Clinical trial NCT06180954
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-09-23; Completion date: 2020-11-06
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the absorption, metabolism, and excretion (AME) profiles of pirtobrutinib (LOXO-305), to identify and characterize metabolites of pirtobrutinib (LOXO-305), and to assess the safety and tolerability of \[14C\] LOXO-305 in Part 1. To determine the absolute bioavailability of pirtobrutinib (LOXO-305), to evaluate the plasma concentration of total radioactivity, to evaluate the urinary excretion of \[14C\] LOXO-305 and total radioactivity, to evaluate the fecal excretion of \[14C\] LOXO-305 and total radioactivity, and to assess the safety and tolerability of pirtobrutinib (LOXO-305), and \[14C\] LOXO-305 in Part 2. Blood tests will be performed to check how much pirtobrutinib (LOXO-305) and \[14C\] LOXO-305 gets into the bloodstream and how long it takes the body to eliminate it.

The study will last up to approximately 60 days for Part 1 and approximately 47 days for Part 2.

Detailed description:

Arms: arm 1: Participants received a single dose of 200 milligram (mg) LOXO-305 radiolabelled with carbon-14, i.e., \[14C\]-LOXO-305 (approximately 200 microcurie radioactivity) administered as an oral solution. arm 2: Participants received:

a single dose of 200 mg LOXO-305 administered as 2×100 mg oral tablets followed 2 hours later by a single dose of less than 100 microgram (μg) of \[14C\]-LOXO-305 (approximately 1 microcurie radioactivity) administered as an intravenous (IV) push over approximately 2 minutes.
Interventions: intervention 1: [14C]-LOXO-305 intervention 2: LOXO-305 intervention 3: [14C]-LOXO-305
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered IV

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Protocol: LOXO-BTK-20007 (Final version 1.0) 
 
 
A Phase I, Open-label, Two-part Study of the Absorption, Metabolism, 
Excretion, and the Absolute Bioavailability of [14C]-LOXO-305 in Healthy 
Male Subjects  
 
 
NCT06180954 
 
 
Approval Date: 29-June-2020 


TITLE PAGE 
Protocol 
A Phase I, Open-label, Two-part Study of the Absorption, Metabolism, 
Excretion, and the Absolute Bioavailability of [14C]-LOXO-305 in Healthy 
Male Subjects 
Protocol Status: Final 
Protocol Date: 29 June 2020 
Protocol Version: 1.0 
Investigational Medicinal Product: LOXO-305 
 
Protocol Reference Number: LOXO-BTK-20007 
Covance Study Number: 8419667 
IND Number: 139876 
 
 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
 
 
Sponsor Signatory: 
 
Principal Investigator: 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
PPD
PPD


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 2 of 69 
PPD


PPD


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 4 of 69 
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): (650) 989-8051 
Sponsor’s Study Contact 
Sponsor’s Medical Contact  
Serious Adverse Event (SAE) 
Reporting 
Email: SAEIntake@covance.com 
Study Site 
Covance Clinical Research Unit, Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
Principal Investigator 
Sub-investigator(s) 
Obtain information from Form FDA 1572 
Clinical Laboratory 
Meriter Laboratories 
36 South Brooks Street 
Madison, WI 53715 
USA 
Bioanalytical Laboratory  
 
Alturas Analytics, Inc. 
1324 Alturas Drive 
Moscow, Idaho 83843 
USA 
PPD
PPD
PPD


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 5 of 69 
Radioanalytical Laboratory (Part 1) 
Covance Laboratories 
3301 Kinsman Boulevard 
Madison, WI 53704 
USA 
Radioanalytical Laboratory and 
Accelerator Mass Spectrometry 
Laboratory (Part 2) 
Pharmaron ABS 
20340 Seneca Meadows Parkway 
Germantown, Maryland 20876 
USA 
Metabolite Profiling and 
Identification (Part 1) 
Q2 Solutions  
5225 Exploration Drive 
Indianapolis IN 46241 
USA 
Radiation Safety Officer  
Statistician 
 
Protocol Medical Writer 
PPD
PPD
PPD


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 6 of 69 
SYNOPSIS 
Study Title 
A Phase I, Open-label, Two-part Study of the Absorption, Metabolism, Excretion, and the 
Absolute Bioavailability of [14C]-LOXO-305 in Healthy Male Subjects 
Objectives 
Part 1: 
The primary objectives of Part 1 of the study are: 
• to determine the mass balance and routes of elimination of [14C]-LOXO-305 
following oral administration of a single dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) in healthy male subjects 
• to assess the pharmacokinetics (PK) of LOXO-305 following a single oral dose of 
[14C]-LOXO-305 
• to determine the whole blood and plasma concentrations of total radioactivity 
following a single oral dose of [14C]-LOXO-305 
• to determine urinary and fecal recovery of total radioactivity following a single oral 
dose of [14C]-LOXO-305 
• to characterize and identify metabolites of LOXO-305 in plasma, urine, and feces 
following a single oral dose of [14C]-LOXO-305. 
Part 2: 
The primary objectives of Part 2 of the study are: 
• to determine the absolute bioavailability of LOXO-305 following a single oral dose of 
200 mg LOXO-305 along with an intravenous (IV) dose of < 100 µg of 
[14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) 
• to evaluate the PK of LOXO-305 and [14C]-LOXO-305 following oral dosing of 
LOXO-305 and IV dosing of [14C]-LOXO-305 
• to evaluate the plasma concentration of total radioactivity following IV dosing of 
[14C]-LOXO-305 
• to evaluate the urinary excretion of [14C]-LOXO-305 and total radioactivity following 
IV dosing of [14C]-LOXO-305 
• to evaluate the fecal recovery of [14C]-LOXO-305 and total radioactivity following IV 
dosing of [14C]-LOXO-305. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 7 of 69 
Part 1: 
The secondary objective of Part 1 of the study is: 
• to assess the safety and tolerability of [14C]-LOXO-305 when administered to healthy 
male subjects. 
Part 2: 
The secondary objective of Part 2 of the study is: 
• to assess the safety and tolerability of LOXO-305 and [14C]-LOXO-305 when 
administered to healthy male subjects. 
Study design 
This study will be an open-label, 2-part, absorption, metabolism, excretion (AME) and 
absolute bioavailability study of [14C]-LOXO-305. Subjects in Part 1 will not participate in 
Part 2, nor will subjects in Part 2 participate in Part 1. Part 1 and Part 2 are independent of 
each other and do not need to be conducted in sequential order. 
Part 1 is designed to evaluate the AME profiles of LOXO-305, to identify and characterize 
metabolites of LOXO-305, and to assess the safety and tolerability of [14C]-LOXO-305. 
Subjects in Part 1 will be administered a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution.  
Part 2 is designed to determine the absolute bioavailability of LOXO-305, to evaluate the 
plasma concentration of total radioactivity, to evaluate the urinary excretion of 
[14C]-LOXO-305 and total radioactivity, to evaluate the fecal excretion of [14C]-LOXO-305 
and total radioactivity, and to assess the safety and tolerability of LOXO-305 and 
[14C]-LOXO-305. Subjects in Part 2 will be administered 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 
push over approximately 2 minutes.  
Six subjects will participate in each part of the study, such that a total of 12 subjects will be 
evaluated in the study. Each subject will participate in either Part 1 or Part 2, but not both. In 
the event of early withdrawal of any subjects and/or in order to ensure 6 subjects complete 
each part of the study, replacement subjects may be enrolled at the discretion of the Sponsor.  
The start of the study is defined as the earliest date a subject who is enrolled in either part of 
the study signs an Informed Consent Form (ICF). Note that enrolled subjects are defined as 
those subjects who are assigned a dose of study drug; this definition excludes screen failure 
subjects. A subject who completes sufficient total radioactivity recovery and metabolite 
sample collection (Part 1 only), or LOXO-305 and [14C]-LOXO-305 (Part 2 only) sampling 
prior to Clinic Discharge is considered to have completed the study. The end of the study is 
defined as the latest date a subject receives the Follow-up Call. The planned duration of study 
conduct for Part 1 is up to 60 days from Screening through the Follow-up Call. The planned 
duration of study conduct for Part 2 is up to 47 days from Screening through the Follow-up 
Call. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 8 of 69 
Part 1: 
After a Screening period of up to 28 days, subjects will check in to the Clinical Research Unit 
(CRU) on Day -1 to confirm eligibility and to become familiar with study procedures. On the 
morning of Day 1, following an overnight fast of at least 10 hours, subjects will receive a 
single oral dose of 200 mg of [14C]-LOXO-305 (containing ~200 µCi) administered as an oral 
solution. Subjects will be confined at the CRU from the time of Check-in (Day -1) until 
Clinic Discharge (between Days 12 and 22). After completing discharge procedures, subjects 
will be discharged from the CRU as early as Day 12 and up to Day 22, provided recovery of 
radioactivity has reached the following threshold values: 
• Plasma radioactivity below the limit of quantification for 2 consecutive collections, 
and 
• ≥ 90% of the radioactive dose is recovered, and  
• ≤ 1% of the radioactive dose per day is recovered in excreta (urine and feces) for 
3 consecutive days on which a fecal sample is collected.   
Sample collection and CRU confinement will continue until discharge criteria are met or the 
maximum stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or 
designee). Subjects will receive a Safety Follow-up Call approximately 7 days after Clinic 
Discharge. 
Samples for determination of LOXO-305 concentrations in plasma, total radioactivity 
concentrations in plasma, whole blood, urine, and feces, and for metabolite 
profiling/characterization will be obtained through at least 264 hours postdose (Day 12), and 
possibly up to 504 hours postdose (Day 22). 
Part 2: 
After a Screening period of up to 28 days, subjects will check in to the CRU on Day -1 to 
confirm eligibility and to become familiar with study procedures. On the morning of Day 1, 
following an overnight fast of at least 10 hours, subjects will receive a single oral dose of 
200 mg of LOXO-305 as 2 × 100-mg tablets and 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 push over approximately 2 minutes. Subjects will be confined at the CRU from the 
time of Check-in (Day -1) until Day 9 and will be discharged from the CRU after completing 
all discharge procedures. Subjects will receive a Follow-up Call approximately 7 days after 
Clinic Discharge. 
Samples for determination of LOXO-305 in plasma, and [14C]-LOXO-305 and total 
radioactivity concentrations in plasma, urine, and feces will be obtained through 192 hours 
postdose (Day 9). 
Both Parts: 
In this study, physical examinations, 12-lead electrocardiograms (ECGs), vital sign 
measurements, How Do You Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation 
parameters, hematology panel, urinalysis (UA; Appendix 2) and recording of concomitant 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 9 of 69 
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 AEs 
(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 Early 
Termination [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 End of Treatment [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. 
Number of subjects 
Six subjects will participate in each part of the study. Each subject will participate in either 
Part 1 or Part 2, but not both. 
In Parts 1 and 2, in the event of early withdrawal of any subjects, and/or to ensure 6 subjects 
complete each part of the study, replacement subjects may be enrolled at the discretion of the 
Sponsor. 
Diagnosis and main criteria for inclusion 
Healthy male subjects between 18 and 55 years of age, inclusive, with a body mass index of 
18.5 to 32.0 kg/m2, inclusive, at Screening. Subjects will be in good general health, based on 
medical history, physical examination findings, vital sign measurements, 12-lead ECG, or 
clinical laboratory evaluations at Screening and/or Check-in (Day -1), as determined by the 
Investigator (or designee). 
Investigational medicinal products, dose, and mode of administration 
Part 1: Subjects will receive a single oral dose of 200 mg of [14C]-LOXO-305 (containing 
~200 µCi) as an oral solution following an overnight fast of at least 10 hours. 
Part 2: Following an overnight fast of at least 10 hours, subjects will receive a single oral 
dose of 200 mg of 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 radioactivity [microtracer]) administered 
as an IV push over approximately 2 minutes. 
Duration of subject participation in the study 
Planned Enrollment/Screening Duration:   
• Part 1; approximately 28 days (Days -29 to -2).  


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 10 of 69 
• Part 2; approximately 28 days (Days -29 to -2).   
Length of CRU Confinement:   
• Part 1; up to 23 days (Days -1 to 22). 
• Part 2; 10 days (Days -1 to 9).   
Planned Study Conduct Duration:  
• Part 1; up to 60 days (Screening to Safety Follow-up Call).  
• Part 2; up to 47 days (Screening to Safety Follow-up Call). 
Endpoints 
Pharmacokinetics: 
Part 1: 
Whenever possible, the following PK parameters will be calculated based on the plasma 
concentrations of LOXO-305 and on plasma and whole blood concentrations of total 
radioactivity: maximum observed concentration (Cmax), time to maximum observed 
concentration (Tmax), area under the concentration-time curve (AUC) from hour 0 to the last 
measurable concentration (AUC0-t), AUC from time 0 extrapolated to infinity (AUC0-inf), 
apparent terminal elimination half-life (t1/2), apparent systemic clearance (CL/F; for LOXO-
305 only), apparent volume of distribution during the terminal phase (Vz/F; for LOXO-305 
only), AUC0-inf of total radioactivity in whole blood/AUC0-inf of total radioactivity in plasma 
(Blood/Plasma AUC Ratio), and AUC0-inf of LOXO-305 in plasma/AUC0-inf of total 
radioactivity in plasma (Plasma LOXO-305/Total Radioactivity AUC Ratio). 
Whenever possible, the following PK parameters will be calculated based on the urine 
concentrations of total radioactivity: amount excreted in urine per sampling interval (Aeu), 
cumulative amount excreted in urine (cumulative Aeu), percentage of dose excreted in urine 
per sampling interval (feu), and cumulative percentage of dose excreted in urine (cumulative 
feu). 
Whenever possible, the following PK parameters will be calculated based on the fecal 
concentrations of total radioactivity: amount excreted in feces per sampling interval (Aef), 
cumulative amount excreted in feces (cumulative Aef), percentage of dose excreted in feces 
per sampling interval (fef), and cumulative percentage of dose excreted in feces 
(cumulative fef). 
In Part 1, the PK parameters for relevant metabolites of LOXO-305 may be calculated, as 
deemed appropriate, based on plasma, urine, and fecal concentration levels. 
Part 2: 
Following oral dosing of LOXO-305, whenever possible, the following PK parameters will 
be calculated based on the plasma concentrations of LOXO-305 and total radioactivity: Cmax, 
Tmax, AUC0-t, AUC0-inf, apparent terminal elimination rate constant (λz), t1/2, absolute 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 11 of 69 
bioavailability (F; for LOXO-305 only), CL/F (for LOXO-305 only), and Vz/F (for LOXO-
305 only). 
Following IV microtracer dosing of [14C]-LOXO-305 (containing ~1 µCi of radioactivity), 
whenever possible, the following PK parameters will be calculated based on the plasma 
concentrations of [14C]-LOXO-305: Cmax, Tmax, AUC0-t, AUC0-inf, t1/2, total clearance (CL), 
volume of distribution during the terminal phase (Vz), and volume of distribution at steady 
state (Vss).  
Whenever possible, the following PK parameters will be calculated for each subject based on 
the urine concentrations of [14C]-LOXO-305 and total radioactivity following IV dosing of 
[14C]-LOXO-305: Aeu, cumulative Aeu, renal clearance (CLR; [14C]-LOXO-305 only), feu, and 
cumulative feu. 
Whenever possible, the following PK parameters will be calculated for each subject based on 
the fecal concentrations of [14C]-LOXO-305 and total radioactivity following IV dosing of 
[14C]-LOXO-305: Aef, cumulative Aef, fef, and cumulative fef. 
Safety: 
Safety will be monitored with AE inquiries, clinical laboratory evaluations, vital sign 
measurements, ECGs, and physical examinations. 
Statistical methods 
For Parts 1 and 2, descriptive statistics (number of observations, arithmetic mean, standard 
deviation, coefficient of variation (CV%), median, minimum, maximum, geometric mean, 
and geometric coefficient of variation) will be calculated for the PK parameters. No formal 
statistical PK analyses are planned. For Parts 1 and 2, descriptive statistics will be calculated 
on the safety parameters. No formal statistical safety analyses are planned. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 12 of 69 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF TABLES AND FIGURES........................................................................................15 
LIST OF ABBREVIATIONS ..................................................................................................16 
1. 
INTRODUCTION ...........................................................................................................19 
1.1. 
Background ............................................................................................................19 
1.2. 
Non-clinical Pharmacokinetics ..............................................................................19 
1.3. 
Summary of Clinical Experience ...........................................................................20 
1.3.1. 
Safety ...........................................................................................................21 
1.3.2. 
Pharmacokinetics .........................................................................................21 
1.4. 
Study Rationale ......................................................................................................24 
1.5. 
Risk Assessment ....................................................................................................24 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................25 
2.1. 
Objectives ..............................................................................................................25 
2.1.1. 
Primary Objectives .......................................................................................25 
2.1.2. 
Secondary Objectives ...................................................................................26 
2.2. 
Endpoints ...............................................................................................................26 
2.2.1. 
Primary Endpoints .......................................................................................26 
2.2.2. 
Secondary Endpoints ...................................................................................27 
3. 
INVESTIGATIONAL PLAN ..........................................................................................28 
3.1. 
Overall Study Design and Plan ..............................................................................28 
3.2. 
Discussion of Study Design ...................................................................................31 
3.3. 
Selection of Doses in the Study .............................................................................31 
4. 
SELECTION OF STUDY POPULATION .....................................................................32 
4.1. 
Screening Procedures .............................................................................................32 
4.2. 
Check-in Procedures (Day -1) ...............................................................................33 
4.3. 
Inclusion Criteria ...................................................................................................34 
4.4. 
Exclusion Criteria ..................................................................................................35 
4.5. 
Subject Number and Identification ........................................................................38 
4.6. 
Removal of Subjects from Study Participation ......................................................39 
5. 
STUDY TREATMENTS .................................................................................................39 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................39 
5.2. 
Study Treatment Administration ............................................................................40 
5.3. 
Randomization .......................................................................................................41 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 13 of 69 
5.4. 
Blinding..................................................................................................................41 
5.5. 
Treatment Compliance ...........................................................................................41 
5.6. 
Drug Accountability...............................................................................................41 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................42 
6.1. 
Concomitant Therapies ..........................................................................................42 
6.2. 
Diet, Fluid, and Activity Control ...........................................................................42 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................43 
7.1. 
Pharmacokinetic Assessments ...............................................................................43 
7.1.1. 
Pharmacokinetic, Total Radioactivity, and Metabolite Profiling Blood 
Sample Collection and Processing ...............................................................43 
7.1.2. 
Pharmacokinetic, Total Radioactivity, and Metabolite Profiling Urine 
and Feces Collection and Processing ...........................................................43 
7.1.3. 
Vomitus Sample Collection .........................................................................44 
7.1.4. 
Analytical Methodology ..............................................................................44 
7.2. 
Safety and Tolerability Assessments .....................................................................44 
7.2.1. 
Adverse Events ............................................................................................44 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................45 
7.2.3. 
Vital Signs ....................................................................................................46 
7.2.4. 
12-Lead Electrocardiogram .........................................................................46 
7.2.5. 
Physical Examination...................................................................................46 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................47 
8.1. 
Determination of Sample Size ...............................................................................47 
8.2. 
Analysis Populations ..............................................................................................47 
8.2.1. 
Pharmacokinetic Population ........................................................................47 
8.2.2. 
Safety Population .........................................................................................47 
8.3. 
Pharmacokinetic Analyses .....................................................................................47 
8.3.1. 
Descriptive Analysis ....................................................................................50 
8.3.2. 
Statistical Methodology ...............................................................................50 
8.4. 
Safety Analysis ......................................................................................................50 
8.5. 
Data Handling and Record Keeping ......................................................................51 
8.6. 
Quality Control and Quality Assurance .................................................................51 
9. 
ADMINSTRATIVE ASPECTS.......................................................................................51 
9.1. 
Change in Protocol .................................................................................................51 
9.2. 
Site Initiation Visit/Investigator Meeting ..............................................................52 
9.3. 
Disclosure ..............................................................................................................52 
9.4. 
Monitoring .............................................................................................................52 
9.5. 
Institutional Review Board ....................................................................................52 
9.6. 
Informed Consent...................................................................................................53 
9.7. 
Records ..................................................................................................................53 
9.8. 
Reference to Declaration of Helsinki/Basic Principles ..........................................53 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 14 of 69 
9.9. 
Financing and Insurance ........................................................................................53 
10. REFERENCES ................................................................................................................54 
11. APPENDICES .................................................................................................................56 
Appendix 1: Adverse Event Reporting ..............................................................................57 
Appendix 2: Clinical Laboratory Evaluations ...................................................................60 
Appendix 3: Total Blood Volume ......................................................................................61 
Appendix 4: Schedule of Assessments ..............................................................................62 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 15 of 69 
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)..............................................................22 
Table 2 Supplied Study Drugs: Part 1 ................................................................................40 
Table 3 Supplied Study Drugs: Part 2 ................................................................................40 
Figure 1 Arithmetic Mean (±SD) Plasma Concentration of LOXO-305 Following 
Daily Oral Administrations on Day 1 (top panel) and Day 8 (bottom panel) of 
Cycle 1 in Cancer Patients ...........................................................................................23 
Figure 2 Study Design Schematic: Part 1 ..........................................................................29 
Figure 3 Study Design Schematic: Part 2 ..........................................................................29 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 16 of 69 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ADL 
Activities of Daily Living 
Aef 
amount excreted in feces 
Aeu 
amount excreted in urine 
ALARA 
as low as (is) reasonably achievable 
AME 
absorption, metabolism, and excretion 
AMS 
accelerator mass spectrometry 
API 
active pharmaceutical ingredient 
ATP 
adenosine triphosphate 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-inf Blood/ 
Plasma Ratio 
area under the concentration-time curve from time 0 extrapolated to 
infinity of whole blood total radioactivity to area under the 
concentration-time curve from time 0 extrapolated to infinity of 
plasma total radioactivity 
AUC0-inf Plasma 
LOXO-305/Total 
Radioactivity Ratio 
area under the concentration-time curve from time 0 extrapolated to 
infinity of plasma LOXO-305 relative to area under the 
concentration-time curve from time 0 extrapolated to infinity of 
plasma total radioactivity 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
AV 
atrioventricular 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BTK 
Bruton’s tyrosine kinase 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
total clearance  
CL/F 
apparent systemic clearance 
CLL 
chronic lymphocytic leukemia 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
COVID-19 
SARS-CoV-2 
CRU 
Clinical Research Unit 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
CV 
coefficient of variation 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 17 of 69 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
F 
absolute bioavailability  
FDA 
Food and Drug Administration 
fef 
percentage of dose excreted in feces 
feu 
percentage of dose excreted in urine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC90 
concentration required for 90% inhibition 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
LSC 
liquid scintillation counting 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHL 
non-Hodgkin lymphoma 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RSI 
Reference Safety Information 
SAE 
serious adverse event 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 18 of 69 
SAP 
Statistical Analysis Plan 
SDD 
spray-dried dispersion 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
tables, figures, and listings 
tmax 
time to maximum observed concentration 
TSH 
thyroid-stimulating hormone 
UA 
urinalysis  
US 
United States 
Vss 
volume of distribution at steady state  
Vz 
volume of distribution  
Vz/F  
apparent volume of distribution 
 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 19 of 69 
1. INTRODUCTION 
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product (IMP).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 ADME properties, and non-covalent 
binding mode.2 These features enable LOXO-305 to achieve pharmacokinetic (PK) exposures 
that exceed the BTK concentration required for 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, 
with more than 300-fold more selective for BTK versus 370 other kinases tested and no 
significant inhibition of non-kinase off-targets at 1 μM, thus limiting the potential for off-
target mediated toxicities. Collectively, these unique properties of LOXO-305 are expected to 
deliver more potent, continuous, and selective inhibition of BTK in a variety of settings, 
potentially resulting in increased efficacy. Of note, the activity of LOXO-305 in diverse 
preclinical model systems supports this underlying hypothesis.2 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate 
binding site of the BTK kinase competitively, with no evidence of irreversible binding.  
1.2. 
Non-clinical Pharmacokinetics 
LOXO-305 had high permeability in vitro, but low aqueous solubility. To reduce the 
variability in oral absorption, a spray-dried dispersion (SDD) tablet formulation was 
developed that showed consistent oral bioavailability of approximately 50% in rats and 80% 
in dogs. The bioavailability of the SDD formulation was also not dependent on feeding state 
in dogs. 
As is common in rodents, oral exposure of LOXO-305 was consistently much higher in 
female rats than in males given the same dose of LOXO-305. The sex difference was also 
apparent after intravenous (IV) administration of LOXO-305. There was no difference in the 
PK of LOXO-305 between sexes of dog, and none is expected in other non-rodent species, 
including humans.  
The volume of distribution (Vz) of LOXO-305 ranged from approximately 2 L/kg in the dog 
to 5 L/kg in the male rat, which indicates that LOXO-305 distributes into tissues. LOXO-305 
had protein binding of approximately 95% in human plasma. A somewhat lower extent of 
binding (approximately 82% to 92%) was observed across mouse, rat, rabbit, and dog. 
LOXO-305 was metabolized slowly by human microsomal fractions and hepatocytes. The 
low rates of metabolism in both these human in vitro systems suggest that LOXO-305 will 
have low clearance in humans. In vitro data with cloned expressed cytochrome P450 (CYP) 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 20 of 69 
enzymes and human liver microsomes indicate that CYP3A4 is the primary CYP enzyme that 
metabolizes LOXO-305. It is also a substrate for direct glucuronidation. 
In long-term hepatocyte incubations, LOXO-305 was metabolized by both oxidation and 
glucuronidation. Inhibition of oxidative metabolism by addition of the P450 inhibitor 
1-aminobenzotriazole showed that oxidative metabolism is CYP dependent. All metabolites 
formed by human hepatocytes were also formed in rat and/or dog hepatocytes supporting the 
use of rat and dog for nonclinical safety assessment. 
Renal clearance of LOXO-305 in male and female rats was negligible. No data on renal 
clearance are available in other species; however, the renal excretion pathway is often 
conserved across species, and therefore no renal clearance would be expected in humans. 
In a Good Laboratory Practice (GLP) in vitro assay for human ether-à-go-go-related gene 
(hERG) activity, the concentration resulting in 50% inhibition for the inhibitory effects of 
LOXO-305 on hERG potassium currents was 32 μM, which is approximately 50-fold 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 dog. The Cmax for this dose was 10000 ng/mL, which is approximately 1.6-fold 
above the predicted Cmax plasma LOXO-305 concentration (6430 ng/mL) at the proposed 
clinical starting dose of 200 mg QD. Furthermore, there were no LOXO-305-related 
abnormalities in rhythm or waveform morphology in the GLP 28-day repeated-dose toxicity 
study in dogs at the low and mid-dose groups based on comparison of predose and postdose 
ECG recordings. The high dose (90/60 mg/kg/dose twice daily [BID]) was not evaluated as 
animals in this group were moribund/debilitated and were terminated on Day 13. Mean QTc 
interval was statistically significantly prolonged (+6%; +15 msec) on Day 26 of the dosing 
phase in males administered 30/10 mg/kg/dose BID compared with controls. The 
prolongation in QTc 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 30/10 mg/kg/dose BID.  
1.3. 
Summary of Clinical Experience 
LOXO-305 is currently being studied in an ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (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. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 21 of 69 
As of 09 April 2020, safety data were available from 172 treated patients, with 300 mg QD as 
the highest dose administered (Section 1.3.1). As of 30 March 2020 (data cutoff date), PK 
data were available from 107 patients (Section 1.3.2). 
1.3.1. 
Safety 
As of 09 April 2020, 172 patients were treated in the first-in-human study 
(LOXO-BTK-18001) and received LOXO-305 at doses ranging from 25 mg QD to 300 mg 
QD. A full summary of treatment-emergent adverse events (TEAEs) for patients in this study 
is provided in the LOXO-305 IB and the Investigator is directed to the safety information 
described in that document.1  
Overall, TEAEs were reported in 123 of 172 treated patients in the safety population and 
were mild or moderate severity (Grade 1 or 2) in 89 of 123 (51.7%) patients and were 
Grade 3 or 4 in severity in 33 of 123 (19.2%) patients. The most frequently reported TEAEs 
occurring in ≥10% of patients were fatigue (12.8% total, 7.0% related) and diarrhea (10.5% 
total, 6.4% related). The most frequently reported drug-related TEAEs (those in > 5% of 
patients) were fatigue (7.0%), diarrhea (6.4%), and contusion (5.2%). All other drug-related 
TEAEs occurred in < 5% of patients each. The most frequently reported Grade ≥ 3 TEAEs 
included neutropenia (4.1% total; 2.9% related), neutrophil count decreased (2.3% total; 1.2% 
related), anemia (1.7% total; 0.6% related), fatigue and platelet count decreased (each 1.2% 
total; each 0.6% related), and hypokalemia (1.2% total; none related).  
Five patients (2.9% of all 172 patients treated) discontinued LOXO-305 because of TEAEs; 
2 of the 5 patients (1.2% of all patients treated) discontinued LOXO-305 because of a 
treatment-related event. One of these patients with mantle cell lymphoma treated in the 
100 mg QD group discontinued due to Grade 3 leukocytosis considered related to study drug. 
Study therapy was held for resolution of leukocytosis and the patient subsequently progressed 
and study therapy was not resumed; the event of leukocytosis was recorded as 
recovered/resolved. The second patient treated in the 150 mg QD group discontinued due to 
Grade 2 myalgia; the myalgia was ongoing. The patient had previously received ibrutinib 
which was discontinued after 3 months of treatment for AEs. 
A total of 5 deaths have been reported for patients treated in this study, LOXO-BTK-18001. 
No deaths were considered related to LOXO-305. 
1.3.2. 
Pharmacokinetics 
As of 30 March 2020, PK data were available from 107 patients enrolled in 
LOXO-BTK-18001. Steady-state PK parameters of LOXO-305 in these cancer patients could 
be derived from data collected on Cycle 1 Day 8 and are shown in Table 1. These data show 
that LOXO-305 is absorbed after oral administration with a median time of maximal 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 the Cycle 1, 
Day 8 predose sample, leading to an estimated plasma half-life of approximately 20 hours. 
Following administration of doses of 100 mg QD higher, mean trough plasma levels of 
LOXO-305 exceeded the concentration required for 90% inhibition (IC90 = 825 ng/mL) of 
BTK in vitro (Figure 1). 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 22 of 69 
Table 1 Pharmacokinetic Parameters of LOXO-305 in Cancer Patients (Study LOXO-
BTK-18001) at Steady State (Cycle 1 Day 8)  
CCI


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 23 of 69 
Figure 1 Arithmetic Mean (±SD) Plasma Concentration of LOXO-305 Following Daily 
Oral Administrations on Day 1 (top panel) and Day 8 (bottom panel) of Cycle 
1 in Cancer Patients 
CCI


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 24 of 69 
1.4. 
Study Rationale 
The purpose of Part 1 of this study is to determine the absorption, metabolism, and excretion 
(AME) of [14C]-LOXO-305 and to characterize and determine the metabolites present in 
plasma, urine, and, where possible, feces in healthy male subjects following a single oral 
administration. Knowledge of the metabolism and excretion of parent drug and its 
metabolites is useful for evaluating the Metabolites in Safety Testing requirements elucidated 
in the Food and Drug Administration (FDA) Guidance9 and International Conference on 
Harmonisation M310 and the likelihood of effects of renal or hepatic impairment on the 
disposition of LOXO-305 and the likelihood for drug-drug interactions with LOXO-305. The 
results from this study may guide future study designs using special populations or evaluating 
the potential for drug-drug interactions. 
The purpose of Part 2 of this study is to determine the absolute bioavailability of LOXO-305 
in a tablet formulation in humans using an IV microtracer of [14C]-LOXO-305 (containing 
~1 µCi radioactivity). Absolute bioavailability information will aid in the planning and 
design of future studies and may be used to interpret PK data from these studies. 
1.5. 
Risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfort from collection of blood samples and other study procedures. The 
dose of LOXO-305 administered in this study is not anticipated to induce any potential risk to 
subjects participating in this study as it is a single dose which does not exceed the highest 
dose safely administered in first-in-human studies.1 More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with LOXO-305 may be 
found in the IB.1 
For Part 1, the planned radioactive dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) is expected to provide a sufficient radioactive signal to achieve the 
study objectives with minimal radiation risk to subjects. Based on the dosimetry analysis in 
pigmented rats, the overall whole-body radiation dose in a male subject after administration 
of a single 100-µCi (3.7-MBq) oral dose of [14C]-LOXO-305 was calculated to be 120 mrem 
(1.2 mSv) when using allometric conversion.11 This value is well below the FDA exposure 
limit of 3000 mrem after a single dose for human isotope studies.12 Based on the PK and 
available dosimetry data, administration of a single 200-µCi (7.4-MBq) oral dose of 
[14C]-LOXO-305 would not be expected to represent a significant radiation exposure risk 
when administered to healthy male subjects in a clinical trial. 
For Part 2, the radioactive dose of ~1 µCi of [14C]-LOXO-305 (microtracer) is only about 
0.5% of the radioactive dose planned for Part 1 and will present minimal radiation risk to 
healthy subjects. The low levels of radioactivity planned for Part 2 will necessitate the use of 
AMS as a highly sensitive analytical technique for quantifying the radioactivity in plasma, 
urine, and fecal samples. The radioactive dose of ~1 µCi together with the use of AMS for 
analysis of radioactivity is expected to allow for completion of study objectives of Part 2 with 
minimal radiation exposure risk to healthy subjects. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 25 of 69 
The potential risk of participating in this study is well managed by the study set-up and is 
considered negligible. The safety monitoring practices employed will include AE reporting, 
vital sign measurements, 12-lead ECG, clinical laboratory evaluations, and physical 
examinations, and are considered adequate to protect the subjects’ safety. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
 Primary Objectives 
Part 1: 
The primary objectives of Part 1 of the study are: 
• to determine the mass balance and routes of elimination of [14C]-LOXO-305 
following oral administration of a single dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) in healthy male subjects 
• to assess the PK of LOXO-305 following a single oral dose of [14C]-LOXO-305 
• to determine the whole blood and plasma concentrations of total radioactivity 
following a single oral dose of [14C]-LOXO-305 
• to determine urinary and fecal recovery of total radioactivity following a single oral 
dose of [14C]-LOXO-305 
• to characterize and identify metabolites of LOXO-305 in plasma, urine, and feces 
following a single oral dose of [14C]-LOXO-305. 
Part 2: 
The primary objectives of Part 2 of the study are: 
• to determine the absolute bioavailability of LOXO-305 following a single oral dose of 
200 mg LOXO-305 along with an IV dose of < 100 µg of [14C]-LOXO-305 
(containing ~1 µCi of radioactivity [microtracer]) 
• to evaluate the PK of LOXO-305 and [14C]-LOXO-305 following oral dosing of 
LOXO-305 and IV dosing of [14C]-LOXO-305 
• to evaluate the plasma concentration of total radioactivity following IV dosing of 
[14C]-LOXO-305 
• to evaluate the urinary excretion of [14C]-LOXO-305 and total radioactivity following 
IV dosing of [14C]-LOXO-305 
• to evaluate the fecal recovery of [14C]-LOXO-305 and total radioactivity following IV 
dosing of [14C]-LOXO-305 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 26 of 69 
2.1.2. 
Secondary Objectives 
Part 1: 
The secondary objective of Part 1 of the study is: 
• to assess the safety and tolerability of [14C]-LOXO-305 when administered to healthy 
male subjects. 
Part 2: 
The secondary objective of Part 2 of the study is: 
• to assess the safety and tolerability of LOXO-305 and [14C]-LOXO-305 when 
administered to healthy male subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
Part 1: 
The primary PK endpoints of LOXO-305 in plasma and total radioactivity in whole blood 
and plasma following oral administration of [14C]-LOXO-305 are as follows: 
• area under the concentration-time curve (AUC) from time 0 extrapolated to infinity 
(AUC0-inf) 
• AUC from hour 0 to the last measurable concentration (AUC0-t) 
• maximum observed concentration (Cmax) 
• tmax 
• apparent terminal elimination half-life (t1/2) 
• apparent systemic clearance (LOXO-305 only; CL/F) 
• apparent volume of distribution (LOXO-305 only; Vz/F) 
• AUC0-inf of plasma LOXO-305 relative to AUC0-inf of plasma total radioactivity 
(AUC0-inf Plasma LOXO-305/Total Radioactivity Ratio) 
• AUC0-inf of whole blood total radioactivity to AUC0-inf of plasma total radioactivity 
(AUC0-inf Blood/Plasma Ratio). 
The primary PK endpoints of total radioactivity in urine are as follows: 
• amount excreted in urine (Aeu) 
• cumulative Aeu 
• percentage of dose excreted in urine (feu) 
• cumulative feu. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 27 of 69 
The primary PK endpoints of total radioactivity in feces are as follows: 
• amount excreted in feces (Aef) 
• cumulative Aef 
• percentage of dose excreted in feces (fef) 
• cumulative fef. 
The primary outcome for metabolites will be derived: 
• metabolic profile of LOXO-305 
• identification of LOXO-305 metabolites. 
Part 2: 
The primary PK endpoints of LOXO-305 and total radioactivity in plasma following oral 
administration of LOXO-305 are as follows: 
• AUC0-inf, AUC0-t, Cmax, tmax, t1/2, CL/F (LOXO-305 only), and Vz/F (LOXO-305 only) 
• absolute bioavailability (F; LOXO-305 only). 
The primary PK endpoints of [14C]-LOXO-305 in plasma following IV administration of 
[14C]-LOXO-305 are as follows: 
• AUC0-inf, AUC0-t, Cmax, tmax, and t1/2 
• total clearance (CL) 
• Vz 
• volume of distribution at steady state (Vss). 
The primary PK endpoints of [14C]-LOXO-305 and total radioactivity in urine collections are 
as follows: 
• Aeu, cumulative Aeu, feu, cumulative feu 
• renal clearance (CLR; [14C]-LOXO-305 only). 
The primary PK endpoints of [14C]-LOXO-305 and total radioactivity in feces collections are 
as follows: 
• Aef, cumulative Aef, fef, cumulative fef. 
Other PK parameters may also be reported. 
2.2.2. 
Secondary Endpoints 
The secondary safety outcome measures for both parts of this study are as follows: 
• monitoring AEs 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 28 of 69 
• clinical laboratory evaluations 
• 12-lead ECG parameters 
• vital sign measurements 
• physical examinations. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be an open-label, nonrandomized, 2-part, AME and absolute bioavailability study of 
[14C]-LOXO-305 in healthy male subjects. Subjects in Part 1 will not participate in Part 2, 
nor will subjects in Part 2 participate in Part 1. Parts 1 and 2 are independent of each other 
and do not need to be conducted in sequential order. 
Part 1 is designed to evaluate the AME profiles of LOXO-305, to identify and characterize 
metabolites of LOXO-305, and to assess the safety and tolerability of [14C]-LOXO-305. 
Subjects in Part 1 will be administered a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution. Six subjects will participate in each part of the 
study. Each subject will participate in either Part 1 or Part 2, but not both. In the event of 
early withdrawal of any subjects and/or to ensure 6 subjects complete each part of the study, 
replacement subjects may be enrolled at the discretion of the Sponsor. 
Part 2 is designed to determine the absolute bioavailability of LOXO-305, to evaluate the 
plasma concentration of total radioactivity, to evaluate the urinary excretion of 
[14C]-LOXO-305 and total radioactivity, to evaluate the fecal excretion of [14C]-LOXO-305 
and total radioactivity, and to assess the safety and tolerability of LOXO-305 and 
[14C]-LOXO-305. Subjects in Part 2 will be administered a single oral dose of 200 mg of 
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 
push over approximately 2 minutes.  
Six subjects will participate in each part of the study. Each subject will participate in either 
Part 1 or Part 2, but not both. 
In the event of early withdrawal of any subjects and/or to ensure 6 subjects complete each 
part of the study, replacement subjects may be enrolled at the discretion of the Sponsor. 
The start of the study is defined as the earliest date a subject who is enrolled in either part of 
the study signs an Informed Consent Form (ICF). A subject who completes sufficient total 
radioactivity and metabolite (Part 1 only), or LOXO-305 and [14C]-LOXO-305 (Part 2 only) 
sampling prior to Clinic Discharge is considered to have completed the study. The end of the 
study is defined as the latest date a subject receives the Follow-up Call. The planned duration 
of study conduct for Part 1 is up to 60 days from Screening through the Follow-up Call. The 
planned duration of study conduct for Part 2 is up to 47 days from Screening through the 
Follow-up Call. 
A schematic of the study design of Part 1 is presented in Figure 1 and a schematic of the 
study design of Part 2 is presented in Figure 2.  


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 29 of 69 
Figure 2 Study Design Schematic: Part 1 
Screening 
Check-in 
Dosinga 
LOXO-305, Total 
Radioactivity 
Concentrations, and 
MetID Sampling 
Clinic (CRU) Dischargeb 
Follow-up 
Callc 
Days -29 to -2 
Day -1 
Day 1 
Day 1 to Clinic 
(CRU) Discharge 
Days 12 to 22 
Approximately 
7 days after 
Clinic (CRU) 
Discharge 
 
CRU Confinement 
 
CRU = Clinical Research Unit; MetID = metabolite profiling and identification 
a Single oral dose of 200 mg of [14C]-LOXO-305 (containing ~200 µCi) administered as an oral solution following an 
overnight fast of at least 10 hours. 
b Subjects will be discharged from the CRU starting on Day 12 if plasma radioactivity is below the limit of quantification for 
2 consecutive collections, and ≥ 90% of the radioactive dose is recovered and ≤ 1% of the radioactive dose per day is 
recovered in excreta (urine and feces) for 3 consecutive days on which a fecal sample is collected. If these criteria are not 
satisfied by the morning of Day 12, subjects will continue to be confined in the CRU until these criteria are met, up to a 
maximum of Day 22. Sample collection and CRU confinement will continue until discharge criteria are met or the maximum 
stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or designee). 
c Subjects will receive a Follow-up Call approximately 7 days after CRU Discharge. 
Figure 3 Study Design Schematic: Part 2 
Screening 
Check-in 
Dosinga 
LOXO-305, 
[14C]-LOXO-305, and 
Total Radioactivity 
Concentrations 
Clinic (CRU) 
Discharge 
Follow-up Callb 
Days -29 to -2 
Day -1 
Day 1 
Day 1 to Day 9 
Day 9 
Approximately 
7 days after 
Clinic (CRU) 
Discharge 
 
CRU Confinement  
 
CRU = Clinical Research Unit 
a Following an overnight fast of at least 10 hours, a single oral dose of 200 mg of LOXO-305 administered as 2 × 100-mg 
tablets and a single intravenous (IV) dose of < 100 µg of [14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) 
administered by IV push 2 hours after the oral dose. 
b Subjects will receive a Follow-up Call approximately 7 days after CRU Discharge. 
Part 1: 
After a Screening period of up to 28 days, subjects will check in to the Clinical Research Unit 
(CRU) on Day -1 to confirm eligibility and to become familiar with study procedures. On the 
morning of Day 1, following an overnight fast of at least 10 hours, subjects will receive a 
single oral dose of 200 mg of [14C]-LOXO-305 (containing ~200 µCi) administered as an oral 
solution. Subjects will be confined at the CRU from the time of Check-in (Day -1) until 
Clinic Discharge (between Days 12 and 22). After completing discharge procedures, subjects 
will be discharged from the CRU as early as Day 12 and up to Day 22, provided recovery of 
radioactivity has reached the following threshold values:  
• Plasma radioactivity below the limit of quantification for 2 consecutive collections, 
and 
• ≥ 90% of the radioactive dose is recovered, and  


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 30 of 69 
• ≤ 1% of the radioactive dose per day is recovered in excreta (urine and feces) for 
3 consecutive days on which a fecal sample is collected.   
Sample collection and CRU confinement will continue until discharge criteria are met or the 
maximum stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or 
designee). Subjects will receive a Follow-up Call approximately 7 days after Clinic 
Discharge. 
Samples for determination of LOXO-305 concentrations in plasma, total radioactivity 
concentrations in plasma, whole blood, urine, and feces, and for metabolite 
profiling/characterization will be obtained through at least 264 hours postdose (Day 12), and 
possibly up to 504 hours postdose (Day 22). A Schedule of Assessments for Part 1 is 
presented in Appendix 4. 
For subjects experiencing emesis within 4 hours following dosing, vomitus will be collected. 
The Medical Monitor (or designee) should be contacted immediately for further instructions 
and to determine if the subject should continue the study. All vomitus collected will be stored 
for possible analysis, as deemed appropriate.  
Part 2: 
After a Screening period of up to 28 days, subjects will check in to the CRU on Day -1 to 
confirm eligibility and to become familiar with study procedures. On the morning of Day 1, 
following an overnight fast of at least 10 hours, subjects will receive a single oral dose of 
200 mg of LOXO-305 as 2 × 100-mg tablets and 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 push over approximately 2 minutes. Subjects will be confined at the CRU from the 
time of Check-in (Day -1) until Day 9 and will be discharged from the CRU after completing 
all discharge procedures. Subjects will receive a Follow-up Call approximately 7 days after 
Clinic Discharge. 
Samples for determination of LOXO-305 concentrations in plasma, and total radioactivity 
and [14C]-LOXO-305 concentrations in plasma, urine, and feces will be obtained through 
192 hours postdose (Day 9). A Schedule of Assessments for Part 2 is presented in 
Appendix 4. 
Part 1 and Part 2 
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation parameters, hematology 
panel, urinalysis (UA; Appendix 2), and recording of concomitant medications will be 
performed at specified times during the study (for specific timepoints and details on each 
study variable, refer to Appendix 4). Adverse events and SAEs will be collected beginning at 
informed consent. Adverse events will be reported throughout the study (ie, from signing of 
the ICF until End of Study [EOS], or until Early Termination [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 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 31 of 69 
the Investigator [or designee], or if the event occurs after study drug administration on Day 1 
through End of Treatment [EOT] or ET regardless of relationship to study drug). From EOT 
or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a Follow-up Phone 
Call) are to be reported. Study completion is defined as the time of the last subject’s 
Follow-up Phone Call. 
3.2. 
Discussion of Study Design 
Part 1 of this study is designed to evaluate the AME kinetics of LOXO-305 using 
radiolabeled drug in healthy adult male subjects to support its further development and 
registration. Part 1 will also allow for identification and characterization of any metabolites of 
LOXO-305 that are produced following oral dosing. Analysis of total radioactivity and 
metabolites in urine and feces will provide information about the extent of urine and fecal 
excretion of LOXO-305 and its metabolites. 
Part 2 is designed to determine the absolute bioavailability of LOXO-305 by comparing its 
plasma exposure following oral dosing to the plasma exposure of [14C]-LOXO-305 following 
IV microtracer administration. The IV microtracer method allows for simultaneous oral and 
IV dosing in the same subjects, which is expected to result in less variability in absolute 
bioavailability estimates. The IV dose of [14C]-LOXO-305 will be administered so that peak 
plasma concentrations of [14C]-LOXO-305 occur approximately at the tmax of LOXO-305 
following oral dosing. Analysis of urine and fecal concentrations of [14C]-LOXO-305 and 
total radioactivity will allow for determination of the amount and percentage of LOXO-305 
excreted unchanged in urine and feces. 
In Part 2, a microtracer (~1 µCi of radioactivity) of [14C]-LOXO-305 will be used. This low 
level of radioactivity necessitates the use of accelerator mass spectrometry (AMS) as a more 
sensitive analytical method for detecting the low levels of radioactivity in plasma, urine, and 
fecal samples. 
The study will be open-label because the study measures are objective outcomes (eg, PK 
parameters, total radioactivity in select biological matrices, metabolite 
profiling/characterization). Female subjects will be excluded to align with regulatory 
guidance. The “as low as (is) reasonably achievable” (ALARA) principle prescribed by the 
FDA12 recommends that radiation exposure to subjects should be kept ALARA; therefore, if 
no specific reason exists to include females (ie, no available data suggest metabolism of 
LOXO-305 is different in females versus males), then the radiation exposure to female 
subjects should ideally be kept at zero by not including females in this radioactivity study and 
only enrolling and dosing male subjects. Conducting the study in healthy subjects will allow 
the evaluation of LOXO-305 metabolism and bioavailability in the absence of concomitant 
medications and comorbidities. The dose, subject population, study duration, and sample 
collection timing are considered adequate to achieve the study objectives. 
3.3. 
Selection of Doses in the Study 
Single oral doses of 200 mg LOXO-305 will be evaluated as this has been chosen as the 
recommended Phase 2 dose for the ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (BRUIN Study). Doses of LOXO-305 from 25 mg QD to 300 mg QD 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 32 of 69 
have been evaluated in the ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (BRUIN Study) in patients with previously treated CLL/SLL or NHL 
with dose escalation up to 300 mg QD approved by the study’s Safety Review Committee. 
The available data demonstrate that LOXO-305 appears safe and well tolerated at these 
doses. At all evaluated doses, including oral doses of up to 300 mg QD, no dose-limiting 
toxicities have been identified in humans.1 A <100 µg dose has been chosen as the IV 
microdose to permit dosing without supporting IV toxicology data.10  
For Part 1, the planned radioactive dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) is expected to provide a sufficient radioactive signal to achieve the 
study objectives with minimal radiation risk to subjects. Based on the dosimetry analysis in 
pigmented rats, the overall whole-body radiation dose in a male subject after administration 
of a single 100-µCi (3.7-MBq) oral dose of [14C]-LOXO-305 was calculated to be 120 mrem 
(1.2 mSv) when using allometric conversion.11 This value is well below the FDA exposure 
limit of 3000 mrem after a single dose for human isotope studies.12 Based on the PK and 
available dosimetry data, administration of a single 200-µCi (7.4-MBq) oral dose of 
[14C]-LOXO-305 would not be expected to represent a significant radiation exposure risk 
when administered to healthy male subjects in a clinical trial. 
For Part 2, the radioactive dose of ~1 µCi of [14C]-LOXO-305 (microtracer) is only about 
0.5% of the radioactive dose planned for Part 1 and will present minimal radiation risk to 
healthy subjects. The low levels of radioactivity planned for Part 2 will necessitate the use of 
AMS as a highly sensitive analytical technique for quantifying the radioactivity in plasma, 
urine, and fecal samples. The radioactive dose of ~1 µCi together with the use of AMS for 
analysis of radioactivity is expected to allow for completion of study objectives of Part 2 with 
minimal radiation exposure risk to healthy subjects. 
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 oxygen saturation, oral temperature, respiratory 
rate, and supine blood pressure [BP] and pulse rate [measured after the subject has 
been supine for at least 5 minutes]; Section 7.2.3) 
8. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 33 of 69 
9. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
10. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), 
hepatitis B virus (HBV) core antibody, human immunodeficiency virus (HIV) 
antibody, and SARS-CoV-2 (COVID-19) via polymerase chain reaction testing (PCR) 
or equivalent Appendix 2) 
11. Hemoglobin A1c (HbA1c) test (Appendix 2) 
12. Estimated glomerular filtration rate (Appendix 2) 
13. Screen for selected drugs of abuse, including cotinine and alcohol (Appendix 2) 
14. Thyroid-stimulating hormone (TSH) test (Appendix 2). 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
1. Review of inclusion/exclusion criteria 
2. Interim medical history, including concomitant medication(s) 
3. Weight and BMI 
4. Complete physical examination (Section 7.2.5) 
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 oxygen saturation, oral temperature, respiratory 
rate, and supine BP and pulse rate [measured after the subject has been supine for at 
least 5 minutes]; Section 7.2.3) 
7. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
8. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
9. Screen for COVID-19 via PCR or equivalent (Appendix 2) 
10. Estimated glomerular filtration rate (Appendix 2) 
11. Screen for selected drugs of abuse, including cotinine and alcohol (Appendix 2) 
12. Compliance with concomitant medications and exclusionary restrictions (Section 6). 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Check-in (Day -1 [as appropriate; #1, Section 4.2]). In addition, 
continued compliance with concomitant medication and other restrictions will be verified. 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to enrollment. Prior to dosing, the Sponsor will provide approval of subjects selected for 
enrollment by the Investigator (or designee). 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 34 of 69 
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, of any race, between 18 and 55 years of age, inclusive, at Screening.  
2. Within BMI range of 18.5 and 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital sign measurements, or clinical laboratory 
evaluations (Appendix 4) at Screening and/or Check-in (Day -1) as assessed by the 
Investigator (or designee). 
4. Subjects who are capable of fathering a child must agree to use 1 of the following 
methods of contraception from the time of the dose administration through 6 months 
after the last dose of LOXO-305 administration: 
a. Sterilization, with documented confirmation of surgical success. Subjects will 
be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, subjects must follow 1 of the contraception 
methods below: 
i. Male condom with spermicide, or 
ii. Subject must ensure that their female partner meets 1 of the following 
criteria: 
1. intrauterine device (IUD) (hormonal IUD; eg, Mirena®). 
Copper IUDs are acceptable (eg, ParaGard®); 
2. established use of oral, implanted, 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 male partner’s study 
drug administration); or 
4. be postmenopausal with amenorrhea for at least 1 year prior to 
dosing and follicle-stimulating hormone serum levels consistent 
with postmenopausal status. 
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 subject is abstinent at the time of signing the ICF but becomes 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 35 of 69 
sexually active through 6 months after study drug administration, he must agree to use 
contraception as described above. 
Sexual intercourse with female partners who are pregnant or breastfeeding should be 
avoided. Subjects are required to refrain from donation of sperm from Check-in 
(Day -1) until 6 months after administration of study drug. 
5. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
6. History of a minimum of 1 bowel movement per day. 
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 the first dose administration (Day 1) 
ii. Symptomatic angina pectoris within 6 months prior to the first dose 
administration (Day 1) 
iii. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to the first dose administration (Day 1) 
iv. Congenital prolonged QT syndrome 
v. Ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
vi. Arrhythmia (excluding benign sinus arrhythmia) or history of 
arrhythmia requiring medical intervention 
vii. Ventricular dysfunction or risk factors for Torsades de Pointes (eg, 
heart failure, cardiomyopathy, family history of Long QT Syndrome) 
viii. Significant screening ECG abnormalities: 
1. left bundle branch block 
2. second degree atrioventricular (AV) block, type 2, or third-
degree AV block 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 36 of 69 
3. QT interval corrected for heart rate using Fridericia’s method 
(QTcF) is > 450 msec 
4. ECG findings deemed abnormal with clinical significance by 
the Investigator (or designee) at Screening, Check-in (Day -1), 
or prior to dosing on Day 1. 
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 oral dosing on Day 1, 
including: 
a. oral 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) 
For these parameters, out-of-range values that are not clinically significant (as determined 
by the Investigator [or designee]) may be repeated twice during Screening, Check-in 
(Day -1), and predose on Day 1. Note: Rechecks of pulse rate and BP values will be 
permitted up to 2 times to confirm eligibility for study participation. Subjects may be 
eligible for participation in the study based on rechecked pulse rate and/or BP values if 
the values fall within the ranges stated above. 
3. Abnormal laboratory values (hematology panel, UA, clinical chemistry panel [fasted 
at least 8 hours], excluding those further defined in exclusion criteria #5, #6, #7, and 
#8 below) determined to be clinically significant by the Investigator (or designee), 
and Sponsor at Screening and/or Check-in (Day -1) as confirmed by repeat 
assessment. 
4. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Check-in (Day -1). 
5. Abnormal liver function tests (LFTs), as defined by aspartate aminotransferase, 
alanine aminotransferase, and serum (total and direct) bilirubin, as well as amylase 
and lipase above the upper limit of the normal range at Screening or Check-in 
(Day -1). Rechecks of LFTs, amylase, and lipase will be permitted up to 2 times to 
confirm eligibility for study participation if the values fall within normal ranges. 
6. Any clinically significant deviations from normal ranges in creatine kinase unless 
approved by the Investigator (or designee) and Sponsor. Rechecks of creatine kinase 
will be permitted up to 2 times to confirm eligibility for study participation if the 
out-of-range values are stable or trending down and the Investigator (or designee) and 
the Sponsor deem that the results are not clinically significant and will not impact 
study conduct. 
7. Estimated glomerular filtration rate of ≤ 90 mL/minute/1.73m2 at Screening or 
Check-in (Day -1) calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation. 
8. Hemoglobin, white blood cell count, and platelet counts below the lower limit of 
normal range at Screening or Check-in (Day -1). Rechecks of hemoglobin, white 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 37 of 69 
blood cell count and platelet counts will be permitted up to 2 times to confirm 
eligibility for study participation if the values fall within normal ranges. 
9. Positive serologic test for HBsAg, HBV core antibody, HCV, or HIV antibody at 
Screening. Subjects who are positive for HCV by antibody will require confirmation 
by PCR before enrollment to detect presence of active virus. Subjects who are HCV 
PCR positive or for whom a PCR is unable to be obtained will not be eligible.  
10. Positive PCR test (or equivalent) for COVID-19 at Screening, Check-in (Day -1) or 
predose on Day 1. Further details regarding COVID-19 testing (including procedures 
who test positive at any time throughout CRU confinement) are specified in a separate 
document. 
11. Subjects with known ongoing alcohol and/or drug abuse within 2 years prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays for drugs 
of abuse (including cotinine and alcohol) conducted during Screening and/or at 
Check-in (Day -1). Tests for drugs of abuse must be negative at both Screening and 
Check-in (Day -1). 
12. Consumption of grapefruit/grapefruit juice or Seville oranges or its juice within 
7 days prior to Check-in (Day -1) and through EOT or ET. 
13. Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours 
prior to Check-in (Day -1) and through EOT or ET, unless deemed acceptable by the 
Investigator (or designee) and Sponsor. 
14. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
15. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
16. Participation in any other investigational study drug trial involving administration of 
any investigational drug in the past 30 days or 5 half-lives (if known), whichever is 
longer, prior to the first dose administration (Day 1). 
17. Use or intention to use any prescription or over-the-counter medications (including 
but not limited to any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers [including herbal products such as St. John’s wort], strong P-glycoprotein 
[P-gp] inhibitors, proton pump inhibitors, antacids, H2 receptor antagonists, and drugs 
that prolong QT/QTc interval, herbal products, natural or herbal supplements) within 
14 days prior to the first dose administration (Day 1) and through EOT or ET, unless 
deemed acceptable by the Investigator (or designee) and Sponsor. 
18. History of a major surgical procedure within 30 days prior to Screening. 
19. History or presence, upon clinical evaluation, of any illness that, in the opinion of the 
Investigator (or designee), would interfere with the ability to provide informed 
consent or comply with study instructions, or that might confound the interpretation 
of the study results, or put the subject at undue risk. 
20. History or clinical manifestation of gastritis, gastrointestinal tract, metabolic, or 
hepatic disorder or other clinical condition that might, in the opinion of the 
Investigator (or designee), and as confirmed by the Sponsor, affect the absorption, 
distribution, biotransformation, or excretion of LOXO-305. 
21. Poor peripheral venous access. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 38 of 69 
22. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
23. Receipt of blood products within 2 months prior to Check-in (Day -1). 
24. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. 
25. Significant history or clinical manifestation of any allergic, dermatological, biliary, 
renal, hematological, pulmonary, cardiovascular (including any prior history of 
cardiomyopathy or cardiac failure), neurological, or psychiatric disorder (as 
determined by the Investigator [or designee]), or cancer within the past 5 years 
(except localized basal cell, squamous, or in situ cancer of the skin). 
Note: subjects with a history of uncomplicated appendectomy and/or hernia repairs 
will be acceptable. 
26. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
27. History of diabetes mellitus; HbA1c ≥ 6.5%. 
28. Has previously completed or withdrawn from any other study investigating 
LOXO-305 and have previously received the investigational product. 
29. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator (or designee), and as confirmed by the Sponsor, within the 30 days prior 
to the first dosing and through EOT or ET. 
30. Exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, computed 
tomography scan, barium meal) or current employment in a job requiring radiation 
exposure monitoring within 12 months prior to Check-in (Day -1). 
31. Part 1 only: Participation in a radiolabeled drug study where exposures are known to 
the Investigator (or designee) within the previous 4 months prior to Check-in (Day -1) 
or participation in a radiolabeled drug study where exposures are not known to the 
Investigator (or designee) within the previous 6 months prior to Check-in (Day -1). 
The total 12-month exposure from this study and a maximum of 2 other previous 
radiolabeled studies within 4 to 12 months prior to this study will be within the Code 
of Federal Regulations (CFR) recommended levels considered safe, per United States 
(US) Title 21 CFR 361.1: less than 5000 mrem whole body annual exposure with 
consideration given to the half-lives of the previous radiolabeled study drugs received. 
32. Part 2 only: Participation in any other radiolabeled investigational study drug trial 
within 12 months prior to Check-in (Day -1). Any previous radiolabeled study drug 
must have been received more than 12 months prior to Check-in (Day -1). 
33. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
4.5. 
Subject Number and Identification 
Subject numbers will consist of 6 digits in which the first set of 3 digits will identify the site 
and the second set of 3 digits will identify the subject (eg, 001-101). If subjects are 
withdrawn by the Investigator (or designee) or voluntarily withdraw prematurely from the 
study, replacement subjects may be enrolled only if deemed necessary by the Sponsor. If 
necessary, as determined by the Sponsor, subjects who fail to complete the treatment or have 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 39 of 69 
insufficient PK data may be replaced. Replacement subjects will be assigned a subject 
number by adding 200 to the last 3 digits of the subject number for the subject they are 
replacing (eg, Subject Number 001-301 replaces Subject Number 001-101). 
4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for 
any reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue 
the study. Subjects may be withdrawn because of the following:  
• change in compliance with inclusion/exclusion criterion that is clinically relevant and 
affects subject safety 
• occurrence of AEs 
• 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 final study day assessments (Appendix 4). The date the 
subject is withdrawn from the study and the reason for withdrawal will be recorded on the 
subject’s electronic Case Report Form (eCRF). All withdrawn subjects with AEs that are 
assessed as related to study drug and which are ongoing at ET may continue to be followed 
until the symptoms or value(s) return to normal, or acceptable levels, as judged by the 
Investigator (or designee) and confirmed by the Sponsor. 
The entire study may be discontinued at the discretion of the Investigator (or designee) or 
Sponsor, based on the occurrence of the following: 
• adverse events 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. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Active pharmaceutical ingredient (API) nonradiolabeled powder and tablets containing 
100 mg LOXO-305) will be supplied by the Sponsor and radiolabeled API (powder) will be 
supplied by the Sponsor (or designee), along with the lot numbers and Certificates of 
Analysis. A Covance CRU licensed pharmacist will manufacture and label the IMP from bulk 
supplies, such that each unit dose contains a total of 200 mg LOXO-305 containing ~ 200 μCi 
of [14C] for the Part 1 oral solution (Table 2) and < 100 μg LOXO-305 containing 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 40 of 69 
approximately 1 μCi [14C] for the Part 2 IV solution (Table 3). The completed drug product 
will be released by a Good Manufacturing Practice (GMP) Quality Auditor under GMP 
conditions prior to administration to subjects. 
Table 2 Supplied Study Drugs: Part 1 
Study Drug 
[14C]-LOXO-305 
LOXO-305 
Forma 
Powder 
Powder 
Strength 
N/A 
N/A 
Specific Activity 
~50 µCi/mg  
N/A 
Supplier 
Loxo Oncology, Inc. 
Loxo Oncology, Inc. 
Manufacturer 
Eurofins BioPharma Product 
Testing 
Olon Ricerca Bioscience 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug(s). 
Table 3 Supplied Study Drugs: Part 2 
Study Drug 
LOXO-305 
[14C]-LOXO-305 
Forma 
Oral Tablet 
Powder 
Strength 
100 mg 
N/A 
Specific Activity 
N/A 
~50 µCi/mg  
Supplier 
Loxo Oncology, Inc. 
Loxo Oncology, Inc. 
Manufacturer 
Bend Research, Inc. 
Eurofins BioPharma Product 
Testing 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug(s). 
The Sponsor will supply a sufficient quantity of the applicable IMP and API for the 
manufacture of the respective unit doses at Covance CRU. All excipients will be sourced by 
Covance. Specific instructions regarding dose preparation will be mutually agreed upon 
between the Sponsor and the appropriate clinical staff and will be presented in a separate 
document. 
The API and IMP will be stored according to the instructions on the label at the CRU in a 
location that is locked with restricted access.  
5.2. 
Study Treatment Administration 
In Part 1, subjects will receive a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution with 240 mL of room temperature water. In Part 2, 
subjects will receive a single oral dose of 200 mg LOXO-305 as 2 × 100-mg tablets with 
240 mL of room temperature water followed 2 hours later by a single dose of < 100 µg 
[14C]-LOXO-305 (containing ~1 µCi radioactivity [microtracer]) as an IV push over 
approximately 2 minutes. In both parts, an additional 100 mL of water may be administered if 
needed. 
In Parts 1 and 2, oral dosing will be preceded by an overnight fast (ie, at least 10 hours) from 
food (not including water) and will be followed by a fast from food (not including water) for 
at least 4 hours post-oral dose. During Part 2, subjects may receive lunch approximately 
2 hours after receiving the IV dose. Except as part of dose administration, subjects will 
restrict their consumption of water for 1 hour prior to oral dose and for 1 hour post-oral dose. 
At all other times during the study, subjects may consume water ad libitum. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 41 of 69 
Each unit dose will be prepared by qualified CRU staff. Each unit dose container will be 
appropriately labeled. 
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be consistently administered the appropriate 
dose at a specific time, the exact dose time of subjects may be staggered to obviate the need 
to have all subjects on precisely the same study schedule. For each dose, the subject’s actual 
dose time will be recorded in the source documents and transcribed into the eCRF. 
Subjects will be instructed not to crush, split, or chew oral LOXO-305 tablets. 
All oral doses will be administered while the subjects are seated and subjects will not be 
permitted to lie supine for 4 hours’ post-oral dose except as necessitated by the occurrence of 
an AE(s) and/or study procedures. Subjects may be asked to be semi-supine/supine for the IV 
dosing. 
Except when they are using the toilet, study subjects will be observed for approximately 
4 hours post-oral dose to ensure that they are not experiencing AEs, becoming nauseated, or 
experiencing emesis. 
5.3. 
Randomization 
This is a nonrandomized study. 
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 administration, visual inspection of the mouth will be 
performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of IMP will be performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies (including all IMP and API) 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 oral unit doses containing 14C, the empty used unit dose containers will undergo 
radioanalysis to determine the amount of any residual radioactivity remaining after dose 
administration and be discarded upon satisfactory completion of the compliance and 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 42 of 69 
accountability procedures. Any unused assembled unit doses will be retained until completion 
of the study. 
At the completion of the study, all unused supplies (including all IMP and API) will be 
disposed of by the CRU, per the Sponsor’s written instructions and/or in accordance with 
local/state/federal guidelines governing waste disposal of investigational drugs and the CRUs 
Standard Operating Procedures. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Paracetamol/acetaminophen (maximum 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 first dose administration (Day 1). 
All prescription/nonprescription and over-the-counter medications (including herbal products, 
natural or herbal supplements, except for paracetamol/acetaminophen as referenced above) 
are prohibited for 14 days prior to dose administration (Day 1) and through EOT or ET, 
unless deemed acceptable by the Investigator (or designee) and Sponsor. This includes but is 
not limited to: moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers (including 
herbal products such as St, John’s wort), strong P-gp inhibitors, proton pump inhibitors, 
antacids, H2-receptor antagonists, and drugs that prolong QT/QTc interval. 
Any medication taken by a subject during the course of the study, including details of its 
dosage, administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without 
prior approval of the Investigator (or designee) and Sponsor, unless its use is deemed 
necessary in a medical emergency. In this case, the use of the concomitant medication will be 
reported as soon as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
While confined at the CRU, subjects will receive a standardized high fiber diet at scheduled 
times that do not conflict with other study-related activities. Pitted prunes or prune juice may 
be given on an as-needed basis to aid in normal bowel function and will not be considered a 
concomitant medication.  
Subjects are required to refrain from use of tobacco, smoking cessation products, and 
nicotine-containing products within 3 months prior to Screening through EOT or ET . 
Consumption of foods or beverages containing grapefruit/grapefruit juice or Seville oranges 
or its juice within 7 days prior to Check-in (Day -1) and through EOT or ET will not be 
allowed unless deemed acceptable by the Investigator (or designee) and Sponsor. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 43 of 69 
Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours prior to 
Check-in (Day -1) and through EOT or ET will not be allowed unless deemed acceptable by 
the Investigator (or designee) and Sponsor. 
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and 
during the period of confinement at the CRU and will otherwise maintain their normal level 
of physical activity through EOT or ET (ie, should not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
Fasting requirements in relation to dosing are described in Section 3.1 and Section 5.2. 
Fasting requirements in relation to collection of blood for clinical laboratory evaluations are 
described in Section 7.2.2 and Appendix 4. 
7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic, Total Radioactivity, and Metabolite Profiling Blood 
Sample Collection and Processing 
Blood samples for PK analysis for determination of LOXO-305, total radioactivity, and 
metabolite profiling and identification in Part 1 and for LOXO-305, [14C]-LOXO-305, and 
total radioactivity in Part 2 will be collected at the times indicated in the Schedule of 
Assessments (Appendix 4). Blood samples will be collected from the contralateral arm to the 
arm/hand used for IV dose administration. Procedures for collection, processing, and 
shipping of blood samples will be detailed in a separate document. 
Processing, storage, and shipping instructions for PK, total radioactivity, and metabolite 
profiling and identification blood samples will be provided in a separate Laboratory Manual. 
The number of blood samples and total blood volume required for PK, total radioactivity, and 
metabolite profiling and identification testing is presented in Appendix 3. 
7.1.2. 
Pharmacokinetic, Total Radioactivity, and Metabolite Profiling Urine and 
Feces Collection and Processing 
Urine will be collected over the time intervals indicated in the Schedule of Assessments in 
Appendix 4 for determination of total radioactivity and metabolite profiling and identification 
for Part 1 and for [14C]-LOXO-305 concentration and total radioactivity in Part 2. Procedures 
for collection, processing, and shipping of urine collections will be detailed in a separate 
document. 
Feces will be collected over the time intervals indicated in the Schedule of Assessments in 
Appendix 4 for determination of total radioactivity in Parts 1 and 2, metabolite profiling and 
identification for Part 1 (where possible), and for measurement of [14C]-LOXO-305 in Part 2. 
If possible, a single baseline fecal sample will be collected from after Check-in on Day -1 
until predose on Day 1. Procedures for collection, processing, and shipping of feces 
collections will be detailed in a separate document. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 44 of 69 
7.1.3. 
Vomitus Sample Collection 
In Part 1, for subjects experiencing emesis within 4 hours following oral dosing, vomitus will 
be collected. Attempts will be made to collect vomitus from subjects experiencing emesis 
after 4 hours postdose. All vomitus collected will be stored for possible analysis as deemed 
appropriate. 
7.1.4. 
Analytical Methodology 
In Parts 1 and 2, plasma concentrations of LOXO-305 will be determined using a validated 
bioanalytical method.  
In Part 1, total radioactivity in plasma, whole blood, urine, and feces will be determined with 
liquid scintillation counting (LSC). Profiling and identification of metabolites in plasma, 
urine, and, where possible, feces will be conducted using standard laboratory procedures.  
In Part 2, concentrations of [14C]-LOXO-305 in plasma, urine, and feces will be determined 
using high performance liquid chromatography fractionation followed by AMS. 
Concentrations of total radioactivity in plasma, urine and feces will be determined using 
AMS and/or LSC. Specifics of the analytical methods will be provided in separate 
documents. 
7.2. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee) or 
Sponsor. 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and any other procedures to be performed at the same timepoint. The order of priority for 
scheduling procedures around a timepoint is (in descending order of priority): 
• dosing 
• PK, total radioactivity, and metabolite profiling and identification blood sampling 
• start and end of urine and fecal collections (for drug assay) 
• vital sign measurements 
• 12-lead ECGs 
• blood and urine samples for clinical laboratory evaluations 
• physical examination. 
7.2.1. 
Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes 
in your health status since Screening/since you were last asked?” at the timepoints specified 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 45 of 69 
in Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in [Day -1], at each 
postdose vital sign measurements, 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 
designee) according to regulatory authority requirements. Refer to Reference Safety 
Information (RSI) 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 EOT and 
ET subjects are not required to be fasted prior to clinical laboratory evaluations], coagulation 
parameters, hematology panel, TSH [Screening only], HbA1c [Screening only], glomerular 
filtration rate [Screening and Check-in (Day -1)] and UA) will be collected at the timepoints 
specified in Appendix 4.  
Screens for HCV antibody, HBV core antibody, HBsAg, and HIV antibody will be performed 
at Screening.  


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 46 of 69 
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 who test positive at any time throughout 
CRU confinement) are specified in a separate document. 
A urine drug screen for selected drugs of abuse (including cotinine and alcohol) will be 
performed at Screening and repeated at Check-in (Day -1) for all subjects.  
The number of blood samples and total blood volume required for clinical laboratory 
evaluations is presented in Appendix 3. A list of the specific evaluations is in Appendix 2. 
7.2.3. 
Vital Signs 
Vital sign measurements (including oxygen saturation, oral temperature, respiratory rate, 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 blood draws, the blood 
draws will be obtained at the scheduled timepoint, and the vital sign measurements will be 
obtained prior to and as close as possible to the scheduled blood draw. 
7.2.4. 
12-Lead Electrocardiogram 
A 12-lead ECG (including 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 
timepoints specified in Appendix 4. The QT interval will be corrected for heart rate by 
Fridericia’s (QTcF = QT/[RR]1/3) formula. 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to and as 
close as possible to the scheduled blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated physical examination will be performed at the timepoints specified 
in Appendix 4. Complete physical examinations will evaluate general appearance and the 
following body systems/organs: dermatological; head and eyes; ears, nose, mouth, and throat; 
pulmonary; cardiovascular; abdominal; lymphatic; musculoskeletal/extremities; and 
neurological. Weight and height will be reported (height only reported during Screening). 
Abbreviated physical examinations will evaluate general appearance and the following body 
systems/organs: dermatological; pulmonary; cardiovascular; abdominal; and neurological. 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 47 of 69 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment of sample size has been conducted as this study does not 
have a hypothesis. The sample size chosen for this study is common in human radiolabeled 
studies and is considered sufficient to achieve the objectives of the study. Six subjects will 
participate in each part of the study. Each subject will participate in either Part 1 or Part 2. In 
the event of early withdrawal of any subjects and/or to ensure 6 subjects complete each part 
of the study, replacement subjects may be enrolled at the discretion of the Sponsor. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of LOXO-305 or 
[14C]-LOXO-305 and have evaluable PK data. At the discretion of the Sponsor, a subject may 
be excluded from the PK summary statistics and statistical analysis. The impact of protocol 
deviations on PK population will be evaluated on a case-by-case basis. 
8.2.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of LOXO-305. 
Subjects will be classified into groups based on actual treatment received. 
8.3. 
Pharmacokinetic Analyses 
Part 1 
Samples for determination of LOXO-305 concentrations in plasma, total radioactivity 
concentrations in plasma, whole blood, urine, and feces, and for metabolite 
profiling/characterization will be obtained through at least 264 hours postdose (Day 12), and 
possibly up to 504 hours postdose (Day 22). Pharmacokinetic parameters (where applicable) 
will be calculated using standard noncompartmental methods. 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-305 and whole blood and plasma concentrations of total 
radioactivity: 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity, calculated using the formula: 
AUC0-inf = AUC0-t + (Clast ÷ λz)  
where Clast is the last quantifiable concentration and λz is the 
apparent terminal elimination rate constant 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal 
rule for increasing and decreasing concentrations 
Cmax 
maximum observed concentration 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 48 of 69 
tmax 
time to maximum observed concentration 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t½ = ln(2)/ λz 
CL/F 
apparent systemic clearance (LOXO-305 only) 
Vz/F 
apparent volume of distribution during the terminal phase 
(LOXO-305 only) 
AUC0-inf Plasma 
LOXO-305/Total 
Radioactivity 
Ratio 
AUC0-inf of plasma LOXO-305 relative to AUC0-inf of plasma total 
radioactivity 
AUC0-inf Blood/ 
Plasma Ratio 
AUC0-inf of whole blood total radioactivity to AUC0-inf of plasma 
total radioactivity 
Whenever possible, the following PK parameters will be calculated for each subject based on 
the urine concentrations of total radioactivity: 
Aeu 
amount excreted in urine per sampling interval 
cumulative Aeu 
cumulative amount excreted in urine 
feu 
percentage of dose excreted in urine per sampling interval, where 
%feu = 100 (Aeu/dose) 
cumulative feu 
cumulative percentage excreted in urine 
Whenever possible, the following PK parameters will be calculated for each subject based on 
the fecal concentrations of total radioactivity: 
Aef 
amount excreted in feces per sampling interval 
cumulative Aef 
cumulative amount excreted in feces 
fef 
percentage of dose excreted in feces per sampling interval, where 
%fef = 100 (Aef/dose) 
cumulative fef 
cumulative percentage excreted in feces 
Additionally, the metabolic profile of LOXO-305 and the identification of LOXO-305 
metabolites will be determined for each subject. Pharmacokinetic parameters for relevant 
metabolites of LOXO-305 may be calculated for each subject in Part 1, as deemed 
appropriate, based on plasma, urine, and/or fecal concentration levels. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 49 of 69 
Part 2 
Samples for determination of LOXO-305 concentrations in plasma, and total radioactivity 
and [14C]-LOXO-305 concentrations in plasma, urine, and feces will be obtained through 
192 hours postdose (Day 9). 
Pharmacokinetic parameters (where applicable) will be calculated using standard 
noncompartmental methods. 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of [14C]-LOXO-305, LOXO-305, and total radioactivity: 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity, calculated using the formula described above 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration, calculated as described above 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t½ = ln(2)/ λz 
CL/F 
apparent systemic clearance (LOXO-305 only) 
Vz/F 
apparent volume of distribution during the terminal phase 
(LOXO-305 only) 
F 
absolute bioavailability, calculated using the formula: 
 
F = AUC0-inf (oral) x Dose (IV) 
 
      AUC0-inf (IV) x Dose (oral) 
CL 
total clearance ([14C]-LOXO-305 only) 
Vz 
volume of distribution ([14C]-LOXO-305 only) 
Vss 
volume of distribution at steady state ([14C]-LOXO-305 only) 
In addition, whenever possible, the following PK parameters will be calculated for each 
subject based on the urine concentrations of [14C]-LOXO-305 and total radioactivity: 
Aeu 
amount excreted in urine 
cumulative Aeu 
cumulative amount excreted in urine 
feu 
percentage of dose excreted in urine, calculated as described above 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 50 of 69 
cumulative feu 
cumulative percentage excreted in urine 
CLR 
renal clearance ([14C]-LOXO-305 only) 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the fecal concentrations of [14C]-LOXO-305 and total radioactivity: 
Aef 
amount excreted in feces 
cumulative Aef 
cumulative amount excreted in feces 
fef 
percentage of dose excreted in feces, calculated as described above 
cumulative fef 
cumulative percentage excreted in feces 
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 
analysis will be performed using SAS Version 9.4 or greater. More details on the analyses 
will be included in the SAP. 
8.3.1. 
Descriptive Analysis 
Plasma and whole blood concentrations and PK parameters will be summarized with 
descriptive statistics (number, arithmetic mean, standard deviation, coefficient of variation 
[CV%], geometric mean, geometric CV%, median, minimum, and maximum). 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. 
8.3.2. 
Statistical Methodology 
No formal statistical analyses are planned. 
8.4. 
Safety Analysis 
All safety assessments, including AEs and SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated and summarized, where possible, using descriptive methodology, as needed, by 
timepoint. Unless otherwise specified, baseline value is defined as the last non-missing 
measurement before administration of LOXO-305 in each part. 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 or higher). Adverse events will be coded 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 51 of 69 
using MedDRA Version 22.1 (or higher). The incidence of AEs will be presented by severity 
and by relationship to study drug as determined by the Investigator or designee (Appendix 1 
for AE reporting). All TEAEs will be summarized by SOC and PT. 
8.5. 
Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a CRU staff member authorized to make 
the change. Changes will be made by striking a single line through erroneous data and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
clinician. 
The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the CRU and verified by the Study Monitor. Data 
will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be 
reviewed by the Covance scientific team. The eCRF and ancillary data will be converted into 
final SAS® datasets following Study Data Tabulation Model or client-provided specifications. 
The final datasets structure will be verified using Web Submission Data Manager®, while the 
dataset content will be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will 
be peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by 
the Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.6. 
Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per client request, and as applicable, according to the contract 
between Covance and the Sponsor. 
9. ADMINSTRATIVE 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). 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 52 of 69 
9.2. 
Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator (or designee) and appropriate CRU staff to familiarize the Investigator (or 
designee) and CRU staff with the materials necessary for conducting the clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, oral 
presentations, abstracts) by the Investigator (or designee) or their representative(s), shall 
require prior notification and review, within a reasonable timeframe, by the Sponsor, and 
cannot be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of 
the Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate a Study Monitor who will be responsible for monitoring this 
clinical trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and 
source documentation completion and retention, and accurate study drug accountability. To 
this end, the Sponsor’s Study Monitor will visit the CRU at suitable intervals and be in 
frequent contact through verbal and written communication. It is essential that the Sponsor’s 
Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Sponsor’s Study Monitor will adhere 
to all requirements for subject confidentiality as outlined in the ICF. The Investigator (or 
designee) and Investigator’s staff will be expected to cooperate with the Sponsor’s Study 
Monitor, to be available during a portion of the monitoring visit to answer questions, and to 
provide any missing information. 
9.5. 
Institutional Review Board 
In accordance with US Title 21 CFR 56, the protocol, advertisement, ICF, and other 
information provided to subjects will be reviewed and approved by the IRB. The Sponsor 
will supply relevant material for the Investigator (or designee) to submit to the IRB for the 
protocol’s review and approval. Verification of the IRB unconditional approval of the 
protocol and the written ICF statement will be transmitted to the Investigator (or designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will be 
transmitted in writing to the Investigator (or designee). If requested, the Investigator (or 
designee) will permit audits by the IRB and regulatory inspections by providing direct access 
to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s (or designee’s) participation in the study. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 53 of 69 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can 
withdraw from the study at any time. In accordance with 21 CFR 50, the informed consent 
process shall be documented by the use of a written ICF approved by the IRB and signed by 
the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
9.7. 
Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each eCRF 
will be retained by the Investigator (or designee). All source documents, records, and reports 
will be retained by the CRU in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the CRU archives. 
9.8. 
Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the US 
CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), Applications for FDA Approval to Market a New Drug (21 CFR 314), and 
Radioactive Drugs for Certain Research Uses (21 CFR 361.1), as appropriate. As such, these 
sections of US Title 21 CFR, along with the applicable International Council for 
Harmonisation (ICH) Guidelines, are commonly known as Good Clinical Practices (GCP), 
which are consistent with the Declaration of Helsinki.  
9.9. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 54 of 69 
10. REFERENCES 
1.  Loxo Oncology, Inc. LOXO-305 - Investigator’s Brochure (Version 3.1). 2020.  
2.  Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, Rothenberg SM, et al. A next 
generation reversible BTK Inhibitor, for overcoming acquired resistance to irreversible 
BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18.  
3.  Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK 
with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 
4;369(1):32–42.  
4.  Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol Off J Am Soc Clin Oncol. 2017 May 1;35(13):1437–43.  
5.  Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to 
acalabrutinib in CLL is mediated primarily by BTK mutations. 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: Safety Testing of Drug 
Metabolites (Revision 1) [Internet]. 2016. Available from: 
http://sp2013.ent.covance.com/sites/LSDS/MedSci/Global_Reg_Affairs/Reg_Writing/Tr
aining Materials/Early Clinical Services/Covance Internal/Study Design 
Principles/Metabolite Profiling 
10.  Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals : ICH [Internet]. [cited 2019 Aug 1]. 
Available from: http://www.ich.org/products/guidelines/safety/safety-
single/article/guidance-on-nonclinical-safety-studies-for-the-conduct-of-human-clinical-
trials-and-marketing-author.html 
11.  Eli Lilly and Company. LOXO-305-DMPK-035 -Pharmacokinetics, Metabolism, and 
Elimination of [14C]LY3527727 in Male and Female Sprague Dawley Rats, and 
Distribution of Radioactivity Associated with [14C]LY3527727 in Male Long Evans 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 55 of 69 
Rats Following a Single Oral Dose of [14C]LY3527727 (LOXO-305) 
(PK/Excretion/QWBA Sections). 2020.  
12.  CFR - Code of Federal Regulations Title 21 [Internet]. [cited 2019 Aug 1]. Available 
from: 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=361.1 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020 
Page 56 of 69 
11. APPENDICES 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 57 of 69 
Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An 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 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 relevant adverse changes in laboratory parameters observed in a subject 
during a clinical study. 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant 
by the Investigator [or designee]), and accidents observed in the context of a clinical trial, 
irrespective of a possible causal relationship with the administration of the trial substance. 
Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• 
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. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 58 of 69 
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 in female partners of male subjects diagnosed 
through EOS or ET (if the subject discontinues from the study and does not complete a 
Follow-up Phone Call) and for up to 90 days after study drug administration should be 
reported by the Investigator (or designee) via email to Covance or the Sponsor’s Clinical 
Safety Representative within 24 hours of first awareness. 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 
If possible, the subject’s 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. 
Subjects will be instructed to notify the Investigator immediately if they discover their sexual 
partner is pregnant. In this instance, the subject’s partner must provide written consent before 
pregnancy information can be collected. When a CRU becomes aware that the female partner 
of a male subject is pregnant, they are to contact the Investigator (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 required pregnancy forms.  
Definition of Serious Adverse Events 
An SAE (by FDA definition) is any adverse drug experience occurring at any dose that 
results in any of the following outcomes: 
• 
Death; 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 59 of 69 
• 
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 one of the above outcomes. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed 
in the Reference Safety Information section of the IB or if it is not listed at the specificity or 
severity that has been observed for an unapproved IMP. 
Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of the 
drug and represent events that are assessed as serious, related, and unexpected. Food and 
Drug Administration-reportable AEs will be reported by the CRU to the Sponsor and the 
responsible IRB. Final determination of whether an event represents a SUSAR will be the 
responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or 
reported, and within 24 hours of any SAE (regardless of whether the event is assessed as 
related or unrelated to study drug) being first recognized or reported, Covance or the 
Sponsor’s Clinical Safety Representative will be notified by the Investigator (or designee) in 
writing using the following email address: 
email: SAEIntake@covance.com 
To report the SAE, the completed report form should be sent by email to Covance or the 
Sponsor’s Clinical Safety Representative within 24 hours of awareness. Incoming reports are 
reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 
The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 60 of 69 
Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel 
(Fasted): 
Hematology Panel: 
 
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 
Coagulation Parameters: 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Human immunodeficiency virus 
(HIV) antibody 
Hepatitis B surface antigen 
(HBsAg) 
Hepatitis B virus (HBV) core 
antibody 
Hepatitis C virus (HCV) 
antibody 
Urinalysis: 
Other Tests: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity  
Protein 
Urobilinogen 
Microscopic examination 
including bacteria, casts, 
crystals, epithelial cells, RBCs, 
and WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Hemoglobin A1c (HbA1c)b 
Estimated glomerular filtration 
ratea,c 
Thyroid-stimulating hormone 
(TSH)b 
SARS-CoV-2 (COVID-19) test 
 
Urine Drug Screen:a 
Including but not limited to the 
following: 
Alcohol (ethanol)  
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine (metabolite)  
Methadone 
Opiates 
Phencyclidine 
Cotinine 
a. Performed at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 61 of 69 
Appendix 3: Total Blood Volume 
The following blood volumes are the maximum that will be withdrawn for each subject. 
Part 1: 
 
 
Up to Day 22a 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical Laboratory evaluations 
  Chemistryb 
  Hematology 
  Coagulation 
Hemoglobin A1c (HbA1c) 
Serology 
Plasma for LOXO-305 
concentration 
Whole blood and plasma for 
total radioactivity 
Plasma for metabolite profiling 
and identification 
Total: 
a Subjects could be discharged on Day 12 if the discharge criteria are met or may be resident within the Clinical Research 
Unit for additional 24-hour sample collections of LOXO-305 concentration in plasma, total radioactivity in blood and 
plasma, LOXO-305 metabolite in plasma, and total radioactivity in urine and feces up to Day 22. Sample collection and 
CRU confinement will continue until discharge criteria are met or the maximum stay is reached, unless otherwise agreed 
upon by the Sponsor and Investigator (or designee). 
b Thyroid stimulating hormone and estimated glomerular filtration rate will be assessed as part of the clinical chemistry 
sample. 
Part 2: 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount 
of blood (mL) 
Clinical Laboratory evaluations 
  Chemistrya 
  Hematology 
  Coagulation 
Hemoglobin A1c (HbA1c) 
Serology 
Plasma for LOXO-305 
concentration 
Plasma for [14C]-LOXO-305 
concentration and total 
radioactivity 
Total: 
a Thyroid stimulating hormone and estimated glomerular filtration rate will be assessed as part of the clinical 
chemistry sample. 
If additional blood samples are required, the maximum blood volume to be withdrawn per 
subject will not exceed 600 mL for Part 1 and 350 mL for Part 2. 
CCI
CCI


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 62 of 69 
Appendix 4: Schedule of Assessments 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 63 of 69 
Schedule of Assessments: Part 1 
Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Day 
Clinic 
Discharge/ 
EOTk or ETu 
Follow-up 
Phone Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day 12 to Day 
22k,u 
7 (±2) days post 
EOT or ETv 
Confined to the CRU 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated Glomerular 
Filtration Rate 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECGe 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Vital Signsf 
Xg,h 
Xg,h 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg, h 
 
HDYF? Inquiryi 
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 
LOXO-305 Dosing 
([14C]-LOXO-305) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for 
LOXO-305 
Concentration 
(Plasma)l 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sampling for 
Total Radioactivity 
(Whole Blood and 
Plasma)l 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sampling for 
Metabolite Profiling 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 64 of 69 
Schedule of Assessments: Part 1 
Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Day 
Clinic 
Discharge/ 
EOTk or ETu 
Follow-up 
Phone Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day 12 to Day 
22k,u 
7 (±2) days post 
EOT or ETv 
and Identification 
(Plasma) m 
Urine Collection for 
Total Radioactivity and 
Metabolite Profiling 
and Identificationn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Feces Collection for 
Total Radioactivity and 
Metabolite Profiling 
and Identificationo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory 
Evaluationsp 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Xq 
 
Hepatitis and HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Testr 
X 
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 
TSH Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; COVID-19 = SARS-CoV-2; CRU = Clinical Research Unit; ECG = electrocardiogram; EOS = End of Study; 
EOT = End of Treatment; ET = Early Termination; 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 based on Screening height. 
d. A complete physical examination will be performed at Check-in (Day -1). An abbreviated physical examination will be performed on the day of Clinic Discharge (EOT) or ET.   


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 65 of 69 
e. 12-lead ECGs will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the scheduled blood draws at 
Screening and Check-in (Day -1), Day 1 (predose and 2 hours after LOXO-305 dosing), Days 4, 9, 14 (if a subject is in the CRU), 19 (if the subject is in the CRU) and on the day of Clinic 
Discharge (EOT) or ET. 
f. Vital sign measurements (supine BP and pulse rate) will be obtained at Screening and Check-in (Day -1), Day 1 (predose and 2 hours after LOXO-305 dosing), and daily (24-hour intervals) 
up to and including day of Clinic Discharge (EOT) or ET. When scheduled at the same nominal times, postdose vital sign measurements are to be performed prior to postdose PK blood 
draws (see Section 7.2). Vital sign measurements should be carried out prior to and as close as possible to having blood drawn. Blood pressure and pulse rate will be measured using the same 
arm for each reading after the subject has been supine for at least 5 minutes. 
g. Oral temperature and respiratory rate will also be obtained at Screening, Check-in (Day -1), and on the day of Clinic Discharge (EOT) or ET. 
h. Oxygen saturation will be measured at Screening, Check-in (Day -1), predose on Day 1, and on the day of Clinic Discharge (EOT) or ET. 
i. An HDYF? inquiry will be performed at Screening (after the ICF is signed), at Check-in (Day -1), at each postdose vital sign measurements, 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. Subjects can be discharged on Day 12 if the following discharge criteria are met: Plasma radioactivity below the limit of quantification for 2 consecutive collections, and ≥ 90% of the 
radioactive dose is recovered, and ≤ 1% of the radioactive dose per day is recovered in excreta (urine and feces) for 3 consecutive days on which a fecal sample is collected. If all discharge 
criteria are not met, subjects will be asked to remain resident within the Clinical Research Unit (CRU) and will continue until these criteria are met, up to a maximum of Day 22. If a subject 
does not meet the discharge criteria on Day 12, additional blood samples will be collected for LOXO-305 plasma, total radioactivity plasma and whole blood concentrations, LOXO-305 
metabolite in plasma, and total radioactivity in urine and feces at 24-hour intervals until the day of Clinic Discharge (EOT or ET). Sample collection and CRU confinement will continue 
until discharge criteria are met or the maximum stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or designee). 
l. Blood samples for determination of LOXO-305 concentration (plasma) and total radioactivity (plasma and whole blood) will be collected prior to dosing (within 30 minutes) and 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours postdose (Day 12). If a subject does not meet the discharge criteria on Day 12, additional blood samples will 
be collected for LOXO-305 plasma and total radioactivity plasma and whole blood concentrations at 24-hour intervals until the day of Clinic Discharge (EOT) or ET. Sample collection and 
CRU confinement will continue until discharge criteria are met or the maximum stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or designee). The allowed 
sampling window for blood samples for determination of LOXO-305 concentration (plasma) and total radioactivity (plasma and whole blood) will be the following: within 15 minutes prior 
to dosing for any of the predose sample timepoints; ± 5 minutes for sampling timepoints within the first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 
minutes for the sampling timepoints ranging from 48 to 504 hours. 
m. Blood samples for metabolite profiling/characterization will be collected at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours postdose (Day 12). If a subject does not 
meet the discharge criteria on Day 12, additional blood samples will be collected for metabolite profiling/characterization at 24-hour intervals until the day of Clinic Discharge (EOT) or ET. 
The allowed sampling window for blood samples for metabolite profiling/characterization will be the following: within 15 minutes prior to dosing for any of the predose sample timepoints; ± 
5 minutes for sampling timepoints within the first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 minutes for the sampling timepoints ranging from 48 to 
504 hours. Sample collection and CRU confinement will continue until discharge criteria are met or the maximum stay is reached, unless otherwise agreed upon by the Sponsor and 
Investigator (or designee). 
n. Urine samples for determination of total radioactivity and metabolite profiling/characterization will be collected from 12 hours prior to dose administration (-12 to 0 hours predose); from 0 to 
6, 6 to 12, and 12 to 24 hours; and for 24-hour intervals up to and including 264 hours postdose (Day 12). If a subject does not meet the discharge criteria on Day 12, additional urine samples 
will be collected at 24-hour intervals until the Day of Clinic Discharge (EOT) or ET.  
o. If possible, a single baseline fecal sample will be collected from after Check-in on Day -1 until just prior to dose administration on Day 1. Postdose fecal samples for determination of total 
radioactivity and metabolite profiling/characterization will be collected from 0 to 24 hours postdose and for 24-hour intervals from Day 2 up to and including 264 hours postdose (Day 12). If 
a subject does not meet the discharge criteria on Day 12, additional fecal samples will be collected at 24-hour intervals until discharge from the CRU (EOT) or ET.   


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 66 of 69 
p. Clinical chemistry panel (fasted for at least 8 hours), coagulation parameters, hematology panel, and UA will be performed. On the day prior to EOT (if the subject completes the study) or 
ET, subjects are not required to be fasted prior to clinical laboratory evaluations.  
q. Clinical laboratory evaluations will be performed on Day 14 (if a subject is in the CRU), Day 19 (if the subject is in the CRU), and on the day prior to Clinic Discharge (EOT) or on the day 
of ET. Clinical laboratory evaluations will be performed on the day prior to subject release from the CRU if the subject completes the study (EOT). Clinical laboratory evaluations will be 
performed on the day of subject release from the CRU if the subject terminates early (ET). 
r. Testing for COVID-19 will be conducted at a minimum at Screening, Check-in (Day -1), and predose on 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. Drugs of abuse urine test, including cotinine and alcohol. Results from the drugs of abuse tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
t. Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 14 days prior to 
study drug administration for prescription medications and non-prescription medications will be recorded on the subject’s electronic Case Report Form. 
u. EOT is defined as when the subject is released from the CRU following completion of all assessments through a minimum of Day 12 up to Day 22. ET is defined as when the subject is 
released from the CRU if the subject terminates the study early. Vital sign measurements, ECG, and abbreviated physical examination results are to be available for review by the Investigator 
(or designee) prior to subject release from the CRU at the EOT. Clinical laboratory results for clinical chemistry, hematology, coagulation, and UA are to be available for review by the 
Investigator (or designee) prior to subject release from the CRU at the EOT visit and prior to subject release from the CRU at the ET visit if available. 
v. To be performed 7 days (± 2 days) following EOT or ET. EOS is defined as when the CRU contacts the subject by a follow-up phone call 7 days (± 2 days) after the EOT visit or ET visit to 
determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-305 (including subjects who are terminated early) will be contacted. 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 67 of 69 
Schedule of Assessments: Part 2 
Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Day 
Clinic Discharge/ 
EOT or ETs 
Follow-up Phone 
Call (EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
7 (±2) days post 
EOT or ETu 
Confined to the CRU 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
 
Estimated Glomerular 
Filtration Rate 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
X 
 
 
 
 
 
 
 
 
X 
 
12-lead ECGe 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
Vital Signsf 
Xg,h 
Xg,h 
Xh 
X 
X 
X 
X 
X 
X 
X 
Xg,h 
 
HDYF? Inquiryi 
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 
LOXO-305 and 
[14C]-LOXO-305 Dosingk  
 
 
X 
 
 
 
 
 
 
 
 
 
Blood Collection for 
LOXO-305 and 
[14C]-LOXO-305 
Concentration (Plasma) and 
Total Radioactivity 
(Plasma)l 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Collection for 
[14C]-LOXO-305 
Concentration and Total 
Radioactivity m 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fecal Collection for Total 
Radioactivity and 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 68 of 69 
Schedule of Assessments: Part 2 
Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Day 
Clinic Discharge/ 
EOT or ETs 
Follow-up Phone 
Call (EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
7 (±2) days post 
EOT or ETu 
[14C]-LOXO-305 
Concentrationn  
Clinical Laboratory 
Evaluationso 
X 
X 
 
 
 
X 
 
 
X 
Xt 
Xt 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Testp 
X 
X 
X 
 
 
 
 
 
 
 
 
 
HbA1c Test 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug Screenq 
X 
X 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medicationsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH Test 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; COVID-19 = SARS-CoV-2; CRU = Clinical Research Unit; ECG = electrocardiogram; EOS = End of Study; 
EOT = End of Treatment; ET = Early Termination; HbA1c = hemoglobin A1c; HDYF? = How Do You Feel?; HIV = human immunodeficiency virus; ICF = Informed Consent Form; IV = 
intravenous; 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 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 9 (EOT) or ET. 
e. 12-lead ECGs will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the scheduled blood draws at 
Screening and Check-in (Day -1), Day 1 (pre-oral and IV LOXO-305 dosing and 2 hours after oral and IV LOXO-305 dosing), Day 4, and Day 9 (EOT) or ET. 
f. Vital sign measurements (supine BP and pulse rate) will be obtained at Screening and Check-in (Day -1), Day 1 (pre-oral and IV LOXO-305 dosing and 2 hours after oral and IV 
LOXO-305 dosing), and daily (24-hour intervals) up to and including Day 9 (EOT) or ET. When scheduled at the same nominal times, postdose vital sign measurements are to be performed 
prior to postdose PK blood draws (see Section 7.2). Vital sign measurements should be carried out prior to and as close as possible to having blood drawn. Blood pressure and pulse rate will 
be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. 
g. Oral temperature and respiratory rate will be obtained at Screening, Check-in (Day -1), and on Day 9 (EOT) or ET. 
h.  Oxygen saturation will be measured at Screening, Check-in (Day -1), predose on Day 1, and on Day 9 (EOT) or ET. 
i. An HDYF? inquiry will be performed at Screening (after the ICF is signed), at Check-in (Day -1), at each postdose vital sign measurement, and at an appropriate time for all other days. 
j. 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 


Protocol 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Protocol Version 1.0, 29 June 2020  
Page 69 of 69 
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. A single oral dose of 200 mg of 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 push over approximately 2 minutes. 
l. Blood samples for determination of LOXO-305 concentration (plasma) will be collected at the following timepoints relative to oral dosing: Prior to oral LOXO-305 dosing (within 30 
minutes) and 0.5, 1, and 2 hours (just prior to IV dosing) after oral LOXO-305 dosing. Blood samples for determination of [14C]-LOXO-305 concentration (plasma) and total radioactivity 
(plasma) will be collected at the following timepoints relative to oral dosing: 2 hours (just prior to IV dosing) after oral LOXO-305 dosing. Blood samples for determination of LOXO-305 
and [14C]-LOXO-305 concentration (plasma) and total radioactivity (plasma) will continue to be collected at the following timepoints relative to the start of IV [14C]-LOXO-305 dosing: 2 
minutes (at end of IV), 10 minutes, 20 minutes, 30 minutes, 45 minutes, and 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hours postdose (Day 9 [EOT]), relative to the start 
of IV [14C]-LOXO-305 dosing (ie, start of LOXO-305 IV push). The allowed sampling window for blood samples for determination of LOXO-305 concentration (plasma) and/or 
[14C]-LOXO-305 concentration (plasma) and total radioactivity will be the following: within 15 minutes prior to dosing (oral or IV) for the predose sample timepoint; ± 1 minute for 
sampling timepoints within the first 30 minutes; ± 5 minutes for sampling timepoints > 30 minutes < 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours and ± 60 minutes 
for the sampling timepoints ranging from 48 to 192 hours. 
m. Urine samples for determination of [14C]-LOXO-305 and total radioactivity will be collected from 12 hours prior to oral dose administration (12 to 0 hours predose); from 0 (time of oral 
dose) to 4 hours postdose relative to the start of IV dose administration; from 4 to 8, 8 to 12, and 12 to 24 hours postdose relative to the start of IV dose administration; and for 24 hour 
intervals up to and including 192 hours postdose (Day 9 [EOT]), relative to the start of IV dose administration.  
n. If possible, a single baseline fecal sample will be collected from after Check-in on Day -1 until just prior to oral dose administration on Day 1. Postdose fecal samples for determination of 
[14C]-LOXO-305 and total radioactivity will be collected from 0 (time of oral dose) to 12 hours postdose relative to the start of IV dose administration; from 12 to 24 hours postdose relative 
to the start of IV dose administration; and for 24-hour intervals up to and including 192 hours postdose (Day 9 [EOT]), relative to the start of IV dose administration.  
o. Clinical chemistry panel (fasted for at least 8 hours), coagulation parameters, hematology panel, and UA will be performed. On Day 8 (if the subject completes the study) or at ET, subjects 
are not required to be fasted prior to clinical laboratory evaluations.  
p. Testing for COVID-19 will be conducted at a minimum at Screening, Check-in (Day -1), and predose on Day 1. Testing for COVID-19 may also be conducted periodically during the 
subject’s CRU confinement, at the discretion of the Investigator (or designee). Tests will be performed by rapid polymerase chain reaction or equivalent. 
q. Drugs of abuse urine test, including cotinine and alcohol. Results from the drug of abuse tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
r. Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 14 days prior 
to study drug administration for prescription medications and non-prescription medications, will be recorded on the subject’s electronic Case Report Form. 
s. EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 9 (EOT). ET is defined as when the subject is released from the CRU if 
the subject terminates the study early. Vital sign measurements, ECG, and abbreviated physical examination results are to be available for review by the Investigator (or designee) prior to 
subject release from the CRU on Day 9 (EOT) or ET. Clinical laboratory results for clinical chemistry, hematology, coagulation, and UA 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. 
t. Clinical laboratory evaluations will be performed on the day prior to subject release from the CRU (Day 8) if the subject completes the study (EOT). Clinical laboratory evaluations will be 
performed on the day of subject release from the CRU if the subject terminates early (ET).   
u. To be performed 7 days (± 2 days) following EOT or ET. EOS is defined as when the CRU contacts the subject by a follow-up phone call 7 days (± 2 days) after the EOT visit or ET visit to 
determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-305 (including subjects who are terminated early) will be 
contacted. 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan: LOXO-BTK-20007 (Final version 1.0) 
 
 
A Phase I, Open-label, Two-part Study of the Absorption, Metabolism, 
Excretion, and the Absolute Bioavailability of [14C]-LOXO-305 in Healthy 
Male Subjects  
 
 
NCT06180954 
 
 
Approval Date: 13-Oct-2020 


TITLE PAGE 
Statistical Analysis Plan 
 A Phase I, Open-label, Two-part Study of the Absorption, Metabolism, 
Excretion, and the Absolute Bioavailability of [14C]-LOXO-305 in Healthy 
Male Subjects  
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 13OCT2020 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20007 
Covance Study: 8419667 
 
 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
 
 
 
Principal Investigator: 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
PPD


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 2 of 25 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objectives .......................................................................................................... 6 
2.2. Secondary Objectives ...................................................................................................... 7 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
3.2. Secondary Endpoints ....................................................................................................... 9 
4. STUDY DESIGN................................................................................................................... 9 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 12 
6. STUDY TREATMENTS ..................................................................................................... 12 
7. DEFINITIONS OF POPULATIONS .................................................................................. 13 
7.1. All Subjects Population ................................................................................................. 13 
7.2. Safety Population .......................................................................................................... 13 
7.3. Pharmacokinetic Population ......................................................................................... 13 
8. STATISTICAL METHODOLOGY .................................................................................... 13 
8.1. General Considerations ................................................................................................. 13 
8.1.1. Calculation of the Summary Statistics ................................................................... 14 
8.1.2. Repeat and Unscheduled Assessments ................................................................... 14 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 15 
8.2. Subject Disposition and Population Assignment .......................................................... 15 
8.3. Demographics and Baseline Characteristics ................................................................. 15 
8.4. Prior and Concomitant Medication ............................................................................... 15 
8.5. Pharmacokinetic Assessments ...................................................................................... 15 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 15 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 21 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 21 
8.6. Safety and Tolerability Assessments ............................................................................ 22 
8.6.1. Adverse Events ....................................................................................................... 22 
8.6.2. Clinical Laboratory Parameters .............................................................................. 23 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 3 of 25 
8.6.3. Vital Signs Parameters ........................................................................................... 23 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 24 
8.6.5. Other Assessments ................................................................................................. 24 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 24 
9. INTERIM ANALYSES ....................................................................................................... 24 
10. CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES .................................. 24 
11. REFERENCES .................................................................................................................. 24 
12. APPENDICES ................................................................................................................... 25 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 4 of 25 
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 
Aef 
amount excreted in feces per sampling interval 
Aeu 
amount excreted in urine per sampling interval 
AME 
absorption, metabolism, and excretion 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-t 
area under the concentration-time curve from time 0 to the last 
quantifiable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CK 
creatine kinase 
CL 
total clearance 
CL/F 
apparent total clearance 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
CRU 
Clinical research unit  
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
F 
absolute bioavailability 
fe 
percentage of dose excreted in urine and feces per sampling interval 
fef 
percentage of dose excreted in feces per sampling interval  
feu 
percentage of dose excreted in urine per sampling interval  
Geom Mean 
geometric mean  
HYDF? 
How Do You Feel? 
λz 
apparent terminal elimination rate constant 
LLOQ 
lower limit of quantification 
ln 
natural log  
LSM 
Least squares mean 
ICF 
informed consent form 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 5 of 25 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MetID 
metabolite profiling and identification 
NC 
not calculated 
NR  
no result 
PK 
pharmacokinetic(s) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
t1/2 
terminal elimination half-life 
tmax 
time to maximum observed concentration 
UA 
urinalysis 
Vss 
volume of distribution at steady state 
Vz 
volume of distribution 
Vz/F 
apparent volume of distribution 
WHODrug 
World Health Organization Drug Dictionary  
 
 
 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 6 of 25 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 29 June 2020) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
2.1. Primary Objectives 
Part 1: 
The primary objectives of Part 1 of the study are: 
● to determine the mass balance and routes of elimination of [14C]-LOXO-305 following 
oral administration of a single dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) in healthy male subjects 
● to assess the PK of LOXO-305 following a single oral dose of [14C]-LOXO-305 
● to determine the whole blood and plasma concentrations of total radioactivity following 
a single oral dose of [14C]-LOXO-305 
● to determine urinary and fecal recovery of total radioactivity following a single oral 
dose of [14C]-LOXO-305 
● to characterize and identify metabolites of LOXO-305 in plasma, urine, and feces 
following a single oral dose of [14C]-LOXO-305. 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 7 of 25 
Part 2: 
The primary objectives of Part 2 of the study are: 
● to determine the absolute bioavailability of LOXO-305 following a single oral dose of 
200 mg LOXO-305 along with an intravenous (IV) dose of < 100 µg of 
[14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) 
● to evaluate the PK of LOXO-305 and [14C]-LOXO-305 following oral dosing of 
LOXO-305 and IV dosing of [14C]-LOXO-305 
● to evaluate the plasma concentration of total radioactivity following IV dosing of 
[14C]-LOXO-305 
● to evaluate the urinary excretion of [14C]-LOXO-305 and total radioactivity following 
IV dosing of [14C]-LOXO-305 
● to evaluate the fecal recovery of [14C]-LOXO-305 and total radioactivity following IV 
dosing of [14C]-LOXO-305. 
2.2. Secondary Objectives 
Part 1: 
The secondary objective of Part 1 of the study is: 
● to assess the safety and tolerability of [14C]-LOXO-305 when administered to healthy 
male subjects. 
Part 2: 
The secondary objective of Part 2 of the study is: 
● to assess the safety and tolerability of LOXO-305 and [14C]-LOXO-305 when 
administered to healthy male subjects. 
3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
Part 1: 
The primary PK endpoints of LOXO-305 in plasma and total radioactivity in whole blood 
and plasma following oral administration of [14C]-LOXO-305 are as follows: 
● area under the concentration-time curve (AUC) from time zero extrapolated to infinity 
(AUC0-inf) 
● AUC from time zero to the last quantifiable concentration (AUC0-t) 
● maximum observed concentration (Cmax) 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 8 of 25 
● time to maximum concentration (tmax) 
● apparent terminal elimination half-life (t1/2) 
● apparent systemic clearance (LOXO-305 only; CL/F) 
● apparent volume of distribution (LOXO-305 only; Vz/F) 
● AUC0-inf of plasma LOXO-305 relative to AUC0-inf of plasma total radioactivity 
(AUC0-inf Plasma LOXO-305/Total Radioactivity Ratio) 
● AUC0-inf of whole blood total radioactivity to AUC0-inf of plasma total radioactivity 
(AUC0-inf Blood/Plasma Ratio). 
The primary PK endpoints of total radioactivity in urine are as follows: 
● amount excreted in urine (Aeu) 
● cumulative Aeu 
● percentage of dose excreted in urine (feu) 
● cumulative feu. 
The primary PK endpoints of total radioactivity in feces are as follows: 
● amount excreted in feces (Aef) 
● cumulative Aef 
● percentage of dose excreted in feces (fef) 
● cumulative fef. 
The primary outcome for metabolites will be derived: 
● metabolic profile of LOXO-305 
● identification of LOXO-305 metabolites. 
Part 2: 
The primary PK endpoints of LOXO-305 in plasma following oral administration of 
LOXO-305 are as follows: 
● AUC0-inf, AUC0-t, Cmax, tmax, t1/2, CL/F, and Vz/F 
● absolute bioavailability (F). 
The primary PK endpoints of [14C]-LOXO-305 in plasma following IV administration of 
[14C]-LOXO-305 are as follows: 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 9 of 25 
● AUC0-inf, AUC0-t, Cmax, tmax, and t1/2 
● total clearance (CL) 
● volume of distribution (Vz) 
● volume of distribution at steady state (Vss). 
The primary PK endpoints of [14C]-LOXO-305 and total radioactivity in urine collections are 
as follows: 
● Aeu, cumulative Aeu, feu, cumulative feu 
● renal clearance (CLR; [14C]-LOXO-305 only). 
The primary PK endpoints of [14C]-LOXO-305 and total radioactivity in feces collections are 
as follows: 
● Aef, cumulative Aef, fef, cumulative fef. 
Other PK parameters may also be reported. 
3.2. Secondary Endpoints 
The secondary safety outcome measures for both parts of this study are as follows: 
● monitoring adverse events (AEs) 
● clinical laboratory evaluations 
● 12-lead electrocardiogram (ECG) parameters 
● vital signs measurements 
● Concomitant medication  
● physical examinations. 
4. STUDY DESIGN  
This will be an open-label, nonrandomized, 2-part, absorption, metabolism, and excretion 
(AME) and absolute bioavailability study of [14C]-LOXO-305 in healthy male subjects. 
Subjects in Part 1 will not participate in Part 2, nor will subjects in Part 2 participate in Part 1. 
Parts 1 and 2 are independent of each other and do not need to be conducted in sequential 
order. 
Part 1 is designed to evaluate the AME profiles of LOXO-305, to identify and characterize 
metabolites of LOXO-305, and to assess the safety and tolerability of [14C]-LOXO-305. 
Subjects in Part 1 will be administered a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution. Six subjects will participate in each part of the 
study. Each subject will participate in either Part 1 or Part 2, but not both. In the event of 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 10 of 25 
early withdrawal of any subjects and/or to ensure 6 subjects complete each part of the study, 
replacement subjects may be enrolled at the discretion of the Sponsor. 
Part 2 is designed to determine the absolute bioavailability of LOXO-305, to evaluate the 
plasma concentration of LOXO-305 and plasma PK of [14C]-LOXO-305 and total radio 
activity, and to evaluate the urinary excretion of [14C]-LOXO-305 and total radioactivity, to 
evaluate the fecal excretion of [14C]-LOXO-305 and total radioactivity, and to assess the 
safety and tolerability of LOXO-305 and [14C]-LOXO-305. Subjects in Part 2 will be 
administered a single oral dose of 200 mg of 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 push over approximately 2 minutes.  
Six subjects will participate in each part of the study. Each subject will participate in either 
Part 1 or Part 2, but not both. 
In the event of early withdrawal of any subjects and/or to ensure 6 subjects complete each 
part of the study, replacement subjects may be enrolled at the discretion of the Sponsor. 
The start of the study is defined as the earliest date a subject who is enrolled in either part of 
the study signs an Informed Consent Form (ICF). A subject who completes sufficient total 
radioactivity recovery (Part 1 only), or LOXO-305 and [14C]-LOXO-305 (Part 2 only) 
sampling prior to Clinic Discharge is considered to have completed the study. The end of the 
study is defined as the latest date a subject receives the Follow-up Call. The planned duration 
of study conduct for Part 1 is up to 60 days from Screening through the Follow-up Call. The 
planned duration of study conduct for Part 2 is up to 47 days from Screening through the 
Follow-up Call. 
A schematic of the study design of Part 1 is presented in Figure 1 and a schematic of the 
study design of Part 2 is presented in Figure 2 
Figure 1 Study Design Schematic: Part 1 
Screening 
Check-in 
Dosinga 
LOXO-305, Total 
Radioactivity 
Concentrations, and 
MetID Sampling 
Clinic Dischargeb 
Follow-up Callc 
Days -29 to -2 
Day -1 
Day 1 
Day 1 to Clinic (CRU) 
Discharge 
Days 12 to 22 
Approximately 
7 days after 
Clinic Discharge 
 
Clinic Confinement 
 
CRU = Clinical Research Unit; MetID = metabolite profiling and identification 
a Single oral dose of 200 mg of [14C]-LOXO-305 (containing ~200 µCi) administered as an oral solution following an 
overnight fast of at least 10 hours. 
b Subjects will be discharged from the CRU starting on Day 12 if plasma radioactivity is below the limit of quantification 
(BLQ) for 2 consecutive collections, and ≥ 90% of the radioactive dose is recovered and ≤ 1% of the radioactive dose per 
day is recovered in excreta (urine and feces) for 3 consecutive days on which a fecal sample is collected. If these criteria are 
not satisfied by the morning of Day 12, subjects will continue to be confined in the CRU until these criteria are met, up to a 
maximum of Day 22. Sample collection and CRU confinement will continue until discharge criteria are met or the maximum 
stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or designee). 
c Subjects will receive a Follow-up Call approximately 7 days after CRU Discharge. 
 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 11 of 25 
Figure 2 Study Design Schematic: Part 2 
Screening 
Check-in 
Dosinga 
LOXO-305, 
[14C]-LOXO-305, and 
Total Radioactivity 
Concentrations 
Clinic 
Discharge 
Follow-up Callb 
Days -29 to -2 
Day -1 
Day 1 
Day 1 to Day 9 
Day 9 
Approximately 
7 days after 
Clinic Discharge 
 
Clinic Confinement  
 
a Following an overnight fast of at least 10 hours, a single oral dose of 200 mg of LOXO-305 administered as 2 × 100-mg 
tablets and a single IV dose of < 100 µg of [14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) administered 
by IV push 2 hours after the oral dose. 
b Subjects will receive a Follow-up Call approximately 7 days after Clinic Discharge. 
Part 1: 
After a Screening period of up to 28 days, subjects will check in to the CRU on Day -1 to 
confirm eligibility and to become familiar with study procedures. On the morning of Day 1, 
following an overnight fast of at least 10 hours, subjects will receive a single oral dose of 
200 mg of [14C]-LOXO-305 (containing ~200 µCi) administered as an oral solution. Subjects 
will be confined at the CRU from the time of Check-in (Day -1) until Clinic Discharge 
(between Days 12 and 22). After completing discharge procedures, subjects will be 
discharged from the CRU as early as Day 12 and up to Day 22, provided recovery of 
radioactivity has reached the following threshold values:  
● Plasma radioactivity BLQ for 2 consecutive collections, and 
● ≥ 90% of the radioactive dose is recovered, and  
● ≤ 1% of the radioactive dose per day is recovered in excreta (urine and feces) for 
3 consecutive days on which a fecal sample is collected.   
Sample collection and confinement will continue until discharge criteria are met or the 
maximum stay is reached, unless otherwise agreed upon by the Sponsor and Investigator (or 
designee). Subjects will receive a Follow-up Call approximately 7 days after Clinic 
Discharge. 
Samples for determination of LOXO-305 concentrations in plasma, total radioactivity 
concentrations in plasma, whole blood, urine, and feces, and for metabolite 
profiling/characterization will be obtained through at least 264 hours postdose (Day 12), and 
possibly up to 504 hours postdose (Day 22).  
For subjects experiencing emesis within 4 hours following dosing, vomitus will be collected. 
The Medical Monitor (or designee) should be contacted immediately for further instructions 
and to determine if the subject should continue the study. All vomitus collected will be stored 
for possible analysis, as deemed appropriate.  
Part 2: 
After a Screening period of up to 28 days, subjects will check in to the CRU on Day -1 to 
confirm eligibility and to become familiar with study procedures. On the morning of Day 1, 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 12 of 25 
following an overnight fast of at least 10 hours, subjects will receive a single oral dose of 
200 mg of LOXO-305 as 2 × 100-mg tablets and 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 push over approximately 2 minutes. Subjects will be confined at the CRU from the 
time of Check-in (Day -1) until Day 9 and will be discharged from the CRU after completing 
all discharge procedures. Subjects will receive a Follow-up Call approximately 7 days after 
Clinic Discharge. 
Samples for determination of LOXO-305 concentrations in plasma, [14C]-LOXO-305 
concentrations in plasma, urine, and feces, and total radioactivity concentrations in urine and 
feces will be obtained through 192 hours postdose (Day 9).  
Part 1 and Part 2: 
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), and recording of concomitant medications will be performed at 
specified times during the study. AEs and serious adverse events (SAEs) will be collected 
beginning at informed consent. AEs will be reported throughout the study (ie, from signing of 
the ICF until End of Study [EOS], or until Early Termination [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 End of Treatment [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. 
5. SAMPLE SIZE JUSTIFICATION  
No formal statistical assessment of sample size has been conducted as this study does not 
have a hypothesis. The sample size chosen for this study is common in human radiolabeled 
studies and is considered sufficient to achieve the objectives of the study. Six subjects will 
participate in each part of the study. Each subject will participate in either Part 1 or Part 2, but 
not both. In the event of early withdrawal of any subjects and/or to ensure 6 subjects 
complete each part of the study, replacement subjects may be enrolled at the discretion of the 
Sponsor. 
6. STUDY TREATMENTS  
In Part 1, the study treatment name to be used in the TFLs is 200 mg [14C]-LOXO-305 oral 
solution.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 13 of 25 
In Part 2, the study treatment name is 2x100mg LOXO-305 Tablets + < 100 µg  [14C] 
LOXO-305 IV Solution. 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those related to COVID-19, will be considered prior to 
database lock for their importance and taken into consideration when assigning subjects to 
populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(LOXO-305). Subjects will be classified into groups based on actual treatment received. 
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of [14C]-LOXO-305 
or LOXO-305 and have at least 1 quantifiable PK concentration, and for whom at least 1 PK 
parameter can be computed. A subject may be excluded from the PK summary statistics if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax. 
8. STATISTICAL METHODOLOGY  
8.1. General Considerations 
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the EOT visit. Any 
subject who discontinued the study will be identified accordingly in the listings. Summaries 
will include the subjects assigned to the relevant population based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, baseline derivation, and changes from baseline.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 14 of 25 
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum. 
● As ET data is not associated with any scheduled timepoint, it will be excluded from all 
calculations of summary statistics.  
● Post dose repeats and unscheduled assessments will not be included in calculation of 
summary statistics.  
For categorical data the following rules will be applied:  
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included.  
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is missing. 
This will ensure that the population size totals are consistent across different 
parameters.  
All protocol deviations and data issues (eg missing data, out of protocol window) that occur 
during the study, including those related to COVID-19, will be considered prior to database 
lock for their severity/impact on how the data will be displayed. 
8.1.2. Repeat and Unscheduled Assessments 
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value.  
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value for each period. 
Post dose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations, with the exception of the baseline derivation (see Section 8.1.3). 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 15 of 25 
8.1.3. Definitions of Baseline and Change from Baseline  
Baseline value is defined as the last non missing measurement before administration of 
LOXO-305 in each part of the study.  
In general, baseline for Part 1 and Part 2 refers to the pre-dose value collected on Day 1. For 
laboratory tests, baseline is the value collected on Day -1. 
If the date/time of the value is incomplete or missing, it will be excluded from the baseline 
calculation, unless the incomplete date/time indicates the value was recorded prior to dosing 
of LOXO-305 in each part of the study.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects.  
See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by part will be provided, based on the all subjects population. 
8.3. Demographics and Baseline Characteristics  
The demographics and baseline characteristics including age, sex, race, ethnicity, height, 
body weight, and body mass index will be listed.  
A summary table by part 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 of LOXO-305. 
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 March 2020. Prior and concomitant 
medications will be listed.  
8.5. Pharmacokinetic Assessments 
8.5.1. Pharmacokinetic Analysis  
Part 1 PK parameters will be determined where possible from plasma concentrations of 
LOXO-305 and whole blood and plasma concentrations of total radioactivity. Part 2 PK 
parameters will be determined from plasma concentrations of LOXO-305, plasma, urine, and 
feces concentrations of [14C]-LOXO-305, and plasma concentrations of total radioactivity, 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 16 of 25 
urine and feces concentrations of total radioactivity. Parameters will be determined using a 
model-independent approach performed using Phoenix WinNonlin (Certara USA, Inc.) 
version 8.1 or higher. Additional PK parameters beyond those listed in subsections below 
may be determined where appropriate. 
PK analysis will be carried out using the actual dose administered (mg for oral doses and µg 
for IV dose) and 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. Calculation of PK parameters for urine and feces 
will be determined using nominal collection intervals. 
In both parts, the whole blood and plasma parameters Cmax, tlast, 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. Part 1 - Mass Balance 
Concentration ratios of whole blood total radioactivity to plasma total radioactivity, 
individual and cumulative mass balance of total radioactivity (amount (Ae) and percentage of  
dose (%fe) recovered as total radioactivity in urine, feces, emesis (if applicable) and total 
excreta in all excreta) will be calculated where possible by Covance radioanalysis laboratory 
and will be reported separately in the radioanalysis report. 
The following PK parameters will be determined for each subject, where possible, from the 
plasma concentrations of LOXO-305 and whole blood and plasma concentrations of total 
radioactivity: 
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mLb area under the concentration-time curve from hour 0 to the time 
of the last quantifiable concentration (tlast)c 
AUC0-inf 
h*ng/mLb area under the concentration-time curve from time 0 
extrapolated to infinityd 
%AUCextrap 
% 
percentage of AUC0-inf due to extrapolation from the last 
quantifiable concentration to infinity 
Cmax 
ng/mLb 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
 
CL/F 
L/h 
apparent systemic clearance (LOXO-305 only) 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
(LOXO-305 only) 
AUC0-inf Plasma 
LOXO-305/Total 
Radioactivity Ratio  
 
AUC0-inf of plasma LOXO-305 relative to AUC0-∞ of plasma 
total radioactivity  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 17 of 25 
AUC0-inf 
Blood/Plasma Total 
Radioactivity Ratio 
 
AUC0-inf of whole blood total radioactivity to AUC0-∞ of plasma 
total radioactivity 
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 For total radioactivity, Cmax and AUC units will be presented as mass equivalents (ng Eq/g and h*ng Eq/g, respectively). 
c Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing and decreasing 
concentrations. 
d Based on the last observed quantifiable concentration 
8.5.1.2. Part 2 - Absolute Bioavailability 
Oral Dose Plasma PK  
The following PK parameters will be calculated for each subject, where possible, based on 
the plasma concentrations of LOXO-305:  
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mL 
area under the concentration-time curve from hour 0 to the time 
of the last quantifiable concentration (tlast)b 
AUC0-inf 
h*ng/mL 
area under the concentration-time curve from hour 0 
extrapolated to infinityc 
%AUCextrap 
% 
percentage of AUC due to extrapolation from the last 
quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent systemic clearance  
Vz/F 
L 
apparent volume of distribution during the terminal phase  
F 
 
absolute bioavailability; expressed as a ratio, calculated as  
 F = AUC0-inf (oral) x Dose (IV) 
       AUC0-inf (IV) x Dose (oral) 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study.  
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing and decreasing 
concentrations. 
c Based on the last observed quantifiable concentration 
IV Dose Plasma PK  
The following PK parameters will be calculated for each subject, where possible, based on 
the plasma concentrations of total radioactivity and [14C]-LOXO-305:  
Parameter 
Unitsa 
Definition 
AUC0-t 
h*pg/mL 
area under the concentration-time curve from hour 0 to the time 
of the last quantifiable concentration (tlast)b 
AUC0-inf 
h*pg/mL 
area under the concentration-time curve from hour 0 
extrapolated to infinityc 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 18 of 25 
%AUCextrap 
% 
percentage of AUC due to extrapolation from the last 
quantifiable concentration to infinity 
Cmax 
pg/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
terminal elimination half-life 
CL 
L/h 
total clearance ([14C]-LOXO-305 only) 
Vz 
L 
volume of distribution during the terminal phase  ([14C]-LOXO-
305 only) 
Vss 
L 
volume of distribution at steady state  ([14C]-LOXO-305 only) 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study.  
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing and decreasing 
concentrations. 
c Based on the last observed quantifiable concentration 
8.5.1.3. Part 2 - IV Dose Excretion PK 
For each subject, the following PK parameters will be calculated, where possible, based on 
the urine concentrations of [14C]-LOXO-305 and total radioactivity: 
Parameter 
Units 
Definition 
Aeu 
µga 
amount excreted in urine per sampling interval 
Cum Aeu 
µga 
cumulative amount excreted in urine 
CLR 
L/h 
renal clearance ([14C]-LOXO-305 only) 
feu 
% 
percentage of dose excreted in urine per sampling interval, 
where %feu = 100 (Aeu/dose) 
Cum feu 
% 
cumulative percentage of dose excreted in urine 
a For total radioactivity, units will be presented as mass equivalents (µg Eq). 
For each subject, the following PK parameters will be calculated, where possible, based on 
the fecal concentrations of [14C]-LOXO-305 and total radioactivity: 
Parameter 
Units 
Definition 
Aef 
µga 
amount excreted in feces per sampling interval 
Cum Aef 
µga 
cumulative amount excreted in feces 
fef 
% 
percentage of dose excreted in feces per sampling interval,  
where %fef = 100 (Aef/dose) 
Cum fef 
% 
cumulative percentage of dose excreted in feces 
a For total radioactivity, units will be presented as mass equivalents (µg Eq). 
In addition, the following excretion parameters will be calculated, where possible, based on 
total radioactivity in total (urine+feces) excreta:  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 19 of 25 
Parameter 
Units 
Definition 
fe 
% 
percentage of dose excreted in urine and feces per sampling interval, 
where fe = feu + fef 
Cum fe 
% 
cumulative percentage of dose excreted in urine and feces, 
calculated as the sum of the fe in urine + feces  
8.5.1.4. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-inf, t1/2, CL/F, CL, Vz/F, Vz, and Vss) 
will only be calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
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. 
8.5.1.5. 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.  
For any partial AUC determination (eg, AUC0-24), nominal time will generally be used for the end 
of the interval. Actual times for partial AUC intervals may be used at the discretion of the 
pharmacokineticist. 
If the extrapolated area is >30%, AUC0-inf (and derived parameters) will be excluded from the 
summary statistics. 


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 20 of 25 
If AUC0-inf cannot be determined reliably for all subjects and/or treatments, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUC0-t may be used in calculation of 
ratios or absolute bioavailability. 
8.5.1.6. Calculation of Excretion Parameters (Part 2) 
The amount of the dose administered recovered over each time interval t1 to t2 (Ae1-t2) in 
urine or feces for [14C]-LOXO-305 and total radioactivity will be calculated as the product of 
urine analyte concentration and urine sample volume or feces analyte concentration and fecal 
sample weight. Where only urine sample weight is supplied, a specific gravity of 1 g/mL will 
be assumed, and it will be considered equivalent to urine volume. Cumulative Aeu or Aef will 
be calculated by summing the respective matrix Aet1-t2 values across collection intervals. 
The percentage of the dose administered recovered (fe) over each time interval t1 to t2 (fet1-t2) 
in urine or feces as [14C]-LOXO-305 and total radioactivity will be calculated for each 
sample collection interval as follows: 
fet1-t2 = (Aet1-t2 / dose) × 100 
Cumulative feu or fef will be calculated by summing the respective matrix fet1-t2 and combined 
matrix fet1-t2 (urine + feces) values in the same manner as Aeu and Aef. 
Renal clearance (CLR) will be calculated over 0-t2 according to the following formula, where 
cumulative Aeu and plasma AUC are calculable to the same end time (t2): 
CLR = Aeu0-t2 / AUC0-t2 
Alternatively, AUC0-inf may be used if urinary excretion of the dose is considered to be 
complete and AUC0-inf is well characterized. 
8.5.1.7. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma and whole blood concentrations 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 or whole blood concentration is missing, it will be set to zero by 
default within Phoenix WinNonlin. 
Urine or feces concentrations that are BLQ will be set to zero for the calculation of Aeut1-t2 
and Aeft1-t2, respectively.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 21 of 25 
8.5.1.8. 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 
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For PK concentration data the following rules will apply: 
● 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 CV% of geometric mean will be reported as not calculated (NC). 
● If there are fewer l than 3 values in the data series, only the minimum, maximum and N 
will be presented. The other summary statistics will be denoted as not calculated (NC). 
For PK parameters the following rule will apply: 
● Geometric mean and coefficient of variation will not be calculated for tlast or tmax. 
PK analysis will use actual times as recorded on the electronic case report form.  
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables by part, mean (+ standard deviation [SD]) figures, overlaying individual 
figures, and individual figures by time postdose will be provided for plasma and whole blood 
PK concentrations. All figures will be produced on both linear and semi-logarithmic scales. 
The +SD bars will only be displayed on the linear scale.  
Summary tables by part will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV%, 
minimum, median, maximum, geometric mean [Geom Mean] and geometric CV% [Geom 
CV%]) will be calculated for plasma LOXO-305 PK parameters. Excluded subjects will be 
listed in the PK parameter tables, but will be excluded from the summary statistics and noted 
as such in the tables.  
Separate summary tables by time interval will be provided for excretion parameters and 
cumulative excretion parameters.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 22 of 25 
No inferential statistical analyses are planned. 
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. All AEs will be assigned severity grade using National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose.  
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator.  
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 
dosing for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized by part 
for the following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by part  
● TEAEs by severity and part 
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by part 
● Treatment-related TEAEs by severity and part 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class and preferred term 
● Preferred term and treatment/part 
● System organ class, preferred term, day of onset, and treatment/part  
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 dosing.  
● 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.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 23 of 25 
● 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 dosing is 01MAY2019/08:00 and recorded start date/time 
of an AE is 03MAY2019, then the minimum possible onset time will be calculated by 
assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).  
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).  
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible, up to Grade 4 in the absence of a 
fatal outcome.  
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters, with changes from baseline, will be listed; any value 
outside the clinical reference range will be flagged, and whether the out of range value was 
deemed clinically significant or not clinically significant will be indicated. Separate listings 
will be provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range. 
The observed results and change from baseline for clinical chemistry, hematology, and 
coagulation parameters will be summarized descriptively by study part and timepoint.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to 0 whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters  
All vital signs parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated  
The observed results and change from baseline for all vital signs parameters will be 
summarized descriptively by part and timepoint.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 24 of 25 
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated.  
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by part and timepoint. QTcF values that are > 450 msec and 
increase from baseline > 30 msec will be flagged in the data listing.  
8.6.5. Other Assessments  
Medical history and physical examination will be listed.  Any physical examination 
abnormalities reported will also be flagged as clinically significant or not clinically 
significant as indicated.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
9. INTERIM ANALYSES  
No interim analyses are planned. 
10. CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There was a minor change from the protocol-specified analyses in Protocol Version 1.0 dated 
29 June 2020. Section 2.2.1 Primary Endpoints stated in Part 2 that “The primary PK 
endpoints of LOXO-305 and total radioactivity in plasma following oral administration of 
LOXO-305 are as follows”, however total radioactivity in plasma will be calculated after the IV 
dose. 
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  


SAP 
CONFIDENTIAL 
Covance Study: 8419667 
Protocol Reference: LOXO-BTK-20007 
Sponsor Final, Version 1.0, 13OCT2020 
Page 25 of 25 
12. APPENDICES 
Appendix 1: 
Document History 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
NA = not applicable