Clinical trial NCT06165146
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-11-10; Completion date: 2020-12-30
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to evaluate the effect of pirtobrutinib (LOXO-305) on single oral dose of repaglinide (CYP2C8 substrate) when administered as multiple doses by conducting the blood tests to measure how much pirtobrutinib (LOXO-305) is in the bloodstream and how the body handles and eliminates pirtobrutinib (LOXO-305) in adult healthy participants. The study will also evaluate the safety and tolerability of pirtobrutinib (LOXO-305). The study is conducted in two periods. Participants will stay in this study for up to 54 days.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 0.5 milligrams (mg) repaglinide tablet, in the morning on Day 1. arm 2: Participants received oral doses of 200 mg pirtobrutinib tablets, once daily (QD) in the morning from Day 2 to Day 11. arm 3: Participants received oral doses of 200 mg pirtobrutinib QD and 0.5 mg repaglinide tablets, in the morning on Day 12.
Interventions: intervention 1: Repaglinide intervention 2: Pirtobrutinib
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol LOXO-BTK-20016
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the 
Effect of Multiple Oral Doses of Pirtobrutinib (LOXO-305) on the Pharmacokinetics 
of Repaglinide (CYP2C8 Substrate) in Healthy Subjects
NCT06165146
Approval date: 07-Oct-2020


TITLE PAGE 
Protocol 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to 
Investigate the Effect of Multiple Oral Doses of LOXO-305 on the 
Pharmacokinetics of Repaglinide (CYP2C8 Substrate) in Healthy Subjects 
Protocol Status: Final  
Protocol Date: 05 October 2020 
Protocol Version: 1.0 
Investigational Medicinal Product: LOXO-305 
Protocol Reference Number: LOXO-BTK-20016 
Covance Study Number: 8425120 
IND Number: 139876 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, Florida 32117 
USA 
Sponsor Signatory: 
Principal Investigator: 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
PPD
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SPONSOR APPROVAL 
I have read the protocol and approve it: 
Date 
07-Oct-20 | 00:12:18 PDT
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Protocol 
Covance Study: 8425120 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20016 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Date 
Protocol Version 1.0, 05 October 2020 
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STUDY IDENTIFICATION 
Sponsor 
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): 
 
Sponsor’s Study Contact 
 
 
Loxo Oncology, Inc. 
Tel (mobile): 
 
Email: 
 
Sponsor’s Medical Contact  
 
Consulting to Loxo Oncology, Inc. 
Tel (mobile): 
 
Email: 
 
Serious Adverse Event (SAE) 
Reporting 
Email: SAEIntake@covance.com 
Study Site 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Principal Investigator 
  
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Tel: 
 
Tel (after hours): 
 
Sub-investigator(s)  
Obtain information from Form FDA 1572 
Clinical Laboratory 
LabCorp - Hollywood 
4200 North 29th Avenue 
Hollywood, FL 33020 
USA 
Bioanalytical Laboratory 
Alturas Analytics, Inc. 
1324 Alturas Drive 
Moscow, Idaho 83843 
USA 
Tel (main): 
 
Email: 
 
Statistician 
 
 
Covance 
PPD
PPD
PPD
PPD
PPD
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PPD
PPD
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Tel: 
 
Email: 
 
Medical Writer 
 
 
Covance 
Tel: 
 
Email: 
 
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SYNOPSIS 
Study Title 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of 
Multiple Oral Doses of LOXO-305 on the Pharmacokinetics of Repaglinide (CYP2C8 
Substrate) in Healthy Subjects 
Objectives 
The primary objective of the study is: 
• to assess the impact of multiple oral doses of LOXO-305 on the pharmacokinetics 
(PK) of a single oral dose of repaglinide (CYP2C8 substrate) in healthy subjects. 
The secondary objective of the study is: 
• to assess the safety and tolerability of multiple oral doses of LOXO-305 when 
administered alone and coadministered with repaglinide in healthy subjects. 
Study Design 
This is a Phase 1, open-label, 2-period, fixed-sequence drug-drug interaction study to 
investigate the effect of multiple oral doses of LOXO-305 on the PK of a single oral dose of 
repaglinide in healthy subjects.  
In Period 1, Day 1, a single 0.5-mg oral dose of repaglinide will be administered in the 
morning following a fast of at least 10 hours prior to dosing. In order to mitigate any side 
effects when dosing with repaglinide on Day 1, on Day -1, subjects will be offered breakfast, 
lunch, dinner, and an optional snack after dinner. On Day 1, subjects will receive a 
standardized light breakfast 15 minutes postdose. In addition, subjects may be provided with 
up to 16 grams (g) of glucose (up to 4 x 4 g chewable tablets) approximately 1-hour postdose, 
if needed. Blood samples for concentrations of repaglinide in plasma will be collected 
.  
In Period 2, on Days 2 through 11, oral doses of 200 mg LOXO-305 will be administered 
once daily (QD) in the morning at the actual time of the Day 1 repaglinide dose (± 1 hour). 
On Days 2 through 11, subjects will fast for at least 2 hours predose and 1-hour postdose with 
the exception of Days 2, 6, and 11 where clinical laboratory evaluations are performed, 
subjects will fast for at least 8 hours predose and 1-hour postdose. On Day 12, 200 mg 
LOXO-305 and 0.5 mg of repaglinide will be co-administered in the morning at the actual 
time of the Day 1 repaglinide dose (± 1 hour), following a fast of at least 10 hours prior to 
dosing.  In order to mitigate any side effects when dosing with repaglinide on Day 12, on Day 
11, subjects will receive breakfast (2 hours after dosing), lunch, dinner, and an optional snack 
after dinner. On Day 12, subjects will receive a standardized light breakfast 15 minutes 
post-LOXO-305 and repaglinide dosing. In addition, subjects may be provided with up to 
16 g of glucose (up to 4 x 4 g chewable tablets) approximately 1-hour post-LOXO-305 and 
repaglinide dosing, if needed. 
, a blood sample for concentrations of 
LOXO-305 in plasma will be collected 
, blood samples for 
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concentrations of repaglinide and LOXO-305 in plasma will be collected 
 
. 
There will be a washout period of 11 days between the dose of repaglinide on Day 1 and the 
dose of repaglinide on Day 12, respectively. 
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 16 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. A follow-up phone call will occur for all 
subjects who received at least 1 dose of study drug (including subjects who are terminated 
early) 7 days (± 2 days) after EOT or ET.  
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form. Note that enrolled subjects are defined as those subjects who are 
assigned a dose of study drug; this definition excludes screen failure subjects. Study 
completion is defined as the time of the last subject’s follow-up. 
In this study, physical examinations, 12-lead electrocardiograms (ECGs), vital sign 
measurements, How Do You Feel? inquiries, clinical chemistry panel, coagulation 
parameters, hematology panel, urinalysis (UA; Appendix 2), and recording of concomitant 
medications will be performed at specified times during the study (for specific timepoints and 
details on each study variable, refer to Appendix 4).  
AEs and SAEs will be collected beginning at informed consent. AEs will be reported 
throughout the study (ie, from signing of the ICF until End of Study [EOS], or until ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as 
subject medical history (if the event is reported as beginning prior to signing of the ICF or if 
the event occurs prior to study drug administration on Day 1 and is assessed as not related to 
study procedures by the Investigator [or designee]) or as AEs (if the event occurs after 
signing of the ICF but prior to study drug administration on Day 1 and is assessed as related 
to study procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From 
EOT or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a follow-up phone 
call) are to be reported. 
Number of Subjects 
Up to sixteen healthy adult male and female subjects (women of non-childbearing potential 
only) will be enrolled. The sample size chosen for this study was selected without statistical 
considerations, but is consistent with previous studies of a similar design. Up to sixteen 
subjects are anticipated to be sufficient to provide a reliable estimate of the magnitude and 
variability of the interaction. 
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Every attempt will be made to enroll at least 4 subjects of each sex in the study. 
Main Criteria for Inclusion 
Male subjects and female subjects of non-childbearing potential, between 18 and 55 years of 
age, inclusive, at Screening, and within body mass index range 18.0 to 32.0 kg/m2, inclusive. 
Subjects will be in good general health, based on medical history, physical examination 
findings, vital sign measurements, 12-lead ECG, or clinical laboratory evaluations at 
Screening and/or Check-in (Day -1), as determined by the Investigator (or designee). 
Investigational Medicinal Products, Dose, and Mode of Administration 
LOXO-305 will be supplied by the Sponsor (or designee) as 100-mg tablets. Repaglinide 
tablets will be supplied by Covance.  
In Period 1, Day 1, a single 0.5 mg oral dose of repaglinide will be administered in the 
morning following a fast of at least 10 hours prior to dosing. In order to mitigate any side 
effects when dosing with repaglinide on Day 1, on Day -1, subjects will be offered breakfast, 
lunch, dinner, and an optional snack after dinner. On Day 1, subjects will receive a 
standardized light breakfast 15 minutes postdose. In addition, subjects may be provided with 
up to 16 g of glucose (up to 4 x 4 g chewable tablets) approximately 1-hour postdose, if 
needed. 
In Period 2, on Days 2 through 11, oral doses of 200 mg LOXO-305 will be administered QD 
in the morning at the actual time of the Day 1 repaglinide dose (± 1 hour). On Days 2 through 
11, subjects will fast for at least 2 hours predose and 1-hour postdose with the exception of 
Days 2, 6, and 11 where clinical laboratory evaluations are performed, subjects will fast for at 
least 8 hours predose and 1-hour postdose. On Day 12, 200 mg LOXO-305 and 0.5 mg of 
repaglinide will be co-administered in the morning at the actual time of the Day 1 repaglinide 
dose (± 1 hour), following a fast of at least 10 hours prior to dosing. In order to mitigate any 
side effects when dosing with repaglinide on Day 12, on Day 11, subjects will receive 
breakfast (2 hours after dosing), lunch, dinner, and an optional snack after dinner. On Day 12, 
subjects will receive a standardized light breakfast 15 minutes post-LOXO-305 and 
repaglinide dosing.  In addition, subjects may be provided with up to 16 g of glucose (up to 
4 x 4 g chewable tablets) approximately 1-hour post-LOXO-305 and repaglinide dosing, if 
needed. 
All study drugs will be administered with approximately 240 mL of water. An additional 
100 mL of water may be administered if needed.  
Duration of Subject Participation in the Study 
Planned Enrollment/Screening Duration: Approximately 28 days (Days -29 to -2).  
Length of Confinement: Up to 17 days (Days -1 to 16). 
Planned Study Conduct Duration: Up to 54 days (Screening through follow-up call).  
 


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Criteria for Evaluation: 
Pharmacokinetics: 
Blood samples for concentrations of repaglinide in plasma will be collected 
 
, a blood sample for concentrations of 
LOXO-305 in plasma will be collected 
 blood samples for 
concentrations of repaglinide and LOXO-305 in plasma will be collected 
 
 
Whenever possible, the following PK parameters will be calculated based on plasma 
concentrations of repaglinide, as appropriate: area under the concentration-time curve (AUC) 
from hour 0 to the last measurable concentration (AUC0-t), AUC from hour 0 extrapolated to 
infinity (AUC0-inf), percentage extrapolation for AUC0-inf (%AUCextrap), maximum observed 
plasma concentration (Cmax), time to maximum observed plasma concentration (tmax), 
apparent terminal elimination rate constant (λZ), apparent systemic clearance (CL/F), 
apparent plasma terminal elimination half-life (t1/2), and apparent volume of distribution 
(Vz/F).Whenever possible, the following PK parameters will be calculated based on plasma 
concentrations of LOXO-305 following multiple dosing, as appropriate: AUC0-t, AUC during 
a dosing interval (AUCtau), apparent systemic plasma clearance at steady state (CL,ss/F), Cmax, 
concentration observed at the end of the dosing interval (Ctrough), and tmax. 
Safety: 
Safety and tolerability will be monitored with AE inquiries, clinical laboratory evaluations, 
vital sign measurements, ECGs, concomitant medications, and physical examinations. 
Statistical Methods 
Pharmacokinetics: 
Plasma concentrations and PK parameters will be summarized with descriptive statistics 
(number, arithmetic mean, standard deviation, coefficient of variation [CV%], geometric 
mean, geometric CV%, median, minimum, and maximum). 
A mixed model will be performed to evaluate the effects of multiple-dose administration of 
LOXO-305 on repaglinide. The mixed effect model will include treatment as a fixed effect 
and subject as a random effect. The analysis will be performed on the ln-transformed PK 
parameters (AUC0-t, AUC0-inf, and Cmax) and will include calculation of least squared (LS) 
means and the difference between treatment LS means, as well as their corresponding 90% 
confidence intervals (CIs). The geometric mean ratios and their 90% CIs of the PK parameter 
for each treatment comparison will be constructed using the exponentiation of the difference 
and the CIs from the mixed effect model. The primary comparison for this study is 0.5 mg 
repaglinide + multiple doses of LOXO-305 versus 0.5 mg repaglinide.  
Safety: 
All safety assessments, including AEs and SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated and summarized where possible, using descriptive methodology, as needed, by 
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treatment and timepoint. Unless otherwise specified, baseline value is defined as the last 
non-missing measurement before administration of study drug on Day 1. No formal statistical 
analyses are planned for the safety data. All safety data will be listed by subject.  
Additional details on the analyses will be included in the Statistical Analysis Plan. 
 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES AND FIGURES........................................................................................14 
LIST OF ABBREVIATIONS ..................................................................................................15 
1. 
INTRODUCTION ...........................................................................................................18 
1.1. 
Background ............................................................................................................18 
1.2. 
Nonclinical Pharmacokinetics and Toxicology .....................................................18 
1.3. 
Potential for Drug-drug Interactions ......................................................................20 
1.4. 
Summary of Clinical Experience ...........................................................................21 
1.4.1. 
Safety ...........................................................................................................21 
1.4.2. 
Pharmacokinetics .........................................................................................22 
1.5. 
Study Rationale ......................................................................................................24 
1.6. 
Risk Assessment ....................................................................................................24 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................27 
2.1. 
Objectives ..............................................................................................................27 
2.1.1. 
Primary Objective ........................................................................................27 
2.1.2. 
Secondary Objective ....................................................................................27 
2.2. 
Endpoints ...............................................................................................................27 
2.2.1. 
Primary Endpoints .......................................................................................27 
2.2.2. 
Secondary Endpoints ...................................................................................28 
3. 
INVESTIGATIONAL PLAN ..........................................................................................29 
3.1. 
Overall Study Design and Plan ..............................................................................29 
3.2. 
Discussion of Study Design ...................................................................................30 
3.3. 
Selection of Doses in the Study .............................................................................31 
4. 
SELECTION OF STUDY POPULATION .....................................................................32 
4.1. 
Screening Procedures .............................................................................................32 
4.2. 
Check-in Procedures (Day -1) ...............................................................................32 
4.3. 
Inclusion Criteria ...................................................................................................33 
4.4. 
Exclusion Criteria ..................................................................................................35 
4.5. 
Subject Number and Identification ........................................................................38 
4.6. 
Removal of Subjects from Study Participation ......................................................38 
5. 
STUDY TREATMENTS .................................................................................................40 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................40 
5.2. 
Study Treatment Administration ............................................................................40 


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5.3. 
Randomization .......................................................................................................41 
5.4. 
Blinding..................................................................................................................41 
5.5. 
Treatment Compliance ...........................................................................................41 
5.6. 
Drug Accountability...............................................................................................41 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................43 
6.1. 
Concomitant Therapies ..........................................................................................43 
6.2. 
Diet, Fluid, and Activity Control ...........................................................................43 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................45 
7.1. 
Pharmacokinetic Assessments ...............................................................................45 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................45 
7.1.2. 
Analytical Methodology ..............................................................................45 
7.2. 
Safety and Tolerability Assessments .....................................................................45 
7.2.1. 
Adverse Events ............................................................................................45 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................46 
7.2.3. 
Vital Signs ....................................................................................................47 
7.2.4. 
12-lead Electrocardiogram ...........................................................................47 
7.2.5. 
Physical Examination...................................................................................47 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................48 
8.1. 
Determination of Sample Size ...............................................................................48 
8.2. 
Analysis Populations ..............................................................................................48 
8.2.1. 
Study Populations ........................................................................................48 
8.3. 
Pharmacokinetic Analysis ......................................................................................48 
8.3.1. 
Descriptive Analysis ....................................................................................50 
8.3.2. 
Statistical Methodology ...............................................................................50 
8.4. 
Safety Analysis ......................................................................................................50 
8.5. 
Data Handling and Record Keeping ......................................................................50 
8.6. 
Quality Control and Quality Assurance .................................................................51 
9. 
ADMINISTRATIVE ASPECTS .....................................................................................52 
9.1. 
Change in Protocol .................................................................................................52 
9.2. 
Site Initiation Visit/Investigator Meeting ..............................................................52 
9.3. 
Disclosure ..............................................................................................................52 
9.4. 
Monitoring .............................................................................................................52 
9.5. 
Institutional Review Board ....................................................................................52 
9.6. 
Informed Consent...................................................................................................53 
9.7. 
Records ..................................................................................................................53 
9.8. 
Reference to Declaration of Helsinki/Basic Principles ..........................................53 
9.9. 
Financing and Insurance ........................................................................................54 
10. REFERENCES ................................................................................................................55 
11. APPENDICES .................................................................................................................56 
Appendix 1: Adverse Event Reporting ..............................................................................57 


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Appendix 2: Clinical Laboratory Evaluations ...................................................................61 
Appendix 3: Total Blood Volume ......................................................................................62 
Appendix 4: Schedule of Assessments ..............................................................................63 
 


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LIST OF TABLES AND FIGURES 
Table 1: Pharmacokinetic Parameters of LOXO-305 in Cancer Patients 
(Study LOXO-BTK-18001) at Steady State (Cycle 1 Day 8) .....................................23 
Table 2: Pharmacokinetic of LOXO-305 Following a Single 200-mg Dose of 
LOXO-305 in Cancer Patients (Study LOXO-BTK-18001, Cycle 1 Day 1) and 
Healthy Subjects (Study LOXO-BTK-20014) .............................................................24 
Table 3: Study Drugs .........................................................................................................40 
Table 4: Example Standardized Light Breakfast Content ..................................................44 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
AE 
adverse event 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
from hour 0 extrapolated to infinity 
AUC0-8 
area under the concentration-time curve from 0 to 8 hours 
AUC0-inf 
area under the concentration-time curve from hour 0 extrapolated to 
infinity 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
AUCtau 
area under the concentration-time curve during a dosing interval 
AV 
atrioventricular 
BCRP 
breast cancer resistance protein 
BID 
twice daily  
BMI 
body mass index 
BP 
blood pressure 
BSEP 
bile salt exporter pump 
BTK 
Bruton’s tyrosine kinase 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent systemic clearance 
CL,ss/F 
apparent systemic clearance at steady state 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
COVID-19 
SARS-CoV-2 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
concentration observed at the end of the dosing interval 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 


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ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
HbA1c 
hemoglobin A1c 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HRT 
hormone-replacement therapy 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
IC90 
90% inhibition 
ICF 
Informed Consent Form 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
Ki 
inhibitory constant 
LFT 
liver function test 
LS 
least squared 
MATE 
multidrug and toxin extrusion protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
NHL 
non-Hodgkin lymphoma 
NOEL 
no observed effect level 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OCT 
organic cation transporter 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAD 
single ascending dose 
SAE 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SDD 
spray-dried dispersion 


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SLL 
small lymphocytic lymphoma 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
apparent plasma terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed plasma concentration 
TSH 
thyroid-stimulating hormone 
UA 
urinalysis 
Vz 
volume of distribution  
Vz/F 
apparent volume of distribution 
WHO 
World Health Organization 
λZ 
apparent terminal elimination rate constant 
 
 


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1. INTRODUCTION 
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product (IMP), LOXO-305.1  
1.1. 
Background 
LOXO-305 (also known as LY3527727) is a selective inhibitor of the Bruton’s tyrosine 
kinase (BTK) being developed by Loxo Oncology. LOXO-305 is distinct from the approved 
BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) in several important ways 
including on the basis of its selectivity, favorable absorption, distribution, metabolism, and 
excretion properties, and non-covalent binding mode.2 The non-covalent binding mode of 
LOXO-305 is unaffected by BTK C481 substitutions, a common mechanism of drug 
resistance described for all available covalent inhibitors.3,4,5,6,7 These features enable 
LOXO-305 dosed orally at 100 mg and higher once daily (QD) to achieve pharmacokinetic 
(PK) exposures that exceed the concentration required for 90% inhibition (IC90) of BTK-wild 
type and BTK C481 at trough and thus deliver tonic BTK target inhibition throughout the 
dosing period, regardless of the intrinsic rate of BTK turnover. LOXO-305 is also a highly 
selective molecule, with more than 300-fold more selectivity for BTK versus 370 other 
kinases tested and no significant inhibition of non-kinase off-targets at 1 μM, thus limiting 
the potential for off-target mediated toxicities. Collectively, these unique properties 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 supports this underlying hypothesis.2 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate 
binding site of the BTK competitively, with no evidence of irreversible binding. 
1.2. 
Nonclinical Pharmacokinetics and Toxicology  
LOXO-305 had high permeability in vitro, but low aqueous solubility. To reduce the 
variability in oral absorption, a spray-dried dispersion (SDD) tablet formulation was 
developed that showed consistent oral bioavailability of approximately 50% in rats and 80% 
in dogs. The bioavailability of the SDD formulation 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 of LOXO-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 (Vz) 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. 
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 


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have low clearance in humans. In vitro data with cloned expressed cytochrome P450 (CYP) 
enzymes and human liver microsomes indicate that CYP3A4 is the primary CYP enzyme that 
metabolizes LOXO-305. It is also a substrate for direct glucuronidation. 
In long-term 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 
formed by human hepatocytes were also formed in rat and/or dog hepatocytes supporting the 
use of rat and dog for nonclinical safety assessment. 
Renal clearance of LOXO-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 
conserved across species, and, therefore, no renal clearance would be expected in humans. 
In a Good Laboratory Practice (GLP) in vitro assay for human ether-à-go-go-related gene 
(hERG) activity, the concentration resulting in 50% inhibition for the inhibitory effects of 
LOXO-305 on hERG potassium currents was 
, which is approximately 
 higher 
than the maximum unbound concentration of LOXO-305 in patients treated with the dose of 
200 mg 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 telemetry-instrumented dog. The maximum observed plasma concentration (Cmax) 
for this dose was 10000 ng/mL, which is approximately 
 above the predicted Cmax 
(
 ng/mL) at the proposed clinical therapeutic dose of 200 mg QD. Furthermore, 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 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 administered 30/10 mg/kg/dose 
BID compared with controls. The prolongation in QTc for males was below the 10% increase 
or the threshold reported for canines exposed to therapeutic concentrations of drugs known to 
cause QT prolongation in humans.8 Therefore, the QTc changes were considered 
physiologically unimportant, 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 arrhythmias in patients. 
There were no LOXO-305-related findings on the central nervous system when evaluated in 
rat functional observational battery tests and locomotor activity assessments after 4 weeks of 
dosing or during recovery at doses of up 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 
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. Additionally, in dogs 
treated for 15 weeks, 2 male dogs at 5 mg/kg BID (the highest dose tested) were observed to 
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have eye lesions via both ophthalmic and microscopic examination. Findings were observed 
in both eyes of these animals and consisted of very slight to slight multifocal to focal areas of 
corneal opacity in the center of the cornea along with constellation histopathological findings 
suggestive of minimal to mild corneal injury. The time of onset of these effects is unknown, 
as ophthalmic exams were only performed prior to the start 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 observed in females. See the IB for additional details.1 
Doses evaluated in the 28-day dog study demonstrated a steep dose response curve for 
toxicity and pronounced changes in hematologic parameters at high exposures.  
LOXO-305 was not mutagenic in 2 bacterial reverse mutation assays and was negative in 
a non-GLP micronucleus assay using Chinese hamster ovary 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, LOXO-305 was negative in a GLP in vivo 
micronucleus assay in rat at doses up to and including a dose of 
. The Cmax at the 
no observed effect level (NOEL) of 
 was 
 for males and 
25,900 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 (50% inhibitory concentration [IC50] 
 µM) 
of CYP1A2, CYP2B6, CYP2C19, and CYP2D6, and weak inhibition of CYP2C8, 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 inhibitory potency of LOXO-305 was increased, suggesting the 
potential for time-dependent inhibition of CYP3A4. Further kinetic evaluation confirmed 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 
concurrent inhibition of CYP3A4 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), 
multidrug and toxin extrusion protein (MATE) 1, and MATE2K. LOXO-305 did not inhibit 
organic anion transporter (OAT) 1 and weakly inhibited organic anion transporting 
polypeptide 1B1 (OATP1B1), organic anion transporting polypeptide 1B3 (OATP1B3), 
organic cation transporter (OCT) 1, OCT2, OAT3, and bile salt exporter pump (BSEP). 
LOXO-305 is a substrate of P-gp and BCRP. It is not a substrate of the hepatic transporters 
OCT1, OATP1B1, OATP1B3, or BSEP. 
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1.4. 
Summary of Clinical Experience 
LOXO-305 is currently 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 starting dose of LOXO-305 was 25 mg QD. 
As of 09 April 2020, safety data were available from 172 treated patients, with 300 mg QD as 
the highest dose administered (Section 1.4.1). As of 30 March 2020 (data cutoff date), PK 
data were available from 107 patients (Section 1.4.2).  
LOXO-305 was recently investigated in 1 study in healthy volunteers (LOXO-BTK-20014). 
LOXO-BTK-20014 is a pilot food-effect crossover study evaluating the effects of food and a 
proton-pump inhibitor (omeprazole) on the PK of LOXO-305 where 10 healthy volunteers 
were given 200 mg of LOXO-305 on 3 separate days, each followed by a washout period. 
Two additional studies are ongoing in healthy volunteers (LOXO-BTK-20006 and 
LOXO-BTK-20017). LOXO-BTK-20006 is a drug-drug interaction (DDI) study evaluating 
the effects of a strong CYP3A4 inhibitor (itraconazole) and a strong CYP3A4 inducer 
(rifampin) on the PK of LOXO-305 where, at the time of protocol development, 3 healthy 
volunteers were given 1 dose of 200 mg of LOXO-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 9 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 of LOXO-305 at 300-mg, up to 600-mg, up to 
800-mg, and up to 900-mg (if necessary), where, at the time of protocol development 
6 healthy volunteers were given a single dose of 300 mg LOXO-305 and 2 healthy volunteers 
were given a single dose of 600 mg LOXO-305. 
1.4.1. 
Safety 
As of 09 April 2020, 172 patients were treated in the first-in-human study 
(LOXO-BTK-18001) and received LOXO-305 at doses ranging from 25 mg QD to 300 mg 
QD. A full summary of treatment-emergent adverse events (TEAEs) for patients in this study 
is provided in the LOXO-305 IB and the Investigator is directed to the safety information 
described in that document.1 
Overall, TEAEs were reported in 123 of 172 treated patients in the safety population and 
were of mild or moderate severity (Grade 1 or 2) in 89 of 123 (51.7%) patients and were 
Grade 3 or 4 in severity in 33 of 123 (19.2%) patients. The most frequently reported TEAEs 
occurring in ≥ 10% of patients were fatigue (12.8% total, 7.0% related) and diarrhea (10.5% 
total, 6.4% related). The most frequently reported drug-related TEAEs (those in > 5% of 
patients) were fatigue (7.0%), diarrhea (6.4%), and contusion (5.2%). All other drug-related 
TEAEs each occurred in < 5% of patients. The most frequently reported Grade ≥ 3 TEAEs 
included neutropenia (4.1% total; 2.9% related), neutrophil count decreased (2.3% total; 1.2% 
related), anemia (1.7% total; 0.6% related), fatigue, leukocytosis, and platelet count 
decreased (each 1.2% total; each 0.6% related), and hypokalemia (1.2% total; none related).  
Five patients (2.9% of all 172 patients treated) discontinued LOXO-305 because of TEAEs; 
2 of the 5 patients (1.2% of all patients treated) discontinued LOXO-305 because of a 


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treatment-related event. One of these patients with mantle cell lymphoma treated in the 
100 mg QD group discontinued due to Grade 3 leukocytosis considered related to study drug. 
Study therapy was held for resolution of leukocytosis and the patient subsequently progressed 
and study therapy was not resumed; the event of leukocytosis was recorded as 
recovered/resolved. The second patient treated in the 150 mg QD group discontinued due to 
Grade 2 myalgia; the myalgia was ongoing. The patient had previously received ibrutinib 
which was discontinued after 3 months of treatment for AEs. 
A total of 5 deaths have been reported for patients treated in this study, LOXO-BTK-18001. 
No deaths were considered related to LOXO-305. 
From AE data reported following LOXO-305 administration in healthy volunteers in the 
LOXO-BTK-20014 study, all TEAEs (headache, nausea, and vomiting) were Grade 1 in 
severity and considered related to LOXO-305. All 3 events were reported by 1 subject and 
resolved within 1 to 1.5 days (data on file at the time of protocol development). From 
preliminary AE data reported following LOXO-305 administration in healthy volunteers in 
the LOXO-BTK-20006 study, all TEAEs (intermittent belching, bloating, insect bite, 
aphthous ulcer, nausea, intermittent diarrhea [x2], muscle twitch) were Grade 1 in severity 
and bloating, intermittent diarrhea, and intermittent belching were considered related to 
LOXO-305. All 7 AEs were reported by 3 subjects and all events resolved prior to End of 
Treatment (EOT; data on file at the time of protocol development). From preliminary AE 
data reported following LOXO-305 administration in healthy volunteers in Cohort 1 of the 
LOXO-BTK-20017 study, there was 1 TEAE (headache), observed in the 300 mg LOXO-305 
Cohort which was Grade 1 in severity and considered related to LOXO-305. The event 
resolved within 2 hours (data on file at the time of protocol development).  
To date, there have been no clinically significant abnormal findings in vital signs and ECG 
data in the studies investigating LOXO-305 conducted in healthy volunteers. 
1.4.2. 
Pharmacokinetics 
As of March 30, 2020, PK data were available from 107 patients enrolled in 
LOXO-BTK-18001. Steady-state PK parameters of LOXO-305 in these cancer patients could 
be derived from data collected on Cycle 1 Day 8 and are shown in Table 1. These data show 
that LOXO-305 is absorbed after oral administration with a median time to maximum 
observed plasma concentration (tmax) of approximately 2 hours and has low clearance 
(Table 1). Due to the limited sampling interval (0 to 8 hours), imputation for the 24-hour 
sample was made from the Cycle 1, Day 8 predose sample, leading to an estimated plasma 
half-life of approximately 20 hours. Following administration of doses of 100 mg QD or 
higher, mean trough plasma levels of LOXO-305 exceeded the IC90 (
 ng/mL) of BTK in 
vitro (Figure 1). 
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Table 1: Pharmacokinetic Parameters of LOXO-305 in Cancer Patients 
(Study LOXO-BTK-18001) at Steady State (Cycle 1 Day 8)  
Dose Level 
N 
Cmax  
(ng/mL) 
Geo mean 
(%CV) 
tmax  
(h)  
Median 
(min, max) 
AUC0-24 
(ng*h/mL)  
Geo mean 
(%CV) 
CL/F  
(L/h) 
Geo mean 
(%CV) 
t1/2 
 (h) 
Geo mean 
(%CV) 
25 mg QD 
5 
50 mg QD 
6 
100 mg QD 
9 
150 mg QD 
20 
200 mg QD 
24 
250 mg QD 
25 
300 mg QD 
18 
Abbreviations: AUC0-24 = area under the concentration-time curve from time 0 to 24 hours; CL/F = apparent oral 
clearance; Cmax = maximum drug concentration, Geo mean = Geometrical mean, N = number of subjects; 
PK = pharmacokinetic; QD = once daily; %CV = coefficient of variation in percent; t1/2 = half-life; tmax = time of 
maximal plasma concentration. 
a. N= 5; b N= 8; c N= 18; d N= 16; e N= 20; f N= 16; g N= 15 
Data cutoff date: March 30, 2020. 
 
 
Data cutoff date: March 30, 2020 
Time (h)
0
2
4
6
8
Mean Concentration (ng/mL)
25 mg (N=5)
50 mg (N=6)
100 mg (N=10)
150 mg (N=20)
200 mg (N=29)
250 mg (N=24)
300 mg (N=18)
Time (h)
0
2
4
6
8
Mean Concentation (ng/mL)
25 mg (N=5)
50 mg (N=6)
100 mg (N=9)
150 mg (N=20)
200 mg (N=24)
250 mg (N=25)
300 mg (N=16)
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Single doses of 200 mg LOXO-305 were investigated in a study in healthy volunteers 
(LOXO-BTK-20014, Pilot Food Effect study) in which the PK was determined. Following a 
single dose of 200 mg LOXO-305 to patients or healthy subjects, area under the 
concentration-time curve from 0 to 8 hours (AUC0-8) was similar between the two groups and 
Cmax was approximately 35% higher in healthy subjects, as shown in the table below (data on 
file at the time of protocol development). 
Table 2: Pharmacokinetic of LOXO-305 Following a Single 200-mg Dose of LOXO-305 
in Cancer Patients (Study LOXO-BTK-18001, Cycle 1 Day 1) and Healthy 
Subjects (Study LOXO-BTK-20014)  
Parameter 
Healthy Volunteersa 
Cancer Patientsb 
Geometric Mean 
CV 
n 
Geometric Mean 
CV 
n 
Abbreviations: AUC0-8 = area under the concentration-time curve from 0 to 8 hours; CV=coefficient of variation; 
Cmax = maximum concentration; n = number of subjects 
a. LOXO-BTK-20014, 200 mg single dose, fasted 
b. LOXO-BTK-18001, 200 mg single dose, fasted 
In healthy volunteers, the geometric mean single-dose Cmax of approximately 
 ng/mL 
following a 200-mg single dose is 
below the NOEL (in rat, Cmax 
) for 
micronuclei induction. Assuming that healthy volunteers have a similar accumulation ratio as 
observed in patients, the typical Cmax at steady state after repeated daily doses of 200 mg 
would be expected to be approximately 
 ng/mL, well below the NOEL threshold. 
1.5. 
Study Rationale 
The objective of DDI studies is to determine whether potential interactions between an 
investigational drug and other drugs exist. Drug-drug interaction studies have an important 
role in drug development,9 and this study is being performed as part of the development 
program for LOXO-305. 
LOXO-305 showed no detectable inhibition (IC50 
 μM) of CYP1A2, CYP2B6, 
CYP2C19, and CYP2D6, and weak inhibition of CYP2C8, CYP2C9, and CYP3A4 with 
inhibitory constant (Ki) values ranging from 
 μM in human liver microsomes. 
After pre-incubation of microsomes with LOXO-305 and nicotinamide adenine dinucleotide 
phosphate for 30 minutes prior to addition of CYP450 probe substrate, the CYP3A4 
inhibitory potency of LOXO-305 was increased, suggesting the potential for time-dependent 
inhibition of CYP3A4. Further kinetic evaluation confirmed that LOXO-305 is a time 
dependent inhibitor of CYP3A4 with a Ki value of 
 μM and a kinact (maximal 
inactivation rate constant) value of 
 h-1 resulting in a Clinact value (inactivation 
clearance) of 
 min-1 mM-1. 
1.6. 
Risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
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primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfort from collection of blood samples and other study procedures. The 
dose of LOXO-305 administered in this study is not anticipated to induce any potential risk to 
subjects participating in this study as the dose does not exceed the highest dose safely 
administered in first in human studies.1  
Doses of LOXO-305 up to 300 mg QD are currently being investigated in the ongoing global 
Phase 1/2 study in cancer patients, LOXO-BTK-18001.  
Single doses of 200 mg LOXO-305 were investigated in a study conducted in healthy 
volunteers (LOXO-BTK-20014) where 10 healthy volunteers were given 200 mg of 
LOXO-305 on 3 separate days, each followed by a washout period. Two additional studies 
are ongoing in healthy volunteers (LOXO-BTK-20006 and LOXO-BTK-20017). 
LOXO-BTK-20006 is a drug-drug interaction study evaluating the effects of a strong 
CYP3A4 inhibitor (itraconazole) and a strong CYP3A4 inducer (rifampin) on the PK of 
LOXO-305 where, at the time of protocol development, 3 healthy volunteers were given 1 
dose of 200 mg of LOXO-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 9 healthy volunteers were given 200 mg of LOXO-305 on 3 separate 
days (2 of which was co-administered with rifampin), each followed by a washout period. 
LOXO-BTK-20017 is a SAD study evaluating the safety and tolerability of LOXO-305 at 
300 mg, up to 600 mg, up to 800 mg, and up to 900 mg (if necessary) where, at the time of 
protocol development 6 healthy volunteers were given a single dose of 300 mg LOXO-305 
and 2 healthy volunteers were given a single dose of 600 mg LOXO-305. 
From AE data reported following LOXO-305 administration in 10 healthy volunteers in the 
LOXO-BTK-20014 study, all TEAEs (headache, nausea, and vomiting) were Grade 1 in 
severity and considered related to LOXO-305. All 3 events were reported by 1 subject and 
resolved within 1 to 1.5 days (data on file at the time of protocol development). From 
preliminary AE data reported following LOXO-305 administration in healthy volunteers in 
the LOXO-BTK-20006 study, all TEAEs (intermittent belching, bloating, insect bite, 
aphthous ulcer, nausea, intermittent diarrhea (x2), muscle twitch) were Grade 1 in severity 
and bloating, intermittent diarrhea and intermittent belching were considered related to 
LOXO-305. All 7 AEs were reported by 3 subjects and all events resolved prior to EOT; data 
on file at the time of protocol development). From preliminary AE data reported following 
LOXO-305 administration in healthy volunteers in Cohort 1 of the LOXO-BTK-20017 study, 
there was 1 TEAE (headache) observed in the 300 mg LOXO-305 cohort which was Grade 1 
in severity and considered related to LOXO-305. The event resolved within 2 hours (data on 
file at the time of protocol development).  
There is a potential risk that multiple doses of LOXO-305 may lead to decreases in white 
blood cells including neutrophils, lymphocytes, monocytes, and eosinophils. Therefore, to 
mitigate any potential immunosuppressive risks during the ongoing SARS-CoV-2 
(COVID-19) pandemic, subjects will remain in the Clinical Research Unit (CRU) for 
100 hours postdose (approximately 5 half-lives) which is Day 16 to allow for LOXO-305 
elimination. In addition, subject’s hematology laboratory results will be reviewed prior to 
discharge from the CRU. More information about the known and expected benefits, risks, and 
reasonably anticipated AEs associated with LOXO-305 may be found in the IB.1 


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The dosing regimen of the oral dose of repaglinide in the current study is consistent with use 
in DDI studies. Hypoglycemia is a possible side effect; however, subjects will be given 
breakfast, lunch, dinner, and an optional snack after dinner on the day before dosing and will 
have a standardized light breakfast (Table 4)15 minutes postdose to mitigate any potential 
side effects. The potential risk of participating in this study and receiving this drug is well 
managed by the study set-up and considered negligible. 
The safety monitoring practices employed by this protocol (ie, reviewing AE reporting, 
conducting physical examinations and clinical laboratory evaluations, measuring vital signs, 
and performing 12-lead ECGs) are considered adequate to protect subjects’ safety. 
 
 


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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is: 
• to assess the impact of multiple oral doses of LOXO-305 on the PK of a single oral 
dose of repaglinide (CYP2C8 substrate) in healthy subjects. 
2.1.2. 
Secondary Objective 
The secondary objective of the study is: 
• to assess the safety and tolerability of multiple oral doses of LOXO-305 when 
administered alone and coadministered with repaglinide in healthy subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of repaglinide following single oral dose administration (as appropriate): 
• area under the concentration-time curve from hour 0 to the last measurable 
concentration (AUC0-t) 
• area under the concentration-time curve from hour 0 extrapolated to infinity 
(AUC0-inf) 
• percentage extrapolation for AUC0-inf (%AUCextrap) 
• Cmax 
• tmax 
• apparent terminal elimination rate constant (λZ) 
• apparent systemic clearance (CL/F) 
• apparent plasma terminal elimination half-life (t1/2) 
• apparent volume of distribution (Vz/F). 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 following multiple dose administration (as appropriate): 
• AUC0-t 
• AUC during a dosing interval (AUCtau) 
• Cmax  


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• concentration observed at the end of the dosing interval (Ctrough) 
• tmax  
• CL/F at steady state (CL,ss/F). 
2.2.2. 
Secondary Endpoints 
Safety and tolerability will be assessed by monitoring AEs and concomitant medications, 
performing physical examinations and clinical laboratory evaluations, measuring vital signs, 
and performing 12-lead ECGs. These safety and tolerability endpoints are deemed adequate 
to detect any safety signals.  
 
 
 


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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 1, open-label, 2-period, fixed-sequence DDI study to investigate the effect of 
multiple oral doses of LOXO-305 on the PK of a single oral dose of repaglinide in healthy 
subjects.  
In Period 1, Day 1, a single 0.5 mg oral dose of repaglinide will be administered in the 
morning, following a fast of at least 10 hours prior to dosing. In order to mitigate any side 
effects when dosing with repaglinide on Day 1, on Day -1, subjects will be offered breakfast, 
lunch, dinner, and an optional snack after dinner. On Day 1, subjects will receive a 
standardized light breakfast (see Section 6.2) 15 minutes postdose. In addition, subjects may 
be provided with up to 16 g of glucose (up to 4 x 4 g chewable tablets) approximately 1-hour 
post-LOXO-305 and repaglinide dosing, if needed.  Blood samples for concentrations of 
repaglinide in plasma will be collected 
.  
In Period 2, on Days 2 through 11, oral doses of 200 mg LOXO-305 will be administered QD 
in the morning at the actual time of the Day 1 repaglinide dose (± 1 hour). On Days 2 through 
11, subjects will fast for at least 2 hours predose and 1-hour postdose with the exception of 
Days 2, 6, and 11 where clinical laboratory evaluations are performed, subjects will fast for at 
least 8 hours predose and 1-hour postdose. On Day 12, 200 mg LOXO-305 and 0.5 mg of 
repaglinide will be co-administered in the morning at the actual time of the Day 1 repaglinide 
dose (± 1 hour), following a fast of at least 10 hours prior to dosing. In order to mitigate any 
side effects when dosing with repaglinide on Day 12, on Day 11, subjects will receive 
breakfast (2 hours after dosing), lunch, dinner, and an optional snack after dinner. On Day 12, 
subjects will receive a standardized light breakfast 15 minutes post-LOXO-305 and 
repaglinide dosing. In addition, subjects may be provided with up to 16 g of glucose (up to 
4 x 4 g chewable tablets) approximately 1-hour post-LOXO-305 and repaglinide dosing, if 
needed. 
, a blood sample for concentrations of LOXO-305 in plasma will be 
 blood samples for concentrations of repaglinide 
and LOXO-305 in plasma will be collected
 
 
There will be a washout period of 11 days between the dose of repaglinide on Day 1 and the 
dose of repaglinide on Day 12, respectively.  
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 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 16 upon completion of all PK and safety assessments or Early Termination (ET) if the 
subject discontinues. A follow-up phone call will occur for all subjects who received at least 
1 dose of study drug (including subjects who are terminated early) 7 days (± 2 days) after 
EOT or ET. The duration of participation is expected to be approximately 54 days (Screening 
through follow-up phone call). 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
CCI
CCI
CCI
CCI


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The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned a dose of study drug; this definition excludes screen failure subjects. 
In this study, physical examinations, 12-lead ECGs, vital 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 
performed at specified times during the study (for specific timepoints and details on each 
study variable, refer to Appendix 4).  
AEs and SAEs will be collected beginning at informed consent. AEs will be reported 
throughout the study (ie, from signing of the ICF until End of Study [EOS], or until ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as 
subject medical history (if the event is reported as beginning prior to signing of the ICF or if 
the event occurs prior to study drug administration on Day 1 and is assessed as not related to 
study procedures by the Investigator [or designee]) or as AEs (if the event occurs after 
signing of the ICF but prior to study drug administration on Day 1 and is assessed as related 
to study procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From 
EOT or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a follow-up phone 
call) are to be reported. 
A Schedule of Assessments is presented in Appendix 4. Study completion is defined as the 
time of the last subject’s follow-up. 
3.2. 
Discussion of Study Design 
Metabolic routes of elimination, including most of those occurring through the CYP family of 
enzymes, can be inhibited or induced by concomitant drug treatment. Changes arising from 
metabolic DDI can be significant and contribute to increases or decreases in the blood and 
tissue concentrations of the parent drug or active metabolite. Increased concentrations of a 
parent drug or its active metabolite can alter the safety and efficacy profile of a drug.  
LOXO-305 has been found to have an inhibitory effect on CYP2C8 in vitro.1 The probe drug 
selected in this study, repaglinide, was chosen as it is a known sensitive substrate for 
CYP2C8. LOXO-305 will be given as multiple oral doses in order to examine its effect on 
repaglinide at steady state, at which maximal inhibition of CYP2C8 should be achieved.  
In order to mitigate any side effects when dosing with repaglinide, subjects will be given 
breakfast, lunch, dinner, and an optional snack on the day before dosing and will have a 
standardized light breakfast 15 minutes postdose. 
The fixed single-sequence design used in this study is typical for drug interaction studies 
where a relatively small number of subjects are required, because it allows intra-subject 
comparisons. This study will be open-label because the primary endpoints are not considered 
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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 
Multiple oral doses of 200 mg LOXO-305 QD will be administered on Days 2 through 
Day 12 to achieve LOXO-305 steady state, ensuring the maximal effect of LOXO-305 when 
coadministered with repaglinide. Doses of LOXO-305 from 25 mg QD to 300 mg QD have 
been evaluated in the ongoing global Phase 1/2 first-in-human study, LOXO-BTK-18001 
(BRUIN Study) in patients with previously treated CLL/SLL or NHL with dose escalation up 
to 300 mg QD approved by the study’s Safety Review Committee. The available data 
demonstrate that LOXO-305 appears safe and well tolerated at these doses. At all evaluated 
doses, including doses of up to 300 mg QD, no dose-limiting toxicities have been identified 
in humans.1 
Repaglinide  
The selected dose for the dose of probe drug repaglinide was based on typical doses for this 
drug and are considered to be high enough to provide sufficient plasma concentrations to 
achieve the objectives of the study.  
 
 


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4. SELECTION OF STUDY POPULATION 
4.1. 
Screening Procedures 
The following screening procedures will be performed for all potential subjects at a visit 
conducted within 28 days of study entry (ie, prior to Check-in [Day -1]): 
1. Inclusion/Exclusion criteria 
2. Informed consent 
3. Demographic data 
4. Medical history (including review of medication[s]) 
5. Height, weight, and body mass index (BMI) 
6. Vital sign measurements (including oral 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) 
7. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
8. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
9. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel and UA; Appendix 2) 
10. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), 
hepatitis B virus (HBV) core antibody, human immunodeficiency virus (HIV) 
antibody, and SARS-CoV-2 (COVID-19) via polymerase chain reaction testing 
([PCR] or equivalent (Appendix 2) 
11. Hemoglobin A1c (HbA1c) test (Appendix 2) 
12. Screen for selected drugs of abuse, including cotinine and alcohol (Appendix 2) 
13. Estimated glomerular filtration rate (eGFR; Appendix 2) 
14. Serum pregnancy test (for female subjects only; Appendix 2) 
15. Follicle-stimulating hormone (FSH) test (for post-menopausal female subjects only; 
Appendix 2) 
16. Thyroid-stimulating hormone (TSH) test (Appendix 2) 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
1. Review of inclusion/exclusion criteria 
2. Interim medical history, including concomitant medication(s) 
3. Weight and BMI 
4. Complete physical examination (Section 7.2.5) 


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5. Vital sign measurements (including oral 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)  
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. 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 selected drugs of abuse, including cotinine and alcohol (Appendix 2) 
10. Screen for COVID-19 via PCR or equivalent (Appendix 2) 
11. eGFR (Appendix 2) 
12. Serum pregnancy test (for female subjects only; Appendix 2) 
13. Compliance with concomitant medications and exclusionary restrictions (Section 6) 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Check-in (Day -1 [as appropriate; #1, Section 4.2]). In addition, 
continued compliance with concomitant medication and other restrictions will be verified. 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to enrollment. Prior to dosing, the Sponsor will provide approval of subjects selected for 
enrollment by the Investigator (or designee). 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria apply 
will be eligible to be enrolled into the study. Safety evaluations may be repeated at the 
discretion of the Investigator (or designee) or Sponsor. 
4.3. 
Inclusion Criteria 
Subjects who meet the following criteria at Screening and Check-in (Day -1), unless 
otherwise specified, may be included in the study: 
1. Males, and females of non-childbearing potential, between 18 and 55 years of age, 
inclusive, at Screening. 
2. Within BMI range 18.0 to 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital sign measurements, or clinical laboratory 
evaluations (Appendix 4) at Screening and/or Check-in (Day -1) as assessed by the 
Investigator (or designee). 
4. Female subjects of non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy, or confirmed tubal occlusion more than 6 months prior to Day 1) or 
post-menopausal (defined as at least 12 months post-cessation of menses without an 
alternative medical cause). Post-menopausal status will be confirmed with a screening 
serum FSH levels consistent with post-menopausal status per the laboratory’s 
reference ranges. All female subjects must have a negative qualitative serum 


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pregnancy test (serum human chorionic gonadotropin; serum quantitative human 
chorionic gonadotropin tests may be used for confirmation as needed) at Screening 
and Check-in (Day -1). Female subjects are required to refrain from donation of ova 
from Check-in (Day -1) until 6 months after Day 12 (or last administration of study 
drug 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 confirmation 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 sterilization is not available, male subjects must 
follow 1 of the contraception methods below from Day 1 through 6 months 
after Day 12 (or last administration of study drug if subject terminates from 
the study early): 
i. Male condom with spermicide, or 
ii. A male subject must ensure that his female partner meets 1 of the 
following criteria: 
1. intrauterine device (IUD) (hormonal IUD; eg, Mirena®). 
Copper IUDs are acceptable (eg, ParaGard®); or 
2. established use of oral, implanted, injected, transdermal, 
intravaginal, or hormonal method of contraception associated 
with inhibition of ovulation; or 
3. non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral 
salpingectomy, bilateral oophorectomy, or confirmed tubal 
occlusion more than 6 months prior to Day 1 for male partner); 
or 
4. be post-menopausal with amenorrhea for at least 12 months 
prior to Day 1 and FSH serum levels consistent with 
post-menopausal status. 
Male subjects who practice true abstinence because of a lifestyle choice (ie, do not 
become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence by a female partner (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. If a male subject is abstinent at the time of signing the ICF 
but becomes sexually active from Check-in (Day -1) through 6 months after Day 12 
(or last administration of study drug if subject terminates from the study early), he 
must agree to use contraception as described above. 
For male subjects, sexual intercourse with female partners who are pregnant, or 
breastfeeding should be avoided from Check-in (Day -1) through 6 months after Day 
12 (or last administration of study drug if subject terminates from the study early), 
unless the male subject uses a condom with spermicide. Male subjects are required to 
refrain from donation of sperm from Check-in (Day -1) through 6 months after Day 
12 (or last administration of study drug if subject terminates from the study early). 


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For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. 
6. Able to understand and provide written informed consent. 
7. Able to comply with all study procedures, including the 16-night stay at the CRU and 
follow-up phone call. 
4.4. 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. History or presence of any of the following, deemed clinically significant by the 
Investigator (or designee), and/or Sponsor: 
a. liver disease 
b. pancreatitis 
c. peptic ulcer disease 
d. intestinal malabsorption 
e. cholecystectomy 
f. gastric reduction surgery 
g. history or presence of clinically significant cardiovascular disease: 
i. Myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to Day 1 
ii. Symptomatic angina pectoris within 6 months prior to Day 1 
iii. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to Day 1 
iv. Congenital prolonged QT syndrome 
v. Ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
vi. Arrhythmia (excluding benign sinus arrhythmia) or history of 
arrhythmia requiring medical intervention 
vii. Ventricular dysfunction or risk factors for Torsades de Pointes (eg, 
heart failure, cardiomyopathy, family history of Long QT Syndrome) 
viii. Significant screening ECG abnormalities: 
1. left bundle-branch block 
2. second-degree atrioventricular (AV) block, type 2, or 
third-degree AV block 
3. QT interval corrected for heart rate using Fridericia’s method 
(QTcF) is > 450 msec 
4. ECG findings deemed abnormal with clinical significance by 
the Investigator (or designee) at Screening, Check-in (Day -1), 
or prior to dosing on Day 1. 


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Rechecks of out-of-range values for these ECG parameters that are 
not clinically significant (as determined by the Investigator [or 
designee]) will be permitted up to 2 times during Screening, 
Check-in (Day -1), and predose on Day 1 to confirm eligibility for 
the study if the values fall within 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, 
including: 
a. oral body temperature > 37.5°C 
b. pulse rate < 50 or > 99 beats per minute  
c. systolic BP < 89 or > 139 mmHg 
d. diastolic BP < 50 or > 89 mmHg 
e. oxygen saturation < 95% (room air). 
Rechecks of out-of-range values for these parameters (oral body temperature, 
pulse rate, BP, and oxygen saturation) that are not clinically significant (as 
determined by the Investigator [or designee]) will be permitted up to 2 times 
during Screening, Check-in (Day -1), and predose on Day 1 to confirm eligibility 
for study participation if the values fall within the ranges stated above. 
3. Clinically significant (as determined by the Investigator [or designee] and Sponsor) 
abnormal laboratory values (hematology panel, UA, clinical chemistry panel [fasted at 
least 8 hours], excluding those further defined in exclusion criteria #5, #6, #7, and #8 
below) at Screening and/or Check-in (Day -1). Rechecks of clinically significant 
out-of-range clinical laboratory results (excluding those further defined in exclusion 
criteria #5, #6, #7, and #8 below) will be permitted up to 2 times during Screening 
and Check-in (Day -1) to confirm eligibility for study participation if the values fall 
within normal ranges or are stabilizing. 
4. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Check-in (Day -1). 
5. Abnormal liver function tests (LFTs), as defined by aspartate aminotransferase, 
alanine aminotransferase, and serum (total and direct) bilirubin, as well as amylase 
and lipase above the upper limit of the normal range at Screening or Check-in 
(Day -1). Rechecks of LFTs, amylase, and lipase above the upper limit of the normal 
range that are not clinically significant (as determined by the Investigator [or 
designee]) will be permitted up to 2 times during Screening and Check in (Day -1) to 
confirm eligibility for study participation if the values fall within normal ranges. 
6. Any clinically significant deviations from normal ranges in creatine kinase unless 
approved by the Investigator (or designee) and Sponsor. Rechecks of out-of-range 
creatine kinase values that are not clinically significant (as determined by the 
Investigator [or designee]) will be permitted up to 2 times during Screening and 
Check in (Day -1) to confirm eligibility for study participation if the values are stable 
or trending down. 
7. eGFR ≤ 80 mL/minute/1.73m2 calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation at Screening or Check-in (Day -1). 


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Rechecks of out-of-range eGFR values that are not clinically significant (as 
determined by the Investigator [or designee]) will be permitted up to 2 times during 
Screening and Check-in (Day -1) to confirm eligibility for study participation if the 
values fall within the range stated above. 
8. Hemoglobin levels < lower limit of normal at Screening or Check-in (Day -1). 
Rechecks of hemoglobin levels < lower limit of normal that are not clinically 
significant (as determined by the Investigator [or designee]) will be permitted up to 
2 times during Screening and Check-in (Day -1) to confirm eligibility for study 
participation if the values fall within the range stated above or are normalizing. 
9. Positive serologic test for HBsAg, HBV core antibody, HCV antibody, or HIV 
antibody at Screening. Subjects who are positive for HCV by antibody will require 
confirmation by PCR before enrollment to detect presence of active virus. Subjects 
who are HCV PCR positive or for whom a PCR is unable to be obtained will not be 
eligible. 
10. Positive PCR test (or equivalent) for COVID-19 at Screening or Check-in (Day -1). 
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. 
11. Known ongoing alcohol and/or drug abuse within 2 years prior to Screening, or 
evidence of such abuse as indicated by the laboratory assays for drugs of abuse 
(including cotinine and alcohol) conducted during Screening and/or at Check-in 
(Day -1). Tests for drugs of abuse must be negative at both Screening and Check-in 
(Day -1). 
12. Consumption of grapefruit/grapefruit juice or Seville oranges or its juice within 
7 days prior to Check-in (Day -1) and through EOT or ET. 
13. Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours 
prior to Check-in (Day -1) and through EOT or ET. 
14. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
15. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
16. Participation in any other investigational study drug trial involving administration of 
any investigational drug in the past 30 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1. 
17. 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; with the exception of 
repaglinide administered for the purposes of this study/in accordance with the 
protocol), strong P-gp inhibitors, proton pump inhibitors, antacids, H2-receptor 
antagonists, and drugs that prolong QT/QTc interval, herbal products, natural or 
herbal supplements, and hormone-replacement therapy [HRT]) within 14 days, or 
5 half lives (if known), whichever is longer, prior to Day 1 and through EOT or ET, 
unless deemed acceptable by the Investigator (or designee) and Sponsor. 
18. History of a major surgical procedure within 30 days prior to Screening. 


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


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• change in compliance with inclusion/exclusion criterion that is clinically relevant and 
affects subject safety 
• occurrence of AEs 
• occurrence of pregnancy 
• non-compliance with study restrictions  
Notification of withdrawal will immediately be made to the Sponsor. In case of withdrawal, 
efforts will be made to perform all final study day assessments (Appendix 4). The date the 
subject is withdrawn from the study and the reason for withdrawal will be recorded on the 
subject’s electronic Case Report Form (eCRF). All withdrawn subjects with AEs that are 
assessed as related to study drug and which are ongoing at ET may continue to be followed 
until the symptoms or value(s) return to normal, or acceptable levels, as judged by the 
Investigator (or designee) and confirmed by the Sponsor. 
The entire study may be discontinued at the discretion of the Investigator (or designee) or 
Sponsor, based on the occurrence of the following: 
• 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 performance of the study; 
• difficulties in the recruitment of subjects; 
• cancellation of drug development. 
In the event that the study is terminated early, the Sponsor or its designee will provide 
specific guidance to the CRU regarding the EOS procedures. 
 
 


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5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the LOXO-305 tablets. Covance will supply repaglinide tablets.  
Table 3: Study Drugs 
Study Drug 
LOXO-305 
Repaglinide 
Forma 
Tablet 
Tablet 
Strength 
100 mg 
0.5 mg 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Bend Research Inc. 
Aurobindo Pharmab 
a Specific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug(s). 
b The manufacturer will be confirmed by the site at the time of drug procurement.  
The tablets containing 100 mg LOXO-305 will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificate of Analysis. It will be provided in 
high-density polyethylene bottles and stored according to the instructions on the label. 
Repaglinide will be sourced by the site and stored according to the instructions on the 
package insert. 
Study drugs will be stored at the CRU in a location that is locked with restricted access. 
The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drugs will be stored in accordance with the labeling. The 
study drugs will be transferred from bulk supplies into the subject’s dose container by 
qualified CRU employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
In Period 1, Day 1, a single 0.5-mg oral dose of repaglinide will be administered in the 
morning following a fast of at least 10 hours. To mitigate any side effects when dosing with 
repaglinide on Day 1, on Day -1, subjects will be offered breakfast, lunch, dinner, and an 
optional snack after dinner. Subjects will receive a standardized light breakfast (see 
Section 6.2) 15 minutes postdose. In addition, subjects may be provided with up to 16 g of 
glucose (up to 4 x 4 g chewable tablets) approximately 1-hour postdose, if needed. 
In Period 2, on Days 2 through 11, oral doses of 200 mg LOXO-305 will be administered QD 
in the morning at the actual time of the Day 1 repaglinide dose (± 1 hour). On Days 2 through 
11, subjects will fast for at least 2 hours predose and 1-hour postdose with the exception of 
Days 2, 6, and 11 where clinical laboratory evaluations are performed, subjects will fast for at 
least 8 hours predose and 1-hour postdose. On Day 12, 200 mg LOXO-305 and 0.5 mg of 
repaglinide will be co-administered in the morning at the actual time of the Day 1 repaglinide 
dose (± 1 hour), following a fast of at least 10 hours prior to dosing. In order to mitigate any 
side effects when dosing with repaglinide on Day 12, on Day 11, subjects will receive 


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breakfast (2 hours after dosing), lunch, dinner, and an optional snack after dinner. On Day 12, 
subjects will receive a standardized light breakfast 15 minutes post-LOXO-305 and 
repaglinide dosing. In addition, subjects may be provided with up to 16 g of glucose (up to 
4 x 4 g chewable tablets) approximately 1-hour post-LOXO-305 and repaglinide dosing, if 
needed. 
All study drugs will be administered orally with approximately 240 mL of water. An 
additional 100 mL of water may be administered if needed. Water will be restricted for 
1-hour predose and 1-hour postdose, with the exception of water administered for dose 
administration.  
Each unit dose will be prepared by qualified CRU staff. Each unit dose container will be 
appropriately labeled. 
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be consistently administered the appropriate 
dose at a specific time, the exact dose time of subjects may be staggered to obviate the need 
to have all subjects on precisely the same study schedule. For each dose, the subject’s actual 
dose time will be recorded in the source documents and transcribed into the eCRF. 
Subjects will be instructed not to crush, split, or chew the study drugs. 
Subjects will not lay supine for 4 hours following LOXO-305 dose administration, except as 
necessitated by the occurrence of an AE(s) and/or study procedure(s). 
5.3. 
Randomization 
This is a non-randomized study. The study has a fixed treatment sequence.  
5.4. 
Blinding 
This is an open-label study. 
5.5. 
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 administration, a visual inspection of the mouth and hands 
will be performed for each subject. 
• At each dose preparation occasion, a predose and postdose inventory of LOXO-305 
and repaglinide will be performed, as appropriate.  
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-305 
and repaglinide tablets. In addition, an accurate drug disposition record will be kept, 
specifying the amount dispensed to each subject and the date of dispensing. This drug 
accountability record will be available for inspection at any time. At the completion of the 


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study, the original drug accountability record will be available for review by the Sponsor 
upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused LOXO-305 tablets will be disposed of by the CRU 
in accordance with the CRU’s SOPs and local/state/federal guidelines governing waste 
disposal of investigational drugs, following the Sponsor’s written authorization. Repaglinide 
tablets will be disposed of by the CRU in accordance with the CRU’s SOPs. 
 
 


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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) and glucose 
(up to 16 g/day [up to 4 x 4 g chewable tablets] on Days 1 and 12 following dosing) are 
acceptable concomitant medications. 
Subjects will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurs within 5 half-lives (if known) or 30 days, 
whichever is longer, prior to Day 1. 
All prescription medications and over-the-counter medications (except for 
paracetamol/acetaminophen and glucose as referenced above) are prohibited for 14 days or 
5 half lives (if known), whichever is longer, prior to Day 1 and through EOT or ET, unless 
deemed acceptable by the Investigator (or designee) and Sponsor. This includes, but is not 
limited to: moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers (including 
herbal products such as St. John’s wort; with the exception of repaglinide administered for 
the purposes of this study/in accordance with the protocol), strong P-gp inhibitors, proton 
pump inhibitors, antacids, H2-receptor antagonists, and drugs that prolong QT/QTc interval, 
herbal products, natural or herbal supplements, and HRT. 
Any medication taken by a subject during the course of the study, including details of its 
dosage, administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without 
prior approval of the Investigator (or designee) and Sponsor, unless its use is deemed 
necessary in a medical emergency. In this case, the use of the concomitant medication will be 
reported as soon as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
Subjects are required to refrain from use of tobacco, smoking cessation products, and 
nicotine-containing products within 3 months prior to Screening through EOT or ET. 
Consumption of foods or beverages containing grapefruit/grapefruit juice or Seville oranges 
or its juice within 7 days prior to Check-in (Day -1) and through EOT or ET will not be 
allowed. 
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 otherwise maintain their normal level 
of physical activity through EOT or ET (ie, should not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
On Day -1 (depending on the time the subject checks into the CRU), subjects will receive 
breakfast, lunch, dinner, and an optional snack after dinner. On Day 11, subjects will receive 
breakfast (2 hours after dosing), lunch, dinner, and an optional snack after dinner. On Day 1 


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and Day 12, subjects will receive a standardized light breakfast (examples of contents are 
detailed in Table 4) 15 minutes post-repaglinide dose.  
Table 4: Example Standardized Light Breakfast Content 
Light Breakfast 
Example 1: 
1 hard-boiled egg 
1 small piece of toast with butter 
1 small apple or banana 
Example 2: 
1 small bowl of cereal or 1 small bagel with cream cheese 
1 small apple or banana 
For the remainder of the time while confined at the CRU, subjects will receive a standard diet 
at scheduled times that do not conflict with other study-related activities. All study drugs will 
be administered orally with approximately 240 mL of water. An additional 100 mL of water 
may be administered if needed. 
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 repaglinide and LOXO-305 plasma levels will be collected 
at the timepoints specified in Appendix 4. The exact time of the study drug administration 
and the actual time of blood sampling for PK analysis will be recorded on the eCRF. 
Processing, storage, and shipping instructions for these PK blood samples will be provided in 
a separate Laboratory Manual. The number of blood samples and total blood volume required 
for PK testing is presented in Appendix 3.  
7.1.2. 
Analytical Methodology 
Plasma concentrations of repaglinide and LOXO-305 will be determined using validated 
bioanalytical methods. Specifics of the bioanalytical methods will be provided in a separate 
document. 
7.2. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee) or 
Sponsor. 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and any other procedures to be performed at the same timepoint. The order of priority for 
scheduling procedures around a timepoint is (in descending order of priority): 
• dosing 
• PK blood sampling 
• vital sign measurements  
• 12-lead ECGs 
• blood and urine samples for clinical laboratory evaluations 
• physical examination. 
7.2.1. 
Adverse Events 
AE definitions; assignment of severity, causality, action taken, and outcome; and procedures 
for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a non-leading HDYF? Question such as “Have there been any changes 
in your health status since Screening/since you were last asked?” at the timepoints specified 
in Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in [Day -1], at each 
postdose vital sign measurement, and at an appropriate time for all other days). Subjects will 
also be encouraged to voluntarily report AEs occurring at any other time through the EOS. 


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AEs, whether volunteered, identified by the subject’s responses to HDYF? Inquiries, or noted 
on physical examination, ECG, vital sign measurements, or clinical laboratory 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 history (if the event is reported as beginning prior to signing of the ICF or if 
the event occurs prior to study drug administration on Day 1 and is assessed as not related to 
study procedures by the Investigator [or designee]) or as AEs (if the event occurs after 
signing of the ICF but prior to study drug administration on Day 1 and is assessed as related 
to study procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From 
EOT or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a follow-up phone 
call) are to be reported. 
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up phone call, all subjects must be followed until EOS. Subjects with AEs that are 
assessed as related to study drug by the Investigator (or designee) which are ongoing at EOS 
may continue to be followed until the symptoms or value(s) return to normal, or acceptable 
levels, as judged by the Investigator (or designee) and confirmed by the Sponsor. The 
Investigator (or designee) should use appropriate judgment in ordering additional tests as 
necessary to monitor the resolution of events. The Sponsor may request that additional safety 
tests be performed. 
Subjects will receive a follow-up phone call 7 days (± 2 days) after EOT or ET to determine 
if any SAE or drug-related AE has occurred since the EOT or ET visit. 
At all times, a subject may be required to remain at the CRU for longer at the discretion of 
the Investigator (or designee). 
Any event that meets the criteria of a suspected unexpected serious adverse reaction 
(SUSAR) will be reported to the Institutional Review Board (IRB) according to CRU policy 
by the Investigator (or designee) and to regulatory authorities by the Sponsor (or Sponsor 
designee) according to regulatory authority requirements. Refer to Reference Safety 
Information in the current IB for LOXO-305 for additional safety information.1 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours; at EOT or 
ET, subjects are not required to be fasted prior to clinical laboratory evaluations], coagulation 
parameters, hematology panel, TSH [Screening only], HbA1c [Screening only], eGFR 
[Screening and Check-in (Day -1)] and UA) will be collected at the timepoints specified in 
Appendix 4. 
Screens for HCV antibody, HbsAg, HBV core antibody, and HIV antibody will be performed 
at Screening.  
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 


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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 drugs of abuse (including cotinine and alcohol) will be 
performed at Screening and repeated at Check-in (Day -1) for all subjects. A serum 
qualitative pregnancy test (female subjects only [serum quantitative may be used for 
confirmation if needed]) and an FSH test (post-menopausal female subjects only) will be 
performed at the timepoints specified in Appendix 4. 
The number of blood samples and total blood volume required for clinical laboratory 
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 oral temperature, respiratory rate, and supine BP, oxygen 
saturation and pulse rate) will be obtained at the timepoints specified in Appendix 4. 
Blood pressure and pulse rate measurements should be performed 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 blood draws, the blood 
draws 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 blood draw. 
7.2.4. 
12-lead Electrocardiogram 
A 12-lead ECG (including heart rate, PR, RR, QRS, and QT interval 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 interval will be corrected for heart rate by 
Fridericia’s (QTcF = QT/[RR]1/3) formula. 
When 12-lead ECGs are scheduled at the same time as blood draws, the 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 blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated physical examination will be performed at the timepoints specified 
in Appendix 4. Complete physical examinations will evaluate general appearance and the 
following body systems/organs: dermatological; head and eyes; ears, nose, mouth, and throat; 
pulmonary; cardiovascular; abdominal; lymphatic; musculoskeletal/extremities; and 
neurological. Weight and height will be reported (height only reported during Screening). 
Abbreviated physical examinations will evaluate general appearance and the following body 
systems/organs: dermatological; pulmonary; cardiovascular; abdominal; and neurological. 
 
 


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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
Up to sixteen healthy adult male and female subjects (women of non-childbearing potential 
only) will be enrolled. The sample size chosen for this study was selected without statistical 
considerations, but is consistent with previous studies of a similar design. Up to sixteen 
subjects are anticipated to be sufficient to provide a reliable estimate of the magnitude and 
variability of the interaction. Replacement subjects may be enrolled only if deemed necessary 
by the Sponsor. Every attempt will be made to enroll at least 4 subjects of each sex in the 
study.   
8.2. 
Analysis Populations 
8.2.1. 
Study Populations 
The PK Population will consist of all subjects who have received a dose of LOXO-305, have 
at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times median tmax for the 
analyte being evaluated. The impact of protocol deviations on 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 (repaglinide and/or LOXO-305). Subjects will be classified into groups based on actual 
treatment received.  
8.3. 
Pharmacokinetic Analysis 
Blood samples for plasma concentration analysis will be collected for the following: 
• Repaglinide:  
o Serial PK blood samples 
.  
• LOXO-305:  
o Serial PK blood samples 
 
.  
o Blood samples 
 
CCI
CCI
CCI


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Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of repaglinide following single dose administration (as 
appropriate): 
AUC0-t 
AUC from hour 0 to the last measurable concentration, calculated using 
the linear trapezoidal rule for increasing and decreasing concentrations 
AUC0-inf 
AUC from hour 0 extrapolated to infinity, calculated using the formula: 
 
 
AUC0-inf = AUC0-t + 
z
t
λ
C
 
where Ct is the last measurable concentration and λZ is the apparent 
terminal elimination rate constant. 
%AUCextrap percentage extrapolation for AUC0-inf 
Cmax 
maximum observed plasma concentration 
tmax 
time to maximum observed plasma concentration 
λZ 
apparent terminal elimination rate constant, where λZ is the magnitude 
of the slope of the linear regression of the log concentration versus time 
profile during the terminal phase 
CL/F 
apparent systemic clearance  
t1/2 
apparent plasma terminal elimination half-life (whenever possible), 
where t½ = ln(2)/λZ 
Vz/F 
apparent volume of distribution during the terminal phase  
Wherever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-305 following multiple dose administration (as 
appropriate): 
AUC0-t 
AUC from hour 0 to the last measurable concentration, calculated using 
the linear trapezoidal rule for increasing and decreasing concentrations 
AUCtau 
area under the concentration-time curve during a dosing interval 
CL,ss/F 
apparent systemic plasma clearance after oral (extravascular) 
administration, calculated as Dose/AUCtau (Day 12) 
Cmax 
maximum observed plasma concentration at steady state 
Ctrough 
concentration observed at the end of the dosing interval 
tmax 
time to reach Cmax. If the maximum value occurs at more than one 
timepoint, tmax is defined as the first timepoint with this value. 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 8.1 or higher (Certara USA Inc.).  
The λZ and t1/2 will be calculated by linear least squares regression analysis using the 
maximum number of points in the terminal log linear phase (eg, 3 or more non-zero plasma 
concentrations).  
Other parameters may be added, as appropriate. Final PK parameters reported will be detailed 
in the Statistical Analysis Plan (SAP). 


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Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analysis will be performed using SAS Version 9.4 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, arithmetic 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 
A mixed model will be performed to evaluate the effects of multiple-dose administration of 
LOXO-305 on repaglinide. The mixed effect model will include treatment as a fixed effect 
and subject as a random effect. The analysis will be performed on the ln-transformed PK 
parameters (AUC0-t, AUC0-inf, and Cmax) and will include calculation of least squared (LS) 
means and the difference between treatment LS means, as well as their corresponding 90% 
confidence intervals (CIs). The geometric mean ratios and their 90% CIs of the PK parameter 
for each treatment comparison will be constructed using the exponentiation of the difference 
and the CIs from the mixed effect model. The primary comparison for this study is 0.5 mg 
repaglinide + multiple-dose of LOXO-305 versus 0.5 mg repaglinide.  
8.4. 
Safety Analysis 
All safety assessments, including AEs and SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated and summarized where possible, using descriptive methodology, as needed, by 
treatment and timepoint. Unless otherwise specified, baseline value is defined as the last 
non-missing measurement before administration of study drug on Day 1. No formal statistical 
analyses are planned for the safety data. All safety data will be listed by subject.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO Drug Global B3, September 2019) and AEs will be coded using MedDRA 
Version 22.1 (or higher). The incidence of AEs will be presented by severity and by 
relationship to study drug as determined by the Investigator ([or designee], Appendix 1 for 
AE reporting). All TEAEs will be summarized by system organ class (SOC) and preferred 
term (PT). 
8.5. 
Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a CRU staff member authorized to make 
the change. Changes will be made by striking a single line through erroneous data and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
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The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the CRU and verified by the Study Monitor. Data 
will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be 
reviewed by the Covance scientific team. The eCRF and ancillary data will be converted into 
final SAS® datasets following Study Data Tabulation Model or client-provided specifications. 
The final datasets structure will be verified using Web Submission Data Manager®, while the 
dataset content will be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will 
be peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by 
the Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.6. 
Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per client request, and as applicable, according to the contract 
between Covance and the Sponsor. 
 
 


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9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator (or designee). 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator (or designee), and the IRB (see Form 
FDA 1572). 
9.2. 
Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator (or designee) and appropriate CRU staff to familiarize the Investigator (or 
designee) and CRU staff with the materials necessary for conducting the clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, oral 
presentations, abstracts) by the Investigator (or designee) or their representative(s), shall 
require prior notification and review, within a reasonable timeframe, by the Sponsor, and 
cannot be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of 
the Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate a Study Monitor who will be responsible for monitoring this 
clinical trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and 
source documentation completion and retention, and accurate study drug accountability. To 
this end, the Sponsor’s Study Monitor will visit the CRU at suitable intervals and be in 
frequent contact through verbal and written communication. It is essential that the Sponsor’s 
Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Sponsor’s Study Monitor will adhere 
to all requirements for subject confidentiality as outlined in the ICF. The Investigator (or 
designee) and Investigator’s staff will be expected to cooperate with the Sponsor’s Study 
Monitor, to be available during a portion of the monitoring visit to answer questions, and to 
provide any missing information. 
9.5. 
Institutional Review Board 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
advertisement, ICF, and other information provided to subjects will be reviewed and 
approved by the IRB. The Sponsor will supply relevant material for the Investigator (or 
designee) to submit to the IRB for the protocol’s review and approval. Verification of the 


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IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator (or designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will be 
transmitted in writing to the Investigator (or designee). If requested, the Investigator (or 
designee) will permit audits by the IRB and regulatory inspections by providing direct access 
to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s (or designee’s) participation in the study. 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can 
withdraw from the study at any time. In accordance with 21 CFR 50, the informed consent 
process shall be documented by the use of a written ICF approved by the IRB and signed by 
the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
9.7. 
Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each eCRF 
will be retained by the Investigator (or designee). All source documents, records, and reports 
will be retained by the CRU in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the CRU archives. 
9.8. 
Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the US 
CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), Applications for FDA Approval to Market a New Drug (21 CFR 314), and 
Radioactive Drugs for Certain Research Uses (21 CFR 361.1), as appropriate. As such, these 
sections of US Title 21 CFR, along with the applicable International Council for 


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Harmonisation (ICH) Guidelines, are commonly known as Good Clinical Practices, which 
are consistent with the Declaration of Helsinki. 
9.9. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
 
 


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10. REFERENCES 
 1.  Loxo Oncology, Inc. LOXO-305 - Investigator’s Brochure (Version 3.1). 24 June 2020.  
2.  Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, Rothenberg SM, et al. A next 
generation reversible BTK Inhibitor, for overcoming acquired resistance to irreversible 
BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18.  
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 Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol Off J Am Soc 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 
acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 
2019;134(Supplement_1).  
6.  Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022–35.  
7.  Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017 
04;129(18):2519–25.  
8.  Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, Haruna M, et al. QT 
PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT 
Interval Prolongation by Human Pharmaceuticals [Internet]. Journal of pharmacological 
sciences. 2005 [cited 2020 Jun 10]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/16493187/ 
9.  Food and Drug Administration. Guidance for Industry: Clinical Drug Interaction Studies 
- Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for 
Industry [Internet]. Food and Drug Administration; 2020 [cited 2020 Sep 25]. Available 
from: https://www.fda.gov/media/134581/download 
 
 
 


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11. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy adult subject, whether or not considered drug-related by 
the Investigator (or designee). A treatment-emergent AE is an AE that starts on or after the 
first administration of study drug. 
The following are all AEs: 
• unfavorable changes in general condition; 
• subjective or objective signs/symptoms; 
• concomitant diseases or accidents; 
• clinically significant adverse changes in laboratory parameters observed in a subject 
during a clinical study. 
AEs comprise all disturbances of general health status, subjective and objective disease 
symptoms (including laboratory abnormalities that are deemed clinically significant by the 
Investigator [or designee]), and accidents observed in the context of a clinical trial, 
irrespective of a possible causal relationship with the administration of the trial substance. 
Categorization of AEs 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2 Moderate: Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)* 
• Grade 3 Severe or medically significant but not immediately life-threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL** 
• Grade 4 Life-threatening consequences: 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 5 (death) is not appropriate for some AEs and therefore is not an option. 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 


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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
• NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (eg, concomitant drugs, therapies, complications, comorbidities) is 
suspected. 
• RELATED = The time course between administration of investigational product and 
the occurrence or worsening of the AE is consistent with a causal relationship and no 
other cause (eg, concomitant drugs, therapies, complications, comorbidities) can be 
identified. 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through EOS or ET (if the subject discontinues from the study and does 
not complete a follow-up phone call) and for up to 90 days after Day 12 (or last 
administration of study drug if subject terminates from the study early) should be reported by 
the Investigator (or designee) via email to Covance or the Sponsor’s Clinical Safety 
Representative within 24 hours of being notified. Covance or the Sponsor’s Clinical Safety 
Representative will then forward the Pregnancy Form to the Investigator (or designee) for 
completion. 
email: SAEIntake@Covance.com 
A subject becoming pregnant while on study drug will immediately be withdrawn from the 
study and ET study procedures will be performed. The subject or partner should be followed 
by the Investigator (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 an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the 
Investigator (or designee) should follow the procedures for reporting an SAE. 
Male subjects will be instructed to notify the Investigator (or designee) immediately if they 
discover their sexual partner is pregnant. In this instance, the partner must provide written 
consent before pregnancy information can be collected. When a 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 Form (as appropriate), 
in addition to completion of the required pregnancy forms. If the Investigator (or designee) 
suspects that a pregnancy was the result of an interaction between the study treatment and the 


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contraceptive method, in addition to the pregnancy the drug interaction should also be 
captured as a separate AE. 
Definition of Serious Adverse Events 
An SAE (by FDA definition) is any adverse drug experience occurring at any dose that 
results in any of the following outcomes: 
• Death; 
• A life-threatening adverse drug experience (ie, one that places the subject, in the view 
of the Investigator [or designee], at immediate risk of death); 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant disability/incapacity; 
• A congenital anomaly/birth defect; 
• An important medical event that may require medical or surgical intervention to 
prevent 1 of the above outcomes. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent 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 IB or if it is not listed at the specificity or 
severity that has been observed for an unapproved IMP. 
Reporting 
The FDA-reportable AEs are AEs that are associated 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 IRB. Final determination of whether 
an event represents a SUSAR will be the responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or 
reported, and within 24 hours of any SAE (regardless of whether the event is assessed as 
related or unrelated to study drug) being first recognized or reported, Covance or the 
Sponsor’s Clinical Safety Representative will be notified by the Investigator (or designee) in 
writing using the following email address: 
email: SAEIntake@Covance.com 
To report the SAE, the completed report form should be sent by email to Covance or the 
Sponsor’s Clinical Safety Representative within 24 hours of awareness. Incoming reports are 
reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 


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The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel 
(Fasted): 
Hematology Panel: 
Other Tests: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase 
(AST) 
Bilirubin (direct and total) 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase  
Creatinine 
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (percent and 
absolute): 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Hemoglobin A1c (HbA1c)b 
Thyroid-stimulating hormone 
(TSH)b 
Estimated glomerular filtration 
ratea,d 
SARS-CoV-2 (COVID-19) test 
Coagulation Parameters: 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Human immunodeficiency virus 
(HIV) antibody 
Hepatitis B surface antigen 
(HBsAg) 
Hepatitis B virus (HBV) core 
antibody 
Hepatitis C virus (HCV) 
antibody 
For Female Subjects only: 
Pregnancy test (serum 
qualitative, serum quantitative 
may be used for confirmation if 
needed)c 
Follicle-stimulating hormone 
(post-menopausal female 
subjects only)b 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity  
Protein 
Urobilinogen 
Microscopic examination 
including bacteria, casts, 
crystals, epithelial cells, RBCs, 
and WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
 
Urine Drug Screen:a 
Including, but not limited to the 
following: 
Alcohol (ethanol)  
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine (metabolite)  
Methadone 
Opiates 
Phencyclidine 
Cotinine 
a. Performed at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Performed at Screening, Check-in (Day -1), and Day 15/End of Treatment (EOT) or Early Termination (ET) only. 
d. Calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
aAt PK sampling timepoints where multiple analytes (ie, repaglinide and LOXO-305) are assessed, a single blood sample 
will be taken for analysis (see Appendix 4). 
b Thyroid stimulating hormone and eGFR will be assessed as part of the clinical chemistry sample.  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 450 mL. 
Assessment 
Approximate Blood 
Volume per Sample 
(mL) 
Maximum 
Number of Blood 
Samples 
Approximate 
Total Volume 
(mL) 
Serology 
8.0 
1 
8.0 
Hemoglobin A1c  
4.0 
1 
4.0 
Repaglinide pharmacokinetic (PK) 
sampling 
4.0 
52a 
208.0 
LOXO-305 PK sampling 
Clinical laboratory evaluations: 
    Hematology  
    Clinical chemistryb 
    Coagulation parameters 
 
4.0 
4.0 
3.0 
 
7 
7 
7 
77.0 
Serum pregnancy test (female subjects 
only) 
4.0 
3 
12.0 
Serum follicle-stimulating hormone 
(post-menopausal female subjects only)  
4.0 
1 
4.0 
Total: 
 
 
313.0 mL  


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Appendix 4: Schedule of Assessments 


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Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Period 1 
Period 2 
Clinic 
Discharge/ 
EOT/ETu 
Follow-up 
Phone Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
7 (± 2) days 
post 
EOT/ETw  
Confined to the CRU 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 eGFR 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECGe 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Sign Measurementsf 
Xg,h 
Xg,h 
Xh 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Xg,h 
 
HDYF? Inquiryi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Repaglinide Dosingk 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
LOXO-305 Dosingl 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Clinical Laboratory 
Evaluationso 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Xv 
Xv 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Testp 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screenq 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medicationsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Tests 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
Xv 
 
FSH Testt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Period 1 
Period 2 
Clinic 
Discharge/ 
EOT/ETu 
Follow-up 
Phone Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
7 (± 2) days 
post 
EOT/ETw  
TSH Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; COVID-19 = SARS-CoV-2; CRF = Case Report Form; CRU = Clinical Research Unit; 
ECG = electrocardiogram; eGFR= estimated glomerular filtration rate; EOS = End of Study; EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HDYF? = How Do You Feel?; HIV = human immunodeficiency virus; ICF = Informed Consent Form PK = pharmacokinetic; QD = once daily; SAE = serious 
adverse event; TSH = thyroid-stimulating hormone; UA = urinalysis. 
a. For details on study procedures, see Section 7.  
b. Interim medical history only. 
c. Height collected at Screening only, body mass index based on Screening height. 
d. A complete physical examination will be performed at Check-in (Day -1) and an abbreviated physical examination will be performed at EOT (Day 16) or ET. 
e. The 12-lead ECGs will be obtained at Screening and Check-in (Day -1), Day 1 (predose), Day 2 (predose, 2 hours after LOXO-305 dosing), Day 6 (predose and 2 hours after LOXO-305 
dosing), Day 12 (predose, and 2 hours after LOXO-305 and repaglinide dosing), and EOT (Day 16, ie, 96 hours after LOXO-305 and repaglinide dosing on Day 12) or ET. When scheduled 
at the same time as blood draws, 12-lead ECGs should be carried out prior to and as close as possible to having blood drawn. The 12-lead ECGs will be collected after the subject has rested 
in the supine position for at least 10 minutes. The allowed sampling window for 12-lead ECGs is ± 30 minutes from the nominal timepoint for all postdose 12-lead ECGs and no less than 
10 minutes prior to dosing for predose 12-lead ECGs. 
f. Vital sign measurements (supine blood pressure [BP] and pulse rate) will be obtained at Screening and Check-in (Day -1), Day 1 (predose), Day 2 (predose, 2 hours after LOXO-305 dosing), 
Day 6 (predose and 2 hours after LOXO-305 dosing), Day 12 (predose, and 2 hours after LOXO-305 and repaglinide dosing), and EOT (Day 16, ie, 96 hours after LOXO-305 and 
repaglinide dosing on Day 12) or ET. When scheduled at the same time as blood draws, vital sign measurements should be carried out prior to and as close as possible to having blood drawn. 
BP and pulse rate will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. The allowed sampling window for vital sign measurements is 
±30 minutes from the nominal timepoint for all postdose vital sign measurements and no less than 10 minutes prior to dosing for predose vital sign measurements. 
g. Oral temperature and respiratory rate will be obtained at Screening and Check-in (Day -1), and EOT (Day 16) or ET. 
h. Oxygen saturation will be measured via pulse oximetry once at Screening, Check-in (Day -1), predose on Day 1, and EOT (Day 16) or ET. The allowed sampling window for predose 
oxygen saturation measurements is no less than 10 minutes prior to dosing. 
i. An HDYF? inquiry 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. AEs and SAEs will be collected beginning at informed consent. AEs will be recorded throughout the study (ie, from signing of the ICF until EOS, or until ET if the subject discontinues from 
the study and does not complete a follow-up phone call), either as subject medical history (if the event is reported as beginning prior to signing of the ICF or if the event occurs prior to study 
drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the ICF but prior to study drug 
administration on Day 1 and is assessed by the Investigator [or designee]) as related to study procedures, or if the event occurs after study drug administration on Day 1 through EOT or ET 
regardless of relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug are to be recorded. All SAEs that develop from the time of ICF signing 
until EOS (or ET if the subject discontinues from the study and does not complete a follow-up phone call) are to be reported. 
k. On Day 1, repaglinide will be administered in the morning following a fast of 10 hours prior to dosing and subjects will receive a standardized light breakfast (examples of contents are 
detailed in Table 4) 15 minutes post-repaglinide dose. On Day 12, 200 mg LOXO-305 and 0.5 mg of repaglinide will be co-administered at the same time in the morning at the actual time of 
the Day 1 repaglinide dose (± 1 hour), following a fast of 10 hours prior to dosing and subjects will receive a standardized light breakfast (examples of contents are detailed in Table 4) 
15 minutes post LOXO-305 and repaglinide dosing.  


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l. On Days 2 through 11, oral doses of 200 mg LOXO-305 will be administered QD in the morning at the actual time of the Day 1 repaglinide dose (± 1 hour). On Days 2 through 11, subjects 
will be fasted for at least 2 hours predose and 1 hour postdose (with the exception of days where clinical laboratory evaluations are performed [Day 2, Day 6, and Day 11, where subjects are 
fasted for 8 hours predose and 1 hour postdose]). On Day 12, 200 mg LOXO-305 and 0.5 mg of repaglinide will be co-administered in the morning at the actual time of the Day 1 repaglinide 
dose (± 1 hour), following a fast of 10 hours prior to dosing and subjects will receive a standardized light breakfast (examples of contents are detailed in Table 4) 15 minutes post-LOXO-305 
and repaglinide dosing.  
m.
n. 
o. 
to be fasted prior to clinical laboratory evaluations. 
p. Testing for COVID-19 will be conducted at a minimum at Screening and Check-in (Day -1). Testing for COVID-19 may also be conducted periodically during the subject’s CRU 
confinement, at the discretion of the Investigator (or designee). Tests will be performed by rapid polymerase chain reaction or equivalent. 
q. Drugs of abuse urine test, including cotinine and alcohol. Results from the drugs of abuse tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
r. Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 14 days, or 
5 half lives (if known), whichever is longer, prior to Day 1 for prescription medications and over-the-counter medication, will be recorded on the subject’s electronic CRF. 
s. Female subjects only. 
t. Post-menopausal female subjects only. 
u. The EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 16 (EOT) or ET. The ET 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 examination results are to be available for review by the Investigator (or 
designee) prior to subject release from the CRU at the EOT visit. Clinical laboratory evaluation results for clinical chemistry, hematology, coagulation, and UA and serum 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 prior to subject release from the CRU 
at the ET visit, if available. 
v. Clinical laboratory evaluations and serum pregnancy test (female subjects only) will be performed on the day prior to subject release from the CRU (Day 15) if the subject completes the 
study (EOT). Clinical laboratory evaluations and serum pregnancy test (female subjects only) will be performed on the day of subject release from the CRU if the subject terminates early 
(ET).  
w. To be conducted 7 days (± 2 days) following EOT (Day 16) or ET. The EOS is defined 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. 
x.
 
y. 
z. Denotes predose sample collection only. 
CCI
CCI

SAP_001.pdf: 
Statistical Analysis Plan LOXO-BTK-20016
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of 
Multiple Oral Doses of Pirtobrutinib (LOXO-305) on the Pharmacokinetics of Repaglinide (CYP2C8 
Substrate) in Healthy Subjects
NCT06165146
Approval date: 18-Dec-2020


TITLE PAGE 
Statistical Analysis Plan 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to 
Investigate the Effect of Multiple Oral Doses of LOXO-305 on the 
Pharmacokinetics of Repaglinide (CYP2C8 Substrate) in Healthy Subjects 
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 18DEC2020 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20016 
Covance Study: 8425120 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, Florida 32117 
USA 
Principal Investigator: 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
PPD


SAP 
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Covance Study: 8425120 
Protocol Reference: LOXO-BTK-20016 
Sponsor Final, Version 1.0, 18DEC2020 
Page 2 of 21 
 
ST-AD-031 Version 01 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objective ........................................................................................................... 6 
2.2. Secondary Objective ....................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN .................................................................................................................. 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 9 
6. STUDY TREATMENTS ....................................................................................................... 9 
7. DEFINITIONS OF POPULATIONS .................................................................................. 10 
7.1. All Subjects Population ................................................................................................. 10 
7.2. Safety Population .......................................................................................................... 10 
7.3. Pharmacokinetic Population ......................................................................................... 10 
8. STATISTICAL METHODOLOGY .................................................................................... 10 
8.1. General .......................................................................................................................... 10 
8.1.1. Calculation of the Summary Statistics ................................................................... 11 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 12 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 12 
8.2. Subject Disposition and Population Assignment .......................................................... 12 
8.3. Demographics and Baseline Characteristics ................................................................. 12 
8.4. Prior and Concomitant Medication ............................................................................... 13 
8.5. Pharmacokinetic Assessments ...................................................................................... 13 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 15 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ............................................................................ 17 
8.6.1. Adverse Events ....................................................................................................... 17 
8.6.2. Clinical Laboratory Parameters .............................................................................. 19 


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Page 3 of 21 
 
ST-AD-031 Version 01 
8.6.3. Vital Signs Parameters ........................................................................................... 19 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 19 
8.6.5. Other Assessments ................................................................................................. 19 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 19 
9. INTERIM ANALYSES ....................................................................................................... 19 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 20 
11. REFERENCES .................................................................................................................. 20 
12. APPENDICES ................................................................................................................... 21 


SAP 
CONFIDENTIAL 
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Protocol Reference: LOXO-BTK-20016 
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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ADaM 
analysis data model 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity  
AUC0-t  
 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
extrapolated to infinity 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval  
CL/F 
apparent systemic clearance 
CLss/F 
apparent systemic clearance at steady state 
Cmax 
maximum observed concentration 
COVID-19 
SARS-CoV-2 
Ctrough 
concentration observed at the end of the dosing interval 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
Geom CV 
Geometric CV  
Geom Mean 
Geometric mean 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
λZ 
apparent terminal elimination rate constant 
ln 
natural log 
LSM 
Least squares mean  
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
not calculated 


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PK 
pharmacokinetic(s) 
QD  
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time to maximum observed concentration 
Vz/F 
apparent volume of distribution at terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
 
 


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ST-AD-031 Version 01 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 05 October 2020) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK) and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
2.1.  Primary Objective 
The primary objective of the study is: 
 to assess the impact of multiple oral doses of LOXO-305 on the PK of a single oral 
dose of repaglinide (CYP2C8 substrate) in healthy subjects. 
2.2. Secondary Objective 
The secondary objective of the study is:  
 to assess the safety and tolerability of multiple oral doses of LOXO-305 when 
administered alone and coadministered with repaglinide in healthy subjects. 
3. STUDY ENDPOINTS  
3.1.  Primary Endpoints  
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of repaglinide following single oral dose administration (as appropriate): 


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 area under the concentration-time curve from hour 0 to the last measurable 
concentration (AUC0-t) 
 area under the concentration-time curve from hour 0 extrapolated to infinity 
(AUC0-inf) 
 percentage extrapolation for AUC0-inf (%AUCextrap) 
 maximum observed plasma concentration (Cmax) 
 time to maximum concentration (tmax) 
 apparent terminal elimination rate constant (λZ) 
 apparent systemic clearance (CL/F) 
 apparent terminal elimination half-life (t1/2) 
 apparent volume of distribution (Vz/F). 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 following multiple dose administration (as appropriate): 
 AUC0-t 
 AUC during a dosing interval (AUCtau) 
 Cmax  
 concentration observed at the end of the dosing interval (Ctrough) 
 tmax  
 CL/F at steady state (CLss/F). 
3.2. Secondary Endpoints 
Safety and tolerability will be assessed by monitoring adverse events (AEs) and concomitant 
medications, performing physical examinations and clinical laboratory evaluations, 
measuring vital signs, and performing 12-lead electrocardiograms (ECGs). These safety and 
tolerability endpoints are deemed adequate to detect any safety signals.  
4. STUDY DESIGN  
This is a Phase 1, open-label, 2-period, fixed-sequence drug-drug interaction study to 
investigate the effect of multiple oral doses of LOXO-305 on the PK of a single oral dose of 
repaglinide in healthy subjects.  
In Period 1, Day 1, a single 0.5 mg oral dose of repaglinide will be administered in the 
morning, following a fast of at least 10 hours prior to dosing. In order to mitigate any side 
effects when dosing with repaglinide on Day 1, on Day -1, subjects will be offered breakfast, 
lunch, dinner, and an optional snack after dinner. On Day 1, subjects will receive a 


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standardized light breakfast 15 minutes postdose. In addition, subjects may be provided with 
up to 16 g of glucose (up to 4 x 4 g chewable tablets) approximately 1-hour post-dose , if 
needed.  Glucose values may be checked for subjects suspected of having low blood sugar or 
being hypoglycemic by fingerstick glucose tests prior to and/or following administration of 
glucose tablets at the discretion of the PI (or designee). Blood samples for concentrations of 
repaglinide in plasma will be collected 
. 
In Period 2, on Days 2 through 11, oral doses of 200 mg LOXO-305 will be administered QD 
in the morning at the actual time of the Day 1 repaglinide dose (± 1 hour). On Days 2 through 
11, subjects will fast for at least 2 hours predose and 1-hour postdose with the exception of 
Days 2, 6, and 11 where clinical laboratory evaluations are performed, subjects will fast for at 
least 8 hours predose and 1-hour postdose. On Day 12, 200 mg LOXO-305 and 0.5 mg of 
repaglinide will be co-administered in the morning at the actual time of the Day 1 repaglinide 
dose (± 1 hour), following a fast of at least 10 hours prior to dosing. In order to mitigate any 
side effects when dosing with repaglinide on Day 12, on Day 11, subjects will receive 
breakfast (2 hours after dosing), lunch, dinner, and an optional snack after dinner. On Day 12, 
subjects will receive a standardized light breakfast 15 minutes post-LOXO-305 and 
repaglinide dosing. In addition, subjects may be provided with up to 16 g of glucose (up to 
4 x 4 g chewable tablets) approximately 1-hour post-LOXO-305 and repaglinide dosing, if 
needed. Glucose values may be checked for subjects suspected of having low blood sugar or 
being hypoglycemic by fingerstick glucose tests prior to and/or following administration of 
glucose tablets at the discretion of the PI (or designee).  
On 
 a
 
 
. 
, blood samples for concentrations of repaglinide 
and LOXO-305 in plasma will be collected 
 
 
There will be a washout period of 11 days between the dose of repaglinide on Day 1 and the 
dose of repaglinide on Day 12, respectively.  
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 16 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. A follow up phone call will occur for all 
subjects who received at least 1 dose of study drug (including subjects who are terminated 
early) 7 days (± 2 days) after EOT or ET. The duration of participation is expected to be 
approximately 54 days (Screening through follow up phone call). 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned a dose of study drug; this definition excludes screen failure subjects. 
CCI
CCI
CCI
CCI
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In this study, physical examinations, 12 lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistry panel, coagulation parameters, hematology panel, 
urinalysis, and recording of concomitant medications will be performed at specified times 
during the study.  
AEs and serious adverse events (SAEs) will be collected beginning at informed consent. AEs 
will be reported throughout the study (ie, from signing of the ICF until End of Study [EOS], 
or until ET if the subject discontinues from the study and does not complete a follow up 
phone call), either as subject medical history (if the event is reported as beginning prior to 
signing of the ICF or if the event occurs prior to study drug administration on Day 1 and is 
assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the 
event occurs after signing of the ICF but prior to study drug administration on Day 1 and is 
assessed as related to study procedures by the Investigator [or designee], or if the event 
occurs after study drug administration on Day 1 through EOT or ET regardless of relationship 
to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by 
the Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow up phone call) are to be reported. 
Study completion is defined as the time of the last subject’s follow up.  
5. SAMPLE SIZE JUSTIFICATION  
Up to 
 adult male and female subjects (women of non-childbearing potential 
only) will be enrolled. The sample size chosen for this study was selected without statistical 
considerations, but is consistent with previous studies of a similar design. Up to 
 
 are anticipated to be sufficient to provide a reliable estimate of the magnitude and 
variability of the interaction. Replacement subjects may be enrolled only if deemed necessary 
by the Sponsor. Every attempt will be made to enroll at least 4 subjects of each sex in the 
study.  
6. STUDY TREATMENTS  
The study treatment sequence name and ordering to be used in the TFLs are presented in 
Table 1. 
Table 1: 
Presentation of Study Treatment Sequence in TFLs  
Study Treatment Sequence 
Order in TFLs 
0.5 mg repaglinide alone/200 mg LOXO-305 QD alone/200 mg LOXO-305 
QD + 0.5 mg repaglinide 
1 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 2.  
CCI
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Table 2: 
Presentation of Study Treatments in TFLs  
Study Treatment 
Order in TFLs 
(PK) 
Order in TFLs 
(all others) 
0.5 mg repaglinide alone 
1 
1 
200 mg LOXO-305 QD alone 
3 
2 
200 mg LOXO-305 QD + 0.5 mg repaglinide 
2 
3 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received. 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those related to SARS-CoV-2 (COVID-19), will be 
considered prior to database lock for their importance and taken into consideration when 
assigning subjects to populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The Safety Population will include all subjects who received at least 1 dose of study drug 
(repaglinide and/or LOXO-305). Subjects will be classified into groups based on actual 
treatment received.  
7.3. Pharmacokinetic Population  
The PK Population will include all subjects who received a dose of LOXO-305, have at least 
1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be computed. 
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times median tmax for the analyte 
being evaluated. The impact of protocol deviations on PK population will be evaluated on a 
case-by-case basis. 
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the EOT visit. Any 
subject who discontinued the study will be identified accordingly in the listings. Summaries 
and statistical analyses will include the subjects assigned to the relevant population based on 
data type. 


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Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, and any parameter 
derivations.  
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum.  
● As ET data is not associated with any scheduled timepoint, it will be excluded from all 
calculations of summary statistics.  
● Post dose repeats and unscheduled assessments will not be included in calculation of 
summary statistics.  
For categorical data the following rules will be applied:  
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included.  
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is missing. 
This will ensure that the population size totals are consistent across different 
parameters.  
All protocol deviations and data issues (eg missing data, out of protocol window) that 
occur during the study, including those related to COVID-19, will be considered prior to 
database lock for their severity/impact on how the data will be displayed. 


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8.1.2. Repeat and Unscheduled Readings  
For vital sign measurements and 12-lead ECG data only, any predose value recorded in 
addition to the original value or a postdose value recorded within 15 minutes of the original 
value will be defined as a repeat value; any postdose value recorded more than 15 minutes 
after the original value will be defined as an unscheduled value. For all other data types (eg, 
laboratory values), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value. 
Post dose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations, with the exception of the baseline derivation (see Section 8.1.3). 
8.1.3. Definitions of Baseline and Change from Baseline 
Baseline value is defined as the last non missing measurement before administration of study 
drug on Day 1. 
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 
of study drug.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects.   
See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment sequence will be provided, based on the all subjects 
population.  
8.3. Demographics and Baseline Characteristics 
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment sequence will be provided, based on the safety population.  


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8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose of Repaglinide. 
Concomitant medication will be defined as medication that starts during or after the first dose 
or starts but does not end prior to the first dose.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 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 of LOXO-305 and repaglinide using noncompartmental methods in validated 
software program Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Repaglinide; following a single dose of repaglinide alone (Day 1) and in combination with 
multiple doses of LOXO-305 (Day 12)  
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mL 
area under the concentration-time curve from hour 0 to the last 
measurable concentration (tlast)b 
AUC0-inf 
h*ng/mL 
area under the concentration-time curve from hour 0 extrapolated 
to infinityc 
%AUCextrap 
% 
percentage extrapolation for AUC0-inf 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time to maximum observed concentration 
λz 
1/h 
apparent terminal elimination rate constant 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent systemic clearance  
Vz/F 
L 
apparent volume of distribution  
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing and decreasing 
concentrations. 
c Based on the last observed quantifiable concentration 
LOXO-305; following daily multiple doses of LOXO-305 and a single dose of repaglinide 
(Day 12) 
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mL 
area under the concentration-time curve from hour 0 to the last 
measurable concentration (tlast)b 
AUCtau 
h*ng/mL 
area under the concentration-time curve during a dosing interval 
Cmax 
ng/mL 
maximum observed concentration 


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Ctrough 
ng/mL 
concentration observed at the end of the dosing interval 
tmax 
h 
time of the maximum observed concentration 
CLss/F 
L/h 
apparent systemic clearance at steady state 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing and decreasing 
concentrations. 
Additional PK parameters may be determined where appropriate. 
PK analysis will be carried out where possible using actual blood sampling times postdose. If 
an actual time is missing, the sample concentration result will be treated as missing unless 
there is scientific justification to include the result using the nominal time.  
The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax. 
8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-inf, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 


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8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of area under the concentration-time curve 
(AUC) will be the inclusion of at least 3 consecutive concentrations above the lower limit of 
quantification. If there are only 3 consecutive concentrations, at least 1 should follow Cmax.  
If the extrapolated area for AUC0-inf is >30%, AUC0-inf (and derived parameters) will be 
excluded from the summary statistics and statistical analysis at the discretion of the sponsor 
or pharmacokineticist.  
If AUC0-inf cannot be determined reliably for all subjects and/or treatments, an alternative 
AUC measure, such as AUC to a fixed time point or AUC0-t, may be used in the statistical 
analysis. 
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rules apply with special situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a Day 1 or Day 12 predose repaglinide plasma concentration is missing, it may be set 
to zero by default. If a Day 12 predose concentration of LOXO-305 is missing, the 
concentration at 24 hours may be used as the predose value. 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value for repaglinide on Days 1 or 12 will be 
considered anomalous and set to missing for the PK analysis. 
8.5.2. Presentation of Pharmacokinetic Data 
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For PK concentration data the following rules will apply: 


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● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
● If any BLQ results (treated as 0) are in a series of summarized data, geometric mean 
(Geom Mean) and coefficient of variation (CV) of geometric mean will be reported as 
not calculated (NC). 
For PK parameters the following rule will apply: 
● Geom Mean and CV will not be calculated for tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment and time postdose will be provided for plasma PK 
concentrations. All PK concentration figures will be produced on both linear and semi-
logarithmic scales, with the exception of figures across all days, which will be produced on 
the linear scale only. The +SD bars will only be displayed on the linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV, 
minimum, median, maximum, Geom Mean and geometric CV [Geom CV]) will be calculated 
for plasma LOXO-305 and repaglinide PK parameters. Excluded subjects will be listed in the 
PK parameter tables, but will be excluded from the statistical analysis and summary statistics 
and noted as such in the tables.  
8.5.3.1. Statistical Analysis 
A statistical analysis will be conducted to investigate the drug-drug interaction of LOXO-305 
on repaglinide for AUC0-t, AUC0-inf, and Cmax. The comparisons of interest are: 
To assess the impact of multiple oral doses of LOXO-305 on the single dose PK of 
repaglinide (AUC0-t, AUC0-inf, and Cmax)  
●  200 mg LOXO-305 co-administered with 0.5 mg repaglinide (Day 12) (test 
treatment) vs 0.5 mg repaglinide (Day 1) (reference treatment). 
The natural log (ln) transformed PK parameters (AUC0-t, AUC0-inf, and Cmax) will be analyzed 
using a mixed model3. The model will include actual treatment as fixed effect, and subject as 
a random effect.  
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test and reference treatments, and corresponding 90% 
confidence interval (CI) will be calculated; these values will then be exponentiated to give the 
geometric least squares mean, geometric mean ratios, and corresponding 90% CI.  


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Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted. 
Mixed Model Analysis 
proc mixed data = <data in>; 
   
  class treatment usubjid; 
  model lpk = treatment / cl residual ddfm = kr; 
  lsmeans treatment / cl pdiff = control('1') alpha = 0.1; 
  random intercept / subject = usubjid;  
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.1. All AEs will be assigned severity grade using National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose repaglinide, or starts prior to the first dose and increases in severity after 
the first dose.  
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator.  
If deemed related to study treatment, the assignment of TEAEs to treatments will be as 
follows:  
● A TEAE occurring during or after Day 1 dosing and prior to Day 2 dosing will be 
assigned to 0.5 mg repaglinide  
● A TEAE occurring during or after Day 2 dosing and prior to Day 12 dosing will be 
assigned to 200 mg LOXO-305 
● A TEAE occurring during or after Day 12 dosing will be assigned to 200 mg LOXO-
305 + 0.5 mg repaglinide 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last dose for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  


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● 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 with TEAEs will be summarized separately for all TEAEs and 
treatment-related TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
For the AE data the following rules will apply:  
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to the first dose.  
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE.  
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, the 
minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of the last dose is 01MAY2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).  
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).  
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible, up to Grade 4 in the absence of a 
fatal outcome.   
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded.  


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8.6.2. Clinical Laboratory Parameters  
All clinical laboratory evaluations, with changes from baseline, will be listed; any value 
outside the clinical reference range will be flagged, and whether the out of range value was 
deemed clinically significant or not clinically significant will be indicated. 
The observed results and change from baseline for clinical chemistry, hematology, and 
coagulation parameters will be summarized descriptively by treatment and timepoint.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to 0 whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters  
All vital signs parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated.  
The observed results and change from baseline for all vital signs parameters will be 
summarized descriptively by treatment and timepoint.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated.  
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by treatment and timepoint. QTcF values that are > 450 msec and 
increase from baseline > 30 msec will be flagged in the data listing.  
8.6.5. Other Assessments  
Medical history and physical examination will be listed. Any physical examination 
abnormalities reported will also be flagged as clinically significant or not clinically 
significant as indicated.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
9. INTERIM ANALYSES  
No interim analyses are planned. 


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10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
 
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
 


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