Section 5.1).  
No abnormal ECG waveforms, arrhythmias or quantitative effects on ECG and 
hemodynamic data were attributed to LOXO-292 administration at single doses up to 
12 mg/kg when given orally to conscious telemetry-instrumented minipigs. In addition, 
there were no ECG changes after 4 weeks of repeat dosing in minipigs. In the 3-month 
repeated-dose study, in female minipigs administered 5 mg/kg/day of LOXO-292, an 
increase in QTc interval was noted on Day 88. As compared with time-matched controls, 
the increase was approximately 12%; as compared with the animals’ predose baseline QTc 
values, the increase was approximately 7%. These low magnitude QTc changes were 
potentially LOXO-292-related but were not considered adverse. 
LOXO-292 had no effects on respiratory function in rats given single doses up to 45 mg/kg, 
the highest dose given. 
Neurobehavioral function, including functional observational behavioral (FOB) tests and 
locomotor activity assessments (LMA), was assessed in the 28-day repeated-dose study in 
rat. Low locomotor activity in the arena was noted in males given 75/45 mg/kg/day and 
females given 150/120 mg/kg/day. Mean forelimb grip strength was also significantly 
decreased in males given 75/45 mg/kg/day. In addition, lower values for fine movements or 
rearing was noted at 75/45 mg/kg/day in males. All findings were generally reversible and 
were attributed to the animals’ poor general condition and body weight changes. Thus, the 
findings were deemed high-dose toxic alterations rather than specific neurological effects. 
Additionally, no microscopic abnormalities in neuronal tissues were found. 
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Table 4-1 
GLP Safety Pharmacology Studies  
Study Category 
Test Species and Study Description  
GLP 
Noteworthy Findings 
hERG 
Transgenic HEK293 cells stably expressing hERG; LOXO-292 
concentrations of 0.3, 1, 3 and 10 μM. 
Yes 
Concentration-dependent inhibition of hERG channel 
observed between 0.3 and 10 μM. IC50 estimated at 1.1 μM.  
Cardiovascular 
Telemetry-instrumented conscious male Göttingen minipigs given 
a single dose of LOXO-292 at 0, 2, 5 and 12 mg/kg PO in Latin 
square design with at least 7 days between doses. Cardiovascular 
data and body temperature collected.  
Yes 
No abnormal ECG waveforms, arrhythmias or quantitative 
effects on ECG and hemodynamic data. No change in body 
temperature at any dose. NOEL for cardiovascular function 
was 12 mg/kg. 
Cardiovascular 
As part of 28-day repeated-dose design in Göttingen minipigs, 
ECGs were recorded pre-dose and once at approximately 2 hours 
post-dose on Day 3 and Day 23 of the dosing phase. Animals were 
given LOXO-292 QD PO at 0, 2, 5 and 12 mg/kg/day for 28 days. 
Animals were anesthetized, and six lead ECGs were recorded. 
A qualitative and quantitative review of ECGs was conducted by 
board certified veterinary cardiologist.  
Yes 
No LOXO-292-related effects were observed on 
electrocardiographic evaluations. NOEL was 12 mg/kg for 
cardiovascular function. 
 
Cardiovascular 
As part of 91-day repeated-dose design in Göttingen minipigs, 
ECGs were recorded once for each sex during the predose phase, 
2 hours (±30 minutes) postdose on Days 4 (all groups) and 86 
(Groups 1 through 3 males) or 88 (Groups 1 through 3 females) of 
the dosing phase, and on Day 26 (Groups 1 through 3 males), 
25 (Groups 1 through 3 females), or 28 (Group 4 males and 
females) of the recovery phase. Animals were given LOXO-292 
QD PO at 0, 2, 5 mg/kg/day for 91 days. Due to moribundity at 
15 mg/kg/day, 3 males and 4 females were sacrificed on Days 
27 (males) and 26 (females) of the dosing phase. The remaining 
animals in this dose group were placed on a 4-week recovery 
period. Animals were anesthetized, and six lead ECGs were 
recorded. A qualitative and quantitative review of ECGs was 
conducted by board certified veterinary cardiologist. 
Yes 
No test article-related abnormalities in rhythm or waveform 
morphology were noted, based on comparisons of predose 
and postdose ECG recordings. No LOXO-292-related 
change in ECG parameters was noted, and all ECGs 
evaluated were quantitatively considered normal in males at 
all doses and the low and high dose (Day 4 only for high 
dose as dosing was stopped due to severe toxicity on Day 
26) females. 
Mean QTc interval and mean QT values were statistically 
significantly different on Day 88 of the dosing phase in 
females administered 5 mg/kg/day (mean QTc value of 
399 ms and mean QT value of 365 ms), compared with 
controls (mean QTc value of 357 ms and mean QT value of 
316 ms) and predose values (mean QTc value of 372 ms 
and mean QT value of 340 ms). Percentage change in QTc 
on Day 88 for females at 5 mg/kg/day compared with the 
time matched percentage change in QTc for controls and 
predose values, showed prolongation in QTc was 
approximately 12% and 7 % increased, respectively. This 
slight increase QTc prolongation was potentially related to 
LOXO-292 administration. Overall, the potential 
LOXO-292-related QTc changes found at 5 mg/kg/day on 
Day 88 in females were of low magnitude and considered 
not adverse. 
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Study Category 
Test Species and Study Description  
GLP 
Noteworthy Findings 
Respiratory 
Male Sprague-Dawley rats (8 per group) given single dose of 
vehicle or LOXO-292 at 5, 20 and 45 mg/kg PO. Respiratory 
function measured using head-out plethysmography. 
Yes 
No respiratory effects detected. NOEL for respiratory 
function was 45 mg/kg. 
Central nervous 
system 
As part of 28-day repeat-dose study design, rats were given 
LOXO-292 at 0, 5, 20 and 75/45 mg/kg/day for males and 0, 15, 
50 and 150/120 mg/kg/day for females QD PO for 28 days. 
Functional observational battery tests and locomotor activity 
assessments conducted pre-dose, on Day 23 of the dosing phase 
and on Week 4 of recovery. 
Yes 
On Day 23 of dosing - increase of low locomotor activity in 
arena in high dose animals. Decrease in mean forelimb grip 
strength in males given 75/45 mg/kg/day. Findings were 
reversible.  
Decrease in number of basic movements and X + Y 
ambulation in males given 75/45 mg/kg/day. Lower mean 
values for fine movements or rearing in males given 
75/45 mg/kg/day. No significant findings during recovery. 
Findings were deemed high dose toxic effects rather than 
specific neurological effects.  
Abbreviations: ECG-electrocardiogram; GLP-Good Laboratory Practices; HEK-human embryonic kidney; hERG-human ether-à-go-go–related gene; IC50-concentration at which 
50% inhibition is achieved; kg-kilogram; mg-milligram; NOEL-no observable effect level; PO-orally; QD-once daily; μM-micromolar. 
 
 
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4.3 
Nonclinical Pharmacokinetics 
4.3.1 
Methods of Analysis 
Liquid chromatographic methods with detection by mass spectrometry (LC-MS) were used to 
quantify LOXO-292 and compound-related products in different matrices, including blood, 
plasma, and selected tissues of animals. The LC-MS methods used for GLP toxicity studies in 
the rat and minipig were validated according to FDA guidance. The calibration curve range was 
10 to 10,000 ng/mL for both species. A stable-label (deuterated) version of LOXO-292 was used 
as internal standard. 
4.3.2 
Absorption 
LOXO-292 has been given orally and IV to mice, rats, dogs, and minipigs. Oral PK has also 
been determined in the monkey. LOXO-292 was absorbed and bioavailable in all species tested. 
Following single and repeated doses at equivalent levels in rats, the exposure of LOXO-292 was 
generally greater in males than females across all studies. For a given dose, males had 
approximately twice the area under the concentration-time curve (AUC) as females. Exposure 
(maximum plasma concentration [Cmax] and area under the concentration-time curve from 
time 0 to 24 hours [AUC0-24]), increased with the increase in dose level in the rat. Exposure 
following repeated doses was generally similar to the exposure following a single dose. A sex 
difference in exposure in rodents is common and does not indicate such a difference should be 
expected in humans. In minipigs, in the 14-, and 28-, and 91-day studies, sex differences in 
LOXO-292 mean Cmax and AUC0-24 values were less than 2-fold. Exposure, as assessed by mean 
Cmax and AUC0-24 values, increased with the increase in dose level in both minipig studies. 
A small degree of accumulation was noted between the first and last day of dosing. 
4.3.3 
Distribution 
Following administration of an oral dose of 3-, 100-, or 300 mg/kg LOXO-292 to mice, the 
brain/plasma ratio of LOXO-292 was approximately 0.03, 0.05, and 0.07, respectively. These 
PK data suggest limited penetration of LOXO-292 into the CNS in mice. However, 
pharmacodynamic studies suggest anti-tumor activity of LOXO-292 in the brain of mice. 
4.3.4 
Plasma Protein Binding and Blood Distribution 
LOXO-292 has protein binding of approximately 97% in human plasma. A similar extent of 
binding was observed in mouse and rat (98% and 97% respectively), whereas dogs and minipigs 
showed a somewhat lower bound fraction (90% and 88%, respectively). 
In mouse, rat, and human blood, the blood-to-plasma ratios were less than 1, suggesting that 
a greater portion of the compound resides in the plasma compartment than in blood cells, 
whereas the blood-to-plasma ratio of LOXO-292 in beagle dog blood cells was approximately 1, 
suggesting that a similar portion of the compound resides in the blood and plasma compartments. 
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4.3.5 
Metabolism 
LOXO-292 was stable during incubation with human whole blood, but metabolized by 
microsomal fractions and hepatocytes from mice, rats, dogs, minipigs, and humans. 
4.3.6 
Metabolites 
The in vitro metabolism of LOXO-292 was studied in liver microsomes and hepatocytes from 
male CD-1 mice, male Sprague-Dawley rats, male beagle dogs, male Göttingen minipigs, and 
humans (mixed sex). In mouse, rat, dog, minipig, and human liver microsomes, the predominant 
metabolite was an N-oxide of LOXO-292. This N-oxide was also formed by mouse, minipig, and 
human hepatocytes. The significant human metabolites detected in vitro were also detected in 
corresponding incubations with rat and/or minipig microsomes and hepatocytes. The N-oxide 
and other minor metabolites were detected in the plasma of rats and minipigs given oral doses 
of LOXO-292. 
4.3.7 
Excretion 
Renal excretion appears to be a minor pathway of elimination of LOXO-292. In minipigs given 
an IV dose of LOXO-292, urine collected through 48 hours after dosing contained 2.63% of the 
administered dose. 
4.3.8 
Exposure in Toxicity Studies Compared to Human Exposure 
At the no-observable-adverse-effect-level (NOAEL) in the 28-day toxicity studies in the rat, 
steady-state exposures (AUCs) were 1.7–2.2 times and 0.7–0.8 times the AUC in humans at the 
dose of 80 mg BID and 160 mg BID, respectively. At the NOAEL in the 91-day toxicity studies 
in the rat, steady-state exposures (AUCs) were 0.8–2.2 times and 0.3–0.8 times the AUC in 
humans at the dose of 80 mg BID and 160 mg BID, respectively. At the NOAEL in the minipig 
in the 28-day toxicity study, AUCs were 1.0 and 0.4 times the AUC in humans at the dose of 
80 mg BID and 160 mg BID, respectively. At the NOAEL in the minipig in the 91-day toxicity 
study, AUCs were 0.2–0.6 and 0.1–0.2 times the AUC in humans at the dose of 80 mg BID and 
160 mg BID, respectively. At the severely toxic dose in 10% of animals (STD 10) established in 
the rat 28-day toxicity study, AUCs were 6.7–11 times and 2.5–4.3 times the AUC in humans at 
the dose of 80 mg BID and 160 mg BID, respectively. At the highest non-severely toxic dose 
(HNSTD) established in the rat 91-day toxicity study, AUCs were 3.5–6.6 times and 1.3–2.5 
times the AUC in humans at the dose of 80 mg BID and 160 mg BID, respectively. At the 
HNSTD established in the male minipig 91-day toxicity study, AUCs were 0.5 times and 
0.2 times the AUC in humans at the dose of 80 mg BID and 160 mg BID, respectively 
(Table 4-2). 
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Table 4-2 
Steady-State Human Pharmacokinetic Parameters of LOXO-292 at Doses 
of 80 mg BID and 160 mg BID, Compared to Exposure at Steady State in 
Toxicity Studies Conducted in Rats and Minipigs 
Species 
Doseb 
Sex 
Cmax 
(ng/mL) 
Steady-State 
AUC0-24 
(ng*h/mL)c 
Actual Exposure in Rat 
and Minipig (Fold over 
Human Exposure) a 
To 80 mg 
BID 
To 160 mg 
BID 
Cmax AUC c Cmax 
AUCc 
Human 
80 mg BID 
M/F 
1400 
22700 
- 
- 
- 
- 
160 mg BID 
M/F 
3180 
55700 
- 
- 
- 
- 
GLP 
28-day 
Rat 
5 mg/kg/day 
M 
1220 
14900 
0.9 
0.7 
0.4 
0.3 
15 mg/kg/day 
F 
3300 
9480 
2.4 
0.4 
1.0 
0.2 
20 mg/kg/day  
M 
4450 
39100 
 
3.2 
2.2 
1.4 
0.7 
50 mg/kg/day 
F 
8380 
50800 
 
6.0 
1.7 
2.6 
0.9 
75/45 mg/kg/day 
M 
11700 
151000 
8.4 
6.7 
3.7 
2.7 
150/120 mg/kg/day 
F 
19100 
260000 
13.6 
11.5 
6.0 
4.7 
GLP  
91-day  
Rat 
2 mg/kg/day 
M 
508 
6030 
0.4 
0.3 
0.2 
0.1 
7.5 mg/kg/day 
F 
1570 
3040 
1.1 
0.1 
0.5 
0.1 
7.5 mg/kg/day 
M 
1490 
18500 
1.1 
0.8 
0.5 
0.3 
25 mg/kg/day 
F 
10700 
50400 
7.6 
2.2 
3.4 
0.9 
20 mg/kg/day 
M 
6780 
80400 
4.8 
3.5 
2.0 
1.4 
75 mg/kg/day 
F 
15700 
149000 
11.2 
6.6 
4.9 
2.7 
GLP 
28-day 
Minipig 
2 mg/kg/day 
M/F 
271 
5180 
0.2 
0.2 
0.1 
0.1 
5 mg/kg/day 
M/F 
560 
10500 
0.4 
0.5 
0.2 
0.2 
12 mg/kg/day 
M/F 
1120 
23200 
0.8 
1.0 
0.4 
0.4 
GLP 
91-day 
Minipig 
2 mg/kg/day 
M/F 
222 
4250 
0.2 
0.2 
0.1 
0.1 
5 mg/kg/dayd 
M/F 
639 
12600 
0.5 
0.6 
0.2 
0.2 
15 mg/kg/day 
M/F 
1150e 
18100e 
0.8 
0.8 
0.4 
0.3 
Abbreviations: AUC-area under the curve; AUC0-24-area under the concentration-time curve from time 0 to 
24 hours; BID-twice daily; Cmax-maximum plasma concentration; GLP-Good Laboratory Practices; HNSTD-highest 
non-severely toxic dose; NOAEL-no-observable-adverse-effect-level; STD10-dose at which 10% of animals have 
severe toxicity. 
a Calculated as (actual animal exposure / human exposure). 
b Underlined values indicate the NOAEL; STD 10 in rat is in bold; HNSTD in male minipig in bold; HNSTD in rat 
is in italics. 
c Cmax and AUC values and margins are for 80 mg BID and 160 mg BID. 
d HNSTD in male minipig was 5 mg/kg/day; NOAEL in male and female minipig was 2 and 5 mg/kg/day, 
respectively. 
e Day 1 data due to early sacrifice and termination of dosing on Day 27 (males) and Day 26 (females). 
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4.4 
Toxicology 
4.4.1 
Repeat-dose Toxicity in Sprague-Dawley Rats 
Four repeated-dose toxicity studies were performed in rats. All included toxicokinetic (TK) 
analyses. Data are tabulated in Table 4-3 for all studies. The GLP 28-day and 91-day repeated-
dose studies are detailed in this section. 
In the GLP 28-day study, rats were given LOXO-292 at 0, 5, 20, or 75/45 mg/kg/day in males 
and 0, 15, 50, or 150/120 mg/kg/day in females for 28 consecutive days by oral gavage followed 
by a 28-day recovery period for a subset of animals. The dose for males originally given 
75 mg/kg/day was reduced to 45 mg/kg/day on Day 11 due to severe toxicity. Similarly, the dose 
for females was reduced from 150 to 120 mg/kg/day on Day 16.  
Two males at 75 mg/kg/day were sacrificed on Day 8, and 1 female at 150/120 mg/kg/day was 
sacrificed on Day 17 due to severe clinical signs. No specific cause(s) for moribundity was 
determined. 
Clinical signs in surviving animals at the high dose included clear oral discharge, discolored red 
hair coat, piloerection, rough hair coat, and white teeth. Changes in incisor teeth did not fully 
reverse clinically, but there was evidence of partial recovery observed microscopically. 
At the high dose, decreases in body weight (males) and decreases in body weight gain (both 
sexes) correlated with decreased food consumption. During the recovery phase, high dose males 
and females lost weight between Days 1 through 8. The teeth lesions likely contributed to the 
body weight decrements in the initial 8 days of recovery, but these effects rebounded in the 
second interval after food in powdered meal form was offered. Despite this rebound, body 
weight changes were considered adverse since they remained lower in the high-dose group even 
after the powdered meal form was offered. 
Findings in the functional observational battery tests and LMA (Section 4.2) were attributed to 
high-dose toxic effects rather than specific neurological effects.  
Clinical pathology changes occurred primarily in the high-dose group and reflected minor bone 
marrow effects (lower platelet and reticulocyte counts), tissue mineralization (higher inorganic 
phosphorus concentration), possible inflammation (increase in total leukocytes; decrease in total 
protein and albumin), and liver effects (higher alanine aminotransferase [ALT], alkaline 
phosphatase [ALP], aspartate aminotransferase [AST] and cholesterol levels), decreased food 
consumption, and dehydration. Clinical pathology findings in animals that survived to terminal 
sacrifice were non-adverse and mostly reversible. Reversible, LOXO-292-related decreases in 
liver and thymus weights occurred in males at 75/45 mg/kg/day with no associated microscopic 
lesions. The following findings were observed microscopically in high dose animals: the white, 
discolored incisors noted grossly showed dysplastic odontoblast epithelium and irregular dentin 
and enamel formation. Teeth lesions were partially reversed. Mineralization occurred in males 
(multi-tissue) and in females (stomach). Minor changes included: epithelial atrophy of the 
tongue; increases in pulmonary alveolar macrophages; acinar cell necrosis and decreased 
zymogen granules of the pancreas; ectasia of crypts/ducts of Brunner’s gland (duodenum) and 
bone marrow hypocellularity. Physeal dysplasia that was dose related was observed in males 
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(≥ 20 mg/kg/day) and females (150/120 mg/kg/day). Neither tissue mineralization or physeal 
dysplasia fully reversed. 
Doses of 20 mg/kg/day of LOXO-292 in males and 50 mg/kg/day in females were the 
NOAEL which corresponded to a mean Cmax of 4450 ng/mL and 8380 ng/mL and AUC0-24 
of 39100 ng*h/mL and 50800 ng*h/mL for males and females, respectively. The STD 10 was 
45 mg/kg/day for males and 120 mg/kg/day for females which corresponded to a mean Cmax 
of 11700 ng/mL and 19100 ng/mL and AUC0-24 of 151000 ng*h/mL and 260000 ng*h/mL 
for males and females, respectively. 
In the GLP 91-day study, rats were given LOXO-292 at 0, 2, 7.5 or 20 mg/kg/day in males and 0, 
7.5, 25, or 75 mg/kg/day in females for 91 consecutive days by oral gavage followed by a 28-day 
recovery period for a subset of animals. 
Non-adverse, clinical observations included: malocclusions, white teeth, and missing teeth and 
thinning haircoat. Teeth abnormalities persisted through the recovery phase. Due to teeth 
abnormalities, several males and females were given powdered meal form during the dosing and 
recovery phases. Minor body weight changes were noted, but were also considered not adverse.  
Additionally, all clinical pathology findings were minor and non-adverse based on Days 42 and 
92 evaluations. The changes reflected minor bone marrow effects (decrease in reticulocytes), 
possible inflammation (decrease in total protein and albumin) and higher phosphorus 
concentration at high doses which may have reflected LOXO-292-related pharmacology even 
though tissue mineralization was not seen microscopically. 
No LOXO-292-related effects on sperm total count, density, motility, or morphology were noted 
during the dosing or recovery phases.  
Key microscopic findings occurred in the testis, epididymis, and vagina. Of lesser importance 
were changes in bone marrow and lung. Non-reversible (after a 28-day recovery period), 
testicular degeneration was detected at ≥ 7.5 mg/kg/day of LOXO-292 and correlated with 
macroscopic observations and decreased testis weights. The epididymis had luminal cell debris 
and reduced luminal sperm in males administered 20 mg/kg/day: changes secondary to effects in 
the testis. These male reproductive changes were adverse at 20 mg/kg/day. Females at 
≥ 25 mg/kg/day showed changes consistent with altered, unstageable, estrus cycle that included 
vaginal mucification. Vaginal changes at 75 mg/kg/day were adverse. Bone marrow 
hypocellularity was a minor high dose effect that correlated with lower reticulocyte counts in 
males. At the high dose, there were minor increases in alveolar macrophage infiltrates in the 
lungs. 
Except for male reproductive findings, all other LOXO-292-related microscopic findings in both 
sexes reversed after a 28-day recovery period. 
The NOAEL was 7.5 mg/kg/day for males and 25 mg/kg/day for females which corresponded to 
Day 91 mean plasma LOXO-292 Cmax and AUC0-24 values of 1490 ng/mL and 10,700 ng/mL, 
and AUC0-24 values of 18,500 h*ng/mL and 50,400 h*ng/mL for males and females, respectively. 
The HNSTD was 20 mg/kg/day for males and 75 mg/kg/day for females which corresponded to 
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Day 91 mean plasma LOXO-292 Cmax of 6780 ng/mL and 15,700 ng/mL, and AUC0-24 values of 
80,400 h*ng/mL and 149,000 h*ng/mL for males and females, respectively. 
4.4.2 
Repeated-Dose Toxicity in the Göttingen Minipig 
Three repeated-dose toxicity studies that included TK analyses were performed in minipigs. Data 
are tabulated in Table 4-3 for all studies. The GLP 28-day and 91-day repeated-dose studies are 
detailed in this section. 
In the GLP 28-day study, minipigs were given LOXO-292 at 0, 2, 5 or 12 mg/kg/day via oral 
gavage for 28 days followed by a 28-day recovery period for a subset of animals. All animals 
survived. No LOXO-292-related effects were observed on clinical observations, body weight, 
ophthalmic examinations, ECG evaluations, organ weights, or macroscopic examinations. 
Clinical pathology effects were minor and non-adverse. Microscopic findings included atrophy 
of the tongue and stomach as well as lymphocyte depletion of lymph nodes. None of the changes 
were adverse and all changes reversed. The NOAEL was 12 mg/kg which corresponded to a 
mean Cmax value of 1120 ng/mL and mean AUC0-24 value of 23200 ng*h/mL on Day 28. 
In the GLP 91-day study, minipigs were given LOXO-292 at 0, 2, 5 or 15 mg/kg/day via oral 
gavage for 91 days followed by a 28-day recovery period for a subset of animals. The dose of 
15 mg/kg/day was not tolerated; 3 males and 4 females were sacrificed on Days 27 (males) and 
26 (females). Dosing was terminated in this dose group and the remaining animals in this group 
were placed on recovery for 4 weeks. Clinical signs included: lameness, reluctance to rise, and 
lateral recumbency, with pain which could not be palliated, red oral discharge, hypoactivity, and 
anorexia.  
Clinical pathology changes in these moribund animals were consistent with an inflammatory 
response, which involved the GI tract as well as physeal changes (minimally higher ALP activity 
and phosphorus concentration), dehydration, and general debilitation. These changes correlated 
with microscopic evidence of inflammation (stomach, esophagus), and growth plate lesions 
(physeal dysplasia). Mucosal atrophy occurred in multiple tissues (tongue, esophagus, stomach). 
Other microscopic findings included testicular degeneration, epididymal lesion (luminal cellular 
debris), and ovarian changes (decreased corpora lutea; corpora luteal cysts). Microscopic 
findings in the testis, epididymis, ovary, femur (growth plate), and upper GI tract were all 
considered adverse. 
At the lower doses of 2 and 5 mg/kg/day, there were no LOXO-292-related clinical or 
ophthalmic observations, and no effects on body weight or body weight change or changes in 
clinical pathology parameters. A slight increase in QTc prolongation (Section 4.2) was noted in 
females at 5 mg/kg/day on Day 88 of the dosing phase and considered not adverse.  
Microscopically, testicular degeneration, epididymal changes (luminal cellular debris) and 
corpora luteal cysts (ovary) were present at LOXO-292 doses of 2 or 5 mg/kg/day. At these 
doses, testicular findings correlated with decreased testis weights and epididymal changes 
correlated with decreased epididymis weights. At ≥ 2 mg/kg/day, testis, epididymis and ovary 
findings persisted during recovery phase, whereas at 15 mg/kg/day, stomach and esophagus 
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lesions were still present. Only testis and epididymis findings were considered adverse at these 
lower doses.  
The NOAEL could not be determined for males following dosing for 13 weeks. However, the 
HNSTD for males and the NOAEL for females were 5 mg/kg/day when administered for 
13 weeks. This corresponded to mean plasma LOXO-292 Cmax and AUC0-24 values of 712 ng/mL 
and 13,200 h*ng/mL, respectively, in males, and 565 ng/mL and 11,900 h*ng/mL, respectively, 
in females on Day 91 of the dosing phase. 
4.4.3 
Genotoxicity 
LOXO-292 was not mutagenic in a GLP in vitro bacterial reverse mutation assay with four 
strains of Salmonella typhimurium (TA100, TA98, TA1535, and TA1537) and at the tryptophan 
locus of Escherichia coli strain WP2 uvrA in the presence or absence of an exogenous metabolic 
activation system.  
LOXO-292 was negative in a GLP in vitro mammalian cell micronucleus assay for the induction 
of micronuclei in HPBL in both the absence and presence of an exogenous metabolic activation 
system. 
A DRF in vivo micronucleus assay was conducted with LOXO-292 in the rat. The dose levels 
tested were 250, 500, 1000, and 2000 mg/kg. Piloerection was observed at all doses in males and 
females at ≥ 500 mg/kg. Moderate weight loss (approximately 10%) was noted in all LOXO-292 
treated males and at ≥ 500 mg/kg in females. The ratio of polychromatic erythrocytes (PCEs) 
/normochromatic erythrocytes (NCEs) or %PCE was reduced in both sexes at all dose levels. 
Males at 1000 and 2000 mg/kg displayed 42 and 47% toxicity, respectively, and females at 1000 
and 2000 mg/kg displayed 52 and 51% toxicity, respectively, which was within the criteria 
(reduction in the PCE/NCE ratio of more than 50%, but not less than to 20% of the control value 
[50–80%]) for selecting a maximum dose to be evaluated for micronucleus induction. Thus, the 
doses of 500, 1000, and 2000 mg/kg were selected for the second DRF assay in male rats which 
included bone marrow histopathology and cytology as endpoints to evaluate bone marrow 
toxicity. These endpoints were included in order to identify the highest dose that does not induce 
marked or severe cytological or histopathological alterations in bone marrow. This second DRF 
in vivo micronucleus assay is in progress. 
4.4.4 
Carcinogenicity 
No carcinogenicity studies have been performed to date with LOXO-292. 
4.4.5 
Reproductive and Developmental Toxicology 
A non-GLP DRF embryo-fetal development study was conducted in rats given LOXO-292 via 
oral gavage at 0, 50, 100, and 200 mg/kg/day during the major period of organogenesis (Day of 
Gestation [DG] 6 through 17). All females survived to the scheduled necropsy. Clinical 
observations of red material on various body surfaces were noted in the 200 mg/kg/day group 
during DG 14–21. A lower mean net body weight and a lower net body weight gain were noted 
in the 200 mg/kg/day group compared to the control group and were considered LOXO-292-
related and adverse. All females in the 100 and 200 mg/kg/day groups had 100% early 
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resorptions, precluding evaluation of fetal weights, sex ratio, and morphology in these groups. 
In the 50 mg/kg/day group, 6 of 8 females had resorbed litters (100% early resorptions); the 
remaining 2 females had primarily early resorptions and only 3 viable fetuses across the 2 litters. 
As a result, a higher mean litter proportion of postimplantation loss and lower mean litter 
proportion of viable fetuses were noted in the 50 mg/kg/day group compared to the control 
group. The 3 viable fetuses in the 50 mg/kg/day group had lower fetal body weights compared to 
the control group means. For the 3 viable fetuses in the 50 mg/kg/day group, 2 fetuses in 1 litter 
were noted with a short tail and the single fetus in the other litter was noted with a small snout 
and localized fetal edema. A short tail was also noted for 1 fetus in the control group. The effects 
on intrauterine growth and survival and fetal morphology were considered LOXO-292-related 
and adverse. The NOAEL for maternal toxicity was 100 mg/kg/day which corresponded to a 
mean AUC and Cmax of 185,000 ng*h/mL and 14,600 ng/mL, respectively, on DG 17. Due to 
embryo lethality noted at all dosage levels, no NOAEL could be determined for embryo-fetal 
development. LOXO-292 is a developmental toxicant and is embryolethal. 
As summarized above in the repeat-dose studies, microscopic findings in male and female 
reproductive systems were identified in the rat and minipig repeated-dose studies of LOXO-292. 
In the minipig, ovarian atrophy characterized as decreased or absence of corpora lutea, number 
and size of follicles and stromal proliferation was present at ≥ 25 mg/kg/day (non-GLP 14-day 
repeated-dose study; Table 4-3). Decreased corpora lutea were also found at 15 mg/kg/day 
(Day 26 of dosing) and corpora luteal cysts (GLP 91-day repeated-dose study) occurred at 
˃ 2 mg/kg/day. Thus, the ovary was a target in the minipig. In the rat, vaginal mucification and 
altered (unstageable) estrous cycle were noted in the 91-day toxicity study. The vagina was a 
new target in this species. In the rat and minipig, the testes and epididymis were new target 
organs identified in the 91-day toxicity studies (Section 4.1.1 and 4.4.2). In both species, the 
microscopic finding was testicular degeneration associated with luminal cell debris and/or 
reduced luminal sperm in the epididymis. Despite adverse testicular changes in the rat that were 
noted microscopically, there were no effects on sperm total count, density, motility, or 
morphology even at the highest dose (20 mg/kg/day, sperm were not analyzed in minipigs). 
In summary, lesions in male reproductive system persisted through the end of the recovery and 
were considered adverse at all doses in the minipig and at 20 mg/kg/day in the rat.
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Table 4-3 
Summary of LOXO-292 Toxicology Program – Repeat-Dose Studies 
Species 
Study Description 
GLP 
Noteworthy Findingsa 
Rat 
Daily (QD) oral dosing for 4 days 
followed by 5-day recovery period; 
Doses: 0, 10, 30 and 
100 mg/kg/day for males and 0, 30, 
100 and 300 mg/kg/day for 
females. 
No 
No mortality. Clinical signs of thinness, hunched posture and piloerection in 
females at 300 mg/kg/day. Body weight loss for females at 300 mg/kg/day; 
decrease body weight gain for males at 100 mg/kg/day correlated with decrease in 
food consumption. 
Rat 
Daily (QD) oral dosing for 14 days; 
Doses: 0, 10, 30, and 
100 mg/kg/day for males and 0, 20, 
60 and 180 mg/kg/day for females.  
No 
No mortality. Microscopic findings were identified in: bone marrow, glandular 
stomach, pancreas, thymus, heart [coronary vasculature], aorta and kidney in male 
rats, and bone marrow, glandular stomach, and pancreas in female rats. These 
tissue changes were more severe in male rats. NOAEL of 10 and 20 mg/kg for 
males and females, respectively. 
Rat 
Daily (QD) oral dosing for 28 days 
with a 28-day recovery period; 
dose levels were 0, 5, 20 and 75/45 
mg/kg/day for males and 0, 15, 50, 
150/120 mg/kg/day for females.  
Yes 
Mortality: 2 males on Day 8 and 1 female on Day 17. Doses for males was 
lowered from 75 to 45 mg/kg/day after a 3-day (Day 8, 9 and 10) dosing holiday. 
For females, dose lowered from 150 to 120 mg/kg/day on Day 16. Females: 
persisting severe clinical signs, given a 3-day dosing holiday (Days 18-20). 
Microscopic targets were bone marrow, liver, physis, multiple tissues 
(mineralization), tongue, pancreas, lung, Brunner’s gland (duodenum) and incisor 
teeth. NOAEL was 20 and 50 mg/kg for males and females, respectively. STD 10 
was 45 and 120 mg/kg for males and females, respectively.  
Rat  
Daily (QD) oral dosing for 91 days 
with a 28-day recovery period; 
Doses: 0, 2 5 and 20 mg/kg/day for 
males and 0, 7.5, 25 and 75 
mg/kg/day for females. 
Yes 
Clinical signs of teeth abnormalities (malocclusion, white teeth, and missing 
teeth) and thinning haircoat at 20 mg/kg/day (males) and 75 mg/kg/day (females). 
Microscopic targets: testis, epididymis, vagina, bone marrow and lung. The 
NOAEL is 7.5 mg/kg/day for males and 25 mg/kg/day for females. The HNSTD 
is 20 mg/kg/day and 75 mg/kg/day for females. 
Minipig 
Daily (QD) oral dosing for 14 days; 
Doses: 0, 5, 25, and 65 mg/kg/day.  
No 
Termination of 65 mg/kg/day dose group due to moribundity on Day 7. 
Unscheduled sacrifice of 1 female administered 25 mg/kg/day on Day 11 due to 
moribundity. Microscopic targets: bone marrow, lymphoid tissues, 
gastrointestinal tract, pancreas, ovary, liver, lung, kidney, and adrenal gland. 
NOAEL was 5 mg/kg.  
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Species 
Study Description 
GLP 
Noteworthy Findingsa 
Minipig 
Daily (QD) oral dosing for 28 days 
with a 28-day recovery period; 
dose levels were 0, 2, 5, and 
12 mg/kg/day.  
Yes 
No mortality. Microscopic targets: tongue, stomach, lymph nodes. NOAEL was 
12 mg/kg. 
Minipig 
Daily (QD) oral dosing for 91 days 
with a 28-day recovery period; 
Doses: 0, 2, 5, and 15 mg/kg/day.  
Yes 
Mortality: 3 males and 4 females at 15 mg/kg/day were sacrificed on Day 27 
(males) and Day 26 (females). The rest of animals in this dose group placed on 
recovery for 4 weeks. Microscopic targets: stomach which was cause of 
moribundity at 15 mg/kg/day. Other microscopic targets at 15 mg/kg/day 
included: physis, testis, epididymis, ovary, esophagus and tongue. Microscopic 
targets at 2 and 5 mg/kg/day after 91 days of dosing included: testis, epididymis, 
and ovary. No NOAEL was established for males. For females the NOAEL was 5 
mg/kg/day. For males the HNSTD was 5 mg/kg/day. 
Abbreviations: DRF-dose range finding GLP-Good Laboratory Practices; HNSTD-highest non-severely toxic dose; kg-kilogram; mg-milligram; NOAEL-no-
observable-adverse-effect-level; QD-once daily; STD 10-severely toxic dose in 10% of the animals. 
a 
Target represents site(s) of microscopic findings 
 
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Table 4-4 
Summary of LOXO-292 Toxicology Program – Genotoxicity and Other Studies 
Species 
Study Description 
GLP 
Findings 
(in vitro) 
Bacterial reverse mutation assay in 
2 strains of Salmonella typhimurium 
No 
LOXO-292 did not induce reverse mutations. 
 
(in vitro) 
Bacterial reverse mutation assay in 4 
strains of Salmonella typhimurium 
(TA100, TA98, TA1535, and 
TA1537) and at the tryptophan locus 
of Escherichia coli strain WP2 uvrA 
in the presence and absence of an 
exogenous metabolic activation 
system 
Yes 
LOXO-292 did not induce reverse mutations. 
(in vitro) 
In Vitro Mammalian Cell 
Micronucleus Assay in HPBL in the 
presence and absence of an 
exogenous metabolic activation 
system. 
 
Yes 
LOXO-292 was negative for the induction of micronuclei in the in vitro 
mammalian micronucleus test using HPBL in the presence of metabolic 
activation and negative with a 24-hour treatment in the absence of metabolic 
activation. In the non-activated 4-hour exposure group, a statistically significant 
increase in micronuclei induction (1.15%) was observed only at the lowest 
precipitating concentration of 150 μg/mL and the effect was dose. The small 
increase in micronucleated cells that was within the historical control range and 
only at a single precipitating concentration in the 4-hour treatment in the absence 
of metabolic activation is concluded by expert judgement to not be biologically 
relevant. Thus, it was concluded that under the conditions of this study, LOXO-
292 was negative for the induction of micronuclei in the presence and absence of 
the exogenous metabolic activation system.  
Rat 
In vivo dose range finding (DRF) in 
vivo micronucleus assay. Single oral 
dose at dose levels were 250, 500, 
1000 or 2000 mg/kg. 
No 
Clinical signs of piloerection in males and females at 500, 1000, and 
2000 mg/kg. Moderate weight loss at all doses in males and at 500, 1000, and 
2000 mg/kg in females.  
The ratio of (PCEs/NCEs [%PCE]) was reduced in both sexes at all dose levels: 
Males displayed 42 and 47 % toxicity at 1000 and 2000 mg/kg, respectively. 
Females at 1000 and 2000 mg/kg displayed 52 and 51% toxicity, respectively.  
In this study, the dose of 2000 mg/kg was the MTD.  
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Species 
Study Description 
GLP 
Findings 
Rat 
Embryo-fetal development study 
Doses of 0, 50, 100 or 
200 mg/kg/day from Gestation Days 
6-17.  
No 
Decrease in mean net body weight and a lower net body weight gain at 
200 mg/kg/day which was considered adverse. 
All females in the 100 and 200 mg/kg/day groups had 100% early resorptions. In 
the 50 mg/kg/day group, 6 of 8 females had resorbed litters (100% early 
resorptions); the remaining 2 females had primarily early resorptions and only 
3 viable fetuses across the 2 litters. The 3 viable fetuses in the 50 mg/kg/day 
group had lower fetal body weights compared to the control group. For the 
3 viable fetuses in the 50 mg/kg/day group, 2 fetuses in 1 litter were noted with a 
short tail and the single fetus in the other litter was noted with a small snout and 
localized fetal edema. A short tail was also noted for 1 fetus in the control group. 
The effects on intrauterine growth and survival and fetal morphology were 
considered LOXO-292-related and adverse. NOAEL for maternal toxicity was 
100 mg/kg/day. No NOAEL was established for embryo-fetal development as 
LOXO-292 was embryo-lethal at all doses.  
(in vitro) 
Molar Extinction Coefficient 
Determination 
No 
Molar extinction coefficient was 18850 L mol-1 cm-1 for LOXO-292. 
(in vitro) 
Neutral red uptake phototoxicity 
assay with BALB/c 3T3 mouse 
fibroblasts 
Yes 
LOXO-292 was not phototoxic. 
 
Abbreviations: GLP-Good Laboratory Practices; HPBL-human peripheral blood lymphocytes; PCE-polychromatic erythrocytes; NCE-normochromatic 
erythrocytes; MTD-maximum tolerated dose. 
 
 
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L o x o O nc ol o g y, I nc.  
 
I n vesti gat or’s Br oc h ure 
L O X O -2 9 2  
 
0 6 J u ne 2 0 1 9  
 
Versi o n 5. 0  
C o nfi de ntial & Pr o prietar y  
P a ge 3 8  
 
5  
E F F E C T S I N H U M A N S  
As of Marc h 3 0, 2 0 1 9, c li nical safet y data were a v aila ble fr o m 4 2 2 patie nts w h o ha ve recei v e d 
L O X O - 2 9 2 fr o m t he acti ve o n g oi n g P has e 1 / 2 st u d y of L O X O -2 9 2 ( St u d y L O X O -R E T - 1 7 0 0 1) 
i n patie nts wit h a d va nce d s oli d t u m ors, i ncl u di n g R E T  f usi o n- p ositi ve N S C L C , M T C , a n d ot her 
t u m ors wit h i ncrease d R E T acti vit y. 
T he data c ut off date f or i nt eri m P K a nal ysis is A pril 1 5, 2 0 1 9 f or St u d y L O X O-R E T - 1 7 0 0 1 
( n = 3 3 5). 
5. 1  
R ati o n ale f or Selecti o n of H u m a n D ose 
T he starti n g d os e of L O X O - 2 9 2 f or t h e P hase 1 st u d y (“A P hase 1/ 2 St u d y of Oral L O X O- 2 9 2 i n 
Patie nts wit h A d va nce d S oli d T u m ors, I ncl u di n g R E T  F usi o n- P ositi ve S oli d T u m ors, Me d ullar y 
T h yr oi d Ca n cer, a n d Ot h er T u m ors wit h R E T Acti vati o n [ LI B R E T T O- 0 0 1])” was 2 0 m g o n ce 
dail y, accor di n g t o t he F D A’s “ G e ner al G ui de f or Starti n g D ose Selecti o n f or a C yt ot o xic A ge nt 
i n Ca ncer Patie nts” a n d “ Esti mati n g t he Ma xi m u m Safe Starti n g D ose i n I nitial Cli nical Trials 
f or T her a pe utics i n A d ult Healt h y V ol u nteers ” (U. S. - F o o d-a n d -Dr u g -A d mi nistrati o n  2 0 0 5 ). 
D osi n g i n a d ults is base d o n fi x e d d osi n g i n m g (as o p p ose d t o m g/ m 2) as t here is n o e vi de n ce 
t hat d osi n g b y B S A  will re d uce i nter-s u bject variati o n i n a d ults, w hile pe diatric patie nts are 
d ose d o n a m g/ m 2 basis. Base d o n precli nical p har mac ol o g y e x peri me nts wit h h u ma n ca ncer 
cells i n vitr o a n d i n m uri ne x e n o graft m o dels, mea ni n gf ul i n hi biti o n of R E T  i n t u m ors is 
e x pecte d t o be ac hie v a bl e wit h oral d ose re gi me ns at t otal dail y d oses  ≥ 4 0 m g/ da y. T he d os a ge 
of 1 6 0 m g  BI D was  selecte d as t he rec o m me n de d P hase 2 d ose ( R P 2 D) bas e d o n safet y d ata  
( N = 8 2) a n d preli mi nar y efficac y dat a i n 6 4 e val u a ble patie nts  treat e d at d oses fr o m 2 0 m g  Q D  
t hr o u g h 2 4 0 m g  BI D (Dril o n  et al. 2 0 1 8). 
5. 2  
P h ar m a c o ki netics  a n d Pr o d uct Met a b olis m i n H u m a ns  
5. 2. 1  
Cli nic al P h ar m ac o l o gy 
5. 2. 1. 1  
A bs or pti o n a n d Bi oa v aila bilit y 
Oral bi oa vaila bilit y of a 1 6 0 -m g d ose of L O X O - 2 9 2 i n  
f or m ulati o n is 7 3 %. 
A p pr o xi matel y 2 4 % a n d 6 9 % of a r a di ola bele d d ose of L O X O- 2 9 2 i n s ol uti o n f or m u lati o n is 
rec o vere d as L O X O- 2 9 2 or its meta b olites i n uri ne a n d feces, res p ecti vel y. 
5. 2. 1. 2  
Effect of F o o d  
T here w as little effect of a hi g h -fat meal o n t he P K of L O X O- 2 9 2 i n a cr oss- o ver st u d y i n 
1 9 healt h y h u m a n v ol u nteers. 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 ti me 0 t he 
ti me of t he last meas ura ble c o nce ntr ati o n) a n d A U C 0- i nf (area u n der t he c o n ce ntrati o n -ti me c ur ve 
fr o m ti me 0 t o i nfi nit y) of L O X O -2 9 2 were  a p pr o xi matel y 9 % hi g her f oll o wi n g a dmi nistrati o n 
of 1 6 0 m g L O X O - 2 9 2 wit h a meal c o m pare d t o fasti n g, w hile Cma x  was a p pr o xi matel y 1 4 % 
l o wer wit h f o o d. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 2 2
C CI

L o x o O nc ol o g y, I nc.  
 
I n vesti gat or’s Br oc h ure 
L O X O -2 9 2  
 
0 6 J u ne 2 0 1 9  
 
Versi o n 5. 0  
C o nfi de ntial & Pr o prietar y  
P a ge 3 9  
 
5. 2. 1. 3  
Effect of O me pr az ole  
L O X O - 2 9 2 has p H- de p e n de nt s ol u bilit y a n d its P K ca n be affecte d b y a ge nts t hat m o dif y gastric 
p H s uc h as pr ot o n p u m p i n hi bit ors (e. g., o me praz ole). U n der  
 c o n diti o ns, f oll o wi n g a 
si n gle d ose of 1 6 0 m g L O X O- 2 9 2 a d mi nistere d t o 2 0 o me praz ole-treate d healt h y v ol u nteers, 
t he A U C a n d C ma x  of L O X O - 2 9 2 were a p pr o xi matel y 6 9 % t o 8 8 % l o w er t ha n f oll o wi n g 
a d mi nistrati o n of L O X O - 2 9 2 u n der  
 c o n diti o ns wit h o ut o me praz ole. 
T he e ff ect of o m e praz ole o n t he P K of L O X O- 2 9 2 is re d uce d w h e n L O X O- 2 9 2 is gi ve n wit h a 
hi g h -cal orie, hi g h-fat meal. T he A U C of L O X O - 2 9 2 f oll o wi n g a d mi nistrati o n of a si n gl e d ose of 
1 6 0 m g wit h a meal t o 2 0 o me praz ole -treate d healt h y v ol u nteers was a p pr o xi mately 2 % hi g her 
t ha n f oll o wi n g 1 6 0 m g L O X O - 2 9 2 gi ve n u n d er  
 c o n diti o ns wit h o ut o me praz ole, alt h o u g h 
C ma x  was a p pr o xi matel y 4 9 % l o wer. 
5. 2. 1. 4  
Effect of C Y P 3 A 4 I n hi bit ors a n d I n d ucers o n t he P K of L O X O- 2 9 2 
I n vitr o, L O X O- 2 9 2 is m eta b olize d b y cl o n e d, e x presse d h u ma n c yt o c hr o m e C Y P 3 A 4, b ut n ot 
C Y P 1 A 2, C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9. T hese data i n dicate t hat C Y P 3 A 4 is res p o nsi ble f or t he 
meta b olis m of L O X O - 2 9 2. 
M ulti ple - d ose a d mi nistrati o n of t he str o n g C Y P 3 A 4 i n hi bit or itrac o naz ole ( 2 0 0 m g Q D) t o 
1 2 healt h y v ol u nteers r es ulte d i n a n i ncreas e of a p pr o xi matel y 1 3 0 % a n d 3 0 % i n L O X O- 2 9 2 
A U C a n d C ma x  f oll o wi n g a si n gle 1 6 0- m g d os e of L O X O- 2 9 2, c o m p are d w he n L O X O -2 9 2 was 
gi ve n al o ne.  
C o n versel y, m ulti ple- d ose a d mi nistrati o n of t he str o n g C Y P 3 A 4 i n d ucer rifa m pi n ( 6 0 0 m g Q D) 
t o 1 2 healt h y v ol u nteers r es ulte d i n a decreas e of a p pr o xi matel y 8 7 % a n d 7 0 % i n L O X O- 2 9 2 
A U C a n d C ma x  f oll o wi n g a si n gle 1 6 0- m g d os e of L O X O- 2 9 2, c o m p are d w he n L O X O -2 9 2 was 
gi ve n al o ne.  
As str o n g C Y P 3 A 4 i n hi bit ors a n d i n d ucers affect t he P K of L O X O- 2 9 2, t heir c o nc urre nt 
a d mi nistrati o n wit h L O X O - 2 9 2 is restricte d. 
5. 2. 1. 5  
Effect of Dr u g Tr a ns p ort ers o n t he P K of L O X O - 2 9 2 
I n vitr o, L O X O- 2 9 2 is a s u bstrate of P- gl yc o pr otei n ( P-g p ) a n d breast ca n cer resista n ce pr otei n 
(B C R P ), b ut is n ot a s u bstrate f or O A T 1, O A T 3, O C T 1, O C T 2, O A T P 1 B 1, O A T P 1 B 3, M A T E 1, 
or M A T E 2 -K. I n a cli nical st u d y, t he P K of L O X O- 2 9 2 was n ot affecte d si g nifica ntl y b y a P-g p 
i n hi bit or. Si m ulta ne o us a d mi nistrati o n of a si n gle 1 6 0- m g oral d ose of L O X O- 2 9 2 wit h t he P-g p 
i n hi bit or rifa m pi n ( 6 0 0 m g) t o 1 2 healt h y  v ol u nt eers res ulte d i n a p pr o xi matel y 6 % a n d 1 9 % 
i ncreas e i n L O X O-2 9 2 A U C 0- 2 4 a n d Cma x , res pecti vel y, c o m pare d t o w h e n L O X O - 2 9 2 w as gi ve n 
al o ne, s h o wi n g n o mea ni n gf ul effect of P- g p i n hi biti o n of t he P K of L O X O- 2 9 2. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 2 3
C CI
C CI
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5.2.1.6 
Effect of LOXO-292 on the PK of other Drugs 
5.2.1.6.1 
CYP2C8 Substrates 
The effect of repeated doses of 160 mg BID LOXO-292 on the PK of repaglinide, a sensitive 
CYP2C8 substrate, was studied in 12 healthy volunteers. Preliminary interim results of this study 
showed that LOXO-292 treatment increased the AUC and Cmax of repaglinide by approximately 
220% and 115%, respectively. LOXO-292 can be considered a moderate inhibitor of CYP2C8. 
Coadministration of LOXO-292 with sensitive CYP2C8 substrates may increase their plasma 
concentrations, which may increase the incidence or severity of adverse reactions. Avoid 
coadministration of LOXO-292 with sensitive CYP2C8 substrates. If coadministration of these 
sensitive CYP2C8 substrates cannot be avoided, patients should be monitored for increased 
adverse reactions of these drugs. 
5.2.1.6.2 
CYP3A4 Substrates 
The effect of repeated doses of 160 mg BID LOXO-292 on the PK of midazolam, a sensitive 
CYP3A4 substrate was also studied in 12 healthy volunteers. Preliminary interim results of this 
study showed that LOXO-292 treatment increased the AUC and Cmax of midazolam by 
approximately 53% and 39%, respectively. Therefore, LOXO-292 can be considered a weak 
inhibitor of CYP3A4. Coadministration of LOXO-292 with sensitive CYP3A4 substrates may 
increase their plasma concentrations, which may increase the incidence or severity of adverse 
reactions. Avoid coadministration of LOXO-292 with sensitive CYP3A4 substrates. If 
coadministration of these sensitive CYP3A4 substrates cannot be avoided, patients should be 
monitored for increased adverse reactions of these drugs. 
5.2.1.6.3 
Other CYP450 Substrates 
In vitro, LOXO-292 showed no significant inhibition (IC50 ≥ 39 μM) of CYP1A2, CYP2B6, 
CYP2C9, CYP2C19, or CYP2D6. 
In human hepatocytes, LOXO-292 (0.03–100 μM) showed weak concentration-dependent 
induction of CYP1A2, CYP2B6, and CYP3A4 mRNA; however, at LOXO-292 concentrations 
of 3 μM or lower, induction of CYP1A2, CYP2B6, and CYP3A4 messenger ribonucleic acid 
(mRNA) and enzymatic activity was less than 20% the level of their respective positive controls 
omeprazole, phenobarbital, and rifampicin. Thus, at clinically relevant doses and exposures in 
humans, LOXO-292 is unlikely to induce the activity of CYP1A2, CYP2B6 or CYP3A4 and is 
unlikely to alter the PK of co-administered drugs that are metabolized by enzymes regulated at 
the gene expression level through ligand-mediated activation of AhR (e.g., CYP1A family), 
CAR (e.g., CYP2B family), or PXR (e.g., CYP3A and CYP2C families). 
5.2.1.6.4 
Drug Transporter Substrates 
In vitro, LOXO-292 inhibited the transporter MATE1 with an IC50 value of 0.67 µM. Therefore, 
LOXO-292 may reduce the clearance of substrates of MATE1 (e.g., creatinine). LOXO-292 
weakly inhibited the transporters OCT2 (12.9 µM), OATP1B1 (18.0 µM), OATP1B3 (8.32 µM), 
BCRP (5.10 to 22.3 µM, depending on assay format). There was no notable inhibition of OAT1, 
OAT3, OCT1, or BSEP (IC50 > 30 µM). 
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5.2.2 
Pharmacokinetics from Patients Treated in Study LOXO-RET-17001 
As of April 15, 2019, preliminary steady-state PK data (Cycle 1 Day 8) were available from 
335 patients enrolled in the Phase 1/2 LOXO-RET-17001 study (Table 5-1). These data show 
that LOXO-292 is absorbed after oral administration with a median Tmax of approximately 
2 hours (Figure 5-1). Although the plasma half-life could not be calculated with certainty 
because of the limited sampling interval (0–8 hours), it appears to be approximately 20 hours. 
Low concentrations of LOXO-292 were recovered as unchanged drug in urine indicates that the 
kidney contributes to overall clearance. Steady-state PK parameters of LOXO-292 in cancer 
patients are shown in Figure 5-1. 
Of note, the mean Cmin (predose, trough concentration) during steady-state treatment with 60 mg 
BID LOXO-292 is approximately 600 ng/mL, which corresponds to a mean plasma free drug 
concentration approximately equal to the concentration at which 90% inhibition is achieved 
(IC90) for inhibition of RET (Figure 5-1); higher doses provide higher trough levels.  
Table 5-1 
Preliminary Pharmacokinetic Parameters of LOXO-292 in Cancer 
Patients (Study LOXO-RET-17001) 
Dose 
N 
Cmax (ng/mL) 
Mean (%CV) 
AUC0-24 (ng*h/mL) 
Mean (%CV) 
CL/F (L/h) 
Mean (%CV) 
20 mg QD 
5 
212 (15.7%) 
2120 (41.6%) 
11.3 (50.7%) 
20 mg BID 
9 
304 (45.4%) 
5080 (51.8%) 
9.59 (44.1%) 
40 mg BID 
16 
606 (47.3%) 
10200 (44.6%) 
9.51 (45.6%) 
60 mg BID 
12 
1160 (38.6%) 
19300 (49.1%) 
7.39 (51.5%) 
80 mg BID 
18 
1400 (37.5%) 
22700 (38.6%) 
8.21 (43.4%) 
120 mg BID 
16 
2580 (35.0%) 
44300 (41.3%) 
6.66 (53.0%) 
160 mg BID 
251 
3180 (41.6%) 
55700 (46.2%) 
7.41 (69.1%) 
200 mg BID 
3 
2810 (38.6%) 
46800 (28.9%) 
9.08 (30.5%) 
240 mg BID 
5 
5340 (18.6%) 
90400 (21.9%) 
5.52 (22.5%) 
Abbreviations: AUC0-24-area under the concentration-time curve from time 0 to 24 hours; BID-twice daily; CL/F-
apparent oral clearance; Cmax-maximum drug concentration, N-number of subjects; PK-pharmacokinetic; QD-once 
daily; %CV-coefficient of variation. 
Data cutoff date: April 15, 2019. 
 
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Figure 5-1 
Preliminary Pharmacokinetics of LOXO-292 on Day 8 (Steady-State) in 
Cancer Patients 
0
2
4
6
8
10
12
10
100
1000
10000
Time (h) on Day 8 (Steady-State)
Concentration of LOXO-292
in Plasma (ng/mL)
20 mg QD (n=5)
20 mg BID (n=9)
40 mg BID (n=16)
60 mg BID (n=12)
80 mg BID (n=18)
120 mg BID (n=16)
160 mg BID (n=251)
200 mg BID (n=3)
240 mg BID (n=5)
RET IC90
 
Abbreviations: BID-twice daily; h-hours; QD-once daily. 
Data cutoff date: April 15, 2019. 
 
5.3 
Efficacy 
As of March 30, 2019, 422 patients were enrolled in Study LOXO-RET-17001 and received 
treatment with LOXO-292. As presented at WCLC 2018 and ATA 2018, with a data cutoff 
of July 19, 2018, among the first 82 patients enrolled in Study LOXO-RET-17001 (LIBRETTO-
001), the overall response rate (ORR) was 68% (95% confidence interval [CI] 51–83%, 
n = 26/38) in RET fusion-positive NSCLC, 78% (95% CI 40–97%, n = 7/9) in RET fusion-
positive thyroid, 50% (n = 1/2) in RET fusion-positive pancreatic, 59% (95% CI 39–77%, 
n = 17/29) in RET-mutant MTC and 0% (n = 0/4) in patients without a known activating RET 
alteration in their cancers (Drilon et al, 2018). Responses did not differ by fusion partner, 
mutation, including the V804M gatekeeper resistance mutation or prior therapies, including 
multikinase inhibitors with anti-RET activity. Confirmed intracranial responses were achieved 
in 100% (n = 5/5: 1 complete response, 4 partial responses) of patients with measurable brain 
metastases. The median duration of response was not reached. A total of 96% (49/51) of 
responding patients were still on treatment (median follow-up of responders 8.8 months). 
5.4 
Safety 
5.4.1 
Study LOXO-RET-17001 
As of March 30, 2019, 422 patients were enrolled in Study LOXO-RET-17001 and received 
treatment; the safety data are based on this safety population. 
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5.4.1.1 
Demographics and Baseline Characteristics 
The demographics and baseline characteristics of the study population are summarized in 
Table 5-2. A total of 422 patients have been treated with LOXO-292 ranging from 20 mg QD to 
240 mg BID. The dose of 160 BID was chosen as the RP2D and 334 (79.1%) patients were 
treated at that dose level as the starting dose, with an additional 49 (11.6%) patients starting at a 
lower dose level and subsequently escalating to 160 mg BID. The data are presented for patients 
at all dose levels combined. 
Table 5-2 
Demographics and Baseline Characteristics: Study LOXO-RET-17001 
(Safety Analysis Set) 
Demographic Characteristic 
All Patients (N = 422) 
Patients by Starting Dose Level (n, %) 
1: 20 mg QD 
 6 (1.4) 
2: 20 mg BID 
10 (2.4) 
3: 40 mg BID 
16 (3.8) 
4: 60 mg BID 
12 (2.8) 
5: 80 mg BID 
 18 (4.3) 
6: 120 mg BID 
17 (4.0)  
7: 160 mg BID 
334 (79.1) 
8: 240 mg BID 
6 (1.4) 
9: 200 mg BID 
3 (0.7)  
Age at Informed Consent/Assent (years) 
Median 
58.0 
Minimum, Maximum 
16, 90 
Sex (n, %) 
Female 
187 (44.3) 
Male 
235 (55.7) 
Race (n, %) 
White 
308 (73.0) 
Black or African American 
11 (2.6) 
American Indian or Alaska Native 
1 (0.2) 
Native Hawaiian or Other Pacific Islander 
2 (0.5) 
Asian 
79 (18.7) 
Other 
19 (4.5) 
Missing 
2 (0.5) 
Ethnicity (n, %) 
Hispanic or Latino 
 22 (5.2) 
Not Hispanic or Latino 
390 (92.4) 
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Demographic Characteristic 
All Patients (N = 422) 
Not Reported 
10 (2.4) 
ECOG Performance Status, n (%) 
0: Normal activity 
 142 (33.6) 
1: Symptoms, but ambulatory 
261 (61.8) 
2: In bed less than 50% of the time 
16 (3.8) 
Data cutoff date: March 30, 2019. 
Notes: Percentage is calculated using the number of subjects in the column heading as the denominator. Baseline is 
defined as the last observation before the administration of the study drug. 
 
5.4.1.2 
Dose-Limiting Toxicities 
During the Phase 1 dose escalation portion of the study, DLTs were reported in 2 patients out of 
6 patients treated at the 240 mg BID dose level: 1 DLT of Grade 3 tumor lysis syndrome and 1 
DLT of Grade 3 thrombocytopenia. The remaining 4 patients treated at this dose level cleared the 
28-day DLT window and continued on study.  
5.4.1.3 
Common Treatment-Emergent Adverse Events 
A total of 402 of the 422 patients treated in Study LOXO-RET-17001 (95.3%) experienced 
at least 1 TEAE (regardless of relationship to study drug) of any grade. The TEAEs were coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC). If a patient experienced more than 1 AE within a single preferred term, that patient is 
counted only once in the frequency for that preferred term.  
Across 9 dose levels ranging from 20 mg QD to 240 mg BID in these 422 patients, treatment-
emergent adverse events (TEAEs) occurring in > 15% patients (Table 5-3) were: dry dry mouth 
(30.8% total; 25.1% related), diarrhea (27.7% total; 12.8% related), hypertension (27.3% total; 
16.8% related), fatigue (22.3% total; 14.5% related), constipation (21.8% total; 10.0% related), 
AST increased (21.6% total; 15.6% related), ALT increased (20.4% total; 15.4% related), 
headache (18.7% total; 6.9% related), nausea (18.0% total; 6.6% related), edema peripheral 
(17.3% total; 9.5% related), and blood creatinine increased (14.9% total; 7.3% related). 
A total of 205 (48.6%) patients across all dose levels had Grade ≥ 3 TEAEs (Table 5-3). The 
most common Grade ≥ 3 TEAEs included hypertension (12.3%; 7.1% related), ALT increased 
(6.2%; 4.7% related), AST increased (4.7%; 3.1% related), hyponatremia (4.3%; 0.2% related), 
ECG QT prolonged (2.8%; 2.1% related), dyspnea and lymphopenia (each 2.6%; 0% and 0.9% 
related, respectively), diarrhea and thrombocytopenia (each 2.1%; 0.7% and 1.7% related, 
respectively). All other Grade ≥ 3 TEAEs occurred in less than 2% of patients overall. Grade 5 
AEs are discussed in Section 5.4.1.5. 
The most common study drug-related TEAEs included dry mouth (25.1%), hypertension 
(16.8%), AST increased (15.6%), ALT increased (15.4%), fatigue (14.5%), diarrhea (12.8%), 
and constipation (10.0%). All other drug-related TEAEs occurred in less than 10% of patients 
overall.  
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Table 5-3 Overall Incidence of TEAEs in ≥ 5% of Patients in Decreasing Order of Frequency, and the Corresponding Events 
of Severity Grade 3/ 4/ 5 and Related Events: LOXO-RET-17001 (Safety Analysis Set) 
MedDRA  
Preferred Term 
All Patients (N = 422) 
Total Patient 
Incidence of TEAEs 
by Frequency (≥ 5%) 
Drug-related 
TEAEs  
TEAEs of Severity 
Grade 3/ 4/ 5 
Drug-related TEAEs of 
Severity Grade 3/ 4/ 5 
Patients with any TEAEs 
402 (95.3) 
340 (80.6) 
205 (48.6) 
95 (22.5) 
Dry mouth 
130 (30.8) 
106 (25.1) 
0 
0 
Diarrhoea 
117 (27.7) 
54 (12.8) 
9 (2.1) 
3 (0.7) 
Hypertension 
115 (27.3) 
71 (16.8) 
52 (12.3) 
30 (7.1) 
Fatigue 
94 (22.3) 
61 (14.5) 
1 (0.2) 
1 (0.2) 
Constipation 
92 (21.8) 
42 (10.0) 
0 
0 
Aspartate aminotransferase increased 
91 (21.6) 
66 (15.6) 
20 (4.7) 
13 (3.1) 
Alanine aminotransferase increased 
86 (20.4) 
65 (15.4) 
26 (6.2) 
20 (4.7) 
Headache 
79 (18.7) 
29 (6.9) 
4 (0.9) 
1 (0.2) 
Nausea 
76 (18.0) 
28 (6.6) 
0 
0 
Oedema peripheral 
73 (17.3) 
40 (9.5) 
0 
0 
Blood creatinine increased 
63 (14.9) 
31 (7.3) 
1 (0.2) 
0 
Thrombocytopenia 
52 (12.3) 
40 (9.5) 
9 (2.1) 
7 (1.7) 
Abdominal pain 
51 (12.1) 
9 (2.1) 
5 (1.2) 
1 (0.2) 
Cough 
48 (11.4) 
5 (1.2) 
0 
0 
Electrocardiogram QT prolonged 
46 (10.9) 
34 (8.1) 
12 (2.8) 
9 (2.1) 
Dyspnea 
45 (10.7) 
4 (0.9) 
11 (2.6) 
0 
Rash 
45 (10.7) 
30 (7.1) 
3 (0.7) 
3 (0.7) 
Pyrexia 
44 (10.4) 
13 (3.1) 
0 
0 
Hypomagnesaemia 
43 (10.2) 
1 (5.6) 
0 
0 
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MedDRA  
Preferred Term 
All Patients (N = 422) 
Total Patient 
Incidence of TEAEs 
by Frequency (≥ 5%) 
Drug-related 
TEAEs  
TEAEs of Severity 
Grade 3/ 4/ 5 
Drug-related TEAEs of 
Severity Grade 3/ 4/ 5 
Arthralgia 
41 (9.7) 
11 (2.6) 
0 
0 
Urinary tract infection 
41 (9.7) 
1 (0.2) 
5 (1.2) 
0 
Vomiting 
41 (9.7) 
13 (3.1) 
0 
0 
Dizziness 
38 (9.0) 
19 (4.5) 
0 
0 
Blood bilirubin increased 
35 (8.3) 
15 (3.6) 
4 (0.9) 
2 (0.5) 
Decreased appetite 
35 (8.3) 
16 (3.8) 
0 
0 
Lymphopenia 
35 (8.3) 
18 (4.3) 
11 (2.6) 
4 (0.9) 
Back pain 
34 (8.1) 
2 (0.5) 
3 (0.7) 
0 
Blood alkaline phosphatase increased 
34 (8.1) 
19 (4.5) 
3 (0.7) 
0 
Dry skin 
34 (8.1) 
20 (4.7) 
0 
0 
Anaemia 
33 (7.8) 
6 (1.4) 
6 (1.4) 
0 
Weight increased 
33 (7.8) 
8 (1.9) 
7 (1.7) 
1 (0.2) 
Hypocalcaemia 
30 (7.1) 
6 (1.4) 
7 (1.7) 
2 (0.5) 
Leukopenia 
30 (7.1) 
22 (5.2) 
2 (0.5) 
1 (0.2) 
Abdominal distension 
29 (6.9) 
15 (3.6) 
1 (0.2) 
0 
Dysphonia 
29 (6.9) 
9 (2.1) 
1 (0.2) 
1 (0.2) 
Hypothyroidism 
28 (6.6) 
12 (2.8) 
0 
0 
Hypokalaemia 
27 (6.4) 
5 (1.2) 
5 (1.2) 
1 (0.2) 
Hyponatraemia 
27 (6.4) 
4 (0.9) 
18 (4.3) 
1 (0.2) 
Insomnia 
27 (6.4) 
4 (0.9) 
0 
0 
Hypoalbuminaemia 
26 (6.2) 
8 (1.9) 
0 
0 
Hyperphosphataemia 
25 (5.9) 
17 (4.0) 
0 
0 
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MedDRA  
Preferred Term 
All Patients (N = 422) 
Total Patient 
Incidence of TEAEs 
by Frequency (≥ 5%) 
Drug-related 
TEAEs  
TEAEs of Severity 
Grade 3/ 4/ 5 
Drug-related TEAEs of 
Severity Grade 3/ 4/ 5 
Rash Maculo-papular 
24 (5.7) 
15 (3.6) 
2 (0.5) 
2 (0.5) 
Stomatitis 
24 (5.7) 
14 (3.3) 
1 (0.2) 
1 (0.2) 
Gastrooesophageal reflux disease 
23 (5.5) 
9 (2.1) 
0 
0 
Upper respiratory tract infection 
23 (5.5) 
0 
2 (0.5) 
0 
Dysgeusia 
22 (5.2) 
19 (4.5) 
0 
0 
Neutropenia 
22 (5.2) 
16 (3.8) 
7 (1.7) 
6 (1.4) 
Oropharyngeal pain 
22 (5.2) 
5 (1.2) 
0 
0 
Data cutoff date: March 30, 2019. 
Abbreviations: AE-adverse event; MedDRA-Medical Dictionary for Regulatory Activities.  
Notes: Percentage is calculated using the number of patients in the column heading as the denominator. Treatment emergent adverse events (TEAEs) are defined 
as adverse events that started on or after the first administration of study drug. If a patient experienced more than 1 adverse event within a preferred term, the 
patient is counted once in that preferred term. 
 
 
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5.4.1.4 
Serious Adverse Events 
A total of 120 of the 422 patients (28.4%) treated in Study LOXO-RET-17001 experienced 
a serious adverse event (SAE) (Table 5-4). SAEs reported in 5 or more patients were dyspnea 
(11 patients, 2.6%), acute kidney injury and pneumonia (each in 7 patients, 1.7% each), ALT 
increased, AST increased, drug hypersensitivity, dysphagia, and hyponatremia (each in 
6 patients, 1.4% each), and abdominal pain (5 patients, 1.2%).  
A total of 23 of the 422 patients (5.5%) experienced an SAE assessed as related to study drug 
(Table 5-4). SAEs assessed as related to study drug that were reported in more than 1 patient 
included: drug hypersensitivity (6 patients, 1.4%), ALT increased and AST increased (3 patients 
each, 0.7% each), hypertension and thrombocytopenia (2 patients each, 0.5% each). 
A total of 13 patients (3.1%) experienced a Grade 5/Fatal SAE. None of the events were 
considered related to study drug. Five of the 13 patient deaths were due to an unrelated SAE: 
sepsis, cardiac arrest, hemoptysis, cerebrovascular accident, and post procedural hemorrhage. 
The remaining 8 patient deaths were attributed to events associated with disease progression. 
Table 5-4 Overall Incidence of SAEs in ≥ 1 Patient in Decreasing Order of Frequency, and 
the Corresponding Related Events: Study LOXO-RET-17001 (Safety Analysis 
Set) 
MedDRA  
Preferred Term 
All Patients (N = 422) 
Total Patient Incidence 
of Treatment-emergent 
SAEs by Frequency 
(> 1 patient) 
Total Patient Incidence 
of Treatment-related 
Treatment-emergent 
SAEs 
Patients with any SAEs  n (%) 
120 (28.4) 
23 (5.5) 
Dyspnea 
11 (2.6) 
0 
Acute kidney injury 
7 (1.7) 
0 
Pneumonia 
7 (1.7) 
0 
Alanine aminotransferase increased 
6 (1.4) 
3 (0.7) 
Aspartate aminotransferase increased 
6 (1.4) 
3 (0.7) 
Drug hypersensitivity 
6 (1.4) 
6 (1.4) 
Dysphagia 
6 (1.4) 
0 
Hyponatraemia 
6 (1.4) 
0 
Abdominal pain 
5 (1.2) 
1 (0.2) 
Hypertension 
4 (0.9) 
2 (0.5) 
Pleural effusion 
4 (0.9) 
0 
Pyrexia  
4 (0.9) 
0 
Sepsis 
4 (0.9) 
0 
Squamous cell carcinoma of the skin 
4 (0.9) 
0 
Acute respiratory failure 
3 (0.7) 
0 
Back pain 
3 (0.7) 
0 
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MedDRA  
Preferred Term 
All Patients (N = 422) 
Total Patient Incidence 
of Treatment-emergent 
SAEs by Frequency 
(> 1 patient) 
Total Patient Incidence 
of Treatment-related 
Treatment-emergent 
SAEs 
Hypocalcaemia 
3 (0.7) 
0 
Lung infection 
3 (0.7) 
0 
Pulmonary embolism 
3 (0.7) 
0 
Thrombocytopenia 
3 (0.7) 
2 (0.5) 
Abdominal pain upper 
2 (0.5) 
1 (0.2) 
Atelectasis 
2 (0.5) 
0 
Basal cell carcinoma 
2 (0.5) 
0 
Blood bilirubin increased 
2 (0.5) 
1 (0.2) 
Cardiac arrest 
2 (0.5) 
0 
Cardiac tamponade 
2 (0.5) 
0 
Confusional state  
2 (0.5) 
0 
Delirium 
2 (0.5) 
1 (0.2) 
Diarrhoea 
2 (0.5) 
1 (0.2) 
Embolism 
2 (0.5) 
0 
Haemoptysis 
2 (0.5) 
0 
Haemorrhage intracranial 
2 (0.5) 
1 (0.2) 
Headache 
2 (0.5) 
0 
Hypercalcaemia 
2 (0.5) 
0 
Hypotension 
2 (0.5) 
0 
Influenza like illness 
2 (0.5) 
0 
Mental status changes 
2 (0.5) 
0 
Muscular weakness 
2 (0.5) 
0 
Pericardial effusion 
2 (0.5) 
0 
Respiratory failure 
2 (0.5) 
0 
Sialoadenitis 
2 (0.5) 
0 
Spinal cord compression 
2 (0.5) 
0 
Upper respiratory tract infection 
2 (0.5) 
0 
Vomiting 
2 (0.5) 
0 
Data cutoff date: March 30, 2019. 
Abbreviations: MedDRA-Medical Dictionary for Regulatory Activities; SAE-serious adverse event.  
Notes: Percentage is calculated using the number of patients in the column heading as the denominator. Treatment 
emergent adverse events (TEAEs) are defined as adverse events that started on or after the first administration of 
study drug. If a patient experienced more than 1 adverse event within a preferred term, the patient is counted once in 
that preferred term. 
 
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5.4.1.5 
Deaths 
Sixteen patients (3.8%) died within 28 days of the last dose of study drug. Eleven patients died 
of their underlying disease and 5 patients died of AEs unrelated to study drug. 
5.4.1.6 
Adverse Events Leading to Study Drug Discontinuation 
Thirteen patients (3.1% of all patients treated) discontinued LOXO-292 because of TEAEs. 
TEAEs considered related to study drug that led to discontinuation occurred in 5 of the 
13 patients (1.2% of all patients treated) and all occurred at the 160 mg BID dose level: acute 
hepatitis (patient withdrew consent after full recovery), tachycardia and erythema (the Sponsor 
considered this AE similar to drug hypersensitivity), drug hypersensitivity, tumor lysis 
syndrome, and ALT increased. All of the events that were considered related to study drug 
resolved (4 patients) or resolved with sequela (1 patient). 
5.5 
Single-Patient Protocols 
As of March 30, 2019, Loxo Oncology has initiated 40 SPPs, Special Access Scheme, 
Compassionate Use, or ATU cases (refer to Table 5-5). All 40 patients were not eligible for 
Study LOXO-RET-17001 and/or were felt to potentially require a different dosing approach to 
achieve clinical benefit than allowed by the ongoing LOXO-RET-17001 study. Because of the 
clinical urgency and desire to achieve meaningful clinical exposures in a time frame that could 
help each patient, a real-time, PK-guided, intra-patient dose escalation approach was used. 
LOXO-292 was administered at doses as high as 240 mg BID in these patients.  
For the SPPs, Special Access Scheme, Compassionate Use, or ATU cases, only SAEs are 
required to be reported. To date, there have been 39 SAEs reported in 15 of the patients 
participating in SPPs. Of the reported SAEs, there have been 4 Grade 5/Fatal events (all 
considered not related to study drug): disease progression (LOXO-RET-17003), respiratory 
failure (LOXO-RET-18006), cardiac arrest (LOXO-RET-18009) and intestinal ischemia 
(LOXO-RET-18041). There have been 3 SARs, which occurred in 2 patients, that have been 
submitted as SUSARs: 1 SAE of (CTCAE v4.03) Grade 3 pleural effusion and 1 SAE of Grade 2 
pericardial effusion in the same patient (LOXO-RET-18031) while on combination therapy with 
LOXO-292 and imatinib for concurrent chronic myelogenous leukemia (CML), and 1 SAE of 
Grade 3 prolonged QTcF in a patient with MTC (LOXO-RET-18033); these 3 events were 
deemed related to the study drug by the Investigator. 
Efficacy data for 2 patients treated in SPPs was recently published (LOXO-RET-17002, 
LOXO-RET-17003) (Subbiah et al. 2018). A patient with RET fusion-positive NSCLC 
(KIF5B-RET) with progressive symptomatic brain metastases after prior MKI therapy achieved a 
confirmed partial response with LOXO-292 treatment, including complete resolution of target 
lesions in the brain. A second patient with RET M918T-mutant MTC (a RET V804M acquired 
resistant mutation in plasma with severe disease-related symptoms of diarrhea, painful ascites 
and decreased performance status) who was previously treated with 6 MKI regimens, achieved a 
confirmed partial response with LOXO-292 treatment and his symptoms resolved. LOXO-292 
was tolerated by both patients without treatment-related SAEs. 
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Table 5-5 
Single Patient Protocols, Special Access Schemes, Compassionate Use, 
and Temporary Authorization Use (ATU) cases with LOXO-292 
Protocol Type 
Protocol Number / Identifier 
Single Patient Protocols 
LOXO-RET-17002, LOXO-RET-17003, LOXO-RET-17004, 
LOXO-RET-18006, LOXO-RET-18007, LOXO-RET-18009, 
LOXO-RET-18010, LOXO-RET-18011, LOXO-RET-18012, 
LOXO-RET-18013, LOXO-RET-18019, LOXO-RET-18021, 
LOXO-RET-18025, LOXO-RET-18027, LOXO-RET-18029, 
LOXO-RET-18030, LOXO-RET-18031, LOXO-RET-18034, 
LOXO-RET-18040, LOXO-RET-18041, LOXO-RET-18042, 
LOXO-RET-18044, LOXO-RET-18045, LOXO-RET-18048, 
LOXO-RET-18049, LOXO-RET-18050, LOXO-RET-18054, 
LOXO-RET-18056, LOXO-RET-18058, LOXO-RET-18059, 
LOXO-RET-19060, LOXO-RET-19064, LOXO-RET-19066, and 
LOXO-RET-19072,  
Special Access Scheme 
LOXO-RET-18005, LOXO-RET-18052 
Compassionate Use 
LOXO-RET-18018, LOXO-RET-18047 
Temporary Authorization Use 
(ATU) 
LOXO-RET-18008, LOXO-RET-18033 
 
5.6 
Marketing Experience 
LOXO-292 is not marketed in any country.  
5.7 
Clinical Experience with Related Molecules 
There are no available clinical data on highly selective RET inhibitors at this time.  
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6 
SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR 
As the FIH study of LOXO-292 (Protocol LOXO-RET-17001) is currently ongoing, potential 
risks, contraindications, and warnings are based on observations from animal testing and the 
clinical exposure (422 patients) to date.  
6.1 
Known and Anticipated Risks 
6.1.1 
Risks Based on Animal Toxicology Studies  
Based on the nonclinical profile, including results from animal toxicology studies, theoretical 
risks of human exposure to LOXO-292 include the following:  
• Loss of appetite 
• Decrease in body weight  
• Increase in total white blood cells, neutrophils, and monocytes 
• Decrease in albumin, increase in globulin, decreased albumin:globulin ratio, decrease 
in total protein  
• Increased body temperature 
• Lethargy, decreased energy 
• Increase in cholesterol and triglycerides 
• Increase in phosphorus 
• Changes in taste sensation and/or development of xerostomia/dry mouth 
• GI symptoms/signs: nausea, vomiting, loose stools, abdominal discomfort  
• Decreases in red cell mass (red blood cell [RBC], hemoglobin, hematocrit) and 
reticulocytes 
• Decrease in platelets 
• Increases in liver function tests (LFTs; including AST, ALT, ALP) 
• Possible pancreas injury  
• Possible QTc prolongation 
• Possible decreased testicular weight  
• Possible increased vaginal mucous and altered menstruation/ovulation  
6.1.2 
Risks Based on Clinical Studies 
As of a clinical data cut-off (March 30, 2019) for the LOXO-RET-17001 FIH dose-finding 
study, the following AEs occurred in ≥ 15% of patients (regardless of attribution to study drug):  
• Dry mouth (30.8% total; 25.1% related) 
• Diarrhea (27.7% total; 12.8% related) 
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• Hypertension (27.2% total; 16.8% related) 
• Fatigue (22.3% total; 14.5% related) 
• Constipation (21.8% total; 10.0% related) 
• AST increased (21.6% total; 15.6% related) 
• ALT increased (20.4% total; 15.4% related) 
• Headache (18.7% total; 6.9% related) 
• Nausea (18.0% total; 6.6% related) 
• Edema peripheral (17.3% total; 9.5% related) 
• Blood creatinine increased (14.9% total; 7.3% related) 
6.2 
Guidance for Investigator on Specific Adverse Events 
6.2.1 
Hypersensitivity Reactions to LOXO-292 
Drug hypersensitivity reactions to LOXO-292 have been reported. These reactions were 
characterized by a maculopapular rash often preceded by a fever with associated 
arthralgias/myalgias during the patient’s first cycle of treatment (typically between Days 7-21) 
which were then followed by at least one of the following systemic signs/symptoms: commonly- 
decreased platelets, increased AST/ALT and/ or less commonly- decreased blood pressure, 
tachycardia and increased creatinine. Most patients (approximately 75%) received prior 
treatment with immune checkpoint inhibitors (ICIs). Prior ICIs may be a contributing factor in 
these patients, as previously described for patients with EGFR-mutant and ALK fusion-positive 
NSCLC treated with selective TKIs after ICIs (Lin et al, 2018; Oshima et al, 2018). Patients 
previously treated with ICIs remain eligible for the study. 
As of the data cutoff of March 30, 2019, there have been 9 (2.1%) patients with an AE of drug 
hypersensitivity reaction to LOXO-292; the events were Grade 3 or higher in 4 of the 9 patients 
(all at the 160 mg BID dose level). The first two patients to experience this event were 
discontinued. Both patients fully recovered following discontinuation of the study drug. 
Following these events, a recommended drug re-exposure strategy (outlined below) was authored 
with input from both the SRC and expert consultants. This has allowed subsequent patients who 
have experienced a drug hypersensitivity reaction to LOXO-292 to continue on study. 
If LOXO-292 drug hypersensitivity is suspected, study drug should be held and treatment with 
steroids at 1 mg/kg prednisone (or equivalent) should be initiated. Upon resolution, LOXO-292 
may be resumed at a reduced dose of 40 mg BID while continuing steroids at the same dose. 
Hypersensitivity has recurred in some patients, typically at 3-6 hours following drug 
administration. If recurrence is severe, LOXO-292 should again be held; patients with mild 
recurrence (e.g., isolated instances of rash or myalgias or low-grade fever) have been able to 
cautiously continue treatment with supportive therapy (e.g., topical treatments, ibuprofen).  
After a minimum of 7 days, and in the absence of clinically significant recurrent drug 
hypersensitivity, the dose of LOXO-292 may be escalated sequentially to 80 mg BID, 120 mg 
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BID and 160 mg BID. Once the patient has tolerated treatment for a minimum of 7 days at the 
final dose, steroids may be tapered slowly. 
To understand the mechanism of this AE, the Sponsor recommends assessment of serum IL-6, 
TNF, and IgE levels with each occurrence of hypersensitivity, at 3 hours after initial drug re-
exposure, and at 3 hours after each dose escalation. Available data currently indicate that it may 
be appropriate to limit such testing to IL-6, which may be used as a measure of reaction severity 
and increasing tolerance with re-exposure.  
6.2.2 
Liver Function Test Abnormalities with LOXO-292 
Three (0.7%) patients experienced AEs of ≥ Grade 3 LFTs increased, 26 (6.2%) patients 
experienced AEs of ≥ Grade 3 ALT increased, and 20 (4.7%) patients experienced AEs of 
≥ Grade 3 AST increased. The majority of these LFT increases were asymptomatic and resolved 
with dose interruption, with LOXO-292 resumed at a lower dose following normalization of the 
LFTs. Some patients experienced concurrent elevated ALP and elevated total bilirubin. There 
have been no patients with LFT abnormalities who met Hy’s law criteria (defined as AST and/or 
ALT > 3× ULN + total bilirubin > 2× ULN + ALP < 2× ULN). LFT abnormalities have been 
monitorable and reversible. 
A minority of patients (4 of 422; 0.9%), have exhibited a first occurrence of an LFT abnormality 
after Cycle 3 Day 15. 
LFT laboratory testing (AST, ALT, total bilirubin, ALP) should be performed every 2 weeks 
through C4D1 and then D1 of every subsequent treatment cycle. 
If a patient experiences ≥ Grade 3 elevated LFT increases, study drug should be held and 
evaluation for potential alternative causes should be conducted (e.g., history of other hepatotoxic 
medications/substances, viral serologies, liver imaging). LFTs should be monitored at least 
weekly until resolution to normal/baseline (depending on the clinical situation, resolution to 
Grade 1 if baseline is normal may be permitted with prior Sponsor approval). If the LFT 
abnormalities do not begin to resolve (or worsen) within 5 days of the AE, a hepatology 
consultation should be considered to evaluate the need for a liver biopsy. Some but not all 
patients were previously treated with immune ICIs, and increased hepatotoxicity has been 
previously associated with sequential ICI therapy and TKIs in NSCLC (Lin et al, 2018). 
Therefore, prior ICIs may be a potential contributing factor in these patients; for some, 
concomitant treatment with steroids correlated with improvement in persistent LFT 
abnormalities. Therefore, in patients in whom there is thought to be an immune component to the 
LFT abnormalities observed, i.e., prior ICI exposure or liver biopsy results demonstrating an 
immune infiltrate, treatment with steroids may be added to the dose interruption 
recommendations below. Patients previously treated with ICIs remain eligible for the study. 
Upon resolution, LOXO-292 may be resumed at a reduced dose of 80 mg BID with weekly LFT 
monitoring. In the absence of recurrent LFT abnormalities, the dose of LOXO-292 may be 
escalated sequentially to 120 mg BID after a minimum of 2 weeks at 80 mg BID, and again to 
160 mg BID, and after a minimum of 4 weeks at 120 mg BID. Once the patient has been treated 
at a stable dose of LOXO-292 for a minimum of 4 weeks without recurrent LFT abnormalities, 
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the frequency of LFT monitoring may be decreased (e.g., every 2 weeks for 2 months and then 
monthly thereafter). For patients who experience ≥ Grade 3 elevated LFTs on a different dose 
than 160 mg BID, the Sponsor should be contacted for additional guidance regarding dose 
modification. 
6.2.3 
Thrombocytopenia with LOXO-292 
Fifty-one patients (12.1%) have experienced a TEAE of thrombocytopenia while on study 
(9.2% judged related to study drug); for 9 patients (2.1%), the TEAE of thrombocytopenia was 
≥ Grade 3 (1.7% judged related to study drug). One patient experienced a DLT of Grade 3 
thrombocytopenia at a dose of 240 mg BID and 2 patients experienced treatment-related AEs 
which were considered serious. Both patients were discovered within the first cycle of treatment 
and both were able to continue on study at a reduced dose of 80 mg BID after recovery.  
A complete blood count (CBC) should be performed during Screening, C1D1, C1D15 and Day 1 
of every subsequent cycle. If a patient is discovered to have thrombocytopenia ≥ Grade 3, study 
drug should be held and the patient should be evaluated for alternative causes 
(medications/substances, viral studies). A hematology consultation may be considered as 
necessary to understand the etiology and to consider a role for concomitant steroid therapy. The 
patient should undergo weekly CBC testing until the event has recovered to normal/baseline. 
Upon recovery, the patient should resume LOXO-292 at a reduced dose (e.g., 120 mg BID or 
80 mg BID) with weekly CBC surveillance for 1 full cycle. The Sponsor should be notified for 
consideration of concomitant steroid therapy and for further dose re-escalation. 
6.2.4 
Hypertension with LOXO-292 
One hundred and fifteen (115; 27.3%) patients have experienced a TEAE of hypertension while 
on study (16.8% considered related to study drug); for 52 patients (12.3%), the TEAE of 
hypertension was ≥ Grade 3 (7.1% judged related to study drug). Most patients have tolerated 
continued therapy while receiving concomitant anti-hypertensive therapy. Only 3 of the 
115 patients with a TEAE of hypertension had their study drug dose reduced as a result of the 
event. Study drug interruptions and dose decreases have been considered on a case by case basis 
dependent upon the clinical judgement of the Investigator. 
All patients should have their blood pressure optimized to a reading of ≤ 140/90 mmHg (if 
necessary) prior to initiation of study drug. If hypertension, defined as a sustained increase in 
blood pressure from baseline on ≥ 2 readings on ≥ 2 separate occasions, or a clinically significant 
elevation requiring acute treatment, occurs, study drug may be interrupted at the discretion of the 
Investigator while a new anti-hypertensive medication regimen is initiated, or a preexisting 
regimen is optimized to a reproducible reading of ≤ 140/90 mmHg. If study drug is interrupted, it 
may be resumed at the same or a lower dose at the discretion of the Investigator. In all cases, the 
patient should continue to undergo regular blood pressure monitoring to ensure adequate blood 
pressure control.  
6.3 
Contraindications, Warnings, and Precautions 
The known and anticipated risks described above are based on the results of preclinical 
toxicology studies and current clinical safety data. Routine monitoring for these risks is outlined 
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L o x o O nc ol o g y, I nc.  
 
I n vesti gat or’s Br oc h ure 
L O X O -2 9 2  
 
0 6 J u ne 2 0 1 9  
 
Versi o n 5. 0  
C o nfi de ntial & Pr o prietar y  
P a ge 5 6  
 
i n t he L O X O -R E T - 1 7 0 0 1 pr ot oc ol a n d/ or sc he d ul e of assess me nts. Cli nical trial patie nts are 
bei n g w ei g he d r e g ularl y a n d as ke d a b o ut t heir a p p etite a n d ot her s y m pt o ms p ossi bl y relate d t o 
pa ncreatic effects, e. g., a b d o mi nal disc o mf ort. L F Ts  are bei n g cl osel y m o nit ore d as part of 
r o uti ne la b orat or y testi n g. Patie n ts are bei n g m o nit ore d f or si g ns/s y m pt o ms of GI  t o xicit y, 
i ncl u di n g c h a n ges i n st o ol a p pear a nce, n a usea, v o miti n g, a n d a b d o mi nal disc o mf ort. Sta n dar d 
he mat ol o g y la b orat or y testi n g  (e. g., c o m plete bl o o d c o u nt) is bei n g us e d  t o m o nit or f or p ossi ble 
he mat ol o g ic t o xicit y as o bser ve d i n a ni mals, t h o u g h si g nifica nt h e mat ol o gi c effects of 
L O X O - 2 9 2 ( ot h er t ha n as descri be d a b o ve) h a ve n ot bee n o bser v e d. Meas ure me nt of i n or ga ni c 
p h os p h or us le vels is a part of t he sta n dar d cli nical c he mistr y p a nel t o m o nit or f or p ossi ble 
h y per p h os p hate mia. Sta n dar d cli nical c h e mistr y p a nels are als o bei n g  e m pl o ye d t o m o nit or f or 
p ossi ble i nfla m mat or y r es p o nses i n a d diti o n t o r o uti ne meas ure me nt of b o d y te m perat ure as part 
of rec or di n g vital si g ns. Ot her s y m pt o ms i n dicati ve of t o xiciti es o bser ve d i n a ni mals (e. g., taste 
c ha n ge or dr y m o ut h c o nsiste nt wit h mi n or a n d re versi ble c ha n ges i n t he t o n g ue ) or ras h (as 
e x perie nce d b y t he 2 p atie nts) wit h h y p erse nsiti vit y reacti o ns o bser ve d i n precli nical t o xic ol o g y 
st u dies are easil y m o nit ore d i n t he cli ni c. I n a d diti o n, patie nts are ma d e a w are of t h e s y m pt o ms 
a n d si g ns of t h ese p ote nti al t o xicities i n t he I nf or me d C o nse nt F or m (I C F). 
Base d o n t h e res ults of t h e t o xic ol o g y pr o gra m, t h e t o xicit y- d os e res p o nse c ur ve w as stee p i n 
b ot h s pecies. T h er ef or e, as o utli ne d i n t he cli nical pr ot oc ol, d oses ha ve b ee n  escalate d ca uti o usl y 
a n d wit h car ef ul m o nit ori n g of t he d ose-e x p os ure, d ose-t o xicit y a n d d ose- efficac y relati o ns hi ps. 
Pri or t o e nr oll me nt of t he first patie nt at eac h d ose le vel, t he Safet y Re vie w C o m mittee  ( S R C) 
re vie we d all a vaila ble s af et y a n d P K data . T o dat e, 9 d oses ha ve bee n st u die d 
( 2 0 m g  Q D →2 4 0 m g BI D ), wit h d ose e x pl orati o n o n g oi n g at a d os e of 2 0 0 m g BI D, a n d wit h 
n o f urt her d ose escalati o n a ntici pate d.  
6. 4  
P h ar m a c o ki netics a n d P ote nti al f or Dr u g I nter acti o ns  
L O X O - 2 9 2 ma y b e gi ve n wit h or wit h o ut f o o d. 
L O X O - 2 9 2 has p H- de p e n de nt s ol u bilit y an d its P K ca n be affecte d b y a ge nts t hat m o dif y gastric 
p H, s uc h as t he pr ot o n p u m p i n hi bit or o me praz ole w hic h re d uce d t he A U C of L O X O- 2 9 2 b y 
6 9 % u n der  
 c o n diti o ns. H o we ver, t h e effect of o me praz ole is re d u ce d w he n L O X O- 2 9 2 is 
gi ve n wit h a hi g h-cal ori e, hi g h-f at diet. Patie nts s h o ul d a v oi d a ge nts t hat m o dif y gastric p H w h e n 
ta ki n g L O X O- 2 9 2. 
L O X O - 2 9 2 is a s u bstrat e  of t he C Y P 3 A 4 meta b olic s yste m;  c o n c o mita nt use of str o n g C Y P 3 A 4 
i n hi bit ors ma y i ncrease L O X O - 2 9 2 e x p os ure b y 1 3 0 % a n d str o n g C Y P 3 A 4 i n d ucers ma y re d uce 
L O X O - 2 9 2 e x p os ure s u bsta ntiall y ( b y 8 7 %); t heref ore, use of str o n g C Y P 3 A 4 i n hi bit ors a n d 
i n d ucers s h o ul d be a v oi d e d w hile ta ki n g L O X O - 2 9 2. 
L O X O - 2 9 2 i n a m o derat e i n hi bit or of C Y P 2 C 8 a n d wea k i n hi bit or of C Y P 3 A 4. 
C oa d mi nistrati o n of L O X O- 2 9 2 wit h se nsiti ve C Y P 2 C 8 or C Y P 3 A 4 s u bstrates ma y i ncrease 
t heir plas ma c o nce ntrati o ns, w hic h ma y i ncrease t he i nci de nce or se v erit y of a d vers e reacti o ns. 
A v oi d c oa d mi nistrati o n of L O X O- 2 9 2 wit h se nsiti ve C Y P 2 C 8 or C Y P 3 A 4 s u bstrates. If 
c oa d mi nistrati o n of t he se se nsiti ve C Y P 2 C 8 or C Y P 3 A 4 s u bstrates ca n n ot be a v oi de d, patie nts 
s h o ul d be m o nit ore d f or i ncreas e d a d v erse reacti o ns of t hese dr u gs. 
L O X O- R E T- 1 8 0 3 2; C A 2 5 4 9 4; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
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In vitro, LOXO-292 in an inhibitor of the drug transporter MATE1 and may reduce the clearance 
of MATE1 substrates (e.g., creatinine). 
6.5 
Reproductive Risks and Use in Pregnancy and Breast Feeding 
LOXO-292 was found to be embryo-lethal at all doses in an embryo-fetal development study in 
rats (Section 4.4.5). In both male rats and male minipigs, decreased testicular weights associated 
with microscopic testicular degeneration associated with luminal cell debris and/or reduced 
luminal sperm in the epididymis was observed, without effects on total sperm counts, density, 
motility, or morphology in the rat (Section 4.4.5). In female rats, vaginal mucification with an 
altered estrous cycle was observed. In female minipigs, ovarian atrophy with decreased or absent 
corpora lutea, number and size of follicles and stromal proliferation and presence of corpora 
lutea cysts were observed (Section 4.1.1 and Section 4.4.5). 
At this time, it is unknown whether these findings in the reproductive organs identified non-
clinically will have an effect on fertility in humans. A stand-alone fertility and early embryonic 
study in rats is planned to better elucidate any potential effects on fertility with LOXO-292-
treatment. There are no clinical studies planned in pregnant women, and it is unknown whether 
LOXO-292 or its metabolites are excreted in human milk.  
For these reasons, patients should be informed of these changes and told that their effects on 
fertility are currently not known. 
Pregnant women and women who are breastfeeding are ineligible for study enrollment. If a study 
participant becomes pregnant during their study participation, LOXO-292 should be 
discontinued immediately and the sponsor should be notified as soon as possible. If the female 
partner of a male study participant becomes pregnant, the sponsor should also be notified as soon 
as possible. 
Men and women of reproductive potential are required to observe conventional and effective 
birth control (barrier method is advised) for the duration of treatment and for 3 months following 
the last dose of study treatment. In addition, women of childbearing potential are required to 
undergo serum pregnancy testing at Screening, and then serum or urine pregnancy testing at 
Day 1 of every treatment cycle.  
Male study participants should refrain from sperm donation during study treatment and for up to 
6 months following the last dose of LOXO-292. 
6.6 
Special Populations 
No information currently exists on the use of LOXO-292 in certain patient subgroups, such as 
patients with renal or hepatic impairment.  
6.7 
Overdose 
No known antidote exists for a LOXO-292 overdose. In the event of an overdose, the patient 
should be monitored with appropriate tests and receive supportive therapy as indicated.  
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6.8 
Reference Safety Information 
As of the clinical data cutoff date of March 30, 2019, LOXO-292 has been administered to 
462 patients in FIH studies with LOXO-292 (422 patients in Clinical Protocol LOXO-RET-
17001 and an additional 40 patients in single patient protocols). The SARs described in 
Table 6-1 will be used in determination of “expectedness” for reporting purposes. Any SAR with 
the same event term reported at a higher grade than listed below will be considered unexpected 
for safety reporting purposes. Additional safety information is presented in Section 5.4. 
Table 6-1 
Serious Adverse Reactions Considered Expected for Safety Reporting 
Purposes 
System Organ Class 
Preferred Term 
Patients Who Received LOXO-292 
in Study LOXO-RET-17001 
(N = 422) 
Serious 
Adverse 
Reactions 
n (%) 
Dose of LOXO-292 
Highest 
Expected 
Grade 
Occurrence 
of Fatal 
SARs 
n (%) 
Occurrence of 
Life-Threatening 
SARs  
n (%) 
Immune System Disorders 
Drug Hypersensitivity  
6 (1.4) 
160 mg BID (3 Grade 2) 
160 mg BID (3 Grade 3) 
 3 
0 
0 
Investigations 
Aspartate 
aminotransferase 
increased 
3 (0.7) 
160 mg BID (1 Grade 3) 
160 mg BID (1 Grade 4) 
200 mg BID (1 Grade 4) 
4 
0 
0 
Alanine 
aminotransferase 
increased  
3 (0.7) 
160 mg BID (1 Grade 3) 
160 mg BID (1 Grade 4) 
200 mg BID (1 Grade 4) 
4 
0 
0 
Respiratory, Thoracic, and Mediastinal Disorders 
Thrombocytopenia 
2 (0.5) 
160 mg BID (1 Grade 3) 
160 mg BID (1 Grade 4) 
4 
0 
0 
Vascular Disorders 
Hypertension 
2 (0.5) 
160 mg BID (1 Grade 3) 
160 mg BID (1 Grade 4) 
3 
0 
0 
Data cutoff date: March 30, 2019. 
Abbreviations: SAR-serious adverse reaction.  
 
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7 
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