Conditions: Healthy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to evaluate the effect of Pirtobrutinib (LOXO-305) on multiple oral doses of digoxin (P-gp substrate) when administered as single and multiple doses by collecting the blood samples and conducting the blood tests to measure how much digoxin is in the bloodstream and how the body handles and eliminates it in healthy participants. The study will also evaluate the safety and tolerability of Pirtobrutinib. Participants will stay in this study for up to 58 days, including screening.

Detailed description:

Arms:
arm 1: Participants received oral dose of

* 0.25 mg digoxin twice daily (BID) on Day 1
* 0.25 mg digoxin once daily (QD) from Day 2 to Day 7
* 200 mg Pirtobrutinib in combination with 0.25 mg digoxin QD starting from Day 8 to Day 16

Interventions: intervention 1: Pirtobrutinib intervention 2: Digoxin
Intervention descriptions: intervention 1: Administered Orally. intervention 2: Administered Orally.

Protocol document:
Prot_000.pdf: 
Protocol J2N-OX-JZNT Version 1
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of Single and Multiple 
Oral Doses of LOXO-305 on the Pharmacokinetics of Multiple Oral Doses of Digoxin (P-Glycoprotein Substrate) 
in Healthy Subjects
NCT06194214
Approval Date: 12-Feb-2021


TITLE PAGE 
Protocol 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to 
Investigate the Effect of Single and Multiple Oral Doses of LOXO-305 on 
the Pharmacokinetics of Multiple Oral Doses of Digoxin (P-Glycoprotein 
Substrate) in Healthy Subjects 
Protocol Status: Final 
Protocol Date: 12 February 2021 
Protocol Version: 1.0 
Investigational Medicinal Product: LOXO-305 
Protocol Reference Number: LOXO-BTK-20021 
Covance Study Number: 8456071 
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 
Coordinating Investigator Study Site: 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Up to 2 additional sites in the United States 
may be utilized. 
Sponsor Signatory: 
Coordinating Investigator: 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
PPD
PPD


Protocol 
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Covance Study: 8456071  
Protocol Reference: LOXO-BTK-20021 
Protocol Version 1.0, 12 February 2021 
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SPONSOR APPROVAL 
I have read the protocol and approve it: 
Date 
12-Feb-21 | 09:58:01 PST
PPD


Protocol
CONFIDENTIAL 
Covance Study: 8456071 
Protocol Reference: LOXO-BTK-20021 
INVESTIGATOR AGREEMENT 
Ihave read the protocol and agree to conductthe study as described herein.
2 leb2ey 
Coordinating Investigator 
Date 
Protocol Version 1.0, 12 February 2021 
Page 3 of 70 
PPD


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Covance Study: 8456071  
Protocol Reference: LOXO-BTK-20021 
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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 Reporting 
Email: SAEIntake@covance.com 
Study Site(s) 
Coordinating Investigator Study Site 
Covance Clinical Research Unit, Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
Up to 2 additional sites in the United States may be 
utilized. 
Coordinating Investigator 
Covance Clinical Research Unit, Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
Tel: (608) 
Tel (after hours): 
Sub-investigator(s) 
Obtain information from Form FDA 1572s 
Clinical Laboratory(s) 
Meriter Laboratories 
36 South Brooks Street 
Madison, WI 53715 
USA 
Each additional site will use their local laboratory for 
safety analyses. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Protocol Reference: LOXO-BTK-20021 
Protocol Version 1.0, 12 February 2021 
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Bioanalytical Laboratory 
Alturas Analytics, Inc. 
1324 Alturas Drive 
Moscow, Idaho 83843 
USA 
Tel (main): 
Email: 
Statistician 
Covance 
Tel: 
Email: 
Protocol Medical Writer 
Covance 
Tel: 
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Protocol 
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Protocol Reference: LOXO-BTK-20021 
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SYNOPSIS 
Study Title 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of 
Single and Multiple Oral Doses of LOXO-305 on the Pharmacokinetics of Multiple Oral 
Doses of Digoxin (P-Glycoprotein Substrate) in Healthy Subjects 
Objectives 
The primary objectives of the study are: 
•
to assess the effect of single and multiple oral doses of LOXO-305 on the
pharmacokinetics (PK) of multiple oral doses of digoxin (P-gp substrate) in healthy
subjects.
•
to assess the PK of LOXO-305 administered with multiple doses of digoxin at steady
state in healthy subjects.
The secondary objective of the study is to assess the safety and tolerability of single and 
multiple oral doses of LOXO-305 when coadministered with multiple oral doses of digoxin. 
Study Design  
This is a Phase 1, open-label, fixed-sequence drug-drug interaction study to investigate the 
effect of single and multiple oral doses of LOXO-305 on the PK of multiple oral doses of 
digoxin (P-gp substrate) in healthy subjects.  
On Day 1, subjects will be administered 0.25 mg digoxin twice daily (BID; loading dose), 
once in the morning and evening. Subjects will be fasted for at least 2 hours predose and 
1-hour postdose for the morning and evening dose.
On Days 2 through 16, oral doses of 0.25 mg digoxin once daily (QD) will be administered 
(total of 17 consecutive doses) at the actual time of the Day 1 morning digoxin dose 
(± 1 hour). On Days 8 through 16 (9 consecutive doses), oral doses of 200 mg LOXO-305 
QD will be coadministered with 0.25 mg digoxin QD, at the actual time of the Day 1 morning 
digoxin dose (± 1 hour). LOXO-305 will be administered first, immediately followed by 
digoxin. On Days 2, 4 through 6, 9 through 11, 13, and 14, subjects will fast for at least 
2 hours predose and 1-hour postdose. On Days 3, 12, and 15 where clinical laboratory 
evaluations are performed, subjects will fast for at least 8 hours predose and 1-hour postdose. 
On Days 7, 8, and 16, subjects will be fasted at least 10 hours predose and 2 hours postdose. 
Blood and urine samples for concentrations of digoxin in plasma and urine and 
 
 Blood samples for concentrations of LOXO-305 and digoxin in plasma 
and 
 Urine samples for concentrations of digoxin and
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To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 20 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. Dosing of digoxin will occur on Days 1 through 
16 and dosing of LOXO-305 will occur on Days 8 through 16. A follow-up phone call will 
occur for all subjects who received at least 1 dose of study drug (including subjects who are 
terminated early) 7 days (± 2 days) after EOT or ET.  
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned to receive a dose of study drug; this definition excludes screen failure 
subjects. Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
In this study, physical examinations, 12-lead electrocardiograms (ECGs), vital sign 
measurements, How Do You Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation 
parameters, hematology panel, urinalysis (Appendix 2), safety monitoring of serum digoxin 
levels, and recording of concomitant medications will be performed at specified times during 
the study (for specific timepoints and details on each study variable, refer to Appendix 4).  
Adverse events (AEs) and serious adverse events (SAEs) will be collected beginning at 
informed consent. Adverse events will be reported throughout the study (ie, from signing of 
the ICF until End of Study [EOS], or until ET if the subject discontinues from the study and 
does not complete a follow-up phone call), either as subject medical history (if the event is 
reported as beginning prior to signing of the ICF or if the event occurs prior to study drug 
administration on Day 1 and is assessed as not related to study procedures by the Investigator 
[or designee]) or as AEs (if the event occurs after signing of the ICF but prior to study drug 
administration on Day 1 and is assessed as related to study procedures by the Investigator [or 
designee], or if the event occurs after study drug administration on Day 1 through EOT or ET 
regardless of relationship to study drug). From EOT or ET through EOS, only AEs assessed 
as related to study drug by the Investigator (or designee) are to be reported. All SAEs that 
develop from the time of ICF signing until EOS (or ET, if the subject discontinues from the 
study and does not complete a follow-up phone call) are to be reported. 
Study completion is defined as the time of the last subject’s follow-up phone call. 
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Protocol Reference: LOXO-BTK-20021 
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Number of Subjects 
Up to 16 healthy adult male and female subjects (women of non-childbearing potential only) 
will be enrolled. 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 must meet the following 
criteria: 
• Between 18 and 55 years of age, inclusive, at Screening 
• Body weight of ≥ 50 kg 
• Within body mass index range 18.0 to 32.0 kg/m2, inclusive 
• In good general health, based on medical history, physical examination findings, vital 
signs, 12-lead ECGs, 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 
Subjects will receive each of the following treatments throughout the study: 
• On Day 1, subjects will be administered oral 0.25 mg digoxin BID (loading dose), 
once in the morning and evening. Subjects will be fasted for at least 2 hours predose 
and 1-hour postdose for the morning and evening dose. Water will be restricted for 
1 hour prior to and 1 hour after dosing with the exception of water administered for 
dose administration. 
• On Days 2 through 16, oral doses of 0.25 mg digoxin QD will be administered (17 
consecutive doses) at the actual time of the Day 1 morning digoxin dose (± 1 hour). 
On Days 8 through 16, oral doses of 200 mg LOXO-305 QD will be coadministered 
with 0.25 mg digoxin QD, at the actual time of the Day 1 morning digoxin dose 
(± 1 hour). LOXO-305 will be administered first, immediately followed by digoxin. 
On Days 2, 4 through 6, 9 through 11, 13, and 14, subjects will fast for at least 2 hours 
predose and 1-hour postdose. On Days 3, 12, and 15 where clinical laboratory 
evaluations are performed, subjects will fast for at least 8 hours predose and 1-hour 
postdose. On Days 7, 8, and 16, subjects will be fasted at least 10 hours predose and 
2 hours postdose. Water will be restricted for 1 hour prior to and 1 hour after dosing 
with the exception of water administered for dose administration. 
All study drugs will be administered orally with approximately 240 mL of water. An 
additional 100 mL of water may be administered if needed.  
Duration of Subject Participation in the Study: 
Planned Enrollment/Screening Duration: Approximately 28 days (Days -29 to -2). 
Length of CRU Confinement: Up to 21 days (Days -1 to 20). 


Protocol 
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Planned Study Conduct Duration: Up to 58 days (Screening through follow-up call). 
Criteria for Evaluation: 
Pharmacokinetics: 
Blood and urine samples for concentrations of digoxin in plasma and urine and 
 
 
 Blood samples for concentrations of LOXO-305 and digoxin in plasma 
and 
 
 Urine samples for concentrations of digoxin and
 
Samples collected for the analysis of plasma and urine concentrations of 
digoxin and plasma concentrations of LOXO-305 may be stored and analyzed 
 
 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of digoxin and LOXO-305: area under the concentration-time curve (AUC) 
from hour 0 to 24 hours postdose (AUC0-24), AUC from hour 0 to the last measurable 
concentration (AUC0-t), AUC during a dosing interval (AUCtau), apparent systemic clearance 
(CL/F), maximum observed plasma concentration (Cmax), time to Cmax (tmax), and mean 
residence time (MRT). 
The following PK parameters will be calculated whenever possible, based on the urine 
concentrations of digoxin: amount of drug excreted unchanged in urine (Ae), fraction of drug 
excreted unchanged in urine (Fe), and renal clearance (CLr). 
Safety: 
Safety will be monitored with HDYF? inquiries, clinical laboratory evaluations, vital sign 
measurements, 12-lead ECGs, physical examinations, and safety monitoring of serum 
digoxin levels. 
Statistical Methods 
Pharmacokinetics: 
The primary analysis planned for this study is a mixed effect model that includes treatment as 
a fixed effect and subject as a random effect. The analysis will be performed on the natural 
log (ln)-transformed PK parameters (AUC0-t, AUC0-24, and Cmax) and 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 comparisons 
of interest will be as follows: 
• Multiple doses of digoxin coadministered with multiple doses of LOXO-305 versus 
multiple doses of digoxin alone. 
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• Multiple doses of digoxin coadministered with a single dose of LOXO-305 versus 
multiple doses of digoxin alone. 
Safety: 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, safety monitoring of serum digoxin levels, physical examination results, concomitant 
medications, and 12-lead ECGs, will be tabulated, and summarized where possible, using 
descriptive methodology by treatment and, as needed, by timepoint. Unless 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. The specific procedures will be 
documented in the Statistical Analysis Plan. 


Protocol 
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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........................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................14 
1. 
INTRODUCTION ...........................................................................................................17 
1.1. Background ................................................................................................................17 
1.2. Nonclinical Pharmacokinetics and Toxicology Summary ........................................17 
1.3. Potential for Drug-drug Interactions ..........................................................................19 
1.4. Summary of Clinical Experience ...............................................................................20 
1.4.1. 
Safety ...........................................................................................................21 
1.4.2. 
Pharmacokinetics .........................................................................................23 
1.5. Study Rationale ..........................................................................................................26 
1.6. Risk Assessment ........................................................................................................26 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................28 
2.1. Objectives ..................................................................................................................28 
2.1.1. 
Primary Objectives .......................................................................................28 
2.1.2. 
Secondary Objective ....................................................................................28 
2.2. Endpoints ...................................................................................................................28 
2.2.1. 
Primary Endpoints .......................................................................................28 
2.2.2. 
Secondary Endpoints ...................................................................................28 
3. 
INVESTIGATIONAL PLAN ..........................................................................................29 
3.1. Overall Study Design and Plan ..................................................................................29 
3.2. Discussion of Study Design .......................................................................................31 
3.3. Selection of Doses in the Study .................................................................................31 
3.3.1. 
LOXO-305 ...................................................................................................31 
3.3.2. 
Digoxin ........................................................................................................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 ............................................................................39 
4.6. Removal of Subjects from Study Participation .........................................................39 
5. 
STUDY TREATMENTS .................................................................................................41 
5.1. Description, Storage, Packaging, and Labeling .........................................................41 


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5.2. Study Treatment Administration ...............................................................................41 
5.3. Randomization ...........................................................................................................42 
5.4. Blinding .....................................................................................................................42 
5.5. Treatment Compliance ...............................................................................................42 
5.6. Drug Accountability ..................................................................................................42 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................44 
6.1. Concomitant Therapies ..............................................................................................44 
6.2. Diet, Fluid, and Activity Control ...............................................................................44 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................46 
7.1. Pharmacokinetic Assessments ...................................................................................46 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................46 
7.1.2. 
Pharmacokinetic Urine Sample Collection and Processing .........................46 
7.1.3. 
Analytical Methodology ..............................................................................46 
7.2. Safety and Tolerability Assessments .........................................................................46 
7.2.1. 
Adverse Events ............................................................................................47 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................48 
7.2.3. 
Vital Signs ....................................................................................................48 
7.2.4. 
12-lead Electrocardiogram ...........................................................................48 
7.2.5. 
Physical Examination...................................................................................49 
7.2.6. 
Safety Digoxin Monitoring ..........................................................................49 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................50 
8.1. Determination of Sample Size ...................................................................................50 
8.2. Analysis Populations .................................................................................................50 
8.3. Pharmacokinetic Analysis .........................................................................................50 
8.3.1. 
Descriptive Analysis ....................................................................................51 
8.3.2. 
Statistical Methodology ...............................................................................51 
8.4. Safety Analysis ..........................................................................................................52 
8.5. Data Handling and Record Keeping ..........................................................................52 
8.6. Quality Control and Quality Assurance .....................................................................53 
9. 
ADMINISTRATIVE ASPECTS .....................................................................................54 
9.1. Change in Protocol ....................................................................................................54 
9.2. Site Initiation Visit/Investigator Meeting ..................................................................54 
9.3. Disclosure ..................................................................................................................54 
9.4. Monitoring .................................................................................................................54 
9.5. Institutional Review Board ........................................................................................54 
9.6. Informed Consent ......................................................................................................55 
9.7. Records ......................................................................................................................55 
9.8. Reference to Declaration of Helsinki/Basic Principles .............................................55 
9.9. Financing and Insurance ............................................................................................56 
10. REFERENCES ................................................................................................................57 


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11. APPENDICES .................................................................................................................58 
Appendix 1: Adverse Event Reporting ...............................................................................59 
Appendix 2: Clinical Laboratory Evaluations .....................................................................63 
Appendix 3: Total Blood Volume .......................................................................................65 
Appendix 4: Schedule of Assessments ...............................................................................66 
 
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) .............................24 
Table 2: Study Drugs .........................................................................................................41 
 
Figure 3: Study Schematic .................................................................................................30 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
Ae 
amount of drug excreted unchanged in urine 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from hour 0 to 24 hours postdose 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
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 
CI 
confidence interval(s) 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent systemic clearance 
CLL 
chronic lymphocytic leukemia 
CLr 
renal clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
SARS-CoV-2 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
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 
ET 
Early Termination 
FDA 
Food and Drug Administration 
Fe 
fraction of drug excreted unchanged in urine 
FSH 
follicle-stimulating hormone 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 


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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 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
IC90 
concentration required for 90% inhibition 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IgM 
immunoglobulin M 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
LFT 
liver function test(s) 
Ln 
natural log 
LS 
least squares 
MATE 
multidrug and toxin extrusion protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
MRT 
mean residence time 
NHL 
non-Hodgkin lymphoma 
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 
RBC 
red blood cell(s) 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDD 
spray-dried dispersion 
SLL 
small lymphocytic lymphoma 


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SOC 
system organ class 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
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 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


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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, 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 These features enable LOXO-305 to 
achieve pharmacokinetic (PK) exposures that exceed the BTK concentration resulting in 90% 
inhibition (IC90) at trough, and thus deliver tonic BTK target inhibition throughout the dosing 
period, regardless of the intrinsic rate of BTK turnover. Moreover, 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 Finally, LOXO-305 is also a 
highly selective molecule that is more than 300-fold more selective for BTK versus 370 other 
kinases tested with no significant inhibition of non-kinase off-targets at 1 µM, thus limiting 
the potential for off-target mediated toxicities. Collectively, these unique 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 (ATP) 
binding site of the BTK kinase competitively. There is no evidence of irreversible binding. 
LOXO-305 has a molecular weight of approximately 500 g/mol. LOXO-305 will be supplied 
as an immediate-release tablet containing 100 mg of drug substance. 
1.2. 
Nonclinical Pharmacokinetics and Toxicology Summary 
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. 


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LOXO-305 was metabolized slowly by human microsomal fractions and hepatocytes. The 
low rates of metabolism in both these human in vitro systems suggest that LOXO-305 will 
have low clearance in humans. In vitro data with clone expressed cytochrome P450 (CYP) 
enzymes and human liver microsomes indicate that CYP3A4 is the 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% inhibitory concentration (IC50) for the 
inhibitory effects of LOXO-305 on hERG potassium currents was 
 μM, which is 
approximately 
 higher than the maximum unbound concentration of LOXO-305 in 
patients treated with the dose of 200 mg once daily (QD). There were no LOXO-305-related 
changes in any cardiovascular endpoints including QTc at single doses up to 60 mg/kg in the 
GLP cardiovascular study in the conscious telemetry-instrumented dog. The maximum 
observed plasma concentration (Cmax) for this dose was 
 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 
electrocardiogram (ECG) recordings. The high dose (90/60 mg/kg/dose twice daily [BID]) 
was not evaluated as animals in this group were moribund/debilitated and were terminated on 
Day 13. Mean QTc interval was statistically significantly prolonged (+6%; +15 msec) on 
Day 26 of the dosing phase in males 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 
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with other BTK inhibitors. Dog-specific changes in lung and large intestine were lesions 
contributing to moribundity in high-dose animals in the 28-day study. Doses evaluated in 
the 28-day dog study demonstrated a steep dose-response curve for toxicity and pronounced 
changes in hematologic parameters at high exposures. Additionally, in dogs treated for 
3 months, 2 male dogs at 5 mg/kg BID (the highest dose tested) were observed to 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 or 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 
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 rats at doses up to and including a dose of 
. The Cmax at the 
no observed effect level of 
 was 
 for males and 
 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 (IC50 > 60 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 (OATP)1B1, 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 September 27, 2020, safety data were available from a total of 330 patients treated in 
the LOXO-BTK-18001 study. This includes 324 patients treated at doses ranging from 25 mg 
QD to 300 mg QD in Phase 1/2 Monotherapy cohorts, and 6 patients treated in Phase 1b 
Combination Arm A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after ramp-up] 
Section 1.4.1).  
As of September 30, 2020, PK data were available from 181 patients enrolled in the 
LOXO-BTK-18001 study (Section 1.4.2). 
As of the date of this protocol, LOXO-305 had been recently investigated in 1 study in 
healthy volunteers (LOXO-BTK-20014), which was completed. LOXO-BTK-20014 was a 
pilot food-effect crossover study evaluating the effects of food and a proton pump inhibitor 
(omeprazole) on the PK of LOXO-305 where 10 healthy volunteers were given 200 mg of 
LOXO-305 on 3 separate days, each followed by a washout period.  
As of the date of this protocol, 7 additional studies were ongoing in healthy volunteers and 
otherwise healthy volunteers with varying degrees of hepatic impairment 
(LOXO-BTK-20006, LOXO-BTK-20017, LOXO-BTK-20007, LOXO-BTK-20008, 
LOXO-BTK-20016, LOXO-BTK-20012, and LOXO-BTK-20011).  
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 this protocol’s 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 12 healthy volunteers were given 200 mg of LOXO-305 
on 3 separate days (2 of which were co-administered with rifampin), each followed by a 
washout period.  
LOXO-BTK-20017 is a single ascending dose study evaluating the safety and tolerability of 
LOXO-305 at 300 mg, 600 mg, 800 mg, and 900 mg doses, where, at the time of this 
protocol’s development, 6 healthy volunteers were given a single dose of 300 mg 
LOXO-305, 6 healthy volunteers were given a single dose of 600 mg LOXO-305, 6 healthy 
volunteers were given a single dose of 800 mg LOXO-305, and 6 healthy volunteers were 
given a single dose of 900 mg LOXO-305.  
LOXO-BTK-20007 is a 2-part study of the absorption, metabolism, excretion, and the 
absolute bioavailability of [14C]-LOXO-305 where, at the time of this protocol’s 
development, 4 subjects were given a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution and 5 subjects were given a single oral dose of 
200 mg LOXO-305 as 2 × 100-mg tablets followed 2 hours later by a single dose of < 100 µg 
of [14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) administered as an IV 
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LOXO-BTK-20008 is a DDI study evaluating the effects of LOXO-305 on the PK of a 
sensitive CYP3A4 substrate (midazolam) where, at the time of this protocol’s development, 
15 healthy volunteers were given 200 mg QD of LOXO-305 on 13 consecutive days (1 day of 
which was co-administered with IV midazolam and 1 day of which was co-administered with 
oral midazolam). 
LOXO-BTK-20016 is a DDI study evaluating the effects of LOXO-305 on the PK of a 
CYP2C8 substrate (repaglinide) where, at the time of this protocol’s development, 16 healthy 
volunteers were given 200 mg QD of LOXO-305 on 11 consecutive days (1 day of which 
was co-administered with oral repaglinide).  
LOXO-BTK-20012 is a hepatic impairment study evaluating the PK profile of LOXO-305 in 
subjects with impaired hepatic function compared to matched-control healthy subjects, 
where, at the time of this protocol’s development, 4 subjects were given a single dose of 
200 mg LOXO-305.  
LOXO-BTK-20011 is a partially double-blind study to evaluate the effect of a single 
supratherapeutic dose of LOXO-305 on the QTc interval corrected for heart rate in healthy 
subjects compared to moxifloxacin and placebo, where, at the time of this protocol’s 
development, 22 subjects had received 1 dose each of  LOXO-305, moxifloxacin, and 
placebo and 1 subject had received 2 doses of either LOXO-305, moxifloxacin, or placebo.  
1.4.1. 
Safety 
As of September 27, 2020, 330 patients were treated in the LOXO-BTK-18001 study and 
received LOXO-305. This includes 324 patients treated at doses ranging from 25 mg QD 
to 300 mg QD in Phase 1/2 Monotherapy cohorts, and 6 patients treated in Phase 1b 
Combination Arm A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after venetoclax 
ramp-up]). A full summary of treatment-emergent adverse events (TEAEs) for patients in the 
study is provided in the LOXO-305 IB and the Investigator is directed to the safety 
information described in that document.1 A summary of safety for LOXO-305 given as 
monotherapy to patients in the LOXO-BTK-18001 study is provided below.  
• In the 324 patients in the Phase 1/2 Monotherapy cohorts, TEAEs reported in ≥ 10% 
of patients (n = 33 or more) were fatigue (20.1% total, 8.3% related), diarrhea (17.0% 
total, 8.6% related), and contusion (13.0% total, 9.0% related). Drug-related TEAEs 
were reported in 156 of 324 patients (48.1%) in the Phase 1/2 Monotherapy cohorts. 
The most frequently reported drug-related TEAEs for LOXO-305 (those in > 5% of 
patients overall) were contusion (9.0%), diarrhea (8.6%), and fatigue (8.3%). All 
other drug-related TEAEs were reported in < 5% of patients (ie, < 17 patients each). 
Treatment-emergent AEs of severity Grade 3 or 4 were reported in 87 of 324 patients 
(26.9%) in the Phase 1/2 Monotherapy cohorts, with 41 (12.7%) of these Grade 3 or 4 
AEs reported as related to study drug.  
On-study death (death within 28 days of the last dose of study drug) due to a Grade 5 (fatal) 
AE was reported in 4 of 324 patients (1.2%) in the Phase 1/2 Monotherapy cohorts. One 
Grade 5 AE, Enterococcus faecium-related septic shock, was considered to be related to 
study drug (further details are provided in the LOXO-305 IB1). All other Grade 5 AEs were 


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considered to be not related to study drug; these included pneumonia fungal, shock, and 
pleural effusion. 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20014 study (headache, nausea, and vomiting), were all Grade 1 in 
severity and considered to be related to LOXO-305. All 3 events were reported by 1 subject 
and resolved within 1 to 1.5 days.  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20006 study (intermittent belching, bloating, insect bite, aphthous ulcer, 
nausea, intermittent diarrhea [x2], muscle twitch), were all Grade 1 in severity, and bloating, 
1 instance of intermittent diarrhea, and intermittent belching were considered to be related to 
LOXO-305 and rifampin. All 7 AEs were reported by 3 subjects and all events resolved prior 
to End of Treatment (EOT; preliminary data on file at the time of this protocol’s 
development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20017 study (headache [observed at the 300 mg LOXO-305 dose], and 
headache [x2], intermittent headache, and petechial rash left thigh [observed at the 900 mg 
LOXO-305 dose]), were all Grade 1 in severity. One instance of headache observed at the 
300 mg LOXO-305 dose and 1 instance observed at the 900 mg LOXO-305 dose, the 
intermittent headache, and the petechial rash left thigh were considered to be related to 
LOXO-305. All 5 AEs were reported by 4 subjects and resolved within 2 hours to 5 days of 
onset (preliminary data on file at the time of this protocol’s development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in Part 1 of the LOXO-BTK-20007 study (bloody nose, headache, loose stool [x2], red 
bumps on left knee, small abrasion to right elbow), were all Grade 1 in severity and headache 
was considered to be related to LOXO-305. All 7 AEs were reported by 4 subjects and all 
events resolved within 1 to 2 days (preliminary data on file at the time of this protocol’s 
development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in Part 2 of the LOXO-BTK-20007 study (tenderness at left venipuncture site [x2], bruising 
to left antecubital secondary to phlebotomy [x2], bruising to right antecubital secondary to 
phlebotomy, and allergic reaction), were all Grade 1 in severity and no events were 
considered to be related to LOXO-305. All 6 AEs were reported by 4 subjects and all events 
resolved within 1 to 2 days (preliminary data on file at the time of this protocol’s 
development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20008 study (injection site pain, nasal congestion, flatulence, 
constipation, increased urinary frequency, facial rash, and sore right arm), were all Grade 1 in 
severity, and flatulence, constipation, and increased urinary frequency were considered to be 
related to LOXO-305. All 7 AEs were reported by 3 subjects and all events resolved within 1 
to 8 days (preliminary data on file at the time of this protocol’s development). 
Adverse events reported following LOXO-305 administration in healthy volunteers in the 
LOXO-BTK-20016 study (petechiae [x4], back pain, nausea, constipation, bilateral leg 
cramps, facial acne, epigastric abdominal pain, and brain fog) were all Grade 1 in severity, 


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and petechiae [x4], constipation, bilateral leg cramps, epigastric abdominal pain, and brain 
fog were considered to be related to LOXO-305. All 11 AEs were reported by 7 subjects and 
all events resolved within 1 to 11 days (preliminary data on file at the time of this protocol’s 
development). 
There have been no TEAEs reported following LOXO-305 administration in healthy 
volunteers and volunteers with varying degrees of hepatic impairment in the 
LOXO-BTK-20012 study to date (preliminary data on file at the time of this protocol’s 
development). 
Adverse events reported following LOXO-305 administration in healthy volunteers in the 
LOXO-BTK-20011 study (headache [x4], dry mouth, rash [various locations; x9], pyuria, 
bacteriuria, intermittent left eye pain, lightheadedness, muscle twitch – right shoulder, 
diarrhea, slight tremor – left hand, constipation, and nausea) were all Grade 1 in severity. All 
23 TEAEs were reported by 10 subjects and all but 8 TEAEs of rash had resolved within 1 to 
9 days (preliminary data on file at the time of this protocol’s development). 
As part of each clinical trial conducted in patients or healthy volunteers, ECG and vital signs 
are performed at intervals specified by the protocol. For study LOXO-BTK-18001 conducted 
in patients, no clinically significant findings of QTc prolongation have been identified in 330 
patients as of September 27, 2020 (LOXO-305 IB1). In addition, there have been no clinically 
significant abnormal findings in vital signs and ECG data in the studies investigating 
LOXO-305 conducted in healthy volunteers as of the date of this protocol (preliminary data 
on file at the time of this protocol’s development). 
1.4.2. 
Pharmacokinetics 
As of September 30, 2020, PK data were available from 181 patients enrolled in the 
LOXO-BTK-18001 study. Steady-state PK parameters of LOXO-305 in these cancer patients 
could be derived from data collected on Cycle 1 Day 8 (Figure 1), and are shown in Table 1. 
These data show that LOXO-305 is absorbed after oral administration with a median time to 
maximum observed plasma concentration (tmax) of approximately 2 hours and low clearance 
(Table 1). Due to the limited sampling interval (0-8 hours), imputation for the 24-hour sample 
was made from Cycle 1 Day 8 predose sample, leading to an estimated plasma half-life of 
approximately 20 hours. Maximum observed plasma concentration and area under the plasma 
concentration-time curve (AUC) of LOXO-305 showed an increase proportional to dose 
(Figure 2). Following administration of the recommended Phase 2 dose (RP2D) 200 mg QD, 
mean trough plasma levels of LOXO-305 exceeded the concentration required for 96% 
inhibition of BTK in vitro (IC50 = 
 ng/mL, IC96 = 
 ng/mL). Further details may be 
found in the IB.1 
Pharmacokinetic data following oral administration of a 200-mg dose of LOXO-305 in tablet 
form in healthy volunteers in the LOXO-BTK-20014 study indicate that there was little effect 
of either a standard meal or the proton pump inhibitor (omeprazole) on the PK of LOXO-305.  
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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) 
AUC0-8 
(ng*h/ mL) 
Geo mean 
(%CV) 
AUC0-24 
(ng*h/mL) 
Geo mean 
(%CV) 
CL/F (L/h) 
Geo mean 
(%CV) 
t1/2 (h) 
Geo mean 
(%CV) 
Ratio 
AUC0-8  
Day 
8/Day 1 
Geo 
mean 
(%CV) 
25 mg QD 
50 mg QD 
100 mg QD 
150 mg QD 
200 mg QD 
250 mg QD 
300 mg QD 
Abbreviations: AUC0-8 = area under the concentration-time curve from time 0 to 8 hours; AUC0-24 = area under 
the concentration-time curve from time 0 to 24 hours; CL/F = apparent oral clearance; Cmax = maximum drug 
concentration; CV = coefficient of variation; Geo mean = Geometrical mean; N = number of subjects; 
QD = once daily; t1/2 = half-life; tmax = time of maximal plasma concentration. 
a N= 4, b N= 5, c N= 8, d N= 18, e N= 64, f N= 21, g N= 16, h N= 73 
SDTM Transfer: September 30, 2020 
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SDTM Transfer: September 30, 2020 
Preliminary and interim plasma concentration data from ongoing study LOXO-BTK-20008 
indicate that the dose of 200 mg QD in healthy volunteers produces a LOXO-305 steady-state 
geometric mean Cmax of 
 ng/mL and AUC from hour 0 to 24 hours postdose (AUC0-24) 
of approximately 
 ng*h/mL. These results indicate that the dose of 200 mg QD in this 
study will provide exposure in the range of the RP2D of LOXO-305 seen in patients, while 
remaining well under the no observed adverse effect level Cmax for genotoxicity of 
approximately 
 ng/mL. 
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. 
In vitro LOXO-305 inhibited P-gp. LOXO-305 may have the potential to raise plasma 
concentrations of drugs that are substrates of P-gp. This study is designed to determine the 
effect of LOXO-305 on the PK of digoxin (P-gp substrate). Digoxin is a substrate for P-gp 
and P-gp efflux plays a major role in both the oral absorption and renal elimination of 
digoxin. Digoxin is commonly used as an index substrate for P-gp in DDI studies.9 
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 
primarily those associated with adverse reactions to the study treatments, although there may 
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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 study or healthy volunteer studies.1 More information about 
the known and expected benefits, risks, and reasonably anticipated AEs associated with 
LOXO-305 may be found in the IB.1 
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 
96 hours postdose (Day 20) to allow for LOXO-305 elimination. In addition, subject’s 
hematology laboratory results will be reviewed prior to discharge from the CRU.  
Digoxin is a natural cardiac glycoside indicated for the treatment of congestive heart failure 
that may also be used to treat atrial fibrillation. Digoxin has a narrow therapeutic window, 
and clinical toxicity can occur, particularly at plasma levels above the normal therapeutic 
range. Despite its narrow therapeutic range, digoxin is often used as a probe substrate for 
P-gp in drug interaction studies as it is not metabolized by CYP450 enzymes; gut bacteria 
have been shown to inactivate digoxin.10 Digoxin is a probe substrate for P-gp as listed by the 
FDA.11 The half-life of digoxin is approximately 1.5 to 2 days. The dose of digoxin chosen 
for this study, 0.25 mg, is well characterized. Adverse effects caused by digoxin toxicity are 
well characterized and easily monitored in the clinical setting, and these effects can be treated 
if required. To monitor for safety, serum digoxin levels will be measured daily (Days 7 
through 15) in a clinical safety laboratory assay. These values are for safety only and will not 
be used to calculate the PK of digoxin.   
The safety monitoring practices employed will include AE reporting, vital sign 
measurements, 12-lead ECGs, clinical laboratory evaluations, physical examinations, and 
safety monitoring of serum digoxin levels and are considered adequate to protect the 
subjects’ safety.  
 
 


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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
The primary objectives of the study are: 
• to assess the effect of single and multiple oral doses of LOXO-305 on the PK of 
multiple oral doses of digoxin (P-gp substrate) in healthy subjects. 
• to assess the PK of LOXO-305 administered with multiple doses of digoxin at steady 
state in healthy subjects. 
2.1.2. 
Secondary Objective 
The secondary objective of the study is to assess the safety and tolerability of single and 
multiple oral doses of LOXO-305 when coadministered with multiple oral doses of digoxin. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of digoxin and LOXO-305 (as appropriate): 
•  AUC0-24 
• AUC from hour 0 to the last measurable concentration (AUC0-t) 
• AUC during a dosing interval (AUCtau) 
• apparent systemic clearance (CL/F) 
• Cmax 
• tmax 
• mean residence time (MRT) 
The following PK parameters will be calculated whenever possible, based on the urine 
concentrations of digoxin: 
• amount of drug excreted unchanged in urine (Ae) 
• fraction of drug excreted unchanged in urine (Fe) 
• renal clearance (CLr) 
2.2.2. 
Secondary Endpoints 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory evaluations, measuring vital signs, recording 12-lead ECGs, and safety 
monitoring of serum digoxin levels. 
 


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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 1, open-label, fixed-sequence DDI study to investigate the effect of single and 
multiple oral doses of LOXO-305 on the PK of multiple oral doses of digoxin (P-gp 
substrate) in healthy subjects.  
On Day 1, subjects will be administered oral 0.25 mg digoxin BID (loading dose), once in the 
morning and evening. Subjects will be fasted for at least 2 hours predose and 1-hour postdose 
for the morning and evening dose.   
On Days 2 through 16, oral doses of 0.25 mg digoxin QD will be administered (total of 17 
consecutive doses) at the actual time of the Day 1 morning digoxin dose (± 1 hour). On 
Days 8 through 16 (9 consecutive doses), oral doses of 200 mg LOXO-305 QD will be 
coadministered with 0.25 mg digoxin QD, at the actual time of the Day 1 morning digoxin 
dose (± 1 hour). LOXO-305 will be administered first, immediately followed by digoxin. On 
Days 2, 4 through 6, 9 through 11, 13, and 14, subjects will fast for at least 2 hours predose 
and 1-hour postdose. On Days 3, 12, and 15 where clinical laboratory evaluations are 
performed, subjects will fast for at least 8 hours predose and 1-hour postdose. On Days 7, 8, 
and 16, subjects will be fasted at least 10 hours predose and 2 hours postdose. Blood and 
urine samples for concentrations of digoxin in plasma and urine and
 
 Blood samples for concentrations of LOXO-305 and digoxin in plasma and
 
 
 Urine samples for concentrations of digoxin and
 
 
  Samples collected for the analysis of plasma and urine concentrations of digoxin 
and for analysis of LOXO-305 in plasma may be stored and analyzed 
 
 
The schematic of the study design is displayed in Figure 3. The start of the study is defined as 
the date the first subject who is enrolled in the study signs an Informed Consent Form (ICF). 
Note that enrolled subjects are defined as those subjects who are assigned to receive a dose of 
study drug; this definition excludes screen failure subjects. Replacement subjects may be 
enrolled only if deemed necessary by the Sponsor. 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the 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 20 upon completion of all PK and safety assessments or Early Termination (ET) if the 
subject discontinues. Dosing of digoxin will occur on Days 1 through 16 and dosing of 
LOXO-305 will occur on Days 8 through 16. A follow-up phone call will occur for all 
CCI
CCI
CCI
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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 58 days (Screening through follow-up phone call). 
Figure 3: Study Schematic 
 
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), safety monitoring of serum digoxin levels, and recording 
of concomitant medications will be performed at specified times during the study (for 
specific timepoints and details on each study variable, refer to Appendix 4).  
Adverse events and serious adverse events (SAEs) will be collected beginning at informed 
consent. Adverse events will be reported throughout the study (ie, from signing of the ICF 
until End of Study [EOS], or until ET if the subject discontinues from the study and does not 
complete a follow-up phone call), either as subject medical history (if the event is reported as 
beginning prior to signing of the ICF or if the event occurs prior to study drug administration 
on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) 
or as AEs (if the event occurs after signing of the ICF but prior to study drug administration 
on Day 1 and is assessed as related to study procedures by the Investigator [or designee], or if 
the event occurs after study drug administration on Day 1 through EOT or ET regardless of 
relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to 
study drug by the Investigator (or designee) are to be reported. All SAEs that develop from 
the time of ICF signing until EOS (or ET, if the subject discontinues from the study and does 
not complete a follow-up phone call) are to be reported. 
A Schedule of Assessments is presented in Appendix 4. Study completion is defined as the 
time of the last subject’s follow-up phone call. 


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3.2. 
Discussion of Study Design 
Metabolic routes of absorption or elimination, including most of those occurring through 
P-gp, 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 or decreased 
concentrations of a parent drug or its metabolites can alter the safety and efficacy profile of a 
drug.  
Digoxin is a well-established P-gp substrate and is used as a probe to assess the P-gp 
modulating potential of other drugs. The effect of LOXO-305 on the PK of digoxin will be 
assessed following multiple doses of digoxin due to the non-linearity of digoxin PK at single 
doses. Urinary digoxin PK will also be assessed because P-gp is expressed in proximal 
tubular cells of the kidney, and any effect of LOXO-305 on P-gp may therefore influence the 
renal clearance of digoxin. The fixed single-sequence design used in this study is typical for 
drug interaction studies because it allows intra-subject comparisons. A single sequence will 
be used to avoid carry-over effects. This study will be open-label because the primary 
endpoints are not considered subjective. 
Conducting the study in healthy adult subjects mitigates the potential confounding effects of 
the disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
3.3.1. 
LOXO-305 
Multiple oral doses of 200 mg LOXO-305 QD will be administered on Days 8 through 
Day 16 to achieve LOXO-305 steady state, ensuring the maximal effect of LOXO-305 when 
the effect on the PK of digoxin is determined on Day 16. While doses of 25 mg QD to 
300 mg QD have been evaluated, LOXO-305 200 mg given QD has been chosen as the 
RP2D for the ongoing global Phase 1/2 first-in-human study, LOXO-BTK-18001 in patients 
with previously treated CLL/SLL or NHL. The available data demonstrate that LOXO-305 
appears safe and well tolerated at these doses. At all evaluated doses, no dose-limiting 
toxicities have been identified in humans.1  
3.3.2. 
Digoxin 
The selected dose of digoxin is based on typical doses for this drug when used as an index 
substrate in DDI studies and is considered to be high enough to provide sufficient plasma 
concentrations to achieve the objectives of the study. Following the initial loading dose and 
given a t1/2 of approximately 1.5 days, digoxin plasma concentrations would be expected to 
achieve steady-state by Day 7 in the absence of LOXO-305. Day 7 has therefore been 
selected for the steady-state digoxin PK sampling and Day 8 has been chosen for the first 
LOXO-305 coadministration. Subjects may be withdrawn if their trough serum digoxin level 
exceeds 2.0 ng/mL and/or they exhibit clinically significant signs or symptoms of digoxin 
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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. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4)
7. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine blood pressure [BP] and pulse rate [measured after the subject 
has been supine for at least 5 minutes]; Section 7.2.3)
8. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1)
9. Clinical laboratory evaluations (Section 7.2.2; clinical 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) immunoglobulin M (IgM) core antibody, human 
immunodeficiency virus (HIV) antibody, and COVID-19 via polymerase chain 
reaction (PCR) testing or equivalent (Appendix 2)
11. Hemoglobin A1c (HbA1c) test (Appendix 2)
12. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen 
(breath or urine; Appendix 2)
13. Estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 2)
14. Serum pregnancy test (for female subjects only; Appendix 2)
15. Follicle-stimulating 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)
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4. Complete physical examination (Section 7.2.5)
5. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4)
6. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine BP and pulse rate [measured after the subject has been supine 
for at least 5 minutes]; Section 7.2.3)
7. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1)
8. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2)
9. Screen for COVID-19 via PCR test (or equivalent; Appendix 2)
10. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen 
(breath or urine; Appendix 2)
11. eGFR calculated using the CKD-EPI equation (Appendix 2)
12. Serum pregnancy test (for female subjects only; Appendix 2)
13. Compliance with concomitant medications and exclusionary 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 Check-in (Day -1). Prior to dosing, the Sponsor will provide approval of subjects 
selected for enrollment by the Investigator (or designee). 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria apply 
will be eligible to be enrolled into the study. Safety evaluations may be repeated at the 
discretion of the Investigator (or designee) or Sponsor. 
4.3. 
Inclusion 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. Body weight of ≥ 50 kg.
3. Within BMI range 18.0 to 32.0 kg/m2, inclusive.
4. 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).
5. 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


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post-menopausal (defined as at least 12 months post-cessation of menses without an 
alternative medical cause). Post-menopausal status will be confirmed with a screening 
serum FSH level consistent with post-menopausal status per the laboratory’s reference 
ranges. All female subjects must have a negative qualitative serum or negative 
qualitative urine pregnancy test (serum human chorionic gonadotropin; quantitative 
serum human chorionic gonadotropin tests may be used for confirmation as needed 
and post-menopausal subjects may be eligible for participation if the results of the 
qualitative serum pregnancy or qualitative urine pregnancy test are positive but the 
quantitative serum human chorionic gonadotropin results are within the laboratory’s 
reference ranges for post-menopausal women) 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 16 (or last administration of study drug if subject terminates 
from the study early).  
6. 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 16 (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 their 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 1 year 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 16 


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(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 16 (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) until 6 months 
after Day 16 (or last administration of study drug if subject terminates from the study 
early). 
For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. 
7. Able to understand and provide written informed consent. 
8. Able to comply with all study procedures, including the 20-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. congestive heart failure ≥ stage 2 per New York Heart Association 
Classification 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 within 6 months prior to 
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vii. ventricular dysfunction including ventricular fibrillation or risk factors 
for Torsades de Pointes (eg, heart failure, cardiomyopathy, family 
history of Long QT Syndrome) 
viii. ECG abnormalities that are clinically significant at Screening, 
Check-in (Day -1), or predose on Day 1, including, but not limited to: 
1. complete left bundle-branch block 
2. first or second-degree atrioventricular (AV) block, type 2, or 
third-degree AV block 
3. QT interval corrected for heart rate (HR) using Fridericia’s 
method (QTcF) > 450 msec  
Subjects with out-of-range ECG values or abnormal ECG 
findings that are not clinically significant will be permitted to 
have ECGs repeated up to 2 times during Screening, Check-in 
(Day -1), and predose on Day 1 to confirm eligibility for study 
participation, if the repeat value(s) are normal/fall outside of 
the ranges stated above. 
2. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital sign 
measurements at Screening, Check-in (Day -1), or prior to dosing on Day 1. 
Out-of-range vital sign measurements are defined as: 
a. body temperature > 37.5°C; 
b. pulse rate < 50 or > 99 beats per minute (bpm); 
c. systolic BP < 89 or > 139 mmHg; 
d. diastolic BP < 50 or > 89 mmHg; 
e. oxygen saturation < 95% (room air).  
Subjects with out-of-range values for these parameters that are not clinically 
significant will be permitted to have vital sign measurements repeated up to 2 times 
during Screening, Check-in (Day -1), and predose on Day 1 to confirm eligibility for 
study participation if the repeat value(s) are normal/fall outside of the ranges stated 
above.  
3. History or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator (or designee), or mentally or legally 
incapacitated or has significant emotional problems at the time of the Screening visit 
or expected during the conduct of the study. 
4. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Check-in (Day -1). 
5. Abnormal laboratory values (hematology panel, UA, clinical chemistry panel [fasted 
at least 8 hours]) that are clinically significant excluding those further defined in 
exclusion criteria #6, #7, #8, #10, #11, and #12 at Screening and/or Check-in 
(Day -1). Subjects with out-of-range clinical laboratory results that are not clinically 
significant (excluding those further defined in exclusion criteria #6, #7, #8, #10, #11, 
and #12) may have laboratory assessments repeated at the Investigator (or designee)’s 
discretion up to 2 times during Screening and Check-in (Day -1) to confirm eligibility 


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for study participation if the repeat value(s) fall within normal ranges or are 
stabilizing. 
6. Abnormal liver function tests (LFTs) as defined by aspartate aminotransferase, 
alanine aminotransferase, and serum (total and direct) bilirubin, as well as amylase, or 
lipase above the upper limit of the normal range per the laboratory’s reference ranges 
at Screening or Check-in (Day -1). Subjects with out-of-range LFTs, amylase, and 
lipase values above the upper limit of normal that are not clinically significant will be 
permitted to have LFTs, amylase, or lipase assessments repeated up to 2 times during 
Screening and Check-in (Day -1) to confirm eligibility for study participation if the 
repeat value(s) fall within normal ranges.  
7. Creatine kinase values above the upper limit of the normal range per the laboratory’s 
reference ranges that are clinically significant at Screening or Check-in (Day -1). 
Subjects with out-of-range creatine kinase values that are not clinically significant 
will be permitted to have the creatine kinase assessments repeated up to 2 times 
during Screening and Check-in (Day -1) to confirm eligibility for study participation 
if the repeat value(s) are stable or normalizing. 
8. Estimated glomerular filtration rate (eGFR) ≤ 90 mL/minute/1.73m2 calculated using 
the CKD-EPI equation at Screening or Check-in (Day -1). Subjects with out-of-range 
eGFR values that are not clinically significant will be permitted to have eGFR 
assessments repeated up to 2 times during Screening and Check-in (Day -1) to 
confirm eligibility for study participation if the repeat value(s) fall above the range 
stated above.  
9. HbA1c ≥ 6.5% at Screening. Subjects with out-of-range HbA1c values that are not 
clinically significant will be permitted to have HbA1c assessments repeated up to 
2 times during Screening to confirm eligibility for study participation if the repeat 
value(s) fall below the range stated above. 
10. Potassium values < 4.0 mEq/L at Screening or Check-in (Day -1). Subjects with 
potassium values < 4.0 mEq/L that are not clinically significant will be permitted to 
have potassium assessments repeated up to 2 times during Screening and Check-in 
(Day -1) to confirm eligibility for study participation if the repeat value(s) fall above 
the range stated above or are normalizing. 
11. Calcium values outside of normal range at Screening or Check-in (Day -1). Subjects 
with calcium values outside of normal range that are not clinically significant will be 
permitted to have calcium assessments repeated up to 2 times during Screening and 
Check-in (Day -1) to confirm eligibility for study participation if the repeat value(s) 
fall within normal range or are normalizing. 
12. Magnesium levels < 2.0 mEq/L at Screening or Check-in (Day -1). Subjects with 
magnesium values < 2.0 mEq/L that are not clinically significant will be permitted to 
have magnesium assessments repeated up to 2 times during Screening and Check-in 
(Day -1) to confirm eligibility for study participation if the repeat value(s) fall above 
the range stated above or are normalizing. 
13. Positive serologic test for HBsAg, HBV IgM core antibody, HCV antibody, or HIV 
antibody at Screening. Subjects who are positive for HBV IgM core antibody or HCV 
antibody require confirmation by PCR before enrollment to detect presence of active 


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virus. Subjects who are HBV core antibody or HCV antibody positive or for whom a 
PCR is unable to be obtained will not be eligible. 
14. 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.  
15. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
16. Significant history or clinical manifestation of any allergic, dermatological, biliary, 
hepatic, gastrointestinal, renal, metabolic, hematological, pulmonary, cardiovascular 
(including any prior history of cardiomyopathy or heart failure), neurological, thyroid, 
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. 
17. 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. 
18. History of a major surgical procedure within 30 days prior to Screening. 
19. 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). 
20. Use of tobacco, smoking-cessation products, or products containing nicotine and 
e-cigarettes (nicotine and non-nicotine), within 3 months prior to Screening and 
through EOT or ET. 
21. Use or intention to use any prescription or over-the-counter medications (including 
but not limited to any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers [including herbal products such as St. John’s wort], CYP2C8 substrates, 
strong P-gp inhibitors, P-gp substrates [with the exception of digoxin administered for 
the purposes of this study/in accordance with the protocol], proton pump inhibitors, 
antacids, H2-receptor antagonists, and drugs that prolong QT/QTc interval, vitamin 
supplements, caffeine, herbal products, natural or herbal supplements, and 
hormone-replacement therapy [HRT]) from 14 days prior to Day 1 or 5 half-lives (if 
known, whichever is longer [except for paracetamol/acetaminophen maximum of 
2 g/day for up to 3 consecutive days during the study]) through EOT or ET, unless 
deemed acceptable by the Investigator (or designee) and Sponsor. 
22. 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. 
23. Consumption of alcohol-containing foods or beverages or caffeine-containing foods 
or beverages (including but not limited to teas [including decaffeinated teas], coffees 
[including decaffeinated coffees], colas [including decaffeinated colas], energy 


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drinks, gum containing caffeine, chocolate, and foods and beverages containing 
chocolate) within 72 hours prior to Check-in (Day -1) and through EOT or ET. 
24. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
25. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator (or designee), within the 30 days prior to Day 1 and through EOT or ET. 
26. 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. 
27. Has previously received LOXO-305 in any other study investigating LOXO-305, 
within 30 days prior to Day 1. 
28. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
29. Poor peripheral venous access. 
30. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
31. Receipt of blood products within 2 months prior to Check-in (Day -1). 
32. 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).  
For subjects who 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). 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number as defined above. 
4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for 
any reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue 
the study. Subjects may be withdrawn because of the following:  


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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  
• intake of non-permitted concomitant medication that might affect subject safety or 
study assessments/objectives, etc. 
Notification of withdrawal will immediately be made to the Sponsor. In case of withdrawal, 
efforts will be made to perform all ET assessments (Appendix 4). The date the subject is 
withdrawn from the study and the reason for withdrawal will be recorded on the subject’s 
electronic Case 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 LOXO-305. Covance will procure adequate quantities of digoxin (Table 2). 
Table 2: Study Drugs 
Study Drug 
Forma 
Strength 
Supplier 
Manufacturerb 
LOXO-305 
Tablet 
2 × 100 mg 
Loxo 
Oncology, Inc. 
Catalent San Diego or Lonza 
Pharma & Biotech 
Digoxin 
Tablet 
0.25 mg  
Covance 
Northstar Rx 
 a Specific ingredients/purity (for LOXO-305; digoxin will be manufactured to USP reference standards) 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 will be stored according to the instructions on the label. 
Digoxin will be supplied by Covance, along with the lot number. Digoxin will be 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 
Subjects will receive each of the following treatments throughout the study: 
• On Day 1, subjects will be administered oral 0.25 mg digoxin BID (loading dose), 
once in the morning and evening. Subjects will be fasted for at least 2 hours predose 
and 1-hour postdose for the morning and evening dose. Water will be restricted for 
1 hour prior to and 1 hour after dosing with the exception of water administered for 
dose administration. 
• On Days 2 through 16, oral doses of 0.25 mg digoxin QD will be administered (total 
of 17 consecutive doses) at the actual time of the Day 1 morning digoxin dose 
(± 1 hour). On Days 8 through 16 (9 consecutive doses), oral doses of 200 mg 
LOXO-305 QD will be coadministered with 0.25 mg digoxin QD, at the actual time 
of the Day 1 morning digoxin dose (± 1 hour). LOXO-305 will be administered first, 
immediately followed by digoxin. On Days 2, 4 through 6, 9 through 11, 13, and 14, 
subjects will fast for at least 2 hours predose and 1-hour postdose. On Days 3, 12, and 
15 where clinical laboratory evaluations are performed, subjects will fast for at least 
8 hours predose and 1-hour postdose. On Days 7, 8, and 16, subjects will be fasted at 
least 10 hours predose and 2 hours postdose. Water will be restricted for 1 hour prior 


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to and 1 hour after dosing with the exception of water administered for dose 
administration. 
All study drugs will be administered orally with approximately 240 mL of water. An 
additional 100 mL of water may be administered if needed.  
Each unit dose will be prepared by qualified CRU staff.  
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be administered the appropriate dose at a 
specific time, the exact dose time of subjects may be staggered to obviate the need to have all 
subjects on precisely the same study schedule. For each dose, the subject’s actual dose time 
will be recorded in the source documents and 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 and digoxin 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 digoxin will be performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-305 
and digoxin tablets received. In addition, an accurate drug disposition record will be kept, 
specifying the amount dispensed to each subject and the date of dispensing. This drug 
accountability record will be available for inspection at any time. At the completion of the 
study, the original drug accountability record will be available for review by the Sponsor 
upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 


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At the completion of the study, all unused LOXO-305 tablets will be disposed of by the CRU, 
in accordance with the CRU’s Standard Operating Procedures (SOPs) and local/state/federal 
guidelines governing waste disposal of investigational drugs, following the Sponsor’s written 
authorization. The digoxin 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) is an 
acceptable concomitant medication. 
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 including but not limited to: 
moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers (including herbal 
products such as St. John’s wort), CYP2C8 substrates, strong P-gp inhibitors, P-gp substrates 
(with the exception of digoxin administered for the purposes of this study/in accordance with 
the protocol), proton pump inhibitors, antacids, H2-receptor antagonists, and drugs that 
prolong QT/QTc interval, herbal products, caffeine, vitamin supplements, natural or herbal 
supplements, and HRT are prohibited for 14 days or 5 half-lives (if known; except for 
paracetamol/acetaminophen as referenced above), whichever is longer, prior to Day 1 and 
through EOT or ET, unless deemed acceptable by the, Investigator (or designee), and 
Sponsor. Any medication taken by a subject during the course of the study, including details 
of its dosage, administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without 
prior approval of the Investigator (or designee) and Sponsor, unless its use is deemed 
necessary in a medical emergency. In this case, the use of the concomitant medication will be 
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 and e-cigarettes (nicotine and non-nicotine) 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-containing foods or beverages or caffeine-containing foods or 
beverages (including but not limited to teas [including decaffeinated teas], coffees [including 
decaffeinated coffees], colas [including decaffeinated colas], energy drinks, gum containing 
caffeine, chocolate, and foods and beverages containing chocolate) 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). 


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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 requirements and water restrictions 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 digoxin, LOXO-305, and for future potential and/or 
exploratory analysis 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 and for 
future potential and/or exploratory analysis will be recorded on the eCRF. 
Processing, storage, and shipping instructions for these PK blood samples and for future 
potential and/or exploratory analysis will be provided in a separate Laboratory Manual. The 
number of blood samples and total blood volume required for PK and for future potential 
and/or exploratory analysis testing is presented in Appendix 3. 
7.1.2. 
Pharmacokinetic Urine Sample Collection and Processing 
Urine samples for PK analysis of digoxin levels will be collected at the timepoints specified 
in Appendix 4. The exact time of the study drug administration and the actual time of urine 
sampling for PK analysis will be recorded on the eCRF. Samples collected for the analysis of 
urine concentrations of digoxin may be stored and analyzed for future exploratory analysis. 
Processing, storage, and shipping instructions for these PK urine samples will be provided in 
a separate Laboratory Manual.  
7.1.3. 
Analytical Methodology 
Plasma concentrations of digoxin and LOXO-305 and urine concentrations of digoxin 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 order of priority): 
• dosing 
• PK blood sampling 
• vital sign measurements* 
• 12-lead ECGs* 
• blood and urine samples for clinical laboratory evaluations 
• physical examination. 


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* When vital sign measurements and 12-lead ECGs are scheduled at the same time as PK 
blood sampling, the PK blood sampling will be obtained at the scheduled timepoint, and the 
vital sign measurements followed by 12-lead ECGs will be obtained prior to and as close as 
possible to the scheduled PK blood sampling. 
7.2.1. 
Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes 
in your health status since Screening/since you were last asked?” at the timepoints specified 
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. 
Adverse events, 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 


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designee) according to regulatory authority requirements. Refer to Reference Safety 
Information in the current IB1 for LOXO-305 for additional safety information. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours; at ET or the 
day before EOT, 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 IgM 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 
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 an alcohol screen 
(urine or breath) will be performed at Screening and repeated at Check-in (Day -1) for all 
subjects. A serum qualitative or urine qualitative pregnancy test (female subjects only 
[quantitative serum human chorionic gonadotropin tests may be used for confirmation as 
needed and post-menopausal subjects may be eligible for participation if the results of the 
qualitative serum pregnancy or qualitative urine pregnancy test are positive but the 
quantitative serum human chorionic gonadotropin results are within the laboratory’s 
reference ranges for post-menopausal women]) 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 body temperature, respiratory rate, oxygen saturation, 
and supine BP and pulse rate) will be obtained at the timepoints specified in Appendix 4. 
Blood pressure and pulse rate measurements should be 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 PK blood draws, the PK 
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 PK blood draw. 
7.2.4. 
12-lead Electrocardiogram 
A 12-lead ECG (including HR, 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 


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timepoints specified in Appendix 4. The QT interval will be corrected for HR by Fridericia’s 
(QTcF = QT/[RR]1/3) formula. 
When 12-lead ECGs are scheduled at the same time as PK blood draws, the PK blood draws 
will be obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to 
and as close as possible to the scheduled PK blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated physical examination will be 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. 
7.2.6. 
Safety Digoxin Monitoring 
Therapeutic drug monitoring of digoxin concentrations (trough levels) in serum will be 
performed before the digoxin dose at the timepoints specified in Appendix 4. The results will 
be made available to the Investigator prior to digoxin dosing the following day. The 
Investigator must review the results prior to administration of the next digoxin dose. 
Additional serum digoxin samples for safety monitoring may be collected at the discretion of 
the Investigator. If a subject's trough serum digoxin level exceeds 2.0 ng/mL and/or they 
exhibit clinically  significant signs or symptoms of digoxin toxicity, that subject may be 
discontinued from the study. Results of the serum digoxin samples collected for safety 
monitoring will not be included in the PK evaluation of digoxin. 
Any subject experiencing signs of acute severe digoxin toxicity will be managed 
appropriately, including, if indicated, urgent transport to a local emergency room.  


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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
Up to 16 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 16 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 
The PK Population will consist of all subjects who have received a dose of LOXO-305 or 
digoxin, 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 tmax. The 
impact of protocol deviations on the PK population will be evaluated on a case-by-case basis. 
The Safety Population will consist of all subjects who have received at least 1 dose of study 
drug (digoxin and/or LOXO-305). Subjects will be classified into groups based on actual 
treatment received. 
8.3. 
Pharmacokinetic Analysis 
Serial blood samples for plasma concentration analysis will be collected at the following 
timepoints: 
• Digoxin and samples 
: 
o 
 following administration alone 
 
 
o 
 following administration with 
LOXO-305 
 
o 
 following administration with LOXO-305.  
o 
 following administration with 
LOXO-305 
 
o  
• LOXO-305 and samples 
:  
o 
 following administration with digoxin 
 
o 
 following administration with digoxin.  
o 
 following administration with digoxin 
. 
Urine samples for concentration analysis of digoxin and
  
CCI
CCI
CCI
CCI
CCI
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CCI
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CCI
CCI


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Samples collected for the analysis of plasma and urine concentrations of digoxin and for 
analysis of LOXO-305 in plasma may be stored and analyzed for future exploratory analysis. 
Whenever possible, the following PK parameters for digoxin and LOXO-305 will be 
calculated for each subject based on the plasma concentrations (as appropriate): 
• area under the concentration time curve (AUC) from hour 0 to 24 hours postdose 
(AUC0-24) 
• AUC from hour 0 to the last measurable concentration (AUC0-t) 
• AUC during a dosing interval (AUCtau) 
• apparent systemic clearance (CL/F) 
• Cmax 
• mean residence time (MRT) 
• time to maximum observed plasma concentration (tmax) 
The following PK parameters will be calculated whenever possible, based on the urine 
concentrations of digoxin: 
• amount of drug excreted unchanged in urine (Ae) 
• fraction of drug excreted unchanged in urine (Fe) 
• renal clearance (CLr) 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 8.1 or higher (Certara USA Inc.).  
Other parameters may be added as appropriate. Final PK parameters reported will be detailed 
in the Statistical Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analyses 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 and urine 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 and urine concentration-time curves (both linear and log linear) 
will be included in the final report. 
8.3.2. 
Statistical Methodology 
The primary analysis planned for this study is a mixed effect model that includes treatment as 
a fixed effect and subject as a random effect. The analysis will be performed on the natural 
log (ln)-transformed PK parameters (AUC0-t, AUC0-24, and Cmax) and include calculation of 


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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 comparisons 
of interest will be as follows: 
• Multiple doses of digoxin coadministered with multiple doses of LOXO-305 versus 
multiple doses of digoxin alone. 
• Multiple doses of digoxin coadministered with a single dose of LOXO-305 versus 
multiple doses of digoxin alone.  
8.4. 
Safety Analysis 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, safety monitoring of serum digoxin levels, physical examination results, concomitant 
medications, and 12-lead ECGs, will be tabulated and summarized where possible, using 
descriptive methodology by treatment, as needed, by 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). Adverse events will be coded using 
Medical Dictionary for Regulatory Activities (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 and preferred term. 
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 
CRU staff member. 
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 Sponsor-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. 


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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 SOPs or per 
Sponsor 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 and/or 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(s) who will be responsible for monitoring this 
clinical trial. The Sponsor’s Study Monitor(s) 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(s) will visit the CRU(s) at suitable intervals (or 
may perform activities remotely as per the Monitoring Plan for this study) and be in frequent 
contact through verbal and written communication. It is essential that the Sponsor’s Study 
Monitor(s) 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(s) 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(s), 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 


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approved by the IRB. The Sponsor will supply relevant material for the Investigator (or 
designee) to submit to the IRB for the protocol’s review and approval. Verification of the 
IRB unconditional approval of the protocol and the written ICF statement will be transmitted 
to the Investigator (or designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will be 
transmitted in writing to the Investigator (or designee). If requested, the Investigator (or 
designee) will permit audits by the IRB and regulatory inspections by providing direct access 
to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s (or designee’s) participation in the study. 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can 
withdraw from the study at any time. In accordance with 21 CFR 50, the informed consent 
process shall be documented by the use of a written ICF approved by the IRB and signed by 
the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject and the other 
will be maintained with the subject’s records. 
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), and Investigational New Drug Application 
(21 CFR 312), as appropriate. As such, these sections of US Title 21 CFR, along with the 


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applicable International Council for Harmonisation 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 4.0). 29 October 
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; S216.  
3.  Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK 
with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 
4;369(1):32–42.  
4.  Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol. 2017 May 1;35(13):1437–43.  
5.  Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to 
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 
10.  Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, Turnbaugh PJ. 
Predicting and manipulating cardiac drug inactivation by the human gut bacterium 
Eggerthella lenta. Science. 2013 Jul 19;341(6143):295–8.  
11.  Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. FDA [Internet]. 2020 Mar 10 [cited 2021 Jan 27]; 
Available from: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interac
tions-table-substrates-inhibitors-and-inducers 


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11. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy adult subject, whether or not considered drug-related by 
the Investigator (or designee). A treatment-emergent adverse event (TEAE) is an AE that 
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 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant 
by the Investigator [or designee]), and accidents observed in the context of a clinical trial, 
irrespective of a possible causal relationship with the administration of the trial substance. 
Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• 
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 End of Study (EOS) or Early Termination (ET; if the subject 
discontinues from the study and does not complete a follow-up phone call) and for up to 
90 days after study drug administration on Day 16 (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 a serious adverse event (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 (eCRF; 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 


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treatment and the 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 the Food and Drug Administration (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 Investigator’s Brochure (IB) or if it is not 
listed at the specificity or severity that has been observed for an unapproved investigational 
medicinal product (IMP). 
Reporting 
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 Institutional Review Board (IRB). 
Final determination of whether an event represents a suspected unexpected serious adverse 
reaction (SUSAR) will be the responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or 
reported, and within 24 hours of any SAE (regardless of whether the event is assessed as 
related or unrelated to study drug) being first recognized or reported, Covance or the 
Sponsor’s Clinical Safety Representative will be notified by the Investigator (or designee) in 
writing using the following email address: 
email: SAEIntake@Covance.com 
To report the SAE, the completed report form should be sent by email to Covance or the 
Sponsor’s Clinical Safety Representative within 24 hours of awareness. Incoming reports are 


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reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 
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 
Safety digoxin levels (serum) 
Coagulation Parameters: 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serologyb: 
Hepatitis B surface antigen 
(HBsAg) 
Hepatitis B virus (HBV) 
immunoglobulin M (IgM) core 
antibody 
Hepatitis C virus (HCV) 
antibody 
Human immunodeficiency virus 
(HIV) antibody 
For Female Subjects Only: 
Pregnancy test (qualitative serum 
or qualitative urine, quantitative 
serum human chorionic 
gonadotropin tests may be used 
for confirmation as needed and 
post-menopausal subjects may 
be eligible for participation if the 
results of the qualitative serum 
pregnancy or qualitative urine 
pregnancy test are positive but 
the quantitative serum human 
chorionic gonadotropin results 
are within the laboratory’s 
reference ranges for 
post-menopausal women)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 occult blood 
is positive) 
Urine Drug Screena: 
Including but not limited to the 
following: 
Alcohol (ethanol)e 
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 19 for 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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e. Urine or breath test. 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject: 
a At PK sampling timepoints where multiple analytes (ie, digoxin and LOXO-305) are assessed, a single blood sample 
will be taken for analysis (see Appendix 4). 
b Thyroid-stimulating hormone (TSH) and estimated glomerular filtration rate (eGFR) will be assessed as part of the clinical 
chemistry sample. 
c Serum concentrations of digoxin will be assessed as part of clinical laboratory evaluations on Days 7, 12, and 15.  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 500 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 (HbA1c) 
4.0 
1 
4.0 
Digoxin pharmacokinetic (PK) 
sampling and future potential and/or 
exploratory analysis sampling 
4.0 
50a 
200.0 
LOXO-305 PK and future potential 
and/or exploratory analysis sampling 
4.0 
Clinical laboratory evaluations: 
    Hematology  
    Clinical chemistryb 
    Coagulation  
 
4.0 
4.0 
3.0 
 
7 
7 
7 
77.0 
Digoxin safety samplesc 
3.0 
9 
27.0 
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: 
332.0 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) 
Treatment Period 
Clinic 
Discharge 
EOT/ETw 
Follow-up Phone 
Call (EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 
20 
7 (± 2) Days Post 
EOT/ETx  
Confined to the CRU 
 
X 
X 
X 
X 
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 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
Vital Sign Measurementsf,g,h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
HDYF? Inquiryi 
X 
X 
X 
X 
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 
X 
X 
X 
X 
Digoxin Dosingk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
LOXO-305 Dosingl 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Clinical Laboratory Evaluationsp 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Serum Digoxin Samples (for Safety 
Monitoring)q 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Testr 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screens 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medicationst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testu 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
FSH Testv 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Treatment Period 
Clinic 
Discharge 
EOT/ETw 
Follow-up Phone 
Call (EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 
20 
7 (± 2) Days Post 
EOT/ETx  
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; 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; BMI calculated based on Screening height. 
d. A complete physical examination will be performed at Check-in (Day -1). An abbreviated physical examination will be performed at Day 20 (EOT) or at ET. 
e. 12-lead ECGs will be obtained at Screening and Check-in (Day -1), Day 1 (predose and 2 hours postdose), once daily on Days 2 to 7 (predose), Day 8 (predose and 2 hours postdose), 
Days 10, 12, and 15 (predose), Day 16 (predose and 2 hours postdose), Day 18, and Day 20 (96 hours postdose on Day 16 [EOT]) or ET. 12-lead ECGs will be collected after the subject has 
rested in the supine position for at least 10 minutes. When scheduled at the same time as PK blood draws, 12-lead ECGs will be obtained prior to and as close as possible to having blood 
drawn. The allowed sampling window for 12-lead ECGs is ± 30 minutes from the nominal 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 BP and pulse rate) will be obtained at Screening, Check-in (Day -1), Day 1 (predose and 2 hours postdose), once daily on Days 2 to 7 (predose), Day 8 
(predose and 2 hours postdose), Days 10, 12, and 15 (predose), Day 16 (predose and 2 hours postdose), Day 18, and Day 20 (96 hours postdose on Day 16 [EOT]) or ET. Blood pressure and 
pulse rate will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. When scheduled at the same time as PK blood draws, vital sign 
measurements should be carried out prior to and as close as possible to having blood drawn. 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. Respiratory rate and body temperature will be obtained at Screening, Check-in (Day -1), and Day 20 (96 hours postdose on Day 16 [EOT]) or ET. 
h. Oxygen saturation will be measured via pulse oximetry at Screening, Check-in (Day -1), predose on Day 1, and Day 20 (96 hours postdose on Day 16 [EOT]) or ET. The allowed sampling 
window for oxygen saturation measurements is ± 30 minutes from the nominal timepoint for all postdose oxygen saturation measurements and no less than 10 minutes prior to dosing for 
predose oxygen saturation measurements. 
i. A HDYF? 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. Adverse events and SAEs will be collected beginning at informed consent. Adverse events will be recorded throughout the study (ie, from signing of the ICF until EOS, or until ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as subject medical history (if the event is reported as beginning prior to signing of the ICF or if the 
event occurs prior to study drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the 
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, oral doses of 0.25 mg digoxin BID (loading dose) will be administered once in the morning and evening. Subjects will be fasted for at least 2 hours predose and 1-hour postdose 
for the morning and evening dose. Water will be restricted for 1 hour prior to and 1 hour after dosing with the exception of water administered for dose administration. On Days 2 through 16, 
oral doses of 0.25 mg digoxin QD will be administered at the actual time of the Day 1 morning digoxin dose (± 1 hour). On Days 8 through 16, oral doses of 200 mg LOXO-305 QD will be 
coadministered with oral doses of 0.25 mg digoxin QD, at the actual time of the Day 1 morning digoxin dose (± 1 hour). LOXO-305 will be administered first, immediately followed by 
digoxin. On Days 2, 4 through 6, 9 through 11, 13, and 14, subjects will fast for at least 2 hours predose and 1-hour postdose. On Days 3, 12, and 15 where clinical laboratory evaluations are 


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performed, subjects will fast for at least 8 hours predose and 1-hour postdose. On Days 7, 8, and 16, subjects will be fasted at least 10 hours predose and 2 hours postdose. Water will be 
restricted for 1 hour prior to and 1 hour after dosing with the exception of water administered for dose administration. 
l. On Day 8 through Day 16, oral doses of 200 mg LOXO-305 QD will be coadministered with oral doses of 0.25 mg digoxin QD in the morning at the actual time of the Day 1 morning 
digoxin dose (± 1 hour). LOXO-305 will be administered first, immediately followed by digoxin. On Days 2, 4 through 6, 9 through 11, 13, and 14, subjects will fast for at least 2 hours 
predose and 1-hour postdose. On Days 3, 12, and 15 where clinical laboratory evaluations are performed, subjects will fast for at least 8 hours predose and 1-hour postdose. On Days 7, 8 and 
16, subjects will be fasted at least 10 hours predose and 2 hours postdose. Water will be restricted for 1 hour prior to and 1 hour after dosing with the exception of water administered for dose 
administration. 
p. Clinical chemistry panel (fasted for at least 8 hours), coagulation parameters, hematology panel, and UA will be performed at Screening, Check-in (Day -1), Day 3 (48 hours postdose 
on Day 1), Day 7 (predose), Day 12 (predose), Day 15 (predose), and Day 19 (72 hours postdose on Day 16, if the subject completes the study [EOT]), or on the day of ET. At ET or the day 
before EOT (Day 19), subjects are not required to be fasted prior to clinical laboratory evaluations.  
q. Serum digoxin level samples for safety monitoring will be collected predose on Days 7 through 15 and at the discretion of the Investigator (or designee).  
r. 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. 
s. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen (urine or breath).  
t. Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved prescription and over-the-counter medications taken 
by a subject within 14 days or 5 half-lives (if known), whichever is longer, prior to Day 1 will be recorded on the subject’s electronic CRF. 
u. Female subjects only. Performed at Screening, Check-in (Day -1), and Day 19 (72 hours postdose on Day 16), if the subject completes the study (EOT) or on the day of ET.  
v. Post-menopausal female subjects only. 
w. End of Treatment is defined as when the subject is released from the CRU following completion of all assessments through Day 20. Early Termination 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 on Day 20 (EOT) or ET. Clinical laboratory 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. 
x. To be conducted 7 days (± 2 days) following EOT or ET. End of Study 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 or digoxin (including subjects who are terminated 
early) will receive a follow-up phone call. 
CCI


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y. Denotes predose sample collection only. 

SAP_001.pdf: 
Statistical Analysis Plan J2N-OX-JZNT Version 1
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of Single and Multiple Oral 
Doses of LOXO-305 on the Pharmacokinetics of Multiple Oral Doses of Digoxin (P-Glycoprotein Substrate) in 
Healthy Subjects
NCT06194214
Approval Date: 20-May-2021


 TITLE PAGE 
Statistical Analysis Plan 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to 
Investigate the Effect of Single and Multiple Oral Doses of LOXO-305 on 
the Pharmacokinetics of Multiple Oral Doses of Digoxin (P-Glycoprotein 
Substrate) in Healthy Subjects  
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 20MAY2021 
Investigational Medicinal Product: LOXO-305 
Protocol Reference: LOXO-BTK-20021 
Covance Study: 8456071 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Coordinating Investigator Study Site: 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Up to 2 additional sites in the United States 
may be utilized. 
Coordinating Investigator: 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
PPD


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ST-AD-031 Version 02 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objectives .......................................................................................................... 6 
2.2. Secondary Objective ....................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
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 .................................................................................... 11 
8.1. General .......................................................................................................................... 11 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 11 
8.1.2. Calculation of the Summary Statistics ................................................................... 12 
8.1.3. Repeat and Unscheduled Readings ........................................................................ 13 
8.1.4. Definitions of Baseline and Change from Baseline ............................................... 13 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Screening Demographics .............................................................................................. 14 
8.4. Prior and Concomitant Medication ............................................................................... 14 
8.5. Pharmacokinetic Assessments ...................................................................................... 14 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 14 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 17 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 18 


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ST-AD-031 Version 02 
8.6. Safety and Tolerability Assessments ............................................................................ 19 
8.6.1. Adverse Events ....................................................................................................... 19 
8.6.2. Clinical Laboratory Parameters .............................................................................. 20 
8.6.3. Vital Signs Parameters ........................................................................................... 20 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 21 
8.6.5. Other Assessments ................................................................................................. 21 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 21 
9. INTERIM ANALYSES ....................................................................................................... 21 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 21 
11. REFERENCES .................................................................................................................. 22 
12. APPENDICES ................................................................................................................... 23 
Appendix 1: 
Document History ................................................................................ 23 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1: 
Presentation of Study Treatments in AE TFLs ..................................................... 10 
Table 2: 
Pharmacokinetic Treatment Labels ....................................................................... 10 
 
Figure 1: 
Study Design ........................................................................................................... 9 
 


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ST-AD-031 Version 02 
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 
Ae 
amount excreted in urine per sampling interval 
AUC0-24 
area under the concentration-time curve from hour 0 to 24 hours 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration  
AUCtau 
area under the concentration-time curve over a dosing interval 
ARAUC 
accumulation ratio base on AUCtau 
BID 
twice daily 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
Cmax 
maximum observed plasma concentration 
CL/F 
apparent systemic clearance 
CLR 
renal clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
Fe 
percentage of dose excreted in urine per sampling interval 
Geom CV 
geometric CV 
Geom Mean 
geometric mean 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
λZ Lower 
start of exponential fit 
λZ N 
number of data points included in the log-linear regression 
λZ Span Ratio 
time period over which λZ was determined as a ratio of t1/2 
λZ Upper 
end of exponential fit 


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ST-AD-031 Version 02 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTlast 
mean residence time based on AUC0-t 
NA 
not applicable 
NC 
not calculated 
NR 
not reported 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time to maximum observed plasma concentration 
WHODrug 
World Health Organization Drug Dictionary  


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ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 12 February 2021) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), 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. Additionally, the SAP 
and TFL shells should be finalized prior to any programming activities commencing.   
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) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, ICH E9 guideline 
Statistical Principles for Clinical Trials. 1,2,3 
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
2.1. Primary Objectives 
The primary objectives of the study are:  
 to assess the effect of single and multiple oral doses of LOXO-305 on the PK of 
multiple oral doses of digoxin (P-glycoprotein [P-gp] substrate) in healthy subjects.  
 to assess the PK of LOXO-305 administered with multiple doses of digoxin at steady 
state in healthy subjects.  
2.2. Secondary Objective 
The secondary objective of the study is to assess the safety and tolerability of single and 
multiple oral doses of LOXO-305 when coadministered with multiple oral doses of digoxin. 


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ST-AD-031 Version 02 
3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of digoxin and LOXO-305 (as appropriate):  
 area under the concentration-time curve from hour 0 to the last measurable 
concentration (AUC0-t) 
 area under the concentration-time curve over a dosing interval (AUCtau) 
 apparent systemic clearance (CL/F)  
 maximum observed plasma concentration (Cmax)  
 time to maximum observed plasma concentration (tmax)  
 mean residence time based on AUC0-t (MRTlast)  
The following PK parameters will be calculated whenever possible, based on the urine 
concentrations of digoxin:  
 amount excreted in urine per sampling interval (Ae)  
 percentage of dose excreted in urine per sampling interval (t1-t2), where %feu = 100 
(Aeu/dose)  
 renal clearance (CLr)  
3.2. Secondary Endpoints 
Safety and tolerability will be assessed by monitoring adverse events (AEs), performing 
physical examinations and clinical laboratory evaluations, measuring vital signs, recording 
12-lead electrocardiograms (ECGs), and safety monitoring of serum digoxin levels. 
4. STUDY DESIGN  
This is a Phase 1, open-label, fixed-sequence drug-drug interaction study to investigate the 
effect of single and multiple oral doses of LOXO-305 on the PK of multiple oral doses of 
digoxin (P-gp substrate) in healthy subjects. 
On Day 1, subjects will be administered oral 0.25 mg digoxin twice daily (BID) (loading 
dose), once in the morning and evening. Subjects will be fasted for at least 2 hours predose 
and 1-hour postdose for the morning and evening dose. 
On Days 2 through 16, oral doses of 0.25 mg digoxin once daily (QD) will be administered 
(total of 17 consecutive doses) at the actual time of the Day 1 morning digoxin dose 
(± 1 hour). On Days 8 through 16 (9 consecutive doses), oral doses of 


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ST-AD-031 Version 02 
200 mg LOXO-305 QD will be coadministered with 0.25 mg digoxin QD, at the actual time 
of the Day 1 morning digoxin dose (± 1 hour). LOXO-305 will be administered first, 
immediately followed by digoxin. On Days 2, 4 through 6, 9 through 11, 13, and 14, subjects 
will fast for at least 2 hours predose and 1-hour postdose. On Days 3, 12, and 15 where 
clinical laboratory evaluations are performed, subjects will fast for at least 8 hours predose 
and 1-hour postdose. On Days 7, 8, and 16, subjects will be fasted at least 10 hours predose 
and 2 hours postdose. Blood and urine samples for concentrations of digoxin in plasma and 
urine and 
 
. Blood samples for concentrations of 
LOXO-305 and digoxin in plasma and 
 
 
 Urine samples for concentrations of 
digoxin and 
 
 
 
 
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 to receive a dose of study drug; this definition excludes screen failure 
subjects. Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 20 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. Dosing of digoxin will occur on Days 1 through 
16 and dosing of LOXO-305 will occur on Days 8 through 16. 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 58 days (Screening through follow-up phone call).  
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistry panel, coagulation parameters, hematology panel, 
urinalysis, safety monitoring of serum digoxin levels, and recording of concomitant 
medications will be performed at specified times during the study.  
The AEs and serious adverse events (SAEs) will be collected beginning at informed consent. 
The 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 
CCI
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CCI


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ST-AD-031 Version 02 
assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the 
event occurs after signing of the ICF but prior to study drug administration on Day 1 and is 
assessed as related to study procedures by the Investigator [or designee], or if the event 
occurs after study drug administration on Day 1 through EOT or ET regardless of relationship 
to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by 
the Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be reported.  
Study completion is defined as the time of the last subject’s follow-up phone call.   
A schematic of the study design is presented in Figure 1.  
Figure 1: Study Design  
 
BID = Twice daily; QD = Once daily; EOT=End of treatment; ET= Early termination 
5. SAMPLE SIZE JUSTIFICATION  
Up to 16 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 16 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.  
6. STUDY TREATMENTS  
The study treatment names and ordering to be used in the TFLs are presented in Table 1.  


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Table 1: 
Presentation of Study Treatments in Safety TFLs  
Study Treatment 
Order in TFLs 
0.25 mg Digoxin Alone 
1 
200 mg LOXO-305 QD + 0.25 mg digoxin QD 
2 
QD = once daily; TFL = table, figure, and listing. 
All TFLs will be based on actual treatments. 
Table 2 shows a list of the PK treatment labels and ordering that will be used in the TFLs.  
Table 2: 
Pharmacokinetic Treatment Labels 
Study Treatment Labels 
Order in TFLs 
0.25 mg Digoxin Alone 
1 
200 mg LOXO-305 Once  + 0.25 mg digoxin QD 
2 
200 mg LOXO-305 QD + 0.25 mg digoxin QD 
3 
QD = once daily; TFL = table, figure, and listing. 
The study treatment sequence names and ordering to be used in the TFLs are presented in 
Table 3.   
Table 3.  
Presentation of Study Treatment Sequences in TFLs 
Study Treatment Sequence 
Order in TFLs 
0.25 mg Digoxin BID (D1) / 0.25 mg Digoxin QD (D2-7) / 200 
mg LOXO-305 QD + 0.25 mg digoxin QD (D8-D16) 
1 
BID = twice daily; QD = once daily; TFL = table, figure, and listing. 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 8.1.1), 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 consist of all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will consist of all subjects who received at least 1 dose of study drug 
(digoxin and/or LOXO-305).   
7.3. Pharmacokinetic Population  
The PK population will consist of all subjects who received a dose of LOXO-305 or digoxin, 
have at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can 


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be computed. A subject may be excluded from the PK summary statistics and statistical 
analysis if the subject has an AE of vomiting that occurs at or before 2 times the median tmax. 
The impact of protocol deviations on the 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 EOS visit. Any 
subject who discontinues the study will be identified accordingly in the listings. Summaries 
and statistical analyses will include the subjects assigned to the relevant population based on 
data type.   
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued 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 a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if a new 
version is issued during the study). Pinnacle 21 Community Validator Version 3.1.0 (or 
higher if a new version is issued during the study) will be utilized to ensure compliance with 
CDISC standards.  
For all statistical analyses, the hypothesis testing will be 2-sided and carried out on 0.05 
significance level, unless specifically stated otherwise.  
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 ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation and changes from baseline.   
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognized potential for: 
● Missed visits, caused by, for example: 


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o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID-19 infections) 
● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access to 
source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country restrictions 
on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries 
At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorized into 2 analysis groups, with and without COVID-19 and related restrictions 
impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with Loxo Oncology, Inc. in advance and identified in the CSR.  
8.1.2. 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.   
● In general, as ET data are not associated with any scheduled timepoint, they will be 
excluded from all calculations of summary statistics and statistical analyses. Exceptions 
may be made where justified.  
● Postdose repeats and unscheduled assessments will not be included in calculations of 
summary statistics. 
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, AE severity), all categories between the possible 
minimum and maximum categories will be included, even if n = 0 for a given category.  


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● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters.  
8.1.3. Repeat and Unscheduled Readings  
For vital signs 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 parameters), any value recorded in addition to the original value will be defined as 
an unscheduled value.  
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value.  
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.4).  
8.1.4. Definitions of Baseline and Change from Baseline 
The baseline will be 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 the first dose.   
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint.   
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline).  
See Section 8.1.3 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 safety population.   


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8.3. Screening Demographics  
The screening demographics 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.  
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose.   
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2020 (or later if a new 
version is issued during the study; see the data management plan [DMP] for more details). 
Prior and concomitant medications will be listed.   
8.5. Pharmacokinetic Assessments   
8.5.1. Pharmacokinetic Analysis  
The following plasma PK parameters will be determined where possible from the plasma 
concentrations of LOXO-305 and digoxin using noncompartmental methods in validated 
software program Phoenix WinNonlin (Certara, Version 8.1 or higher): 
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 over a dosing intervalb 
(tau=24 hours) 
Cmax 
ng/mL 
maximum observed plasma concentration 
tmax 
H 
time to maximum observed plasma concentration 
CL/F 
L/h 
apparent systemic clearance  
MRTlast 
H 
mean residence time (based on AUC0-t) 
ARAUC 
NA 
accumulation ratio base on AUCtau (LOXO-305 only) 
NA  Not applicable 
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  
For each subject, the following urine PK parameters will be calculated, whenever possible, 
based on the urine concentrations of digoxin: 
Parameter 
Unitsa 
Definition 
Ae 
mg 
amount excreted in urine per sampling interval (t1-t2) 
CLR 
L/h 
renal clearance  


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%feu 
% 
percentage of dose excreted in urine per sampling interval (t1-t2), 
where 
 
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. 
Additional PK parameters may be determined where appropriate, e.g. terminal elimination 
half-life (t1/2) after last dose (Day 16) with sample collections up to 96 hours postdose. 
The 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 following will be reported only if t1/2 is calculable. The start of the terminal elimination 
phase for each subject will be defined by the pharmacokinetic software and confirmed 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) and its associated half-life (t1/2) 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. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
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 
NA = Not applicable. 
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. 
CCI


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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 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.  
8.5.1.3. Calculation of Urinary Parameters 
The amount of the dose administered recovered (Ae) in urine for digoxin urine collection 
interval (t1-t2) will be calculated as the product of urine concentration and urine volume. 
 
 A total cumulative Ae0-x h will be 
calculated by summing the Aet1-t2 values over the 0-x h interval, where x = end of the last 
collection time interval. 
The percentage of the administered dose for digoxin recovered over the time interval t1 to t2 
(Fet1-t2) will be calculated for each urine collection interval as follows: 
Cumulative fe0-x h will be calculated by summing the fet1-t2 values over the 0-x h period in the 
same manner as Ae0-x h. 
Renal clearance (CLR) will be calculated over 0-t according to the following formula, where 
cumulative Ae and AUC are calculable to the same end time (t): 
8.5.1.4. 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 predose plasma concentration is missing, it may be set to the concentration value at 
24 hours postdose after repeated QD doses. 
Urine concentrations that are BLQ will be set to 0 for the calculation of Aet1-t2. 
CCI
CCI
CCI


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8.5.1.5. 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 will be considered anomalous and set to 
missing for the PK analysis. 
8.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed.  
Summary tables, arithmetic 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-linear and 
linear-logarithmic scales, with the exception of figures across all days, which will be 
produced on the linear-linear scale only. The +SD bars will only be displayed on the 
linear-linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV, 
minimum, median, maximum, geometric mean [Geom Mean] and geometric CV [Geom CV] 
will be calculated for plasma and urine LOXO-305 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.   
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax.   
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For plasma PK concentration data the following rules will apply: 
● 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 
and coefficient of variation (CV) of geometric mean will be reported as not calculated 
(NC). 
Urine concentration data will be listed only. 
For PK parameters the following rule will apply: 
● For the calculation of summary statistics of PK parameters, all not reported (NR) and 
NC values in a data series will be set to missing. 


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● The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
● Geometric mean and CV will not be calculated for tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
A statistical analysis will be conducted to investigate the drug-drug interaction on the PK of 
the following comparisons: 
Plasma PK only 
 Multiple doses of digoxin coadministered with a single dose of LOXO-305 versus 
multiple doses of digoxin alone.  
Plasma and urine PK  
 Multiple doses of digoxin coadministered with multiple doses of LOXO-305 versus 
multiple doses of digoxin alone.  
The natural log-transformed4 PK parameters (AUC0-t, AUCtau, Cmax,Ae0-x h and CLR) will be 
analyzed using a mixed effect model.5 The model will include actual treatment as a 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.  
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.  
An example of the SAS code that will be used are as follows: 
Mixed Model Analysis  
proc mixed data = <data in>; 
  by parcat1n parcat1 pkday paramn param; 
  class trtan usubjid; 
  model lpk = trtan / cl residual ddfm = kr2; 
  lsmeans trtan / 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>; 


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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 23.0 (or higher if a new version is issued during the study). All AEs will be assigned 
a severity grade using National Cancer Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 (or higher if a new version is issued during the study).   
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, 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 (LOXO-305 and digoxin), as determined by the investigator.  
The assignment of TEAEs to treatments will be as follows:  
● A TEAE occurring during or after Day 1 dosing will be assigned to 
0.25 mg digoxin alone. 
● A TEAE occurring during or after Day 8 dosing of LOXO-305 will be assigned to 
200 mg LOXO-305 QD + 0.25 mg digoxin QD. 
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 associated dose for TEAEs only. Where the last associated dose is referring to the last 
dose received prior to the start of a TEAE.   
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  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  


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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 a subject experienced multiple TEAEs 
with the same preferred term for the same treatment, this will be counted as 1 TEAE 
for that treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters and their 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.  
Summary tables by treatment and timepoint will be provided for clinical chemistry, 
hematology, and coagulation parameters, and their changes from baseline, as applicable.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, <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 and their changes from baseline will be listed, as applicable; 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.   


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Summary tables by treatment and timepoint will be provided for all vital signs parameters 
and their changes from baseline, as applicable.   
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters and their 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.  
Summary tables by treatment and timepoint will be provided for all 12-lead ECG parameters, 
along with their changes from baseline.  
QT interval corrected for heart rate using Fridericia’s formula (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, physical examination and digoxin concentrations will be listed. Any 
physical examination abnormalities reported and abnormal digoxin concentrations 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.  
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
The primary endpoint “area under the concentration-time curve from hour 0 to 24 hours 
(AUC0-24)” has been removed as this is a repeat of the following primary endpoint “area 
under the concentration-time curve over a dosing interval (AUCtau)” since for this study tau is 
equal to 24 hours. 


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11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
4. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. 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 and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable 


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