Clinical trial NCT06180980
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2021-01-04; Completion date: 2021-03-08
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study is to conduct blood tests to measure how much pirtobrutinib (LOXO-305) is in the bloodstream and how the body handles and eliminates pirtobrutinib (LOXO-305) after meals and on an empty stomach. The study will also evaluate the safety and tolerability of pirtobrutinib (LOXO-305). Participants will stay in this study for up to 53 days (screening through follow-up call).

Detailed description:

Arms: arm 1: Participants received a single oral dose of 200 milligrams (mg) of pirtobrutinib administered in the morning on Day 1, under fasted conditions (Treatment A) followed by 200 mg pirtobrutinib administered orally in the morning on Day 8, under fed condition (Treatment B). A washout period of 7 days was maintained between Treatments A and B. arm 2: Participants received a single oral dose of 200 mg pirtobrutinib administered in the morning on Day 1, under fed conditions (Treatment B) followed by 200 mg of pirtobrutinib administered orally in the morning on Day 8, under fasted conditions (Treatment A). A washout period of 7 days was maintained between Treatments A and B.
Interventions: intervention 1: Pirtobrutinib
Intervention descriptions: intervention 1: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol LOXO-BTK-20009
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to Investigate the 
Effect of Food on the Pharmacokinetics of a Single Oral Dose of Pirtobrutinib 
(LOXO-305) in Healthy Subjects
NCT06180980 
Approval date: 02-December-2020 


Protocol 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to 
Investigate the Effect of Food on the Pharmacokinetics of a Single Oral 
Dose of LOXO-305 in Healthy Subjects 
Sponsor: 
Loxo Oncology, Inc. 
Protocol Status: Final 
Protocol Date: 1 December 2020 
Protocol Version: 1.0 
Investigational Medicinal Product: LOXO-305 
Protocol Reference Number: LOXO-BTK-20009 
Covance Study Number: 8419688 
IND Number: 139876 
Coordinating Investigator Study Site: 
A wholly owned subsidimy of Eli Lilly and 
Company 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
SJ)onsor Signato1y: 
PPD 
USA 
Up to 2 additional sites in the United States 
may be utilized. 
Coordinating Investigator: 
PPD 
Inf 01mation described herein is confidential and may be disclosed only with the express 
written pe1mission of the Sponsor. 


Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
02-Dec-20 I 08:28:39 PST 
Date 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Date 
Protocol Version 1.0, l December 2020 
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Protocol 
Covance Study: 8419688 
Sponsor 
Sponsor's Study Contact 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
STUDY IDENTIFICATION 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Tel (main): (650) 989-8051 
PPD 
PPD 
Loxo Oncology~h=1c_. __ _ 
Tel (mobile : PPD 
Email: PPD 
Sponsor's Medical Contact 
PPD 
Consulting to Loxo Oncology, Inc. 
Tel (mobileLJPPD 
Email: PPD 
Serious Adverse Event Rep01ting 
Email: SAEintake@covance.com 
Study Site(s) 
Coordinating Investigator Study Site 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Up to 2 additional sites in the United States may be 
utilized. 
Coordinating Investigator 
Sub-investigator( s) 
Clinical Laborat01y(s) 
PPD 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 3 211 7 
USA 
Tel: 
=--c---
Tel after lioursfE_PD 
Obtain information from Fonn FDA 1572s 
LabCorp - Hollywood 
4200 No11h 29th A venue 
Hollywood, FL 33020 
USA 
Each additional site will use their local laborat01y for 
safety analyses. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
Bioanalytical Laborat01y 
Statistician 
Protocol Medical Writer 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Alturas Analytics, Inc. 
1324 Alturas Drive 
Moscow~ Idaho 83843 
USA 
Tel (main): (208) 883-3400 
Email: jzimmer@alturasanalytics.com 
PPD 
Covance 
Tel: 
D 
Em 
PD 
Covance 
Tel: +44 (Q)l 13 301 3554 
Email: PPD 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
SYNOPSIS 
Study Title 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to Investigate the Effect of 
Food on the Pha1macokinetics (PK) of a Single Oral Dose of LOXO-305 in Healthy Subjects 
Objectives 
The primary objective of the study is to assess the effect of food on the PK of a single oral 
dose of LOXO-305 under fasted and fed conditions in healthy adult subjects. 
The seconda1y objective of the study is to assess the safety and tolerability of a single oral 
dose ofLOXO-305 with and without food in healthy adult subjects. 
Study Design 
This is a Phase 1, open-label, randomized, 2-way crossover study to investigate the effect of 
food on the single oral dose PK ofLOXO-305 in healthy adult subjects. 
A single oral dose ofLOXO-305 will be administered under fasted conditions (Treatment A) 
and fed conditions (Treatment B). Pharmacokinetic sampling will be obtained for 168 hours 
after administration of each dose of LOXO-305 (ie, on Days 1 and 8). The 2 treatment 
sequences will be AB and BA. 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 of200 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. Water will be restricted for 1 hour p1ior to and 1 
hour 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 stai1ing a high-fat breakfast. Water will be restricted for 1 
hour prior to and 1 hour after dosing. High-fat breakfasts should be entirely consumed within 
30 minutes. 
Blood samples for the analysis of plasma concentrations of LOXO-305 will be collected from 
predose through 168 hours post.dose for each Treatment A and Treatment B. 
There will be a washout pe1iod of 7 days between the doses ofLOXO-305 administered in 
Treatments A and B. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 15 upon completion of all PK and safety assessments or Eai·ly 
Te1mination (ET) if the subject discontinues. Subjects will be dosed on Day 1 and Day 8. A 
follow-up phone call will occur for all subjects who received at least 1 dose of study drng 
(including subjects who are te1minated early) 7 days(± 2 days) after EOT or ET. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
The sta1t of the study is defined as the date the first subject who is emolled in the study signs 
an Info1med Consent Fo1m (ICF). Note that emolled subjects are defined as those subjects 
who are assigned to receive a dose of study d1ug; this definition excludes screen failure 
subjects. Replacement subjects may be emolled only if deemed necessa1y by the Sponsor. 
In this study, physical examinations, 12-lead electrocardiograms (ECGs), vital sign 
measurements, How Do You Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation 
parameters, hematology panel, urinalysis (UA; Appendix 2), and recording of concomitant 
medications will be perfmmed at specified times during the study (for specific timepoints and 
details on each study variable, refer to Appendix 4). 
Adverse events (AEs) and serious adverse events (SAEs) will be collected beginning at 
info1med 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), eith.er as subject medical histo1y (if the event is 
repmted 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 p1ior to study mug 
administration on Day 1 and is assessed as related to study procedures by the Investigator [ or 
designee], or if the event occms after study diug administration on Day 1 through EOT or ET 
regardless of relationship to study drng). From EOT or ET through EOS, only AEs assessed 
as related to study di11g by the Investigator (or ,designee) are to be repo1ted. All SAEs that 
develop from the time ofICF signing until EOS (or ET, if the subject discontinues from the 
study and does not complete a follow-up phone call) are to be repo1ted. 
Study completion is defined as the time of the last subject's follow-up phone call. 
Number of Subjects 
Up to 20 healthy adult male and female subjects (women of non-childbearing potential only) 
will be emolled. This is a Phase 1 study and the sample size is consistent with previous 
studies of a similar design. Up to 20 subjects are anticipated to be sufficient to provide a 
reliable estimate of the magnitude and variability of the food effect. 
Eve1y attempt will be made to emoll at least 3 subjects of each sex in the study. 
Main Criteria for Inclusion 
Male subjects, and female subjects of non-childbearing potential must meet the following 
crite1ia: 
• 
Between 18 and 55 years of age, inclusive, at Screening 
• 
Within body mass index (BMI) range 18.0 to 32.0 kg/m2, inclusive, at Screening 
• 
In good general health, based on medical histmy, physical examination findings, vital 
signs, 12-lead ECG, or clinical laboratory evaluations at Screening and/or Check-in 
(Day -1), as dete1mined by the Investigator (or designee) 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Covance Study: 8419688 
Investigational Medicinal Products, Dose, and Mode of Administration 
Subjects will receive each of the following treatments once throughout the study: 
• 
Treatment A (Fasted) - Day 1 or Day 8: single oral dose of200 mg LOXO-305 
(2 x 100-mg tablets) following a fast of at least 10 hours prior to and 4 hours after the 
LOXO-305 dose. Water will be restricted for 1 hour prior to and 1 hour after dosing, 
with the exception of water administered for dose administration. 
• 
Treatment B (Fed) - Day 1 or Day 8: single oral dose of200 mg LOXO-305 
(2 x 100-mg tablets) approximately 30 minutes after stat.ting a high-fat breakfast. 
Water will be restricted for 1 hour prior to and 1 hour after dosing, with the exception 
of water administered for dose administration. The high-fat breakfast should be 
entirely consumed within 30 minutes. 
All study drugs will be administered orally with approximately 240 mL of water. 
LOXO-305 will be supplied by the Sponsor as 100-mg tablets for oral administration. 
Duration of Subject Participation in the Study: 
Planned Emollment/Screening Duration: Approximately 28 days (Days -29 to -2). 
Length ofCRU Confinement: Up to 16 days (Days -1 to 15). 
Planned Study Conduct Duration: Up to 53 days (Screening through follow-up call). 
Criteria for Evaluation: 
Pharmacokinetics: 
Serial PK blood samples for the analysis of plasma concentrations ofLOXO-305 will be 
collected from predose through 168 hours post-LOXO-305 administration in Treatment A 
and Treatment B. 
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 
(AUC) from hour Oto 24 hours postdose (AUC0-24), AUC from hour Oto the last measurable 
concentration (AUCo-t), AUC from hour 0 extrapolated to infinity (AU Co-inf), percentage 
extrapolation for AUCo-inf(¾AUCextrap), maximum observed plasma concentration (Cmax), 
time to Cmax (tmax), apparent terminal elimination rate constant Ch), apparent systemic 
cleai·ance (CL/F), apparent plasma terminal elimination half-life(!½), and apparent volume of 
distribution (VJ F). 
Safety: 
Safety will be monitored with HDYF? inquiries, clinical laborat01y evaluations, vital sign 
measurements, 12-lead ECGs, and physical examinations. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
Statistical Methods 
Pharmacokinetics: 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
The primary PK analysis planned for this study is a mixed effect model including planned 
treatment sequence, 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)-transfonned 
PK parameters (AUCo-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 conesponding 90% 
confidence inte1vals (Cls). The geometric mean ratios and their 90% Cls of the PK parameter 
for each treatment comparison will be constrncted using the exponentiation of the difference 
and the Cls from the mixed effect model. The compalison of interest is Treatment B 
compared with Treatment A. 
Safety: 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laborato1y 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated, and summarized where possible, using descriptive methodology by treatment and, 
as needed, by timepoint. Unless othe1wise specified, baseline value is defined as the last 
non-missing measurement before administration of LOXO-305. No formal statistical analyses 
are planned for the safety data. All safety data will be listed by subject. 
The specific procedures will be documented in the Statistical Analysis Plan. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
SPONSOR APPROVAL .......................................................................................................... .2 
INVESTIGATOR AGREEMENT ............................................................................................ .3 
STIJDY IDENTIFICATION ..................................................................................................... 4 
SYNOPSIS ................................................................................................................................. 6 
TABLE OF CONTENTS ......................................................................................................... 10 
LIST OF TABLES AND FIGURES ................. ....................................................................... 12 
LIST OF ABBREVIATIONS .................................................................................................. 13 
1. 
INTRODUCTION ........................................................................................................... 16 
1.1. Background ................................................................................................................ 16 
1.2. Nonclinical Pha1macokinetics and Toxicology Summary ........................................ 16 
1.3. Potential for Dmg-drug Interactions .......................................................................... 18 
1.4. Summaiy of Clinical Experience ............................................................................... 19 
1.4.1. 
Safety ........................................................................................................... 20 
1.4.2. 
Phannacokinetics ......................................................................................... 21 
1.5. Study Rationale .......................................................................................................... 24 
1.6. Risk Assessment ........................................................................................................ 24 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................. 26 
2.1. Objectives ........................................... ....................................................................... 26 
2.1.1. 
Prima1y Objective ........................................................................................ 26 
2.1.2. 
Secondaiy Objective .................................................................................... 26 
2.2. Endpoints ................................................................................................................... 26 
2.2.1. 
Prima1y Endpoints ....................................................................................... 26 
2.2.2. 
Seconda1y Endpoints ................................................................................... 26 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 27 
3 .1. Overall Study Design and Plan .................................................................................. 27 
3.2. Discussion of Study Design ....................................................................................... 28 
3.3. Selection of Doses in the Study ................................................................................ .29 
4. 
SELECTION OF STUDY POPULATION ..................................................................... 30 
4.1. Screening Procedures ................................................................................................. 30 
4.2. Check-in Procedures (Day -1) ................................................................................... 30 
4.3. Inclusion Criteria ....................................................................................................... 31 
4.4. Exclusion Criteria ...................................................................................................... 33 
4.5. Subject Number and Identification ............................................................................ 36 
4.6. Removal of Subjects from Study Pa1ticipation ......................................................... 37 
5. 
STUDYTREATMENTS ................................................................................................. 38 
5.1. Description, Storage, Packaging, and Labeling ......................................................... 38 
5.2. Study Treatment Administration ............................................................................... 38 
5.3. Randomization ........................................................................................................... 39 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
5.4. Blinding ..................................................................................................................... 39 
5.5. Treatment Compliance ............................................................................................... 39 
5.6. Drng Accountability .................................................................................................. 39 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ............................... .41 
6.1. Concomitant Therapies .............................................................................................. 41 
6.2. Diet, Fluid, and Activity Control.. ............................................................................. 41 
7. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 43 
7 .1. Phaimacokinetic Assessments ................................................................................... 43 
7 .1.1. 
Phannacokinetic Blood Sample Collection and Processing ........................ 43 
7 .1.2. 
Analytical Methodology ............................................................................. .43 
7.2. Safety and Tolerability Assessments ......................................................................... 43 
7.2.1. 
Adverse Events ............................................................................................ 43 
7.2.2. 
Clinical Laborat01y Evaluations ................................................................. .44 
7.2.3. 
Vital Signs .................................................................................................... 45 
7.2.4. 
12-lead Electrocardiogram ........................................................................... 45 
7.2.5. 
Physical Examination .................................................................................. .45 
8. 
SAMPLE SIZE AND DATA ANALYSIS ...................................................................... 46 
8.1. Determination of Sample Size ................................................................................... 46 
8.2. Analysis Populations ................................................................................................ .46 
8.3. Phannacokinetic Analysis ......................................................................................... 46 
8. 3 .1. 
Descriptive Analysis .................................................................................... 4 7 
8.3.2. 
Statistical Methodology .............................................................................. .47 
8.4. Safety Analysis .......................................................................................................... 47 
8.5. Data Handling and Record Keeping .......................................................................... 48 
8.6. Quality Control and Quality Assmance .................................................................... .48 
9. 
ADMINISTRATIVE ASPECTS ..................................................................................... 49 
9.1. Change in Protocol .................................................................................................... 49 
9.2. Site Initiation Visit/Investigator Meeting .................................................................. 49 
9.3. Disclosure .................................................................................................................. 49 
9.4. Monito1ing ................................................................................................................. 49 
9.5. Institutional Review Board ........................................................................................ 49 
9.6. Infonned Consent ...................................................................................................... 50 
9.7. Records ...................................................................................................................... 50 
9.8. Reference to Declaration of Helsinki/Basic Principles ............................................. 50 
9. 9. Financing and Insurance ............................................................................................ 51 
10. REFERENCES ................................................................................................................ 52 
11. APPENDICES ................................................................................................................. 53 
Appendix 1: Adverse Event Rep01ting ............................................................................... 54 
Appendix 2: Clinical Laborato1y Evaluations ..................................................................... 58 
Appendix 3: Total Blood Volume ....................................................................................... 59 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Appendix 4: Schedule of Assessments ............................................................................... 60 
LIST OF TABLES AND FIGURES 
Table 1: Phannacokinetic Parameters ofLOXO-305 in Cancer Patients 
(Study LOXO-BTK-18001) at Steady State (Cycle 1 Day 8) ............................. 22 
Table 2: Study Drng ........................................................................................................... 38 
Table 3: High-fat Breakfast Content ........... ....................................................................... 42 
Figure 2: Dose-Exposure Conelation Assessed by AUCo-s vs Dose for Cycle 1 Day 8 ... 24 
Figure 3: Study Schematic ................................................................................................. 28 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Abbreviation 
%AUCextrap 
ADL 
AE 
AUC 
AUC0-24 
AUC0-inf 
AUC0-t 
AV 
BCRP 
BID 
BMI 
BP 
BSEP 
BTK 
CFR 
CI 
CKD-EPI 
CL/F 
CLL 
Cmax 
COVID-19 
CRF 
CRU 
CTCAE 
CV 
CYP 
ECG 
eCRF 
eGFR 
EOS 
EOT 
ET 
FDA 
FSH 
GLP 
HbAlc 
HBsAg 
LIST OF ABBREVIATIONS 
Definition 
percentage extrnpolation fo1· area under the concentration-time curve 
from hour O extrapolated to infinity 
Activities of Daily Living 
adverse event 
area under the concentration-time curve 
area under the concentration-time curve from hour O to 24 hours postdose 
area under the concentration-time curve from hour O extrapolated to 
infinity 
area under the concentration-time curve from hour O to the last 
measurable concentration 
atrioventTicular 
breast cancer resistance protein 
twice daily 
body mass index 
blood pressure 
bile salt expmter pump 
Brnton' s tyrosine kinase 
Code of Federal Regulations 
confidence interval( s) 
Chronic Kidney Disease Epidemiology Collaboration 
apparent systemic clearance 
chronic lymphocytic leukemia 
maximum observed plasma concentration 
SARS-CoV-2 
Case Repmt F mm 
Clinical Research Unit 
Common Te1minology Criteria for Adverse Events 
coefficient of va1iation 
cytochrome P450 
electrocardiogram 
electronic Case Report Fmm 
estimated glomernlar filtration rate 
End of Study 
End of Treatment 
Early Te1mination 
Food and Drng Administration 
follicle-stimulating hmmone 
Good Laboratmy Practice 
hemoglobin Ale 
hepatitis B surface antigen 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
HBV 
HCV 
HDYF? 
hERG 
HIV 
HR 
HRT 
1B 
ICso 
IC9o 
ICF 
ICH 
IgM 
IMP 
IRB 
TIJD 
IV 
LFT 
Ln 
LS 
MATE 
MedDRA 
mRNA 
MRT 
NHL 
OAT 
OATP 
OATPlBl 
OATP1B3 
OCT 
PCR 
P-gp 
PK 
QD 
QTcF 
RBC 
RP2D 
SAD 
SAE 
SAP 
SD 
SDD 
hepatitis B vims 
hepatitis C vims 
How Do You Feel? 
hmnan ether-a-go-go-related gene 
hmnan immunodeficiency vims 
heart rate 
hormone replacement therapy 
Investigator's Brochure 
50% inhibito1y concentration 
concentration required for 90% inhibition 
Informed Consent Form 
International Council for/Conference on Harmonisation 
immunoglobulin M 
investigational medicinal product 
Institutional Review Board 
intrauterine device 
intravenous 
liver function test( s) 
natural log 
least squares 
multidrng and toxin extrnsion protein 
Medical Dictionary for Regulatmy Activities 
messenger RNA 
mean residence time 
non-Hodgkin lymphoma 
organic anion transpmter 
organic anion transpmting polypeptide 
organic anion transporting polypeptide lB 1 
organic anion transpo1ting polypeptide 1B3 
organic cation transporter 
polymerase chain reaction 
P-glycoprotein 
phannacokinetic( s) 
once daily 
QT interval conected for heait rate using Fridericia's method 
red blood cell( s) 
recommended Phase 2 dose 
single ascending dose 
serious adverse event( s) 
Statistical Analysis Plan 
standard deviation 
spray-dried dispersion 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
SLL 
soc 
SOP 
SUSAR 
TEAE 
TFLs 
tmax 
TSH 
UA 
Vz 
VJF 
WBC 
WHO 
Az 
small lymphocytic lymphoma 
system organ class 
Standard Operating Procedure 
suspected unexpected serious adverse reaction 
apparent plasma terminal elimination half-life 
treatment-emergent adverse event 
tables, figures, and listings 
time to maximmn observed plasma concentration 
thyroid-stimulating ho1mone 
urinalysis 
volume of distribution 
apparent volume of distribution 
white blood cell( s) 
W odd Health Organization 
apparent te1minal elimination rate constant 
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Protocol 
Covance Study: 8419688 
1. INTRODUCTION 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Refer to the Investigator's Brochure (IB) for detailed infonnation concerning the available 
pha1macology, toxicology, drng metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product, LOX0-305.1 
1.1. 
Background 
LOXO-305 (also known as LY3527727) is a selective inhibitor of the Brnton's tyrosine 
kinase (BTK) being developed by Loxo Oncology. LOXO-305 is distinct from the approved 
BTK inhibitors (ibmtinib, acalabmtinib, and zanubmtinib) in several impmiant ways 
including on the basis of its selectivity, favorable absmption, distribution, metabolism, and 
excretion prope1ties, and non-covalent binding mode.2 These features enable LOXO-305 to 
achieve phaimacokinetic (PK) exposures that exceed the BTK concentration resulting in 90% 
inhibition (IC90) at trough, and thus deliver tonic BTK target inhibition throughout the dosing 
period, regardless of the intrinsic rate ofBTK hunover. Moreover, the non-covalent binding 
mode ofLOXO-305 is unaffected by BTK C481 substitutions, a common mechanism of dmg 
resistance described for all available covalent inhibitors_3,4,s,6,7 Finally, LOXO-305 is also a 
highly selective molecule that is more than 300-fold more selective for BTK versus 370 other 
kinases tested with no significant inhibition of non-kinase off-targets at 1 µM, thus limiting 
the potential for off-target mediated toxicities. Collectively, these unique prope1ties of 
LOXO-305 are expected to deliver more potent, continuous, and selective inhibition of BTK 
in a variety of settings, potentially resulting in increased efficacy. Of note, the activity of 
LOXO-305 in diverse preclinical model systems suppmts this underlying hypothesis.2 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate (ATP) 
binding site of the BTK kinase competitively. There is no evidence of ineversible binding. 
LOXO-305 has a moleculai· weight of approximately 500 g/mol. LOXO-305 will be supplied 
as an immediate-release tablet containing 25 mg or 100 mg of dmg substance. 
1.2. 
Nonclinical Pharmacokinetics and Toxicology Summary 
LOXO-305 had high pe1meability in vitro, but low aqueous solubility. To reduce the 
variability in oral abso1ption, a spray-dried dispersion (SDD) tablet fo1mulation was 
developed that showed consistent oral bioavailability of approximately 50% in rats and 80% 
in dogs. The bioavailability of the SDD fo1mulation was also not dependent on feeding state 
in dogs. 
As is common in rodents, oral exposure of LOXO-305 was consistently much higher in 
female rats than in males given the same dose ofLOXO-305. The sex difference was also 
apparent after intravenous (IV) administration of LOXO-305. There was no difference in the 
PK of LOXO-305 between sexes of dog, and none is expected in other non-rodent species, 
including humans. 
The volume of distribution 0/z) of LOXO-305 ranged from approximately 2 L/kg in the dog 
to 5 L/kg in the male rat, which indicates that LOXO-305 distributes into tissues. LOXO-305 
had protein binding of approximately 95% in human plasma. A somewhat lower extent of 
binding (approximately 82% to 92%) was observed across mouse, rat, rabbit, and dog. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
LOXO-305 was metabolized slowly by human microsomal fractions and hepatocytes. The 
low rates of metabolism in both these human in vitro systems suggest that LOXO-305 will 
have low clearance in humans. In vitro data with clone expressed cytochrome P450 (CYP) 
enzymes and human liver microsomes indicate that CYP3A4 is the prima1y CYP enzyme that 
metabolizes LOXO-305. It is also a substrate for direct glucuronidation. 
In long-te1m hepatocyte incubations, LOXO-305 was metabolized by both oxidation and 
glucuronidation. Inhibition of oxidative metabolism by addition of the P450 inhibitor 
1-aminobenzotriazole showed that oxidative metabolism is CYP dependent. All metabolites 
fmmed by human hepatocytes were also formed in rat and/or dog hepatocytes suppmting the 
use of rat and dog for nonclinical safety assessment. 
Renal clearance ofLOXO-305 in male and female rats was negligible. No data on renal 
clearance are available in other species; however, the renal excretion pathway is often 
conse1ved across species, and therefore no renal clearance would be expected in humans. 
In a Good Laboratmy Practice (GLP) in vitro assay for human ether-a-go-go-related gene 
(hERG) activity, the concentration resulting in 50% inhibito1y concentration (ICso) for the 
inhibito1y effects ofLOXO-305 on hERG potassium cunents was_
, which is 
approximately- higher than the maximum unbound concentrat10n ofLOXO-305 in 
patients treated with the dose of 200 mg once daily (QD). There were no LOXO-305-related 
changes in any cardiovascular endpoints including QTc at single doses up to 60 mg/kg in the 
GLP cardiovascular study in the conscious telemetiy-instnnnented dog. The maximmn 
obse1ved plasma concentrntion (Cmax) for this dose was-
ng/mL, which is 
approximately- above the predicted C=ix -ng/mL) at the proposed clinical 
therapeutic dose of200 mg QD. Furthe1more, there were no LOXO-305-related 
abnormalities in rhythm or waveform morphology in the GLP 28-day repeated-dose toxicity 
study in dogs at the low and mid-dose groups based on comparison of predose and postdose 
electrocardiogram (ECG) recordings. The high dose (90/60 mg/kg/dose twice daily [BID]) 
was not evaluated as animals in this group were moribund/debilitated and were terminated on 
Day 13. Mean QTc interval was statistically significantly prolonged ( +6%; + 15 msec) on 
Day 26 of the dosing phase in males administe1·ed 30/10 mg/kg/dose BID compared with 
conti·ols. The prolongation in QTc for males was below the 10% increase or the threshold 
reported for canines exposed to therapeutic concenu-ations of drngs known to cause QT 
prolongation in humans.8 Therefore, the QTc changes were considered physiologically 
unimpmtant, and thus not deemed to be adverse. Together, these data indicate that 
LOXO-305 has a low risk of inducing delayed ventricular repolarization, prolongation of the 
QTc interval, and unstable anhythrnias in patients. 
There were no LOXO-305-related findings on the central ne1vous system when evaluated in 
rat functional obse1vational battery tests and locomotor activity assessments after 4 weeks of 
dosing or dming recove1y at doses ofup to 500 mg/kg/dose BID in male rats and 
175 mg/kg/dose BID in female rats as part of the GLP 28-day repeat-dose study. 
LOXO-305 had no effect on respiration rate in the dog at doses up to 10 mg/kg/dose BID. 
Targets of toxicity were characterized in repeated-dose studies conducted in 2 relevant 
toxicity species. Certain targets (the hematopoietic and lymphoid systems) were found in 
both the rat and the dog. Rat-specific changes in the pancreas are species-specific and seen 
Protocol Version 1. 0, 1 December 2020 
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CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
with other BTK inhibitors. Dog-specific changes in lung and large intestine were lesions 
contributing to moribundity in high-dose animals in the 28-day study. Doses evaluated in 
the 28-day dog study demonstrated a steep dose-response cmve for toxicity and pronounced 
changes in hematologic parameters at high exposures. Additionally, in dogs treated for 
3 months, 2 male dogs at 5 mg/kg BID (the highest dose tested) were obse1ved to have eye 
lesions via both ophthalmic and microscopic examination. Findings were obse1ved in both 
eyes of these animals and consisted of ve1y slight to slight multifocal or focal areas of corneal 
opacity in the center of the cornea along with constellation histopathological findings 
suggestive of minimal to mild corneal injmy. The tin1e of onset of these effects is unknown, 
as ophthalmic exams were only performed prior to the sta1t of dosing and during the last 
week of the study; however, no eye effects were observed in the previous 28-day study. No 
ocular findings were obse1ved in females. See the IB for additional details. 1 
LOXO-305 was not mutagenic in 2 bacte1ial reverse mutation assays and was negative in a 
non-GLP micronucleus assay using Chinese hamster ova1y cells. LOXO-305 was positive for 
the induction of micronuclei via an aneugenic mechanism in the absence and presence of the 
exogenous metabolic activation system in a GLP in vitro micronucleus assay in human 
peripheral blood lymphocytes. However, LOX0-305 was negative in a GLP in vivo 
micronucleus assay in rats at doses up to and including a dose o-
The Cmax at the 
no obse1ved effect level of-
mg/kg was -
ng/mL for males and-
ng/mL for 
females. 
LOXO-305 was not found to be phototoxic when evaluated in an in vitro neutral red uptake 
phototoxicity assay. 
1.3. 
Potential for Drug-drug Interactions 
LOXO-305 showed no detectable inhibition (ICso-) ofCYPlA2, CYP2B6, 
CYP2Cl9, and CYP2D6, and weak inhibition ofCYP2C8, CYP2C9, and CYP3A4 in human 
liver microsomes. After pre-incubation of microsomes with LOXO-305 and nicotinamide 
adenine dinucleotide phosphate prior to addition of CYP450 probe substrate, the CYP3A4 
inhibito1y potency of LOXO-305 was increased, suggesting the potential for time-dependent 
inhibition of CYP3A4. Fm1her kinetic evaluation confinned that LOXO-305 is a 
time-dependent inhibitor of CYP3A4. 
In an in vitro hepatocyte assay, LOXO-305 induced messenger RNA (mRNA) for CYP3A4, 
CYP3A5, CYP2B6, and CYP2C19. For both CYP2B6 and CYP2C19, an increase in activity 
was seen. For CYP3A4, LOXO-305 did not cause an increase in activity, likely due to 
concunent inhibition ofCYP3A4 by LOXO-305. LOXO-305 caused a decrease in mRNA for 
CYP1A2 but did not lead to a reduction of CYP1A2 activity. In the study, CYP2D6, 
CYP2C8, and CYP2C9 mRNA were not induced. 
In vitro LOXO-305 inhibited P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), 
multidrng and toxin extrnsion protein (MATE) 1, and MATE2K. LOXO-305 did not inhibit 
organic anion transpo1ter (OAT) 1 and weakly inhibited organic anion transpmiing 
polypeptide (OATP)lBl, OATP1B3, organic cation transporter (OCT) 1, OCT2, OAT3, and 
bile salt expo11er pump (BSEP). 
LOXO-305 is a substrate of P-gp and BCRP. It is not a substrate of the hepatic transpo1iers 
OCTl, OATP1B1, OATP1B3, or BSEP. 
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Protocol 
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1.4. 
Summary of Clinical Experience 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
LOXO-305 is cmTently being studied in an ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (the BRUIN Study), in patients with previously treated chronic 
lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) or non-Hodgkin 
lymphoma (NHL). The sta1ting dose ofLOXO-305 was 25 mg QD. 
As of September 27, 2020, safety data were available from a total of 330 patients treated in 
the LOXO-BTK-18001 study. This includes 324 patients treated at doses ranging from 25 mg 
QD to 300 mg QD in Phase 1/2 Monotherapy coho1ts, and 6 patients treated in Phase lb 
Combination Alm A (LOXO-305 200 mg QD p lus venetoclax 400 mg QD [after ramp-up] 
Section 1.4.1). 
As of September 30, 2020, PK data were available from 181 patients emolled in the 
LOXO-BTK-18001 study (Section 1.4.2). 
As of November 23, 2020, LOXO-305 had been recently investigated in 1 study in healthy 
volunteers (LOXO-BTK-20014), which was completed. LOXO-BTK-20014 was a pilot 
food-effect crossover study evaluating the effects of food and a proton pump inhibitor 
(omeprazole) on the PK ofLOXO-305 where 10 healthy volunteers were given 200 mg of 
LOXO-305 on 3 separate days, each followed by a washout period. 
As of November 23, 2020, fom additional studies were ongoing in healthy volunteers 
(LOXO-BTK-20006, LOXO-BTK-20017, LOXO-BTK-20007, and LOXO-BTK-20008). 
LOXO-BTK-20006 is a drng-drng interaction study evaluating the effects of a strong 
CYP3A4 inhibitor (itraconazole) and a strong CYP3A4 inducer (Iifampin) on the PK of 
LOXO-305 where, at the time of this protocol's development, 3 healthy volunteers were 
given 1 dose of 200 mg ofLOXO-305, 12 healthy volunteers were given 200 mg of 
LOXO-305 on 2 separate days (1 of which was co-administered with itraconazole), each 
followed by a washout period, and 12 healthy volunteers were given 200 mg of LOXO-305 
on 3 separate days (2 of which were co-administered with rifampin), each followed by a 
washout period. 
LOXO-BTK-20017 is a single ascending dose (SAD) study evaluating the safety and 
tolerability ofLOXO-305 at 300 mg, 600 mg, 800 mg, and 900 mg doses, where, at the time 
of this protocol's development, 6 healthy volunteers were given a single dose of 300 mg 
LOXO-305, 6 healthy volunteers were given a single dose of 600 mg LOXO-305, 6 healthy 
volunteers were given a single dose of 800 mg LOXO-305, and 6 healthy volunteers were 
given a single dose of 900 mg LOXO-305. 
LOXO-BTK-20007 is a 2-pait study of the absorption, metabolism, excretion, and the 
absolute bioavailability of [14C]-LOXO-305 where, at the time of this protocol's 
development, 4 subjects were given a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 ~LCi) as an oral solution and 5 subjects were given a single oral dose of 
200 mg LOXO-305 as 2 x 100-mg tablets followed 2 hours later by a single dose of< 100 ~Lg 
of [14C]-LOXO-305 (containing ~ l ~1Ci of radioactivity [microtracer]) administered as an IV 
push over approximately 2 minutes. 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
LOXO-BTK-20008 is a drug-drug interaction study evaluating the effects ofLOXO-305 on 
the PK of a sensitive CYP3A4 substrate (midazolam) where, at the time of this protocol's 
development, 15 healthy volunteers were given 200 mg QD of LOXO-305 on 13 consecutive 
days (1 day of which was co-administered with IV midazolam and 1 day of which was 
co-administered with oral midazolam). 
1.4.1. 
Safety 
As of September 27, 2020, 330 patients were treated in the LOXO-BTK-18001 study and 
received LOXO-305. This includes 324 patients treated at doses ranging from 25 mg QD 
to 300 mg QD in Phase 1/2 Monotherapy coho1ts, and 6 patients treated in Phase lb 
Combination Ann A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after venetoclax 
ramp-up]). A full summa1y of treatment-emergent adverse events (TEAEs) for patients in the 
study is provided in the LOXO-305 1B and the Investigator is directed to the safety 
information described in that document.1 A summa1y of safety for LOXO-305 given as 
monotherapy to patients in the LOXO-BTK-18001 study is provided below. 
• 
In the 324 patients in the Phase 1/2 Monotherapy cohmts, TEAEs repo1ted in 2': 10% 
of patients (n = 33 or more) were fatigue (20.1 % total, 8.3% related), dianhea (17.0% 
total, 8.6% related), and contusion (13.0% total, 9.0% related). Drug-related TEAEs 
were reported in 156 of 324 patients ( 48.1 %) in the Phase 1/2 Monotherapy coho1ts. 
The most frequently repo1ted diug-related TEAEs for LOXO-305 (those in > 5% of 
patients overall) were contusion (9.0%), diaiThea (8.6%), and fatigue (8.3%). All 
other drug-related TEAEs were reported in < 5% of patients (ie, < 17 patients each). 
Treatment-emergent AEs of severity Grade 3 or 4 were repmted in 87 of 324 patients 
(26.9%) in the Phase 1/2 Monotherapy cohorts, with 41 (12.7%) of these Grade 3 or 4 
AEs repmted as related to study drng. 
• 
On-study death ( death within 28 days of the last dose of study diug) due to a Grade 5 
(fatal) AE was repmted in 4 of 324 patients (1.2%) in the Phase 1/2 Monotherapy 
coho1ts. One Grade 5 AE, Enterococcus faecium-related septic shock, was considered 
to be related to study drug (fuither details are provided in the LOXO-305 IB).1 All 
other Grade 5 AEs were considered to be not related to study diug; these included 
pneumonia fungal, shock, and pleural effusion. 
Treatment-emergent AEs repmted following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20014 study (headache, nausea, and vomiting), were all Grade 1 in 
severity and considered to be related to LOXO-305. All 3 events were repmted by 1 subject 
and resolved within 1 to 1.5 days. 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20006 study (intennittent belching, bloating, insect bite, aphthous ulcer, 
nausea, intem1ittent dianhea [x2], muscle twitch), were all Grade 1 in severity, and bloating, 
1 instance of inte1mittent dianhea, and intermittent belching were considered to be related to 
LOXO-305 and rifampin. All 7 AEs were repo1ted by 3 subjects and all events resolved prior 
to End of Treatment (EOT; preliminaiy data on file at the time of this protocol's 
development). 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Treatment-emergent AEs repmted following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20017 study (headache [observed at the 300 mg LOXO-305 dose], and 
headache [x2], intermittent headache, and petechial rash left thigh [ obseived at the 900 mg 
LOXO-305 dose]), were all Grade 1 in severity. One instance of headache obseived at the 
300 mg LOXO-305 dose and 1 instance obseived at the 900 mg LOXO-305 dose, the 
intermittent headache, and the petechial rash le ft thigh were considered to be related to 
LOXO-305. All five AEs were repoited by 4 subjects and resolved within 2 hours to 5 days 
of onset (preliminaiy data on file at the time of this protocol's development). 
Treatment-emergent AEs repmted following LOXO-305 administration in healthy volunteers 
in Pait 1 of the LOXO-BTK-20007 study (bloody nose, headache, loose stool [x2], red 
bumps on left knee, small abrasion to right elbow), were all Grade 1 in severity and headache 
was considered to be related to LOXO-305. All 7 AEs were reported by 4 subjects and all 
events resolved within 1 to 2 days (preliminaiy data on file at the time of this protocol's 
development). 
Treatment-emergent AEs repmied following LOXO-305 administration in healthy volunteers 
in Pait 2 of the LOXO-BTK-20007 study (tenderness at left venipuncture site [x2], brnising 
to left antecubital secondaiy to phlebotomy [x2], bruising to right antecubital secondaiy to 
phlebotomy, and allergic reaction), were all Grade 1 in severity and no events were 
considered to be related to LOXO-305. All 6 AEs were repoited by 4 subjects and all events 
resolved within 1 to 2 days (preliminaiy data on file at the time of this protocol's 
development). 
Treatment-emergent AEs repoited following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20008 study (injection site pain, nasal congestion, flatulence, 
constipation, increased urina1y frequency, facial rash, and skin tear from tape at IV site), were 
all Grade 1 in severity, and flatulence, constipation, and increased urinaiy frequency were 
considered to be related to LOXO-305. All 7 AEs were repmted by 3 subjects and all events 
resolved within 1 to 8 days (preliminaiy data on file at the time of this protocol's 
development). 
As pait of each clinical trial conducted in patients or healthy volunteers, ECG and vital signs 
are perfoimed at inteivals specified by protocol. For study LOXO-BTK-18001 conducted in 
patients, no clinically significant findings of QTc prolongation have been identified in 330 
patients as of September 27, 2020 (LOXO-305 1B 1). In addition, there have been no 
clinically significant abnmmal findings in vital signs and ECG data in the studies 
investigating LOXO-305 conducted in healthy volunteers as of November 23, 2020 
(preliminaiy data on file at the time of this protocol's development). 
1.4.2. 
Pharmacokinetics 
As of September 30, 2020, PK data were available from 181 patients enrolled in the 
LOXO-BTK-18001 study. Steady-state PK parameters ofLOXO-305 in these cancer patients 
could be derived from data collected on Cycle 1 Day 8 (Figure 1 ), and are shown in Table 1. 
These data show that LOXO-305 is absorbed after oral administration with a median tin1e to 
maximum obseived plasma concentration (tmax) of approximately 2 hours and low clearance 
(Table 1 ). Due to the limited sampling inteival (0-8 hours), imputation for the 24-hour sample 
was made from Cycle 1 Day 8 predose sample, leading to an estimated plasma half-life of 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
approximately 20 hours. Maximum observed plasma concentration and area under the plasma 
concentration-time cmve (AUC) ofLOXO-305 showed increase proportional to dose 
(Figure 2). Following administration of the recommended Phase 2 dose (RP2D) 200 mg QD, 
mean trough plasma levels ofLOXO-305 exceeded the concentrntion required for 96% 
inhibition ofBTK in vitro (ICso=I ng/mL, IC96= • 
ng/mL). Fmther details may be 
found in the IB.1 
Phannacokinetic data following oral administration of a 200-mg dose ofLOXO-305 in tablet 
form in healthy volunteers in the LOXO-BTK-20014 study indicate that there was little effect 
of either a standard meal or the proton pump inhibitor omeprazole on the PK of LOXO-305. 
Table 1: Pharmacokinetic Parameters of LOXO-305 in Cancer Patients 
(Study LOXO-BTK-18001) at Steady State (Cycle 1 Day 8) 
Ratio 
AUCo.s 
Day 
Cmax 
AUCo.s 
AUCo.24 
8/Day 1 
(ng/mL) 
fmax {h) 
(ng*h/ mL) (ng*h/mL) CL/F (L/h) 
tm(h) 
Geo 
Geo mean 
Median 
Geo mean 
Geo mean 
Geo mean Geo mean 
mean 
Dose Level 
N 
(%CV) 
(min, max) 
(%CV) 
(%CV) 
(%CV) 
(%CV) 
(%CV) 
25mgQD 
5 
734 
2 (1, 8) 
4240 
9800 
1.55' 
18.2' 
1.44 
(11.0%) 
(12.4%) 
(25.8%) 
(69.6%) 
(60.1%) 
(23.0%) 
50mgQD 
6 
1420 
1.5 (1, 4) 
8660 
20100 
2,62b 
}7,6b 
1.51 
(19.2%) 
(24.7%) 
(34.9%) 
(36.7%) 
(39.6%) 
(25.9%) 
lOOmgQD 
9 
3910 
2 (1, 4) 
22000 
52400 
0.968c 
22.2c 
1.88 
(35.6%) 
(37.2%) 
(39.7%) 
(63.0%) 
(33.9%) 
(42.8%) 
150mgQD 
20 
4680 
2 (1, 8) 
28000 
64400 
1.36d 
18.ld 
1.74 
(29.1%) 
(29.6%) 
(39.6%) 
(66.7%) 
(51.8%) 
(24.9%) 
200mgQD 
99 
5770 
2 (1, 8) 
36900 
91000 
1.14• 
19.9· 
1.69h 
(47.7%) 
(40.8%) 
(42.0%) 
(61.8%) 
(56.2%) 
(29.6%) 
250mg QD 
25 
8100 
2 (1, 4) 
49700 
111000 
1.26f 
17.4r 
1.68 
(28.1%) 
(31.3%) 
(38.7%) 
(1.08%) 
(50.6%) 
(24.5%) 
300mgQD 
17 
10700 
2 (1, 4) 
65800 
158000 
1.63g 
30.lg 
2.15 
(26.6%) 
(35.9%) 
(49.2%) 
(42.5%) 
(102%) 
(31.2%) 
Abbreviations: AUCo.s - area under the concentration-time curve from time O to 8 hours; AUCo.24 - area under 
the concentration-time cmve from time O to 24 hours; CVF = apparent oral clearance; Cmax = maximmn drug 
concentration; Geo mean = Geometrical mean; N = number of subjects; QD = once daily; CV = coefficient of 
vaiiation; t112 - half-life; 4nax = time of maximal plasma concentration. 
a N= 4, b N= 5, c N= 8, dN= 18, e N= 64, fN= 21, g N= 16, h N= 73 
SDTM Transfer: September 30, 2020 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
0 
0 
2 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
25 erg (N=5) 
-
-o -
· 
50 erg (N=6) 
--.--
100 mg (N=10) 
---o---
150 mg (N=20) 
.... " ... · .. · .. · 
200 mg (N=90) 
- ·- D-·-
250 mg (N=25) 
-
--~
·-
·· 
300 mg (N=20) 
.... ....... --·------j 
-----
........................................ ....... .. 
---
-----
:.:-~~--==--~=:.:-2=-~ 
------~--------
4 
Time (h) 
-...... 
6 
25 erg (N=5) 
-
-0- -
· 
50 erg (N=6) 
8 
-
_ ,,__ -
100 erg (N=B) 
-
-
-l),... -
-
150 erg (N=20) 
·· .... ..... · 
200 erg (N=90) 
-
·-O-·-
250erg(N=25) 
- ··-+·- ·· 
300 erg (N=18) 
··-··- ·•-. 
-·-·-
--··- ··- · ·- ·•-
... 
·- ·-·-·----·--·-
.. .. . ' ..... '. . . . ~... . . . . ' 
---------
---0-- -
-
-
2 
4 
Time (h) 
6 
8 
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Protocol 
Covance Study: 8419688 
SDTM Transfer: September 30, 2020 
1.5. 
Study Rationale 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
The study is designed to detemline the effect food may have on the PK profile of LOXO-305 
in healthy adult subjects. 
The effect of food will be assessed by measuring the change in the PK of LOXO-305 after 
dosing under fed conditions (with a high-fat breakfast) versus fasting condition. According to 
regulato1y guidance, the test meal provided will be a high-fat and high-calorie meal, 
containing between 800 to 1000 calories ( comp1ising approximately 150 calories from 
protein, 250 calories from carbohydrates, and 500 - 600 calories from fat).9 
The LOXO-BTK-20014 study which was previously conducted used a "standard meal" as 
this is considered to be more consistent with the diet which the patient population LOXO-305 
is intended to treat (patients with previously treated CLL/SLL, Waldenstrom 
macroglobulinemia, marginal zone lymphoma, and other B-cell NHL) n01mally consume. 
1.6. 
Risk Assessment 
Subjects in the cmTent study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of pa1ticipation are 
primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfo1t 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 pruticipating in this study as the dose does not exceed the highest dose safely 
administered in first-in-human study or healthy volunteer studies.1 More info1mation about 
the known and expected benefits, 1isks, and reasonably anticipated AEs associated with 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
LOXO-305 may be found in the IB. 1The safety monitoring practices employed will include 
AE repo11ing, vital sign measurements, 12-lead ECGs, clinical laborat01y evaluations, and 
physical examinations, and are considered adequate to protect the subjects' safety. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to assess the effect of food on the PK of a single oral 
dose of LOXO-305 under fasted and fed conditions in healthy adult subjects. 
2.1.2. 
Secondary Objective 
The secondaiy objective of the study is to assess the safety and tolerability of a single oral 
dose of LOXO-305 with and without food in healthy adult subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): 
• 
AUC from hour 0 to 24 hours postdose (AUCo-24) 
• 
AUC from hour Oto the last measurable concentrntion (AUCo-t) 
• 
AUC from hour 0 extrapolated to infinity (AUCo-inf) 
• 
percentage extrapolation for AUC0-inf(¾AUCextrap) 
• 
apparent systemic clearance (CL/F) 
• 
apparent plasma tenninal elimination half-life (t½) 
• 
Cmax 
• 
tmax 
• 
apparent te1minal elimination rate constant (lz) 
• 
apparent systemic clearance (CL/F) 
• 
apparent volume of distribution at the te1minal phase 01 zlF) 
2.2.2. 
Secondary Endpoints 
Safety and tolerability will be assessed by monitoring AEs, perfo1ming physical examinations 
and clinical laboratmy evaluations, measuring vital signs, and recording 12-lead ECGs. 
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Protocol 
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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
This is a Phase 1, open-label, randomized, 2-way crossover study to investigate the effect of 
food on the single oral dose PK ofLOXO-305 in healthy adult subjects. 
A single oral dose ofLOXO-305 will be administered under fasted conditions (Treatment A) 
and fed conditions (Treatment B). Pharmacokinetic sampling will be obtained for 168 hours 
after administration of each dose of LOXO-305 (ie, on Days 1 and 8). The 2 treatment 
sequences will be AB and BA. Subjects will be randomly assigned to 1 of the 2 treatment 
sequences, according to a randomization scheme issued by Covance. Up to 20 healthy adult 
male and female subjects (women of non-childbeai·ing potential only) will be enrolled. 
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. Water will be restricted for 1 hour p1ior to and 1 
hour after dosing with the exception of water administered for dose administration. 
In Treatment B, a single oral dose of200 mg LOXO-305 will be administered in the morning 
on Day 1 or Day 8 (according to the randomization scheme), approximately 30 minutes after 
sta1ting a high-fat breakfast. Water will be restJ·icted for 1 hour prior to and 1 hour after 
dosing with the exception of water administered for dose administration. High-fat breakfasts 
should be entirely consumed within 30 rninutes. 
Blood samples for the analysis of plasma concentrations ofLOXO-305 will be collected from 
predose through 168 hours postdose for Treatment A and Treatment B. 
There will be a washout pe1iod of 7 days between the doses ofLOXO-305 administered in 
Treatments A and B. 
The schematic of the study design is displayed in Figure 3. The start of the study is defined as 
the date the first subject who is enrolled in the study signs an Inf01med Consent Form (ICF). 
Note that emolled subjects are defined as those subjects who are assigned to receive a dose of 
study mug; this definition excludes screen failure subjects. Replacement subjects may be 
enrolled only if deemed necessa1y by the Sponsor. 
Subjects who are dete1mined to be screen faihll"es are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day-1) until EOT on 
Day 15 upon completion of all PK and safety assessments or Eai·ly Termination (ET) if the 
subject discontinues. Subjects will be dosed on Day 1 and Day 8. A follow-up phone call will 
occur for all subjects who received at least 1 dose of study drng (including subjects who are 
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te1minated early) 7 days (± 2 days) after EOT or ET. The dmation of pa1ticipation is expected 
to be approximately 53 days (Screening through follow-up phone call). 
Figure 3: Study Schematic 
11 
Days -28 to -2 
1 1 
Day •1 
II 
11 
Days 1 to 7 
Day 1 
l 
Treatment A or 
Treatment B 
PK Sampling: 
Day 1: Predose through 
168 hours postodose 
II 
II 
1 1 
Days 8 to 15 
I 
I Day 8 I 
I Day 15 I 
l 
Treatment A or 
Treatment B 
l 
Clinic Discharge 
EOT/ET 
PK Sampling: 
Day 8: Predose through 
168 hours ostdose 
Safety Assessments: From signing the ICF to follow-up phone call 
7 (:I: 21 days 
after Discharge 
Abbreviations: EOT = End of Treatment; ET= Early Termination; ICF"' Informed Consent Form; PK"' pharmacokinetic. 
h1 this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? (HDYF?) inquiries, clinical chemistJ.y panel, coagulation parameters, hematology 
panel, mi.nalysis (UA; Appendix 2), and recording of concomitant medications will be 
perfo1med at specified times during the study (for specific timepoints and details on each 
study variable, refer to Appendix 4). 
Adverse events and serious adverse events (SAEs) will be collected beginning at informed 
consent. Adverse events will be rep01ted 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 administJ.·ation 
on Day 1 and is assessed as not related to study procedures by the hlvestigator [ or designee]) 
or as AEs (if the event occurs after signing of the ICF but prior to study drug adminisu-ation 
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 diug). From EOT or ET through EOS, only AEs assessed as related to 
study diug by the hlvestigator ( or designee) are to be rep01ted. All SAEs that develop from 
the time ofICF signing until EOS (or ET, if the subject discontinues from the study and does 
not complete a follow-up phone call) are to be 1·epo1ted. 
A Schedule of Assessments is presented in Appendix 4. Study completion is defined as the 
time of the last subject's follow-up phone call. 
3.2. 
Discussion of Study Design 
The effect of food will be assessed by measuring the change in the PK ofLOXO-305 after 
dosing under fed conditions (with a high-fat breakfast) versus fasting condition. According to 
regulat01y guidance, the test meal provided will be a high-fat and high-calorie meal, 
containing between 800 to 1000 calories ( comprising approximately 150 calories from 
protein, 250 calories from carbohydi·ates, and 500 - 600 calories from fat).9 
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Subjects will be randomized to treatment sequences to minimize assignment bias. The 2 
treatment sequences will be AB and BA. Subjects will be randomly assigned to 1 of the 2 
treatment sequences, according to the randomization scheme issued by Covance. A crossover 
design is used to reduce the residual variability as eve1y subject acts as their own control. The 
washout pe1iod of 7 days between LOXO-305 doses in Treatments A and Bis considered 
sufficient to prevent canyover effects of the treatments. This study will be open-label because 
the prima1y endpoints are not considered subjective. 
Conducting the study in healthy adult subjects mitigates the potential confounding effects of 
the disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
LOXO-305 
A single oral dose of 200 mg LOXO-305 will be evaluated as this dose level given QD has 
been chosen as the recommended Phase 2 dose for the ongoing global Phase 1/2 
first-in-human study, LOXO-BTK-18001 in patients with previously treated CLL/SLL or 
NHL. The available data demonstrate that LOXO-305 appears safe and well tolerated at these 
doses. At all evaluated doses, no dose-limiting toxicities have been identified in humans.1 
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4. SELECTION OF STUDY POPULATION 
4.1. 
Screening Procedures 
The following screening procedures will be perforn1ed for all potential subjects at a visit 
conducted within 28 days of study ently (ie, prior to Check-in [Day -1 ]): 
1. Inclusion/Exclusion criteria 
2. Infmmed consent 
3. Demographic data 
4. Medical history (including review of medication[s]) 
5. Height, weight, and body mass index (BMI) 
6. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
7. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine blood pressure [BP] and pulse rate [ measured after the subject 
has been supine for at least 5 minutes]; Section 7.2.3) 
8. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7 .2.1) 
9. Clinical laboratory evaluations (Section 7.2.2; clinical chemistiy panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
10. Screens for hepatitis C vims (HCV) antibody, hepatitis B smface antigen (HBsAg), 
hepatitis B vims (HBV) immunoglobulin M (lgM) core antibody, human 
immunodeficiency vims (HIV) antibody, and SARS-CoV-2 (COVID-19) via 
polymerase chain reaction (PCR) testing or equivalent (Appendix 2) 
11. Hemoglobin Ale (HbAlc) test (Appendix 2) 
12. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen 
(breath or urine; Appendix 2) 
13. Estimated glomemlar filtration rate (eGFR) calculated using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 2) 
14. Serum pregnancy test (for female subjects only; Appendix 2) 
15. Follicle-stimulating hmmone (FSH) test (for post-menopausal female subjects only; 
Appendix 2) 
16. Thyroid-stimulating hmmone (TSH) test (Appendix 2) 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to th.e 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 
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4. Complete physical examination (Section 7.2.5) 
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 sign measurements (including body temperature, respiratory rate, oxygen 
saturation, 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, hematology panel, and UA; Appendix 2) 
9. Screen for COVID-19 via PCR test (or equivalent; Appendix 2) 
10. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen 
(breath or urine; Appendix 2) 
11. eGFR calculated using the CKD-EPI equation (Appendix 2) 
12. Serum pregnancy test (for female subjects only; Appendix 2) 
13. Compliance with concomitant medications and exclusionary restr·ictions (Section 6) 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Check-in (Day -1 [as appropriate; #1, Section 4.2]). In addition, 
continued compliance with concomitant medication and other restr'ictions will be verified. 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to Check-in (Day -1). 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 C.-iteria 
Subjects who meet the following criteria at Screening and Check-in (Day -1), unless 
othe1wise 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, detennined by no clinically significant findings from medical histo1y, 
physical examination, 12-lead ECG, vital sign measurements, or clinical laborato1y 
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 pe1manently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy, or confamed tubal occlusion more than 6 months prior to Day 1) or 
post-menopausal (defined as at least 12 months post-cessation of menses without an 
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alternative medical cause). Post-menopausal status will be confinned with a screening 
serum FSH level consistent with post-menopausal status per the laborato1y's reference 
ranges. All female subjects must have a negative qualitative serum pregnancy test 
(se1um human chorionic gonadotropin; serum quantitative human chorionic 
gonadotropin tests may be used for confmnation as needed) at Screening and 
Check-in (Day -1 ). Female subjects are required to refrain from donation of ova from 
Check-in (Day -1) until 6 months after Day 8 ( or last administration of study drng if 
subject terminates from the study early). 
5. Male subjects who are capable of fathering a child must agree to use 1 of the 
following methods of contraception: 
a. Male sterilization, with documented confomation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in 
(Day -1), or 
b. If documentation of surgical stei-ilization is not available, male subjects must 
follow 1 of the contraception methods below from Day 1 through 6 months 
after Day 8 (or last administration of study drug if subject te1minates from the 
study early): 
1. Male condom with spermicide, or 
11. A male subject must ens11re that their female partner meets 1 of the 
following cliteria: 
1. intrauterine device (TTJD) (hormonal TTJD; eg, Mirena®). 
Copper TTJDs are acceptable ( eg, ParaGard®); or 
2. established use of oral, implanted, injected, transde1mal, 
intravaginal, or honnonal method of contraception associated 
with inhibition of ovulation; or 
3. non-childbearing potential, defined as being pennanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral 
salpingectomy, bilateral oophorectomy, or confirmed tubal 
occlusion more than 6 months prior to Day 1 for male pa1tner); 
or 
4. be post-menopausal with amenonhea for at least 1 year prior to 
Day 1 and FSH serum levels consistent with post-menopausal 
status. 
Male subjects who practice trne abstinence because of a lifestyle choice (ie, do not 
become abstinent just for the pmpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence by a female paitner ( eg, calendar, 
ovulation, symptothe1mal, 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 from Check-in (Day-1) through 6 months after Day 8 (or 
last administration of study drug if subject te1minates from the study early), he must 
agree to use contraception as described above. 
For male subjects, sexual intercourse wjth female pa1tners who ai·e pregnant, or 
breastfeeding should be avoided from Check-in (Day -1) through 6 months after 
Day 8 ( or last administration of study drng if subject tenninates from the study early), 
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unless the male subject uses a condom with spennicide. Male subjects are required to 
refrain from donation of spe1m from Check-in (Day -1) until 6 months after Day 8 ( or 
last administration of study drng if subject te1minates from the study early). 
For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. 
6. Able to understand and provide written inf01med consent. 
7. Able to comply with all study procedures, including the 15-night stay at the CRU and 
follow-up phone call. 
4.4. 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. Hist01y or presence of any of the following, deemed clinically significant by the 
Investigator (or designee), and/or Sponsor: 
a. liver disease 
b. pancreatitis 
C. peptic ulcer disease 
d. intestinal malabsorption 
e. cholecystectomy 
f. gastric reduction smge1y 
g. histo1y or presence of clinically significant cardiovascular disease: 
i. myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to Day 1 
11. symptomatic angina pect.oris within 6 months prior to Day 1 
111. congestive hea1t failure 2 stage 2 per New York Herut Association 
Classification within 6 months prior to Day 1 
iv. congenital prolonged QT syndrome 
v. ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
v1. anhythmia ( excluding benign sinus anhythmia) or histo1y of 
anhythmia requiring medical inte1vention within 6 months prior to 
Day 1 
vii. ventricular dysfunction or risk factors for Torsades de Pointes (eg, 
hea1t failure, cardiomyopathy, family hist01y of Long QT Syndrome) 
v111. ECG abn01malities that are clinically significant at Screening, 
Check-in (Day -1), or predose on Day 1, including, but not limited to: 
1. complete left bundle-branch block 
2. second-degree at:J:ioventricular (AV) block, type 2, or 
third-degree AV block 
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3. QT inte1val conected for hea1t rate (HR) using Fridericia's 
method (QTcF) > 450 msec 
Subjects with out-of-range ECG values or abno1mal ECG 
findings that are not clinically significant will be pe1mitted to 
have ECGs repeated up to 2 times during Screening, Check-in 
(Day-1), and predose on Day 1 to confirm eligibility for study 
pa1ticipation, if tbe repeat value(s) are normal/fall outside of 
the ranges stated above. 
2. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital sign 
measurements at Screening, Check-in (Day -1), or prior to dosing on Day 1. 
Out-of-range vital sign measurements are defined as: 
a. body temperature > 37.5°C; 
b. pulse rate < 50 or > 99 beats per minute (bpm); 
c. systolic BP < 89 or > 139 mmHg; 
d. diastolic BP < 50 or > 89 mm.Hg; 
e. oxygen saturation < 95% (room air). 
Subjects with out-of-range values for these parameters that are not clinically 
significant will be permitted to have vital sign measurements repeated up to 2 times 
during Screening, Check-in (Day -1), and predose on Day 1 to confnm eligibility for 
study participation if the repeat value(s) are n01mal/fall outside of the ranges stated 
above. 
3. Histo1y or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator ( or designee), or mentally or legally 
incapacitated or has significant emotional problems at the time of the Screening visit 
or expected dming the conduct of the study. 
4. Clinically significant abn01mality, as determined by the Investigator (or designee), 
from physical examination at Check-in (Day-1). 
5. Abn01mal laborat01y values (hematology panel, UA, clinical chemistty panel [fasted 
at least 8 hours]) that are clinically significant excluding those further defined in 
exclusion crite1ia #6, #7, and #8 at Screening and/or Check-in (Day -1). Subjects with 
out-of-range clinical laborato1y results that are not clinically significant (excluding 
those further defined in exclusion criteria #6, #7, and #8) may have laborato1y 
assessments repeated at the Investigator (or designee)'s discretion up to 2 times 
dming Screening and Check-in (Day-1) to confmn eligibility for study pa1ticipation 
if the repeat value(s) fall within n01mal ranges or are stabilizing. 
6. Abn01mal liver function tests (LFTs) as defined by aspa11ate aminott·ansferase, 
alanine aminou-ansferase, and sernm (total and direct) bilirubin, as well as amylase, or 
lipase above the upper limit of the nonnal range per the laborat01y's reference ranges 
at Screening or Check-in (Day -1). Subjects with out-of-range LFTs, amylase, and 
lipase values above the upper limit of no1mal that are not clinically significant will be 
pe1mitted to have LFTs, amylase, or lipase assessments repeated up to 2 times during 
Screening and Check-in (Day -1) to confi1m eligibility for study participation if the 
repeat value(s) fall within no1mal ranges. 
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7. Creatine kinase values above the upper limit of the nmmal range per the laboratmy's 
reference ranges that are clinically significant at Screening or Check-in (Day -1). 
Subjects with out-of-range creatine kinase values that are not clinically significant 
will be pe1mitted to have the creatine kinase assessments repeated up to 2 times 
during Screening and Check-in (Day -1) to confnm eligibility for sh1dy pa1ticipation 
if the repeat value(s) are stable or n01malizing. 
8. Estimated glomernlar filtration rate (eGFR) :=:: 80 mL/minute/l.73m2 calculated using 
the CKD-EPI equation at Screening or Check-in (Day -1). Subjects with out-of-range 
eGFR values that are not clinically significant will be pe1mitted to have eGFR 
assessments repeated up to 2 times during Screening and Check-in (Day -1) to 
confum eligibility for study participation if the repeat value(s) fall above the range 
stated above. 
9. HbAlc 6.5% at Screening. Subjects with out-of-range HbAlc values that are not 
clinically significant will be pe1mitted to have HbAlc assessments repeated up to 2 
times during Screening to confum eligibility for sh1dy participation if the repeat 
value( s) fall below the range stated above. 
10. Positive serologic test for HBsAg, HBV IgM core antibody, HCV antibody, or HIV 
antibody at Screening. Subjects who are positive for HBV IgM core antibody or HCV 
antibody require confnmation by PCR before emollment to detect presence of active 
vims. Subjects who are HBV core antibody or HCV antibody positive or for whom a 
PCR is unable to be obtained will not be eligible. 
11. Positive PCR test (or equivalent) for COVID-19 at Screening or Check-in (Day-1). 
Flnther details regarding COVID-19 testing (including procedures for subjects who 
test positive at any time throughout CRU confinement) are specified in a separate 
document. 
12. Histmy of congenital non-hemolytic hyperbilirnbineinia (eg, Gilbe1t's syndrome). 
13. Significant hist01y or clinical manifestation of any allergic, de1matological, biliaiy, 
hepatic, gastrointestinal, renal, metabolic, hematological, pulmonaiy, cardiovascular 
(including any prior histo1y of cardiomyopathy or hea1t failure), neurological, or 
psychiatric disorder (as dete1mined by the Investigator [or designee]), or cancer 
within the past 5 years ( except localized basal cell, squamous, or in situ cancer of the 
skin). Note: subjects with a hist01y of appendectomy and/or hernia repairs will be 
acceptable. 
14. Histmy or presence, upon clinical evaluation, of any illness that, in the opinion of the 
Investigator (or designee), would interfere with the ability to provide informed 
consent or comply with study instrnctions, or that Inight confound the interpretation 
of the study results, or put the subject at undue risk. 
15. Histo1y of a major surgical procedure within 30 days prior to Screening. 
16. Known ongoing alcohol and/or drng abuse within 2 yeai·s prior to Screening, or 
evidence of such abuse as indicated by the laboratory assays for drngs of abuse 
(including cotinine and alcohol) conducted during Screening and/or at Check-in 
(Day-1). Tests for drngs of abuse must be negative at both Screening and Check-in 
(Day -1). 
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17. Use of tobacco, smoking-cessation products, or products containing nicotine and 
e-cigarettes (nicotine and non-nicotine), within 3 months prior to Screening and 
through EOT or ET. 
18. 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 [including herbal products such as St. John's wort], CYP2C8 substrates, 
strong P-gp inhibitors, proton pump inhibitors, antacids, Hi-receptor antagonists, and 
chugs that prolong QT/QTc interval, vitamin supplements, herbal products, natural or 
herbal supplements, and hormone-replacement therapy [HRT]) from 14 days prior to 
Day 1 or 5 half-lives (if known, whichever is longer [except for 
paracetamol/acetaminophen maximum of 2 g/day for up to 3 consecutive days during 
the study]) through EOT or ET, unless deemed acceptable by the Investigator (or 
designee) and Sponsor. 
19. Consumption of grapefrnit/grapefh1it juice or Seville oranges or its juice within 
7 days prior to Check-in (Day -1) and through EOT or ET. 
20. Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours 
prior to Check-in (Day-1) and through EOT or ET. 
21. Histo1y of significant hypersensitivity, intolerance, or allergy to any drng compound, 
food, or other substance, unless approved by the Investigator (or designee). 
22. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator (or designee), within the 30 days p1ior to Day 1 and through EOT or ET. 
23. Pa11icipation in any other investigational study chug trial involving administration of 
any investigational chug in the past 30 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1. 
24. Has previously received LOXO-305 in any other study investigating LOXO-305, 
within 30 days prior to Day 1. 
25. Strenuous exercise within 5 days prior to Check-in (Day-1) and through EOT or ET. 
26. Poor peripheral venous access. 
27. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
28. Receipt of blood products within 2 months piior to Check-in (Day -1). 
29. Subjects who, in the opinion of the Investigator (or designee), should not pa1ticipate 
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 ). 
For subjects who are withch·awn by the Investigator (or designee) or voluntarily withch·aw 
prematurely from the study, replacement subjects will be emolled only if deemed necessaiy 
by the Sponsor. 
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If necessary, as detennined 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 200 to the last 3 digits of the subject number for the subject they are 
replacing (eg, Subject Number 001-301 replaces Subject Number 001-101). 
Subjects who are determined to be screen failiues ar·e permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility c1iteria upon re-screen. Re-screened subjects will be provided a new subject 
number as defined above. 
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 
• 
occunence of AEs 
• 
occunence of pregnancy 
• 
non-compliance with study restrictions 
• 
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 Sponsor. In case of withdrawal, 
effo1ts will be made to perfo1m all ET 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 Repo1t Fonn (eCRF). All withdrawn subjects with AEs that are assessed as 
related to study drng and which are ongoing at ET may continue to be followed until the 
symptoms or value( s) re tum to 1101mal, or acceptable levels, as judged by the Investigator ( or 
designee) and confnmed by the Sponsor. 
The entire study may be discontinued at the discretion of the Investigator (or designee) or 
Sponsor, based on the occunence of the following: 
• 
AEs unknown to date with respect to their nature, severity, and/or duration 
• 
increased frequency and/or severity and/or duration of known AEs 
• 
medical or ethical reasons affecting the continued perfo1mance of the study 
• 
difficulties in the recrnitment of subjects 
• 
cancellation of drng 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. 
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5. STUDY TREATMENTS 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
5.1. 
Description, Storage, Packaging, and Labeling 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study chug (Table 2). 
Table 2: Study Drug 
Study Drug 
LOXO-305 
Forma 
Tablet 
Strength 
100mg 
Supplier 
Loxo Oncology, Inc. 
Manufacturer 
Bend Research, Inc 
• Specific ingredients/pmity will be identified in the Certificate of Analysis ( or equivalent) that is supplied with 
the study drug(s). 
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 will be stored according to the instructions on the label. 
Study chug will be stored at the CRU in a location that is locked with restricted access. 
The bulk dmg container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study ch11g will be stored in accordance with the labeling. The 
study chug will be transfened from bulk supplies into the subject's dose container by 
qualified CRU employees. Each unit dose container will be approp1iately labeled. 
5.2. 
Study Treatment Administration 
Subjects will receive each of the following treatments once throughout the study: 
Treatment A 
• 
A single oral dose of 200 mg LOXO-305 as 2 x 100 mg tablets 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. Water will be restricted for 1 hour prior to and 1 hour after 
dosing with the exception of water administered for dose administration. 
TreatmentB 
• 
A single oral dose of 200 mg LOXO-305 as 2 x 100 mg tablets will be administered 
in the morning on Day 1 or Day 8, approximately 30 minutes after sta1ting a high-fat 
breakfast. Water will be restricted for 1 hour p1ior to and 1 hour after dosing with the 
exception of water administered for dose administration. High-fat breakfasts should 
be entirely consumed within 30 minutes. 
Administration ofLOXO-305 in Treatments A and B (on Day 1 or Day 8) should occur at 
approximately the same time (ie, within 15 minutes). 
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LOXO-305 will be administered orally with approximately 240 mL of water. Water will be 
restricted for I-hour predose and I-hour postdose, with the exception of water administered 
for dose administration. 
Each unit dose will be prepared by qualified CRU staff. 
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be 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 trnnscribed into the eCRF. 
Subjects will be instructed not to cmsh, split, or chew the study drng. 
Subjects will not lay supine for 4 hours following LOXO-305 dose administ:I·ation, except as 
necessitated by the occmTence of an AE(s) and/or study procedure(s). 
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 crite1ia 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 conesponding product 
according to the randomization scheme generated by Covance. 
Subjects will receive each treatment (A and B) on one occasion. The treatments will be 
administered on Day I (Treatment A or B) and Day 8 (Treatment A or B). The sequences to 
be used in the randomization will be AB and BA. 
5.4. 
Blinding 
This is an open-label study. 
S.S. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• 
All doses will be administered under the supervision of suitably qualified CRU staff. 
• 
Immediately after oral dose administr·ation, a visual inspection of the mouth and 
hands will be perfo1med for each subject. 
• 
At each dose preparation occasion, a predose and postdose invento1y ofLOXO-305 
will be perf01med. 
5.6. 
D1·ug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt ofLOXO-305 
tablets received. In addition, an accurate drng disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This mug accountability record 
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will be available for inspection at any time. At the completion of the study, the original drng 
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 
satisfacto1y 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 will be disposed ofby the CRU, 
in accordance with the CRU's Standard Operating Procedures (SOPs) and local/state/federal 
guidelines governing waste disposal of investigational dtugs, following the Sponsor's written 
autholization. 
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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. 
Subjects will refrain from pa1ticipation in any other investigational study drug trial in which 
receipt of any investigational drng occurs within 5 half-lives (if known) or 30 days, 
whichever is longer, p1ior to Day 1. 
All presc1iption medications and over-the-counter medications including but not limited to: 
moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers (including herbal 
products such as St. John's wo1t), CYP2C8 substrates, strong P-gp inhibitors, proton pump 
inhibitors, antacids, H2-receptor antagonists, and drngs that prolong QT/QTc interval, herbal 
products, vitamin supplements, natural or herbal supplements, and HRT are prohibited for 
14 days or 5 half-lives (if known), whichever is longer (except for 
paracetamol/acetaminophen as referenced above), prior to Day 1 and through EOT or ET, 
unless deemed acceptable by the, Investigator (or designee), and Sponsor. 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 
rep01ted 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 and e-cigarettes (nicotine and non-nicotine), within 3 months 
prior to Screening through EOT or ET. 
Consumption of foods or beverages containing grapefrnit/grapefrnit 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. 
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. 
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 othe1wise maintain their nonnal level 
of physical activity through EOT or ET (ie, should not begin a new exercise program or 
pa1ticipate in any unusually strenuous physical exe1iion). 
In Treatment A, subjects will be fasted for at least 10 hours prior to dosing until 4 hours 
postdose, after which a meal will be provided. Water will be restricted for 1 hour p1ior to and 
1 hour after dosing. In Treatment B, subjects will consume a high-fat breakfast (contents are 
detailed in Table 3) before dosing. Aside from the 240 mL of water to be ingested with 
Treatment A and Treatment B, water will be restricted for 1 hour prior to and 1 hour after 
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dosing. The high-fat breakfast should contain between 800 to 1000 calories (comprising 
approximately 150 calories from protein, 250 calories from carbohydrates, and 500 - 600 
calories from fat). 9 Subjects should start the meal 30 minutes prior to administration of 
LOXO-305 and eat this meal in 30 minutes or less. LOXO-305 should be administered 
30 minutes after start of the meal. 
Administration ofLOXO-305 in Treatments A and B (on Day 1 or Day 8) should occur at 
approximately the same time (ie, within 5 minutes). 
Table 3: High-fat Breakfast Content 
High-fat Breakfast 
2 eggs fried in butter 
2 strips of bacon 
2 slices of toast with butter 
4 oz of hash brown potatoes (fried with butter) 
8 oz (240 mL) of whole milk 
While confined at the CRU, subjects will receive a standard diet at scheduled times that do 
not conflict with other study-related activities. 
Fasting 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 plasma concentrations ofLOXO-305 will be collected at 
the timepoints specified in Appendix 4. The exact time of the study drng administration and 
the actual time of blood sampling for PK analysis will be recorded on the eCRF. 
Processing, storage, and shipping instrnctions for these PK blood samples will be provided in 
a separate Laborato1y 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 ofLOXO-305 in plasma will be detennined 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. 
Eve1y effort will be made to schedule and perfonn the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and any other procedures to be perf01med at the same timepoint. The order of priority for 
scheduling procedures around a timepoint is (in order of priority): 
• 
dosing 
• 
PK blood sampling 
• 
vital sign measurements * 
• 
12-lead ECGs * 
• 
blood and urine samples for clinical laborat01y evaluations 
• 
physical examination. 
* When vital sign measurements and 12-lead ECGs are scheduled at the same time as PK 
blood sampling, the PK blood sampling will be obtained at the scheduled timepoint, and the 
vital sign measurements followed by 12-lead ECGs will be obtained p1ior to and as close as 
possible to the scheduled PK blood sampling. 
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 
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in Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in [Day-1], at each 
postdose vital sign measurement, and at an appropriate time for all other days). Subjects will 
also be encouraged to volunta1ily report AEs occuning at any other time through the EOS. 
Adverse events, whether volunteered, identified by the subject's responses to HDYF? 
inquii·ies, or noted on physical examination, ECG, vital sign measurements, or clinical 
laborat01y evaluations, 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 hist01y (if the event is rep01ted as beginning 
prior to signing of the ICF or if the event occurs prior to study diug adininistration 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 di11g adininistration on Day 1 
and is assessed as related to study procedures by the Investigator [ or designee ], or if the event 
occurs after study di11g administration on Day 1 through EOT or ET regardless of relationship 
to study diug). From EOT or ET through EOS, only AEs assessed as related to study diug by 
the Investigator (or designee) are to be repo1ted. All SAEs that develop from the time ofICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be rep01ted. 
Unless a subject withdi·aws consent or is withdrnwn 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 diug by the Investigator ( or designee) which are ongoing at EOS 
may continue to be followed until the symptoms or value(s) return to n01mal, or acceptable 
levels1 as judged by the Investigator (or designee) and confnmed by the Sponsor. The 
h1vestigator ( or designee) should use appropliate judgment in ordering additional tests as 
necessruy to monitor the resolution of events. The Sponsor may request that additional safety 
tests be pe1fo1med. 
Subjects will receive a follow-up phone call 7 days (± 2 days) after EOT or ET to detennine 
if any SAE or mug-related AE has occurred since the EOT or ET visit. 
At all times, a subject may be requii·ed 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) accordii1g to CRU policy 
by the Investigator (or designee) and to regulato1y authorities by the Sponsor (or Sponsor 
designee) according to regulato1y authority requirements. Refer to Reference Safety 
Infonnation in the cmTent 1B1 for LOXO-305 for additional safety inf01mation. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laborato1y evaluations (clinical chemistiy panel [fasted at least 8 hours; at ET or the 
day before EOT, subjects are not required to be fasted prior to clinical laborato1y 
evaluations], coagulation parameters, hematology panel, TSH [Screening only], HbAlc 
[Screening only], eGFR [Screening and Check-in (Day -1)], and UA) will be collected at the 
tiinepoints specified in Appendix 4. 
Screens for HCV antibody, HBsAg, HBV IgM core antibody, and HIV antibody will be 
perfo1med at Screening. 
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Testing for COVID-19 via PCR (or equivalent) will be performed at the timepoints specified 
in Appendix 4. Testing for COVID-19 may also be conducted periodically during the 
subject's CRU confinement, at the discretion of the Investigator (or designee). Further details 
regarding COVID-19 testing (including procedures for subjects who test positive at any time 
throughout CRU confinement) are specified in a separate document. 
A urine drug screen for selected chugs of abuse (including cotinine) and an alcohol screen 
(urine or breath) will be performed at Screening and repeated at Check-in (Day-1) for all 
subjects. A se1um qualitative pregnancy test (female subjects only [ se1um quantitative may 
be used for confamation, if needed]) and an FSH test (post-menopausal female subjects only) 
will be perfo1med at the timepoints specified in Appendix 4. 
The number of blood samples and total blood volume required for clinical laborato1y 
evaluations are presented in Appendix 3. A list of the specific evaluations is in Appendix 2. 
7.2.3. 
Vital Signs 
Vital sign measurements (including body temperature, respirato1y rate, oxygen saturation, 
and supine BP and pulse rate) will be obtained at the timepoints specified in Appendix 4. 
Blood pressure and pulse rate measurements should be perfo1med using the same arm for 
each reading and measurements should be taken after the subject has been resting in the 
supine position for at least 5 minutes. 
When vital sign measurements are scheduled at the same time as PK blood draws, the PK 
blood ch·aws will be obtained at the scheduled timepoint, and the vital sign measurements will 
be obtained prior to and as close as possible to the scheduled PK blood draw. 
7.2.4. 
12-lead Electrocardiogram 
A 12-lead ECG (including HR, PR, RR, QRS, and QT inte1val parameters) will be obtained 
after the subject has been resting for at least 10 minutes in the supine position at the 
timepoints specified in Appendix 4. The QT inte1val will be conected for HR by Fridericia's 
(QTcF = QT/[RR]113) fo1mula. 
When 12-lead ECGs are scheduled at the same tin1e as PK blood draws, the PK blood draws 
will be obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to 
and as close as possible to the scheduled PK blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated physical examination will be perfo1med at the timepoints specified 
in Appendix 4. Complete physical examinations will evaluate general appearance and the 
following body systems/organs: dennatological; head and eyes; ears, nose, mouth, and throat; 
pulmona1y; cardiovascular; abdominal; lymphatic; musculoskeletal/extremities; and 
neurological. Weight and height will be repo1ted (height only repo1ied during Screening). 
Abbreviated physical examinations will evaluate general appearance and the following body 
systems/organs: de1matological; pulmona1y; cardiovascular; abdominal; and neurological. 
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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
Up to 20 healthy adult male and female subjects (women of non-childbearing potential only) 
will be emolled. This is a Phase 1 study and the sample size is consistent with previous 
studies of a similar design. Up to 20 subjects are anticipated to be sufficient to provide a 
reliable estimate of the magnitude and variability of the food effect. The highest 
within-subject coefficient ofva1iation observed in LOXO-BTK-20014 was 20.9% for Cmax. A 
sample size of 20 subjects (10 per treatment sequence) will provide approximately 80% 
power to have the respective 90% Cls for the geometric mean ratios for Cmax and AUC values 
between fed and fasted treatments are within the interval of 80% to 125%, assuming a 
within-subject coefficient of variation of20.9% and that the expected ratio of means is 1.05. 
Replacement subjects may be emolled only if deemed necessaiy by the Sponsor. 
Eve1y attempt will be made to emoll at least 3 subjects of each sex in the study. 
8.2. 
Analysis Populations 
The PK Population will consist of all subjects who have received a dose of study drng, 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 summa1y statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before tmax. The impact of protocol 
deviations on the PK population will be evaluated on a case-by-case basis. 
The Safety Population will consist of all subjects who have received at least 1 dose of study 
drug. 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): 
• 
area under the concentration-time curve (AUC) from hour Oto 24 hours postdose 
(AUCo-24) 
• 
AUC from hour 0 to the last measurable concentration (AUCo-t) 
• 
AUC from hour 0 extrapolated to infinity (AUCo-inf) 
• 
percentage extrapolation for AUCo-inf (%AUCextrap) 
• 
apparent systemic clearance (CL/F) 
• 
Cmax 
• 
mean residence time (MRT) 
• 
apparent plasma terminal elimination half-life (t½) wherever possible, where ti12= 
natural log (2)/'Az 
• 
time to maximum observed plasma concentration (tmax) 
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• 
apparent terminal elimination rate constant 0-z) 
• 
apparent volume of dis1l.-ibution at tenninal phase (V z1F) 
Phannacokinetic calculations will be perfo1med using commercial software such as Phoenix 
TM 
WinNonlin® Version 8.1 or higher (Certara USA Inc.). 
Other parameters may be added as appropriate .. Final PK parameters rep01ted will be detailed 
in the Statistical Analysis Plan (SAP). 
Phannacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analyses will be pe1fo1med using SAS® Version 9.4 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, alithmetic mean, standard deviation, coefficient of variation [CV%], geometric 
mean, geometric CV%, median, minimum, and maximum). 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. 
8.3.2. 
Statistical Methodology 
The prima1y PK analysis planned for this study is a mixed effect model including planned 
u·eatment sequence, and actual u·eatlnent as fixed effects and subject within planned 
treatment sequence as a random effect will be used to analyze the natural log (ln)-t1·ansf01med 
PK parameters (AUCo-t, AUC0-inf, and Cmax) and will include calculation of least squared (LS) 
means and the difference between u-eatlnent LS means, as well as their co1Tesponding 90% 
confidence intervals (Cis). The geomeu·ic mean ratios and their 90% Cis of the PK parameter 
for each u·eatment comparison will be const111cted using the exponentiation of the difference 
and the Cis from the mixed effect model. The comparison of interest is Treatlnent B 
compared with Treatment A. 
8.4. 
Safety Analysis 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated and summa1ized where possible, using descriptive methodology, as needed, by 
timepoint. Unless otherwise specified, baseline value is defined as the last non-missing 
measurement before adrninisu·ation of study drug on Day 1 and Day 8. No formal statistical 
analyses are plam1ed 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, September 2019). Adverse events will be coded using 
Medical Dictionaiy for Regulato1y Activities (MedDRA) Version 22.1 (or higher). The 
incidence of AEs will be presented by severity and by relationship to study drng as 
determined by the Investigator or designee (Appendix 1 for AE rep01ting). All TEAEs will be 
summarized by system organ class and prefe1Ted tenn. 
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Data Handling and Record Keeping 
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Any changes to inf01mation 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 enoneous data and clearly 
entering the conect data (eg, vR,sBg a.1~a right data). If the reason for the change is not 
apparent, a brief explanation for the change will be w1itten adjacent to the change by the 
CRU staff member. 
The Data Management Plan will be approved hy the Sponsor. 
Data will be validated dming 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 ancillaiy data will be conve1ted into 
final SAS® datasets following Study Data Tabulation Model or Sponsor-provided 
specifications. The final datasets stI1.1cture 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 diy nm and data review meetings. 
The peer review will be perfo1med by independent programmers following the quality contr·ol 
process and programming checklists. 
8.6. 
Quality Control and Quality Assurance 
Quality contr·ol and quality assurance will be pe1f01med according to Covance SOPs or per 
Sponsor request, and as applicable, according to the contr·act between Covance and the 
Sponsor. 
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9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
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Protocol Reference: LOXO-BTK-20009 
There will be no alterations in the protocol without agreement between the Sponsor and the 
hlvestigator (or designee). 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, hlvestigator (or designee), and the IRB (see Form 
FDA 1572). 
9.2. 
Site Initiation Visit/Investigator Meeting 
Prior to the sta1t of the clinical study, the representative(s) of the Sponsor and/or Sponsor will 
meet with the Investigator (or designee) and approp1iate CRU staff to familia1ize the 
Investigator (or designee) and CRU staff with the materials necessary for conducting the 
clinical study. 
9.3. 
Disclosure 
All inf01mation provided regarding the study, as well as all information 
collected/documented dming the study, will be regarded as confidential. The hlvestigator ( or 
designee) agrees not to disclose such info1mation in any way without prior written pe1mission 
from the Sponsor. 
Any publication of the results, in pa.it 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 
caI1I1ot be made in violation of the Sponsor's confidentiality restrictions or to the detriment of 
the Sponsor's intellectual property rights. 
9.4. 
Monitoring 
Covance (on behalf of the Sponsor) will designate Study Monitors who will be responsible 
for monitoring this clinical trial. Covance's Study Monitor will monitor the study conduct, 
proper eCRF and source documentation completion and retention, and accurate study drng 
accountability. It is essential that Covance's Study Monitors have access to all documents 
(related to the study and the individual pa1ticipants) at any time these are requested. In tum, 
Covance's Study Monitors 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 Covance's Study Monitors. 
9.5. 
Institutional Review Board 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
adve1tisement, ICF, and other inf01mation 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 ). 
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The IRB will be inf 01med 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 pe1mit audits by the IRB and regulato1y 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 Repmt following the completion, 
tem1ination, or discontinuation of the Investigator's (or designee's) pa1ticipation in the study. 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are caITied out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
Tue Investigator ( or designee) will explain the nature of the study and the action of the test 
product. Tue subjects will be inf 01med that participation is volunta1y and that they can 
withdraw from the study at any time. In accordance with 21 CFR 50, the info1med 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 pe1fonned. 
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. 
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 transfened to the Sponsor (or designee). Copies of each eCRF 
will be retained by the Investigator ( or designee ). All source documents, records, and repo1ts 
will be retained by the CRU in accordance with 21 CFR 312.62(c). 
All prima1y data, or copies thereof ( eg, laboratory records, eCRFs, data sheets, 
conespondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessa1y for the reconstrnction and 
evaluation of any study repo1t, 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), and Investigational New Drng Application 
(21 CFR 312), as appropriate. As such, these sections of US Title 21 CFR, along with the 
applicable ICH Guidelines, are commonly known as Good Clinical Practices, which are 
consistent with the Declaration of Helsinki. 
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9.9. 
Financing and Insurance 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Financing and insurance will be addressed in a separate agreement. 
Protocol Version 1. 0, 1 December 2020 
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Protocol 
Covance Study: 8419688 
10. REFERENCES 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
1. Loxo Oncology, Inc. LOXO-305 - Investigator's Brochure (Version 4.0). 29 October 
2020. 
2. Brandhuber B, Gomez E, Smith S, Ea1y T, Spencer S, Rothenberg SM, et al. A next 
generation reversible BTK Inhibitor, for overcoming acquired resistance to ineversible 
BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18; S216. 
3. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK 
with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 
4;369(1):32-42. 
4. Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrntinib in Chronic Lymphocytic Leukemia_ J Clin 
Oncol. 2017 May 1;35(13):1437- 43. 
5. Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to 
acalabrntinib in CLL is mediated primarily by BTK mutations. Blood. 
2019;134(Supplement_l). 
6. Chiron D, Di Libe1to M, Martin P, Huang X, Shannan J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition ovenides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022- 35. 
7. Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrntinib resistance in Waldenstrom macroglobulinemia. Blood. 2017 
04;129(18):2519- 25. 
8. Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, Hanrna M, et al. QT 
PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT 
Inte1val Prolongation by Human Phaimace11ticals [Internet]. Journal of pharmacological 
sciences. 2005 [cited 2020 Jun 10]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/16493187 / 
9. Food and Drng Administration. Guidance for Industly, Draft Guidance: Assessing the 
Effects of Food on Drngs in INDs and NDAs - Clinical Phannacology Considerations 
[Internet]. Food and Drng Administration; 2019. Available from: 
https://www.fda.gov/media/121313/download 
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11. APPENDICES 
Protocol Version 1. 0, 1 December 2020 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
An adverse event (AE; or adverse expe1ience) is defined as any untoward medical occmTence 
expelienced by a patient or healthy adult subject, whether or not considered drng-related by 
the Investigator (or designee). A treatment-emergent adverse event (TEAE) is an AE that 
sta1ts on or after the first administration of study drng. 
The following are all AEs: 
• 
unfavorable changes in general condition 
• 
subjective or objective signs/symptoms 
• 
concomitant diseases or accidents 
• 
clinically significant adverse changes in laborato1y parameters observed in a subject 
dming a clinical study 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laborato1y abno1malities that are deemed clinically significant 
by the Investigator [ or designee ]), and accidents observed in the context of a clinical tiial, 
inespective 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 
Te1minology C1iteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• 
Grade 1 Mild: Asymptomatic or Inild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• 
Grade 2 Moderate: Minimal, local, or noninvasive intervention indicated; lilniting 
age-appropriate instlllIIlental Activities of Daily Living (ADL)* 
• 
Grade 3 Severe or meclically significant but not immediately life-threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; lilniting 
self-care ADL ** 
• 
Grade 4 Life-threatening consequences: An event that puts the subject at 
immediate risk of death 
• 
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 S ( death) is not appropriate for some AEs and therefore is not an option. 
+ Instrumental ADL refer to preparing meals, shopping for groce1ies, 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 
bedtidden. 
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Protocol 
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CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
The Investigator ( or designee) will make a determination of the relationship of the AE to the 
study drng using a 2-categoiy system according to the following guidelines: 
• 
NOT RELATED= Tue time course between the administration of investigational 
product and the occmTence or worsening of the AE rnles out a causal relationship 
and another cause (eg, concomitant drugs, therapies, complications, comorbidities) 
is suspected 
• 
RELATED= The time course between administration of investigational product 
and the occmTence or worsening of the AE is consistent with a causal relationship 
and no other cause (eg, concomitant drngs, therapies, complications, comorbidities) 
can be identified 
An AE is associated with the use of the drng if there is a reasonable possibility that the 
experience may have been caused by the drng. 
Pregnancy 
As info1mation is available, a pregnancy (including pregnancy in female pa1tners of male 
subjects) diagnosed through End of Study (EOS) or Early Termination (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 drng administration on Day 8 ( or last administration of study drng if 
subject terminates from the study early) should. be repmted 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 F01m to the Investigator (or designee) for completion. 
email: SAEintake@Covance.com 
A subject becoming pregnant while on study dn1g will immediately be withdrawn from the 
study and ET study procedures will be performed. The subject or pa1tner should be followed 
by the Investigator (or designee) until completion of the pregnancy. If the pregnancy ends for 
any reason before the anticipated date, the Investigator ( or designee) should notify Covance 
or the Sponsor's Clinical Safety Representative. At the completion of the pregnancy, the 
Investigator (or designee) 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, 
postprutum complication, spontaneous abo1tion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator (or designee) should follow the procedures for repo1ting an SAE. 
Male subjects will be instrncted to notify the Investigator (or designee) immediately if they 
discover their sexual pa1tner is pregnant. In this instance, the pa1tner must provide written 
consent before pregnancy information can be collected. When a Clinical Research Unit 
(CRU) becomes aware that the female partner of a male subject is pregnant, they are to 
contact the Investigator (or designee) 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 Case Report Fmm (eCRF; as 
appropriate), in addition to completion of the required pregnancy fo1ms. If the Investigator 
(or designee) suspects that a pregnancy was the result of an interaction between the study 
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CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
treatment and the contraceptive method, in addition to the pregnancy the drng interaction 
should also be captured as a separate AE. 
Definition of Serious Adverse Events 
An SAE by the Food and Drug Administration (FDA) definition is any adverse drug 
experience occuning at any dose that results in any of the following outcomes: 
• 
Death; 
• 
A life-threatening adverse drng experience (ie, one that places the subject, in the 
view of the Investigator [ or designee], at immediate risk of death) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/biI1h defect 
• 
An important medical event that may requiI·e medical or surgical inte1vention to 
prevent 1 of the above outcomes 
lmpo1tant medical events that may not result in death, be life-threatening, or requiI·e 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may .-equire medical or surgical inte1vention to 
prevent 1 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 obse1ved for an unapproved investigational 
medicinal product (IMP). 
Repo11ing 
The FDA-reportable AEs are AEs that are asso,ciated with the use of the drug and represent 
events that are assessed as serious, related, and unexpected. The FDA-reportable AEs will be 
reported by the CRU to the Sponsor and the responsible Institutional Review Board (IRB). 
Final detennination 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 repo1t the SAE, the completed report fonn should be sent by email to Covance or the 
Sponsor's Clinical Safety Representative within 24 hours of awareness. Incoming repo1ts are 
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CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
reviewed during normal business hours. Additional rep011ing instrnctions and the SAE Rep011 
Form are provided in the Study Manual. 
The IRB will be notified of any FDA-rep011able 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 summa1y of the AE. 
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Protocol 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Appendix 2: Clinical Laboratory Evaluations 
Clinical Che1nisti·y Panel 
Hematology Panel: 
Other Tests: 
(Fasted): 
Alanine aminotransferase (ALT) Hematocrit 
Hemoglobin Ale (HbAi c? 
Albumin 
Hemoglobin 
Thyroid-stimulating hormone 
Alkaline phosphatase (ALP) 
Mean corpuscular hemoglobin 
(TSH/ 
Amylase 
Mean corpuscular hemoglobin 
Estimated glomerular filtration 
Aspaitate aminotransferase 
concenn·ation 
ratea,d 
(AST) 
Mean corpuscular volume 
SARS-CoV-2 (COVID-19) test 
Bilirubin ( direct and total) 
Platelet count 
Coagulation Parameters: 
Blood urea nin·ogen 
Red blood cell (RBC) count 
Pa1t ial thromboplastin time 
Calcium 
RBC disnibution width 
Chl01ide 
White blood cell (WBC) count 
Prothrombin time 
International nonnalized ratio 
Cholesterol 
WBC differential (percent and 
Creatine kinase 
absolute): 
Sernlogy:h 
Creatinine 
Basophils 
Hepatitis B smface antigen 
Glucose 
Eosinophils 
(HBsAg) 
fron 
Lymphocytes 
Hepatitis B virus (HBV) 
Lipase 
Monocytes 
immunoglobulin M (IgM) core 
Magnesium 
Neun·ophils 
antibody 
Phosphoms 
Hepatitis C vims (HCV) 
Potassium 
antibody 
Sodium 
Human immunodeficiency vim s 
Total protein 
Triglyceiides 
(HIV) antibody 
U1ic acid 
For Female Subjects Only: 
Pregnancy test (semm 
U1inalysis: 
qualitative, sernm quantitative 
Bilirubin 
may be used for confumation if 
Color and appearance 
neededt 
Follicle-stimulating hormone 
Urine Drug Screen:a 
Glucose 
(post-menopausal female 
Including but not limited to the 
Ketones 
subjects only)b 
Leukocyte esterase 
following: 
Nitii te 
Alcohol ( ethanolt 
Occult blood 
Amphetamines 
pH and specific gravity 
Bai·biturates 
Protein 
Benzodiazepines 
Urobilinogen 
Cannabinoids 
Microscopic examination 
Cocaine (metabolite) 
including bacte1i.a, casts, 
Methadone 
c1ystals, epithelial cells, RBCs, 
Opiates 
and WBCs (if protein, leukocyte 
Phencyclidine 
esterase, nitrite, or occult blood 
Cotinine 
is positive) 
a. Perfonned at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Perfonned at Screening, Check-in (Day -1), and Day 14 for End of Treatment (EOT) or Early Tennination 
(ET) only. 
d. Calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 
e. Urine or breath test. 
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Appendix 3: Total Blood Volume 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
The following blood volumes will be withdrawn for each subject: 
Appro:ximate Blood 
Maximum 
Approximate 
Volume per Sample Number of Blood Total Volume 
Assessment 
(mL) 
Samples 
(mL) 
Serology 
8.0 
1 
8.0 
Hemoglobin Ale (HbAlc) 
4.0 
1 
4.0 
LOXO-305 Pha1macokinetic (PK) 
4.0 
39 
156.0 
sampling 
Clinical laborato1y evaluations: 
Hematology 
4.0 
6 
66.0 
Clinical chemisuy 
4.0 
Coagulation 
3.0 
Semm pregnancy test (female subjects 
4.0 
3 
12.0 
only) 
Semm follicle-stimulating h01mone 
4.0 
1 
4.0 
!(post-menopausal female subjects only) 
Total: 
250.0 mL 
• Thyroid stimulating hormone (TSH) and estimated glomernlar filtration rate (eGFR) will be assessed as part. of the clinical 
chemist1y sample. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 500 mL. 
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Protocol 
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Appendix 4: Schedule of Assessments 
Protocol Version 1. 0, 1 December 2020 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
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Protocol 
Covance Study: 8419688 
Period 1 
Screening 
Check-in 
(Days -29 to -2) 
(Day -1) 
1 
2 
3 
4 
5 
Study Procedures• 
Confined to the CRU 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Crite1ia 
X 
X 
Infonned Consent 
X 
Demographics 
X 
Medical Histmy 
X 
X1' 
Height/W eiimt/BMI 
xc 
X 
Physical Examinatimi 
X 
12-lead ECG• 
X 
X 
X 
X 
Vital Si2:n Measurementsr,g,h 
X 
X 
X 
X 
X 
X 
X 
HDYF? lnqui1yi 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEs.i 
X 
X 
X 
X 
X 
X 
X 
LOXO-305 Dosing 
X1' 
Clinical Laboratmy Evaluations" 
X 
X 
X 
eGFR 
X 
X 
Hepatitis and HIV Screen 
X 
COVID-19 Screen° 
X 
X 
HbAlc Test 
X 
Drug ScreenP 
X 
X 
Prior and Concomitant 
X 
X 
X 
X 
X 
X 
X 
Medicationsq 
Semm Pregnancy Test' 
X 
X 
FSHTest" 
X 
TSH Test 
X 
6 
7 
8 
9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
X 
X 
X 
X 
X 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Clinic 
Follow-up 
Period 2 
Discharge/ 
Phone Call 
EOT/ET' 
(EOS) 
7 (± 2) days 
10 11 12 13 14 
15 
post 
EOT/ET" 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; BMI = body mass index; BP= blood pressure; COVID-19 = SARS-Co V-2; CRF = Case Report F01m; CRU = Clinical Research Unit; 
ECG = electrocardiogram; eGFR = estimated glomemlar filtration rate; EOS = End of Study; EOT = End of Treatment; ET= Early Termination; FSH = follicle-stimulating hormone; HbAlc = 
hemoglobin Ale; HDYF? = How Do You Feel?; HIV = human inmmnodeficiency vims; ICF = Informed Consent Form; PK = pha1macok:inetic; SAE = serious adverse event; 
TSH = thyroid-stimulating honnone; UA = urinalysis. 
a. For details on study procedures, see Section 7. 
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Protocol 
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b. Interim medical history only. 
c. Height collected at Screening only; BMI calculated based on Screening height. 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
d. A complete physical examination will be perfonned at Check-in (Day -1). An abbreviated physical examination will be perfo1med at Day 15 (EOT) or at ET. 
e. 12-lead ECGs will be obtained at Screening and Check-in (Day -1 ), Day 1 (predose ), Day 4 (72 hours post dose on Day 1 ), Day 8 (predose ), Day 11 (72 hours postdose on Day 8), and Day 15 
(168 hours postdose on Day 8 [EOT]) or ET. 12-lead ECGs will be collected after the subject bas rested in the supine position for at least 10 minutes. When scheduled at the same ti.me as PK 
blood draws, 12-lead ECGs will be obtained prior to and as close as possible to having blood drawn. The allowed sampling window for 12-lead ECGs is± 30 minutes from the nominal 
ti.mepoint for all postdose 12-lead ECGs and no less than 10 minutes p1ior to dosing for predose 12-lead ECGs. 
f. Vital sign measurements (supine BP and pulse rate) will be obtained at Screening, Check-in (Day -1), Day 1 (predose, 2 hours after dosing), daily on Days 2 through 7 (24, 48, 72, 96, 120, 
and 144 hours postdose on Day 1), Day 8 (predose, 2 hours after dosing), daily on Days 9 through 14 (24, 48, 72, 96, 120 and 144 hours postdose on Day 8), and on Day 15 (168 hours 
postdose on Day 8 [EOT]) or ET. Blood pressure and pulse rate will be measured using the saine ann for each reading after the subject has been supine for at least 5 minutes. When 
scheduled at the same tin1e as PK blood draws, vital sign measurements should be canied out prior to and as close as possible to having blood drawn. The allowed sampling window for vital 
sign measm·ements is ± 30 minutes from the nominal timepoint for all postdose vital sign measurements and no less than 1 O minutes prior to dosing for predose vital sign measurements. 
g. Respi.rato1y rate and body temperature will be obtained at Screening, Check-in (Day -1 ), and Day 15 (I 68 hours postdose on Day 8 [EOT]) or ET. 
h. Oxygen saturation will be measured via pulse oximetry at Screening, Check-in (Day -1), predose on Day 1, and Day 15 (EOT; 168 hours postdose on Day 8) or ET. The allowed sampling 
window for oxygen saturation measurements is± 30 minutes from the nominal timepoint for all postdose oxygen saturation measurements and no less than 10 minutes prior to dosing for 
predose oxygen saturation measurements. 
i. A HDYF? inquily will be performed at Screening (after the ICF is signed), at Check-in (Day -1), at each postdose vital sign measurement, and at an appropriate time for all other days. 
j. 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 llllti.l EOS, or lllltil ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as subject medical histo1y (if the event is repo1ted as beginning p1ior to signing of the ICF or if the 
event occurs p1ior to study dmg administration on Day 1 and is assessed as not related to study procedm·es by the Investigator [ or designee]) or as AEs (if the event occurs after signing of the 
ICF but p1ior to study drug administration on Day 1 and is assessed by the Investigator [ or des.ignee]) as related to study procedures, or if the event occurs after study dmg administration on 
Day l through EOT or ET regardless of relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug are to be recorded. All SAEs that develop from 
the tilne ofICF 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. 
k. On Day 1, LOX0-305 will be admilristered in the moming, either following a fast of at least 10 hours prior to and 4 hours after LOX0-305 adnrini.stration (with water restricted for l hour 
prior to and l hour post-LOXO-305 administration) or approximately 30 nrinutes after the start of a high-fat breakfast (with water restricted for 1 hour p1ior to and 1 hour post-LOXO-305 
administration), according to the treatment sequence the subject is randomly assigned to. High-fat breakfast should be entirely consumed within 30 minutes. 
L On Day 8, LOXO-305 will be adnrini.stered in the monring at approximately the same ti.me as LOXO-305 was ad1ni.ni.stered on Day I(+/- 15 minutes), either following a fast ofat least 
10 hours prior to and 4 hours after LOXO-305 administration (with water restricted for 1 hour prior to and 1 hour post-LOXO-305 administration) or approximately 30 nrinutes after the start 
of a high-fat breakfast (with water restricted for 1 hour p1ior to and I hour post-LOXO-305 administration), according to the treatment sequence the subject is randomly assigned to. High-fat 
breakfast should be entirely consumed within 30 1ni.nutes. 
Ill. 
n. Clilrical chenristiy panel (fasted for at least 8 hours), coagulation parameters, hematology panel, and UA will be perfonned at Screening, Check-in (Day -1 ), Day 4 (72 hours postdose on 
Day 1), Day 7 (144 hours postdose on Day 1), Day 11 (72 hours postdose on Day 8), and Day 14 (144 hours postdose on Day 8, if the subject completes the study [EOT]), or on the day of 
ET. At ET or the day before EOT (Day 14), subjects are not required to be fasted prior to clilri,ca! laborato1y evaluations. 
o. Testing for COVID-19 will be conducted at a 1nininlum at Scree1ring and Check-in (Day -1). Testing for COVID-19 may also be conducted periodically dming the subject's CRU 
confmement, at the discretion of the Investigator (or designee). Tests will be performed by rapid polymerase chain reaction or equivalent. 
p. Urine dmg screen for dmgs of abuse (including cotini.ne) and alcohol screen (mine or breath). 
Protocol Version 1.0, 1 December 2020 
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CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
q. Prior and concomitant medication administration will be recorded beginning at infonned consent. In addition, all Investigator-approved presc1iption and over-the-counter medications taken 
by a subject within 14 days or 5 half-lives (if known), whichever is longer, p1ior to Day 1 will be recorded on the subject's electronic CRF. 
r. Female subjects only. Pe1fonned at Screening, Check-in (Day-1), and Day 14 (144 hours postdose on Day 8), if the subject completes the study (EOT) or on the day of ET. 
s. Post-menopausal female subjects only. 
t. End of Treatment is defined as when the subject is released from the CRU following completion of all assessments through Day 15. Early Tennination is defined as when the subject is 
released from the CRU if the subject terminates the study early. Vital sign measurements, ECG, and abbreviated physical exaniination results are to be available for review by the Investigator 
(or designee) prior to subject release from the CRU on Day 15 (EOT) or ET. Clinical laboratory results (for clinical chemistty, hematology, coagulation, and UA) and semm pregnancy test 
results (female subjects only) are to be available for review by the Investigator (or designee) prior to subject release from the CRU at the EOT visit and p1ior to subject release from the CRU 
at the ET visit, if available. 
u. To be conducted 7 days(± 2 days) following EOT or ET. End of Study is defmed as when the subject is contacted by the CRU for a follow-up phone call 7 days(± 2 days) after the EOT visit 
or ET visit to determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-305 (including subjects who are terminated early) will 
receive a follow-up phone call. 
Protocol Version 1.0, 1 December 2020 
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SAP_001.pdf: 
Statistical Analysis Plan LOXO-BTK-20009 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to Investigate the Effect of 
Food on the Pharmacokinetics of a Single Oral Dose of Pirtobrutinib (LOXO-305) in 
Healthy Subjects
NCT06180980 
Approval date: 11-May-2021 


Statistical Analysis Plan 
A Phase I, Open-Label, Randomized, 2-Way Crossover Study to 
Investigate the Effect of Food on the Pharmacokinetics of a Single Oral 
Dose of LOXO-305 in Healthy Subjects 
SAP Status: Sponsor Final 
SAP Version: 2.0 
SAP Date: 1 lMA Y2021 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20009 
Covance Study: 8419688 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidia1y of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Coordinating Investigator: 
PD 
Coordinating Investigator Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 3 2117 
USA 
Up to 2 additional sites in the United States 
may be utilized. 
Infonnation described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


SAP 
Covance Study: 8419688 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1.1. Prima1y Objective ..................................................................................................... 6 
2.1.2. Secondary Objective ........................ ......................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3 .1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondaiy Endpoints ....................................................................................................... 7 
4. STUDY DESIGN ................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ............... ......................................................................... 9 
6. STUDY TREATMENTS ....................................................................................................... 9 
7. DEFINITIONS OF POPULATIONS ........... ....................................................................... 10 
7.1. All Subjects Population ................................................................................................. 10 
7.2. Safety Population .......................................................................................................... 10 
7.3. Pham1acokinetic Population ......................................................................................... 10 
8. STATISTICAL METHODOLOGY .................................................................................... 11 
8.1. General ................................................... ....................................................................... 11 
8.1.1. Calculation of the Summa1y Statistics ................................................................... 11 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 12 
8.1.3. Defmitions of Baseline and Change from Baseline ............................................... 12 
8.1.4. Period Specific Study Day ..................................................................................... 12 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Demographics ............................................................................................................... 13 
8.4. Prior and Concomitant Medication ............................................................................... 13 
8.5. Pham1acokinetic Assessments ...................................................................................... 13 
8.5.1. Phannacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation Phaimacokinetic Parameters .............................................................. 16 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ............................................................................ 17 
8.6.1. Adverse Events ....................................................................................................... 17 
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8.6.2. Clinical Laboratory Parameters .............................................................................. 19 
8.6.3. Vital Signs Results ................................................................................................. 19 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 19 
8.6.5. Other Assessments .......................... ....................................................................... 19 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
9. INTERIM ANALYSES ....................................................................................................... 20 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 20 
11. REFERENCES .................................................................................................................. 20 
12. APPENDICES ................................................................................................................... 21 
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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs ]). 
%AUCextrap 
ADaM 
AE 
AUC 
AUCo-24 
AUCo-inf 
AUCo-t 
BLQ 
CDISC 
CI 
CL/F 
Cmax 
CRU 
CSR 
CTCAE 
CV 
ECG 
EOS 
EOT 
ET 
Geom CV 
Geom Mean 
ICF 
ICH 
Az 
Az Lower 
Az N 
Az Span Ratio 
Az Upper 
LSM 
MedDRA 
percentage extrapolation for area under the concentration-time curve 
extrapolated to infinity 
analysis data model 
adverse event 
area under the concentration-time cmve 
area m1der the concentration-time cmve from hour Oto 24 hours 
postdose 
area under the concentration-time cmve from hour 0 extrapolated to 
infinity 
area under the concentration-time cmve from hour 0 to the last 
measurable concentration 
below the lin1it of quantification 
Clinical Data Interchange Standards Cons01tium 
confidence interval 
apparent systemic clearance 
maximum observed plasma concentration 
Clinical Research Unit 
clinical study rep01t 
Common Terminology Criteria for Adverse Events 
coefficient of variation 
electrocardiogram 
End of Study 
End of Treatment 
Early Termination 
geometric CV 
geometric mean 
Informed Consent Fonn 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Hlllllan Use 
appar·ent terminal elimination rate constant 
start of exponential fit 
nlllllber of data points included in the log-linear regression 
time period over which Az was dete1mined as a ratio of ti,2 
end of exponential fit 
least squares mean 
Medical Dictionary for Regulat01y Activities 
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MRTinf 
NC 
NR 
PK 
QTcF 
R2-adj 
SAE 
SAP 
SD 
TEAE 
TFL 
t112 
tmax 
VJF 
WHODrng 
mean residence time based on area under the concentrntion-time curve 
from time O extrapolated to infinity 
not calculated 
not reported 
pha1macokinetic( s) 
QT interval conected for heait rate using Fridericia 's formula 
adjusted coefficient for dete1mination of exponential fit 
serious adverse event( s) 
statistical analysis plan 
standard deviation 
treatment-emergent adverse event 
Table, figure, and listing 
apparent plasma te1minal elilnination half-life 
time to maximum observed plasma concentration 
apparent volume of distribution at the te1minal phase 
World Health Organization Drng Dictionruy 
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1. INTRODUCTION 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 1 December 2020) and electronic case repo1t fo1m. 
This SAP describes the planned analysis of the phaimacokinetic (PK) and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study repmt (CSR) is provided in the accompanying TFL shells document. 
In general, the analyses are based on info1mation from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of infmmation 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 ai·e 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 perfo1med 
and will be identified accordingly in the CSR. ... .t\ny 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 Ha1monisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2 
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES 
2.1.1. Primary Objective 
The p1imary objective of the study is to assess the effect of food on the PK of a single oral 
dose of LOXO-305 under fasted and fed conditions in healthy adult subjects. 
2.1.2. Secondary Objective 
The secondary objective of the study is to assess the safety and tolerability of a single oral 
dose of LOXO-305 with and without food in healthy adult subjects. 
3. STUDY ENDPOINTS 
3.1. Primary Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 (as approp1iate): 
• 
area under the concentration-time curve (AUC) from hour Oto 24 hours postdose 
(AUCo-24) 
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• 
area under the concentration-time curve from hour O to the last measurable 
concentration (AUCo-t) 
• 
area under the concentrntion-time cmve from hour O extrapolated to infinity (AUCo-
inf) 
• 
percentage extrapolation for AUCo-inf (%AUCextrap) 
• 
apparent systemic clearance (CL/F) 
• 
apparent plasma tenninal elimination half-life (ti12) 
• 
maximum observed plasma concentration (Cmax) 
• 
time to maximum obse1ved plasma concentration (tmax) 
• 
apparent te1minal elimination rate constant (Az) 
• 
apparent volume of distribution at the te1minal phase 01 JF) 
3.2. Secondary Endpoints 
Safety and tolerability will be assessed by monitoring adverse events (AEs ), perforn1ing 
physical examinations and clinical laborato1y evaluations, measuring vital signs, and 
recording 12 lead electrocardiograms (ECGs). 
4. STUDY DESIGN 
This is a Phase 1, open-label, randomized, 2-way crossover study to investigate the effect of 
food on the single oral dose PK ofLOXO-305 in healthy adult subjects. 
A single oral dose of LOXO-305 will be administered under fasted conditions (Treatment A) 
and fed conditions (Treatment B). PK sampling will be obtained for 168 hours after 
administration of each dose ofLOXO-305 (ie, on Days 1 and 8). The 2 treatment sequences 
will be AB and BA. Subjects will be randomly assigned to 1 of the 2 treatment sequences, 
according to a randomization scheme issued by Covance. Up to 20 healthy adult male and 
female subjects (women of non-childbearing potential only) will be emolled. 
fu Treatment A, a single oral dose of200 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 p1ior to and 4 hours after dosing. Water will be restricted for 1 hour prior to and 
1 hour after dosing with the exception of water administered for dose administration. 
fu Treatment B, a single oral dose of200 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 high-fat breakfast. Water will be restr.-icted for 1 hour prior to and 1 hour after 
dosing with the exception of water administered for dose administration. High-fat breakfasts 
should be entirely consumed within 30 minutes. 
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Blood samples for the analysis of plasma concentrations ofLOXO-305 will be collected from 
predose through 168 hours postdose for Treatment A and Treatment B. 
There will be a washout period of7 days between the doses ofLOXO-305 administered in 
Treatments A and B. 
A schematic of the study design is presented in Figure 1. The sta1t of the study is defined as 
the date the first subject who is enrolled in the study signed an Inf01med Consent F01m (ICF). 
Note that enrolled subjects are defined as those subjects who are assigned to receive a dose of 
study drng; this definition excludes screen failure subjects. Replacement subjects may be 
enrolled only if deemed necessa1y by the Sponsor. 
Subjects who are dete1mined to be screen faihues are pe1mitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day-1) until End of 
Treatment (EOT) on Day 15 upon completion of all PK and safety assessments or Early 
Te1mination (ET) if the subject discontinues. Subjects will be dosed on Day 1 and Day 8. A 
follow-up phone call will occur for all subjects who received at least 1 dose of study drng 
(including subjects who are te1minated early) 7 days (± 2 days) after EOT or ET. The 
duration of participation is expected to be approximately 53 days (Screening through follow-
up phone call). 
Figure 1: 
Study Design 
11 
Days -28 to -2 
11 
Day -1 
11 
1 1 
Days 1 to 7 
I Day 1 
l 
Treatment A or 
Treatment B 
PK Samplin,g: 
Day 1: Predose tlhrough 
168 hours post<lose 
11 
11 
11 
Days 8 to 15 
I 
I Day 8 I 
I Day 1s I 
l 
Treatment A or 
Treatment B 
l 
Clinic Discharge 
EOT/ET 
PK Sampling: 
Day 8: Predose through 
168 hours ostdose 
7 (:I: 2) days 
after Discharge 
Safety Assessments: From signing the ICF to follow-up phone call 
Abbreviations: EOT = End ofTreatment; ET = Early Termination; ICF = Informed Consent Form; PK = pharmacokinetic. 
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? Inquiries, clinical chemist1y panel, coagulation parameters, hematology panel, 
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urinalysis, and recording of concomitant medications will be pe1f01med at specific times 
during the study. 
The AEs and serious adverse events (SAEs) will be collected beginning at info1med consent. 
The AEs will be repo1ted 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 repmted as beginning 
prior to signing of the ICF or if the event occurs prior to study drng 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 drng administration on Day 1 
and is assessed as related to study procedures by the Investigator [ or designee ], or if the event 
occurs after study drng administration on Day 1 through EOT or ET regardless of relationship 
to study drng). From EOT or ET through EOS, only AEs assessed as related to study dtug by 
the Investigator (or designee) are to be repo1ted. 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 repo1ted. 
Study completion is defined as the time of the last subject's follow-up phone call. 
S. SAMPLE SIZE JUSTIFICATION 
Up 
healthy adult male and female subjects (women of non-childbearing potential only) 
will be emolled. This is a Phase 1 study and the sample size is consistent with previous 
studies of a similar design. Up 
subjects are anticipated to be sufficient to provide a 
reliable estimate of the magnitude and variability of the food effect. The highest 
within-subject coefficient of variation (CV) observed in LOXO-BTK-20014 was 
for 
Cmax. A sample size of 
will provide approximately 
80% power to have the respective 90% confidence intervals (Cls) for the geometric mean 
ratios for Cmax and AUC values between fed and fasted treatments are within the interval of 
80.00% to 125.00%, assuming a within-subject CV of 
and that the expected ratio of 
means is __ Replacement subjects may be em·olled only if deemed necessary by the 
Sponsor. 
Eve1y attempt will be made to emoll at least 3 subjects of each sex in the study. 
6. STUDY TREATMENTS 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 1. 
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Table 1: 
P1·esentation of Study Treatments in TFLs 
Study Treatment 
200 mg LOXO-305 (Fasted) 
200 mg LOXO-305 (Fed) 
Abbreviation 
Order in TFLs 
A 
1 
B 
2 
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 
200 mg LOXO-305 (Fasted) on Day 1/ 
200 mg LOXO-305 (Fed) on Day 8/ 
200 mg LOXO-305 (Fed) on Day 1/ 
200 mg LOXO-305 (Fasted) on Day 8/ 
Abbreviation 
Order in TFLs 
AB 
1 
BA 
2 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
ti-eatments received. 
7. DEFINITIONS OF POPULATIONS 
Any protocol deviations, including those related to COVID-19, will be considered prior to 
database lock for their impmtance 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 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. 
7.3. Pharmacokinetic Population 
The PK Population will consist of all subjects who have received 1 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 summa1y statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times the median tmax. The 
impact of protocol deviations on the PK population will be evaluated on a case-by-case basis. 
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8. STATISTICAL METHODOLOGY 
8.1. General 
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the EOT visit. Any 
subject who discontinued the study will be identified accordingly in the listings. Summaries 
and statistical analyses will include the subjects assigned to the relevant population based on 
data type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study). 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data futerchange 
Standards Conso1tium (CDISC) ADaM Version 2.1 ( or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher ifupversioned 
during the study). Pinnacle 21 Community Validator Version 3.1.0 (or higher ifupversioned 
during the study) will be utilized to ensure compliance with CDISC standards. 
Where reference is made to 'all calculations', tbis includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation and changes from baseline, and any 
parameter derivations. 
8.1.1. Calculation of the Summary Statistics 
For continuous data the following rnles will be applied: 
• 
Missing values will not be imputed, unless specifically stated othe1wise. 
• 
Umounded data will be used in the calculation of summa1y statistics. 
• If the number of subjects with valid observations (n) <3, sununary statistics will not 
be calculated, with the exception of n, minimum, and maximum. 
• 
As ET data is not associated with any scheduled timepoint, it will be excluded from 
all calculations of summary statistics. 
• 
Postdose repeats and unscheduled assessments will not be included in calculation of 
summa1y statistics. 
For categorical data the following rnles 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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• 
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 othe1wise. A 
'missing' categ01y will be included for any parameter for which info1mation is 
missing. This will ensure that the population size totals are consistent across different 
parameters. 
All protocol deviations and data issues (eg missing data, out of protocol window) that occur 
during the study, including those related to COVID-19, will be considered prior to database 
lock for their seve1ity/impact on how the data will be displayed. 
8.1.2. Repeat and Unscheduled Readings 
For vital sign measurements 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 postdose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
dete1mining the baseline value for each period. 
Postdose repeats, unscheduled values, 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 on Day 1 and Day 8. 
If the date/time of the value is incomplete or missing, it will be excluded from the baseline 
calculation, unless the incomplete date/time indicates the value was recorded prior to dosing 
on Day 1 and Day 8. 
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. 
8.1.4. Period Specific Study Day 
Period specific study day is defined as per Table 3 for ECG and Vital signs and Table 4 for 
clinical laborato1y parameters. 
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Table 3: ECG and Vitals Study day 
Period 
P~riod Specific Study Day 
Baseline 
Day 1 
Day2 
Day 3 
Day 4 
Day 5 
Day 6 
Day7 
1 
1 (pre-dose) 
2 
8 (pre-dose) 
1 (post dose) 2 
8 (post dose) 9 
3 
4 
5 
6 
10 
11 
12 
13 
Table 4: Clinical laboratory parameters Study day 
Period 
Baseline 
Day 2 
Day 3 
1 
Day -1 
2 
Day 7 Period 1 
Period Specific Study Day 
Day4 
Day 5 
Day 6 
4 
10 
7 
14 
Day 7 
7* 
14 
*Day 7 measurements will be summarized at day 7 for period 1 used as baselines for the 
period 2. 
8.2. Subject Disposition and Population Assignment 
Subject disposition and population assignment will be listed. 
A summa.iy table by treatment sequence will be provided, based on the all subjects 
population. 
8.3. Demographics 
The demographics including age, sex, race, ethnicity, height, body weight, and body mass 
index will be listed. 
A summa1y 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 sta.iis dming or after the first dose or sta.iis but 
does not end prior to the first dose. 
Prior and concomitant medications will be coded using the World Health Organization Drng 
Dictionary (WHODrng) Global, Fmmat B3, Version September 2020. 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 ofLOXO-305 using noncompartmenta1 methods in validated software 
program Phoenix WinNonlin (Ceriara, Version 8.1 or higher): 
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Parameter 
Unitsa 
AUCo-1 
h*ng/mL 
AUCo-24 
h*ng/mL 
AUCo-inf 
h*ng/mL 
%AUCex1rap 
% 
Cinax 
ng/mL 
tmax 
h 
A,z 
1/h 
t112 
h 
CL/F 
L/h 
V,/F 
L 
MRTinf 
h 
Definition 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
area under the concentration-time cmve from hom O to the last 
measmable concentration (t1as1? 
area under the concentration-time cmve from hom O to 24 homs 
postdoseb 
area under the concentration-time cmve from hom O extrnpolated 
to infinity" 
percentage extrapolation for AUCo-inf 
maximum obse1ved plasma concentration 
time to maximum obse1ved plasma concentration 
apparent tenninal elilnination rate constant 
apparent tenninal elilnination half-life 
apparent systelnic clearance 
apparent volume of distiibution at tenninal phase 
mean residence time (based on AUCo-inf) 
• Units are based on concentration units (provided by the bioanalytical lab or prefeITed units for presentation of PK 
parameters) and dose units used in the study. 
b Area under the concentration-tin1e curve will be calculated using the linear trapezoidal mle for increasing and decreasing 
concentrations. 
c Based on the last observed quantifiable concentration 
Additional PK parameters may be dete1mined where appropriate. 
The PK analysis will be cani.ed out where possible using actual blood sampling times 
postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time. 
The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occunence of Cmax. 
8.5.1.1. Criteria for the Calculation of Appa1·ent Terminal Elimination Rate Constant 
and Half-life 
The start of the te1minal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent te1minal elimination rate constant (11.,z) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for dete1mination of exponential fit (R2-adj) of the regression line is ?.0.7. 
Parameters requiring 11.,z for their calculation (eg, AUC0-inf, ti12, CL/F, VJF, and MRT) will 
only be calculated if the R2-adj value of the regression line is ?.0.7. 
The following regression-related diagnostic PK parameters will be dete1mined, when 
possible: 
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Parameter 
Units 
'A,,_ Upper 
h 
'A,,_ Lower 
h 
'A,,_N 
NA 
'A,,_ Span Ratio 
NA 
R2-adj 
NA 
Definition 
end of exponential fit 
strut of exponential fit 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
number of data points included in the log-linear regression 
time pe1iod over which 'A,,_ was detemlined as a ratio of t112 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the detennination of "Az (ie, the difference between 
"Az Upper and )vz. Lower) should be 2'.:2 half-lives. If the "Az Span Ratio is <2, the robustness of 
the t112 values will be discussed in the CSR. 
8.5.1.2. Criteria for Calculation and Reportilng of Area Under the Concentration-time 
Curve 
The ininimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should follow Cmax. 
AUCo-inf values where the percentage extrapolation is less than 30% will be reported. 
AUCo-infvalues where the percentage extrapolation is greater than 30% will be listed but 
excluded from descriptive statistics and statistical analysis. 
If AUCo-inf cannot be detennined reliably for all subjects and/or treatments, an alternative 
AUC measme, such as AUCo-t, may be used in the statistical analysis for food effect. 
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rnles apply with special situations defined below: 
• If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
• Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have tenninated and any fm1her quantifiable concentrations will be 
set to inissing for the calculation of the PK parameters, unless they are considered to be 
a trne characteristic of the profile of the drng. 
• If a Day 1 or Day 8 predose plasma concentration is missing, it may be set to O by 
default within Phoenix WinNonlin. 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
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Any quantifiable predose concentration value for LOXO-305 on Day 1 will be considered 
anomalous and set to missing for the PK analysis. 
If the predose concentration is >5% of Cmax in the second period, all PK concentration and 
parameter data will be excluded from the summa1y statistics and statistical analysis for that 
period. 
8.5.1.5. Presentation of Pharmacokinetic Data 
fudividual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summa1y statistics. 
For PK concentration data the following rnles will apply: 
• Values that are BLQ will be set to O for the calculation of summaiy statistics. 
• Atithmetic mean or median values that are BLQ will be presented as 0. 
• If any BLQ results (treated as 0) are in a series of summarized data, geometric mean 
and CV of geometric mean will be repo1ted as not calculated (NC). 
8.5.2. Presentation Pharmacokinetic Parameters 
• For the calculation of summaiy statistics of PK paran1eters, all not repmted (NR) and 
not calculated (NC) values in a data series will be set to missing. 
• The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
8.5.3. Pharmacokinetic Statistical Methodology 
All PK concentrations and parameters will be listed. 
Summary tables, mean(+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment and tin1e postdose will be provided for plasma PK 
concentrations. All PK concentration figures will be produced on both linear and semi-
logarithmic scales. The +SD bars will only be displayed on the linear scale. 
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summaiy 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; geometric mean and CV will not be 
calculated for tmax. Excluded subjects will be listed in the PK pai·ameter tables, but will be 
excluded from the statistical analysis and summa1y statistics and noted as such in the tables. 
fudividual and mean plasma concentration time curves (both linear and log-linear) will be 
included in the final CSR. 
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8.5.3.1. Statistical Analyses 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
A statistical analysis will be conducted to investigate the food effect on the t1eatment by 
compaling Treatment B (Fed) to Treatment A (Fasted) for AUCo-t, AUCo-inf, and Cmax, using 
Treatment A as reference. 
The natural log (ln)-transfonned3 PK parameters will be analyzed using a mixed model.4 The 
model will include planned t1eatment sequence, period, and actual treatment as fixed effects, 
and subject within planned treatment sequence as a random effect. 
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the fed and fasted treatments, and conesponding 90% Cls will 
be calculated; these values will then be back-transfom1ed to give the geometiic least square 
mean (GLSM), ratio of GLSMs, and conespouding 90% Cls. 
For each PK parameter separately, it will be concluded that there is absence of a food effect 
on the ti·eatment if the 90% CI for the ratio of GLSMs is completely contained within the 
predefined interval of (80.00%, 125.00%). This procedure is equivalent to Schuirmam1's5 two 
one-sided tests at the 0.05 level of significance. 
Additionally, the pooled estimate (across all tJ.·eatments) of the within-subject coefficient of 
variation (CV) will be calculated, and residual plots will be produced to assess the adequacy 
of the model(s) fitted. 
Example of the SAS code that will be used is as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
class trtan aperiod trtseqp usubjid; 
model lpk = trtan aperiod trtseqp / c l residual ddfrn 
kr; 
lsrneans trtan / c l pdiff = control ( ' 1 ') a l pha = 0 . 1 ; 
random i ntercept/ subject = usubjid(trtseqp); 
ods output l srneans = <data out>; 
ods output diffs = <data out>; 
ods output covparrns = <data out>; 
run; 
8.6. Safety and Tolerability Assessments 
8.6.1. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatmy Activities (MedDRA) 
Version 23.0. All AEs will be assigned severity grade using National Cancer Institute 
Common Te1mir10logy Criteria for Adverse Events (CTCAE) Version 5.0. 
A treatment-emergent adverse event (TEAE) will be defined as an AE that sta1ts during or 
after the first dose, or starts p1ior to the first dose and increases in severity after the first dose. 
A tJ.·eatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as dete1mined by the investigator. 
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Protocol Reference: LOXO-BTK-20009 
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 summa1ized for the 
following categories: 
• 
TEAEs ( overall, serious, leading to discontinuation, and leading to death) by 
treatment 
• 
TEAEs by severity and treatment 
• 
Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment 
• 
Treatment-related TEAEs by severity and treatment 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following: 
• 
System organ class, pref eITed te1m, and treatment 
• 
PrefeITed te1m and treatment 
For the AE data the following rnles will apply: 
• 
For the derivation ofTEAE status: If the sta1t date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete sta1t 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 strut date/time of an AE is missing, onset time 
will not be calculated. If the sta1t date/time of an AE is incomplete, where possible, 
the minimum possible onset time will be calculated and presented in '~DD:HH:MM' 
fo1mat (eg, if the date/time of the last dose is 01MAY2019/08:00 and recorded sta1t 
date/time of an AE is 03MA Y2019, then the minimum possible onset time will be 
calculated by assuming the AE started at the first hour and minute of 03MA Y2019 
[03MAY2019/00:00], thus will be presented as onset time ~01:16:00 in the listing). 
• 
For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the sta11 or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in 'g)D:HH:MM' 
fo1mat (eg, if the sta11 of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MA Y2019, then the maximum possible duration will be calculated by 
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assuming the AE ended at the last hour and minute of 03MA Y2019 
[03MAY2019/23:59], thus will be presented as duration ::=;02:15:59 in the listing). 
• 
For the calculation of summa1y statistics: If a subject experienced multiple TEAEs 
with the same prefened te1m 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 laborato1y 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. Separate listings 
will be provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range. 
The observed results and change from baseline for clinical chemistry, hematology, and 
coagulation parameters will be summarized descriptively by treatment and period specific 
timepoint. 
Values recorded as <x, ::=;x, >x, or ~x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summaiy statistics, and presentation in the figures, 
<x and ::=;x values will be set to 0, whereas >x and ~x values will be set to x. 
8.6.3. Vital Signs Results 
All vital 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 results will be summarized 
descriptively by treatment and period specific timepoint. 
8.6.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters, with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated. 
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by treatment and period specific timepoint. QTcF values that are > 
450 msec and increase from baseline > 30 msec will be flagged in the data listing. 
8.6.5. Other Assessments 
Medical histo1y and physical examination will be listed. Any physical examination 
abn01malities reported will also be flagged as clinically significant or not clinically 
significant as indicated. 
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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 interim 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 Ha1monised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 Febmary 1998. 
2. ICH. ICH Harmonised Tripaitite Guideline: Strncture and content of clinical study rep01ts 
(E3). 30 November 1995. 
3. Keene ON. The log transfonnation 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. Schuiima1m DJ. A comparison of the two one-sided tests procedme 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 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20009 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
Final Version 2.0 
NA= not applicable 
NA 
NA; the first version. 
11MAY2021 
Period added as fixed effect to mixed model to 
co1Tespond with the 2x2 study design. This was 
implemented p1ior to database lock. 
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