Clinical trial NCT05134350
Conditions: Healthy Volunteers
Sponsor: Loxo Oncology, Inc.
Start date: 2020-02-06; Completion date: 2020-03-23
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study is to learn about how food and a PPI (omeprazole) affect LOXO-305 in healthy participants. Participation could last about nine weeks.

Detailed description:

Arms: arm 1: * Period 1: Single oral dose of 200 milligram (mg) LOXO-305 (Fasted state) on Day 1 (Treatment A)
* Period 2: Single oral dose of 200 mg LOXO-305 (Fed state) on Day 8 (Treatment B)
* Period 3: Single oral dose of 40 mg Omeprazole (Fasted state) on Day 15 to 17 and single oral dose of 200 mg LOXO-305 + 40 mg Omeprazole (Fasted state) on Day 18 (Treatment C)

A washout period of 7 days was maintained between each treatment period. arm 2: * Period 1: Single oral dose of 200 mg LOXO-305 (Fed state) on Day 1 (Treatment B)
* Period 2: Single oral dose of 200 mg LOXO-305 (Fasted state) on Day 8 (Treatment A)
* Period 3: Single oral dose of 40 mg Omeprazole (Fasted state) on Day 15 to 17 and single oral dose of 200 mg LOXO-305 + 40 mg Omeprazole (Fasted state) on Day 18 (Treatment C)

A washout period of 7 days was maintained between each treatment period.
Interventions: intervention 1: LOXO-305 intervention 2: Omeprazole
Intervention descriptions: intervention 1: LOXO-305 orally. intervention 2: Omeprazole Orally.

Protocol documents:
Prot_000.pdf: 
 
Protocol: LOXO-BTK-20014 Version 2.0 
 
 
A Phase 1, Open Label, Randomized, 2-Way Crossover, 3-Period Study to Evaluate the Eﬀect of Food 
and a Proton Pump Inhibitor on the PharmacokineƟcs of LOXO-305 in Healthy Adult Subjects 
 
 
NCT05134350 
 
 
Approval Date: 29-Jan-2020  


TI T L E P A G E 
Pr ot oc ol 
A P h ase 1, O pe n-l a bel, R a n d o mize d, 2- W a y Cr oss o ver, 3- Peri o d St u d y t o 
E v al u ate t he Effect of F o o d a n d a Pr ot o n P u m p I n hi bit or o n t he 
P h ar m ac o ki netics of L O X O- 3 0 5 i n He alt h y A d ult S u bjects 
Pr ot oc ol Stat us: Fi nal 
Pr ot oc ol Date: 2 9 J a n uar y 2 0 2 0 
Pr ot oc ol Versi o n: 2. 0 
 
I n v esti gati o nal Me dici nal Pr o d uct: L O X O- 3 0 5 
 
 
Pr ot oc ol Refere n ce N u m ber: L O X O- B T K- 2 0 0 1 4 
C o va nce St u d y N u m ber: 8 4 2 2 3 2 9  
I N D N u m ber: 1 3 9 8 7 6 
 
 
S p o ns or:  
L o x o O nc ol o g y, I nc.  
A w h oll y o w n e d s u bsi diar y of Eli Lill y a n d 
C o m pa n y  
7 0 1 Ga te wa y B o ule v ar d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0  
U S A  
St u d y Site:  
C o va nce Cli nical Researc h U nit I nc.  
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0  
Da yt o n a Beac h, F L 3 2 1 1 7  
U S A  
 
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d m a y b e discl ose d o nl y wit h t he e x press 
writte n per missi o n of t he S p o ns or. 
P P D
P P D


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 2 of 5 4 
S P O N S O R A P P R O V A L 
I h a ve rea d t he pr ot oc ol a n d a p pr o ve it: 
 
 
 
 
 
          Date 
P P D


Pr ot o c ol 
C o v a n c e St u d y:  8 4 2 2 3 2 9 
C O N FI D E N T I A L 
Pr ot o c ol  R ef er e n c e:  L O X O- B T K- 2 0 0 1 4 
I N V E S T I G A T O R A G R E E M E N T 
I h a v e  r ea d t h e pr ot o c ol  a n d a gr e e  t o c o n d u ct t h e st u d y as d e s cri b e d  h er ei n. 
Pr ot o c o l V e rs io n 2. 0, 2 9 J an u m y 2 0 2 0 
P a g e 3 of 5 4 
P P D


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 4 of 5 4 
S T U D Y I D E N TI FI C A TI O N 
S p o ns or 
L o x o O nc ol o g y, I nc. 
A w h oll y o w n e d s u bsi diar y of Eli Lill y a n d C o m p a n y 
7 0 1 Gate wa y B o ule v ar d, S uite 4 2 0  
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0  
U S A  
 
S p o ns or’s St u d y C o ntact  
 
L o x o O nc ol o g y,  I nc. 
 
 
 
S p o ns or’s Me dical C o nta ct 
  
C o ns ulti n g t o L o x o O nc ol o g y, I nc.  
 
 
Seri o us a d verse e ve nt ( S A E) 
re p orti n g 
E mail:  S A EI nta ke @ C o va nce.c o m  
St u d y Site 
C o va nce Cli nical Researc h U nit ( C R U), I nc. 
1 9 0 0 Mas o n A ve n u e, S uite 1 4 0 
Da yt o n a Beac h, F L 3 2 1 1 7 
U S A  
 
Pri nci pal I n v esti gat or 
 
Me dical Direct or  
C o va nce Cli nical Researc h U nit I nc.  
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0  
Da yt o n a Beac h, F L 3 2 1 1 7  
U S A  
 
S u b-i n vesti gat or(s) 
O btai n i nf or mati o n fr o m F or m F D A 1 5 7 2 
Cli nical La b orat ories 
La b C or p - H oll y w o o d 
4 2 0 0 N ort h 2 9 t h A ve n ue 
H oll y w o o d, F L 3 3 0 2 0  
U S A 
Bi oa nal ytical La b orat or y 
Alt uras A nal yt ics, I nc. 
1 3 2 4 Alt uras Dri ve  
M osc o w, I da h o 8 3 8 4 3 
U S 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


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 5 of 5 4 
Statisticia n 
 
C o va nce  
 
Me dical Writer 
 
C o va nce  
 
P P D
P P D
P P D
P P D


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 6 of 54 
SYNOPSIS 
Study Title 
A Phase 1, Open-label, Randomized, 2-Way Crossover, 3-Period Study to Evaluate the Effect 
of Food and a Proton Pump Inhibitor on the Pharmacokinetics of LOXO-305 in Healthy 
Adult Subjects 
Objectives 
The primary objectives of the study are: 
x to assess the effect of food on the pharmacokinetics (PK) of LOXO-305 administered 
under fasted conditions and after a standard meal in healthy adult subjects 
x to assess the effect of a gastric pH change on the PK of LOXO-305 after multiple-
doses of a proton pump inhibitor (PPI; omeprazole) in healthy adult subjects 
The secondary objective of the study is: 
x to determine the safety and tolerability of a single dose of LOXO-305 administered 
with and without food and in the presence of a PPI (omeprazole) in healthy adult 
subjects 
Study Design 
This is a Phase 1, open-label, randomized, 2-way crossover, 3-period study. A single oral 
dose of LOXO-305 will be administered under fasted conditions (Treatment A) and fed 
conditions (Treatment B). Multiple oral doses of omeprazole will be administered once daily 
from Day 15 through Day 18, with a single oral dose of LOXO-305 co-administered with 
omeprazole under fasting conditions on Day 18 (Treatment C).  PK sampling will be obtained 
for 168 hours after administration of each dose of LOXO-305 (ie, on Days 1, 8, and 18). The 
2 treatment sequences will be ABC and BAC. Subjects will be randomly assigned to 1 of the 
2 treatment sequences, according to the randomization scheme issued by Covance. 
In Treatment A, a single oral dose of 200 mg LOXO-305 will be administered in the morning 
on Day 1 or Day 8, following a fast of at least 10 hours prior to and 4 hours after dosing. In 
Treatment B, a single oral dose of 200 mg LOXO-305 will be administered in the morning on 
the Day 1 or Day 8, approximately 30 minutes after starting a standard breakfast. In 
Treatment C, a single oral dose of 40 mg omeprazole will be administered in the morning on 
Days 15, 16 and 17, following a fast of at least 8 hours prior to omeprazole dosing, followed 
by a standard breakfast administered approximately 1 hour after dosing.  On Day 18, a single 
oral dose of 40 mg omeprazole will be co-administered with a single oral dose of 200 mg 
LOXO-305 in the morning, following a fast of at least 10 hours prior to and 4 hours after 
omeprazole and LOXO-305 co-administration.  All standard breakfasts should be entirely 
consumed within 30 minutes.   
Following administration of LOXO-305 in each treatment, blood samples for PK analysis of 
LOXO-305 will be taken up to 168 hours postdose.  


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 7 of 5 4 
T here will be a was h o ut peri o d of 7 da ys b et wee n t he d oses of L O X O- 3 0 5 a d mi nistere d i n 
Treat me nts A a n d B, a n d a was h o ut peri o d of 7 da ys bet w ee n t he d os es of L O X O- 3 0 5 
a d mi nistere d i n Treat me nts A or B a n d t h e first d ose of o me praz ole i n Treat me nt C.  
T o assess t heir eli gi bilit y t o e nter t he st u d y, p ote ntial s u bj ects will be scree ne d wit hi n 2 8 da ys 
( Da ys - 2 9 t o - 2) a n d be a d mitte d to t he Cli nical Researc h U nit ( C R U) o n D a y - 1 ( C hec k-i n). 
Re place me nt s u bjects ma y be e nr olle d o nl y if d ee me d necess ar y b y t he S p o ns or. 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k-i n ( Da y - 1) u ntil E n d of 
Treat me nt ( E O T) o n D a y 2 5, f oll o wi n g c o m pleti o n of all P K a n d s afet y ass ess me nts or Earl y 
Ter mi nati o n ( E T) if t he s u bjec t disc o nti n ues. A f oll o w- u p p h o ne call will occ ur f or all 
s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g (i ncl u di n g s u bjects w h o are ter mi nate d 
earl y) 7 d a ys ( ± 2 da ys) after E O T or E T. 
I n t his st u d y, p h ysi cal e x a mi nati o ns, 1 2-lea d ele ctr ocar di o gra ms ( E C Gs), vital si gns, H o w D o 
Y o u Feel?  ( HD Y F?) i n q uiries, cli nical c he mistr y  pa nel, c oa g ulat i o n para meters, C K, 
c o m plete bl oo d c o u nt ( C B C), uri nal ysis ( U A; A p pe n di x  2 ) a n d c o nc o mita nt me dicati on 
rec or di n g will be perf or me d at Scree ni n g a n d at s pecifie d ti mes d uri ng  t he st u d y (f or s pecific 
ti me p oi nts a n d details o n eac h st u d y varia ble, refer t o  A p pe n di x 4 ). A d verse e ve nts ( A Es) 
a n d seri o us a d v erse  e ve nts ( S A Es) will be c ollecte d be gi n ni n g at i nf or me d c o nse nt. A d vers e 
e ve nts will be rep ort e d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of  the I nf or me d C o nse nt F or m 
[IC F]  u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m  t he st u d y a n d 
d oes n ot c o m plete a  f oll ow- u p p h o ne  call), eit her as s u bject medica l hist or y (if t h e e ve nt is 
rep orte d as be gi n ni n g p ri or t o si g ni n g of t he I C F o r if t he e vent o cc urs pri or  t o st u d y dr ug  
a d mi nistrati o n o n Da y 1 a n d is assesse d as n ot rel ate d t o st u d y  pr oce d ur es b y  t he In vesti gat or 
[ or desi g nee]) or as A Es (if t he e ve nt o cc urs after si g ni n g of t he I C F b ut pri or t o st u d y  dr ug  
a d mi nistrati o n o n Da y 1 a n d is assesse d as relate d t o st u d y pr o ce d ures b y the I n vesti gat or [ or 
desi g nee], or if t he e v e nt occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T 
re gar dl ess of rel ati o ns hi p t o st u d y dr ug ). Fr o m E O T or E T t hr o u g h E O S, o nl y  A Es ass ess e d 
as relate d t o st u d y  dr ug  b y  the I n v esti gat or ( or desi g nee) are t o be re p orte d. All S A Es t hat 
de vel o p fr o m t he ti me of  I C F si g ni n g u ntil E O S ( or E T, if t he su bject disc o nti n ues fr o m t he 
st u d y a n d d o es n ot c o m plete a f oll o w- u p p h o n e call) are  t o be re p ort e d. St u d y c o m pleti o n is 
defi ne d as t he ti me of t h e last s u bject’s f oll o w- u p p h o ne call.  
N u m ber of S u bjects 
 
T his is a p hase 1 st u d y a n d t he s a m ple siz e is n ot 
base d u p o n a n y f or mal p o wer calc ulati o ns b ut is c o nsiste nt wit h  pre vi o us st u dies of a si milar 
desi g n. 
 
If s u bjects are wit h dra w n b y t he I n v esti gat or ( or desi g nee) or v ol u ntaril y wit h dra w 
pre mat urel y fr o m t he st u d y, re place me nt s u bjects ma y b e e nr olle d o nl y if d ee me d necessar y 
b y t he S p o ns or. 
C CI
C CI


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 8 of 54 
Main Criteria for Inclusion 
Male subjects, and female subjects of non-childbearing potential, between 18 and 55 years of 
age, inclusive, at Screening, and within body mass index (BMI) range 18.0 to 32.0 kg/m2, 
inclusive. Subjects will be in good general health, based on medical history, physical 
examination findings, vital signs, 12-lead electrocardiogram (ECG), or clinical laboratory 
tests at Screening and/or Check-in (Day -1), as determined by the Investigator (or designee). 
Investigational Medicinal Product, Dose, and Mode of Administration 
LOXO-305 will be supplied by the Sponsor as 100-mg tablets for oral administration.  
Omeprazole will be supplied by Covance as 40-mg capsules for oral administration. 
Treatment A (Fasted): 
x Day 1 or Day 8 (Treatment A): single oral dose of 200 mg LOXO-305 (2 × 100-mg 
tablets) following a fast of at least 10 hours prior to and 4 hours after the LOXO-305 
dose. 
Treatment B (Fed): 
x Day 1 or Day 8 (Treatment B): single oral dose of 200 mg LOXO-305 (2 × 100-mg 
tablets) approximately 30 minutes after starting a standard breakfast. The standard 
breakfast should be entirely consumed within 30 minutes. 
Treatment C (Fasted): 
x Days 15, 16, and 17 (Treatment C): single oral dose of 40 mg omeprazole (1 × 40-mg 
capsule) in the morning following a fast of at least 8 hours prior to the omeprazole 
dose, followed by a standard breakfast administered approximately 1 hour after 
dosing.  The standard breakfasts should be entirely consumed within 30 minutes.   
x Day 18 (Treatment C): single oral dose of 40 mg omeprazole (1 × 40-mg capsule) co-
administered with a single oral dose of 200 mg LOXO-305 (2 × 100-mg tablets), 
following a fast of at least 10 hours prior to and 4 hours after dosing.  
All study drugs will be administered with approximately 240 mL of water. An additional 
100 mL of water may be administered if needed. 
There will be a washout period of 7 days between the doses of LOXO-305 administered in 
Treatments A and B, and a washout period of 7 days between the doses of LOXO-305 
administered in Treatments A or B and the first dose of omeprazole in Treatment C. 
Duration of Subject Participation in the Study: 
Planned Study Conduct Duration: up to 63 days. 
Screening Period: 
Planned Enrollment/Screening Duration: up to 28 days (Day -29 to Day -2). 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 9 of 54 
Length of Confinement: 
A total of 26 days (25 nights), from the time of Check-in (Day -1) through 168-hour postdose 
PK blood draw for Treatment C and EOT assessments (Day 25). 
Follow-up Phone Call (EOS): 7 days (± 2 days) after EOT or ET. 
Criteria for Evaluation: 
Pharmacokinetics: 
Serial PK blood samples for the analysis of plasma concentrations of LOXO-305 will be 
collected from predose through 168 hours post-LOXO-305 administration for each treatment. 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): area under the concentration-time curve from 
Hour 0 to 24 hours postdose, as calculated by the linear trapezoidal method (AUC0-24), area 
under the concentration-time curve from Hour 0 to the last measurable concentration 
(AUC0-t), area under the concentration-time curve extrapolated to infinity (AUC0-inf), 
extrapolation for area under the concentration-time curve (%AUCextrap), maximum observed 
plasma concentration (Cmax), time to maximum observed concentration (tmax), apparent 
terminal elimination rate constant (λZ), apparent systemic clearance (CL/F). The parameter 
will be calculated by linear least squares regression analysis using the maximum number of 
points in the terminal log linear phase (eg, 3 or more non-zero plasma concentrations), and 
apparent terminal elimination half-life (t½). 
No value for AUC0-inf, CL/F, or t½ will be reported for cases that do not exhibit a terminal log 
linear phase in the concentration-time profile.  
No PK parameters will be calculated for subjects with 2 or fewer consecutive timepoints with 
quantifiable concentrations. 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. 
Safety: 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory tests, measuring vital signs, and recording ECGs. 
Statistical Methods 
Pharmacokinetics: 
A mixed effect model including planned treatment sequence, period, and actual treatment as 
fixed effects and subject within planned treatment sequence as a random effect will be used 
to analyze the natural log (ln)-transformed PK parameters (AUC0-24, AUC0-t, AUC0-inf, and 
Cmax) and will include calculation of least squared (LS) means and the difference between 
treatment LS means, as well as their corresponding 90% confidence intervals (CIs). The 
geometric means ratios (GMR) and their 90% confidence intervals (CIs) of the PK parameter 
for each treatment comparison will be constructed using the exponentiation of the difference 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 10 of 54 
and the CIs from the mixed effect model. The treatment comparisons of interest include 
Treatment A versus Treatment B and Treatment A versus Treatment C. 
Safety: 
All safety assessments, including AEs and SAEs, vital signs measurements, clinical 
laboratory results, physical examination results, concomitant medications, and 12-lead ECGs, 
will be tabulated and summarized, where possible, using descriptive methodology, as needed, 
by timepoint. Unless otherwise specified, baseline value is defined as the last non-missing 
measurement before administration of LOXO-305 in each treatment period. No formal 
statistical analyses are planned for the safety data. All safety data will be listed by subject. 
Additional details on the analyses will be included in the Statistical Analysis Plan (SAP). 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 11 of 54 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES ...................................................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................14 
1.
INTRODUCTION ...........................................................................................................16 
1.1. Background ................................................................................................................16 
1.2. Non-clinical Pharmacokinetics ..................................................................................16 
1.3. Summary of Clinical Experience ...............................................................................17 
1.3.1. 
Safety ...........................................................................................................17 
1.3.2. 
Pharmacokinetics .........................................................................................17 
1.4. Study Rationale ..........................................................................................................18 
1.5. Benefit-risk Assessment ............................................................................................19 
2.
OBJECTIVES AND ENDPOINTS .................................................................................19 
2.1. Objectives ..................................................................................................................19 
2.2. Endpoints ...................................................................................................................19 
3.
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1. Overall Study Design and Plan ..................................................................................20 
3.2. Discussion of Study Design .......................................................................................21 
3.3. Selection of Doses in the Study .................................................................................22 
3.3.1. 
LOXO-305 ...................................................................................................22 
3.3.2. 
Omeprazole ..................................................................................................22 
4.
SELECTION OF STUDY POPULATION .....................................................................23 
4.1. Screening Procedures .................................................................................................23 
4.2. Check-in Procedures (Day -1) ...................................................................................23 
4.3. Inclusion Criteria .......................................................................................................24 
4.4. Exclusion Criteria ......................................................................................................25 
4.5. Subject Number and Identification ............................................................................28 
4.6. Removal of Subjects from Study Participation .........................................................29 
5.
STUDY TREATMENTS .................................................................................................29 
5.1. Description, Storage, Packaging, and Labeling .........................................................29 
5.2. Study Treatment Administration ...............................................................................30 
5.3. Randomization ...........................................................................................................31 
5.4. Blinding .....................................................................................................................31 
5.5. Treatment Compliance ...............................................................................................31 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 12 of 54 
5.6. Drug Accountability ..................................................................................................31 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................31 
6.1. Concomitant Therapies ..............................................................................................31 
6.2. Diet, Fluid, and Activity Control ...............................................................................32 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................33 
7.1. Pharmacokinetic Assessments ...................................................................................33 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................33 
7.1.2. 
Analytical Methodology ..............................................................................33 
7.2. Safety and Tolerability Assessments .........................................................................33 
7.2.1. 
Adverse Events ............................................................................................33 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................34 
7.2.3. 
Vital Signs ....................................................................................................35 
7.2.4. 
12-lead Electrocardiogram ...........................................................................35 
7.2.5. 
Physical Examination...................................................................................35 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................35 
8.1. Determination of Sample Size ...................................................................................35 
8.2. Analysis Populations .................................................................................................36 
8.2.1. 
Study Populations ........................................................................................36 
8.3. Pharmacokinetic Analysis .........................................................................................36 
8.3.1. 
Descriptive Analysis ....................................................................................37 
8.3.2. 
Statistical Methodology ...............................................................................37 
8.4. Safety Analysis ..........................................................................................................37 
8.5. Data Handling and Record Keeping ..........................................................................37 
8.6. Quality Control and Quality Assurance .....................................................................38 
9. 
ADMINISTRATIVE ASPECTS .....................................................................................38 
9.1. Change in Protocol ....................................................................................................38 
9.2. Site Initiation Visit/Investigator Meeting ..................................................................38 
9.3. Disclosure ..................................................................................................................38 
9.4. Monitoring .................................................................................................................39 
9.5. Institutional Review Board ........................................................................................39 
9.6. Informed Consent ......................................................................................................39 
9.7. Records ......................................................................................................................40 
9.8. Reference to Declaration of Helsinki/Basic Principles .............................................40 
9.9. Financing and Insurance ............................................................................................40 
10. REFERENCES ................................................................................................................40 
11. APPENDICES .................................................................................................................42 
Appendix 1: Adverse Event Reporting ...............................................................................43 
Appendix 2: Clinical Laboratory Evaluations .....................................................................47 
Appendix 3: Total Blood Volume .......................................................................................48 
Appendix 4: Schedule of Assessments ...............................................................................49 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 13 of 54 
Appendix 5: Protocol Amendment Summary of Changes ..................................................53 
 
LIST OF TABLES 
Table 1: Preliminary Pharmacokinetic Parameters of LOXO-305 in Patients with 
Cancer (Study LOXO-BTK-18001) ....................................................................18 
Table 2: Study Drug ...........................................................................................................29 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 14 of 54 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
%AUCextrap 
extrapolation for area under the concentration-time curve 
ADL 
Activities of Daily Living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose 
AUC0-inf 
area under the concentration-time curve extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last measurable 
concentration 
BMI 
body mass index 
BP 
blood pressure 
BTK 
Bruton’s tyrosine kinase 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval(s) 
CK 
creatine kinase 
CL/F 
apparent systemic clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GI 
gastrointestinal tract 
GMR 
geometric means ratios 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 


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HDYF? 
How Do You Feel? 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ICH 
International Council for/Conference on Harmonisation 
IUD 
intrauterine device 
LFT 
liver function test(s) 
Ln 
natural log 
LS 
least squared 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MZL 
marginal zone lymphoma 
NHL 
non-Hodgkin lymphoma 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 
PT 
preferred term 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell(s) 
SAE 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed concentration 
TSH 
thyroid-stimulating hormone 
UA 
urinalysis 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WM 
Waldenstrom’s macroglobulinemia 
λZ 
apparent terminal elimination rate constant 
 
 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 1 6 of 5 4 
1.  I N T R O D U C TI O N 
Refer t o t he I n v esti gat or ’s Br oc h ure (I B) f or d etaile d i nf or mati o n c o ncer ni n g t he a vaila ble 
p har mac ol o g y, t o xic ol o g y, dr u g m eta b olis m, cli nical st u dies, a n d a d v erse e ve nt ( A E) pr ofile 
of t he i n vesti gati o nal me dici nal pr o d uct (I M P). 1 
1. 1.  
B ac k gr o u n d 
L O X O- 3 0 5 (als o k n o w n as L Y 3 5 2 7 7 2 7) is a sel ecti ve i n hi bit or of t he B r ut o n’s t yr osi ne 
ki nase ( B T K) bei n g d e vel o pe d b y L o x o O nc ol o g y. I n e nz y me a n d ce ll ular assa ys, 
L O X O- 3 0 5 p ote ntl y i n hi bits wil d-t y p e- B T K a n d t he B T K C 4 8 1 S-ac q u ire d resista nce 
m utati o n w hic h res ults fr o m a seri ne s u bstit uti o n at p ositi o n 4 8 1. T his i n hi bit or y acti vit y 
c orrel ate d wit h si g nifi ca nt i n hi biti o n of gr o wt h of B T K- d e pe n de nt h u ma n l y m p h o ma cell 
li nes. C 4 8 1 S m utati o ns (a n d ot her s u bstit uti o ns of t his c ystei ne resi d ue) are cli nicall y 
i m p orta nt beca use t h e y ma y e x plai n m ore t ha n half t he cas es of ac q uire d resista nce t o 
c o m merciall y a v aila ble c o vale nt B T K i n hi bit ors i n patie nts wit h  c hr o nic l y m p h oc ytic 
le u ke mia ( C L L), a n d h a v e als o bee n i de ntifi e d i n W al de nstr o m’s macr o gl o b uli nemia  ( W M) 
a n d ma ntle cell l y m p h o m a ( M C L) patie nts. 2 – 5
 
 
Irre v ersi ble B T K i n hi bit ors li ke i br uti ni b a n d acala br uti ni b have tra nsf or m e d t he treat me nt 
la n dsca pe of se veral B T K- de pe n d e nt B-cell mali g na n cies, i ncl u din g C L L, W M, M C L, a n d 
mar gi n al z o ne l y m p h o ma ( M Z L). H o w e ver, t he efficac y of t hese a g e nts i n t he l o n g ter m is 
li mite d b y t h e de vel o p me nt of m utati o ns i n B T K, m ost c o m m o nl y thr o u g h B T K C 4 8 1 
s u bstit uti o n m utati o ns t hat pre ve nt c o v ale nt bi n di n g a n d i n activati o n of B T K b y irre versi ble 
i n hi bit ors. A d diti o nall y, half of patie nts w h o disc o nti n ue i br uti ni b t hera p y ha ve A Es w hic h 
are attri b ute d t o off-tar get effects a n d li mit l o n g-ter m use of  i br uti ni b. T heref ore, a m ore 
p ote nt a n d selecti ve i n hi bit or of B T K wit h a cti vit y a gai nst B T K - wt a n d C 4 8 1 m uta nt B T K 
ma y pr o vi d e cli nical be n efit t o patie nts wit h B-cell mali g na nci es w here treat me nt wit h 
irre versi ble B T K i n hi bit ors has faile d. 
L O X O- 3 0 5 is a s mall m olec ule t hat was d esi g n e d t o bl oc k t he a de n osi ne tri p h os p hate ( A T P) 
bi n di n g site of t he B T K ki nase c o m petiti vel y a n d has si n gle di g it na n o m ol ar acti vit y a gai nst 
B T K- wt a n d C 4 8 1 S. T here is n o e vi de nce of c o v ale nt or irre versi ble bi n di n g. L o x o O nc ol o g y 
is i nitiati n g t he cli nical de vel o p m e nt of L O X O- 3 0 5 f or t he treat me nt of patie nts wit h 
pre vi o usl y tr eate d C L L/s mall l y m p h o c ytic l y m p h o ma ( S L L), W M, M C L, M Z L, a n d ot her 
B-cell n o n- H o d g ki n l y m p h o ma ( N H L). 
1. 2.  
N o n-cli nic al P h ar m a c o ki netics 
I n n o n-cli nical st u dies, L O X O- 3 0 5 w as meta b olize d sl o wl y b y h u ma n micr os o mal fracti o ns 
a n d he pat oc yt es. T he l o w rates of  meta b olis m i n b ot h t hese h u man i n vitr o s yste ms s u g gest 
t hat L O X O- 3 0 5 will ha v e l o w cleara nce i n h u ma ns. I n vitr o data wit h cl o ne d e x presse d 
c yt o c hr o me P 4 5 0 ( C Y P) e nz y mes a n d h u ma n li ver micr os o mes i n dica te t h at C Y P 3 A 4 is t he 
pri mar y e nz y m e t hat meta b olizes L O X O- 3 0 5. 
T here w as ver y little met a b olis m of L O X O- 3 0 5 i n h u ma n he pat oc yt es a n d t he o nl y 
meta b olite detecte d was a gl u c ur o ni de of L O X O- 3 0 5. T he gl uc ur o n i de f or me d b y t he h u m a n 
C CI


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hepatocytes was also formed by rat and dog hepatocytes, supporting the use of rat and dog for 
non-clinical safety assessment. 
Renal clearance of LOXO-305 in male and female rats was negligible. No renal clearance 
data are available in other species, but this pathway is often conserved across species and 
therefore, no renal clearance is expected in humans. 
1.3. 
Summary of Clinical Experience 
LOXO-305 is currently being studied in an ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001, in patients with previously treated CLL/SLL or NHL. The starting dose 
of LOXO-305 was 25 mg once daily (QD). 
As of 27 September 2019 (data cutoff date), safety data were available from 28 treated 
patients, with 200 mg QD as the highest dose administered (Section 1.3.1). As of 
25 October 2019, Day 8 of Cycle 1 pharmacokinetic (PK) data were available from 25 
patients (Section 1.3.2). 
1.3.1. 
Safety 
As of 27 September 2019, 27 (96.4%) of the 28 patients were continuing treatment; 1 patient 
in the 25 mg QD cohort discontinued treatment due to progressive disease and withdrew 
consent. 
Overall, 22 (78.6%) patients experienced at least 1 treatment-emergent AE (TEAE), 
regardless of relationship to study drug. Treatment-emergent AEs were coded according to 
the Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and 
preferred term (PT). Across the 25 mg to 200-mg QD dose range, the most frequently 
reported TEAEs (> 10% of patients), regardless of relationship to study drug, were fatigue 
(25.0%), diarrhea (17.9%), anemia (14.3%), arthralgia (10.7%), back pain (10.7%), increased 
blood bilirubin (10.7%), contusion (10.7%), and maculo-papular rash (10.7%). 
As of the data cut off of 27 September 2019, most TEAEs were mild or moderate (Grade 1 
or 2) in severity. Grade 3 TEAEs have been reported in 2 patients to date, 1 with neutropenia 
and 1 with leukocytosis, the latter also reported as a serious AE (SAE). Both of these were 
assessed by the Investigator as related to the study drug. 
1.3.2. 
Pharmacokinetics 
As of 25 October 2019, preliminary steady-state PK data (Day 8 of Cycle 1) were available 
from 25 patients enrolled in LOXO-BTK-18001. These data demonstrate that LOXO-305 is 
absorbed after oral administration with a median time to maximum observed concentration 
(tmax) of approximately 2 hours and low clearance (Table 1). 
Although the plasma half-life could not be calculated with certainty because of the limited 
sampling interval (0 to 8 hours), it appears to be approximately 18 hours. Steady-state PK 
parameters of LOXO-305 in these cancer patients are presented in Table 1. Following 
administration of the 100 mg QD, 150 mg QD, or 200 mg QD, mean unbound trough plasma 
levels of LOXO-305 exceeded the concentration required for 90% inhibition (IC90) of the 
C481S mutant of BTK in vitro. 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 1 8 of 5 4 
1. 4.  
St u d y R ati o n ale 
T he st u d y is desi g ne d t o deter mi ne t he d osi n g c o n diti o ns w hic h mi g ht affect t he P K pr ofile of 
L O X O- 3 0 5 i n he alt h y a d ult s u bjects.  
T his st u d y will s u p p ort assess me nt of earl y p h ase dr u g c o m bi nati o ns of F D A-a p pr o ve d 
pr o d ucts wit h L O X O- 3 0 5 as part of  t he o n g oi n g cli nical trial, LO X O- B T K- 1 8 0 0 1. F or 
a p pr o ve d pr o d u cts, a d mi nistrati o n will f oll o w s pecificati o ns of  t he U nite d States pac ka ge 
i nsert, w hic h ma y s pecif y a d mi nistrati o n wit h “f o o d”, n ot s pecificall y a “ hi g h fat meal”. A 
“sta n dar d meal” is c o nsi dere d m or e c o nsiste nt wit h t he f o o d c o nditi o ns i de ntifie d i n t he 
pac ka ge i nsert of t he a p pr o ve d pr o d ucts t hat will be assesse d i n c o m bi nati o n wit h 
L O X O- 3 0 5 .6 T he effect of f o o d will be assesse d b y me as uri n g t he c h a n ge i n t he P K of 
L O X O- 3 0 5 after d osi n g u n der fe d c o n diti o ns ( wit h a sta n dar d bre a kfast) v ers us fasti n g 
c o n diti o n. I n c o nsi d erati o n of t he diet w hic h t he p atie nt p o p ul ati o n L O X O- 3 0 5 is i nte n de d t o 
treat ( patie nts wit h pr e vi o usl y treate d C L L/ S L L, W M, M C L, M Z L, a n d ot her B-cell N H L) 
n or mall y c o ns u m e, a sta n dar d brea kfast h as bee n c h ose n as t he m eal wit h w hic h t o 
a d mi nister L O X O- 3 0 5 u n der fe d c o n diti o ns ( Treat me nt B). 
T he a q ue o us s ol u bilit y of L O X O- 3 0 5 is si milar acr oss t he ra n ge of p H i n t h e gastr oi ntesti nal 
( GI) tr ac k 
 a n d t heref ore t here is u nli kel y t o be a n effect of GI p H m o dificati o n o n t he s ol u bilit y a n d 
s u bse q ue nt oral a bs or pti o n of L O X O- 3 0 5 fr o m t he GI tract. H o we ver, L O X O- 3 0 5 is 
f or m ulate d wit h e x ci pie nts t hat ca use rel ease of L O X O- 3 0 5 fr o m t he f or m ulati o n t o be 
s o me w hat sl o wer u n der aci dic c o n diti o ns t ha n ne utral c o n diti o ns, a n d t he cli nical i m pact of 
t his sl o wer diss ol uti o n is u n k n o w n. T he effect of re d uce d st o mac h aci dit y o n t he P K of 
L O X O- 3 0 5 will be teste d i n t his st u d y b y raisi n g t he gastric p H  wit h o me praz ole, a pr ot o n 
p u m p i n hi bit or ( P PI). 
A P PI was s electe d o v er ot her a ntaci ds dr u gs b eca use t his dr u g class is c o nsi dere d t o 
s u p press gastric aci d secreti o n t o a greater e xte nt a n d f or a lo n ger d urati o n t ha n s o me ot her 
gastri c p H-el e vati n g a ge nts, s uc h as H 2 bl oc kers a n d a ntaci ds.  
C CI
C CI


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1.5. 
Benefit-risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfort from collection of blood samples and other study procedures. The 
dose of LOXO-305 administered in this study is not anticipated to induce any potential risk to 
subjects participating in this study as it is a single dose which does not exceed the highest 
dose safely administered in first in human studies.1 More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with LOXO-305 may be 
found in the IB.1 
The potential risk of participating in this study is well managed by the study set-up and is 
considered negligible. The safety monitoring practices employed will include AE reporting, 
vital signs, 12-lead electrocardiogram (ECG), clinical laboratory evaluations, and physical 
examinations, and are considered adequate to protect the subjects’ safety. 
2. OBJECTIVES AND ENDPOINTS
2.1. 
Objectives 
The primary objectives of the study are: 
x to assess the effect of food on the PK of LOXO-305 administered under fasted 
conditions and after a standard meal in healthy adult subjects 
x to assess the effect of a gastric pH change on the PK of LOXO-305 after multiple-
doses of a PPI (omeprazole) in healthy adult subjects 
The secondary objective of the study is: 
x to determine the safety and tolerability of a single dose of LOXO-305 administered 
with and without food and in the presence of a PPI (omeprazole) in healthy adult 
subjects 
2.2. 
Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): 
x area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal method (AUC0-24) 
x area under the concentration-time curve from Hour 0 to the last measurable 
concentration (AUC0-t) 
x area under the concentration-time curve extrapolated to infinity (AUC0-inf) 
x extrapolation for area under the concentration-time curve (%AUCextrap) 
x maximum observed plasma concentration (Cmax) 
x time to maximum observed concentration (tmax) 


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x apparent terminal elimination rate constant (λZ) 
x apparent systemic clearance (CL/F) 
x apparent terminal elimination half-life (t½). 
No value for AUC0-inf, CL/F, or t½ will be reported for cases that do not exhibit a terminal log 
linear phase in the concentration-time profile. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive timepoints with 
quantifiable concentrations. 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory tests, measuring vital signs, and 12-lead ECGs. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 1, open-label, randomized, 2-way crossover, 3-period study. A single oral 
dose of LOXO-305 will be administered under fasted conditions (Treatment A) and fed 
conditions (Treatment B). Multiple oral doses of omeprazole will be administered once daily 
from Day 15 through Day 18, with a single oral dose of LOXO-305 co-administered with 
omeprazole under fasted conditions on Day 18 (Treatment C). PK sampling will be obtained 
for 168 hours after administration of each dose of LOXO-305 (ie, on Days 1, 8, and 18). The 
2 treatment sequences will be ABC and BAC. Subjects will be randomly assigned to 1 of the 
2 treatment sequences, according to a randomization scheme issued by Covance. 
In Treatment A, a single oral dose of 200 mg LOXO-305 will be administered in the morning 
on Day 1 or Day 8 (according to the randomization scheme), following a fast of at least 
10 hours prior to and 4 hours after dosing. In Treatment B, a single oral dose of 200 mg 
LOXO-305 will be administered in the morning on Day 1 or Day 8 (according to the 
randomization scheme), approximately 30 minutes after starting a standard breakfast. In 
Treatment C, a single oral dose of 40 mg omeprazole will be administered in the morning on 
Days 15, 16 and 17, following a fast of at least 8 hours prior to omeprazole dosing, followed 
by a standard breakfast administered approximately 1 hour after dosing.  On Day 18, a single 
oral dose of 40 mg omeprazole will be co-administered with a single oral dose of 200 mg 
LOXO-305 in the morning, following a fast of at least 10 hours prior to and 4 hours after 
omeprazole and LOXO-305 co-administration. Standard breakfasts should be entirely 
consumed within 30 minutes. Serial PK blood samples for the analysis of plasma 
concentrations of LOXO-305 will be collected from predose through 168 hours postdose for 
each treatment.  
There will be a washout period of 7 days between the doses of LOXO-305 administered in 
Treatments A and B, and a washout period of 7 days between the doses of LOXO-305 
administered in Treatments A or B and the first dose of omeprazole in Treatment C.  


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To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 25 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. A follow-up phone call will occur for all 
subjects who received at least 1 dose of study drug (including subjects who are terminated 
early) 7 days (± 2 days) after EOT or ET. 
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned a dose of study drug; this definition excludes screen failure subjects. 
In this study, physical examinations, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) 
inquiries, clinical chemistry panel, coagulation parameters, creatine kinase (CK), complete 
blood count (CBC), urinalysis (UA; Appendix 2) and recording of concomitant medications 
will be performed at specified times during the study (for specific timepoints and details on 
each study variable, refer to Appendix 4). Adverse events and SAEs will be collected 
beginning at informed consent. Adverse events will be reported throughout the study (ie, 
from signing of the ICF until End of Study [EOS], or until ET if the subject discontinues 
from the study and does not complete a follow-up phone call), either as subject medical 
history (if the event is reported as beginning prior to signing of the ICF or if the event occurs 
prior to study drug administration on Day 1 and is assessed as not related to study procedures 
by the Investigator [or designee]) or as AEs (if the event occurs after signing of the ICF but 
prior to study drug administration on Day 1 and is assessed as related to study procedures by 
the Investigator [or designee], or if the event occurs after study drug administration on Day 1 
through EOT or ET regardless of relationship to study drug). From EOT or ET through EOS, 
only AEs assessed as related to study drug by the Investigator (or designee) are to be 
reported. All SAEs that develop from the time of ICF signing until EOS (or ET, if the subject 
discontinues from the study and does not complete a follow-up phone call) are to be reported. 
Study completion is defined as the time of the last subject’s follow-up phone call. 
3.2. 
Discussion of Study Design 
Overall 
The study is designed to determine the dosing conditions which might affect the PK profile of 
LOXO-305 in healthy adult subjects. 
The effect of food will be thus assessed by measuring the change in the PK of LOXO-305 
after dosing under fed conditions (with a standard breakfast) versus fasting condition.  This 
study will support assessment of early phase drug combinations of FDA-approved products 
with LOXO-305 as part of the ongoing clinical trial, LOXO-BTK-18001. For approved 
products, administration will follow specifications of the United States product insert, which 
may specify administration with “food”, not specifically a “high fat meal”. A “standard meal” 
is considered more consistent with the food conditions identified in the package insert of the 
approved products that will be assessed in combination with LOXO-305. In consideration of 
the diet which the patient population LOXO-305 is intended to treat (patients with previously 
treated CLL/SLL, WM, MCL, MZL, and other B-cell NHL) normally consume, a standard 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 2 2 of 5 4 
brea kfast has bee n c h ose n as t he meal wit h w hic h  t o a d mi nister L O X O- 3 0 5  u n der 
fe d c o n diti o ns ( Treat me nt  B). 6 
T he a q ue o us s ol u bilit y of L O X O- 3 0 5 is si milar acr oss t he ra n ge of p H i n t h e GI trac k (e. g. 
L o x o O nc ol o g y I nc., d ata o n file) a n d t heref ore 
t here is u nli kel y t o b e a n effect of GI p H m o dificati o n o n t he s ol u bilit y a n d s u bse q ue nt oral 
a bs or pti o n of L O X O- 3 0 5 fr o m t he GI tr act. H o we ver, L O X O- 3 0 5 is f or m ulate d wit h 
e x ci pie nts t hat ca use rele ase of L O X O- 3 0 5 fr o m t he f or m ulati o n t o be s o me w hat sl o wer 
u n der aci dic c o n diti o ns t ha n ne ut ral c o n diti o ns, a n d t he cli nical i m pact of t his sl o wer 
diss ol uti o n is u n k n o w n. T he effect of re d uce d st o mac h aci dit y o n t he P K of L O X O- 3 0 5 will 
be teste d i n t his st u d y b y raisi n g t he gastric p H wit h o me praz o le, a P PI. 
A P PI was s electe d o v er ot her a ntaci ds dr u gs b eca use t his dr u g class is c o nsi dere d t o 
s u p press gastric aci d secreti o n t o a greater e xte nt a n d f or a lo n ger d urati o n t ha n s o me ot her 
gastri c p H-el e vati n g a ge nts, s uc h as H 2 bl oc kers a n d a ntaci ds.  
S u bjects will be ra n d o mize d t o t reat me nt se q ue nces t o mi ni mize assi g n me nt bias. T he 2 
treat me nt se q ue n ces will be A BC a n d B A C. S u bje cts will be ra n d o ml y assi g ne d t o 1 of t he 2 
treat me nt se q ue n ces, acc or di n g t o t he ra n d o mizati o n sc he me iss ue d b y C o v a nce. A cr oss o ver 
desi g n is use d t o r e d uce t he resi d ual varia bilit y as e ver y s u bj ect acts as t heir o w n c o ntr ol. T he 
was h o ut peri o d of 7 da ys bet wee n L O X O- 3 0 5 d os es i n Treat me nts A a n d B a n d t he was h o ut 
peri o d of 7 da ys b et wee n t he d oses of L O X O- 3 0 5 a d mi nistere d i n Treat me nts A or B a n d t h e 
first d ose of o me praz ole i n Treat me nt C is c o nsi dere d s uffici e nt t o pre ve nt carr y o v er effects 
of t he treat me nts.  
C o n d ucti n g t he st u d y i n healt h y a d ult s u bjects miti gates t he p o te ntial c o nf o u n di n g effects of 
t he disease state a n d c o n c o mita nt me dicati o ns. 
3. 3.  
Selecti o n of D oses i n t he St u d y 
3. 3. 1.  
L O X O- 3 0 5 
Si n gle oral d oses of 2 0 0 m g L O X O- 3 0 5 will be e val uate d as t his is t he a ntici pate d 
t hera pe utic d os e le vel.  D oses of L O X O- 3 0 5 fr o m  2 5  m g Q D t o 2 0 0  mg  Q D  ha ve be e n 
e val uate d i n a P has e 1/ 2 first-i n- h u ma n st u d y i n p atie nts wit h  pre vi o usl y  treate d C L L/ S L L  or  
N H L  wit h o n g oi n g  d ose escalati o n a b o v e 2 0 0  mg Q D as a p pr o ve d b y  t he stu d y’s Safet y  
Re vie w C o m mittee. T he a vaila ble data d e m o nstrat e t hat L O X O- 3 0 5 a p pears safe a n d  well 
t olerate d at t hese d oses. At a ll e val uate d d oses, i ncl u di n g d oses ab o ve 2 0 0 m g  Q D, n o d ose-
li miti n g t o xicities ha ve bee n i de ntifie d i n h u ma ns.1 
3. 3. 2.  
O me pr az ole 
A d ose of 4 0 m g o me praz ole o nce dail y is wit hi n t he rec o m me n d e d  d ose as prescri be d i n t he 
la beli n g.7 I n a d diti o n, m ulti ple d oses f or 4 co nsec uti ve da ys will e ns ure  ma xi m u m i n hi biti o n 
of aci d se creti o n b y o me praz ole, beca us e t he i n hi bit or y effect of o me praz ole o n aci d 
secreti o n i ncreas es wit h r e peate d o n ce- d ail y d osi n g, reac hi n g a platea u after 4 da ys. 
C CI


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4. SELECTION OF STUDY POPULATION
4.1. 
Screening Procedures 
The following screening procedures will be performed for all potential subjects at a visit 
conducted within 28 days of study entry (ie, prior to Check-in [Day -1]): 
1. Inclusion/exclusion criteria
2. Informed consent
3. Demographic data
4. Medical history (including review of medication[s])
5. Height, weight, and body mass index (BMI)
6. Complete physical examination (Section 7.2.5)
7. 12-lead ECG measured after the subject has been resting in the supine position for at
least 10 minutes (Section 7.2.4)
8. Vital signs (including oral temperature, respiratory rate, and supine blood pressure
[BP] and pulse rate [measured after the subject has been supine for at least 5 minutes];
Section 7.2.3)
9. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1)
10. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least
8 hours], coagulation parameters, CK, CBC, and UA; Appendix 2)
11. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg),
and human immunodeficiency virus (HIV) antibody (Appendix 2)
12. Hemoglobin A1c (HbA1c) test (Appendix 2)
13. Screen for selected drugs of abuse, including cotinine and an alcohol breath test
(Appendix 2)
14. Serum pregnancy test (for female subjects only; Appendix 2)
15. Follicle-stimulating hormone (FSH) test (for post-menopausal female subjects only;
Appendix 2)
16. Thyroid-stimulating hormone (TSH) test (Appendix 2)
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
1. Review of inclusion/exclusion criteria
2. Interim medical history, including concomitant medication(s)
3. Weight and BMI
4. Abbreviated physical examination (Section 7.2.5)


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5. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
6. Vital signs (including oral temperature, respiratory rate, and supine BP and pulse rate 
[measured after the subject has been supine for at least 5 minutes]; Section 7.2.3) 
7. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
8. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, CK, CBC, and UA; Appendix 2) 
9. Screen for selected drugs of abuse, including cotinine and an alcohol breath test 
(Appendix 2) 
10. Serum pregnancy test (for female subjects only; Appendix 2) 
11. Compliance with concomitant medications and exclusionary restrictions (Section 6) 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Day -1 (as appropriate; #1, Section 4.2). In addition, continued 
compliance with concomitant medication and other restrictions will be verified. 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to enrollment. Prior to dosing, the Sponsor will provide approval of subjects selected for 
enrollment by the Investigator (or designee). 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria apply 
will be eligible to be enrolled into the study. Safety evaluations may be repeated at the 
discretion of the Investigator (or designee) or Sponsor. 
4.3. 
Inclusion Criteria 
Subjects who meet the following criteria at Screening and Check-in (Day -1), unless 
otherwise specified, may be included in the study: 
1. Males, and females of non-childbearing potential, between 18 and 55 years of age, 
inclusive, at Screening. 
2. Within BMI range 18.0 to 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, or clinical laboratory 
evaluations (Appendix 4) at Screening and/or Check-in (Day -1) as assessed by the 
Investigator (or designee). 
4. Female subjects of non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy, or confirmed tubal occlusion more than 6 months prior to study drug 
administration) or post-menopausal (defined as at least 12 months post-cessation of 
menses without an alternative medical cause). Post-menopausal status will be 
confirmed with a screening serum FSH level ≥ 40 mIU/mL. All female subjects must 
have a negative qualitative serum pregnancy test (serum human chorionic 
gonadotropin, serum quantitative human chorionic gonadotropin tests may be used for 
confirmation as needed) at Screening and Check-in (Day -1). 


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5. Male subjects who are capable of fathering a child must agree to use 1 of the 
following methods of contraception from the time of the dose administration through 
6 months after the last dose of LOXO-305 administration: 
a. 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). If 
documentation is not available, male subjects must follow 1 of the contraception 
methods below: 
i. Male condom with spermicide, or 
ii. A male subject must ensure that their female partner meets 1 of the 
following criteria: 
1. intrauterine device (IUD) (hormonal IUD; eg, Mirena®). 
Copper IUDs are acceptable (eg, ParaGard®); 
2. established use of oral, implanted, transdermal, intravaginal, or 
hormonal method of contraception associated with inhibition of 
ovulation; or 
3. bilateral tubal ligation or, 
4. be postmenopausal with amenorrhea for at least 1 year prior to 
dosing and FSH serum levels consistent with postmenopausal 
status. 
Male subjects who practice true abstinence because of a lifestyle choice (ie, do not 
become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence by a female partner (eg, calendar, 
ovulation, symptothermal, post-ovulation 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 through EOS, he must agree to use contraception as 
described above. 
For male subjects, sexual intercourse with female partners who are pregnant, or 
breastfeeding should be avoided. Male subjects are required to refrain from donation 
of sperm from Check-in (Day -1) until 6 months after administration of study drug. 
For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. 
6. Able to understand and provide written informed consent. 
7. Able to comply with all study procedures, including the 25-night stay at the CRU and 
follow-up phone call. 
4.4. 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. History or presence of any of the following, deemed clinically significant by the 
Investigator (or designee), and/or Sponsor: 
i. liver disease 
ii. pancreatitis 


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iii. peptic ulcer disease 
iv. intestinal malabsorption 
v. gastric reduction surgery 
vi. history or presence of clinically significant cardiovascular disease: 
vii. Myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to the first dose administration (Day 1) 
viii. Symptomatic angina pectoris within 6 months prior to the first dose 
administration (Day 1) 
ix. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to the first dose administration (Day 1) 
x. Congenital prolonged QT syndrome 
xi. Ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
xii. Arrhythmia (excluding benign sinus arrhythmia) or history of 
arrhythmia requiring medical intervention 
xiii. Ventricular dysfunction or risk factors for Torsades de Pointes (eg, 
heart failure, cardiomyopathy, family history of Long QT Syndrome) 
xiv. Significant screening ECG abnormalities: 
1. left bundle-branch block 
2. second-degree atrioventricular (AV) block, type 2, or 
third-degree AV block 
3. QT interval corrected for heart rate using Fridericia’s method 
(QTcF) is > 450 msec 
2. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
i. oral body temperature > 37.5°C; 
ii. pulse rate < 50 or > 99 beats per minute (bpm); 
iii. systolic BP < 89 or > 139 mmHg; 
iv. diastolic BP < 50 or > 89 mmHg. 
For these parameters, out-of-range values that are not clinically significant (as 
determined by the Investigator or designee) may be repeated twice during Screening, 
Check-in (Day -1), and predose on Day 1. Note: Rechecks of pulse rate and BP values 
will be permitted up to 2 times to confirm eligibility for study participation. Subjects 
may be eligible for participation in the study based on rechecked pulse rate and/or BP 
values if the values fall within the ranges stated above. 
3. Abnormal laboratory values (CBC, UA, clinical chemistry panel [fasted at least 
8 hours], excluding those further defined in exclusion criteria #5, #6, and #7 below) 
determined to be clinically significant by the Investigator (or designee), and Sponsor 
at Screening and/or Check-in (Day -1) as confirmed by repeat assessment. 


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4. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Screening and/or Check-in (Day -1). 
5. Abnormal liver function tests (LFTs), as defined by aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), and serum (total and direct) bilirubin, as well as 
amylase and lipase above the upper limit of the normal range at Screening or 
Check-in (Day -1). Rechecks of LFTs, amylase, and lipase will be permitted up to 
2 times to confirm eligibility for study participation if the values fall within normal 
ranges. 
6. Any clinically significant deviations from normal ranges in CK unless approved by 
the Investigator (or designee) and Sponsor. Rechecks of CK will be permitted up to 
2 times to confirm eligibility for study participation if the out-of-range values are 
stable or trending down and the Investigator (or designee) and the Sponsor deem that 
the results are not clinically significant and will not impact study conduct. 
7. Estimated creatinine clearance ≤ 90 mL/minute at Screening or Check-in (Day -1) 
calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation. 
8. Positive serologic test for HBsAg, HCV, or HIV antibody at Screening.  
9. Subjects with known ongoing alcohol and/or drug abuse within 2 years prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays and alcohol 
breath tests conducted during Screening and/or at Check-in (Day -1). Alcohol breath 
tests must be negative at both Screening and Check-in (Day -1). 
10. Consumption of grapefruit/grapefruit juice or Seville oranges or its juice within 
7 days prior to Check-in (Day -1) and through EOT or ET. 
11. Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours 
prior to Check-in (Day -1) and through EOT or ET, unless deemed acceptable by the 
Investigator (or designee) and Sponsor. 
12. Positive urine screen for drugs of abuse at Screening or Check-in (Day -1). 
13. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
14. History of significant hypersensitivity, intolerance, or allergy to any drug compound 
(including omeprazole), food, or other substance, unless approved by the Investigator 
(or designee). 
15. Participation 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 dose administration (Day 1). 
16. Use or intention to use any prescription or over-the-counter medications (including 
but not limited to any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers, strong P-glycoprotein (P-gp) inhibitors, PPIs [with the exception of 
omeprazole administered for the purposes of this study/in accordance with the 
Protocol], antacids, H2-receptor antagonists, and drugs that prolong QT/QTc interval, 
herbal products, natural or herbal supplements, and hormone-replacement therapy 
[HRT]) within 14 days prior to the first dose administration (Day 1) and through EOT 
or ET, unless deemed acceptable by the Investigator (or designee) and Sponsor. 
17. History of a major surgical procedure within 30 days prior to Screening. 


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18. History or presence, upon clinical evaluation, of any illness that, in the opinion of the 
Investigator, would interfere with the ability to provide informed consent or comply 
with study instructions, or that might confound the interpretation of the study results, 
or put the subject at undue risk. 
19. History of gastritis, gastrointestinal tract, or hepatic disorder or other clinical 
condition that might, in the opinion of the Investigator or designee, and as confirmed 
by the Sponsor, affect the absorption, distribution, biotransformation, or excretion of 
LOXO-305. 
20. Poor peripheral venous access. 
21. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
22. Receipt of blood products within 2 months prior to Check-in (Day -1). 
23. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. 
24. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, biliary, renal, hematological, pulmonary, cardiovascular (including any prior 
history of cardiomyopathy or cardiac failure), gastrointestinal, neurological, or 
psychiatric disorder (as determined by the Investigator), or cancer within the past 
5 years (except localized basal cell, squamous, or in situ cancer of the skin). 
Note: subjects with a history of uncomplicated cholecystectomy, appendectomy 
and/or hernia repairs will be acceptable. 
25. History of diabetes mellitus; HbA1c ≥ 6.5%. 
26. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
27. Have previously completed or withdrawn from any other study investigating 
LOXO-305 and have previously received the investigational product. 
28. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator (or designee), and as confirmed by the Sponsor, within the 30 days prior 
to the first dosing and through EOT or ET. 
29. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
4.5. 
Subject Number and Identification 
Subject numbers will consist of 6 digits in which the first set of 3 digits will identify the site 
and the second set of 3 digits will identify the subject (eg, 001-101). If subjects are 
withdrawn by the Investigator (or designee) or voluntarily withdraw prematurely from the 
study, replacement subjects may be enrolled only if deemed necessary by the Sponsor. If 
necessary, as determined by the Sponsor, subjects who fail to complete the treatment or have 
insufficient PK data may be replaced. Replacement subjects will be assigned a subject 
number by adding 100 to the last 3 digits of the subject number for the subject they are 
replacing (eg, Subject Number 001-201 replaces Subject Number 001-101). 


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4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for 
any reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue 
the study. Subjects may be withdrawn because of the following: change in compliance with 
inclusion/exclusion criterion that is clinically relevant and affects subject safety, occurrence 
of AEs, occurrence of pregnancy, intake of non-permitted concomitant medication that might 
affect subject safety or study assessments/objectives, etc. Notification of withdrawal will 
immediately be made to the Study Monitor. In case of withdrawal, efforts will be made to 
perform all final study day assessments (Appendix 4). The date the subject is withdrawn from 
the study and the reason for withdrawal will be recorded on the subject’s electronic Case 
Report Form (eCRF). All withdrawn subjects with AEs that are assessed as related to study 
drug and which are ongoing at ET may continue to be followed until the symptoms or 
value(s) return to normal, or acceptable levels, as judged by the Investigator (or designee) and 
confirmed by the Sponsor. 
The entire study may be discontinued at the discretion of the Investigator (or designee) or 
Sponsor, based on the occurrence of the following: 
x adverse events unknown to date with respect to their nature, severity, and/or duration; 
x increased frequency and/or severity and/or duration of known AEs; 
x medical or ethical reasons affecting the continued performance of the study; 
x difficulties in the recruitment of subjects; 
x cancellation of drug development. 
In the event that the study is terminated early, the Sponsor or its designee will provide 
specific guidance to the CRU regarding the EOS procedures. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study drug (Table 2). 
Table 2: Study Drug  
Study Drug 
LOXO-305 
Omeprazole 
Form 
Tablet 
Capsule 
Strength 
100 mg 
40 mg 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Catalent San Diego or Lonza Pharma & 
Biotech 
 Sandoz, Inc. 
Note: for LOXO-305, specific manufacturer and purity will be identified in the Certificate of Analysis (or equivalent) that is 
supplied with the study drug. 


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The tablets containing 100 mg LOXO-305 will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificate of Analysis. It will be provided in 
high-density polyethylene bottles and stored according to the instructions on the label. 
The capsules containing 40 mg of omeprazole will be supplied by the site, along with the lot 
numbers. Omeprazole will be provided in high-density polyethylene bottles and stored 
according to the instructions on the label. 
Study drugs will be stored at the CRU in a location that is locked with restricted access. 
The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drugs will be stored in accordance with the labeling. The 
study drugs will be transferred from bulk supplies into the subject’s dose container by 
qualified CRU employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
In Treatment A, a single oral dose of 200 mg LOXO-305 will be administered in the morning 
on Day 1 or Day 8, following a fast of at least 10 hours prior to and 4 hours after dosing.  
In Treatment B, a single oral dose of 200 mg LOXO-305 will be administered in the morning 
on Day 1 or Day 8, approximately 30 minutes after starting a standard breakfast. Standard 
breakfasts should be entirely consumed within 30 minutes. 
In Treatment C, a single oral dose of 40 mg omeprazole will be administered in the morning 
on Days 15, 16 and 17, following a fast of at least 8 hours prior to omeprazole dosing, 
followed by a standard breakfast administered approximately 1 hour after dosing.  On 
Day 18, a single oral dose of 40 mg omeprazole will be co-administered with a single oral 
dose of 200 mg LOXO-305 in the morning, following a fast of at least 10 hours prior to and 4 
hours after omeprazole and LOXO-305 co-administration. All study drugs will be 
administered orally with approximately 240 mL of water. An additional 100 mL of water 
may be administered if needed. 
Each unit dose will be prepared by qualified CRU staff. Each unit dose container will be 
appropriately labeled. 
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be consistently administered the appropriate 
dose at a specific time, the exact dose time of subjects may be staggered to obviate the need 
to have all subjects on precisely the same study schedule. For each dose, the subject’s actual 
dose time will be recorded in the source documents and transcribed into the eCRF. 
Subjects will be instructed not to crush, split, or chew the study drugs. 
Subjects will not lay supine for 4 hours following LOXO-305 dose administration, except as 
necessitated by the occurrence of an AE(s) and/or study procedure(s). 


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5.3. 
Randomization 
Subjects 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 randomization identification number (in accordance with the requirements in 
Section 4.5 and the randomization scheme generated by Covance) prior to the time of the first 
dose, different from the screening number, and will receive the corresponding product 
according to the randomization scheme generated by Covance.  
Subjects will receive each treatment (A, B, and C) on one occasion. The treatments will be 
administered on Days 1 (Treatment A or B), 8 (Treatment A or B), and Days 15-18 
(Treatment C). The sequences to be used in the randomization will be ABC and BAC.  
5.4. 
Blinding 
This is an open-label study. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
x All doses will be administered under the supervision of suitably qualified CRU staff. 
x Immediately after dose administration, a visual inspection of the mouth and hands 
will be performed for each subject. 
x At each dose preparation occasion, a predose and postdose inventory of LOXO-305 
and omeprazole (as appropriate) will be performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-305 
tablets and omeprazole capsules received. In addition, an accurate drug disposition record 
will be kept, specifying the amount dispensed to each subject and the date of dispensing. This 
drug accountability record will be available for inspection at any time. At the completion of 
the study, the original drug accountability record will be available for review by the Sponsor 
upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused LOXO-305 tablets and omeprazole capsules will 
be disposed of by the CRU, following the Sponsor’s written/emailed instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Paracetamol/acetaminophen (maximum of 2 g/day for up to 3 consecutive days) is an 
acceptable concomitant medication. 


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Subjects will refrain from use of any prescription or nonprescription medications/products 
during the study until the EOT or ET, unless the Investigator (or designee) and/or Sponsor 
have given their prior consent. 
Subjects will refrain from 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). 
All prescription and over-the-counter medications (including HRT, herbal products, natural 
or herbal supplements, except for paracetamol/acetaminophen as referenced above) are 
prohibited for 14 days prior to dose administration (Day 1) and through EOT or ET, unless 
deemed acceptable by the Investigator (or designee) and Sponsor. This includes but is not 
limited to: moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers, strong P-gp 
inhibitors, PPIs [with the exception of omeprazole administered for the purposes of this 
study/in accordance with the Protocol], antacids, H2-receptor antagonists, and drugs that 
prolong QT/QTc interval. 
Any medication taken by a subject during the course of the study, including details of its 
dosage, administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without 
prior approval of the Investigator (or designee) and Sponsor, unless its use is deemed 
necessary in a medical emergency. In this case, the use of the concomitant medication will be 
reported as soon as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
Subjects are required to refrain from use of tobacco, smoking cessation products, and 
nicotine-containing products within 3 months prior to Screening through EOT or ET. 
Consumption of foods or beverages containing grapefruit/grapefruit juice or Seville oranges 
or its juice within 7 days prior to Check-in (Day -1) and through EOT or ET will not be 
allowed unless deemed acceptable by the Investigator (or designee) and Sponsor. 
Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours prior to 
Check-in (Day -1) and through EOT or ET will not be allowed unless deemed acceptable by 
the Investigator (or designee) and Sponsor. 
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and 
during the period of confinement at the CRU and will otherwise maintain their normal level 
of physical activity through EOT or ET (ie, should not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
While confined at the CRU, subjects will receive a standard diet at scheduled times that do 
not conflict with other study-related activities. 
Dietary requirement in relation to dosing are described in Section 3.1 and Section 5.2. 


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7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for PK analysis of LOXO-305 plasma levels will be collected at the 
timepoints specified in Appendix 4. The exact time of the study drug administration and the 
actual time of blood sampling for PK analysis will be recorded on the eCRF. 
Processing, storage, and shipping instructions for these PK blood samples will be provided in 
a separate Laboratory Manual. The number of blood samples and total blood volume required 
for PK testing is presented in Appendix 3. 
7.1.2. 
Analytical Methodology 
Concentrations of LOXO-305 in plasma will be determined using a validated bioanalytical 
method. Specifics of the bioanalytical methods will be provided in a separate document. 
7.2. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee) or 
Sponsor. 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and any other procedures to be performed at the same timepoint. The order of priority for 
scheduling procedures around a timepoint is (in descending order of priority): 
x dosing 
x PK blood sampling 
x vital signs assessments 
x 12-lead ECGs 
x blood and urine samples for clinical laboratories 
x physical examination. 
7.2.1. 
Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes 
in your health status since Screening/since you were last asked?” at the timepoints specified 
in Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in [Day -1], at each 
postdose vital signs assessment, and at an appropriate time for all other days). Subjects will 
also be encouraged to voluntarily report AEs occurring at any other time through the EOS. 


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Adverse events, whether volunteered, identified by the subject’s responses to HDYF? 
inquiries, or noted on physical examination, ECG, vital signs assessments, or laboratory tests, 
will be recorded throughout the study (ie, from signing of the ICF until EOS [or ET if the 
subject discontinues from the study and does not complete a follow-up phone call]), either as 
subject medical history (if the event is reported as beginning prior to signing of the ICF or if 
the event occurs prior to study drug administration on Day 1 and is assessed as not related to 
study procedures by the Investigator [or designee]) or as AEs (if the event occurs after 
signing of the ICF but prior to study drug administration on Day 1 and is assessed as related 
to study procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From 
EOT or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a follow-up phone 
call) are to be reported. 
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up phone call, all subjects must be followed until EOS. Subjects with AEs that are 
assessed as related to study drug by the Investigator (or designee) which are ongoing at EOS 
may continue to be followed until the symptoms or value(s) return to normal, or acceptable 
levels, as judged by the Investigator or designee and confirmed by the Sponsor. The 
Investigator (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. 
Subjects will receive a follow-up phone call 7 days (± 2 days) after EOT or ET to determine 
if any SAE or drug-related AE has occurred since the EOT or ET visit. 
At all times, a subject may be required to remain at the CRU for longer at the discretion of 
the Investigator (or designee). 
Any event that meets the criteria of a suspected unexpected serious adverse reaction 
(SUSAR) will be reported to the Institutional Review Board (IRB) according to 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 in the current IB1 for LOXO-305 for expected adverse reactions. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours], coagulation 
parameters, CK, CBC, TSH [Screening only], HbA1c [Screening only], and UA) will be 
collected at the timepoints specified in Appendix 4. 
Screens for HCV antibody, HBsAg, and HIV antibody will be performed at Screening. A 
urine drug screen for selected drugs of abuse (including cotinine) and an alcohol breath test 
will be performed at Screening and repeated at Check-in (Day -1) for all subjects. A serum 
qualitative pregnancy test (female subjects only [serum quantitative may be used for 
confirmation if needed]) and an FSH test (post-menopausal female subjects only) will be 
performed at the timepoints specified in Appendix 4. 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 3 5 of 5 4 
T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d f or  cli nic al la b orat or y 
e val uati o ns is prese nte d i n A p pe n di x 3 . A list of t he s pecific e val uati o ns is i n A p pe n di x 2 . 
7. 2. 3.  
Vit al Si g ns 
Vital si g ns (i ncl u di n g oral te m perat ure, res pirat or y rate, a n d s u pi ne B P a n d p ulse rate) will be 
o btai ne d at t he ti me p oi nts s pecifie d i n  A p pe n di x 4 . 
Bl o o d press ur e a n d p ulse rate meas ure me nts s h o ul d be perf or me d usi n g t he sa me ar m f or 
eac h rea di n g a n d m eas ur e me nts s h o ul d be ta ke n after t he s u bject  h as bee n r esti n g i n t he 
s u pi ne p ositi o n f or at least 5 mi n utes. 
W he n vital si g ns assess me nts are sc h e d ule d at t he sa me ti me as bl o o d dra ws, t he bl o o d dra ws 
will be o btai ne d at t he sc he d u le d ti me p oi nt, a n d t he vital si g ns will be o btai ne d pri or t o a n d 
as cl ose as p ossi ble t o t he sc he d ule d bl o o d dra w. 
7. 2. 4.  
1 2-le a d Electr oc a r di o gr a m 
A 1 2-lea d E C G (i n cl u di n g P R, R R , Q R S, a n d Q T i nter val para meters) will be o btai ne d aft er 
t he s u bject has bee n resti n g f or at least 1 0 mi n utes i n t he s u pi ne p ositi o n at t he ti me p oi nts 
s pecifie d i n A p pe n di x 4 . T he Q T i nter val will be c orrect e d f or h eart rate b y Fri deri cia’s 
( Q Tc F = Q T/[ R R]1/ 3) f or m ula. 
W he n 1 2-lea d E C Gs are sc he d ule d at t he s a me ti me as bl o o d dra ws , t he bl o o d dra ws will be 
o btai ne d at t he sc he d ul e d ti me p oi nt, a n d t he 1 2-lea d E C Gs will be o btai ne d pri or t o a n d as 
cl ose as p ossi ble t o t he sc he d ule d bl o o d dra w. 
7. 2. 5.  
P h ysic al E x a mi n ati o n 
A c o m plete or a b bre viat e d p h ysical e x a mi nati o n will be perf or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . C o m plete p h ysical e x a mi nati o ns will e val uate ge neral a p p eara nce a n d t he 
f oll o wi n g b o d y s yste ms/ or ga ns: der mat ol o gical; h ea d a n d e yes; ears, n ose, m o ut h, a n d t hr oat; 
p ul m o nar y; c ar di o vas c ular; a b d o mi nal; l y m p hatic; m usc ul os keleta l/e xtre mities; a n d 
ne ur ol o gi cal. W ei g ht a n d hei g ht will be re p orte d ( hei g ht o nl y r e p orte d d uri n g Scree ni n g). 
A b bre viate d p h ysic al e x a mi nati o ns will e val uate ge neral a p peara n ce a n d t h e f oll o wi n g b o d y 
s yste ms/ or ga ns: der mat ol o gic al; p ul m o nar y; car di o v asc ular; a b d omi nal; a n d ne ur ol o gical. 
8.  S A M P L E SI Z E A N D D A T A A N A L Y SI S 
8. 1.  
Deter mi n ati o n of S a m ple Size 
 
T his is a p hase 1 st u d y a n d t he s a m ple siz e is n ot 
base d u p o n a n y f or mal p o wer calc ulati o ns b ut is c o nsiste nt wit h  pre vi o us st u dies of a si milar 
desi g n. 
 
C CI
C CI


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8.2. 
Analysis Populations 
8.2.1. 
Study Populations 
The PK Population will consist of all subjects who have received a dose of LOXO-305, have 
at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times median time to 
maximum concentration. 
The Safety Population will consist of all subjects who have received at least 1 dose of 
LOXO-305. Subjects will be classified into groups based on actual treatment received. 
8.3. 
Pharmacokinetic Analysis 
Serial PK blood samples for the analysis of plasma concentrations of LOXO-305 will be 
collected from predose through 168 hours post-LOXO-305 dose for each treatment. 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-305 (as appropriate): 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal method  
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for 
increasing and decreasing concentrations 
AUC0-inf 
AUC extrapolated to infinity, calculated using the formula: 
 
 
AUC0-inf = AUC0-t + 
z
t
λ
C  
where Ct is the last measurable concentration and λZ is the apparent terminal 
elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC 
Cmax 
 
maximum observed plasma concentration 
tmax 
 
time to maximum observed concentration 
λZ 
apparent terminal elimination rate constant, where OZ is the magnitude of the 
slope of the linear regression of the log concentration versus time profile 
during the terminal phase 
CL/F  
apparent systemic clearance 
t½ 
apparent terminal elimination half-life (whenever possible), where 
t½ = ln(2)/λZ 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 8.1 or higher (Certara USA Inc.). 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed 
in the Statistical Analysis Plan (SAP). 


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Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analysis will be performed using SAS£ Version 9.3 or greater. More details on the analyses 
will be included in the SAP. 
8.3.1. 
Descriptive Analysis 
Plasma concentrations and PK parameters will be summarized with descriptive statistics 
(number, arithmetic mean, standard deviation, coefficient of variation [CV%], geometric 
mean, geometric CV%, median, minimum, and maximum). 
8.3.2. 
Statistical Methodology 
The primary PK analysis planned for this study is a mixed effect model including planned 
treatment sequence, period, and actual treatment as fixed effects and subject within planned 
treatment sequence as a random effect will be used to analyze the natural log (ln)-transformed 
PK parameters (AUC0-24, AUC0-t, AUC0-inf, and Cmax) and will include calculation of least 
squared (LS) means and the difference between treatment LS means, as well as their 
corresponding 90% confidence intervals (CIs). The geometric mean ratios (GMR) and their 
90% CIs of the PK parameter for each treatment comparison will be constructed using the 
exponentiation of the difference and the CIs from the mixed effect model. 
The comparisons of interest are as follows: 
x Treatment A compared with Treatment B 
x Treatment A compared with Treatment C 
8.4. 
Safety Analysis 
All safety assessments, including AEs and SAEs, vital signs measurements, clinical 
laboratory results, physical examination results, concomitant medications, and 12-lead ECGs, 
will be tabulated and summarized, where possible, using descriptive methodology, as needed, 
by timepoint. Unless otherwise specified, baseline value is defined as the last non-missing 
measurement before administration of LOXO-305 in each treatment period. No formal 
statistical analyses are planned for the safety data. All safety data will be listed by subject. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO Drug Global B3, 01 March 2019). The incidence of AEs will be presented 
by severity and by relationship to study drug as determined by the Investigator (Appendix 1 
for AE reporting). All TEAEs will be summarized by SOC and PT, using MedDRA Version 
22.0. 
8.5. 
Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a CRU staff member authorized to make 
the change. Changes will be made by striking a single line through erroneous data and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
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The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the CRU and verified by the Study Monitor. Data 
will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be 
reviewed by the Covance scientific team. The eCRF and ancillary data will be converted into 
final SAS® datasets following Study Data Tabulation Model or client-provided specifications. 
The final datasets structure will be verified using Web Submission Data Manager®, while the 
dataset content will be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will 
be peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by 
the Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.6. 
Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per client request, and as applicable, according to the contract 
between Covance and the Sponsor. 
9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator (or designee). 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator (or designee), and the IRB (see Form 
FDA 1572). 
9.2. 
Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator (or designee) and appropriate CRU staff to familiarize the Investigator (or 
designee) and CRU staff with the materials necessary for conducting the clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, oral 
presentations, abstracts) by the Investigator (or designee) or their representative(s), shall 
require prior notification and review, within a reasonable timeframe, by the Sponsor, and 


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cannot be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of 
the Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate a Study Monitor who will be responsible for monitoring this 
clinical trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and 
source documentation completion and retention, and accurate study drug accountability. To 
this end, the Sponsor’s Study Monitor will visit the CRU at suitable intervals and be in 
frequent contact through verbal and written communication. It is essential that the Sponsor’s 
Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Sponsor’s Study Monitor will adhere 
to all requirements for subject confidentiality as outlined in the ICF. The Investigator (or 
designee) and Investigator’s staff will be expected to cooperate with the Sponsor’s Study 
Monitor, to be available during a portion of the monitoring visit to answer questions, and to 
provide any missing information. 
9.5. 
Institutional Review Board 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
advertisement, ICF, and other information provided to subjects will be reviewed and 
approved by the IRB. The Sponsor will supply relevant material for the Investigator (or 
designee) to submit to the IRB for the protocol’s review and approval. Verification of the 
IRB unconditional approval of the protocol and the written ICF statement will be transmitted 
to the Investigator (or designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will be 
transmitted in writing to the Investigator (or designee). If requested, the Investigator (or 
designee) will permit audits by the IRB and regulatory inspections by providing direct access 
to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s (or designee’s) participation in the study. 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can 
withdraw from the study at any time. In accordance with 21 CFR 50, the informed consent 
process shall be documented by the use of a written ICF approved by the IRB and signed by 
the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 


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9.7. 
Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each eCRF 
will be retained by the Investigator (or designee). All source documents, records, and reports 
will be retained by the CRU in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the CRU archives. 
9.8. 
Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the US 
CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), Applications for FDA Approval to Market a New Drug (21 CFR 314), and 
Radioactive Drugs for Certain Research Uses (21 CFR 361.1), as appropriate. As such, these 
sections of US Title 21 CFR, along with the applicable International Council for 
Harmonisation (ICH) Guidelines, are commonly known as Good Clinical Practices (GCP), 
which are consistent with the Declaration of Helsinki.  
9.9. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
10. REFERENCES 
1.  Loxo Oncology, Inc. LOXO-305 – Investigator’s Brochure (Version 2). 18 November 
2019.  
2.  Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022–35.  
3.  Woyach JA, Furman RR, Liu T-M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance 
mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 
12;370(24):2286–94.  
4.  Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol. 2017 May 1;35(13):1437–43.  
5.  Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017 
04;129(18):2519–25.  


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6.  Food and Drug Administration. Guidance for Industry, Draft Guidance: Assessing the 
Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations 
[Internet]. Food and Drug Administration; 2019. Available from: 
https://www.fda.gov/media/121313/download 
7.  Sandoz Inc. OMEPRAZOLE - omeprazole capsule, delayed release (HIGHLIGHTS OF 
PRESCRIBING INFORMATION). 2018.  


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11. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy adult subject, whether or not considered drug-related by 
the Investigator (or designee). A treatment-emergent adverse event (TEAE) is an AE that is 
reported after a dose of study drug. 
The following are all AEs: 
x 
unfavorable changes in general condition; 
x 
subjective or objective signs/symptoms; 
x 
concomitant diseases or accidents; 
x 
clinically relevant adverse changes in laboratory parameters observed in a subject 
during a clinical study. 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant 
by the Investigator or designee), and accidents observed in the context of a clinical trial, 
irrespective of a possible causal relationship with the administration of the trial substance. 
Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
x 
Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
x 
Grade 2 Moderate: Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)* 
x 
Grade 3 Severe or medically significant but not immediately life-threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL** 
x 
Grade 4 Life-threatening consequences: An event that puts the subject at 
immediate risk of death 
x 
Grade 5 Death related to AE. 
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. 
* 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. 


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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
x 
NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship 
and another cause (eg, concomitant drugs, therapies, complications, comorbidities) 
is suspected 
x 
RELATED = The time course between administration of investigational product 
and the occurrence or worsening of the AE is consistent with a causal relationship 
and no other cause (eg, concomitant drugs, therapies, complications, comorbidities) 
can be identified. 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through EOS or ET (if the subject discontinues from the study and does 
not complete a follow-up phone call) and for up to 90 days after study drug administration 
should be reported by the Investigator (or designee) via email to Covance or the Sponsor’s 
Clinical Safety Representative within 24 hours of being notified. Covance or the Sponsor’s 
Clinical Safety Representative will then forward the Pregnancy Form to the Investigator for 
completion. 
email: SAEIntake@Covance.com 
A subject becoming pregnant while on study drug will immediately be withdrawn from the 
study and ET study procedures will be performed. The subject or partner should be followed 
by the Investigator until completion of the pregnancy. If the pregnancy ends for any reason 
before the anticipated date, the Investigator should notify Covance or the Sponsor’s Clinical 
Safety Representative. At the completion of the pregnancy, the Investigator will document 
the outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for 
immediate classification as a serious adverse event (SAE; ie, postpartum complication, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator 
should follow the procedures for reporting an SAE. 
Male subjects will be instructed to notify the Investigator immediately if they discover their 
sexual partner is pregnant. In this instance, the partner must provide written consent before 
pregnancy information can be collected. When a CRU becomes aware that the female partner 
of a male subject is pregnant, they are to contact the Investigator immediately (within 
24 hours of the CRU staff becoming aware of the event) in addition to notifying Covance or 
the Sponsor’s Clinical Safety Representative via email. 
All pregnancies should be recorded on the AE electronic eCRF (as appropriate), in addition 
to completion of the required pregnancy forms. If the Investigator suspects that a pregnancy 
was the result of an interaction between the study treatment and the contraceptive method, in 
addition to the pregnancy the drug interaction should also be captured as a separate AE. 


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Definition of Serious Adverse Events 
An SAE (by Food and Drug Administration [FDA] definition) is any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
x 
Death; 
x 
A life-threatening adverse drug experience (ie, one that places the subject, in the 
view of the Investigator [or designee], at immediate risk of death); 
x 
Inpatient hospitalization or prolongation of existing hospitalization; 
x 
A persistent or significant disability/incapacity; 
x 
A congenital anomaly/birth defect; 
x 
An important medical event that may require medical or surgical intervention to 
prevent one of the above outcomes. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on 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 this definition. 
Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed 
in the Reference Safety Information section of the Investigator’s Brochure (IB) or if it is not 
listed at the specificity or severity that has been observed for an unapproved investigational 
medicinal product (IMP). 
Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of the 
drug and represent events that are assessed as serious, related, and unexpected. Food and 
Drug Administration-reportable AEs will be reported by the CRU to the Sponsor and the 
responsible Institutional Review Board (IRB). Final determination of whether an event 
represents a suspected unexpected serious adverse reaction (SUSAR) will be the 
responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or 
reported, and within 24 hours of any SAE (regardless of whether the event is assessed as 
related or unrelated to study drug) being first recognized or reported, Covance or the 
Sponsor’s Clinical Safety Representative will be notified by the Investigator or designee in 
writing using the following email address: 
email: SAEIntake@Covance.com 
To report the SAE, the completed report form should be sent by email to Covance or the 
Sponsor’s Clinical Safety Representative within 24 hours of awareness. Incoming reports are 
reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 


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Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020  
Page 46 of 54 
The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020  
Page 47 of 54 
Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel 
(Fasted): 
Complete Blood Count (CBC): 
Other Tests: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase 
(AST) 
Bilirubin (direct and total) 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase (CK) 
Creatinine 
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (percent and 
absolute): 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Hemoglobin A1c (HbA1c)b 
Thyroid-stimulating hormone 
(TSH)b 
Coagulation Parameters: 
Activated partial thrombin time 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Human immunodeficiency virus 
(HIV) antibody 
Hepatitis B surface antigen 
(HBsAg) 
Hepatitis C virus (HCV) 
antibody 
For Female Subjects only: 
Pregnancy test (serum 
qualitative, serum quantitative 
may be used for confirmation if 
needed)c 
Follicle-stimulating hormone 
(post-menopausal female 
subjects only)b 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity  
Protein 
Urobilinogen 
Microscopic examination 
including bacteria, casts, 
crystals, epithelial cells, RBCs, 
and WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Estimated creatinine clearancea 
Urine Drug Screen:a 
Including but not limited to the 
following: 
Alcohol (ethanol) (breath test) 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine (metabolite)  
Methadone 
Opiates 
Phencyclidine 
Cotinine 
a. Performed at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Performed at Screening, Check-in (Day -1), and End of Treatment (EOT)/Early Termination (ET) only. 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0  
Pa ge 4 8 of 5 4 
A p pe n di x 3: T ot al Bl o o d V ol u me 
T he f oll o wi n g bl o o d v ol u mes will be wit h dra w n f or eac h s u bj ect partici p ati n g i n t his st u d y: 
If e xtra bl o o d sa m ples are re q uir e d, t he ma xi m u m bl o o d v ol u me to be wit h dra w n per s u bject 
will n ot e x cee d 4 0 0 m L.  
Assess me nt 
A p pr o xi m ate Bl o o d 
V ol u me per S a m ple 
( m L) 
M a xi m u m 
N u m ber of Bl o o d 
S a m ples 
A p pr o xi m ate 
T ot al V ol u me 
( m L) 
Ser ol o g y 
He m o gl o bi n A 1c ( H b A 1c) 
Pri mar y p har mac o ki netic ( P K) sa m pli n g 
Cli nical la b orat or y tests: 
    C o m plete bl o o d c o u nt ( C B C) 
    Cli nical c he mistr y pa nel 
    C oa g ulati o n para meters 
Ser u m pre g na nc y test (fe male s u bjects 
o nl y) 
Ser u m f ollicle-sti m ulati n g h or m o ne ( F S H; 
p ost- me n o pa usal fe male s u bj ects o nl y) 
T h yr oi d-sti m ulati n g h or m o ne ( T S H) 
C CI


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 49 of 54 
Appendix 4: Schedule of Assessments


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 5 0 of 5 4 
  
St u d y Pr oce d ures a 
Scree ni n g 
( D a ys - 2 9 
t o - 2) 
C hec k-i n 
( D a y - 1) 
 
 
 
St u d y D a ys 
Cli nic 
Disc h ar ge/ 
E O T 
( D a y 2 5) 
or E T v 
F oll o w
-u p 
P h o ne 
C all 
( E O S) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7  1 8  1 9  2 0  2 1  
 
 
2 2 
 
 
2 3 
 
 
2 4 
 
7 ( ± 2) 
d a ys 
p ost 
E O T 
or E T w  
C o nfi ne d t o t he C R U 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
I ncl usi o n/ E xcl usi o n 
Criteria 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d C o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y 
X 
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht/ Wei g ht/ B MI 
X 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical 
E xa mi nati o n d 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
1 2-lea d E C G e 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Vital Si g ns f 
X g 
X g 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X g 
 
H D Y F? I n q uir y h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A Es/ S A Es i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
L O X O- 3 0 5 D osi n g 
 
 
X j 
 
 
 
 
 
 
X k 
 
 
 
 
 
 
 
 
 
X m  
 
 
 
 
 
 
 
 
O me praz ole D osi n g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X l X l X l X m  
 
 
 
 
 
 
 
 
Cli nical La b orat or y 
E val uati o ns p 
X  
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
He patitis a n d HI V 
Scree n 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H b A 1c T est q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr u g Scree n r 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 51 of 54 
Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Days 
Clinic 
Discharge/ 
EOT 
(Day 25) 
or ETv 
Follow
-up 
Phone 
Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 
7 (±2) 
days 
post 
EOT 
or ETw 
Prior and 
Concomitant 
Medicationss 
X 
X 
X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
Serum Pregnancy 
Testt 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
FSH Testu 
X 
TSH Test 
X 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; CBC = complete blood count; CK = creatine kinase; CRU = Clinical Research Unit; 
ECG = electrocardiogram; EOS = End of Study; EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HDYF? = How Do You 
Feel?; HIV = human immunodeficiency virus; ICF = Informed Consent Form; PK = pharmacokinetic; SAE = serious adverse event; TSH = thyroid-stimulating hormone; UA = urinalysis. 
a. For details on study procedures, see Section 7.
b. Interim medical history only.
c. Weight and BMI (based on Screening height) only.
d. A complete physical examination will be performed at Screening. An abbreviated physical examination will be performed at Check-in (Day -1) and at EOT (Day 25).
e. 12-lead ECGs will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the scheduled blood draws at
Screening and Day -1, Day 1 (predose and 2 hours after LOXO-305 dosing), Day 4 (ie, 72 hours after LOXO-305 dosing on Day 1), Day 8 (predose), Day 11 (ie, 72 hours after LOXO-305
dosing on Day 8), Day 15 (predose), Day 18 (predose), Day 21 (ie, 72 hours after LOXO-305 dosing on Day 18), and at EOT/Day 25 (168 hours after LOXO-305 dosing on Day 18) or ET.
f. Vital signs measurements (supine BP and pulse rate) will be obtained at Screening and Day -1, Day 1 (predose and 2, 4, 8, and 12 hours after LOXO-305 dosing), Day 2 (ie 24 hours after
LOXO-305 dosing on Day 1),  Day 4 (ie, 72 hours after LOXO-305 dosing on Day 1), Day 8 (predose and 2, 4, 8, and 12 hours after LOXO-305 dosing [on Day 8]), Day 9 (ie 24 hours after
LOXO-305 dosing on Day 8), Day 11 (ie, 72 hours after LOXO-305 dosing on Day 8), Day 15 (predose), Day 18 (predose and 2 hours after LOXO-305 dosing on Day 18), Day 21 (ie, 72
hours after LOXO-305 dosing on Day 18), and at EOT/Day 25 (168 hours after LOXO-305 dosing on Day 18) or ET. Vital signs measurements should be carried out prior to and as close as
possible to having blood drawn. Blood pressure and pulse rate will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes.
g. Oral temperature and respiratory rate will also be obtained at at Screening, Day -1, and at EOT/Day 25 (168 hours after LOXO-305 dosing on Day 18) or ET.
h. An HDYF? inquiry will be performed at Screening (after the ICF is signed), at Check-in (Day -1), at each postdose vital signs assessment, and at an appropriate time for all other days.
i. Adverse events and SAEs will be collected beginning at informed consent. Adverse events will be recorded throughout the study (ie, from signing of the ICF until EOS, or until ET if the
subject discontinues from the study and does not complete a follow-up phone call), either as subject medical history (if the event is reported as beginning prior to signing of the ICF or if the
event occurs prior to study drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 5 2 of 5 4 
I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d b y t h e I n vesti gat or [ or desi g nee]) as relate d t o st u d y pr oce d ures, or if t h e e ve nt occ urs after st u d y dr u g a d mi nistrati o n  o n 
Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o  st u d y dr u g are t o be rec or de d. All S A Es t h at de vel o p fr o m 
t h e ti me of I C F si g ni n g u ntil E O S ( or E T if t h e s u bject disc o nti n ues fr o m t h e st u d y a n d d oes n ot c o m plete a f oll o w- u p p h o ne call) are t o be re p orte d. 
j. O n Da y 1, L O X O- 3 0 5 will be a d mi nistere d i n t h e m or ni n g, eit her f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after t he L O X O- 3 0 5 d ose or a p pr o xi matel y 3 0 mi n utes after t he 
start of a sta n dar d brea kfast, acc or di n g t o t h e treat me nt se q uence t he s u bject is ra n d o ml y assi g ne d t o. Sta n dar d brea kfast s h o ul d be e ntirel y c o ns u me d wit hi n 3 0 mi n utes. 
k.  O n Da y 8, L O X O- 3 0 5 will be a d mi nistere d i n t h e m or ni n g, eit her f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after t he L O X O- 3 0 5 d ose or a p pr o xi matel y 3 0 mi n utes after t he 
start of a sta n dar d brea kfast, acc or di n g t o t h e treat me nt se q uence t he s u bject is ra n d o ml y assi g ne d t o. Sta n dar d brea kfast s h o ul d be e ntirel y c o ns u me d wit hi n 3 0 mi n utes. 
l. O n Da ys 1 5, 1 6, a n d 1 7 o me praz ole will be a d mi nistere d i n t h e m or ni n g f oll o wi n g a fast of at least 8 h o urs pri or t o t he o me pra z ole d ose, f oll o we d b y a sta n dar d brea kfast a d mi nistere d 
a p pr o xi matel y 1 h o ur after d osi n g.  Sta n dar d brea kfast s h o ul d b e e ntirel y c o ns u me d wit hi n 3 0 mi n utes. 
m.  O n Da y 1 8, L O X O- 3 0 5 a n d o me praz ole will be c o-a d mi nistere d i n t he m or ni n g, f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after t he o me praz ole a n d L O X O- 3 0 5 c o-
a d mi nistrati o n. 
p.  Cli nical c he mistr y pa nel i n cl u di n g C K (faste d at least 8 h o urs) , c oa g ulati o n para meters, C B C, a n d U A will be perf or me d at Scree ni n g, C hec k-i n ( Da y - 1), Da ys 4, 7, 1 1, 1 7, 2 1, a n d at E O T 
( Da y 2 5) or E T. 
q.  He m o gl o bi n A 1c test perf or me d at Scree ni n g o nl y. 
r. Alc o h ol breat h test a n d dr u gs of a b use uri ne test, i ncl u di n g c o ti ni ne. Res ults fr o m t h e alc o h ol a n d dr u g tests will be use d t o deter mi n e s u bject eli gi bilit y per t h e i n cl usi o n/e xcl usi o n criteria. 
s. Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de d be gi n ni n g at i nf or me d c o nse nt. I n a d diti o n, all I n vesti gat or- a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 3 0 da ys pri or t o  
st u d y dr u g a d mi nistrati o n f or prescri pti o n me dicati o ns, a n d 1 4 da ys pri or t o st u d y dr u g a d mi nistrati o n f or n o n- prescri pti o n me dicati o ns, will be rec or de d o n t h e s u bject’s electr o nic Case 
Re p ort F or m. 
t. Fe male s u bjects o nl y. 
u.  P ost- me n o pa usal fe male s u bjects o nl y. 
v.  E O T is d efi n e d as w he n t h e s u bject is release d fr o m t h e C R U f ol l o wi n g c o m pleti o n of all assess me nts t hr o u g h Da y 2 5. E T is d efin e d as w he n t h e s u bject is release d fr o m t h e C R U if t h e 
s u bject ter mi n ates t h e st u d y earl y. Vital si g ns, E C G, a n d safety la b orat or y res ults f or cli nical c he mistr y, he mat ol o g y, c oa g ul ati o n, a n d U A ar e t o be a vaila ble f or re vie w b y t h e I n vesti gat o r or 
desi g nee pri or t o s u bject release fr o m t h e C R U at t h e E O T or E T  visit. 
w.  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 O S is d efi n e d as w he n t he C R U c o ntacts t h e s u bject b y a f oll o w- u p p h o n e call 7 da ys ( ± 2 da ys) afte r t he E O T visit or E T visit t o 
deter mi n e if a n y S A E or st u d y dr u g-relate d A E has o cc urre d si nc e t h e E O T or E T visit. All s u bjects w h o recei ve d L O X O- 3 0 5 (i n cl u di n g s u bjects w h o are ter mi n ate d earl y) will be c o ntacte d. 
C CI


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 2 2 3 2 9 
Pr ot oc ol Refere n ce: L O X O- B T K- 2 0 0 1 4 
Pr ot oc ol Versi o n 2. 0, 2 9 J a n uar y 2 0 2 0 
Pa ge 5 3 of 5 4 
A p pe n di x 5: Pr ot oc ol A me n d m e nt S u m m a r y of C h a n ges 
Pr ot oc ol Versi o n 2. 0 ( dat e d 2 9 t h J a n uar y 2 0 2 0) i nc or p orate d t he f oll o wi n g c ha n ges i n 
Pr ot oc ol Versi o n 1. 0 ( dat e d 1 4 t h J a n uar y 2 0 2 0): 
 T he st u d y d urati o n has b ee n e xte n de d t o i ncl u de a n a d diti o nal t reat me nt 
( Treat me nt C) t o ass ess t he effect of a gastric p H c ha n ge o n t h e p h ar mac o ki netics 
( P K) of L O X O- 3 0 5 after m ulti ple- d oses of a pr ot o n p u m p i n hi bit or ( P PI; 
o me praz ole). T he f oll o wi n g c h a n ges w ere m a de: 
o  T he d urati o n of c o nfi ne me nt i n t he C li nical Researc h U nit has bee n 
e xte n de d fr o m 1 6 da ys ( Da y - 1 t o Da y 1 5) t o 2 6 da ys ( Da y - 1 t o Da y 2 5).  
o  Cli nic Disc har ge/ E n d of Treat me nt  ( E O T) ass ess me nts t hat were 
c o n d ucte d o n Da y 1 5 will n o w be c o n d ucte d o n D a y 2 5. 
o  Earl y Ter mi nati o n ( E T) assess me nts t hat were c o n d ucte d as per t he 
assess me nts o n Da y 1 5 will n o w be  c o n d ucte d as p er t he assess m ents o n 
Da y 2 5. 
o  All s u bjects will be a d mi nistere d a d ose of 4 0 m g o me praz ole o n ce d ail y 
fr o m Da y 1 5 t hr o u g h D a y 1 8, wit h a si n gle oral d ose of 2 0 0 m g LO X O-
3 0 5 c o-a d mi nistere d wit h o me praz ole o n Da y 1 8 ( Treat me nt C).  
o  T he treat me nt se q u e nces A B a n d B A t o be us e d i n t he ra n d o mizati o n ha ve 
bee n u p date d t o A B C a n d B A C.  
o  O n Da y 1 5 t o Da y 1 7, si n gle oral d oses of 4 0 m g o me praz ole will  be 
a d mi nistere d f oll o wi n g a fast of at least 8 h o urs pri or t o d osi n g, f oll o we d 
b y a sta n dar d brea kfast a d mi nistere d a p pr o xi matel y 1 h o ur after  d osi n g. 
O n Da y 1 8, a si n gle oral d ose of 4 0 m g o m e praz ole will be c o-
a d mi nistere d wit h a si n gl e oral d ose of 2 0 0 m g L O X O- 3 0 5 i n t he m or ni n g, 
f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g 
o me praz ole a n d L O X O- 3 0 5 c o-a d mi nistrati o n. 
o  T here will be a was h o ut peri o d of 7 da ys b et wee n d osi n g of L O X O - 3 0 5 o n 
Da y 8 a n d t he first d ose of o me praz ole o n Da y 1 5.  
o  A d diti o nal safet y m o nit ori n g ass ess me nts will be c o n d ucte d as f oll o ws: 
- 
C o nc o mita nt me dicati o n, a d verse e ve nt, a n d s eri o us a d verse e ve n t 
m o nit ori n g, a n d H o w d o y o u feel ? I n q uir y will be c o n d ucte d o n 
Da y 1 5 t hr o u g h Da y 2 5.  
- 
Vital si g ns ( bl o o d press ure a n d p ul se rate) a n d ele ctr ocar di o gra m 
assess me nts will be c o n d ucte d at Da y 1 5 ( pre d os e), Da y 1 8 
( pre d ose a n d 2 h o urs after L O X O- 3 0 5 d osi n g o n Da y 1 8), a n d 
Da y 2 1 (ie, 7 2 h o urs after L O X O- 3 0 5 d osi n g o n Da y 1 8). 
- 
Cli nical la b orat or y e val u ati o ns will be c o n d ucte d o n Da y 1 7 a n d  
Da y 2 1. 
C CI


Protocol 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Protocol Version 2.0, 29 January 2020 
Page 54 of 54 
o Rationale for the amended study design and selection of omeprazole dose 
has been included.  
LOXO-305 is formulated with excipients that cause release of LOXO-305 from the 
formulation to be somewhat slower under acidic conditions than neutral conditions, and the 
clinical impact of this slower dissolution is unknown. The additional treatment will allow the 
Sponsor to assess the effect of reduced stomach acidity on the PK of LOXO-305 by raising 
the gastric pH with omeprazole, a PPI. 
Additionally, the following clarifications and updates were made:  
x Previously, the Schedule of Assessments incorrectly stated that oral body temperature 
and respiratory rate assessments would be conducted on Day 1, Day 4, Day 8, and 
Day 11; the Schedule of Assessments has been updated to reflect that oral body 
temperature and respiratory rate assessments will be conducted at Screening, Day -1, 
and EOT/Day 25 or ET only.  
x Exclusion criterion #8 has been updated to remove the requirement for polymerase 
chain reaction confirmation to detect presence of an active virus before enrolment for 
subjects who are positive for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV), or human immunodeficiency virus (HIV) by antibody. Therefore, any subject 
who is positive for HBsAg, HCV, or HIV by antibody will be excluded.  
x The PK parameter, area under the concentration-time curve from hour 0 to 24 hours 
(AUC0-24), will be analysed as part of the mixed effects model.  
x The inclusion of the PK parameter, apparent first order terminal elimination rate 
constant (Kel), is redundant as apparent terminal elimination rate constant (λZ) will be 
calculated.  
x The statistical comparisons of interest are now: 
o Treatment A compared with Treatment B 
o Treatment A compared with Treatment C. 
x In exclusion criterion #16 and concomitant medications and other restrictions, it has 
been clarified that while concomitant medication of PPIs is prohibited, this is with the 
exception of omeprazole administered for the purposes of this study and in 
accordance with the Protocol.  
Minor updates:  
x The synopsis and study title was updated accordingly to the changes in the protocol 
body, as applicable. 
x The amendment/version number and date were updated throughout the protocol. 
x Typographical errors and formatting errors were corrected, and minor clarifications 
were made, as necessary. 
 
 

SAP_001.pdf: 
 
LOXO-BTK-20014 StaƟsƟcal Analysis Plan Version 2.0 
 
 
A Phase 1, Open Label, Randomized, 2-Way Crossover, 3-Period Study to Evaluate the Eﬀect of Food 
and a Proton Pump Inhibitor on the PharmacokineƟcs of LOXO-305 in Healthy Adult Subjects 
 
 
NCT05134350 
 
 
Approval Date: 21-May-2020  


TI T L E P A G E  
St atistic al A n al ysis Pl a n  
A P h ase 1, O pe n -l a bel, R a n d o mize d, 2-W a y Cr oss o ver, 3 -Peri o d St u d y t o 
E v al u ate t he Effect of F o o d a n d a Pr ot o n P u m p I n hi bit or o n t he 
P h ar m ac o ki netics of L O X O -3 0 5 i n He alt h y A d ult S u bjects  
S A P Stat us: S p o ns or   
S A P Versi o n: 2  
S A P Date: 2 1 M A Y 2 0 2 0  
I n v esti gati o nal Pr o d uct: L O X O -3 0 5  
Pr ot oc ol Refere n ce : L O X O -B T K -2 0 0 1 4  
C o va nce St u d y : 8 4 2 2 3 2 9  
 
 
S p o ns or:  
L o x o O nc ol o g y, I nc.  
A w h oll y o w n e d s u bsi diar y of Eli Lill y a n d 
C o m pa n y  
7 0 1 Gate wa y B o ule v ar d, S uite 4 2 0  
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0  
U S A  
St u d y Site:  
C o va nce Cli nical Researc h U nit I nc.  
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0  
Da yt o n a Beac h, F L 3 2 1 1 7  
U S A  
 
 
 
Pri nci pal I n v esti gat or:  
 
 
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d m a y b e discl ose d o nl y wit h t he e x press 
writte n per mi ssi o n of t he sp o ns or.  
 
P P D


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 2 of 20 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
4. STUDY DESIGN................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 8 
6. STUDY TREATMENTS ....................................................................................................... 8 
7. DEFINITIONS OF POPULATIONS .................................................................................... 9 
7.1. All Subjects Population ................................................................................................... 9 
7.2. Safety Population ............................................................................................................ 9 
7.3. Pharmacokinetic Population ........................................................................................... 9 
8. STATISTICAL METHODOLOGY .................................................................................... 10 
8.1. General .......................................................................................................................... 10 
8.1.1. Calculation of the Summary Statistics ................................................................... 10 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 11 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 11 
8.2. Subject Disposition and Population Assignment .......................................................... 11 
8.3. Screening Demographics and Baseline Characteristics ................................................ 11 
8.4. Prior and Concomitant Medication ............................................................................... 12 
8.5. Pharmacokinetic Assessments ...................................................................................... 12 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 12 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 14 
8.5.3. Presentation Pharmacokinetic Parameters.............................................................. 15 
8.5.4. Pharmacokinetic Statistical Methodology .............................................................. 15 
8.6. Safety and Tolerability Assessments ............................................................................ 16 
8.6.1. Adverse Events ....................................................................................................... 16 
8.6.2. Clinical Laboratory Parameters .............................................................................. 18 
8.6.3. Vital Signs Parameters ........................................................................................... 18 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 18 
8.6.5. Other Assessments ................................................................................................. 19 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 3 of 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 19 
9. INTERIM ANALYSES ....................................................................................................... 19 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 19 
11. REFERENCES .................................................................................................................. 19 
12. APPENDICES ................................................................................................................... 20 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 4 of 20 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]). 
ADaM 
analysis data model 
AE 
adverse event 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours 
postdose 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration 
AUC0-inf 
AUC extrapolated to infinity 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
extrapolated to infinity 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit  
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination  
GLSM 
geometric least squares mean 
ICF 
informed consent form  
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
Z 
apparent terminal elimination rate constant 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 5 of 20 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
t1/2 
apparent terminal elimination half-life  
tmax 
time to maximum observed concentration 
WHODrug 
World Health Organization Drug Dictionary  
 
 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 6 of 20 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 2.0 
dated 29 January 2020) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
The primary objectives of the study are: 
● to assess the effect of food on the PK of LOXO-305 administered under fasted 
conditions and after a standard meal in healthy adult subjects 
● to assess the effect of a gastric pH change on the PK of LOXO-305 after multiple-doses 
of a proton pump inhibitor (PPI) (omeprazole) in healthy adult subjects. 
The secondary objective of the study is: 
● to determine the safety and tolerability of a single dose of LOXO-305 administered 
with and without food and in the presence of a PPI (omeprazole) in healthy adult 
subjects. 
3. STUDY ENDPOINTS  
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): 
● area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal method (AUC0-24) 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 7 of 20 
● area under the concentration-time curve from Hour 0 to the last measurable 
concentration (AUC0-t) 
● area under the concentration-time curve extrapolated to infinity (AUC0-inf) 
● extrapolation for area under the concentration-time curve (%AUCextrap) 
● maximum observed plasma concentration (Cmax) 
● time to maximum observed concentration (tmax) 
● apparent terminal elimination rate constant (λZ) 
● apparent systemic clearance (CL/F) 
● apparent terminal elimination half-life (t1/2). 
Safety and tolerability will be assessed by monitoring adverse events (AEs), performing 
physical examinations and clinical laboratory tests, measuring vital signs, and 12-lead 
electrocardiograms (ECGs).  
4. STUDY DESIGN  
This is a Phase 1, open-label, randomized, 2-way crossover, 3-period study. A single oral 
dose of LOXO-305 will be administered under fasted conditions (Treatment A) and fed 
conditions (Treatment B). Multiple oral doses of omeprazole will be administered once daily 
from Day 15 through Day 18, with a single oral dose of LOXO-305 co-administered with 
omeprazole under fasted conditions on Day 18 (Treatment C). PK sampling will be obtained 
for 168 hours after administration of each dose of LOXO-305 (ie, on Days 1, 8, and 18). The 
2 treatment sequences will be ABC and BAC. Subjects will be randomly assigned to 1 of the 
2 treatment sequences, according to a randomization scheme issued by Covance. 
In Treatment A, a single oral dose of 200 mg LOXO-305 will be administered in the morning 
on Day 1 or Day 8 (according to the randomization scheme), following a fast of at least 
10 hours prior to and 4 hours after dosing. In Treatment B, a single oral dose of 200 mg 
LOXO-305 will be administered in the morning on Day 1 or Day 8 (according to the 
randomization scheme), approximately 30 minutes after starting a standard breakfast. In 
Treatment C, a single oral dose of 40 mg omeprazole will be administered in the morning on 
Days 15, 16 and 17, following a fast of at least 8 hours prior to omeprazole dosing, followed 
by a standard breakfast administered approximately 1 hour after dosing.  On Day 18, a single 
oral dose of 40 mg omeprazole will be co-administered with a single oral dose of 200 mg 
LOXO-305 in the morning, following a fast of at least 10 hours prior to and 4 hours after 
omeprazole and LOXO-305 co-administration. Standard breakfasts should be entirely 
consumed within 30 minutes. Serial PK blood samples for the analysis of plasma 
concentrations of LOXO-305 will be collected from predose through 168 hours postdose for 
each treatment.  
There will be a washout period of 7 days between the doses of LOXO-305 administered in 
Treatments A and B, and a washout period of 7 days between the doses of LOXO-305 
administered in Treatments A or B and the first dose of omeprazole in Treatment C.  


S A P  
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 2 2 3 2 9  
Pr ot oc ol Refere n ce: L O X O -B T K -2 0 0 1 4  
S p o ns or  Fi nal, Versi o n 2 , 2 1 M A Y 2 0 2 0  
Pa ge 8  of 2 0  
T o assess t heir eli gi bilit y t o e nter t he st u d y, p ote ntial s u bjects will be scree ne d wit hi n 2 8  da ys 
( Da ys -2 9 t o  -2) a n d be a d mitte d t o t he Cli nical Researc h U nit ( C R U) o n Da y  -1 ( C hec k -i n). 
Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d necess ar y b y t he S p o ns or.  
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k -i n ( Da y -1) u ntil E n d of 
Treat me nt ( E O T) o n Da y 2 5 u p o n c o m pleti o n of all P K a n d safet y assess m e nts or Earl y 
Ter mi nati o n ( E T) if t he s u bject disc o nti n ues. A f oll o w -u p p h o ne call will occ ur f or all 
s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g (i ncl u di n g s u bjects w h o ar e ter mi nate d 
earl y) 7 d a ys ( ±  2  da ys) after E O T or E T.  
T he start of t he st u d y is d efi ne d as t he d ate t he first s u bject w h o is e nr olle d i n t he st u d y si g ns 
a n I nf or me d C o ns e nt F or m (I C F). N ote t h at e nr oll e d s u bjects are defi n e d as t h ose s u bjects 
w h o are assi g n e d a d ose of st u d y dr u g; t his defi niti o n e xcl u des scree n fail ure s u bjects.  
I n t his st u d y, p h ysi cal e x a mi nati o ns, 1 2-lea d E C Gs, vital si g ns, H o w D o Y o u Feel? i n q uiries, 
cli nical c he mistr y pa nel, c oa g ulati o n para meters, creati ne ki n ase, c o m plete bl o o d c o u n t, 
uri nal ysis a n d rec or di n g of c o nc o mita nt me dicati o ns will be perf or me d at s pecifie d ti mes 
d uri n g t he st u d y. T he A Es a n d seri o us a d verse e v e nts ( S A Es) will be c ollecte d be gi n ni n g at 
i nf or me d c o nse nt. T h e A Es will be re p orte d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F 
u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d o es n ot 
c o m plete a f oll o w -u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as 
be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n 
o n Da y  1 a n d is assess e d as n ot relate d t o st u d y pr oce d ures b y t h e I n vesti gat or [ or desi g nee]) 
or as A Es (if t he e ve nt oc c urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n 
o n Da y  1 a n d is  assess e d as relate d t o st u d y pr oce d ures b y t he I n v esti gat or [ or desi g n ee], or if 
t he e ve nt oc c urs aft er st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of 
relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es ass esse d as relat ed t o 
st u d y dr u g b y t he I n vesti gat or ( or desi g n ee) are t o be re p ort e d. All S A Es t hat de vel o p fr o m 
t he ti me of I C F si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes 
n ot c o m plete a f oll o w -u p p h o ne call) are t o be re p orte d. St u d y c o m pleti o n is defi ne d as t he 
ti me of t he last s u bject’s f oll o w-u p p h o ne call.   
5.  S A M P L E SI Z E J U S TI FI C A TI O N   
 
 T his is a p hase 1 st u d y a n d t he s a m ple siz e is n ot 
base d u p o n a n y f or mal p o wer calc ulati o ns b ut is c o nsiste nt wit h pre vi o us st u dies of a si milar 
desi g n.  
E ver y atte m pt will be ma de t o e nr oll at least 2 s u bjects of eac h se x i n t he st u d y.  
6.  S T U D Y T R E A T M E N T S   
T he st u d y tr eat me nt na m es, a b bre vi ati o ns, a n d or deri n g t o b e use d i n t he T F Ls are pres e nte d 
i n Ta ble 1 .  
C CI


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 9 of 20 
Table 1: 
Presentation of Study Treatments in TFLs  
Study Treatment 
Abbreviation 
Order in 
TFLs 
200 mg LOXO-305 (Fasted) 
A 
1 
200 mg LOXO-305 (Fed) 
B 
2 
200 mg LOXO-305 + 40 mg Omeprazole (Fasted) 
C 
3 
40 mg Omeprazole alone (Fasted) 
OMP alone 
4 
The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 2. 
Table 2: 
Presentation of Study Treatment Sequences in TFLs  
Study Treatment Sequence 
Abbreviation 
Order in 
TFLs 
200 mg LOXO-305 (Fasted) on Day 1/ 
200 mg LOXO-305 (Fed) on Day 8/ 
40 mg Omeprazole (Fasted) on Days 15 to 17/ 
200 mg LOXO-305 + 40 mg Omeprazole (Fasted) on Day 18 
A/B/C 
1 
200 mg LOXO-305 (Fed) on Day 1/ 
200 mg LOXO-305 (Fasted) on Day 8/ 
40 mg Omeprazole (Fasted) on Days 15 to 17/ 
200 mg LOXO-305 + 40 mg Omeprazole (Fasted) on Day 18 
B/A/C 
2 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received. 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(LOXO-305). Subjects will be classified into groups based on actual treatment received. 
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of LOXO-305, have 
at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times the median tmax. 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 10 of 20 
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the end-of-treatment 
visit. Any subject who discontinued the study will be identified accordingly in the listings. 
Summaries and statistical analyses will include the subjects assigned to the relevant 
population based on data type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline. 
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum. 
● As Early Termination measurements are not associated with any scheduled timepoint, it 
will be excluded from all calculations of summary statistics.  
● Post dose repeats and unscheduled assessments will not be included in calculation of 
summary statistics.  
For categorical data the following rules will be applied:  
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included.  


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CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 11 of 20 
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is missing. 
This will ensure that the population size totals are consistent across different 
parameters.  
8.1.2. Repeat and Unscheduled Readings  
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value.  
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value for each period. 
Post dose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations, with the exception of the baseline derivation (see Section 8.1.3).  
8.1.3. Definitions of Baseline and Change from Baseline  
Baseline value is defined as the last non missing measurement before administration of 
LOXO-305 in each treatment period. In general, baseline refers to the pre-dose value 
collected on Day 1 Treatment A or B, Day 8 Treatment A or B, and Day 18 Treatment C. For 
laboratory tests, baseline is the value collected on Day -1 Treatment A or B, Day 7 Treatment 
A or B, and Day 17 Treatment C.. If the date/time of the value is incomplete or missing, it 
will be excluded from the baseline calculation, unless the incomplete date/time indicates the 
value was recorded prior to the last dose. 
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects. 
See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment sequence will be provided, based on the all subjects 
population. 
8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed.  


SAP 
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Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 12 of 20 
A summary table by treatment sequence will be provided, based on the safety population. 
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2019. Prior and concomitant 
medications will be listed. 
8.5. Pharmacokinetic Assessments 
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of LOXO-305 using non-compartmental methods performed using Phoenix 
WinNonlin (Certara USA, Inc.) version 8.1 or higher: 
Parameter 
Definition 
Cmax 
maximum observed plasma concentration 
tmax 
time to maximum observed concentration 
AUC0-24 
area under the concentration-time curve (AUC) from Hour 0 to 24 hours 
postdose, calculated using the linear trapezoidal rule for increasing and 
decreasing concentrations 
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for 
increasing and decreasing concentrations 
AUC0-inf 
AUC extrapolated to infinity, calculated using the formula: 
AUC0-inf = AUC0-t + 
z
t
λ
C
 
where Ct is the last measurable concentration and Z is the apparent 
terminal elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC0-inf 
Z 
apparent terminal elimination rate constant, where Z is the magnitude of 
the slope of the linear regression of the log concentration versus-time 
profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (whenever possible),  
where t1/2 = natural log (ln)(2)/Z 
CL/F 
apparent systemic clearance 
Additional PK parameters may be determined where appropriate. The number of points used 
to estimate Z, the lower and upper points used in estimation, Z span ratio, and the adjusted 
coefficient for determination of exponential fit (R2 adjusted) will be presented in a listing. 


SAP 
CONFIDENTIAL 
Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
Page 13 of 20 
The PK analysis will, where possible, be carried out using actual postdose times recorded in 
the raw data. If actual times are missing, nominal times may be used with sponsor approval.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Cmax and tmax will be obtained directly from the plasma concentration-time profiles. For 
multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported. 
8.5.1.1. Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
Concentration values that are below the level of quantification (BLQ) will be set to zero, with 
defined exceptions as follows; 
 Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
 If there are late positive concentration values following 2 BLQ concentration values in 
the apparent terminal phase, these values will be evaluated. If these values are 
considered to be anomalous, they will be set to missing. 
 If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
 If a predose concentration is missing, it may be set to zero in PK analysis by default 
within Phoenix WinNonlin. 
8.5.1.2. Criteria for the Calculation of an Apparent Terminal Elimination Rate 
Constant and Half-Life 
8.5.1.2.1. Number of Data Points 
At least 3 data points will be included in the regression analysis and preferably should not 
include Cmax. 
8.5.1.2.2. Goodness of Fit 
When assessing terminal elimination phases, the adjusted coefficient of determination for 
exponential fit (R2 adjusted) will be used as a measure of the goodness of fit of the data 
points to the determined line.  
Regression-based parameters (AUC0-inf, λZ, t1/2, and CL/F) will only be calculated if the R2 
adjusted value of the regression line is greater than or equal to 0.7. 
8.5.1.2.3. Period of Estimation 
The time period used for the estimation of apparent terminal elimination rate constant, where 
possible, will be over at least 2 half-lives.  


SAP 
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Covance Study: 8422329 
Protocol Reference: LOXO-BTK-20014 
Sponsor Final, Version 2, 21MAY2020 
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Where the terminal elimination rate constant is estimated over a time period of less than 
2 half-lives, it will be flagged in the data listings at the discretion of the Pharmacokineticist, 
and the robustness of the value should be discussed in the CSR. 
8.5.1.3. Calculation of AUC 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive plasma concentrations above the lower limit of quantification, with at least one 
of these concentrations following Cmax. 
For any partial AUC determination (eg. AUC0-24), nominal time will generally be used for the 
end of the interval. Actual times for partial AUC intervals may be used at the discretion of the 
Pharmacokineticist.  
AUC0-inf values where the percentage extrapolation is less than 20% will be reported. 
AUC0-inf values where the percentage extrapolation is between 20 to 30% will be flagged and 
included in the summary statistics and statistical analysis, whilst AUC0-inf values where the 
percentage extrapolation is >30% will be reported but excluded from summary statistics and 
statistical analysis.   
8.5.1.4. Anomalous Values 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
the CSR. 
Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
Subjects with positive predose values >5% of Cmax may be excluded from the summary 
statistics and statistical analysis at the discretion of the Pharmacokineticist. 
8.5.2. Presentation of Pharmacokinetic Data 
8.5.2.1. Presentation Pharmacokinetic Plasma Drug Concentration Data 
The following rules will be applied if there are values that are BLQ or if there are missing 
values (eg, no result [NR]) in plasma concentration data series to be summarized. 
 For the calculation of summary statistics, BLQ values will be set to zero. 
 If an embedded BLQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics. 
 Where there is NR, these will be set to missing. 
 If there are less than 3 values in the data series, only the minimum, maximum and N 
will be presented. The other summary statistics will be denoted as not calculated (NC). 
BLQ is considered a value. 


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 If all the values are BLQ, then the arithmetic mean, arithmetic standard deviation (SD), 
median, minimum and maximum will be presented as zero, and the geometric mean 
and geometric coefficient of variation (CV) will be denoted as NC. 
 If the value of the arithmetic mean or median is below the lower limit of quantification, 
these values will be presented as zero and the geometric mean and geometric CV will 
be denoted as NC. 
8.5.3. Presentation Pharmacokinetic Parameters 
For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
8.5.4. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables, mean (+ SD) figures, overlaying individual figures, and individual figures 
by treatment and time postdose will be provided for plasma PK concentrations. All PK 
concentration figures will be produced on both linear and semi-logarithmic scales, with the 
exception of figures across all days, which will be produced on the linear scale only. The 
+SD bars will only be displayed on the linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV%, 
minimum, median, maximum, geometric mean [Geom Mean] and geometric CV% [Geom 
CV%]) will be calculated for plasma LOXO-305 PK parameters. Excluded subjects will be 
listed in the PK parameter tables, but will be excluded from the summary statistics and noted 
as such in the tables. 
8.5.4.1. Statistical Analyses 
A statistical analysis will be conducted to investigate the food effect on the single dose 
administration of LOXO-305 and the drug-drug interaction of Omeprazole on the PK of 
LOXO-305 for AUC0-24, AUC0-t, AUC0-inf, and Cmax. The comparisons of interest are: 
  200 mg LOXO-305 (Fed) (test treatment) vs ‘200 mg LOXO-305 (Fasted) (reference 
treatment) i.e. Treatment B Vs Treatment A 
 200 mg LOXO-305 + 40 mg Omeprazole (Fasted) (test treatment) vs 200 mg LOXO-
305 (Fasted) (reference treatment) i.e. Treatment C Vs Treatment A 
The natural log (ln)-transformed3 PK parameters will be analyzed using a mixed model.4 The 
model will include planned treatment sequence, and actual treatment as fixed effects, and 
subject within planned treatment sequence as a random effect.  


S A P  
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 2 2 3 2 9  
Pr ot oc ol Refere n ce: L O X O -B T K -2 0 0 1 4  
S p o ns or  Fi nal, Versi o n 2 , 2 1 M A Y 2 0 2 0  
Pa ge 1 6  of 2 0  
F or eac h P K para meter s e parat el y, t h e least s q uares mea n ( L S M) f or eac h treat me nt, 
differe n ce i n L S Ms bet w ee n t he fe d a n d faste d treat me nts, a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val ( CI) will be calc ulate d; t hes e val ues will t he n be e x p o ne ntiate d  t o gi v e t he 
ge o m etric least s q uare m ea n s ( GL S M), ge o metric mea n rati os ( G M R) , a n d c orres p o n di n g 
9 0 % CI s. 
T his pr oce d ure is e q ui val e nt t o Sc h uir ma n n’s 5 t w o o ne-si de d tests at t he 0. 0 5 le vel of 
si g nifica n ce.  
A d diti o nall y, t he p o ole d esti mate (acr oss all treat me nts) of t he wit hi n -s u bject C V will be 
calc ulate d, a n d resi d ual pl ots will be pr o d uce d t o assess t he a de q uac y of t he m o del(s) fitte d.   
E x a m ple of t he S A S c o de t hat will be u se d are as f oll o ws: 
Mi xe d M o del A n al ysis  
8. 6.  S afet y a n d T oler a bilit y Assess me nt s  
8. 6. 1.  A d verse E ve nts   
All A Es  will be c o de d usi n g t he Me dic al Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A ) 
Versi o n 2 2 .1 . All A Es will be assi g ne d s e verit y gra de usi n g Nati o nal Ca ncer I nstit ute 
C o m m o n Ter mi n ol o g y Crite ria f or A d verse E ve nts ( C T C A E) Versi o n 5 .0 . 
A treat me nt -e mer ge nt a d verse e v e nt ( T E A E) will be defi ne d as a n A E t hat starts d uri n g or 
after t he first d ose, or starts pri or t o t he first d ose a n d i ncreases i n se verit y after t he first d ose. 
A treat me nt -relate d T E A E will be defi ne d as a  T E A E wit h a relati o ns hi p of  relate d t o t he 
st u d y treat me nt ( L O X O-3 0 5  or O me praz ole ), as d eter mi ne d b y t he i n vesti gat or. 
T he assi g n me nt of T E A Es t o t he ass ociate d treat me nts will be as f oll o ws: 
● A T E A E  occ urri n g d uri n g or after Da y  1 d osi n g a n d pri or t o Da y 8  d osi n g will be 
assi g ne d t o ‘2 0 0 m g L O X O -3 0 5 ( Faste d)’ or ‘ 2 0 0 m g L O X O -3 0 5 ( Fe d)’ de pe n di n g o n 
t he s u bject’s fasti n g stat us pri or t o Da y 1 d osi n g. 
C CI


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● A TEAE occurring during or after Day 8 dosing and prior to Day 15 dosing will be 
assigned to ‘200 mg LOXO-305 (Fasted)’ or ‘200 mg LOXO-305 (Fed)’ depending on 
the subject’s fasting status prior to Day 8 dosing. 
● A TEAE occurring during or after Day 15 dosing and prior to Day 18 dosing will be 
assigned to ‘40 mg Omeprazole (Fasted)’. 
● A TEAE occurring during or after Day 18 dosing will be assigned to ‘200 mg 
LOXO-305 + 40 mg Omeprazole (Fasted)’. 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last dose for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, and leading to discontinuation) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, and leading to discontinuation) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment 
● System organ class, preferred term, day of onset, and treatment  
For the AE data the following rules will apply:  
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to the first dose.  
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE.  
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, the 
minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of the last dose is 01MAY2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).  


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● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).  
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible, up to Grade 4 in the absence of a 
fatal outcome.  
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters with change from baseline, will be listed; any value outside 
the clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. Separate listings will be 
provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range. 
The observed results and change from baseline for clinical chemistry, complete blood count, 
and coagulation parameters will be summarized descriptively by treatment group and 
timepoint. Boxplots of the observed values will also be provided.    
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to 0, whereas >x and ≥x values will be set to x. 
8.6.3. Vital Signs Parameters  
All vital signs parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. 
The observed results and change from baseline for all vital signs parameters will be 
summarized descriptively by treatment group and timepoint. Boxplots of the observed values 
will also be provided.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. 
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by treatment group and timepoint. Boxplots of the observed values 


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will also be provided. QTcF values that are > 450 msec and increase from baseline > 30 msec 
will be flagged in the data listing.  
8.6.5. Other Assessments  
Medical history and physical examination will be listed. Any physical examination 
abnormalities reported will also be flagged as clinically significant or not clinically 
significant as indicated.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES  
No inferential statistical analyses are planned. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
4. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
5. 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(6):657-680. 


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12. APPENDICES 
Appendix 1: 
Document History 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
Final, Version 2.0 
21MAY2020 
Update wording in sections 8.6.2-8.6.4 to make clear 
that summary tables to include changes from baseline. 
Removed referencing of upversioning for MEDRA 
and CTCAE as same versions will be used throughout 
study. 
NA = not applicable