An Open-Label, Fixed-Sequence Study to Evaluate the Effect of Multiple Doses of LOXO-292 on the Single Dose Pharmacokinetics of Repaglinide in Healthy Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol Amendment J2G-OX-JZJS (1) 
An Open-Label, Fixed-Sequence Study to Evaluate the Effect of Multiple Doses of 
LOXO-292 on the Single Dose Pharmacokinetics of Repaglinide in Healthy Adult Subjects
NCT05469113 
Approval Date: 20-Feb-2019

Page 1 
Clinical Protocol 
An Open-Label, Fixed-Sequence Study to Evaluate the Effect of Multiple Doses of 
LOXO-292 on the Single Dose Pharmacokinetics of Repaglinide in Healthy Adult 
Subjects 
Celerion Project No.: CA26434 
Sponsor Project No.: LOXO-RET-18026 
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. 

C O N FI D E N TI A L 
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 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  
1 9 Fe br u ar y 2 0 1 9 
b y 
Fi nal Pr ot oc ol, A me n d m e nt 1 
Peri o d 1 was d ose d o n Fe br uar y 1 5, 2 0 1 9 a n d 4 s u bjects 
e x perie nce d h y p o gl yce mia e ve nts . These s u bj ects ha d gl u c ose 
val ues u n der 6 0 m g/ d L p ost d ose a n d were gi ve n a d diti o nal 
gl uc ose p er t he resc u e i nter ve nti o ns o utli ne d i n t he pr ot oc ol. 
S u bjects’  val ues rec o vere d after l u nc h. H o we v er, d ue t o t he 
u n k n o w n i nteracti o n of L O X O - 2 9 2 o n re pa gli ni de, a d diti o nal 
safet y meas ures will be i m ple me nte d  f or Peri o d 2. 
T he pr ot oc ol is t heref ore bei n g a me n de d t o ( 1) a d d gl uc ose 
m o nit ori n g at 0. 5, 1. 5, a n d 3 h o urs p ost d ose o n Da y 1 0 of 
Peri o d  2, ( 2) i ncrease t he d ose of gl uc ose fr o m 1 2 g t o 1 6 g 
a d mi nistere d i m me diatel y f oll o wi n g D a y  1 0 d osi n g i n Peri o d  2, 
a n d ( 3) a d mi nister a n a d diti o nal 1 6 g of gl uc ose at 1  h o ur p ost d ose 
o n Da y 1 0 of Peri o d  2 (a p pr o xi matel y re pa gli ni de T ma x). 
T he ref ore Secti o n 5 S y n o psis, S u m mar y of St u d y Desi g n a n d 
D osa ge, D osa ge F or m, R o ute, a n d D ose Re gi me n s u bsecti o ns, 
Secti o n 6. 2, St u d y E ve nts Fl o w C hart, Peri o d 2, Secti o n 8. 2. 2 
Rati o nale f or t he D os e Selecti o n a n d D ose R e gi me n, Secti o n  1 0. 1 
O verall St u d y Desi g n a n d Pla n , a n d Secti o n 1 2. 1 Treat me nts 
A d mi nistere d were u p dat e d. 
Secti o n  1 3. 2. 5. 2 was u p d ate d t o i ncl u de i ntra m usc ular gl u ca g o n as 
a resc u e me dicati o n a n d t o i n dicate t hat s u bject will be offere d t he 
place me nt of a n I V cat heter f or resc ue t h era p y . 
I n a d diti o n, t he N ote t o File creat e d o n J a n uar y 3 1, 2 0 1 9 was 
i nc or p orate d i nt o t his a m e n d me nt. T h us, t he f oll o wi n g state me nt 
was a d de d at t he e n d of t he last se nte nce i n  Secti o n  1 3. 2. 5. 1: “I n 
a d diti o n, the PI or d esi g n ee ma y a d mi ni ster a d diti o nal oral 
gl uc ose, 1 6  g of gl uc ose ( 4  x 4 g c he w a ble ta blets), if t he bl o o d 
gl uc ose ( m o nit ore d b y fi n ger stic k) at a n y of t he s pecifie d ti me 
p oi nts is < 6 0 m g/ d L or at a n y ot her ti me base d o n e val uati o n of 
s y m pt o ms. F or s u bjects wit h bl o o d gl uc ose < 6 0 m g/ d L, 
i nter ve nti o n meas ure m e nts o utli ne d i n pr ot oc ol Secti o n 1 3. 2. 5. 2 
will be f oll o we d .” 
Als o , t he first para gra p h i n Secti o n 1 5. 6 was u p date d t o reflect t he 
c orrect pr ocess wit h re gar ds t o  rec or d k ee pi n g a n d si g ni n g of t he 
case r e p ort f or ms.  
1 0 J a n uar y 2 0 1 9 
b y 
Fi nal  Pr ot oc ol 
P P D
P P D

{
D o c u Si g n e d b y: 
I 
 
V 
Si g n er N a m e :
, M D , P h D 
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 : 2/ 2 0 /2 0 1 9 2: 0 5 :0 8 P M E S T 
0 1 A 6 C 8 3 0 E C 5 1 4 5 8 4 8 D E 6 0 8 7 9 B A D 6 9 C B A 
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 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 5 
3  
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 a n d Me dical Writer 
2 2- 2 4 Lis b ur n R o a d
Belfast, N ort her n Irela n d, B T 9 6 A D
Tel.:  
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 ntact: 
Tel.:
Fa x: 
Bi o a n al ytic al L a b or at or y  f or 
Re p a gli ni de  a n d L O X O - 2 9 2 
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 
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

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
Page 6 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
and/or 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.: +1 402 476-2811 
Fax: +1 402 939-0428 

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
Page 7 
4 
TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY ............................................................................. 2 
2 PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ......................... 3 
3 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................ 5 
4 TABLE OF CONTENTS ................................................................................................. 7 
5 SYNOPSIS ....................................................................................................................... 10 
6 STUDY EVENTS FLOW CHART ............................................................................... 13 
6.1 
Period 1 ................................................................................................................... 13 
6.2 
Period 2 ................................................................................................................... 16 
7 ABBREVIATIONS ......................................................................................................... 19 
8 INTRODUCTION........................................................................................................... 22 
8.1 
Background ............................................................................................................. 22 
8.1.1 
LOXO-292 ................................................................................................ 22 
8.1.2 
Repaglinide ............................................................................................... 24 
8.2 
Rationale .................................................................................................................. 25 
8.2.1 
Rationale for this Study and Study Design ............................................... 25 
8.2.2 
Rationale for the Dose Selection and Dose Regimen ............................... 25 
8.2.3 
Rationale for Primary Endpoints .............................................................. 26 
8.3 
Risks and/or Benefits to Subjects ............................................................................ 26 
9 OBJECTIVES AND ENDPOINTS ............................................................................... 27 
9.1 
Objectives ................................................................................................................ 27 
9.2 
Endpoints ................................................................................................................. 27 
10 STUDY DESIGN ............................................................................................................. 28 
10.1 Overall Study Design and Plan ............................................................................... 28 
10.1.1 
Confinement, Return Visits, and Follow-Up ............................................ 28 
10.1.2 
End of Study Definition ............................................................................ 29 
11 STUDY POPULATION ................................................................................................. 30 
11.1 Inclusion Criteria ..................................................................................................... 30 
11.2 Exclusion Criteria .................................................................................................... 31 
11.3 Early Termination of Subjects from the Study ........................................................ 34 
11.4 Study Restrictions ................................................................................................... 34 
11.4.1 
Prohibitions and Concomitant Medication ............................................... 34 
11.4.2 
Meals ......................................................................................................... 35 
11.4.3 
Activity ..................................................................................................... 36 
12 TREATMENTS............................................................................................................... 37 

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CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
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12.1 Treatments Administered ........................................................................................ 37 
12.2 Dose Modification ................................................................................................... 37 
12.3 Method of Treatment Assignment ........................................................................... 38 
12.4 Blinding ................................................................................................................... 38 
12.5 Treatment Compliance ............................................................................................ 38 
13 STUDY ASSESSMENTS AND PROCEDURES ......................................................... 39 
13.1 Screening ................................................................................................................. 39 
13.2 Safety Assessments ................................................................................................. 39 
13.2.1 
Physical Examination................................................................................ 39 
13.2.2 
Vital Signs ................................................................................................. 39 
13.2.3 
ECG Monitoring ....................................................................................... 40 
13.2.4 
Body Weight ............................................................................................. 40 
13.2.5 
Glucose Monitoring .................................................................................. 40 
13.2.5.1 Blood Glucose .......................................................................... 40 
13.2.5.2 Rescue Intervention for Hypoglycemia ................................... 40 
13.2.6 
Clinical Laboratory Tests .......................................................................... 41 
13.2.7 
Adverse Events ......................................................................................... 42 
13.2.7.1 Adverse Event Definition ......................................................... 42 
13.2.7.2 Monitoring ............................................................................... 42 
13.2.7.3 Reporting .................................................................................. 43 
13.2.7.4 Serious Adverse Event ............................................................. 44 
13.3 Pharmacokinetic Assessments ................................................................................. 45 
13.3.1 
Blood Sampling and Processing ............................................................... 45 
13.3.2 
Pharmacokinetic Parameters ..................................................................... 46 
13.3.3 
Analytical Method .................................................................................... 47 
13.4 Blood Volume Drawn for Study Assessments ........................................................ 47 
14 STATISTICAL CONSIDERATIONS .......................................................................... 48 
14.1 Sample Size Determination ..................................................................................... 48 
14.2 Population for Analyses .......................................................................................... 48 
14.3 Statistical Analyses ................................................................................................. 48 
14.3.1 
Pharmacokinetic Analyses ........................................................................ 48 
14.3.1.1 Descriptive Statistics ................................................................ 48 
14.3.1.2 Analysis of Variance ................................................................ 48 
14.3.1.3 Steady State Analysis (Period 2 only) ...................................... 49 
14.3.1.4 Ratios and Confidence Intervals .............................................. 49 
14.3.2 
Safety Analyses ......................................................................................... 49 
15 STUDY ADMINISTRATION ....................................................................................... 51 

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CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
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15.1 Ethics ....................................................................................................................... 51 
15.1.1 
Institutional Review Board ....................................................................... 51 
15.1.2 
Ethical Conduct of the Study .................................................................... 51 
15.1.3 
Subject Information and Consent.............................................................. 51 
15.1.4 
Confidentiality .......................................................................................... 51 
15.2 Termination of the Study ......................................................................................... 52 
15.3 Data Quality Assurance ........................................................................................... 52 
15.4 Direct Access to Source Data/Documents .............................................................. 52 
15.5 Drug Supplies, Packaging and Labeling ................................................................. 52 
15.6 Data Handling and Record Keeping ........................................................................ 53 
15.7 Report Format ......................................................................................................... 53 
15.8 Publication Policy ................................................................................................... 53 
16 REFERENCES ................................................................................................................ 54 
LIST OF TABLES 
Table 1: 
Blood Volume during the Study .................................................................... 47 

C O N FI D E N TI A L 
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 1 0 
5  
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  – Dr u g - dr u g i nteracti o n ( D DI) st u d y 
St u d y O bjecti ve s: 
Pri m ar y:  
T o i n vesti gate t h e effect of m ulti ple -d ose L O X O - 2 9 2 o n t he 
si n gle- d os e p har mac o ki n etics ( P K) of re pa gli ni de, a se nsiti ve 
c yt o c hr o me P 4 5 0 ( C Y P ) 2 C 8 s u bstrate, i n healt h y a d ult s u bjects. 
Sec o n d ar y:  
1)
T o e val uate t he si n gle - d ose P K of L O X O - 2 9 2 a d mi nistere d
al o ne a n d t he m ulti ple -d ose P K of L O X O - 2 9 2 wit h
c oa d mi nistrati o n of re p a gli ni de  i n healt h y a d ult s u bjects.
2)
T o deter mi ne t he safet y a n d t olera bilit y of m ulti ple - d ose
L O X O - 2 9 2 wit h a n d wit h o ut c oa d mi nistrati o n of
rep a gli ni de i n healt 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 n o pe n- la bel, 2- p eri o d, fi x e d-se q ue nce st u d y. 
I n Peri o d 1, Da y  1, a si n gle oral d ose of re pa gli ni d e will be 
a d mi nistere d . P har mac o ki netic ( P K) sa m pli n g f or re pa gli ni de 
will be c ollecte d pre d ose a n d f or 1 6 h o urs p ost d os e.  
I n Peri o d 2, oral d oses of L O X O - 2 9 2 will be a d mi nistere d 
t wice-dail y ( BI D) f or 1 0 c o nsec uti ve da ys ( Da ys 1 t o 1 0). T he 
si n gle d ose of re p a gli ni de will be c oa d mi nistere d wit h t he si n gle 
d ose of L O X O - 2 9 2 o n t he m or ni n g of Da y 1 0. P h ar mac o ki netic  
sa m pli n g f or re pa gli ni de will be c ollecte d pre d ose a n d f or 
1 6 h o urs f oll o wi n g re pa gli ni de d osi n g o n Da y 1 0. 
P har mac o ki netic sa m pli n g  i n plas ma f or L O X O - 2 9 2 will be 
c ollecte d pre- m or ni n g d ose a n d f or 1 2 h o urs f oll o wi n g t he 
m or ni n g d ose o n D a y 1 a n d Da y 1 0 ; a pre- m or ni n g d ose s a m ple 
f or L O X O- 2 9 2 will als o be c ollecte d o n 
. 
I n b ot h p eri o ds, gl uc ose will be a d mi nistere d i m me diatel y 
f oll o wi n g re pa gli ni de d osi n g a n d, o n D a y 1 0 of P eri o d 2, at 
a p pr o xi matel y 1 h o ur p ost d ose. 
T here will be a was h o ut peri o d of 2 4 h o urs bet w ee n  t he 
re pa gli ni de d ose i n Peri o d 1 a n d t he first L O X O - 2 9 2 d ose i n 
Peri o d 2. 
T he cli nic al res earc h u nit ( C R U)  will c o ntact all s u bjects w h o 
receiv 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 
C CI

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
Page 11 
terminate from study early [ET]) at the End of Study (EOS, as 
defined in the Study Events Flowchart, Section 6) by a follow up 
phone call (FU). The EOS/FU phone call will be performed 
7 ± 2 days after the End of Treatment (EOT) visit or ET visit (as 
defined in the Study Events Flowchart, Section 6) to determine if 
any serious adverse event (SAE) or study drug related adverse 
event (AE) has occurred since the EOT or ET visit.  
Number of Subjects: 
Sixteen (16), healthy, adult male and female (women of 
non-childbearing potential only) subjects will be enrolled. Every 
attempt will be made to enroll at least 3 subjects of each sex. 
Dosage, Dosage Form, 
Route, and Dose 
Regimen: 
Treatments are described as follows: 
Treatment A (Period 1): 0.5 mg repaglinide (1 x 0.5 mg tablet) at 
Hour 0 on Day 1. 
Treatment B (Period 2): 160 mg LOXO-292 (2 x 80 mg capsules) 
administered BID, approximately every 
12 hours, for 10 consecutive days with 
the Day 10 morning single dose of 
160 mg LOXO-292 (2 x 80 mg capsules) 
coadministered with 0.5 mg repaglinide 
(1 x 0.5 mg tablet) (within ± 1 hour of 
the dosing time of the Day 1 morning 
dose of Period 2). 
Each dose of LOXO-292 and repaglinide will be administered 
orally with approximately 240 mL of room temperature water. 
When LOXO-292 and repaglinide are administered concurrently 
on Day 10, 240 mL only of room temperature water will be 
administered for both drugs.  
On Day 1 of Period 1, immediately following administration of 
repaglinide, subjects will be provided with 12 g of glucose 
(3 x 4 g chewable tablets). On Day 10 of Period 2, immediately 
following administration of repaglinide and at approximately 
1 hour after administration of repaglinide, subjects will be 
provided with 16 g of glucose (4 x 4 g chewable tablets). An 
additional 100 mL of room temperature water may be taken if 
required. 

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CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
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Key Assessments: 
Pharmacokinetics: 
The following PK parameters will be calculated for repaglinide 
in plasma, as appropriate:  
Period 1, Day 1 and Period 2, Day 10: AUC0-t, AUC0-inf, 
AUC%extrap, Cmax, Tmax, Kel, t½, CL/F, and Vz/F. 
The following PK parameters will be calculated for LOXO-292 
in plasma, as appropriate: 
Period 2, Day 1 after the morning dose: AUC0-12, AUC0-t, 
Cmax, and Tmax; and  
Period 2, Day 10 after the morning dose: AUCtau, Cmax,ss, 
Ctrough, Tmax,ss, and CL,ss/F. 
An analysis of variance (ANOVA) will be performed on the 
repaglinide natural log (ln)-transformed AUC0-t, AUC0-inf, and 
Cmax, using the appropriate statistical procedure. 
Safety: 
All safety assessments, including AEs and SAEs, vital sign 
measurements, clinical laboratory results, physical examination 
results, glucose monitoring, concomitant medications, and ECG 
interpretations, will be tabulated and summarized where 
possible, using descriptive methodology by treatment and by 
timepoint. 

C O N FI D E N TI A L  
C A 2 6 4 3 4 (L O X O -R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 1 3 
6  
S T U D Y E V E N T S F L O W C H A R T  
6. 1  
Peri o d 1  
St u d y Pr oc e d ur e a 
Scr b  
St u d y D a ys i n Peri o d 1 c 
D a ys → 
-1
1  
H o urs → 
C -I d
0  
0. 2 5  
0. 5  
0. 7 5  
1  
1. 5  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 2  
1 6  e 
A d mi nistr ati ve Pr oce d ures  
I nf or me d C o nse nt  
X  
I ncl usi o n/ E xcl usi o n Criteria 
X  
X  
Me dical Hist or y  
X  
S afet y E v al u ati o ns 
F ull P h ysical E xa mi n ati o n f 
X 
A b bre viate d P h ysical E xa mi n ati o n f 
X 
Hei g ht  
X  
Wei g ht  
X  
X 
1 2 -Lea d Safet y E C G  g
X  
X  
X  i 
X  
Vital Si g ns ( H R, B P, a n d  R R)  h  
X  
X  
X i 
X  
X  
X  
Vital Si g ns ( T)  
X  
X i 
He m, Ser u m C he m   j, C o a g, a n d U A 
X  
X  
He m o gl o bi n ( H b) A 1 c  
X  
T h yr oi d sti m ulati n g h or m o n e  
X  
Gl uc ose M o nit ori n g k  
X l 
X  
X  
X  
X  
X  
Ser u m Pre g Test ( ♀ o nl y)  
X  
X  
Ser u m F S H ( P M P ♀ o nl y)  
X  
Uri ne Dr u g , C oti ni n e, a n d Alc o h ol Scree n  
X  
X  
HI V/ He patitis Scree n  
X  
A E M o nit ori n g  m  
X  
 < -----------------------------------------------------------------  X  -------------------------------------------------------------->  
C o n Me ds M o nit ori n g  
X  
 < -----------------------------------------------------------------  X  -------------------------------------------------------------->  
St u d y Dr u g A d mi nistr ati o n / 
P h ar m ac o ki netics  
Re pa gli ni de A d mi nistrati o n  
X 
Gl uc ose A d mi nistrati o n  
X n  
Bl o o d f or Re pa gli ni d e  P h ar mac o ki n etics  o 
C CI

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
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Study Procedure a 
Scr b 
Study Days in Period 1 c 
Days → 
-1
1 
Hours → 
C-I d
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
16 e 
Other Procedures 
Confinement in the CRU p 
 <-------------------------------------------------------------------------  X  --------------------------------------------------------------> 
Visit 
X 
Period 1 footnotes: 
a: 
For details on Procedures, refer to Section 13. 
b: 
Within 28 days prior to the first study drug administration (i.e., repaglinide). 
c: 
There will be a washout period of 24 hours between the repaglinide dose in Period 1 and the first LOXO-292 dose in Period 2. Subjects are confined to the 
CRU from C-I (Day -1, Period 1) through EOT (Period 2) or ET, including throughout the washout period. 
d: 
Subjects will be admitted to the CRU at C-I (Day -1, Period 1), at the time indicated by the CRU.  
e: 
In Period 1, the 16-hour postdose sample on Day 1, will be either on Day 1 or Day 2, depending on the time of dosing on Day 1. 
f: 
Symptom-driven physical examination(s) 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. 
g: 
Subjects are to be supine for 10 minutes prior to ECG assessment. ECGs will be obtained prior to and as close as possible to the scheduled blood draws if 
scheduled at the same time. 
h: 
Vital signs (HR, BP, and RR) will be obtained at Screening, C-I (Day -1, Period 1), predose, at 0.75 hours (± 10 minutes), 2 hours (± 10 minutes), and 
4 hours (± 10 minutes). Vital sign measurements should be carried out prior to and as close as possible to having blood drawn. BP and HR will be 
measured using the same arm for each reading. Subjects are to be supine for 5 minutes prior to vital sign assessments.  
i: 
To be performed within 2 hours prior to dosing. 
j: 
Samples for serum chemistry will be obtained following a fast of at least 12 hours at Screening and at C-I (Day -1, Period 1); 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 being taken. 
k: 
All glucose measurements will be done with a glucose monitor and will be performed by finger stick. 
l: 
Prior to dosing. 
m: 
AEs and SAEs will be recorded 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 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 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 

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 1 5 
re gar dless  of  relati o ns hi p  t o  st u d y  dr u g). Fr o m  E O T  or  E T  t hr o u g h  E O S  o nl y  A Es  assesse d  as  relate d  t o  st u d y  dr ug b y  t he  PI  ( or  desi g nee)  are  t o  be 
re p orte d. All S A Es t hat de vel o p fr o m t he ti me of I C F si g ni n g u ntil E O S ( or E T if t he s u bj ect disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w 
u p call) are t o be re p orte d.  
n: 
Gl uc ose will be a d mi nistere d i m me di atel y f oll o wi n g re pa gli ni de d osi n g. 
o:  
p: 
S u bj ects are c o nfi ne d t o t he C R U fr o m C -I ( Da y -1, P eri o d 1)  t hr o u g h E O T  ( P eri o d 2) or E T, i ncl u di n g t hr o u g h o ut t he was h o ut peri o d.  
A b bre viati o ns:  ♀ = Fe males,  A E  = A d verse  e ve nts,  B P  = Bl o o d  press ure,  C -I = C hec k -i n,  C he m = C he mistr y,  C oa g  =  c oa g ulat i o n,  C o n Me ds = C o nc o mita nt 
me dicati o n,  C R U  = Cli nical  researc h  u nit,  E C G  = Electr ocar di o gra m,  E O S  =  E n d  of St u d y , E O T  =  E n d  of Treat me nt ,  E T  = Earl y  ter mi n ati o n, 
F S H  = F ollicle -sti m ulati n g  h or m o ne,  He m = He mat ol o g y,  HI V  = H u ma n  i m m u n o defi cie nc y  vir us,  H R  = Heart  r ate, 
I C F  =  I nf or me d  C o ns e nt  F or m, 
PI  = Pri nci pal I n vesti gat or, P M P  = P ost me n o pa usal, Pre g  = Pre g na nc y, R R  = Res pirat or y rate, Scr  = Scree ni n g, T  = T e m perat ure, U A  = Uri nal ysis.   
C CI

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 1 6 
6. 2  
Peri o d 2  
St u d y Pr oc e d ur es a 
St u d y D a ys i n Peri o d 2 b  
D a ys → 
1  
2  
H o urs → 
0  
0. 2 5  
0. 5  
0. 7 5  
1  
1. 5  
2  
3  
4  
6  
8  
1 2  
0  
1 2  
S afet y E v al u ati o ns 
A b bre viate d P h ysical E xa m c
X d  
1 2 -Lea d  Safet y E C G  e
X d  
X  
X  j 
Vital Si g ns ( H R B P , a n d R R) f 
X d  
X  
X  
X  
X j 
He m, Ser u m C he m g, C o a g, a n d U A 
X  d  
A E M o nit ori n g  h  
< -------------------------------------------------------------  X  ---------------------------------------------------------->  
C o n Me ds M o nit ori n g  
< -------------------------------------------------------------  X  ---------------------------------------------------------->  
St u d y Dr u g A d mi nistr ati o n / P h a r m a c o ki netic  
L O X O -2 9 2 A d mi nistrati o n  
X 
X  
X  
X 
Bl o o d  f or L O X O-2 9 2 P h ar mac o ki n etic  i 
Ot he r Pr oc e d ur es  
C o nfi ne me nt i n t h e C R U 
 < ------------------------------------------------------------------  X  --------------------------------------------------------->  
St u d y Pr oc e d ur es  a 
St u d y D a ys i n Peri o d 2 b  
D a ys → 
3  
4  
5  
6  
7  
8
9  
H o urs → 
0  
1 2  
0  
1 2  
0  
1 2  
0  
1 2  
0  
1 2  
0  
1 2  
0  
1 2  
S afet y E v al u ati o ns  
Wei g ht  
X  j 
1 2 -Lea d Safet y E C G  e
X  j 
X  j 
X  j 
X  j 
X   j 
X  j 
X  j 
Vital Si g ns ( H R , B P , a n d R R) f 
X  j 
X  j 
X  j 
X  j 
X  j 
X  j 
X  j 
He m, Ser u m C he m g, C o a g, a n d U A 
X  j 
X  j 
A E M o nit ori n g  h 
< ---------------------------------------------------------------------  X  ---------------------------------------------------------------->  
C o n Me ds M o nit ori n g  
< ---------------------------------------------------------------------  X  ---------------------------------------------------------------->  
St u d y Dr u g A d mi nistr ati o n / 
P h ar m ac o ki netic  
L O X O -2 9 2 A d mi nistrati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d f or L O X O -2 9 2 P h ar mac o ki n etics  i 
Ot he r Pr oc e d ur es  
C o nfi ne me nt i n t h e C R U 
< -----------------------------------------------------------------------  X  ---------------------------------------------------------->  
C CI
C CI

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 1 7 
St u d y Pr oc e d ur es a 
St u d y D a ys i n Peri o d 2 b  
E O S/ F U
 o
Da ys → 
1 0  
Cli nic Disc har ge/ Da y  1 1  
( E O T or E T ) 
H o urs → 
0  
0. 2 5  
0. 5  
0. 7 5  
1  
1. 5  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 2  
1 6 k 
2 4  
Safet y E val uati o ns 
Wei g ht  
X n 
1 2 -Lea d Safet y E C G  e
X  j 
X  
X n 
Vital Si g ns ( H R, B P, a n d R R)  f 
X  j 
X  
X  
X  
X n 
Vital Si g ns ( T)  
X n 
He m, Ser u m C he m g, C o a g, a n d U A 
X  j 
X n 
Gl uc ose m o nit ori n g l 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ser u m Pre g  
X n 
A E M o nit ori n g  h
< --------------------------------------------------------------------------X  -------------------------------------------------------------->  
X 
C o n Me ds M o nit ori n g  
< -----------------------------------------------------------------------  X  -------------------------------------------------------------->  
St u d y Dr u g A d mi nistr ati o n / 
P h ar m ac o ki netic  
L O X O -2 9 2 A d mi nistrati o n  
X  
X  
Re pa gli ni de  A d mi nistrati o n  
X  
Gl uc ose A d mi nistrati o n   
X m  
X  m  
Bl o o d f or L O X O -2 9 2 P h ar mac o ki n etics  i 
Bl o o d f or Re pa gli ni d e P h ar mac o ki n etics  i 
Ot he r Pr oc e d ur es  
C o nfi ne me nt i n t h e C R U 
 < --------------------------------------------------------------------------- X  ------------------------------------------------------------->  
P eri o d 2 f o ot n otes:  
a: 
F or details o n Pr oce d ures, refer t o Secti o n  1 3 . 
b:  
T here will be a was h o ut peri o d of 2 4  h o urs bet wee n t he re pa gli ni de d ose i n P eri o d 1 a n d t he first L O X O-2 9 2 d ose i n P eri o d 2. S u bj ects are c o nfi ne d t o t he 
C R U fr o m C -I ( Da y -1, P eri o d 1 ) t hr o u g h E OT ( P eri o d 2) or E T, i ncl u di n g t hr o u g h o ut t he was h o ut peri o d.  
c: 
S y m pt o m -dri ve n  p h ysical  e xa mi nati o n(s)  ma y  be  perf or me d  at  ot her  ti mes,  at  t he  PI’s  or  desi g nee’s  discreti o n.  Sc he d ule d  a b bre viate d  p h ysical 
e xa mi nati o ns will i ncl u de, at a  mi ni m u m, e xa mi nati o n of res pirat or y, car di o vasc ular, a n d gastr oi ntesti nal s yste ms, wit h t he o pti o n f or f urt her e xa mi nati o n 
of a d diti o nal s yste ms as necessar y base d o n re p orte d s y m pt o ms/ A Es.  
d:  
T o be perf or me d pri or t o Da y 1 d osi n g . 
e: 
S u bj ects are t o be s u pi ne f or 1 0 mi n utes pri or t o E C G assess me nt. E C Gs will be o btai ne d pri or t o a n d as cl ose as p ossi ble t o t he sc he d ule d bl o o d dra ws if 
sc he d ule d at t he sa me ti me 
f: 
Vital si g ns ( H R, B P, a n d R R) will be o btai ne d at pre d ose, at 0. 7 5 h o urs  ( ± 1 0 mi n utes), 2 ho urs  ( ± 1 0 mi n utes), a n d 4 h o urs ( ± 1 0 mi n utes) o n Da ys 1 a n d 
1 0, pri or t o t he m or ni n g d ose o n Da ys 2 t hr o u g h 9  a n d at E O T  ( or E T). Vital si g n meas ur e me nts s h o ul d be carrie d o ut pri or t o a n d as cl ose as p ossi ble t o 
C CI

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 1 8 
ha vi n g  bl o o d  dra w n.  B P  a n d  H R  will  be  meas ure d  usi n g  t he  sa me  ar m  f or  eac h  rea di n g.  S u bj ects  are  t o  be  s u pi ne  f or  5  mi n utes  pri or  t o  vital  si g n 
assess me nts. 
g: 
Sa m ples  f or ser u m c he mistr y  will be o btai ne 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 hec k -i n ( Da y -1, P eri o d 1) ; at ot her sc he d ule d 
ti mes, ser u m c he mistr y tests will be perf 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 hec ks, s u bj ects ma y n ot ha ve faste d f or 1 2 
or 8 h o urs pri or t o t he ti me t hat t he ser u m c he mistr y sa m ple is bei n g ta ke n.  
h: 
A Es a n d S A Es will be rec or de d be gi n ni n g at i nf or me d c o ns e nt.  All A Es will be rec or de d t hr o u g h o ut t he st u d y (i.e., fr o m si g ni n g of t he I C F u ntil E O S or 
E T  if  t he  s u bj ect  disc o nti n ues  fr o m  t he  st u d y  a n d  d oes  n ot  c o m plete  a  f oll o w  u p  call),  eit her  as  s u bj ect  me dical  hist or y  (if  t he  e ve nt  is  re p orte d  as 
be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 of P eri o d 1 a n d is assesse d as n ot relate d t o st u d y 
pr oce d ures  b y t he PI [ or desi g nee] ) or as A Es (if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 of P eri o d 1 a n d 
is assesse d as relate d t o st u d y pr oce d ures b y t he PI [ or desi g nee] , or if t he e ve nt occ urs aft er st u d y dr u g a d mi nistrati o n o n Da y 1 of P eri o d 1 re gar dless of 
relati o ns hi p t o st u d y dr u g). Fr o m E O T  or E T  t hr o u g h E O S o nl y A Es assesse d as relate d t o st u d y dr u g b y t he PI ( or desi g nee) are t o be re p orte d.  All S A Es 
t hat de vel o p fr o m t he ti me of I C F si g ni n g u ntil E O S ( or E T if t he s u bj ect disc o nti n ues fr o m t he stu d y a n d d oes n ot c o m plete a f oll o w u p call) are t o be 
re p orte d. 
i: 
j: 
k: 
l: 
All gl uc ose meas ure me nts will  be d o ne wit h a gl uc ose m o nit or  a n d will be perf or me d b y fi n ger stic k . 
m: 
Gl uc ose will be a d mi nistere d i m me diatel y f oll o wi n g re pa gli ni de d osi n g  a n d at a p pr o xi mat el y 1 h o ur p ost d ose  (after t he P K sa m ple). 
n: 
T o be perf or me d at t he E O T ( Da y 1 1 , P eri o d 2), or pri or t o E T fr o m t he st u d y. E O T is defi ne d as w he n t he s u bj ect is release d fr o m t he C R U f oll o wi n g 
c o m pleti o n of all assess me nts t hr o u g h Da y 1 1 of P eri o d 2.  E T is defi ne d as w he n t he s u bj ect is release d fr o m t he C R U if t he s u bj ect ter mi nates t he st u d y 
earl y.  Vital Si g n, E C G, a n d S af et y la b orat or y res ults f or ser u m c he mistr y, he mat ol o g y, c oa g ulati o n, a n d uri nal ysis are t o be a vaila ble f or re vie w b y t he PI 
or desi g nee pri or t o s u bj ect release fr o m t he C R U at t he E O T or E T visit. 
o: 
T o be perf or me d 7 da ys ( ± 2 da ys) f oll o wi n g E O T or E T.   E n d of St u d y ( E O S) is defi ne d as w he n t he C R U will c o ntact  t he s u bj ect b y a f oll o w u p p h o ne 
call 7 ± 2 da ys after t he E O T visit or E T visit t o deter mi ne if a n y S A E or st u d y dr u g relat e d A E has occ urre d si nce t he E O T o r E T visit. All s u bj ects w h o 
recei ve d L O X O -2 9 2 (i ncl u di n g s u bj ects w h o ter mi nate t he st u d y earl y) will be c o ntacte d . 
A b bre viati o ns:  A E  = A d verse  e ve nts,  B P  = Bl o o d  press ure, C-I = C hec k -i n,  C he m = C he mistr y,  C oa g  =  c oa g ulati o n,  C o n Me ds  = C o nc o mita nt  me dicati o n, 
C R U  = Cli nical  researc h  u nit,  E C G  = Electr ocar di o gra m,  E O S  = E n d  of  St u d y, E O T  = E n d -of -Treat me nt , E T  =  earl y  ter mi nati o n,  F U  = F oll o w -u p, 
He m  = He mat ol o g y, H R  = He art rate, I C F = I nf or me d c o nse nt f or m, R R  = Res pirat or y rat e, S A E = Seri o us a d verse e ve nt, T = T e m perat ure, U A  = Uri nal ysis.   
C CI

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
Page 19 
7 
ABBREVIATIONS 
~ 
Approximately  
μM 
Micromolar 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC%extrap 
Percent of AUC0-inf extrapolated  
AUC0-12 
The area under the concentration-time curve, from time 0 to the 
12 hour timepoint 
AUC0-t 
Area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration (t) 
AUCtau 
Area under the concentration-time curve during a dosing 
interval (tau), at steady state 
AUC0-inf 
Area under the concentration-time curve, from time 0 
extrapolated to infinity 
BID 
Twice daily 
bpm 
Beats per minute 
BMI 
Body mass index 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F 
Apparent total plasma clearance after oral (extravascular) 
administration 
CL,ss/F 
Apparent total plasma clearance after oral (extravascular) 
administration 
cm 
Centimeter 
Cmax 
Maximum observed concentration  
Cmax,ss 
Maximum observed concentration at steady-state. 
CRF 
Case report form 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
Page 20 
Ctrough 
Concentration observed at the end of the dosing interval 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FU 
Follow up 
g 
Gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HbA1c 
Hemoglobin (Hb) A1c 
HBsAg 
Hepatitis B surface antigen 
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 for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
Kel 
Apparent terminal elimination rate constant 
kg 
Kilogram 
LFT 
Liver function test 
LSMs 
Least-squares means 
m2 
Meters squared 

CONFIDENTIAL 
CA26434 (LOXO-RET-18026), Final Protocol, Amendment 1 19FEB2019 
Page 21 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
No. 
Number 
OATP 
Organic anion transporting protein 
oz 
Ounces 
P-gp
P-glycoprotein
PCR
Polymerase chain reaction
PI
Principal Investigator
PK
Pharmacokinetic(s)
QA
Quality Assurance
QTc
Corrected value of the interval between the Q and T waves on the 
electrocardiogram tracing 
RET 
Rearranged during transfection 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse events  
Tmax 
Time to reach maximum observed concentration 
Tmax,ss 
Time to reach maximum observed concentration at steady-state 
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 

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 2 2 
8  
I N T R O D U C TI O N 
8. 1  
B ac k gr o u n d 
8. 1. 1  
L O X O - 2 9 2 
L O X O - 2 9 2 is s mall m olec ule a n d a s electi ve i n hi bit or of t he rearra n ge d d uri n g tra nsfecti o n 
( R E T) rece pt or t yr osi ne ki nase desi g ne d t o c o m p etiti vel y bl oc k t he a d e n osi ne tri p h os p hate 
bi n di n g site of t he ki nase. L O X O- 2 9 2 w as at least 2 5 0-f ol d m ore selecti ve f or R E T t ha n f or 
9 8 % of 3 2 9 ot her ki nas 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 use d si g nifica nt c yt ot o xicit y i n h u ma n ca ncer cell li nes t hat 
har b ore d e n d o ge n o us, cli nicall y r ele va nt R E T ge n e alterati o ns b ut was m uc h less c yt ot o xic 
a gai nst h u ma n ca n cer cell li nes wit h o ut R E T alterati o ns. P ote nt a n d selecti ve i n hi biti o n of 
R E T ma y pr o vi d e cli nical be nefit t o s u bjects wit h mali g na n cies d ue t o o nc o ge ni c alterati o ns 
i n R E T or wit h ot her mec ha nis ms of i ncrease d R E T acti vit y. 
N o ncli nic al  
Car diac safet y of L O X O - 2 9 2 was e val u ate d i n a G o o d La b orat or y Practice ( G L P) i n vitr o 
assa y f or h u ma n et her -a-g o -g o relate d ge ne  ( h E R G) acti vit y, i n a G L P i n vi v o st u d y i n 
c o nsci o us tele metr y-i nstr u me nte d mi ni pi gs, a n d i n a G L P 2 8-da y re peat - d ose t o xic ol o g y 
st u d y ( wit h E C G m o nit ori n g) i n mi ni pi gs. L O X O- 2 9 2 ha d a 5 0 % i n hi bit or y c o nce ntrati o n 
 i n t he G L P h E R G assa y, w hic h is a p pr o xi matel y 
t ha n t he pre dicte d m a xi m u m u n b o u n d c o nce ntrati o n at t he d ose of 8 0 m g a n d 1 6 0 m g 
res pecti vel y t wice dail y ( BI D). T here were n o L O X O- 2 9 2-relate d c ha n ges i n a n y 
car di o vas c ular e n d p oi nts i ncl u di n g Q T i nter v al c orrecte d f or heart rat e ( Q T c) at d oses u p t o 
1 2 m g/ k g i n t he saf et y p h ar mac ol o g y car di o vas c ular st u d y i n c o nsci o us mi ni pi gs. 
F urt her m ore, t her e were n o L O X O- 2 9 2- relate d E C G c ha n ges i n t he 2 8-d a y re peat - d ose 
t o xicit y st u d y i n mi ni pi gs at t he hi g h d ose of 1 2 m g/ k g. T o get her, t hese d ata i n dicate t hat 
L O X O - 2 9 2 has a l o w ris k of i n d uci n g d ela ye d v e ntric ular re p ol arizati o n, pr ol o n gati o n of t h e 
Q Tc i nter val, a n d u nsta ble arr h yt h mias. 
A d mi nistrati o n of L O X O - 2 9 2 at si n gle d os es u p t o 4 5 m g/ k g i n male rats h a d n o  effect o n 
res pirat or y f u ncti o n. 
P ote ntial effects of L O X O - 2 9 2 o n t he ce ntral ner v o us s yste m were e v al uate d as part of t he 
G L P  2 8-d a y re p eat - d os e st u d y i n rats, i n f u ncti o nal o bser vati o nal batter y tests a n d l oc o m ot or 
acti vit y ass ess me nts. Fi n di n gs were li mite d t o a ni mals recei vi n g t he hi g h d ose  o n wee k  4 of 
t he d osi n g p has e, a n d w ere attri b ute d t o p o or ge n eral b o d y c o n diti o n a n d w ei g ht c h a n ges 
ass ociate d wit h L O X O -2 9 2 a d mi nistrati o n rat her t ha n s pecific n e ur ol o gical effects. 
A d diti o nall y, n o micr osc o pic a b n or malities i n ne ur o nal tiss ues were f o u n d. 
I n t o xic ol o g y st u dies of L O X O- 2 9 2 t hat w ere c o n d ucte d i n t he rat a n d mi ni pi g, t he pri mar y 
pat h ol o gic fi n di n gs f or b ot h s pecies were i n t he t o n g ue, p a ncreas, b o n e marr o w a n d 
l y m p h oi d tiss ues; w hile t he gastr oi ntesti nal tract a n d o varies were tar get tiss ues i n mi ni pi g. 
Ot her tar get tiss ues i de ntifie d i n t he rat i ncl u de d: m ulti -tiss ue mi neralizati o n, p h yseal 
cartila ge, i ncis or t eet h, l u n g, Br u n ner’s gla n d, a n d p ossi bl y li ver. Assess me nt of d oses 
ass ociate d wit h m ori b u n dit y/ d eat h re veal e d a stee p d ose res p o nse c ur ve f or b ot h s pecies. 
C CI
C CI

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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, 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 studies suggest that the pharmacokinetic 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 the Breast Cancer Resistance Protein. 
Refer to the Investigator’s Brochure 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 have been attributed to study drug. A small number of patients have experienced 

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Grade 3 or higher liver function test (LFT) abnormalities, considered related to the study 
drug, occurring between 20 - 56 days after starting LOXO-292. These changes were 
asymptomatic and resolved with dose interruption. LOXO-292 was resumed at a lower dose 
following normalization of the LFTs.  
As of August 24 2018, PK data were available from 141 patients (from the global Phase 1/2 
study). LOXO-292 is absorbed after oral administration with a median time to maximum 
concentration (Tmax) of approximately 2 hours. Although the PK sampling of LOXO-292 
was not long enough to adequately characterize AUC0-inf, the half-life appears to be 
20 hours. Low concentrations of LOXO-292 were recovered as unchanged drug in urine 
indicating that the kidney contributes to overall clearance. 
As of September 14, 2018, Loxo Oncology has initiated 16 single patient protocols, Special 
Access Scheme, or Temporary Authorization Use cases to provide access to LOXO-292 for 
patients with clinical need not meeting eligibility criteria for the ongoing global Phase 1/2 
study. To date, no TEAEs have been attributed to study drug for these patients. 
Preliminary PK data available from ongoing studies (LOXO-RET-18014 and LOXO-RET-
18015) being conducted in healthy subjects indicate that LOXO-292 has an estimated 
terminal t½ of approximately 24 hours after a single dose. 
8.1.2 Repaglinide 
Repaglinide is a blood glucose-lowering drug of the meglitinide class used as an adjunct to 
diet and exercise, in the management of type 2 diabetes mellitus. It lowers blood glucose 
levels by stimulating release of insulin from the pancreas, repaglinide closes ATP-dependent 
potassium channels in the beta cell membrane, leading to an opening of calcium channels, 
and the resultant calcium influx induces insulin secretion. (Full Prescribing information of 
repaglinide tablet, 2017).  
Following oral administration, repaglinide is completely absorbed from the gastrointestinal 
tract. After single and multiple oral doses, peak plasma levels (Cmax) occurs within 1 hour 
(Tmax). Repaglinide is eliminated from the bloodstream with a half-life of approximately 
1 hour. The mean absolute bioavailability of repaglinide is 56%. When repaglinide was 
administered with food, the mean Tmax was unchanged, but the mean Cmax and AUC were 
decreased 20% and 12.4%, respectively. Repaglinide is metabolized in the liver by oxidative 
biotransformation and direct conjugation with glucuronic acid to metabolites. These 
metabolites do not contribute to the glucose-lowering effect of repaglinide. Within 96 hours 
after dosing with carbon-14-repaglinide as a single, oral dose, approximately 90% of the 
radiolabeled drug was recovered in feces and approximately 8% was recovered in urine. Only 
0.1% of the dose is cleared in the urine as parent compound. Repaglinide is a pregnancy 
category C drug (Full Prescribing information of repaglinide tablet, 2017).  
As per the FDA Guidance for Drug Interaction Studies, repaglinide is a sensitive substrate 
for CYP2C8 and is also a substrate the transporter organic anion transporting protein 
(OATP) 1B1 (FDA, 2017). Repaglinide dosage adjustments are recommended in patients 

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taking concomitant strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 
inducers (Full Prescribing information of repaglinide tablet, 2017). 
8.2 
Rationale 
8.2.1 Rationale for this Study and Study Design 
Metabolic routes of elimination, including most of those occurring through the CYP family 
of enzymes, can be inhibited or induced by concomitant drug treatment. Changes arising 
from metabolic DDI can be significant and contribute to increases or decreases in the blood 
and tissue concentrations of the parent drug or active metabolite. Increased concentrations of 
a parent drug or its active metabolite can alter the safety and efficacy profile of a drug.  
LOXO-292 was not metabolized by cloned, expressed human cytochrome CYP1A2, 
CYP2C8, CYP2C9, CYP2C19, and CYP2D6. CYP3A4 was able to metabolize LOXO-292. 
Data from in vitro studies indicate that LOXO-292 showed weak inhibition of CYP2C8 and 
CYP2C9 with IC50 values of 3.4 and 39 μM, respectively. This study will be conducted to 
evaluate the potential effect of LOXO-292 on the CYP2C8 enzyme in vivo. Repaglinide 
selection as a substrate is based on previous widespread use as a suitable established marker 
of CYP2C8 activity and it is recommended to be used as a CYP2C8 sensitive probe by the 
FDA (FDA, 2017). Repaglinide is also a substrate for OATP1B1, but LOXO-292 is not 
OATP1B1 inhibitor. 
A fixed-sequence design has been selected. This design will reduce the study duration. The 
washout period between the repaglinide dosing is considered sufficient to prevent carryover 
effects of the preceding treatment.  
8.2.2 Rationale for the Dose Selection and Dose Regimen 
LOXO-292: A dose of 160 mg LOXO-292 BID (320 mg/day) was selected because it is a 
dose that has been administered to cancer patients and preliminary safety and PK data show 
that this dose is likely at or near a recommended Phase 2 dose for further study in cancer 
patients. The dose of 160 mg BID should provide sufficient levels of LOXO-292 to assess 
the PK properties being investigated. LOXO-292 will be administered BID for 10 days to 
ensure steady-state is attained and there is maximum inhibition of the CYP2C8 enzyme. As 
of a July 19, 2018 data cut-off date, safety data was available from 153 patients with 240 mg 
BID (480 mg/day) as the highest dose administered. Two (2) DLTs of tumor lysis syndrome 
and Grade 3 thrombocytopenia at the 240 mg BID dose level have been reported. 
Repaglinide: A 0.5 mg dose of repaglinide was selected as it is the recommended starting 
dose, according to the full prescribing information for Prandin® (repaglinide) tablets, for 
patients whose hemoglobin (Hb) A1c is less than 8% and have not taken repaglinide 
previously. For patients whose HbA1c is 8% or greater the starting dose is 1 or 2 mg orally 
taken before each meal. Thus, the oral 0.5 mg dose in this study is expected to be safe and 
well tolerated.  

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Glucose: Immediately following each administration of repaglinide in each period, subjects 
will be provided with 12 g of glucose (3 x 4 g chewable tablets) to counteract the 
glucose-lowering effects of repaglinide. 
Following the necessity to administer additional glucose in Period 2 following repaglinide 
dosing, 16 g of glucose (4 x 4 g chewable tablets) instead of 12 g of glucose (3 x 4 g 
chewable tablets) will be given immediately following repaglinide administration in Period 2. 
An additional 16 g of glucose (4 x 4 g chewable tablets) will also be administered at 
approximately 1 hour postdose in Period 2, the expected Tmax time for repaglinide. 
8.2.3 Rationale for Primary Endpoints 
The primary PK endpoints will include AUC0-t, AUC0-inf, and Cmax, as these parameters 
describe the exposure of repaglinide and are thought to be the most relevant PK parameters 
for the purpose of evaluating an interaction. 
8.3 
Risks and/or Benefits to Subjects 
The dose of LOXO-292 administered in this study is not anticipated to induce any significant 
risk or benefit to subjects participating in this study as it does not exceed the highest daily 
total dose safely administered in the ongoing global Phase 1/2 Study (LOXO-RET-17001 
[Investigator’s Brochure 2018]). 
The dose of repaglinide administered in this study is not anticipated to result in any 
significant risk to healthy subjects participating in the study as it is a single dose 
administered according to the dosing recommendations found in the full prescribing 
information for repaglinide as the starting dose in diabetic patients (Full Prescribing 
information of repaglinide tablet, 2017). Repaglinide can potentially lower glucose in healthy 
subjects. As a precaution, glucose will be administered to subjects following repaglinide 
dosing and glucose levels will be monitored up to 9 hours following each repaglinide 
administration during the study. 
The safety monitoring practices employed by this protocol (i.e., 12-lead ECG, vital signs, 
clinical laboratory tests, glucose monitoring, AE monitoring, 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. 

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9 
OBJECTIVES AND ENDPOINTS 
9.1 
Objectives 
Primary: 
To investigate the effect of multiple-dose LOXO-292 on the single-dose PK of repaglinide, a 
sensitive CYP2C8 substrate, in healthy adult subjects. 
Secondary: 
1) To evaluate the single-dose PK of LOXO-292 administered alone and the multiple-dose
PK of LOXO-292 with coadministration of repaglinide in healthy adult subjects.
2) To determine the safety and tolerability of multiple-dose LOXO-292 with and without
coadministration of repaglinide in healthy adult subjects.
9.2 
Endpoints 
Pharmacokinetics: 
The primary PK endpoints for repaglinide will include, as appropriate, AUC0-t, AUC0-inf, 
AUC%extrap, Cmax, Tmax, Kel, t½, CL/F, and Vz/F.  
The secondary PK endpoints for LOXO-292 will include, as appropriate following the morning 
dosing, AUC0-12, AUC0-t, Cmax, and Tmax on Day 1 of Period 2 and AUCtau, Cmax,ss, 
Ctrough, Tmax,ss, and CL,ss/F on Day 10 of Period 2. 
Safety: 
Safety endpoints will include 12-lead ECGs, physical examinations, vital signs, glucose 
monitoring, clinical laboratory tests, and AEs. 

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 2 8 
1 0  S T U D Y D E SI G N  
1 0. 1  O ver all St u d y Desi g n a n d Pl a n  
T his is a n o pe n la bel, 2- p eri o d, fi x e d-se q ue nce st u d y. 
Si xtee n ( 1 6), healt h y, a d ult male a n d fe male  ( w o me n of n o n-c hil d beari n g p ote ntial o nl y) 
s u bjects will be e nr olle d. E ver y atte m pt will be ma de t o e nr oll at least 3 s u bjects of eac h se x. 
Scree ni n g of s u bjects will occ ur wit hi n 2 8  da ys pri or t o t he first d osi n g i n Peri o d 1, Da y 1 (i. e., 
re pa gli ni de). 
I n Peri o d 1, Da y 1, a si n gle oral d ose of re pa gli ni d e will be a d mi nistere d. P har mac o ki netic 
sa m pli n g f or re pa gli ni de will be c ollecte d pre d ose a n d f or 1 6 h o urs p ost d os e as o utli ne d i n t he 
St u d y E ve nts Fl o w C hart ( Secti o n  6).  
I n Peri o d 2, oral d oses of L O X O- 2 9 2 will be a d mi nistere d BI D f or 1 0 c o ns ec ut i ve da ys 
( Da ys 1 t o 1 0). T he si n gl e d ose of re pa gli ni de will be c oa d mi nistere d wit h t he si n gle d os e of 
L O X O - 2 9 2 o n t he m or ni n g of Da y 1 0. P har mac o ki netic sa m pli n g f or re p a gli ni de will be 
c ollecte d pr e d ose a n d f or 1 6 h o urs f oll o wi n g re pa gli ni de d osi n g o n Da y 1 0. P har mac o ki netic 
sa m pli n g i n plas ma f or L O X O- 2 9 2 will be c ollecte d
. 
I n bot h p eri o ds, gl uc ose will be a d mi nistere d i m me diatel y f oll o wi n g re pa gli ni de d osi n g  o n 
Da y  1 of Peri o d 1 a n d Da y 1 0 of Peri o d 2 a n d, o n Da y 1 0 of Peri o d 2, at a p pr o xi matel y 1 h o ur 
p ost d ose. 
T here will be a was h o ut peri o d of 2 4 h o urs bet w ee n t he re p a gli ni de d ose i n Peri o d 1 a n d t he 
first L O X O- 2 9 2 d ose i n Peri o d 2. 
Safet y a n d t oler a bilit y will be assesse d t hr o u g h E O T or E T  b y m o nit ori n g A Es, perf or mi n g 
p h ysical e x a mi nati o ns, gl uc ose m o nit ori n g, a n d cli nical la b orat or y tests, meas uri n g vital si g ns, 
a n d rec or di n g E C Gs.  
Ti mi n g of all st u d y pr oce d ures ar e i n dicate d i n t he St u d y E ve nts Fl o w C hart ( Secti o n  6). 
S u bjects ma y be re place d at t he discreti o n of t he  S p o ns or. 
1 0. 1. 1  C o nfi ne me nt , Ret ur n Visits , a n d F oll o w-U p  
S u bjects will be h o use d t hr o u g h E O T or E T  b e gi n ni n g i n Peri o d 1, Da y - 1, at t he ti me 
i n dicate d b y t he C R U, u ntil after c o m pleti o n of st u d y pr o ce d ures i n Peri o d 2, Da y 1 1  ( E O T) or 
E T  st u d y pr o ce d ur es. E O T is defi ne d as t he d a y o n w hic h t he s u bject is rel ease d fr o m t he 
C R U, f oll o wi n g all st u d y pr oce d ur es (see St u d y E ve nts Fl o w C hart, Secti o n  6). La b orat or y 
res ults are t o be a vaila ble f or re vie w b y t he PI or d esi g nee pri or t o releas e fr o m t he cli nic o n 
Da y 1 1  of Peri o d 2. At all ti mes, a s u bject ma y b e re q uire d t o re mai n at t he C R U  f or l o n ger at 
t he discreti o n of t he PI or desi g nee a n d/ or S p o ns or.  
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The CRU will contact all subjects who received at least one dose of study drug (including 
subjects who terminate from study early [ET]) at the EOS (as defined in the Study Events 
Flowchart, Section 6) by a follow up phone call (FU). The EOS/FU phone call will be 
performed 7 ± 2 days after the EOT visit or ET visit (as defined in the Study Events Flowchart, 
Section 6) to determine if any SAE or study drug related AE has occurred since the EOT or ET 
visit.  
10.1.2 End of Study Definition 
The end of study is defined as the day on which the subject completes the follow-up phone call 
(see Study Events Flow Chart (Section 6). 
Study Completion applies to the clinical conduct of the study overall (last subject’s Follow-up 
phone call). 
 

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11 STUDY POPULATION 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to enrollment. The Sponsor will provide approval of subjects for enrollment prior to 
dosing. 
11.1 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study: 
1. Healthy, adult, male or female (of non-childbearing potential only), 18-55 years of age,
inclusive, at screening.
2. Continuous non-smoker who has not used tobacco- and/or nicotine-containing products for
at least 3 months prior to the first dosing and through EOT or ET.
3. Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kg/m2 at screening and have a minimum weight
of at least 50 kg at screening.
4. Hemoglobin (Hb) A1c value < 6.5 % at screening and fasting glucose ≤ 126 mg/dL.
5. Medically healthy with no clinically significant medical history, physical examination,
laboratory profiles, vital signs or ECGs, as deemed by the PI or designee, and as confirmed
by the Sponsor. Liver function tests (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST]), and serum (total and direct) bilirubin, as well as amylase and
lipase, must be within the upper limit of normal for the laboratory used by the clinical site
at screening and Check-in (Day -1, Period 1). Rechecks of the liver function tests (ALT and
AST) and serum (total and direct) bilirubin, as well as amylase and lipase will be permitted
up to two times to confirm subject eligibility. Subjects may be eligible for participation in
the study based on rechecked values if the PI (or designee), with agreement from the
Sponsor, feels that the results are not clinically significant, and will not impact study
conduct.
6. A female of non-childbearing potential: must have undergone one of the following
sterilization procedures at least 6 months prior to the first dosing:
•
hysteroscopic sterilization;
•
bilateral tubal ligation or bilateral salpingectomy;
•
hysterectomy;
•
bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status. 

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7.
Males who are capable of fathering a child must agree to use one of the following methods
of contraception from the time of the dose administration through 6 months after the last
dose:
Male sterilization, with documented confirmation of surgical success. Male subjects will be
surgically sterile for at least 90 days prior to Check-in (Day -1, Period 1). If documentation
is not available, male subjects must follow the contraception methods below:
a.
Male condom with spermicide, and
b. For a female partner of male study participant:
1.Intrauterine device (IUD) (hormonal IUD; e.g., Mirena®). Copper IUDs
are acceptable (e.g., ParaGard®);
2.Established use of oral, implanted, transdermal, or hormonal method of
contraception associated with inhibition of ovulation; or
3.Bilateral tubal ligation.
Males who practice true abstinence because of a lifestyle choice (i.e., do not become 
abstinent just for the purpose of study participation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the ICF but becomes 
sexually active during the study, he must agree to use contraception as described above. 
Male subjects should ensure that condoms with spermicide are used from the time of the 
study drug administration until 6 months after the last dose of study drug when having 
intercourse with female partners who are pregnant or breast feeding. Male subjects are 
required to refrain from donation of sperm from Check-in (Day -1, Period 1) until 6 months 
after the last dose of study drug. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do 
not apply.  
8. Understands the study procedures in the informed consent form (ICF) and be willing and
able to comply with the protocol.
11.2 Exclusion Criteria 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in
the opinion of the PI or designee, and as confirmed by the Sponsor.

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3. History of any illness that, in the opinion of the PI or designee, and as confirmed by the
Sponsor, might confound the results of the study or poses an additional risk to the subject
by their participation in the study.
4. History or presence of diabetes or history of prior episode(s) of hypoglycemia.
5. History of gastritis, gastrointestinal tract, or hepatic disorder or other clinical condition that
might, in the opinion of the PI or designee, and as confirmed by the Sponsor, affect the
absorption, distribution, biotransformation, or excretion of LOXO-292 or repaglinide.
6. History or presence of alcoholism or drug abuse within the past 2 years prior to the first
dosing.
7. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or
related compounds, or inactive ingredients.
8. History or presence of:
•
liver disease,
•
pancreatitis,
•
peptic ulcer disease,
•
intestinal malabsorption,
•
gastric reduction surgery,
•
history or presence of clinically significant cardiovascular disease:
o
myocardial infarction or cerebrovascular thromboembolism within 6 months prior
to first dosing
o
symptomatic angina pectoris
o
New York Heart Association Class ≥2 congestive heart failure
o
congenital prolonged QT syndrome
o
ventricular pre-excitation syndrome (Wolff-Parkinson White syndrome)
o
arrhythmia or history of arrhythmia requiring medical intervention
o
ventricular dysfunction or risk factors for Torsades de Pointes (e.g., heart failure,
cardiomyopathy, family history of Long QT Syndrome)
o
significant screening ECG abnormalities:

Left bundle-branch block

Second degree atrioventricular (AV) block, type 2, or third-degree AV block

Frederica corrected QTc (QTcF) interval is >450 msec

ECG findings deemed abnormal with clinical significance by the PI or
designee at screening and prior to Period 1, Day 1 dosing.

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9. Female subjects of childbearing potential.
10. Female subjects with a positive pregnancy test or who are lactating.
11. Positive urine drug or alcohol results at Screening or Check-in (Day -1, Period 1).
12. Positive cotinine test at Screening or Check-in (Day -1, Period 1).
13. Positive results at Screening for human immunodeficiency virus (HIV), hepatitis B surface
antigen (HBsAg) or hepatitis C virus (HCV). Subjects who are positive for hepatitis B
virus, HCV, or HIV by antibody will require confirmation by polymerase chain reaction
(PCR) before enrollment to detect presence of active virus. Subjects who are PCR positive
will not be eligible.
14. Subjects with at-rest (i.e., supine for at least 5 minutes) diastolic BP of <50 or >89 mmHg
and/or supine systolic BP of <89 or >139 mmHg at Screening, Check-in (Day -1, Period 1),
and prior to dosing on Day 1 of Period 1. Rechecks of blood pressure values will be
permitted up to two times to confirm eligibility for study participation. Subjects may be
eligible for participation in the study based on rechecked values if the PI (or designee),
with agreement from the Sponsor, feels that the results are not clinically significant, and
will not impact study conduct.
15. Supine heart rate is lower than 45 bpm or higher than 99 bpm at Screening, Check-in
(Day -1, Period 1), and prior to dosing on Day 1 of Period 1. Rechecks of heart rate values
will be permitted up to two times to confirm eligibility for study participation. Subjects
may be eligible for participation in the study based on rechecked values if the PI (or
designee), with agreement from the Sponsor, feels that the results are not clinically
significant, and will not impact study conduct.
16. Estimated creatinine clearance <90 mL/min at Screening or Check-in (Day -1, Period 1).
17. Unable to refrain from or anticipates the use of any drug, including prescription and
non-prescription medications, herbal remedies, or vitamin supplements for 14 days prior to
the first dosing and through EOT or ET. After first dosing, acetaminophen (up to 2 g per
24 hours) may be administered at the discretion of the PI or designee.
18. Unable to refrain from or anticipates the use of any drugs known to be an inhibitor or
inducer of CYP2C8, CYP3A4/5, or P-gp (including St. John’s Wort), or inhibitor of
OATP1B1, for 28 days prior to the first dosing and through EOT or ET. Appropriate
sources (e.g., Flockhart TableTM) will be consulted to confirm lack of PK interaction with
study drug.
19. Unable to refrain from or anticipates the use of any proton pump inhibitors, antacids and
H2-receptor antagonists from 14 days prior to the first dosing and through EOT or ET.
20. Unable to refrain from or anticipates the use of any drug that prolongs the QT/QTc interval
for 14 days prior to the first dosing and through EOT or ET.

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21. Has been on a diet incompatible with the on-study diet, in the opinion of the PI or designee,
and as confirmed by the Sponsor, within the 30 days prior to the first dosing and through
EOT or ET.
22. Donation of blood or significant blood loss within 56 days prior to the first dosing.
23. Plasma donation within 7 days prior to the first dosing.
24. Participation in previous investigational trial with LOXO-292.
25. Dosing in any other investigational study drug trial involving administration of any
investigational drug in the past 30 days or 5 half-lives (if known), whichever is longer,
prior to the first dosing.
11.3 Early Termination of Subjects from the Study 
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the PI or designee for the following 
reasons: 
•
AEs.
•
Difficulties in blood collection.
•
Positive pregnancy test.
•
Positive urine drug and alcohol test.
A subject may be withdrawn by the PI, designee, or the Sponsor if either considers enrollment 
of the subject into the study is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons. Prompt notification to the Sponsor of withdrawal of any subject 
should be provided. 
Subjects who withdraw from the study will undergo early termination from the study 
procedures as outlined in the Study Events Flow Chart (Section 6).  
11.4 Study Restrictions 
11.4.1 Prohibitions and Concomitant Medication 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 
•
Xanthines/Caffeine: 24 hours prior to first dosing and through EOT or ET (small
amounts of caffeine derived from normal foodstuffs e.g., 250 mL/8 oz./1 cup
decaffeinated coffee or other decaffeinated beverage, per day, with the exception of
espresso; 45 g/1.5 oz. chocolate bar, per day, would not be considered a deviation to
this restriction);
•
Alcohol: 48 hours prior to first dosing and through EOT or ET;

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•
Grapefruit/Seville orange and their juices: 14 days prior to first dosing and through
EOT or ET;
•
Other Fruit Juice: 72 hours prior to first dosing and through EOT or ET;
Participation in any other investigational study drug trial in which receipt of any investigational 
drug occurs within 5 half-lives (if known) or 30 days, whichever is longer, prior to first dose 
administration (Day 1, Period 1) is prohibited. 
Any prescription or over-the-counter medications (including, herbal products, natural or herbal 
supplements) will be prohibited for at least 14 days prior to dosing through EOT or ET.  
All prescription or non-prescription medications that are inhibitors or inducers of CYP2C8, 
CYP3A4/5, or P-gp (including St. John’s Wort), or inhibitors of OATP1B1, for 28 days prior 
to the first dosing and through EOT or ET.  
Any proton pump inhibitors, antacids and H2-receptor antagonists from 14 days prior to the 
first dosing and through EOT or ET. 
Any drug that prolongs the QT/QTc interval for 14 days prior to the first dosing and through 
EOT or ET. 
From Day -1 through EOT or ET, any concurrent medication including both prescription and 
non-prescription drugs must be discussed with the PI (or designee), and/or Sponsor prior to 
use, unless appropriate medical care necessitates that therapy should begin before the PI (or 
designee) and/or Sponsor can be consulted. Following study drug administration on Day 1, 
acetaminophen (up to 2 g per 24 hours) may be administered at the discretion of the PI (or 
designee).  
If deviations occur, the PI or designee in consultation with the Sponsor if needed will decide on 
a case-by-case basis whether the subject may continue participation in the study. 
All medications taken (including vitamins and supplements) by subjects during the course of 
the study will be recorded. 
11.4.2 Meals 
Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour 
after each study drug administration, but will be allowed ad libitum at all other times. Other 
fluids may be given as part of meals and snacks but will be restricted at all other times 
throughout the confinement period. 
In Period 1, Day 1, 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. 
In Period 2, Days 1 to 9 and for the evening dose on Day 10, subjects will fast for at least 2 
hours prior to each dose (morning and evening, as appropriate) and will continue the fast for at 
least 1 hour postdose.  

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In Period 2, Day 10 morning dose, 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.  
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. 
11.4.3 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours post morning dose, 
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. 
There is no specific restriction of activity after dosing in the evening doses. 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of 
the study. 
Use of any tobacco- and/or nicotine-containing products will be prohibited through EOT or 
ET. 

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12 TREATMENTS 
12.1 Treatments Administered 
LOXO-292 will be supplied as 80 mg capsules. 
Repaglinide will be supplied as 0.5 mg tablets.  
Glucose will be provided as 4 g chewable tablets. 
Treatments are described as follows: 
Treatment A (Period 1): 
0.5 mg repaglinide (1 x 0.5 mg tablet) at Hour 0 on Day 1. 
Treatment B (Period 2): 
160 mg LOXO-292 (2 x 80 mg capsules) administered BID, 
approximately every 12 hours, for 10 consecutive days with the 
Day 10 morning single dose of 160 mg LOXO-292 (2 x 80 mg 
capsules) coadministered with 0.5 mg repaglinide (1 x 0.5 mg 
tablet) (within ± 1 hour of the dosing time of the Day 1 morning 
dose of Period 2). 
Each dose of LOXO-292 and repaglinide will be administered orally with 240 mL of room 
temperature water. When LOXO-292 and repaglinide are administered concurrently, 240 mL 
only of room temperature water will be administered for both drugs.  
The dose of repaglinide on Day 1 of Period 1 and the coadministered morning doses of 
LOXO-292 and repaglinide on Day 10 of Period 2 will be preceded by an overnight fast of at 
least 10 hours. All other doses will be preceded by a 2-hour fast and followed by a 1 hour 
postdose fast.  
On Day 1 of Period 1, immediately following administration of repaglinide, subjects will be 
provided with 12 g of glucose (3 x 4 g chewable tablets). On Day 10 of Period 2, immediately 
following administration of repaglinide and at approximately 1 hour after administration of 
repaglinide, subjects will be provided with 16 g of glucose (4 x 4 g chewable tablets). An 
additional 100 mL of room temperature water may be taken if required. 
Subjects will be instructed not to crush, split, or chew the LOXO-292 capsules or repaglinide 
tablets, and will be instructed to chew the glucose tablets. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period.  
The exact clock time of dosing will be recorded. 
12.2 Dose Modification 
The dose and administration of the study drugs to any subject may not be modified. If 
necessary a subject must be discontinued for the reasons described in Section 11.3. 

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12.3 Method of Treatment Assignment 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of the first dosing, different from the screening 
number, and will receive the corresponding product.  
Subjects will receive each treatment on one occasion in a fixed sequence. The sequence to be 
used will be AB.  
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 001).  
12.4 Blinding 
This is an open-label study.  
12.5 Treatment Compliance 
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses of LOXO-292 and repaglinide. 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 drugs were 
ingested. Consumption of glucose tablets will also be verified. 

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13 STUDY ASSESSMENTS AND PROCEDURES 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be performed 
at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI or designee and/or the Sponsor for 
reasons related to subject safety. 
For this study, the blood collections for repaglinide and LOXO-292 are the critical parameters 
and need to be collected as close to the exact time point as possible. All other procedures 
should be completed as close to the prescribed/scheduled time as possible, but can be 
performed prior or after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
13.1 Screening 
Within 28 days prior to the first dosing on Day 1 of Period 1, medical history and demographic 
data, including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI (kg/m2) and 
history of tobacco use will be recorded. Each subject will have a physical examination, vital 
sign measurements (heart rate, blood pressure, temperature, and respiratory rate), 12-lead ECG, 
and the laboratory tests of serum chemistry, serology, thyroid stimulating hormone, pregnancy 
(females), FSH (postmenopausal females), hematology, amylase, lipase, hepatic and renal 
function and additional tests as noted in Section 13.2.6. 
13.2 Safety Assessments 
13.2.1 Physical Examination 
Full and abbreviated physical examination will be performed as outlined in the Study Events 
Flow Chart (Section 6).  
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.  
13.2.2 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 6). 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 supine position (at least 5 minutes), except when they are supine or semi-reclined because 
of study procedures and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the PI or 
designee. 

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Blood pressure and heart rate will be measured using the same arm for each reading. Vital 
signs (HR, BP, and RR) will be obtained at Screening, Day -1 (Period 1), predose, at 
0.75 hours (± 10 minutes), 2 hours (± 10 minutes), and 4 hours (± 10 minutes) on Days 1 
(Periods 1 and 2) and 10 (Period 2), and prior to the morning doses on Days 2 through 9 
(Period 2) and at EOT (or ET). Vital sign measurements should be carried out prior to and as 
close as possible to having blood drawn. 
13.2.3 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Section 6). 
Additional ECGs may be taken at any other times, if deemed necessary by the PI or designee. 
ECGs will be performed with subjects in a supine position (at least 10 minutes). All ECG 
tracings will be reviewed by the PI or designee. 
ECGs will be measured at Screening, Day -1, predose and 2 hours postdose on Day 1 
(Periods 1 and 2) and Day 10 (Period 2), prior to the morning doses on Days 2 through 9 
(Period 2) and at EOT (or ET). ECGs will be obtained prior to and as close as possible to the 
scheduled blood draws if scheduled at the same time. 
13.2.4 Body Weight 
Body weight (kg) will be reported as outlined in the Study Events Flow Chart (Section 6). 
13.2.5 Glucose Monitoring 
13.2.5.1 
Blood Glucose 
Blood glucose determinations will be performed as outlined in the Study Events Flow Chart 
(Section 6).  
All measurements will be done with a glucose monitor and will be performed by finger stick. 
Subjects who manifest hypoglycemic symptoms such as faintness, sweatiness, tachycardia, and 
headache, may have their blood glucose monitored by finger stick at any time during the study, 
at the discretion of the PI. In addition, the PI or designee may administer additional oral 
glucose, 16 g of glucose (4 x 4 g chewable tablets), if the blood glucose (monitored by finger 
stick) at any of the specified time points is < 60 mg/dL or at any other time based on evaluation 
of symptoms. For subjects with blood glucose < 60 mg/dL, intervention measurements outlined 
in protocol Section 13.2.5.2 will be followed. 
13.2.5.2 
Rescue Intervention for Hypoglycemia 
The following steps may be followed at the discretion of the PI: 
The subject should be placed in a semi recumbent position. A conscious subject who is safely 
able to take food/drink by mouth should ingest 15-20 g of glucose. A glucose measurement 
should be taken 15 minutes later. If hypoglycemia persists, the treatment should be repeated. 

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Once the blood glucose concentration exceeds 70 mg/dL, the subject should consume a full 
meal containing at least 60 g of carbohydrate. 
Following administration of food, blood glucose concentrations should be measured every 
10-15 minutes for the first hour, every 30 minutes for an additional 2 hours, then hourly until
blood glucose concentrations have been demonstrated to be stable within the normal range for
at least 3 hours and, if present, symptoms have resolved. Oral supplementation may be
attempted up to three times prior to intervention with intravenous (IV) dextrose. If a subject
displays any signs/symptoms of instability, in the opinion of the PI, IV dextrose will be used
immediately. If oral glucose and IV dextrose cannot be administered in an emergency situation,
intramuscular glucagon will be used.
Subjects will be offered placement of an IV catheter in the event that dextrose is required. The 
IV catheter should be placed on the opposite arm from which the PK blood draws are taken. 
If subject remains hypoglycemic and there has been no resolution of any associated symptoms 
despite the interventions described above, the subject should be rapidly transferred to a 
location where definitive care (i.e., an Emergency Room or Intensive Care Unit) is available. 
13.2.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart (Section 6). 
In addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI or designee.  
Hematology 
Serum Chemistry* 
•
Hemoglobin
•
Mean corpuscular hemoglobin
concentration
•
Mean corpuscular volume
•
Hematocrit
•
Red blood cell (RBC) count
•
RBC distribution width
•
Platelet count
•
White blood cell/leukocyte (WBC)
count
•
WBC/leukocyte differential (absolute
and percent):

Basophils

Eosinophils

Lymphocytes

Monocytes

Neutrophils
Coagulation 
•
Prothrombin Time/International
normalized ratio
•
Activated partial thromboplastin time
•
Blood Urea Nitrogen
•
Bilirubin (total and direct)
•
Alkaline phosphatase
•
AST
•
ALT
•
Uric acid
•
Albumin
•
Total protein
•
Iron
•
Calcium
•
Sodium
•
Potassium
•
Magnesium
•
Chloride
•
Glucose (fasting)
•
Creatinine**
•
Cholesterol
•
Triglycerides
•
Phosphorus
•
Creatine kinase
•
Amylase
•
Lipase

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Urinalysis 
Additional Tests 
•
pH
•
Color and appearance
•
Specific gravity
•
Protein***
•
Glucose
•
Ketones
•
Bilirubin
•
Blood***
•
Nitrite***
•
Urobilinogen
•
Leukocyte esterase***
•
HIV test****
•
HBsAg****
•
HCV****
•
Urine drug screen

Opiates

Opioids 
(methadone, 
oxycodone, 
and
fentanyl)

Amphetamines

Barbiturates

Benzodiazepines

Cocaine metabolite

Cannabinoids

Phencyclidine
•
Urine alcohol screen
•
Cotinine
•
Serum pregnancy test
(for females only)
•
FSH (for postmenopausal females only)****
•
HbA1c
•
Thyroid stimulating hormone****
*
Samples for serum chemistry will be obtained following a fast of at least 12 hours at Screening and at
Check-in (Day -1); 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 being taken.
** At Screening and prior to dosing (Day -1 of Period 1), creatinine clearance will be calculated using the 
Cockcroft-Gault formula. 
*** If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination 
(for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
**** Performed at Screening only. 
13.2.7 Adverse Events 
13.2.7.1 
Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
13.2.7.2 
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) visit, subjects will be asked how they 
are feeling prior to check out from the CRU. During the EOS/follow-up phone call, subjects 

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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. 
13.2.7.3 
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  
The PI or designee will review each AE and assess its relationship to drug treatment (yes 
[related] or no [unrelated]). 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.  

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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. 
13.2.7.4 
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 
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. 

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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 3 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. 
13.3 Pharmacokinetic Assessments 
13.3.1 Blood Sampling and Processing 
For all subjects, blood samples for the determination of repaglinide and LOXO-292 will be 
collected at scheduled time points as delineated in the Study Events Flow Chart (Section 6). 
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately. 
Blood collections in Periods 1 and 2 performed outside of the sample collection windows 
defined in the Study Events Flow Chart (Section 6) will be considered deviations. 
* Where a scheduled blood draw coincides with a scheduled dosing, the blood draw is to be
taken prior to dosing

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13.3.2 Pharmacokinetic Parameters 
PK parameters for plasma repaglinide in Period 1, Day 1, and Period 2, Day 10, 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. 
CL/F: 
Apparent total plasma clearance after oral (extravascular) 
administration, calculated as Dose/AUC0-inf. 
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. 
Vz/F: 
Apparent volume of distribution during the terminal elimination phase 
after oral (extravascular) administration, calculated as 
(Dose/AUC0-inf) x Kel. 
PK parameters for plasma LOXO-292 in Period 2, Day 1 and Day 10, will be calculated as 
follows after the morning dose, 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 (Day 1). 
AUC0-12: 
The area under the concentration-time curve, from time 0 to the 12 hour 
timepoint, as calculated by the linear trapezoidal method (Day 1). 
AUCtau: 
The area under the concentration-time curve during a dosing 
interval (tau) at steady state (Day 10). 

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 4 7 
C L,ss/ F:  
A p pare nt t otal plas ma cleara n ce after oral (e xtra vasc ular) 
a d mi nistrati o n, calc ulate d as D ose/ A U Cta u ( D a y 1 0 ). 
C ma x:  
Ma xi m u m o bser ve d c o nce ntrati o n ( Da y 1).  
C ma x,ss:  
Ma xi m u m o bser ve d c o nce ntrati o n at stea d y -st ate ( Da y 1 0 ). 
Ctr o u g h:  
C o nce ntrati o n o bser v e d at t he e n d of t he d osi n g i nter val  ( D a ys 2 t o 1 0). 
T ma x:  
Ti me t o reac h C ma x. If t he ma xi m u m val ue occ urs at m ore t ha n o ne 
ti me p oi nt, T ma x is defi ne d as t he first ti me p oi nt wit h t his val ue 
( Da y 1).  
T ma x,ss:  
Ti me t o reac h C ma x,ss. If t he ma xi m u m val ue occ urs at m ore t ha n o ne 
ti me p oi nt, T ma x,ss is defi ne d as t he first ti me p oi nt wit h t his val ue 
( Da y 1 0 ). 
N o P K para met ers will be calc ul ate d f or s u bjects wit h 2 or fe wer c o nsec uti ve ti me p oi nts wit h 
detecta ble c o nce ntrati o ns.  
I n di vi d ual a n d m ea n plas ma c o nce ntrati o n ti me c ur ves ( b ot h li near a n d l o g-li near) will be 
i ncl u de d i n t he fi nal Cli nical St u d y Re p ort . 
1 3. 3. 3  A n al ytic al Met h o d 
Sa m ples will be a nal yze d f or plas ma re pa gli ni de a n d L O X O - 2 9 2 usi n g vali date d bi oa nal ytical 
met h o ds. Sa m ples fr o m s u bjects t o be assa ye d are s pecifie d i n Secti o n  1 4. 2. 
1 3. 4  Bl o o d V ol u me Dr a w n f or St u d y Assess me nts  
T a ble 1: 
Bl o o d V ol u me d uri n g t he St u d y  
S a m ple T y pe  
N u m ber of 
Ti me P oi nts  
A p pr o xi m ate V ol u me per 
Ti me P oi nt * ( m L)  
A p pr o xi m ate S a m ple 
V ol u me O ver C o urse 
of St u d y ( m L)  
Scree ni n g la b orat or y safet y tests (i ncl u di n g he mat ol o g y, 
ser u m c h e mistr y, c oa g ulati o n, ser ol o g y, F S H (f or 
p ost me n o pa usal fe male s u bjects o nl y) a n d ser u m 
pre g n a nc y (f or f e male s u bjects o nl y)  
O n -st u d y he mat ol o g y, ser u m c he mistr y, c oa g ulati o n, a n d 
ser u m pre g na nc y ([ w he n c ollecte d at t he sa me ti me] f or 
fe male s u bjects o nl y) 
Bl o o d f or L O X O -2 9 2  a n d re pa gli ni de 
T otal Bl o o d V ol u me ( m L) → 
*
Re prese nts t h e lar gest c ollecti o n t u b e t h at ma y b e use d f or t his (a s maller t u b e ma y b e use d).  O n e 4 m L t u be will be
use d at eac h bl o o d dra w ti me p oi nt, i n cl u di n g w h e n L O X O -2 9 2 a n d re p a gli ni d e  bl o o d dra w  ti me p oi nts c oi n ci de o n Da y 
. 
* *  
If  a d diti o n al  safet y or  P K  a n al ysis  is  n ecessar y  t o  o btai n  s ufficie nt  plas ma/ser u m  f or  a n al ysis,  a d diti o nal  bl o o d 
(i n cl u di n g bl o o d dra w n f or gl u c ose m o nit ori n g fi n ger stic ks) ma y b e o btai n e d  ( u p t o a ma xi m u m of  
).  
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14 STATISTICAL CONSIDERATIONS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
14.1 Sample Size Determination 
Based on in vitro data, it is anticipated that LOXO-292 may inhibit the CYP2C8 enzyme and 
therefore affect the repaglinide PK profile. Sixteen (16) subjects are considered sufficient to 
evaluate the magnitude of this interaction.  
14.2 Population for Analyses 
PK Population: Plasma samples from all subjects will be assayed even if the subjects do not 
complete the study. All subjects who comply sufficiently with the protocol and display an 
evaluable PK profile (e.g., exposure to treatment, availability of measurements and absence of 
major protocol violations) will be included in the statistical analyses.  
Safety Population: All subjects who received at least one dose of either of the study drugs will 
be included in the safety evaluations. 
14.3 Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by Celerion 
and agreed upon with the Sponsor. This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoints definition and/or its 
analysis will also be reflected in a protocol amendment. Additional statistical analyses other 
than those described in this section may be performed if deemed appropriate.  
14.3.1 Pharmacokinetic Analyses 
14.3.1.1 
Descriptive Statistics 
Values will be calculated for the respective plasma concentrations and the PK parameters listed 
in Section 13.3 for repaglinide and LOXO-292 using appropriate summary statistics to be fully 
outlined in the SAP.  
14.3.1.2 
Analysis of Variance 
An ANOVA will be performed on the ln-transformed AUC0-t, AUC0-inf, and Cmax of 
repaglinide. The ANOVA model will include treatment as fixed effect and subject as the 
random effect. Each ANOVA will include calculation of least-squares means (LSMs), the 
difference between treatment LSMs, the standard error and 90% confidence intervals 
associated with this difference.  

C O N FI D E N TI A L  
C A 2 6 4 3 4 ( L O X O-R E T -1 8 0 2 6), Fi nal Pr ot oc ol , A me n d me nt 1 1 9 F E B 2 0 1 9 
Pa ge 4 9 
1 4. 3. 1. 3  
Ste a d y St ate A n al ysis ( Peri o d 2 o nl y) 
A stea d y state a n al ysis will be perf or me d o n t he l n -tra nsf or me d m or ni n g pre d ose C tr o u g h 
c o nce ntr ati o ns f or L O X O- 2 9 2, o n Da ys 
, usi n g Hel mert c o ntrasts (Ma ga nti et al, 
2 0 0 8 ). A d diti o nal pre d os e Ctr o u g h ma y b e use d f or t he stea d y-stat e a nal ysis t o gat her m ore 
i nf or mati o n o n stea d y-state attai n me nt. 
Hel mert c o ntr asts are c o nstr ucte d s uc h t hat eac h ti me p oi nt is c o m pare d t o t he mea n of t he 
s u bse q ue nt ti me p oi nt. Stea d y state is c o n cl u de d at t he ti me p oi nt w here n o m ore statistical 
differe n ce ca n be o bs er v e d. T he c o ntrasts will be:  
C o m paris o n 1: Ctr o u g h Da y  
C o m paris o n 2: Ctr o u g h Da y  
C o m paris o n 3: Ctr o u g h Da y  
C o m paris o n 4: Ctr o u g h Da y  
C o m paris o n 5: Ctr o u g h Da y  
C o m paris o n 6: Ctr o u g h Da y  
C o m paris o n 6: Ctr o u g h Da y  
C o m paris o n 7: Ctr o u g h Da y  
1 4. 3. 1. 4  
R ati os a n d C o nfi de nce I nter v als 
Rati os of L S Ms will be calc ulate d usi n g t he e x p o ne ntiati o n of t he differe nce bet wee n treat me nt 
L S M s fr o m t he a nal yses o n t he l n-tra nsf or me d re p a gli ni de A U C 0 -t, A U C 0-i nf, a n d C ma x  
w he n re p a gli ni de is c oa d mi nistere d wit h L O X O - 2 9 2 ( Treat me nt B) v ers us w he n a d mi nistere d 
al o ne ( Tr eat me nt  A).  T h ese rati os will be e x presse d as a perce nta ge rel ati ve t o t he refere nce 
treat me nt ( Tr eat me nt A).  
C o nsiste nt wit h t he t w o o ne- si de d test (Sc h uir ma n n, 1 9 8 7 ), 9 0 % c o nfi d e nce i nter val ( CIs) f or 
t he rati os will be deri ve d b y e x p o ne ntiati o n of t he CIs o btai ne d f or t he differe nce b et wee n 
treat me nt L S Ms r es ulti n g fr o m t he a nal yses o n t h e l n-tra nsf or me d re pa gli ni de A U C 0 -t, 
A U C 0 -i nf, a n d C ma x  w he n re pa gli ni de is c o a d mi nistere d wit h L O X O - 2 9 2 ( Treat me nt B) 
vers us w he n a d mi nistere d al o ne ( Treat me nt A ). T he CIs will be e x presse d as a perce nta ge 
relati ve t o t he refer e nce treat me nt ( Treat me nt A).  
1 4. 3. 2  S af et y A n al yses 
All safet y data will be p o p ulate d i n t he i n di vi d ual C R Fs. All safet y data will be liste d b y 
s u bjects. 
D osi n g dat es a n d ti mes will be liste d b y s u bject.  
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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, glucose monitoring, 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 listed by subject and coded using the WHO drug dictionary. 
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15 STUDY ADMINISTRATION 
15.1 Ethics 
15.1.1 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 
15.1.2 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). 
15.1.3 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. 
15.1.4 Confidentiality 
All members of the Investigator’s staff have signed confidentiality agreements with Celerion. 
By signing this protocol, the Investigator and Celerion staff will regard all information 
provided by the Sponsor and all information obtained during the course of the study as 
confidential.  
The Investigator 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 Investigator who will ensure that it is revealed only to the Sponsor, 
IRB, or regulatory authorities for the purposes of trial monitoring, auditing or official 

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inspections. As required, in the case of an event where medical expenses are the responsibility 
of the Sponsor, personal information i.e., full name, social security details etc., may be released 
to the Sponsor. Appropriate precautions will be taken to maintain confidentiality of medical 
records and personal information in strictest confidence and in accordance with local data 
protection laws. 
15.2 Termination of the Study 
Celerion reserves the right to terminate the study in the interest of subject welfare. 
Sponsor reserves the right to suspend or terminate the study at any time. 
15.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant to 
the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, GCP and GLP requirements as well as applicable 
regulatory requirements and local laws, rules and regulations relating to the conduct of the 
clinical study. 
The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit 
checks are then performed for appropriate databases as a validation routine using SAS® or 
comparable statistical program to check for missing data, data inconsistencies, data ranges, etc. 
Corrections are made prior to database lock. 
15.4 Direct Access to Source Data/Documents 
Celerion will ensure that the Sponsor, IRB, and inspection by domestic and foreign regulatory 
authorities will have direct access to all study-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event that other 
study-related monitoring should be done by other parties, they will be required to sign a 
confidentiality agreement prior to any monitoring and auditing. 
15.5 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of the LOXO-292 capsules to allow completion 
of this study. Celerion will provide sufficient quantities of repaglinide and chewable glucose 
tablets to allow completion of the study. The lot numbers and expiration dates (where 
available) of the study drugs supplied will be recorded in the final Clinical Study Report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be retained by Celerion, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. Any remaining supplies that 

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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. 
15.6 Data Handling and Record Keeping 
Celerion standard CRFs will be supplied. CRFs are produced and may be printed off from the 
database and made available to the designated study team members. The CRFs are also stored 
electronically. Each CRF book is reviewed and signed by the PI. The final signed CRFs are 
provided to the Sponsor on CD. 
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 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. 
15.7 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).  
15.8 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. 

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16 REFERENCES 
Food and Drug Administration. Guidance for Industry: Drug Interaction Studies – Study 
Design, Data Analysis, Implications for Dosing, and Clinical Implications (Draft Guidance 
October 2017) published on the website 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.ht 
m. 
LOXO-292. Investigator’s Brochure. Loxo Oncology, Inc. Version 4.0. 01-Oct-2018. 
Maganti L, Panebianco DL, Maes AL. Evaluation of Methods for Estimating Time to Steady 
State with Examples from Phase 1 Studies. AAPS J. 2008 10(1):141–147. 
National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), 
Revised: Nov-2017 (v5.0). Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf. 
Prandin® (repaglinide) Tablet, full prescribing information (electronic monograph) (document 
revised: 02/2017). Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020741s041s042lbl.pdf. 
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach 
for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 
1987;15:657-80.