Clinical trial NCT06190678
Conditions: Healthy Renal Insufficiency
Sponsor: Eli Lilly and Company
Start date: 2021-02-01; Completion date: 2021-06-04
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to measure how much of pirtobrutinib (LOXO-305) gets into the bloodstream and how long it takes the body to eliminate it in participants with impaired kidney function and healthy participants. The side effects and tolerability of pirtobrutinib will also be evaluated. Participation could last around 46 days.

Detailed description:

Arms: arm 1: Participants with normal renal function (eGFR \>= 90 mL/min/1.73 m2) received a single dose of Pirtobrutinib 200 milligrams (mg) administered orally on Day 1. arm 2: Participants with severe renal impairment (eGFR: \< 30 mL/min/1.73 m2) received a single dose of Pirtobrutinib 200 mg administered orally on Day 1.
Interventions: intervention 1: Pirtobrutinib
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol J2N-OX-JZNG Version 2.0
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Phalmacokinetic Study of 
LOXO-305 Administered to Fasted Renally Impaired Male and Female Subjects and Fasted Matched-control 
Healthy Subjects
NCT06190678
Approval Date: 17-Feb-2021 


Pr ot oc ol  
A n O pe n -l a bel, N o nr a n d o mize d, Si n gle-d ose, P ar allel -gr o u p, S afet y, 
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Pr ot oc ol Date: 1 7 Fe br uar y 2 0 2 1  
Pr ot oc ol Versi o n: 2. 0 
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Pr ot oc ol Refere nce N u m ber: L O X O -B T K -2 0 0 1 3 
C o va nce St u d y N u m ber: 8 4 1 9 6 9 2  
I N D N u m ber: 1 3 9 8 7 6 
S p o ns or:  
L o x o  O nc ol o g y, I nc.  
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St u d y Site: 
M ulti ple Sites  
S p o ns or Si g nat or y: 
Pri nci pal I n vesti gat or: 
M ulti ple I n vesti gat ors  
I nf or mati o n descri be d herei n is c o nfi de ntial a n d ma y be discl ose d o nl y wit h t he e x press 
writte n per missi o n of t he S p o ns or.  
P P D


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
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Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 3 of 75 
 
 
 
INVESTIGATOR AGREEMENT 
 
I have read the protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
 
 
Name, Qualifications 
Date 
Principal Investigator 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 4  of 7 5  
 
 
 
S T U D Y I D E N TI FI C A TI O N  
 
S p o ns or  
L o x o O nc ol o g y,  I nc. 
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d C o m pa n y 
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S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
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Tel ( m o bile): 
 
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Tel ( office): 
 
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Seri o us A d verse E ve nt ( S A E) 
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Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 5 of 75 
 
 
 
SYNOPSIS 
 
Study Title 
 
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and 
Pharmacokinetic Study of LOXO-305 Administered to Fasted Renally Impaired Male and 
Female Subjects and Fasted Matched-control Healthy Subjects 
 
Objectives 
 
The primary objective of the study is to evaluate the pharmacokinetic (PK) profile of 
LOXO-305 in subjects with impaired renal function compared to matched-control healthy 
subjects. 
 
The secondary objective of the study is to evaluate safety and tolerability of LOXO-305 in 
subjects with impaired renal function and matched-control healthy subjects. 
 
Study Design 
 
This study is an open-label, nonrandomized, multi-center, single-dose, parallel-group study to 
determine the PK, safety, and tolerability of LOXO-305 administered orally at a dose of 
200 mg to fasted adult males and females with impaired renal function and healthy subjects 
with normal renal function. Renal function will be classified based on the baseline estimated 
glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) study equation. Baseline eGFR will be obtained for all subjects 
(ie, subjects with renal impairment and matched-control healthy subjects) by taking the 
mean of the eGFR obtained from Screening and from historical values obtained within 
a 3-month period from Screening. If no historical eGFR value is available, a second 
Screening eGFR sample will be taken during the Screening period ( 14 days apart) and 
the mean of the 2 values will be used as the baseline eGFR for group assignment. 
Individual eGFR values recorded for each measurement contributing to the subject mean 
baseline value must fall within the specified eGFR ranges for each group (ie, matched-control 
healthy subjects and subjects with severe renal impairment [and subjects with mild and/or 
moderate renal impairment, if they are enrolled]) to categorize subjects’ renal impairment 
status. The eGFR based on CKD-EPI equation will be repeated at Check-in (Day -1) to 
confirm renal impairment status. For matched-control healthy subjects, a single assessment of 
actual creatinine clearance computed over a 24-hour urine collection may be used in place of 
the eGFR (based on the CKD-EPI equation), at the Investigator’s (or designee’s) discretion. 
 
Subjects with severe renal impairment (Group 4), and matched-control healthy subjects with 
normal renal function (Group 1) will begin enrolling in the study first. Subjects will be 
recruited so that up to 8 subjects with severe renal impairment and up to 8 subjects with 
normal renal function are enrolled, with the goal of having at least 6 subjects with severe 
renal impairment and at least 6 matched-control healthy subjects complete the study. 
 
Subjects will be enrolled within the following groups based on their eGFR values calculated 
using the CKD-EPI equation at Screening and repeated at Check-in (Day -1) as judged by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor: 


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 6 of 75 
 
 
 
• Group 1: Matched-control healthy subjects with normal renal function (eGFR: 
≥ 90 mL/min/1.73 m2) 
• Group 4: Subjects with severe renal impairment (eGFR: < 30 mL/min/1.73 m2) 
Continuous review of the safety data and PK data (if available) from up to 8 subjects with 
severe renal impairment and up to 8 matched-control healthy subjects with normal renal 
function will be conducted after these subjects have completed all study-related assessments 
through 72 hours (approximately 3 half-lives) postdose, at a minimum. The safety data will 
include adverse events (AEs) and serious AEs (SAEs), vital signs, physical examinations, 
electrocardiograms (ECGs), and clinical laboratory evaluations. 
 
Following continuous review of the safety data and PK data from up to 8 subjects with severe 
renal impairment (Group 4) and up to 8 matched-control healthy subjects with normal renal 
function (Group 1), subjects with mild renal impairment (Group 2) and/or moderate renal 
impairment in (Group 3) may be enrolled if deemed necessary by the Sponsor. If no clinically 
relevant effect on PK is observed in subjects in Group 1 and Group 4, enrollment of subjects 
in Group 2 and/or Group 3 will not occur. 
 
If the Sponsor deems it necessary to enroll subjects with mild and/or moderate renal 
impairment, subjects will be recruited so that up to 8 subjects with mild renal impairment, up 
to 8 subjects with moderate renal impairment, and up to an additional 16 matched-control 
healthy subjects with normal renal function may be enrolled, with the goal of having at least 
6 subjects with mild renal impairment and at least 6 subjects with moderate renal impairment 
and their matched-control healthy subjects complete the study. Enrollment and dosing for 
subjects in Group 2 and/or Group 3 may only occur after the safety and PK data for subject(s) 
in Group 1 and Group 4 through a minimum of 72 hours postdose are reviewed and the 
Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed 
with dosing. 
 
Subjects will be enrolled within the following groups based on their eGFR values calculated 
using the CKD-EPI equation at Screening and repeated at Check-in (Day -1) as judged by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor: 
 
• Group 2: Subjects with mild renal impairment (60 ≤ eGFR < 90 mL/min/1.73 m2) 
• Group 3: Subjects with moderate renal impairment (30 ≤ eGFR < 60 mL/min/1.73 m2) 
Baseline eGFR will be obtained for all subjects (ie, subjects with renal impairment and 
matched-control healthy subjects) by taking the mean of the eGFR obtained from 
Screening and from historical values obtained within a 3-month period from Screening. 
If no historical eGFR value is available, a second Screening eGFR sample will be taken 
during the Screening period ( 14 days apart) and the mean of the 2 values will be used 
as the baseline eGFR for group assignment. Individual eGFR values recorded for each 
measurement contributing to the subject mean baseline value must fall within the specified 
eGFR ranges for each group (ie, matched-control healthy subjects and subjects with severe 
renal impairment [and subjects with mild and/or moderate renal impairment, if they are 
enrolled]) to categorize subjects’ renal impairment status. The eGFR based on CKD-EPI 
equation will be repeated at Check-in (Day -1) to confirm renal impairment status. For 
matched-control healthy subjects, a single assessment of actual creatinine clearance 


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 7 of 75 
 
 
 
computed over a 24-hour urine collection may be used in place of the eGFR (based on the 
CKD-EPI equation), at the Investigator’s (or designee’s) discretion. 
 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by 
age (± 10 years), body mass index (BMI; ± 20%), and sex to the completed renal impairment 
subject(s). Should another renal impairment subject be identified with whom an already 
enrolled healthy subject is demographically matched, the healthy subject may also be 
matched with that impaired subject as long as the impaired subject is in a different renal 
impairment group. Each subject with normal renal function may be matched with up to 1 
subject within each renal impairment group. 
 
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned a dose of study drug; this definition excludes screen failure subjects. 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Covance Medical Monitor and the 
Sponsor, feels that the subject may meet eligibility criteria upon re-screen. Re-screened 
subjects will be provided a new subject number. 
 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 8 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. Subjects will be dosed on Day 1. A follow-up 
phone call will occur for all subjects who received a dose of study drug (including subjects 
who are terminated early) 7 days (± 2 days) after EOT or ET. 
 
Pharmacokinetic samples will be obtained through 168 hours postdose. 
 
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 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. 


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 8 of 75 
 
 
 
Number of Subjects 
 
A total of up to 24 subjects with renal impairment (up to 8 subjects with severe impairment, 
and, if necessary, up to 8 subjects with moderate impairment, and/or up to 8 subjects with 
mild impairment, per eGFR using the CKD-EPI equation) and approximately 8 to 24 
matched-control healthy subjects with normal renal function will be enrolled in the study 
with the goal of having at least 6 subjects from each renal impairment group enrolled in the 
study and at least 6 subjects with normal renal function complete the study. 
 
Main Criteria for Inclusion 
 
Male subjects and female subjects of non-childbearing potential, between 18 and 75 years of 
age, inclusive, at Screening, and within BMI range 18.5 to 40.0 kg/m2, inclusive. Subjects 
will be in good general health, except for additional specific inclusion criteria related to 
subjects with renal impairment, based on medical history, physical examination findings, 
vital sign measurements, 12-lead ECG, and clinical laboratory evaluations at Screening 
and/or Check-in (Day -1), as determined by the Investigator (or designee). 
 
Investigational Medicinal Products, Dose, and Mode of Administration 
 
LOXO-305 will be supplied by the Sponsor (or designee) as 100-mg tablets for oral 
administration. 
 
On the morning of Day 1, after at least an 8-hour fast, a single oral dose of 200 mg 
LOXO-305 will be administered with approximately 240 mL of water. No food will be 
allowed for up to 2 hours postdose. Water will be restricted for 1-hour predose and 1-hour 
postdose, with the exception of water administered for dose administration. Glucose tablets 
may be administered as needed for treatment of hypoglycemia in renally impaired subjects 
with diabetes. 
 
Duration of Subject Participation in the Study: 
 
Planned Enrollment/Screening Duration: Approximately 28 days (Days -29 to -2). 
Length of CRU Confinement: Up to 9 days (Days -1 to 8). 
Planned Study Conduct Duration: Up to 46 days (Screening through follow-up call). 
 
Criteria for Evaluation: 
 
Pharmacokinetics: 
 
Serial PK blood samples for the analysis of plasma concentrations of LOXO-305 will be 
collected from predose through 168 hours postdose. A sample for assessment of unbound 
plasma concentrations of LOXO-305 will be collected predose. 
 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): area under the concentration-time curve 
(AUC) from hour 0 to the last measurable concentration (AUC0-t), AUC from hour 0 
extrapolated to infinity (AUC0-inf), percentage extrapolation for AUC0-inf (%AUCextrap), 


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 9 of 75 
 
 
 
maximum observed plasma concentration (Cmax), time to maximum observed plasma 
concentration (tmax), apparent terminal elimination rate constant (λZ), apparent systemic 
clearance (CL/F), apparent plasma terminal elimination half-life (t½), mean residence time 
(MRT), unbound fraction (fu), and apparent volume of distribution during the terminal phase 
(Vz/F). 
 
The fu value determined for each subject will be used to calculate the following unbound 
LOXO-305 PK parameters for each individual subject: Unbound Cmax (Cmax,u), unbound 
AUC0-t (AUC0-t,u), unbound AUC0-inf (AUC0-inf,u), unbound CL/F (CL/F,u), and unbound Vz/F 
(Vz/F,u). 
 
Safety: 
 
Safety will be monitored with How Do You Feel? inquiries, clinical laboratory evaluations, 
vital sign measurements, 12-lead ECGs, and physical examinations. 
 
Statistical Methods 
 
Pharmacokinetics 
 
The primary analysis planned for this study is to evaluate the PK of LOXO-305 after a single 
dose in subjects with renal impairment compared to subjects with normal renal function. 
 
Paired t-tests will be performed to assess the differences in PK parameters (AUC0-t, AUC0-inf, 
and Cmax) between each renal impairment group versus the corresponding matched-control 
healthy group with respect to 1 to 1 matching. The analysis will be based on the natural log 
(ln)-transformed PK parameters. Geometric mean ratios and their corresponding 90% 
confidence intervals (CIs) will be calculated using the exponentiation of the mean difference 
and the CIs obtained for the difference in mean between each renal impairment group and the 
matched-control healthy group. 
 
In addition, an analysis of covariance (ANCOVA) will be performed on the ln-transformed 
AUC0-t, AUC0-inf, and Cmax. The ANCOVA model will contain a categorical factor of 
population for subjects with varied-degree renal impairment (severe, moderate, and mild) and 
matched-control healthy subjects, a categorical covariate (sex), and continuous covariates 
(age and BMI). Ratios of least squares means and 90% CIs will be calculated using the 
exponentiation of the difference between renal function cohort least squares means from the 
ANCOVA analyses on the ln-transformed AUC0-t, AUC0-inf, and Cmax. In addition, an 
ANCOVA will be performed on the ln-transformed AUC0-t,u, AUC0-inf,u, and Cmax,u. 
 
The specific procedures will be documented in the Statistical Analysis Plan (SAP). 
 
The relationship between LOXO-305 PK parameters (ie, Cmax and AUC) and measures of 
renal function (such as eGFR and creatinine clearance) may be explored using a linear 
regression approach or other methods, as indicated in the SAP. The effect of covariates such 
as age, BMI, and sex may be investigated. 


Protocol 
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Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 10 of 75 
 
 
 
Safety 
 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated, and summarized where possible, using descriptive methodology by renal function 
group and, as needed, by timepoint. Unless otherwise specified, baseline value is defined as 
the last non-missing measurement before administration of LOXO-305. No formal statistical 
analyses are planned for the safety data. All safety data will be listed by subject. 
 
Additional details on the analyses will be included in the Statistical Analysis Plan. 


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 11 of 75 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................ 1 
SPONSOR APPROVAL .......................................................................................................... 2 
INVESTIGATOR AGREEMENT ............................................................................................ 3 
STUDY IDENTIFICATION .................................................................................................... 4 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS ........................................................................................................ 11 
LIST OF TABLES AND FIGURES ....................................................................................... 13 
LIST OF ABBREVIATIONS ................................................................................................. 14 
1. 
INTRODUCTION .......................................................................................................... 17 
1.1. Background ............................................................................................................... 17 
1.2. Nonclinical Pharmacokinetics and Toxicology Summary ........................................ 17 
1.3. Potential for Drug-drug Interactions ......................................................................... 19 
1.4. Summary of Clinical Experience .............................................................................. 20 
1.4.1. 
Safety .......................................................................................................... 21 
1.4.2. 
Pharmacokinetics ........................................................................................ 24 
1.5. Study Rationale ......................................................................................................... 26 
1.6. Risk Assessment ....................................................................................................... 27 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................ 29 
2.1. Objectives ................................................................................................................. 29 
2.1.1. 
Primary Objective ....................................................................................... 29 
2.1.2. 
Secondary Objective ................................................................................... 29 
2.2. Endpoints .................................................................................................................. 29 
2.2.1. 
Primary Endpoints ...................................................................................... 29 
2.2.2. 
Secondary Endpoints .................................................................................. 29 
3. 
INVESTIGATIONAL PLAN ......................................................................................... 30 
3.1. Overall Study Design and Plan ................................................................................. 30 
3.2. Discussion of Study Design ...................................................................................... 33 
3.3. Selection of Doses in the Study ................................................................................ 33 
4. 
SELECTION OF STUDY POPULATION .................................................................... 35 
4.1. Screening Procedures ................................................................................................ 35 
4.2. Check-in Procedures (Day -1) .................................................................................. 36 
4.3. Inclusion Criteria ...................................................................................................... 36 
4.4. Exclusion Criteria ..................................................................................................... 39 
4.5. Subject Number and Identification ........................................................................... 44 
4.6. Removal of Subjects from Study Participation......................................................... 45 
4.7. Matching Process ...................................................................................................... 46 
5. 
STUDY TREATMENTS .................................................................................................47 
5.1. Description, Storage, Packaging, and Labeling ........................................................ 47 
5.2. Study Treatment Administration .............................................................................. 47 


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5.3. Randomization .......................................................................................................... 48 
5.4. Blinding .................................................................................................................... 48 
5.5. Treatment Compliance .............................................................................................. 48 
5.6. Drug Accountability ................................................................................................. 48 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ............................... 49 
6.1. Concomitant Therapies ............................................................................................. 49 
6.2. Diet, Fluid, and Activity Control .............................................................................. 49 
7. 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 51 
7.1. Pharmacokinetic Assessments .................................................................................. 51 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ....................... 51 
7.1.2. 
Analytical Methodology ............................................................................. 51 
7.2. Safety and Tolerability Assessments ........................................................................ 51 
7.2.1. 
Adverse Events ........................................................................................... 51 
7.2.2. 
Clinical Laboratory Evaluations ................................................................. 52 
7.2.3. 
Vital Signs ................................................................................................... 53 
7.2.4. 
12-lead Electrocardiogram .......................................................................... 53 
7.2.5. 
Physical Examination .................................................................................. 54 
8. 
SAMPLE SIZE AND DATA ANALYSIS ..................................................................... 55 
8.1. Determination of Sample Size .................................................................................. 55 
8.2. Interim Analysis ........................................................................................................ 55 
8.3. Analysis Populations ................................................................................................ 56 
8.4. Pharmacokinetic Analysis......................................................................................... 56 
8.4.1. 
Descriptive Analysis ................................................................................... 57 
8.4.2. 
Statistical Methodology .............................................................................. 57 
8.5. Safety Analysis ......................................................................................................... 58 
8.6. Data Handling and Record Keeping ......................................................................... 58 
8.7. Quality Control and Quality Assurance .................................................................... 59 
9. 
ADMINISTRATIVE ASPECTS .................................................................................... 60 
9.1. Change in Protocol ................................................................................................... 60 
9.2. Site Initiation Visit/Investigator Meeting ................................................................. 60 
9.3. Disclosure ................................................................................................................. 60 
9.4. Monitoring ................................................................................................................ 60 
9.5. Institutional Review Board ....................................................................................... 60 
9.6. Informed Consent ..................................................................................................... 61 
9.7. Records ..................................................................................................................... 61 
9.8. Reference to Declaration of Helsinki/Basic Principles ............................................. 61 
9.9. Financing and Insurance ........................................................................................... 62 
10. REFERENCES ................................................................................................................63 
11. APPENDICES ................................................................................................................ 64 
Appendix 1: Adverse Event Reporting .............................................................................. 65 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 1 3  of 7 5  
 
 
A p pe n di x 2: Cli nical  La b orat or y E val uati o ns  .................................................................... 6 9  
A p pe n di x 3: T otal  Bl o o d  V ol u me  ...................................................................................... 7 0  
A p pe n di x 4: Sc he d ule  of  Assess me nts ............................................................................... 7 1  
A p pe n di x 5: Pr ot oc ol A me n d me nt S u m mar y  of  C ha n ges  ................................................. 7 5  
 
 
LI S T O F T A B L E S A N D FI G U R E S  
Ta ble 1: P har mac o ki netic Para meters of L O X O -3 0 5 i n Ca ncer Patie nts  
( St u d y L O X O-B T K -1 8 0 0 1) at Stea d y State ( C ycle 1  Da y  8)  ............................ 2 4  
Ta ble 2: S u bject Gr o u p a n d N u m ber  of  S u bjects  ............................................................. 4 5  
Ta ble 3:  St u d y Dr u g  .......................................................................................................... 4 7  
 
Fi g ure 3: St u d y  Desi g n  Sc he matic  .................................................................................... 3 2  
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
from hour 0 extrapolated to infinity 
ADL 
Activities of Daily Living 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve from hour 0 extrapolated to 
infinity 
AUC0-inf,u 
unbound area under the concentration-time curve from hour 0 
extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
AUC0-t,u 
unbound area under the concentration-time curve from hour 0 to the last 
measurable concentration 
AV 
atrioventricular 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BSEP 
bile salt exporter pump 
BTK 
Bruton’s tyrosine kinase 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CI 
confidence interval(s) 
CL/F 
apparent systemic clearance 
CL/F,u 
unbound apparent systemic clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
Cmax,u 
unbound maximum observed plasma concentration 
COVID-19 
SARS-CoV-2 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 


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FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
fu 
unbound fraction 
GLP 
Good Laboratory Practice 
hERG 
human ether-à-go-go-related gene 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
IC90 
concentration required for 90% inhibition 
ICF 
Informed Consent Form 
IgM 
immunoglobulin M 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
LFT 
liver function test(s) 
ln 
natural log 
MATE 
multidrug and toxin extrusion protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
MRT 
mean residence time 
NHL 
non-Hodgkin lymphoma 
NOEL 
no observed effect level 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event(s) 
SAD 
single ascending dose 
SAP 
Statistical Analysis Plan 
SDD 
spray-dried dispersion 
SLL 
small lymphocytic lymphoma 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
apparent plasma terminal elimination half-life 


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TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed plasma concentration 
TSH 
thyroid-stimulating hormone 
UA 
urinalysis 
Vz 
volume of distribution 
Vz/F 
apparent volume of distribution 
Vz/F,u 
unbound apparent volume of distribution 
WHO 
World Health Organization 
λZ 
apparent terminal elimination rate constant 


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1. INTRODUCTION 
 
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product , LOXO-305.1 
1.1. 
Background 
 
LOXO-305 (also known as LY3527727) is a selective inhibitor of the Bruton’s tyrosine 
kinase (BTK) being developed by Loxo Oncology. LOXO-305 is distinct from the approved 
BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) in several important ways 
including on the basis of its selectivity, favorable absorption, distribution, metabolism, and 
excretion properties, and non-covalent binding mode.2 These features enable LOXO-305 to 
achieve pharmacokinetic (PK) exposures that exceed the BTK concentration resulting in 90% 
inhibition (IC90) at trough, and thus deliver tonic BTK target inhibition throughout the dosing 
period, regardless of the intrinsic rate of BTK turnover. Moreover, the non-covalent binding 
mode of LOXO-305 is unaffected by BTK C481 substitutions, a common mechanism of drug 
resistance described for all available covalent inhibitors.3,4,5,6,7 Finally, LOXO-305 is also a 
highly selective molecule that is more than 300-fold more selective for BTK versus 370 other 
kinases tested with no significant inhibition of non-kinase off-targets at 1 μM, thus limiting 
the potential for off-target mediated toxicities. Collectively, these unique properties of 
LOXO-305 are expected to deliver more potent, continuous, and selective inhibition of BTK 
in a variety of settings, potentially resulting in increased efficacy. Of note, the activity of 
LOXO-305 in diverse preclinical model systems supports this underlying hypothesis.2 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate 
binding site of the BTK competitively. There is no evidence of irreversible binding. 
LOXO-305 has a molecular weight of approximately 500 g/mol. LOXO-305 will be supplied 
as an immediate-release tablet containing 100 mg of drug substance. 
 
1.2. 
Nonclinical Pharmacokinetics and Toxicology Summary 
 
LOXO-305 had high permeability in vitro, but low aqueous solubility. To reduce the 
variability in oral absorption, a spray-dried dispersion (SDD) tablet formulation was 
developed that showed consistent oral bioavailability of approximately 50% in rats and 80% 
in dogs. The bioavailability of the SDD formulation was also not dependent on feeding state 
in dogs. 
 
As is common in rodents, oral exposure of LOXO-305 was consistently much higher in 
female rats than in males given the same dose of LOXO-305. The sex difference was also 
apparent after intravenous 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. 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 1 8  of 7 5  
 
 
 
L O X O -3 0 5 was meta b olize d sl o wl y b y h u ma n micr os o mal fracti o ns a n d he pat oc ytes. T he 
l o w rates of meta b olis m i n b ot h t hese h u ma n i n vitr o s yste ms s u g gest t hat L O X O-3 0 5 will 
ha ve l o w cleara nce i n h u ma ns. I n vitr o data wit h cl o ne d e x presse d c yt oc hr o me P 4 5 0 ( C Y P) 
e nz y mes a n d h u ma n li ver micr os o mes i n dicate t hat C Y P 3 A 4 is t he pri mar y C Y P e nz y me t hat 
meta b olizes L O X O -3 0 5. It is als o a s u bstrate f or direct gl uc ur o ni dati o n.  
 
I n l o n g-ter m he pat oc yte i nc u bati o ns, L O X O-3 0 5 was meta b olize d b y b ot h o xi dati o n a n d 
gl uc ur o ni dati o n. I n hi biti o n of o xi dati ve meta b olis m b y a d diti o n of t he P 4 5 0 i n hi bit or  
1 -a mi n o be nz otriaz ole s h o we d t hat o xi dati ve meta b olis m is C Y P de pe n de nt. All meta b olites 
f or me d b y h u ma n he pat oc ytes were als o f or me d i n rat a n d/ or d o g he pat oc ytes s u p p orti n g t he 
use of rat a n d d o g f or n o ncli nical safet y assess me nt.  
Re nal cleara nce of L O X O -3 0 5 i n male a n d fe male rats was ne gli gi ble. N o data o n re nal 
cleara nce are a vaila ble i n ot her s pecies; h o we ver, t he re nal e xcreti o n pat h wa y is ofte n 
c o nser ve d acr oss s pecies, a n d t heref ore n o re nal cleara nce w o ul d be e x pecte d i n h u ma ns.  
 
I n a G o o d La b orat or y Practice ( G L P) i n vitr o assa y f or h u ma n et her-à-g o -g o -relate d ge ne 
( h E R G) acti vit y, t he c o nce ntrati o n res ulti n g i n 5 0 % i n hi bit or y c o nce ntrati o n (I C5 0) f or t he 
i n hi bit or y effects of L O X O-3 0 5 o n h E R G p otassi u m c urre nts was 
 μ M, w hic h is 
a p pr o xi matel y 
 hi g her t ha n t he ma xi m u m u n b o u n d c o nce ntrati o n of L O X O-3 0 5 i n 
patie nts treate d wit h t he d ose of 2 0 0 m g Q D. T here were n o L O X O -3 0 5 -relate d c ha n ges i n 
a n y car di o vasc ular e n d p oi nts i ncl u di n g Q Tc at si n gle d oses u p t o 6 0 m g/ k g i n t he G L P 
car di o vasc ular st u d y i n t he c o nsci o us tele metr y -i nstr u me nte d d o g. T he ma xi m u m o bser ve d 
plas ma c o nce ntrati o n ( C ma x ) f or t his d ose was  
 n g/ m L, w hic h is a p pr o xi matel y 
 
a b o ve t he pre dicte d C ma x ( 
 n g/ m L) at t he pr o p ose d cli nical t hera pe utic d ose of 2 0 0 m g 
Q D. F urt her m ore, t here were n o L O X O -3 0 5 -relate d a b n or malities i n r h yt h m or wa vef or m 
m or p h ol o g y i n t he G L P 2 8 -da y re peate d -d ose t o xicit y st u d y i n d o gs at t he l o w - a n d mi d-d ose 
gr o u ps base d o n c o m paris o n of pre d ose a n d p ost d ose electr ocar di o gra m ( E C G) rec or di n gs.  
T he hi g h d ose ( 9 0/ 6 0 m g/ k g/ d ose t wice dail y [ BI D]) was n ot e val uate d as a ni mals i n t his 
gr o u p were m ori b u n d/ de bilitate d a n d were ter mi nate d o n Da y 1 3. Mea n Q Tc i nter val was 
statisticall y si g nifica ntl y pr ol o n ge d ( + 6 %; + 1 5 msec) o n Da y 2 6 of t he d osi n g p hase i n males 
a d mi nistere d 3 0/ 1 0 m g/ k g/ d ose BI D c o m pare d wit h c o ntr ols. T he pr ol o n gati o n i n Q Tc f or 
males was bel o w t he 1 0 % i ncrease or t he t hres h ol d re p orte d f or ca ni nes e x p ose d t o 
t hera pe utic c o nce ntrati o ns of dr u gs k n o w n t o ca use Q T pr ol o n gati o n i n h u ma ns.8  T heref ore, 
t he Q Tc c ha n ges were c o nsi dere d p h ysi ol o gicall y u ni m p orta nt, a n d t h us n ot dee me d t o be 
a d verse. T o get her, t hese data i n dicate t hat L O X O -3 0 5 has a l o w ris k of i n d uci n g dela ye d 
ve ntric ular re p olarizati o n, pr ol o n gati o n of t he Q Tc i nter val, a n d u nsta ble arr h yt h mias i n 
patie nts.  
 
T here were n o L O X O -3 0 5 -relate d fi n di n gs o n t he ce ntral ner v o us s yste m w he n e val uate d i n 
rat f u ncti o nal o bser vati o nal batter y tests a n d l oc o m ot or acti vit y assess me nts after 4 wee ks of 
d osi n g or d uri n g rec o ver y at d oses of u p t o 5 0 0 m g/ k g/ d ose BI D i n male rats a n d  
1 7 5 m g/ k g/ d ose BI D i n fe male rats as part of t he G L P 2 8 -da y re peat -d ose st u d y.  
 
L O X O -3 0 5 ha d n o effect o n res pirati o n rate i n t he d o g at d oses u p t o 1 0 m g/ k g/ d ose BI D.  
C CI
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C CI
C CI
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Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 1 9  of 7 5  
 
 
 
Tar gets of t o xicit y were c haracterize d i n re peate d d ose st u dies c o n d ucte d i n 2 rele va nt 
t o xicit y s pecies. Certai n tar gets (t he he mat o p oietic a n d l y m p h oi d s yste ms) were f o u n d i n 
b ot h t he rat a n d t he d o g. Rat -s pecific c ha n ges i n t he pa ncreas are s pecies-s pecific a n d see n 
wit h ot her B T K i n hi bit ors. D o g -s pecific c ha n ges i n l u n g a n d lar ge i ntesti ne were lesi o ns 
c o ntri b uti n g t o m ori b u n dit y i n hi g h -d ose a ni mals i n t he 2 8 -da y st u d y. D oses e val uate d i n 
t he 2 8-da y d o g st u d y de m o nstrate d a stee p d ose -res p o nse c ur ve f or t o xicit y a n d pr o n o u nce d 
c ha n ges i n he mat ol o gic para meters at hi g h e x p os ures. A d diti o nall y, i n d o gs treate d f or 3 
m o nt hs, 2 male d o gs at 5 m g/ k g BI D (t he hi g hest d ose teste d) were o bser ve d t o ha ve e ye 
lesi o ns via b ot h o p ht hal mic a n d micr osc o pic e xa mi nati o n. Fi n di n gs were o bser ve d i n b ot h 
e yes of t hese a ni mals a n d c o nsiste d of ver y sli g ht t o sli g ht m ultif ocal or f ocal areas of c or neal 
o pacit y i n t he ce nter of t he c or nea al o n g wit h c o nstellati o n hist o pat h ol o gical fi n di n gs 
s u g gesti ve of mi ni mal t o mil d c or neal i nj ur y. T he ti me of o nset of t hese effects is u n k n o w n, 
as o p ht hal mic e xa ms were o nl y perf or me d pri or t o t he start of d osi n g a n d d uri n g t he last 
wee k of t he st u d y; h o we ver, n o e ye effects were o bser ve d i n t he pre vi o us 2 8 -da y st u d y. N o 
oc ular fi n di n gs were o bser ve d i n fe males. See t he I B f or a d diti o nal  details. 1  
 
L O X O -3 0 5 was n ot m uta ge nic i n 2 bacterial re verse m utati o n assa ys a n d was ne gati ve i n a 
n o n -G L P micr o n ucle us assa y usi n g C hi nese ha mster o var y cells. L O X O -3 0 5 was p ositi ve f or 
t he i n d ucti o n of micr o n uclei via a n a ne u ge nic mec ha nis m i n t he a bse nce a n d prese nce of t he 
e x o ge n o us meta b olic acti vati o n s yste m i n a G L P i n vitr o micr o n ucle us assa y i n h u ma n 
peri p heral bl o o d l y m p h oc ytes. H o we ver, L O X O -3 0 5 was ne gati ve i n a G L P i n vi v o 
micr o n ucle us assa y i n rats at d oses u p t o a n d i ncl u di n g a d ose of  
 m g/ k g. T he C
ma x at t he 
n o o bser ve d effect le vel ( N O E L) of  
 m g/ k g was  
 n g/ m L f or males a n d  
 n g/ m L f or fe males. 
 
L O X O -3 0 5 was n ot f o u n d t o be p h ot ot o xic w he n e val uate d i n a n i n vitr o ne utral re d u pta ke 
p h ot ot o xicit y assa y.  
 
1. 3.  
P ote nti al f or Dr u g -dr u g  I nter acti o ns 
 
L O X O -3 0 5 s h o we d n o detecta ble i n hi biti o n (I C 5 0 > 6 0 µ M) of C Y P 1 A 2, C Y P 2 B 6, 
C Y P 2 C 1 9, a n d C Y P 2 D 6, a n d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 i n h u ma n 
li ver micr os o mes. After pre-i nc u bati o n of micr os o mes wit h L O X O-3 0 5 a n d nic oti na mi de 
a de ni ne di n ucle oti de p h os p hate pri or t o a d diti o n of C Y P 4 5 0 pr o be s u bstrate, t he C Y P 3 A 4 
i n hi bit or y p ote nc y of L O X O-3 0 5 was i ncrease d, s u g gesti n g t he p ote ntial f or ti me -de pe n de nt 
i n hi biti o n of C Y P 3 A 4. F urt her ki netic e val uati o n c o nfir me d t hat L O X O-3 0 5 is a ti me 
de pe n de nt i n hi bit or of C Y P 3 A 4.  
I n a n i n vitr o he pat oc yte assa y, L O X O-3 0 5 i n d uce d messe n ger R N A ( m R N A) f or C Y P 3 A 4, 
C Y P 3 A 5, C Y P 2 B 6, a n d C Y P 2 C 1 9. F or b ot h C Y P 2 B 6 a n d C Y P 2 C 1 9, a n i ncrease i n acti vit y 
was see n. F or C Y P 3 A 4, L O X O -3 0 5 di d n ot ca use a n i ncrease i n acti vit y, li kel y d ue t o 
c o nc urre nt i n hi biti o n of C Y P 3 A 4 b y L O X O -3 0 5. L O X O -3 0 5 ca use d a decrease i n m R N A f or 
C Y P 1 A 2 b ut di d n ot lea d t o a re d ucti o n of C Y P 1 A 2 acti vit y. I n t he st u d y, C Y P 2 D 6, 
C Y P 2 C 8, a n d C Y P 2 C 9 m R N A were n ot i n d uce d.  
 
I n vitr o L O X O-3 0 5 i n hi bite d P -gl yc o pr otei n ( P -g p), breast ca ncer resista nce pr otei n ( B C R P), 
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n ( M A T E) 1, a n d M A T E 2 K. L O X O -3 0 5 di d n ot i n hi bit 
or ga nic a ni o n tra ns p orter ( O A T) 1 a n d wea kl y i n hi bite d or ga nic a ni o n tra ns p orti n g  
C CI
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polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, OAT3, and 
bile salt exporter pump (BSEP). 
 
LOXO-305 is a substrate of P-gp and BCRP. It is not a substrate of the hepatic transporters 
OCT1, OATP1B1, OATP1B3, or BSEP. 
 
1.4. 
Summary of Clinical Experience 
 
LOXO-305 is currently being studied in an ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (the BRUIN Study), in patients with previously treated chronic 
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or non-Hodgkin 
lymphoma (NHL). The starting dose of LOXO-305 was 25 mg QD. 
 
As of September 27, 2020, safety data were available from a total of 330 patients treated in 
the LOXO-BTK-18001 study. This includes 324 patients treated at doses ranging from 25 mg 
QD to 300 mg QD in Phase 1/2 Monotherapy cohorts, and 6 patients treated in Phase 1b 
Combination Arm A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after ramp-up] 
Section 1.4.1). 
 
As of September 30, 2020, PK data were available from 181 patients enrolled in the 
LOXO-BTK-18001 study (Section 1.4.2). 
 
As of the date of this protocol, LOXO-305 had been recently investigated in 1 study in 
healthy volunteers (LOXO-BTK-20014), which is completed. LOXO-BTK-20014 was a pilot 
food-effect crossover study evaluating the effects of food and a proton-pump inhibitor 
(omeprazole) on the PK of LOXO-305 where 10 healthy volunteers were given 200 mg of 
LOXO-305 on 3 separate days, each followed by a washout period. 
 
As of the date of this protocol, 9 additional studies were ongoing in healthy volunteers and 
otherwise healthy volunteers with varying degrees of hepatic impairment 
(LOXO-BTK-20006, LOXO-BTK-20017, LOXO-BTK-20007, LOXO-BTK-20008, 
LOXO-BTK-20016, LOXO-BTK-20012, LOXO-BTK-20011, LOXO-BTK-20010, and 
LOXO-BTK-20009). 
 
LOXO-BTK-20006 is a drug-drug interaction study evaluating the effects of a strong 
CYP3A4 inhibitor (itraconazole) and a strong CYP3A4 inducer (rifampin) on the PK of 
LOXO-305 where, at the time of this protocol’s development, 3 healthy volunteers were 
given 1 dose of 200 mg of LOXO-305, 12 healthy volunteers were given 200 mg of 
LOXO-305 on 2 separate days (1 of which was co-administered with itraconazole), each 
followed by a washout period, and 12 healthy volunteers were given 200 mg of LOXO-305 
on 3 separate days (2 of which were co-administered with rifampin), each followed by a 
washout period. 
 
LOXO-BTK-20017 is a single ascending dose study evaluating the safety and tolerability of 
LOXO-305 at 300 mg, 600 mg, 800 mg, and 900 mg doses, where, at the time of this 
protocol’s development, 6 healthy volunteers were given a single dose of 300 mg 
LOXO-305, 6 healthy volunteers were given a single dose of 600 mg LOXO-305, 6 healthy 
volunteers were given a single dose of 800 mg LOXO-305, and 6 healthy volunteers were 
given a single dose of 900 mg LOXO-305. 


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LOXO-BTK-20007 is a 2-part study of the absorption, metabolism, excretion, and the 
absolute bioavailability of [14C]-LOXO-305 where, at the time of this protocol’s 
development, 4 subjects were given a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution and 5 subjects were given a single oral dose of 
200 mg LOXO-305 as 2 × 100-mg tablets followed 2 hours later by a single dose of < 100 µg 
of [14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) administered as an IV 
push over approximately 2 minutes. 
 
LOXO-BTK-20008 is a DDI study evaluating the effects of LOXO-305 on the PK of a 
sensitive CYP3A4 substrate (midazolam) where, at the time of this protocol’s development, 
15 healthy volunteers were given 200 mg QD of LOXO-305 on 13 consecutive days (1 day of 
which was co-administered with IV midazolam and 1 day of which was co-administered with 
oral midazolam). 
 
LOXO-BTK-20016 is a DDI study evaluating the effects of LOXO-305 on the PK of a 
CYP2C8 substrate (repaglinide) where, at the time of this protocol’s development, 16 healthy 
volunteers were given 200 mg QD of LOXO-305 on 11 consecutive days (1 day of which 
was co-administered with oral repaglinide). 
 
LOXO-BTK-20012 is a hepatic impairment study evaluating the PK profile of LOXO-305 in 
subjects with impaired hepatic function compared to matched-control healthy subjects, 
where, at the time of this protocol’s development, 5 subjects were given a single dose of 
200 mg LOXO-305. 
 
LOXO-BTK-20010 is a DDI study evaluating the effects of LOXO-305 on the PK of a probe 
drug cocktail (200 mg caffeine [tablet], 40 mg omeprazole [capsule], and 10 mg warfarin 
[tablet]) where, at the time of this protocol’s development, 12 healthy volunteers were given 
1 dose of probe drug cocktail alone and 200 mg QD of LOXO-305 alone on 2 consecutive 
days. 
 
LOXO-BTK-20009 is a formal food-effect crossover study evaluating the effects of food the 
PK of LOXO-305 where, at the time of this protocol’s development, 20 healthy volunteers 
were given at least 1 dose of 200 mg of LOXO-305. 
 
LOXO-BTK-20011 is a partially double-blind study to evaluate the effect of a single 
supratherapeutic dose of LOXO-305 on the QTc interval corrected for heart rate in healthy 
subjects compared to moxifloxacin and placebo, where, at the time of this protocol’s 
development, 22 subjects had received 1 dose each of LOXO-305, moxifloxacin, and 
placebo and 1 subject had received 2 doses of either LOXO-305, moxifloxacin, or placebo. 
 
1.4.1. 
Safety 
 
As of September 27, 2020, 330 patients were treated in the LOXO-BTK-18001 study and 
received LOXO-305. This includes 324 patients treated at doses ranging from 25 mg QD to 
300 mg QD in Phase 1/2 Monotherapy cohorts, and 6 patients treated in Phase 1b 
Combination Arm A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after venetoclax 
ramp-up]). A full summary of treatment-emergent adverse events (TEAEs) for patients in the 
study is provided in the LOXO-305 IB and the Investigator is directed to the safety 
information described in that document.1 A summary of safety for LOXO-305 given as 
monotherapy to patients in the LOXO-BTK-18001 study is provided below. 


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• In the 324 patients in the Phase 1/2 Monotherapy cohorts, TEAEs reported in ≥ 10% 
of patients (n = 33 or more) were fatigue (20.1% total, 8.3% related), diarrhea (17.0% 
total, 8.6% related), and contusion (13.0% total, 9.0% related). Drug related TEAEs 
were reported in 156 of 324 patients (48.1%) in the Phase 1/2 Monotherapy cohorts. 
The most frequently reported drug-related TEAEs for LOXO-305 (those in > 5% of 
patients overall) were contusion (9.0%), diarrhea (8.6%), and fatigue (8.3%). All 
other drug-related TEAEs were reported in < 5% of patients (ie, <17 patients each). 
Treatment-emergent AEs of severity Grade 3 or 4 were reported in 87 of 324 patients 
(26.9%) in the Phase 1/2 Monotherapy cohorts, with 41 (12.7%) of these Grade 3 or 4 
AEs reported as related to study drug. 
 
On-study death (death within 28 days of the last dose of study drug) due to a Grade 5 (fatal) 
AE was reported in 4 of 324 patients (1.2%) in the Phase 1/2 Monotherapy cohorts. One 
Grade 5 AE, Enterococcus faecium-related septic shock, was considered to be related to 
study drug (further details are provided in the LOXO-305 IB1). All other Grade 5 AEs were 
considered to be not related to study drug; these included pneumonia fungal, shock, and 
pleural effusion. 
 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20014 study (headache, nausea, and vomiting), were all Grade 1 in 
severity and considered to be related to LOXO-305. All 3 events were reported by 1 subject 
and resolved within 1 to 1.5 days. 
 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20006 study (intermittent belching, bloating, insect bite, aphthous ulcer, 
nausea, intermittent diarrhea [x2], muscle twitch), were all Grade 1 in severity, and bloating, 
1 instance of intermittent diarrhea, and intermittent belching were considered to be related to 
LOXO-305 and rifampin. All 7 AEs were reported by 3 subjects and all events resolved prior 
to End of Treatment (EOT; preliminary data on file at the time of this protocol’s 
development). 
 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20017 study (headache [observed at the 300 mg LOXO-305 dose], and 
headache [x2], intermittent headache, and petechial rash left thigh [observed at the 900 mg 
LOXO-305 dose]), were all Grade 1 in severity. One instance of headache observed at the 
300 mg LOXO-305 dose and 1 instance observed at the 900 mg LOXO-305 dose, the 
intermittent headache, and the petechial rash left thigh were considered to be related to 
LOXO-305. All 5 AEs were reported by 4 subjects and resolved within 2 hours to 5 days of 
onset (preliminary data on file at the time of this protocol’s development). 
 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in Part 1 of the LOXO-BTK-20007 study (bloody nose, headache, loose stool [x2], red 
bumps on left knee, small abrasion to right elbow), were all Grade 1 in severity and headache 
was considered to be related to LOXO-305. All 7 AEs were reported by 4 subjects and all 
events resolved within 1 to 2 days (preliminary data on file at the time of this protocol’s 
development). 
 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in Part 2 of the LOXO-BTK-20007 study (tenderness at left venipuncture site [x2], bruising 


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to left antecubital secondary to phlebotomy [x2], bruising to right antecubital secondary to 
phlebotomy, and allergic reaction), were all Grade 1 in severity and no events were 
considered to be related to LOXO-305. All 6 AEs were reported by 4 subjects and all events 
resolved within 1 to 2 days (preliminary data on file at the time of this protocol’s 
development). 
 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20008 study (injection site pain, nasal congestion, flatulence, 
constipation, increased urinary frequency, facial rash, and sore right arm), were all Grade 1 in 
severity, and flatulence, constipation, and increased urinary frequency were considered to be 
related to LOXO-305. All 7 AEs were reported by 3 subjects and all events resolved within 1 
to 8 days (preliminary data on file at the time of this protocol’s development). 
 
Adverse events reported following LOXO-305 administration in healthy volunteers in the 
LOXO-BTK-20016 study (petechiae [x4], back pain, nausea, constipation, bilateral leg 
cramps, facial acne, epigastric abdominal pain, and brain fog) were all Grade 1 in severity, 
and petechiae [x4], constipation, bilateral leg cramps, epigastric abdominal pain, and brain 
fog were considered to be related to LOXO-305. All 11 AEs were reported by 7 subjects and 
all events resolved within 1 to 11 days (preliminary data on file at the time of this protocol’s 
development). 
 
There have been no TEAEs reported following LOXO-305 administration in healthy 
volunteers and volunteers with varying degrees of hepatic impairment in the 
LOXO-BTK-20012 and LOXO-BTK-20010 studies to date (preliminary data on file at the 
time of this protocol’s development). 
 
Adverse events reported following LOXO-305 administration in healthy volunteers in the 
LOXO-BTK-20009 study (petechial rash and lightheadedness) were both Grade 1 in severity 
and petechial rash was considered to be related to LOXO-305. The 2 AEs were reported by 2 
subjects and the events resolved within 1 to 6 days (preliminary data on file at the time of this 
protocol’s development). 
 
Adverse events reported following LOXO-305 administration in healthy volunteers in the 
LOXO-BTK-20011 study (headache [x4], dry mouth, rash [various locations; x9], pyuria, 
bacteriuria, intermittent left eye pain, lightheadedness, muscle twitch – right shoulder, 
diarrhea, slight tremor – left hand, constipation, and nausea) were all Grade 1 in severity. All 
23 TEAEs were reported by 10 subjects and all but 8 TEAEs of rash had resolved within 1 to 
9 days (preliminary data on file at the time of this protocol’s development). 
 
As part of each clinical trial conducted in patients or healthy volunteers, ECG and vital signs 
are performed at intervals specified by the protocol. For study LOXO-BTK-18001 conducted 
in patients, no clinically significant findings of QTc prolongation have been identified in 330 
patients as of September 27, 2020 (LOXO-305 IB1). In addition, there have been no clinically 
significant abnormal findings in vital signs and ECG data in the studies investigating 
LOXO-305 conducted in healthy volunteers as of the date of this protocol (preliminary data 
on file at the time of this protocol’s development). 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 2 4  of 7 5  
 
 
 
1. 4. 2.  
P h ar m ac o ki netics  
 
As of Se pte m ber 3 0, 2 0 2 0, P K data were a vaila ble fr o m 1 8 1 patie nts e nr olle d i n t he  
L O X O -B T K -1 8 0 0 1 st u d y. Stea d y -state P K para meters of L O X O-3 0 5 i n t hese ca ncer patie nts 
c o ul d be deri ve d fr o m data c ollecte d o n C ycle 1 Da y 8 ( Fi g ure 1 ), a n d are s h o w n i n Ta ble 1 . 
T hese data s h o w t hat L O X O -3 0 5 is a bs or be d after oral a d mi nistrati o n wit h a me dia n ti me t o 
ma xi m u m o bser ve d plas ma c o nce ntrati o n (t ma x ) of a p pr o xi matel y 2 h o urs a n d l o w cleara nce 
(Ta ble 1 ). D ue t o t he li mite d sa m pli n g i nter val ( 0-8 h o urs), i m p utati o n f or t he 2 4 -h o ur sa m ple 
was ma de fr o m C ycle 1, Da y 8 pre d ose sa m ple, lea di n g t o a n esti mate d plas ma half -life of 
a p pr o xi matel y 2 0 h o urs. Ma xi m u m o bser ve d plas ma c o nce ntrati o n a n d area u n der t he plas ma 
c o nce ntrati o n -ti me c ur ve ( A U C) of L O X O-3 0 5 s h o we d a n i ncrease pr o p orti o nal t o d ose 
(Fi g ure 2 ). F oll o wi n g a d mi nistrati o n of t he rec o m me n de d P hase 2 d ose ( R P 2 D) 2 0 0 m g Q D, 
mea n tr o u g h plas ma le vels of L O X O -3 0 5 e xcee de d t he c o nce ntrati o n re q uire d f or 9 6 % 
i n hi biti o n of B T K i n vitr o (I C5 0 = 
 n g/ m L, I C9 6 =  
 n g/ m L). F urt her details ma y be 
f o u n d i n t he I B.1  
 
P har mac o ki netic data f oll o wi n g oral a d mi nistrati o n of a 2 0 0 -m g d ose of L O X O -3 0 5 i n ta blet 
f or m i n healt h y v ol u nteers i n t he L O X O-B T K -2 0 0 1 4 st u d y i n dicate t hat t here was little effect 
of eit her a sta n dar d meal or t he pr ot o n p u m p i n hi bit or ( o me praz ole) o n t he P K of L O X O -3 0 5.  
 
T a ble 1: P h ar m ac o ki netic P ar a meters of L O X O -3 0 5 i n C a ncer P atie nts 
( St u d y L O X O-B T K -1 8 0 0 1) at Ste a d y St ate ( C ycle 1 D a y 8)  
 
 
 
 
 
 
 
 
 
R ati o  
 
 
 
 
 
 
 
 
A U C 0 -8  
 
 
 
 
 
 
 
 
D a y  
 
 
C m a x  
 
A U C 0 -8  
A U C 0 -2 4  
 
 
8/ D a y 1  
 
 
( n g/ m L) 
tm a x ( h) 
( n g * h/ m L) ( n g * h/ m L) C L/ F ( L/ h)  
t1/ 2 ( h) 
Ge o  
 
 
Ge o me a n  
Me di a n  
Ge o me a n  
Ge o me a n  
Ge o me a n  Ge o me a n  
me a n  
D ose Le vel  
N  
( % C V) 
( mi n, m a x) 
( % C V) 
( % C V) 
( % C V) 
( % C V) 
( % C V) 
2 5 m g Q D  
5 0 m g Q D  
1 0 0 m g Q D  
1 5 0 m g Q D  
2 0 0 m g Q D  
2 5 0 m g Q D  
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 2 5  of 7 5  
 
 
 
 
 
 
 
 
D ose Le vel  
 
 
 
 
 
N  
 
 
 
C m a x 
( n g/ m L) 
Ge o me a n 
( % C V) 
 
 
 
 
tm a x ( h) 
Me di a n 
( mi n, m a x) 
 
 
 
A U C 0 -8  
( n g * h/ m L) 
Ge o me a n 
( % C V) 
 
 
 
A U C 0 -2 4  
( n g * h/ m L) 
Ge o me a n 
( % C V) 
 
 
 
 
C L/ F ( L/ h) 
Ge o me a n 
( % C V) 
 
 
 
 
t1/ 2 ( h) 
Ge o me a n 
( % C V) 
R ati o 
A U C 0 -8  
D a y 
8/ D a y 1 
Ge o 
me a n 
( % C V) 
3 0 0 m g Q D  
A b bre viati o ns: A U C 0 -8 =  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 8 h o urs; A U C0 -2 4 =  area u n der 
t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; C L/ F = a p pare nt oral cleara nce; Cma x  = ma xi m u m dr u g 
c o nce ntrati o n; C V = c oefficie nt of variati o n; Ge o mea n = Ge o metrical mea n; N = n u m ber of s u bjects; Q D = 
o nce dail y; t 1/ 2 =  half -life; tma x  = ti me of ma xi mal plas ma c o nce ntrati o n.  
a N = 4, b N = 5, c N = 8, d N = 1 8, e N = 6 4, f N = 2 1, g N = 1 6, h N = 7 3  
S D T M Tra nsfer: Se pte m ber 3 0, 2 0 2 0  
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 2 6  of 7 5  
 
 
 
 
 
 
 
S D T M Tra nsfer: Se pte m ber 3 0, 2 0 2 0  
 
1. 5.  
St u d y  R ati o n ale  
 
T his st u d y is bei n g c o n d ucte d t o pr o vi de i nf or mati o n t o de vel o p d osi n g rec o m me n dati o ns f or 
L O X O -3 0 5 i n s u bjects wit h re nal i m pair me nt acc or di n g t o t he F o o d a n d Dr u g A d mi nistrati o n 
( F D A) G ui da nce f or I n d ustr y.9  S u bjects wit h re nal i m pair me nt ma y ha ve c o m pr o mise d dr u g  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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disposition due to their renal disease and severity of disease. Results from this study will 
provide information on the safety, tolerability, and exposure of LOXO-305 in participants 
with renal impairment and participants with normal renal function. 
 
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 
consideration of this, subjects with renal impairment assessed as severe (estimated glomerular 
filtration rate [eGFR]: < 30 mL/min/1.73 m2), along with matched-control healthy subjects 
with normal renal function, will begin enrolling into the study first. If a clinically relevant 
difference is observed in the PK of subject(s) with severe renal impairment compared to 
matched-control healthy subjects during continuous review of the safety and PK data, then 
subjects with renal impairment assessed as mild (60 ≤ eGFR < 90 mL/min/1.73 m2) and/or 
moderate (30 ≤ eGFR < 60 mL/min/1.73 m2), along with additional matched-control healthy 
subjects (if needed) will be enrolled, to determine the extent of the effect of varying severities 
of renal impairment on the PK of LOXO-305. Enrollment of subjects with mild and/or 
moderate renal impairment will only be initiated if deemed necessary by the Sponsor 
following the continuous review of safety and PK data from severe renal impairment subjects 
and their matched-control healthy subjects. If no clinically relevant effect on PK is observed, 
enrollment of mild and/or moderate subjects will not occur. 
 
The PK profile of subjects with impaired renal function will be compared to subjects with 
normal renal function (eGFR: ≥ 90 mL/min/1.73 m2). 
1.6. 
Risk Assessment 
 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfort from collection of blood samples and other study procedures. More 
information about the known and expected benefits, risks, and reasonably anticipated AEs 
associated with LOXO-305 may be found in the IB.1 
Single doses of 200 mg LOXO-305 were investigated in a study conducted in healthy 
volunteers (LOXO-BTK-20014) where 10 healthy volunteers were given 200 mg of 
LOXO-305 on 3 separate days, each followed by a washout period. Two additional studies 
are ongoing in healthy volunteers (LOXO-BTK-20006 and LOXO-BTK-20017). 
LOXO-BTK-20006 is a drug-drug interaction study evaluating the effects of a strong 
CYP3A4 inhibitor (itraconazole) and a strong CYP3A4 inducer (rifampin) on the PK of 
LOXO-305 where, at the time of protocol development, 6 healthy volunteers were given 1 
dose of 200 mg of LOXO-305, 12 healthy volunteers were given 200 mg of LOXO-305 on 2 
separate days (1 of which was co-administered with itraconazole), each followed by a 
washout period, and 9 healthy volunteers were given 200 mg of LOXO-305 on 3 separate 
days (2 of which were co-administered with rifampin), each followed by a washout period. 
LOXO-BTK-20017 is a SAD study evaluating the safety and tolerability of LOXO-305 at 
300 mg, up to 600 mg, up to 800 mg, and up to 900 mg (if necessary) where, at the time of 
protocol development 6 healthy volunteers were given a single dose of 300 mg LOXO-305 
and 6 healthy volunteers were given a single dose of 600 mg LOXO-305. 


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From AE data reported following LOXO-305 administration in 10 healthy volunteers in the 
LOXO-BTK-20014 study, all TEAEs (headache, nausea, and vomiting) were Grade 1 in 
severity and considered related to LOXO-305. All 3 events were reported by 1 subject and 
resolved within 1 to 1.5 days (data on file at the time of protocol development). From 
preliminary AE data reported following LOXO-305 administration in healthy volunteers in 
the LOXO-BTK-20006 study, all TEAEs (intermittent belching, bloating, insect bite, 
aphthous ulcer, nausea, intermittent diarrhea [x2], muscle twitch) were Grade 1 in severity 
and bloating, intermittent diarrhea, and intermittent belching were considered related to 
LOXO-305. All 7 AEs were reported by 3 subjects and all events resolved prior to EOT (data 
on file at the time of protocol development). From preliminary AE data reported following 
LOXO-305 administration in healthy volunteers in Cohort 1 of the LOXO-BTK-20017 study, 
there was one TEAE (headache) observed in the 300 mg LOXO-305 cohort which was 
Grade 1 in severity and considered related to LOXO-305. The event resolved within 2 hours 
(data on file at the time of protocol development). 
 
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. 


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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
 
The primary objective of the study is to evaluate the PK profile of LOXO-305 in subjects 
with impaired renal function compared to matched-control healthy subjects. 
 
2.1.2. 
Secondary Objective 
 
The secondary objective of the study is to evaluate safety and tolerability of LOXO-305 in 
subjects with impaired renal function and matched-control healthy subjects. 
 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305: 
 
• Cmax 
• tmax 
• AUC from hour 0 to the last measurable concentration (AUC0-t) 
• AUC from hour 0 extrapolated to infinity (AUC0-inf) 
• percentage extrapolation for AUC0-inf (%AUCextrap) 
• apparent terminal elimination rate constant (λz) 
• apparent plasma terminal elimination half-life (t½) 
• apparent systemic clearance (CL/F) 
• apparent volume of distribution during the terminal phase (Vz/F) 
• 
mean residence time (MRT). 
In addition, a single blood sample will be collected predose to determine the unbound 
fraction (fu) of LOXO-305 in plasma and, whenever possible, the following PK parameters 
will be calculated for unbound LOXO-305 using fu: unbound Cmax (Cmax,u), unbound AUC0-t 
(AUC0-t,u), unbound AUC0-inf (AUC0-inf,u), unbound CL/F (CL/F,u), and unbound Vz/F 
(Vz/F,u). 
 
2.2.2. 
Secondary Endpoints 
 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory evaluations, measuring vital signs, and recording ECGs. 


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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
 
This study is an open-label, nonrandomized, multi-center, single-dose, parallel-group study to 
determine the PK, safety, and tolerability of LOXO-305 administered orally at a dose of 
200 mg to fasted adult males and females with impaired renal function and healthy subjects 
with normal renal function. Renal function will be classified based on the baseline eGFR 
calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) study 
equation.10 Baseline eGFR will be obtained for all subjects (ie, subjects with renal 
impairment and matched-control healthy subjects) by taking the mean of the eGFR 
obtained from Screening and from historical values obtained within a 3-month period 
from Screening. If no historical eGFR value is available, a second Screening eGFR 
sample will be taken during the Screening period ( 14 days apart) and the mean of the 
2 values will be used as the baseline eGFR for group assignment. Individual eGFR values 
recorded for each measurement contributing to the subject mean baseline value must fall 
within the specified eGFR ranges for each group (ie, matched-control healthy subjects and 
subjects with severe renal impairment [and subjects with mild and/or moderate renal 
impairment, if they are enrolled]) to categorize subjects’ renal impairment status. The eGFR 
based on CKD-EPI equation will be repeated at Check-in (Day -1) to confirm renal 
impairment status. For matched-control healthy subjects, a single assessment of actual 
creatinine clearance computed over a 24-hour urine collection may be used in place of the 
eGFR (based on the CKD-EPI equation), at the Investigator’s (or designee’s) discretion. 
Subjects with severe renal impairment (Group 4), and matched-control healthy subjects with 
normal renal function (Group 1) will begin enrolling in the study first. Subjects will be 
recruited so that up to 8 subjects with severe renal impairment and up to 8 subjects with 
normal renal function are enrolled, with the goal of having at least 6 subjects with severe 
renal impairment and at least 6 matched-control healthy subjects complete the study. 
 
Subjects will be enrolled within the following groups based on their eGFR values calculated 
using the CKD-EPI equation10 at Screening and repeated at Check-in (Day -1) as judged by 
the Investigator (or designee), Covance Medical Monitor, and Sponsor: 
 
• Group 1: Matched-control healthy subjects with normal renal function (eGFR: 
≥ 90 mL/min/1.73 m2) 
• Group 4: Subjects with severe renal impairment (eGFR: < 30 mL/min/1.73 m2) 
Continuous review of the safety data and PK data (if available) from up to 8 subjects with 
severe renal impairment and up to 8 matched-control healthy subjects with normal renal 
function will be conducted after these subjects have completed all study-related assessments 
through 72 hours (approximately 3 half-lives) postdose, at a minimum. The safety data will 
include AEs and serious AEs (SAEs), vital signs, physical examinations, ECGs, and clinical 
laboratory evaluations. 
 
Following continuous review of the safety data and PK data from up to 8 subjects with severe 
renal impairment (Group 4) and up to 8 matched-control healthy subjects with normal renal 
function (Group 1), subjects with mild renal impairment (Group 2) and/or moderate renal 
impairment in (Group 3) may be enrolled if deemed necessary by the Sponsor. If no clinically 


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relevant effect on PK is observed in subjects in Group 1 and Group 4, enrollment of subjects 
in Group 2 and/or Group 3 will not occur. 
 
If the Sponsor deems it necessary to enroll subjects with mild and/or moderate renal 
impairment, subjects will be recruited so that up to 8 subjects with mild renal impairment, up 
to 8 subjects with moderate renal impairment, and up to an additional 16 matched-control 
healthy subjects with normal renal function may be enrolled, with the goal of having at least 
6 subjects with mild renal impairment and at least 6 subjects with moderate renal impairment 
and their matched-control healthy subjects complete the study. Enrollment and dosing for 
subjects in Group 2 and/or Group 3 may only occur after the safety and PK data for subject(s) 
in Group 1 and Group 4 through a minimum of 72 hours postdose are reviewed and the 
Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed 
with dosing. 
 
Subjects will be enrolled within the following groups based on their eGFR values calculated 
using the CKD-EPI equation10 at Screening and repeated at Check-in (Day -1) as judged by 
the Investigator (or designee), Covance Medical Monitor, and Sponsor: 
 
• Group 2: Subjects with mild renal impairment (60 ≤ eGFR < 90 mL/min/1.73 m2) 
• Group 3: Subjects with moderate renal impairment (30 ≤ eGFR < 60 mL/min/1.73 m2) 
Baseline eGFR will be obtained for all subjects (ie, subjects with renal impairment and 
matched-control healthy subjects) by taking the mean of the eGFR obtained from 
Screening and from historical values obtained within a 3-month period from Screening. 
If no historical eGFR value is available, a second Screening eGFR sample will be taken 
during the Screening period ( 14 days apart) and the mean of the 2 values will be used 
as the baseline eGFR for group assignment. Individual eGFR values recorded for each 
measurement contributing to the subject mean baseline value must fall within the specified 
eGFR ranges for each group (ie, matched-control healthy subjects and subjects with severe 
renal impairment [and subjects with mild and/or moderate renal impairment, if they are 
enrolled]) to categorize subjects’ renal impairment status. The eGFR based on CKD-EPI 
equation will be repeated at Check-in (Day -1) to confirm renal impairment status. For 
matched-control healthy subjects, a single assessment of actual creatinine clearance 
computed over a 24-hour urine collection may be used in place of the eGFR (based on the 
CKD-EPI equation), at the Investigator’s (or designee’s) discretion. 
 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by 
age (± 10 years), body mass index (BMI; ± 20%), and sex to the completed renal impairment 
subject(s). Should another renal impairment subject be identified with whom an already 
enrolled healthy subject is demographically matched, the healthy subject may also be 
matched with that impaired subject as long as the impaired subject is in a different renal 
impairment group. Each subject with normal renal function may be matched with up to 1 
subject within each renal impairment group. 
 
The schematic of the study design is displayed in Figure 3. The start of the study is defined as 
the date the first subject who is enrolled in the study signs an Informed Consent Form (ICF). 
Note that enrolled subjects are defined as those subjects who are assigned a dose of study 
drug; this definition excludes screen failure subjects. Replacement subjects may be enrolled 
only if deemed necessary by the Sponsor. 


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To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and will be admitted to the Clinical Research Unit (CRU) on Day -1 
(Check-in). Subjects who are determined to be screen failures are permitted to be re-screened 
if the Investigator (or designee), with agreement from the Covance Medical Monitor and the 
Sponsor, feels that the subject may meet eligibility criteria upon re-screen. Re-screened 
subjects will be provided a new subject number. 
 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until EOT on Day 8 
upon completion of all PK and safety assessments or Early Termination (ET) if the subject 
discontinues. Subjects will be dosed on Day 1. A follow-up phone call will occur for all 
subjects who received a dose of study drug (including subjects who are terminated early) 
7 days (± 2 days) after EOT or ET. The duration of participation is expected to be up to 
46 days (Screening through follow-up phone call). 
 
On the morning of Day 1, after at least an 8-hour fast, a single oral dose of 200 mg 
LOXO-305 will be administered with approximately 240 mL of water. No food will be 
allowed for up to 2 hours postdose. Glucose tablets may be administered as needed for 
treatment of hypoglycemia in renally impaired subjects with diabetes. For instructions 
regarding food and water intake, refer to Section 6.2. Pharmacokinetic samples will be 
obtained through 168 hours postdose. 
 
Figure 3: Study Design Schematic 
ICF = Informed Consent Form; PK = pharmacokinetic. 
Note: Single oral dose of LOXO-305 at 200 mg administered orally after at least an 8-hour fast. 
 
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 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 


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occurs after study drug administration on Day 1 through EOT or ET regardless of relationship 
to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by 
the Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be reported. 
 
A Schedule of Assessments is presented in Appendix 4. Study completion is defined as the 
time of the last subject’s follow-up. 
 
3.2. 
Discussion of Study Design 
 
A single-dose, parallel design is the standard design to investigate the PK of a drug in 
subjects with renal impairment. A parallel design is required to include subjects with renal 
impairment and matched-control healthy subjects with normal renal function. A single dose 
level of 200 mg LOXO-305 will be used because it is the dose intended for registration. The 
study will be open-label because the primary endpoints are objective rather than subjective. 
 
Matched-control healthy subjects with normal renal function will be enrolled in this study to 
serve as a reference group for interpretation of the results. Based on nonclinical and clinical 
data, and the known PK profile of the compound, the duration of the treatment period is 
considered adequate to achieve the study objectives.1 Oral doses were chosen because this is 
the intended clinical route of administration. 
 
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 
consideration of this, subjects with renal impairment assessed as severe (eGFR: 
< 30 mL/min/1.73 m2), along with matched-control healthy subjects, will begin enrolling into 
the study first. If a clinically relevant difference is observed in the PK of subject(s) with 
severe renal impairment compared to matched-control healthy subjects during continuous 
review of the safety and PK data, then subjects with renal impairment assessed as mild (60 ≤ 
eGFR < 90 mL/min/1.73 m2) and/or moderate (30 ≤ eGFR < 60 mL/min/1.73 m2), along with 
additional matched-control healthy subjects (if needed) will be enrolled, to determine the 
extent of the effect of varying severities of renal impairment on the PK of LOXO-305. 
Enrollment of subjects with mild and/or moderate renal impairment will only be initiated if 
deemed necessary by the Sponsor following the continuous review of safety and PK data 
from severe renal impairment subjects and their matched-control healthy subjects (see 
Section 8.2). If no clinically relevant effect on PK is observed, enrollment of mild and/or 
moderate subjects will not occur. 
3.3. 
Selection of Doses in the Study 
LOXO-305 
Single oral doses of 200 mg LOXO-305 will be evaluated as this dose level given QD has 
been chosen as the recommended Phase 2 dose for the ongoing global Phase 1/2 
first-in-human study, LOXO-BTK-18001 (BRUIN Study). Doses of LOXO-305 from 25 mg 
QD to 300 mg QD have been evaluated in the ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (BRUIN Study) in patients with previously treated CLL/SLL or NHL 
with dose escalation up to 300 mg QD approved by the study’s Safety Review Committee. 


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The available data demonstrate that LOXO-305 appears safe and well tolerated at these 
doses. At all evaluated doses, no dose-limiting toxicities have been identified in humans.1 


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4. SELECTION OF STUDY POPULATION 
 
A total of up to 24 subjects with renal impairment (up to 8 subjects with severe impairment, 
and, if necessary, up to 8 subjects with moderate impairment, and/or up to 8 subjects with 
mild impairment, per eGFR using the CKD-EPI equation) and approximately 8 to 24 
matched-control healthy subjects with normal renal function will be enrolled in the study 
with the goal of having at least 6 subjects from each renal impairment group enrolled in the 
study and at least 6 subjects with normal renal function complete the study. Healthy subjects 
will be matched demographically to renally impaired subjects as noted in Section 3.1. 
 
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 BMI 
6. Complete physical examination (Section 7.2.5) 
7. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
8. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine blood pressure [BP] and pulse rate [measured after the subject 
has been supine for at least 5 minutes]; Section 7.2.3) 
9. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
10. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
11. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), 
hepatitis B virus (HBV) immunoglobulin M (IgM) core antibody, human 
immunodeficiency virus (HIV) antibody, and SARS-CoV-2 (COVID-19) via 
polymerase chain reaction (PCR) testing or antigen testing (or equivalent, as 
determined by the Investigator [or designee] with agreement from the Sponsor; 
Appendix 2) 
12. Hemoglobin A1c (HbA1c) test (Appendix 2) 
13. Screen for selected drugs of abuse, including cotinine (matched-control healthy 
subjects only) and alcohol (breath or urine test [Appendix 2]) 
14. eGFR (Appendix 2) 
15. Pregnancy test (for female subjects only; Appendix 2) 
16. Follicle-stimulating hormone (FSH) test (for post-menopausal female subjects only; 
Appendix 2) 


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17. Thyroid-stimulating hormone (TSH) test (Appendix 2) 
4.2. 
Check-in Procedures (Day -1) 
 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
 
1. Review of inclusion/exclusion criteria 
2. Interim medical history, including concomitant medication(s) 
3. Weight and BMI 
4. Abbreviated physical examination (Section 7.2.5) 
5. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
6. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine BP and pulse rate [measured after the subject has been supine 
for at least 5 minutes]; Section 7.2.3) 
7. HDYF? Inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
8. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
9. Screen for COVID-19 via PCR or antigen testing (or equivalent, as determined by the 
Investigator [or designee] with agreement from the Sponsor; Appendix 2) 
10. Screen for selected drugs of abuse, including cotinine (matched-control healthy 
subjects only) and alcohol (breath or urine test [Appendix 2]) 
11. eGFR (Appendix 2) 
12. Pregnancy test (for female subjects only; Appendix 2) 
13. Compliance with concomitant medications and exclusionary restrictions (Section 6) 
 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Check-in (Day -1 [as appropriate; #1, Section 4.2]). In addition, 
continued compliance with concomitant medication and other restrictions will be verified. 
 
The Covance Medical Monitor will review medical history and all screening evaluations for 
potential subjects prior to Check-in (Day -1). Prior to dosing, the Covance Medical Monitor 
and Sponsor will provide approval of subjects selected for enrollment by the Investigator (or 
designee). 
 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria apply 
will be eligible to be enrolled into the study. Safety evaluations may be repeated at the 
discretion of the Investigator (or designee), Covance Medical Monitor, 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: 


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All subjects: 
 
1. Males, and females of non-childbearing potential, between 18 and 75 years of age, 
inclusive, at Screening. 
2. Within BMI range 18.5 to 40.0 kg/m2, inclusive. 
3. In good health, except for additional specific inclusion criteria related to subjects with 
renal impairment, determined by no clinically significant findings from medical 
history, physical examination, 12-lead ECG, vital sign measurements, or clinical 
laboratory evaluations (Appendix 4) at Screening and/or Check-in (Day -1) as 
assessed by the Investigator (or designee). 
4. Female subjects of non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy, or confirmed tubal occlusion more than 6 months prior to Day 1) or 
post-menopausal (defined as at least 12 months post-cessation of menses without an 
alternative medical cause). Post-menopausal status will be confirmed with a screening 
serum FSH level consistent with post-menopausal status per the laboratory’s reference 
ranges. All female subjects must have a negative qualitative serum or negative 
qualitative urine pregnancy test (serum human chorionic gonadotropin; serum 
quantitative human chorionic gonadotropin tests may be used for confirmation as 
needed and post-menopausal subjects may be eligible for participation if the results of 
the qualitative serum pregnancy or qualitative urine pregnancy test are positive but the 
quantitative serum human chorionic gonadotropin results are within the laboratory’s 
reference ranges for post-menopausal women) at Screening and Check-in (Day -1). 
Female subjects are required to refrain from donation of ova from Check-in (Day -1) 
until 6 months after Day 1. 
5. Male subjects who are capable of fathering a child must agree to use 1 of the 
following methods of contraception: 
a. Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in 
(Day -1), or 
b. If documentation is not available, male subjects must follow 1 of the 
contraception methods below from Day 1 through 6 months after Day 1: 
i. Male condom with spermicide, or 
ii. A male subject must ensure that their female partner meets 1 of the 
following criteria: 
1. intrauterine device (IUD) (hormonal IUD; eg, Mirena®). 
Copper IUDs are acceptable (eg, ParaGard®); or 
2. established use of oral, implanted, injected, transdermal, 
intravaginal, or hormonal method of contraception associated 
with inhibition of ovulation; or 
3. non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation bilateral 
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occlusion more than 6 months prior to Day 1 for male partner); 
or 
4. be post-menopausal with amenorrhea for at least 1 year prior to 
Day 1 and FSH serum levels consistent with post-menopausal 
status. 
Male subjects who practice true abstinence because of a lifestyle choice (ie, do not 
become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence by a female partner (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. If a male subject is abstinent at the time of signing the ICF 
but becomes sexually active from Check-in (Day -1) through 6 months after Day 1, he 
must agree to use contraception as described above. 
For male subjects, sexual intercourse with female partners who are pregnant or 
breastfeeding should be avoided from Check-in (Day -1) through 6 months after 
Day 1, unless the male subject uses a condom with spermicide. Male subjects are 
required to refrain from donation of sperm from Check-in (Day -1) through 6 months 
after Day 1. 
For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. 
6. Able to understand and provide written informed consent. 
7. Able to comply with all study procedures, including the 8-night stay at the CRU and 
follow-up phone call. 
Additional inclusion criteria for matched-control healthy subjects only: 
8. Matched to subjects with mild and/or moderate and/or severe renal impairment in sex, 
age (± 10 years), and BMI (± 20%). Note: Each matched-control healthy subjects may 
be matched with up to 1 subject within each renal impairment group. 
9. Baseline eGFR ≥ 90 mL/min/1.73 m2 at Screening and repeated at Check-in (Day -1) 
based on CKD-EPI equation.10 A single assessment of actual creatinine clearance 
evaluated over a 24-hour urine collection may be used in place of the eGFR (based on 
the CKD-EPI equation) for matched-control healthy subjects, at the Investigator’s (or 
designee’s) discretion. Individual eGFR values recorded for each measurement 
contributing to the subject mean baseline value must fall within the specified eGFR 
range for a matched-control healthy subject (≥ 90 mL/min/1.73 m2). Rechecks of 
eGFR or creatinine clearance values will be permitted up to 2 times during Screening 
and Check-in (Day -1) to confirm eligibility for study participation. 
Additional inclusion criteria for subjects with renal impairment: 
10. Considered to have mild, moderate, or severe renal impairment (of any etiology) that 
has been clinically stable (no acute episodes of illness due to deterioration in renal 
function) for at least 1 month prior to Screening per the Investigator (or designee), 
Sponsor, and Covance Medical Monitor and are likely to remain stable throughout 
EOS. To be classified as having renal impairment, subjects must have baseline eGFR 
based on the CKD-EPI equation10 at Screening (and confirmed at Day -1) as follows: 
a. Severe renal impairment: < 30 mL/min/1.73 m2 


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b. Moderate renal impairment: ≥ 30 and < 60 mL/min/1.73 m2 
c. Mild renal impairment: ≥ 60 and < 90 mL/min/1.73 m2 
Baseline eGFR will be obtained by taking the mean of the eGFR obtained from 
Screening and from historical values obtained within a 3-month period from 
Screening. If no historical eGFR value is available, a second Screening eGFR 
sample (using the CKD-EPI equation) will be taken during the Screening period 
( 14 days apart) and the mean of the 2 values will be used as the baseline eGFR 
for group assignment. Individual eGFR values recorded for each measurement 
contributing to the subject mean baseline value must fall within the specified 
eGFR ranges for each group (ie, subjects with severe renal impairment [and 
subjects with mild and/or moderate renal impairment, if they are enrolled]) to 
categorize subjects’ renal impairment status. The eGFR based on CKD-EPI 
equation will be repeated at Check-in (Day -1) to confirm renal impairment status. 
Rechecks of eGFR values will be permitted up to 2 times during Screening and 
Check-in (Day -1) to confirm eligibility for study participation. 
11. Subject is not currently or has not previously been on hemodialysis, including 
peritoneal dialysis. 
12. Currently on a stable medication regimen, defined as not starting new drug(s) or 
significantly changing drug dosage(s) within 30 days prior to Day 1. Concomitant 
medications administered within 30 days prior to Day 1 must be approved by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor. Subjects must be 
able to withhold the use of these medications for 2 hours predose and 4 hours 
postdose on Day 1, unless approved by the Investigator (or designee) Covance 
Medical Monitor, and Sponsor. 
13. Anemia secondary to renal disease will be acceptable if hemoglobin is ≥ 8 g/dL and 
anemia symptoms are not clinically significant. Must have ≥ 35,000 platelets. 
4.4. 
Exclusion Criteria 
 
The following will exclude potential subjects from the study: 
 
All subjects: 
 
1. History or presence of any of the following, deemed clinically significant by the 
Investigator (or designee), Covance Medical Monitor, and/or Sponsor: 
a. liver disease 
b. pancreatitis 
c. peptic ulcer disease 
d. intestinal malabsorption 
e. gastric reduction surgery 
f. history or presence of clinically significant cardiovascular disease: 
i. myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to Day 1 
ii. symptomatic angina pectoris within 6 months prior to Day 1 


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iii. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to Day 1 
iv. congenital prolonged QT syndrome 
v. ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
vi. arrhythmia (excluding benign sinus arrhythmia) or history of 
arrhythmia requiring medical intervention 
vii. ventricular dysfunction or risk factors for Torsades de Pointes (eg, 
heart failure, cardiomyopathy, family history of Long QT Syndrome) 
viii. clinically significant screening ECG abnormalities including, but not 
limited to: 
1. complete left bundle-branch block 
2. second-degree atrioventricular (AV) block, type 2, or 
third-degree AV block 
2. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs except that appendectomy 
and hernia repair will be allowed. Bariatric surgery and cholecystectomy will not be 
allowed. 
3. Esophageal banding within 3 months prior to Check-in (Day -1) or required any other 
treatment for gastrointestinal bleeding within 6 months prior to Check-in (Day -1). 
4. Clinically significant (as determined by the Investigator [or designee]) abnormal 
clinical laboratory results (hematology panel, UA, clinical chemistry panel [fasted at 
least 8 hours], excluding those further defined in inclusion criteria #9 and #10 above 
and exclusion criteria #28, #29, #30, #36 and #41 below) at Screening or Check-in 
(Day -1). Rechecks of clinically significant abnormal clinical laboratory results 
(excluding those further defined in inclusion criteria #9 and #10 above and exclusion 
criteria #28, #29, #30, #36 and #41 below) will be permitted up to 2 times during 
Screening and Check-in (Day -1) to confirm eligibility for study participation if the 
values fall within normal ranges or are stabilizing. 
5. History or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator (or designee), and as confirmed by the 
Covance Medical Monitor and the Sponsor, or mentally or legally incapacitated or has 
significant emotional problems at the time of the Screening visit or expected during 
the conduct of the study. 
6. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Screening and/or Check-in (Day -1). 
7. Positive serologic test for HBsAg, HBV IgM core antibody, HCV antibody or HIV 
antibody at Screening. Subjects who are positive for HBV IgM core antibody or HCV 
antibody require confirmation by PCR before enrollment to detect presence of active 
virus. Subjects who are HBV core antibody or HCV antibody positive or for whom a 
PCR is unable to be obtained will not be eligible. 
8. Positive PCR test or antigen testing (or equivalent, as determined by the Investigator 
[or designee] with agreement from the Sponsor) for COVID-19 at Screening or 


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Check-in (Day -1). Further details regarding COVID-19 testing (including procedures 
for subjects who test positive at any time throughout CRU confinement) are specified 
in a separate document. 
9. 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. 
10. 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 [matched-control healthy subjects only] 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), unless the positive drug 
screen is due to prescription drug use that is approved by the Investigator (or 
designee), Covance Medical Monitor, and Sponsor. 
11. Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours 
prior to Check-in (Day -1) and through EOT or ET. 
12. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
13. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
14. Participation in any other investigational study drug trial where administration of any 
investigational drug occurred within 30 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1. 
15. 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 vitamin supplements, herbal products such as St. John’s wort), 
strong CYP2C8 substrates, strong P-gp inhibitors, proton-pump inhibitors, antacids, 
H2-receptor antagonists, and drugs that prolong QT/QTc interval, natural or herbal 
supplements, and hormone replacement therapy (HRT) within 14 days or 5 half-lives 
(if known), whichever is longer, prior to Day 1 and through EOT or ET, unless 
deemed acceptable by the Covance Medical Monitor, Investigator (or designee), and 
Sponsor or, if the subject is renally impaired, needed to stabilize the subject’s 
underlying medical condition (or concurrent baseline conditions) and deemed 
acceptable by the Medical Monitor, Investigator (or designee), and Sponsor, and 
provided that the subject has been on a stable dose for a minimum of 30 days prior to 
Day 1. 
16. History of a major surgical procedure within 30 days prior to Screening. 
17. History or presence, upon clinical evaluation, of any illness that, in the opinion of the 
Investigator (or designee), would interfere with the ability to provide informed 
consent or comply with study instructions, or that might confound the interpretation 
of the study results, or put the subject at undue risk. 
18. Poor peripheral venous access. 
19. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
20. Receipt of blood products within 2 months prior to Check-in (Day -1). 


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21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator or designee, and as confirmed by the Covance Medical Monitor and the 
Sponsor, within the 30 days prior to dosing and through EOT or ET. 
23. Any medication (including over-the-counter) that would significantly alter eGFR, 
which, by the determination of the Investigator (or designee), and as confirmed by the 
Covance Medical Monitor and the Sponsor, might interfere with the study (eg, 
cimetidine) will be prohibited at least 2 weeks or 5 half-lives (if known), whichever is 
longer, prior to dosing and through EOT or ET. 
24. Has completed or withdrawn from any other study investigating LOXO-305, and have 
previously received the investigational medicinal product within the last 30 days. 
Additional exclusion criteria for matched-control healthy subjects: 
25. QT interval corrected for heart rate using Fridericia’s method (QTcF) of > 450 msec 
at Screening, Check-in (Day -1), or predose on Day 1. Rechecks of out-of-range 
QTcF values that are not clinically significant (as determined by the Investigator [or 
designee]) will be permitted up to 2 times during Screening, Check-in (Day -1), and 
predose on Day 1 to confirm eligibility for study participation if the values fall within 
the range stated above. 
26. Abnormal ECG findings deemed clinically significant by the Investigator (or 
designee) at Screening, Check-in (Day -1), or prior to dosing on Day 1. 
27. Out-of-range, at-rest (ie, supine for at least 5 minutes) vital sign measurements at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
a. body temperature > 37.5°C; 
b. pulse rate < 50 or > 99 bpm; 
c. systolic BP < 89 or > 139 mmHg; 
d. diastolic BP < 50 or > 89 mmHg; 
e. oxygen saturation < 95% (room air). 
Rechecks of out-of-range values for these parameters (body temperature, pulse rate, 
BP, and oxygen saturation) that are not clinically significant (as determined by the 
Investigator [or designee]) will be permitted up to 2 times during Screening, Check-in 
(Day -1), and predose on Day 1 to confirm eligibility for study participation if the 
values fall within the ranges stated above. 
28. Abnormal LFTs, as defined by aspartate aminotransferase, alanine aminotransferase, 
and serum (total and direct) bilirubin, as well as amylase and lipase above the upper 
limit of the normal range at Screening or Check-in (Day -1). Rechecks of LFTs, 
amylase, and lipase above the upper limit of the normal range that are not clinically 
significant (as determined by the Investigator [or designee]) will be permitted up to 2 
times during Screening and Check-in (Day -1) to confirm eligibility for study 
participation if the values fall within normal ranges or are stable or normalizing as 
judged by the Investigator (or designee), and confirmed by the Covance Medical 
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29. Any clinically significant deviations from normal ranges in creatine kinase unless 
approved by the Covance Medical Monitor, Investigator (or designee), and Sponsor. 
Rechecks of out-of-range creatine kinase values that are not clinically significant (as 
determined by the Investigator [or designee]) will be permitted up to 2 times during 
Screening and Check-in (Day -1) to confirm eligibility for study participation if the 
values are stable or normalizing as judged by the Investigator (or designee), and 
confirmed by the Covance Medical Monitor and the Sponsor. 
30. Hemoglobin below the lower limit of normal range at Screening or Check-in (Day -1). 
Recheck of hemoglobin below the lower limit of normal range that is not clinically 
significant (as determined by the Investigator [or designee]) will be permitted up to 2 
times during Screening and Check-in (Day -1) to confirm eligibility for study 
participation if the values are stable or normalizing as judged by the Investigator (or 
designee), and confirmed by the Covance Medical Monitor and the Sponsor. 
31. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. 
32. Significant history or clinical manifestation of any allergic, dermatological, biliary, 
hepatic, gastrointestinal, renal, metabolic, hematological, pulmonary, cardiovascular 
(including any prior history of cardiomyopathy or heart failure), neurological, or 
psychiatric disorder (as determined by the Investigator [or designee]). Note: subjects 
with a history of appendectomy and/or hernia repairs will be acceptable. 
33. History of diabetes mellitus (as evidenced by HbA1c ≥ 6.5% at Screening). 
34. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
Additional exclusion criteria for subjects with renal impairment: 
35. QTcF value of > 450 msec for subjects with mild or moderate renal impairment or 
> 470 msec for subjects with severe renal impairment at Screening, Check-in 
(Day -1), or predose on Day 1. Rechecks of out-of-range QTcF values that are not 
clinically significant (as determined by the Investigator [or designee]) will be 
permitted up to 2 times during Screening, Check-in (Day -1), and predose on Day 1 to 
confirm eligibility for study participation if the values fall within the range stated 
above. 
36. Has rapidly fluctuating renal function; or has demonstrated or suspected renal artery 
stenosis. Rapidly fluctuating renal function is defined as a difference in baseline and 
historical eGFR values that results in a change of renal impairment classification 
category over at least 3 months for subjects with historical eGFR values available at 
the time of Screening, or a difference in eGFR values that results in a change of renal 
impairment classification category for the 2 screening measurements (≥ 14 days apart) 
for subjects with no historical eGFR values available at the time of Screening. 
37. Has had a renal transplant, a nephrectomy, or is a subject with a known history of 
nephrotic syndrome. 
38. Unable to refrain from or anticipates the use of any medication or substance 
(including prescription or over-the-counter medications, vitamin supplements, natural 
or herbal supplements) from 14 days, or 5 half lives (if known), whichever is longer, 
prior to dosing and through EOT or ET, unless it is a prescription or over-the-counter 
medication or, needed to stabilize the subject’s underlying medical condition (or 


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concurrent baseline conditions) which has been approved by the Investigator (or 
designee) with agreement from the Covance Medical Monitor and the Sponsor, and 
provided they have been on a stable regimen for at least 30 days prior to dosing and 
are able to withhold use for 2 hours predose and 4 hours postdose on the day of dose 
administration (Day 1) unless approved by the Investigator (or designee), with 
agreement from the Covance Medical Monitor and Sponsor. 
39. Has required new medication for renal disease within 30 days prior to Check-in 
(Day -1). 
40. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
a. Body temperature > 37.5°C; 
b. Pulse rate < 50 or > 99 bpm; 
c. Systolic BP < 89 or > 150 mmHg; 
d. Diastolic BP < 50 or > 95 mmHg; 
e. Oxygen saturation < 95% (room air). 
Rechecks of out-of-range values for these parameters (body temperature, pulse rate, 
BP, and oxygen saturation) that are not clinically significant (as determined by the 
Investigator [or designee]; based on the age and renal impairment status) will be 
permitted up to 2 times during Screening, Check-in (Day -1), and predose on Day 1 to 
confirm eligibility for study participation if the values fall within the ranges stated 
above. 
41. Values outside the normal ranges for creatine kinase, LFTs, amylase, and lipase may 
be acceptable as consistent with the subject’s renal condition (if stable for 1 month 
prior to Screening), and if the Investigator (or designee), the Covance Medical 
Monitor, and the Sponsor feel that the results are not clinically significant (based on 
age and renal impairment status). 
42. Smoking more than 10 cigarettes per day or equivalent (eg, e-vapor cigarette, pipe, 
cigar, chewing tobacco, nicotine patch, nicotine gum) throughout the confinement 
period of the study (EOT or ET); unable or being unwilling to refrain from the use of 
tobacco- or nicotine-containing products for 2 hours prior to dosing and 4 hours after 
dose administration on Day 1. 
43. History of unstable diabetes mellitus (as evidenced by HbA1c ≥ 10.0% at Screening). 
Medications for the treatment of diabetes mellitus must be reviewed and approved by 
the Investigator (or designee), the Covance Medical Monitor, and the Sponsor. 
44. History of cancer within the past 5 years (except localized basal cell, squamous, or in 
situ cancer of the skin). 
45. Recent history of paracentesis (within 30 days prior to Screening). 
4.5. 
Subject Number and Identification 
 
Subjects will be assigned into groups based on their level of renal function (Table 2) and will 
be assigned a number by CRU staff based on the assigned group. Assignment of numbers 
within each group will be in ascending order and no numbers will be omitted. Subject number 


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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, 001-100). Subject numbers will be identified by group 
(eg, subject numbering will be as follows for Site 001): 
 
• Group 1: Matched-control healthy subjects: 001-100 through 001-199 
• Group 2: Subjects with mild renal impairment: 001-200 through 001-299 
• Group 3: Subjects with moderate renal impairment: 001-300 through 001-399 
• Group 4: Subjects with severe renal impairment: 001-400 through 001-499. 
Subject numbers will be used on all study documentation. For subjects who are withdrawn by 
the Investigator (or designee) or who voluntarily withdraw prematurely from the study, 
replacement subjects will be enrolled only if deemed necessary by the Sponsor. If necessary, 
as determined by the Sponsor, subjects who fail to complete the treatment or have insufficient 
PK data may be replaced. Replacement subjects will be assigned a subject number by adding 
400 to the last 3 digits of the subject number for the subject they are replacing (eg, Subject 
Number 001-501 replaces Subject Number 001-101). Subjects who are determined to be 
screen failures are permitted to be re-screened if the Investigator (or designee), with 
agreement from the Covance Medical Monitor and the Sponsor, feels that the subject may 
meet eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number as defined above. 
 
Table 2: Subject Group and Number of Subjects 
 
Group 
Description of Renal Functiona 
N 
1 
Matched Normal Renal Function 
Up to 8 to 24b 
2b 
Mild Renal Impairment 
Up to 8 
3b 
Moderate Renal Impairment 
Up to 8 
4 
Severe Renal Impairment 
Up to 8 
a Renal function determined using the eGFR assessment. 
b Group 2 and Group 3 (and additional matched-control healthy subjects) will only be enrolled if deemed 
necessary. 
 
4.6. 
Removal of Subjects from Study Participation 
 
Subjects will be informed that they are free to withdraw from the study at any time and for 
any reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue 
the study. Subjects may be withdrawn because of the following: 
 
• change in compliance with inclusion/exclusion criterion that is clinically relevant and 
affects subject safety 
• occurrence of AEs 
• occurrence of pregnancy 
• intake of non-permitted concomitant medication that might affect subject safety or 
study assessments/objectives, etc. 
 
Notification of withdrawal will immediately be made to the Study Monitor. In case of 
withdrawal, efforts will be made to perform all ET assessments (Appendix 4). The date the 


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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), 
Sponsor, or Covance Medical Monitor 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. 
 
4.7. 
Matching Process 
 
A matched-control healthy subject will be matched to the completed renal impairment 
subject(s) (age [± 10 years], BMI [± 20%], and sex). An individual matched-control healthy 
subject may be matched with up to 1 subject within each renal impairment group (ie, to a 
maximum of 3 renally impaired subjects across the study [1 mild, 1 moderate, and 1 severe], 
but to no more than 1 subject in each impairment group). A listing of the matched subjects 
will be included in the Clinical Study Report. 


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5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study drug (Table 3). 
 
Table 3: Study Drug 
 
Study Drug 
LOXO-305 
Forma 
Tablet 
Strength 
100 mg 
Supplier 
Loxo Oncology, Inc. 
Manufacturer 
Bend Research, Inc. 
a Specific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug. 
 
The tablets containing 100 mg LOXO-305 will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificate of Analysis. It will be provided in 
high-density polyethylene bottles and stored according to the instructions on the label. 
Study drug will be stored at the CRU in a location that is locked with restricted access. 
The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drug will be transferred from bulk supplies into the subject’s 
dose container by qualified CRU employees. Each unit dose container will be appropriately 
labeled. 
 
5.2. 
Study Treatment Administration 
 
Subjects will receive a single dose of LOXO-305, given orally as two 100-mg tablets 
(200 mg total dose) in the morning on Day 1. 
 
The study drug will be administered orally with approximately 240 mL of water. An 
additional 100 mL of water may be administered if needed. Doses will be preceded by a fast 
of at least 8 hours from food (not including water) and will be followed by a fast from food 
(not including water) for up to 2 hours postdose. Water will be restricted for 1-hour predose 
and 1-hour postdose, with the exception of water administered for dose administration. 
Glucose tablets may be administered as needed for treatment of hypoglycemia in renally 
impaired subjects with diabetes. 
 
Each unit dose will be prepared by qualified CRU staff. 
 
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be administered the appropriate dose at a 
specific time, the exact dose time of subjects may be staggered to obviate the need to have all 
subjects on precisely the same study schedule. For each dose, the subject’s actual dose time 
will be recorded in the source documents and transcribed into the eCRF. 


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Subjects will be instructed not to crush, split, or chew the study drug. 
 
Subjects will not lay supine for 4 hours following LOXO-305 dose administration, except as 
necessitated by the occurrence of an AE(s) and/or study procedure(s). 
 
5.3. 
Randomization 
 
This is a non-randomized study. The study has a fixed treatment sequence. 
 
5.4. 
Blinding 
 
This is an open-label study. 
 
5.5. 
Treatment Compliance 
 
The following measures will be employed to ensure treatment compliance: 
 
• All doses will be administered under the supervision of suitably qualified CRU staff 
• Immediately after oral dose administration, a visual inspection of the mouth and 
hands will be performed for each subject 
• At each dose preparation occasion, a predose and postdose inventory of LOXO-305 
will be performed 
5.6. 
Drug Accountability 
 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-305 
tablets received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
 
At the completion of the study, all unused LOXO-305 tablets will be disposed of by the CRU, 
following the Sponsor’s written/emailed instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
 
Subjects will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurs within 5 half-lives (if known) or 30 days, 
whichever is longer, prior to Day 1. 
 
All prescription medications and over-the-counter medications (including moderate or strong 
CYP3A4 and/or CYP3A5 inhibitors or inducers [including herbal products such as St. John’s 
wort], strong CYP2C8 substrates, strong P-gp inhibitors, proton-pump inhibitors, antacids, 
H2-receptor antagonists, and drugs that prolong QT/QTc interval, vitamin supplements, 
natural or herbal supplements, medications that would significantly alter eGFR [eg, 
cimetidine], and HRT) are prohibited for 14 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1 and through EOT or ET, unless deemed acceptable by the Covance 
Medical Monitor, Investigator (or designee), and Sponsor or, if the subject is renally 
impaired, needed to stabilize the subject’s underlying medical condition (or concurrent 
baseline conditions) as described below. 
 
For renally impaired subjects, the use of prescription and over-the-counter medications that 
are needed to stabilize the subject’s underlying medical condition (or concurrent baseline 
conditions) and deemed acceptable by the Covance Medical Monitor, Investigator (or 
designee), and Sponsor are allowed, provided that the subject has been on a stable dose for a 
minimum of 30 days prior to Day 1. Renally impaired subjects must be able to withhold the 
use of these medications for 2 hours predose and 4 hours postdose on Day 1, unless approved 
by the Covance Medical Monitor, Investigator (or designee), and Sponsor. Short-term 
medication adjustments may be made upon consultation with the Covance Medical Monitor, 
Investigator (or designee), and Sponsor per the Medical Responsibility Plan. The use of 
additional medications is to be avoided from 14 days prior to Day 1 until EOT or ET unless 
required to treat an AE. All concomitant medications needed to stabilize the subject’s 
underlying medical condition (or concurrent baseline conditions) will be reviewed by the 
Covance Medical Monitor, Investigator (or designee), and Sponsor prior to subject approval. 
 
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 Covance Medical Monitor, 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 
 
Matched-control healthy 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. Renally impaired subjects are required to refrain from the use of 
tobacco- and nicotine-containing products within 2 hours prior to dosing and for 4 hours 
postdose. 


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Consumption of foods or beverages containing grapefruit/grapefruit juice or Seville oranges 
or its juice within 7 days prior to Check-in (Day -1) and through EOT or ET will not be 
allowed. 
 
Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours prior to 
Check-in (Day -1) and through EOT or ET will not be allowed. 
 
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and 
during the period of confinement at the CRU and will otherwise maintain their normal level 
of physical activity through EOT or ET (ie, should not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
 
While confined at the CRU, subjects will receive a standard diet at scheduled times that do 
not conflict with other study-related activities. Water will be restricted for 1-hour predose and 
1-hour postdose, with the exception of water administered for dose administration. Glucose 
tablets may be administered as needed for treatment of hypoglycemia in renally impaired 
subjects with diabetes. 
 
Fasting requirement in relation to dosing are described in Section 3.1 and Section 5.2. 


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7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
 
Blood samples for PK analysis of plasma concentrations of LOXO-305 and unbound 
LOXO-305 will be collected at the timepoints specified in Appendix 4. The exact time of the 
study drug administration and the actual time of blood sampling for PK analysis will be 
recorded on the eCRF. 
 
Processing, storage, and shipping instructions for these PK blood and unbound LOXO-305 
samples will be provided in a separate Laboratory Manual. The number of blood samples and 
total blood volume required for PK testing and unbound LOXO-305 is presented in 
Appendix 3. 
 
7.1.2. 
Analytical Methodology 
 
Concentrations of LOXO-305 in plasma will be determined using a validated bioanalytical 
method. Specifics of the bioanalytical methods will be provided in a separate document. The 
concentrations of total and unbound LOXO-305 will be determined in a sample of predose 
plasma fortified with a known concentration of LOXO-305. The fu will be calculated based 
on total and unbound LOXO-305 levels. Samples of plasma may be analyzed for exploratory 
analyses of metabolites. If such analyses are conducted, the results will be reported separately 
by the Sponsor. 
 
7.2. 
Safety and Tolerability Assessments 
 
Safety evaluations may be repeated at the discretion of the Covance Medical Monitor, 
Investigator (or designee), or Sponsor. 
 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and any other procedures to be performed at the same timepoint. The order of priority for 
scheduling procedures around a timepoint is (in descending order of priority): 
 
• dosing 
• PK blood sampling 
• vital sign measurements 
• 12-lead ECGs 
• blood and urine samples for clinical laboratory evaluations 
• physical examination. 
7.2.1. 
Adverse Events 
 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 


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


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Screens for HCV antibody, HBsAg, HBV IgM core antibody, and HIV antibody will be 
performed at Screening. 
 
Testing for COVID-19 via PCR or antigen testing (or equivalent, as determined by the 
Investigator [or designee] with agreement from the Sponsor) will be performed at the 
timepoints specified in Appendix 4. Testing for COVID-19 may also be conducted 
periodically during the subject’s CRU confinement, at the discretion of the Investigator (or 
designee). Further details regarding COVID-19 testing (including procedures for subjects 
who test positive at any time throughout CRU confinement) are specified in a separate 
document. 
 
A urine drug screen for selected drugs of abuse (including cotinine [matched-control healthy 
subjects only] and alcohol [urine or breath test]) will be performed at Screening and repeated 
at Check-in (Day -1) for all subjects. A serum qualitative or urine qualitative pregnancy test 
(female subjects only [quantitative serum human chorionic gonadotropin tests may be used 
for confirmation as needed and post-menopausal subjects may be eligible for participation if 
the results of the qualitative serum pregnancy or qualitative urine pregnancy test are positive 
but the quantitative serum human chorionic gonadotropin results are within the laboratory’s 
reference ranges for post-menopausal women]) and an FSH test (post-menopausal female 
subjects only) will be performed at the timepoints specified in Appendix 4. 
 
The number of blood samples and total blood volume required for clinical laboratory 
evaluations is presented in Appendix 3. A list of the specific evaluations is in Appendix 2. 
 
7.2.3. 
Vital Signs 
 
Vital sign measurements (including body temperature, respiratory rate, oxygen saturation, 
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 heart rate, PR, RR, QRS, and QT interval parameters) will be 
obtained after the subject has been resting for at least 10 minutes in the supine position at the 
timepoints specified in Appendix 4. The QT interval will be corrected for heart rate by 
Fridericia’s (QTcF = QT/[RR]1/3) formula. 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to and as 
close as possible to the scheduled blood draw. 


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7.2.5. 
Physical Examination 
 
A complete or abbreviated physical examination will be performed at the timepoints specified 
in Appendix 4. Complete physical examinations will evaluate general appearance and the 
following body systems/organs: dermatological; head and eyes; ears, nose, mouth, and throat; 
pulmonary; cardiovascular; abdominal; lymphatic; musculoskeletal/extremities; and 
neurological. Weight and height will be reported (height only reported during Screening). 
Abbreviated physical examinations will evaluate general appearance and the following body 
systems/organs: dermatological; pulmonary; cardiovascular; abdominal; and neurological. 


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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
 
A total of up to 24 subjects with renal impairment (up to 8 subjects with severe impairment, 
and, if necessary, up to 8 subjects with moderate impairment, and/or up to 8 subjects with 
mild impairment, per eGFR using the CKD-EPI equation) and approximately 8 to 24 
matched-control healthy subjects with normal renal function will be enrolled in the study 
with the goal of having at least 6 subjects from each renal impairment group enrolled in the 
study and at least 6 subjects with normal renal function complete the study. The sample size 
chosen for this study was based upon precedent set by other PK studies of similar nature and 
was not based on power calculations to detect statistically significant differences among 
groups. This number is considered a sufficient sample size to evaluate the PK of LOXO-305 
under various degrees of renal function. 
 
8.2. 
Interim Analysis 
 
Subjects with renal impairment assessed as severe, along with matched-control healthy 
subjects, will begin enrolling in the study first. Continuous review of the safety data and PK 
data (if available) from up to 8 subjects with severe renal impairment and up to 8 
matched-control healthy subjects with normal renal function will be conducted after these 
subjects have completed all study-related assessments through 72 hours (approximately 3 
half-lives) postdose, at a minimum. The safety data will include AEs and SAEs, vital signs, 
physical examinations, ECGs, and clinical laboratory evaluations. 
 
If a clinically relevant difference is observed in the PK of subject(s) with severe renal 
impairment compared to matched-control healthy subjects during continuous review of the 
safety and PK data, then subjects with renal impairment assessed as mild (60 ≤ eGFR 
< 90 mL/min/1.73 m2) and/or moderate (30 ≤ eGFR < 60 mL/min/1.73 m2), along with 
additional matched-control healthy subjects (if needed) will be enrolled, to determine the 
extent of the effect of varying severities of renal impairment on the PK of LOXO-305. 
Enrollment of subjects with mild and/or moderate renal impairment will only be initiated if 
deemed necessary by the Sponsor following the continuous review of safety and PK data 
from severe renal impairment subjects and their matched-control healthy subjects. If no 
clinically relevant effect on PK is observed, enrollment of mild and/or moderate subjects will 
not occur. 
 
Enrollment and dosing for remaining subjects in Group 2 and/or Group 3 may only occur 
after the data for Group 1 and Group 4 are reviewed and the Covance Medical Monitor, 
Investigator (or designee), and Sponsor agree it is safe to proceed with dosing. 
 
Subjects will be recruited for Group 2 and/or Group 3 so that up to 8 subjects with mild renal 
impairment, up to 8 subjects with moderate renal impairment, and up to an additional 16 
matched-control healthy subjects with normal renal function may be enrolled, with the goal 
of having at least 6 subjects with mild renal impairment and at least 6 subjects with moderate 
renal impairment and their matched-control healthy subjects complete the study. 
 
Teleconferences will occur as needed between the Covance Medical Monitor, Investigator (or 
designee), and Sponsor to discuss PK, safety, and tolerability data. 


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8.3. 
Analysis Populations 
 
The PK Population will consist of all subjects who have received a dose of study drug, have 
at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times median tmax. The impact 
of protocol deviations on the PK population will be evaluated on a case-by-case basis. 
 
The Safety Population will consist of all subjects who have received at least 1 dose of study 
drug. Subjects will be classified into groups based on actual treatment received. 
 
8.4. 
Pharmacokinetic Analysis 
 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-305: 
 
Cmax 
maximum observed plasma concentration 
tmax 
time to maximum observed plasma concentration 
AUC0-t 
AUC from hour 0 to the last measurable concentration, 
calculated using the linear trapezoidal rule for increasing and 
decreasing concentrations 
AUC0-inf 
AUC from hour 0 extrapolated to infinity, calculated using 
the formula: 
Ct 
AUC0-inf  = AUC0-t  + λz 
 
where Ct is the last measurable concentration and Z is the 
apparent terminal elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC0-inf 
Z 
apparent terminal elimination rate constant, where Z is the 
magnitude of the slope of the linear regression of the log 
concentration versus-time profile during the terminal phase 
t1/2 
apparent plasma terminal elimination half-life (whenever 
possible), where t1/2 = natural log (2)/Z 
CL/F 
apparent systemic clearance 
Vz/F 
apparent volume of distribution during the terminal phase 
MRT 
mean residence time 
fu 
unbound fraction, calculated as unbound concentration 
divided by total concentration 
 
The fu value determined for each subject will be used to calculate the following unbound 
LOXO-305 PK parameters for each individual subject: 
 
Cmax,u 
Unbound Cmax, calculated as Cmax*fu 
AUC0-t,u 
Unbound AUC0-t, calculated as AUC0-t*fu 


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AUC0-inf,u 
Unbound AUC0-inf, calculated as AUC0-inf*fu 
CL/F,u 
Unbound CL/F, calculated as Dose/AUC0-inf,u 
Vz/F,u 
Unbound Vz/F, calculated as CL/F,u/Z 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 8.1 or higher (Certara USA Inc.). 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed 
in the Statistical Analysis Plan (SAP). 
 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analyses will be performed using SAS Version 9.4 or greater. More details on the analyses 
will be included in the SAP. 
 
8.4.1. 
Descriptive Analysis 
 
Plasma concentrations and PK parameters will be summarized by renal function classification 
with descriptive statistics (number, arithmetic mean, standard deviation, coefficient of 
variation [CV%], geometric mean, geometric CV%, median, minimum, and maximum). In 
addition, summary statistics for unbound LOXO-305 will be tabulated by renal function 
classification. 
 
8.4.2. 
Statistical Methodology 
 
The primary analysis planned for this study is to evaluate the PK of LOXO-305 after a single 
dose in subjects with renal impairment compared to subjects with normal renal function. 
 
Paired t-tests will be performed to assess the differences in PK parameters (AUC0-t, AUC0-inf, 
and Cmax) between each renal impairment group versus the corresponding matched-control 
healthy group with respect to 1 to 1 matching. The analysis will be based on the natural log 
(ln)-transformed PK parameters. Geometric mean ratios and their corresponding 90% 
confidence intervals (CIs) will be calculated using the exponentiation of the mean difference 
and the CIs obtained for the difference in mean between each renal impairment group and the 
matching healthy control group. 
 
In addition, an analysis of covariance (ANCOVA) will be performed on the ln-transformed 
AUC0-t, AUC0-inf, and Cmax. The ANCOVA model will contain a categorical factor of 
population for subjects with varied-degree renal impairment (severe, moderate, and mild) and 
matched-control healthy subjects, a categorical covariate (sex), and continuous covariates 
(age and BMI). Ratios of least squares means and 90% CIs will be calculated using the 
exponentiation of the difference between renal function cohort least squares means from the 
ANCOVA analyses on the ln-transformed AUC0-t, AUC0-inf, and Cmax. In addition, an 
ANCOVA will be performed on the ln-transformed AUC0-t,u, AUC0-inf,u, and Cmax,u. 
 
The relationship between LOXO-305 PK parameters (ie, Cmax and AUC) and measures of 
renal function (such as eGFR and creatinine clearance) may be explored using a linear 
regression approach or other methods. The effect of covariates such as age, BMI, and sex 
may be investigated. 


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The specific procedures will be documented in the SAP. 
 
8.5. 
Safety Analysis 
 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated, and summarized where possible, using descriptive methodology by renal function 
group and, as needed, by timepoint. Unless otherwise specified, baseline value is defined as 
the last non-missing measurement before administration of LOXO-305. No formal statistical 
analyses are planned for the safety data. All safety data will be listed by subject. 
 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO Drug Global B3, September 2019). Adverse events will be coded using 
Medical Dictionary for Regulatory Activities Version (MedDRA) 22.1 (or higher). The 
incidence of AEs for each renal function group (matched control healthy subjects, mild, 
moderate, and severe) will be presented by severity and by relationship to study drug as 
determined by the Investigator or designee (Appendix 1 for AE reporting). All TEAEs will be 
summarized by system organ class and preferred term, with a breakdown by renal function 
group. 
 
8.6. 
Data Handling and Record Keeping 
 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a CRU staff member authorized to make 
the change. Changes will be made by striking a single line through erroneous data and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
CRU staff member. 
 
The Data Management Plan will be approved by the Sponsor. 
 
Data will be validated during data entry by the CRU and verified by the Study Monitor. Data 
will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be 
reviewed by the Covance scientific team. The eCRF and ancillary data will be converted into 
final SAS® datasets following Study Data Tabulation Model or Sponsor-provided 
specifications. The final datasets structure will be verified using Web Submission Data 
Manager®, while the dataset content will be peer reviewed by an independent programmer. 
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. 


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8.7. 
Quality Control and Quality Assurance 
 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per Sponsor request, and as applicable, according to the contract 
between Covance and the Sponsor. 


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9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator (or designee). 
 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator (or designee), and the IRB (see Form 
FDA 1572). 
 
9.2. 
Site Initiation Visit/Investigator Meeting 
 
Prior to the start of the clinical study, the representative(s) of the Sponsor and/or Sponsor will 
meet with the Investigator (or designee) and appropriate CRU staff to familiarize the 
Investigator (or designee) and site 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 
 
Covance (on behalf of the Sponsor) will designate Study Monitors who will be responsible 
for monitoring this clinical trial. Covance’s Study Monitor will monitor the study conduct, 
proper eCRF and source documentation completion and retention, and accurate study drug 
accountability. It is essential that Covance’s Study Monitors have access to all documents 
(related to the study and the individual participants) at any time these are requested. In turn, 
Covance’s Study Monitors will adhere to all requirements for subject confidentiality as 
outlined in the ICF. The Investigator (or designee) and Investigator’s staff will be expected to 
cooperate with Covance’s Study Monitors. 
 
9.5. 
Institutional Review Board 
 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
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). 


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


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9.9. 
Financing and Insurance 
 
Financing and insurance will be addressed in a separate agreement. 


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10. REFERENCES 
1. Loxo Oncology, Inc. LOXO-305 - Investigator’s Brochure (Version 4.0). 29 October 
2020. 
 
2. Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, Rothenberg SM, et al. A next 
generation reversible BTK Inhibitor, for overcoming acquired resistance to irreversible 
BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18; S216. 
 
3. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK 
with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 
4;369(1):32–42. 
 
4. Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol. 2017 May 1;35(13):1437–43. 
 
5. Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to 
acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 
2019;134(Supplement_1). 
 
6. Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022–35. 
 
7. Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017 
04;129(18):2519–25. 
 
8. Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, Haruna M, et al. QT 
PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT 
Interval Prolongation by Human Pharmaceuticals [Internet]. Journal of pharmacological 
sciences. 2005 [cited 2020 Jun 10]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/16493187/ 
 
9. Food and Drug Administration. Guidance for Industry: Pharmacokinetics in Patients with 
Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling [Internet]. Food and Drug Administration; 2010 [cited 2020 Jan 27]. Available 
from: https://www.fda.gov/media/78573/download 
 
10. Levey AS, Stevens LA, et al. The CKD-EPI Creatinine Equation [Internet]. 2009 [cited 
2021 Feb 15]. Available from: http://nephron.com/epi_equation 


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11. APPENDICES 


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


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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
 
• 
NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship 
and another cause (eg, concomitant drugs, therapies, complications, comorbidities) 
is suspected 
• 
RELATED = The time course between administration of investigational product 
and the occurrence or worsening of the AE is consistent with a causal relationship 
and no other cause (eg, concomitant drugs, therapies, complications, comorbidities) 
can be identified 
 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
 
Pregnancy 
 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through End of Study or Early Termination (ET; if the subject 
discontinues from the study and does not complete a follow-up phone call) and for up to 
90 days after Day 1 should be reported by the Investigator (or designee) via email to Covance 
or the Sponsor’s Clinical Safety Representative within 24 hours of being notified. Covance or 
the Sponsor’s Clinical Safety Representative will then forward the Pregnancy Form to the 
Investigator (or designee) for completion. 
 
email: SAEIntake@Covance.com 
 
A subject becoming pregnant while on study drug will immediately be withdrawn from the 
study and ET study procedures will be performed. The subject or partner should be followed 
by the Investigator (or designee) until completion of the pregnancy. If the pregnancy ends for 
any reason before the anticipated date, the Investigator (or designee) should notify Covance 
or the Sponsor’s Clinical Safety Representative. At the completion of the pregnancy, the 
Investigator (or designee) will document the outcome of the pregnancy. If the outcome of the 
pregnancy meets the criteria for immediate classification as a serious adverse event (SAE; an 
SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator (or designee) should follow the procedures for 
reporting an SAE. 
 
Male subjects will be instructed to notify the Investigator (or designee) immediately if they 
discover their sexual partner is pregnant. In this instance, the partner must provide written 
consent before pregnancy information can be collected. When a Clinical Research Unit 
(CRU) becomes aware that the female partner of a male subject is pregnant, they are to 
contact the Investigator (or designee) immediately (within 24 hours of the CRU staff 
becoming aware of the event) in addition to notifying Covance or the Sponsor’s Clinical 
Safety Representative via email. 
 
All pregnancies should be recorded on the AE electronic Case Report Form (as appropriate), 
in addition to completion of the required pregnancy forms. If the Investigator (or designee) 
suspects that a pregnancy was the result of an interaction between the study treatment and the 


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


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reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 
 
The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 


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Appendix 2: Clinical Laboratory Evaluations 
 
Clinical Chemistry Panel 
(Fasted): 
Hematology Panel: 
Other Tests: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bilirubin (direct and total) 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase 
Creatininef 
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (percent and 
absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Hemoglobin A1cb 
Thyroid-stimulating hormoneb 
Estimated glomerular filtration rate 
(eGFR)a,d,f 
SARS-CoV-2 (COVID-19) test 
Coagulation Parameters: 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Human immunodeficiency virus 
antibody 
Hepatitis B surface antigen 
Hepatitis B virus IgM core antibody 
Hepatitis C virus antibody 
For Female Subjects only: 
Pregnancy test (serum qualitative or 
urine qualitative, serum quantitative 
human chorionic gonadotropin tests 
may be used for confirmation if 
needed and post-menopausal 
subjects may be eligible for 
participation if the results of the 
qualitative serum pregnancy or 
qualitative urine pregnancy test are 
positive but the quantitative serum 
human chorionic gonadotropin 
results are within the laboratory’s 
reference ranges for post- 
menopausal women)c 
Follicle-stimulating hormone 
(post-menopausal female subjects 
only)b 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity 
Protein 
Urobilinogen 
Microscopic examination including 
bacteria, casts, crystals, epithelial 
cells, RBCs, and WBCs (if protein, 
leukocyte esterase, nitrite, or occult 
blood is positive) 
Urine Drug Screen:a 
Including but not limited to the 
following: 
Alcohol (ethanol)e 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine (metabolite) 
Methadone 
Opiates 
Phencyclidine 
Cotinine (healthy subjects only) 
a. Performed at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Performed at Screening, Check-in (Day -1), and Day 7/Early Termination (ET) only. 
d. Calculated using the using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 
e. Urine or breath test. 
f. Baseline eGFR will be obtained by taking the mean of the eGFR obtained from Screening and from historical values 
obtained within a 3-month period from Screening. If no historical eGFR value is available, a second Screening eGFR 
sample (using the CKD-EPI equation) will be taken during the Screening period ( 14 days apart) and the mean of the 2 
values will be used as the baseline eGFR for group assignment. Individual eGFR values recorded for each measurement 
contributing to the subject mean baseline value must fall within the specified eGFR ranges for each group (ie, subjects 
with severe renal impairment [and subjects with mild and/or moderate renal impairment, if they are enrolled]) to 
categorize subjects’ renal impairment status. The eGFR based on CKD-EPI equation will be repeated at Check-in 
(Day -1) to confirm renal impairment status. For matched-control healthy subjects, a single assessment of actual 
creatinine clearance computed over a 24-hour urine collection may be used in place of the eGFR (based on the CKD-EPI 
equation), at the Investigator’s (or designee’s) discretion. 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject: 
Purpose 
Approximate Blood 
Volume per Sample 
(mL) 
Maximum 
Number of Blood 
Samples 
Approximate 
Total Volume 
(mL) 
Serology 
4 
1 
4 
Hemoglobin A1c 
4 
1 
4 
Pharmacokinetic (PK) Sampling 
4 
20 
80 
Unbound Drug PK Sampling 
4 
1 
4 
Clinical Laboratory Evaluations: 
Hematology 
Clinical Chemistrya 
Coagulation Parameters 
4 
4 
3 
5 
6b 
5 
20 
24 
15 
Serum Pregnancy Test (females only) 
2 
3 
6 
Serum Follicle-stimulating Hormone 
Test (postmenopausal females only) 
2 
1 
2 
Thyroid-stimulating Hormone 
2 
1 
2 
Total: 
161 mL 
a Estimated glomerular filtration rate will be assessed as part of the clinical chemistry sample. 
b A second Screening eGFR sample may be taken during the Screening period if needed for baseline eGFR assessment. 
 
 
Note: Although the total maximum volume to be analyzed is anticipated to be approximately 
161 mL, due to the variability in sampling requirements at different laboratories, the total 
volume of blood collected from each subject may vary. 


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 71 of 75 
 
 
 
Appendix 4: Schedule of Assessments 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 7 2  of 7 5  
 
 
 
St u d y Pr oce d ures a  
Scree ni n g 
( D a ys -2 9 t o -2)  
C hec k -i n 
( D a y -1)  
St u d y C o n d uct  
C R U Disc h ar ge/ E O T or E T t 
F oll o w -u p P h o ne C all ( E O S)  
D a y 1  
D a ys 2 t o 7  
D a y 8  
7 ( ± 2) d a ys p ost E O T or E T v  
C o nfi ne d t o t he C R U  
 
X  
X  
X  
X  
 
I ncl usi o n/ E xcl usi o n Criteri a 
X  
X  
 
 
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
De m o gr a p hics  
X  
 
 
 
 
 
Me dic al Hist or y  
X  
X b  
 
 
 
 
Hei g ht/ Wei g ht/ B MI  
X c 
X c 
 
 
 
 
P h ysic al E x a mi n ati o n d  
X  
X  
 
 
X  
 
1 2 -Le a d E C G e 
X  
X  
X  
X  
X  
 
Vit al Si g ns f 
X g, h  
X g, h  
X h  
X  
X g, h  
 
H D Y F ? I n q uir y i 
X  
X  
X  
X  
X  
X  
A Es/ S A Es j 
X  
X  
X  
X  
X  
X  
L O X O -3 0 5 D ose k  
 
 
X  
 
 
 
Cli nic al L a b or at or y E v al u ati o ns n  
X  
X  
 
X u  
X u  
 
C O VI D -1 9 Test o  
X  
X  
 
 
 
 
e G F R 
X  
X  
 
 
 
 
He p atitis a n d HI V Scree n  
X  
 
 
 
 
 
H b A 1c Test  
X  
 
 
 
 
 
Dr u g Scree n p  
X  
X  
 
 
 
 
Pri or a n d C o nc o mit a nt Me dic ati o ns q  
X  
X  
X  
X  
X  
X  
Pre g n a nc y Test r 
X  
X  
 
X u  
X u  
 
F S H Test s 
X  
 
 
 
 
 
T S H Test  
X  
 
 
 
 
 
A b bre viati o ns: A E = a d verse e ve nt; B MI = b o d y mass i n de x; B P = bl o o d press ure; C O VI D -1 9 = S A R S -C o V -2; C R F = Case Re p ort F or m; C R U = Cli nical Researc h U nit;  
E C G = electr ocar di o gra m; e G F R = esti mate d gl o mer ular filtrati o n rate; E O S = E n d of St u d y; E O T = E n d of Treat me nt; E T = Earl y Ter mi nati o n; F S H = f ollicle -sti m ulati n g h or m o ne; H b A 1c = 
he m o gl o bi n A 1c; H D Y F? = H o w D o Y o u Feel?; HI V = h u ma n i m m u n o deficie nc y vir us; I C F = I nf or me d C o nse nt F or m; P K = p har mac o ki net ic; S A E = seri o us a d verse e ve nt; T S H = 
t h yr oi d-sti m ulati n g h or m o ne; U A = uri nal ysis. 
a. F or details o n st u d y pr oce d ures, see Secti o n  7 . 
b.  I nteri m me dical hist or y o nl y.  
c. Hei g ht c ollecte d at Scree ni n g o nl y; B MI base d o n Scree ni n g  hei g ht.  
d.  A  c o m plete  p h ysical  e xa mi nati o n will  be  perf or me d  at Scree ni n g  a n d E O T  ( Da y 8, 1 6 8  h o urs  p ost d ose)  or  E T.  A n  a b bre viate d p h ysical  e xa mi nati o n will  be  perf or me d  at C hec k -i n ( Da y -1).  
e. 1 2 -lea d E C Gs will be o btai ne d at Scree ni n g a n d C hec k-i n ( Da y -1), Da y 1 ( pre d ose a n d 3 h o urs p ost d ose), Da y 3 ( 4 8 h o urs p ost d ose), a n d E O T ( Da y 8, 1 6 8 h o urs p ost d ose) or E T. W he n 
sc he d ule d at t he sa me ti me as bl o o d  dra ws, 1 2 -lea d E C Gs  will  be  c ollecte d  after t he s u bject has  reste d i n t he s u pi ne p ositi o n  f or at least 1 0 mi n utes  a n d will  be  o btai ne d  pri or  t o a n d as cl ose 
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 2  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 3  
Pr ot oc ol Versi o n 2. 0, 1 7 Fe br uar y 2 0 2 1  
Pa ge 7 3  of 7 5  
 
 
 
as p ossi ble t o t he sc he d ule d bl o o d dra ws. T he all o we d sa m pli n g wi n d o w f or 1 2 -lea d E C Gs is ± 3 0 mi n utes fr o m t he n o mi nal ti me p oi nt f or all p ost d ose 1 2-lea d E C Gs a n d n o less t ha n 
1 0 mi n utes pri or t o d osi n g f or pre d ose 1 2 -lea d E C Gs. 
f. Vital si g n meas ure me nts (s u pi ne B P a n d p ulse rate) will be o btai ne d at Scree ni n g, C hec k -i n ( Da y -1), Da y 1 ( pre d ose, 2 h o urs after d osi n g), dail y o n Da ys 2 t hr o u g h 7 ( 2 4, 4 8, 7 2, 9 6, 1 2 0, 
a n d 1 4 4 h o urs p ost d ose), a n d at E O T ( Da y 8, 1 6 8 h o urs p ost d ose) or E T. W he n sc he d ule d at t he sa me ti me as bl o o d dra ws, vital si g n meas ure me nts s h o ul d be carrie d o ut pri or t o a n d as cl ose 
as p ossi ble t o ha vi n g bl o o d dra w n. Bl o o d press ure a n d p ulse rate will be meas ure d usi n g t he sa me ar m f or eac h rea di n g after t he s u bject has bee n s u pi ne f or at least 5 mi n utes. T he all o we d 
sa m pli n g wi n d o w f or vital si g n meas ure me nts is ± 3 0 mi n utes fr o m t he n o mi nal ti me p oi nt f or all p ost d ose vital si g n meas ure me nt s a n d n o less t ha n 1 0 mi n utes pri or t o d osi n g f or pre d ose 
vital si g n  meas ure me nts.  
g.  B o d y te m perat ure a n d res pirat or y rate will be o btai ne d at Scree ni n g, C hec k -i n ( Da y -1), a n d at E O T ( Da y 8, 1 6 8 h o urs p ost d ose) or  E T.  
h.  O x y ge n sat urati o n meas ure d b y p ulse o xi metr y will be meas ure d at Scree ni n g, C hec k -i n ( Da y -1), pre d ose o n Da y 1, a n d at E O T ( Da y 8, 1 6 8 h o urs p ost d ose) or E T. T he all o we d sa m pli n g 
wi n d o w f or o x y ge n sat urati o n meas ure me nts is ± 3 0 mi n utes fr o m t he n o mi nal ti me p oi nt f or all p ost d ose o x y ge n sat urati o n meas ur e me nts a n d n o less t ha n 1 0 mi n utes pri or t o d osi n g f or 
pre d ose o x y ge n sat urati o n  meas ure me nts.  
i. A  H D Y F?  i n q uir y will be  perf or me d  at Scree ni n g  (after t he I C F is si g ne d), at C hec k -i n ( Da y -1),  at eac h p ost d ose  vital  si g n meas ure me nts,  a n d at a n a p pr o priate ti me f or  all ot her  da ys.  
j. A d verse e ve nts a n d S A Es will be c ollecte d be gi n ni n g at i nf or me d c o nse nt. A d verse e ve nts will be rec or de d t hr o u g h o ut t he st u d y  (ie, fr o m si g ni n g of t he I C F u ntil E O S, or u ntil E T if t he 
s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w-u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if t h e 
e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d as n ot relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee]) or as A Es (if t he e ve nt occ urs after si g ni n g of t he 
I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d b y t he I n vesti gat or [ or desi g nee]) as relate d t o st u d y proce d ures, or if t he e ve nt occ urs after st u d y dr u g a d mi nistrati o n o n 
Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p t o st u d y dr u g. Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o  st u d y dr u g are t o be rec or de d. All S A Es t hat de vel o p fr o m 
t he ti me of I C F si g ni n g u ntil E O S ( or E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w-u p p h o ne call) are t o be  re p orte d. 
k.  O n Da y 1, L O X O -3 0 5 will be d ose d i n t he m or ni n g. L O X O -3 0 5 will be a d mi nistere d f oll o wi n g a fast of at least 8 h o urs pre d ose a n d u p t o 2 h o urs  p ost d ose.  
n.  Cli nical c he mistr y pa nel (faste d f or at least 8 h o urs), c oa g ulati o n para meters, he mat ol o g y pa nel, a n d U A will be perf or me d at  Scree ni n g, C hec k -i n ( Da y -1), Da y 2 ( 2 4 h o urs p ost d ose), Da y 5 
( 9 6 h o urs p ost d ose), a n d Da y 7 ( 1 4 4 h o urs p ost d ose), if t he s u bject c o m pletes t he st u d y ( E O T) or o n t he da y of E T. Cli nical la b orat or y e val uati o ns will be perf or me d o n t he da y pri or t o 
s u bject release fr o m t he C R U if t he s u bject c o m pletes t he st u d y ( E O T). Cli nical la b orat or y e val uati o ns will be perf or me d o n t he da y of s u bject release fr o m t he C R U if t he s u bject ter mi nates 
earl y ( E T). At E T or t he da y bef ore E O T ( Da y 7), s u bjects are n ot re q uire d t o be faste d pri or t o cli nical la b orat or y e val uati o ns. T he all o we d sa m pli n g wi n d o w f or cli nical c he mistr y pa nel, 
c oa g ulati o n para meters, he mat ol o g y pa nel, a n d U A is wit hi n t he sa me da y t hat t he y are  re q uire d. 
o.  Testi n g f or C O VI D -1 9 will be c o n d ucte d at a mi ni m u m of Scree ni n g a n d C hec k -i n ( Da y -1). Testi n g f or C O VI D -1 9 ma y als o be c o n d ucte d peri o dicall y d uri n g t he s u bject’s C R U 
c o nfi ne me nt, at t he discreti o n of t he I n vesti gat or ( or desi g nee). Tests will be perf or me d b y ra pi d p ol y merase c hai n reacti o n or a nti ge n testi n g ( or e q ui vale nt, as deter mi ne d b y t he I n vesti gat or 
[ or desi g nee] wit h a gree me nt fr o m t he S p o ns or).  
p.  Dr u gs of a b use uri ne test, i ncl u di n g c oti ni ne ( matc he d -c o ntr ol healt h y s u bjects o nl y) a n d alc o h ol ( uri ne or breat h test). Res ults fr o m t he dr u gs of a b use tests will be use d t o dete r mi ne s u bject 
eli gi bilit y per t he i ncl usi o n/e xcl usi o n criteria.  
q.  Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de d be gi n ni n g at i nf or me d c o nse nt. I n a d diti o n, all I n vesti gat or -a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 3 0 da ys pri or t o 
Da y 1 f or prescri pti o n me dicati o ns (f or re nal i m pair me nt s u bjects o nl y), a n d f or all prescri pti o n a n d o ver -t he-c o u nter me dicati o ns, t h ose ta ke n 1 4 da ys or 5 half -li ves (if k n o w n), w hic he ver is 
l o n ger, pri or t o Da y 1 will be rec or de d o n t he s u bject’s electr o nic C R F.  
r. Fe male s u bjects o nl y. Perf or me d at Scree ni n g, C hec k -i n ( Da y -1), a n d Da y 7 ( 1 4 4 h o urs p ost d ose), if t he s u bject c o m pletes t he st u d y ( E O T) or o n t he da y of E T. Pre g na nc y tests will be 
perf or me d o n t he da y pri or t o s u bject release fr o m t he C R U if t he s u bject c o m pletes t he st u d y  ( E O T). 
s. P ost -me n o pa usal fe male s u bjects  o nl y.  
C CI


Protocol 
Covance Study: 8419692 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20013 
Protocol Version 2.0, 17 February 2021 
Page 74 of 75 
 
 
 
t. EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 8. ET is defined as when the subject is released from the CRU if the 
subject terminates the study early. Vital sign measurements, ECG, and physical examination results are to be available for review by the Investigator (or designee) prior to subject release 
from the CRU at the EOT visit (Day 8) or ET. Clinical laboratory results (for clinical chemistry, hematology, coagulation, and UA) and pregnancy test results (female subjects only) are to be 
available for review by the Investigator (or designee) prior to subject release from the CRU at the EOT visit and prior to subject release from the CRU at the ET visit if available. 
u. Clinical laboratory evaluations and pregnancy test (female subjects only) will be performed on the day prior to subject release from the CRU (Day 7) if the subject completes the study 
(EOT). Clinical laboratory evaluations and pregnancy test (female subjects only) will be performed on the day of subject release from the CRU if the subject terminates early (ET). 
v.  To be conducted 7 days (± 2 days) following EOT or ET. EOS is defined as when the subject is contacted for a follow-up phone call 7 days (± 2 days) after the EOT visit or ET visit to 
determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-305 (including subjects who are terminated early) will receive a 
follow-up phone call. 


Protocol Version 2.0, 17 February 2021 
Page 75 of 75 
 
 
Protocol 
CONFIDENTIAL 
Covance Study: 8419692 
Protocol Reference: LOXO-BTK-20013 
 
 
Appendix 5: Protocol Amendment Summary of Changes 
 
Protocol Version 2.0 (dated 17 February 2021) incorporated the following changes in 
Protocol Version 1.0 (dated 29 October 2020): 
 
• A reference to the CKD-EPI equation to be used to calculate estimated glomerular 
filtration rate has been added. 
• The version of the Investigator Brochure referenced has been updated and the 
Protocol has been updated based on this and data from ongoing clinical studies. 
• Allowance of qualitative urine pregnancy testing, in addition to serum qualitative 
pregnancy testing. 
• Clarification that post-menopausal female subjects requiring a quantitative serum 
human chorionic gonadotropin test may be eligible for participation in the study if the 
values fall within the normal ranges for post-menopausal females. 
• Exclusion criterion #35 has been updated to exclude patients with severe renal 
impairment with a QT interval corrected for heart rate using Fridericia’s method 
of > 470 msec, instead of > 480 msec. 
• An additional electrocardiogram assessment has been added at 3 hours postdose on 
Day 1. 
• Clarification that polymerase chain reaction or antigen testing for SARS-CoV-2 
(COVID-19) can be used to confirm there is no active infection. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan J2N-OX-JZNG  Version 1.0
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Pharmacokinetic Study of 
LOXO-305 Administered to Fasted Renally Impaired Male and Female Subjects and Fasted Matched-control Healthy 
Subjects
NCT06190678
Approval Date: 08-Mar-2021


TITLE PAGE 
Statistical Analysis Plan 
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, 
Tolerance, and Pharmacokinetic Study of LOXO-305 Administered to 
Fasted Renally Impaired Male and Female Subjects and Fasted 
Matched-control Healthy Subjects 
SAP Status: Sponsor Final 
SAP Version: 1.0 
SAP Date: 08MAR021 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20013 
Covance Study: 8419692 
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: 
Multiple Sites 
Principal Investigator: 
Multiple Investigators 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


SAP 
CONFIDENTIAL 
Covance Study: 8419692 
Protocol Reference: LOXO-BTK-20013 
Sponsor Final, Version 1.0, 08MAR2021 
Page 2 of 23 
 
ST-AD-031 Version 01 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objective ........................................................................................................... 6 
2.2. Secondary Objective ....................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 10 
6. STUDY TREATMENT AND RENAL FUNCTION GROUPS ......................................... 11 
7. DEFINITIONS OF POPULATIONS .................................................................................. 11 
7.1. All Subjects Population ................................................................................................. 11 
7.2. Safety Population .......................................................................................................... 11 
7.3. Pharmacokinetic Population ......................................................................................... 11 
8. STATISTICAL METHODOLOGY .................................................................................... 12 
8.1. General .......................................................................................................................... 12 
8.1.1. Calculation of the Summary Statistics ................................................................... 12 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 13 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 13 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Demographics and Baseline Characteristics ................................................................. 14 
8.4. Prior and Concomitant Medication ............................................................................... 14 
8.5. Pharmacokinetic Assessments ...................................................................................... 14 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 14 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 16 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 17 
8.6. Safety and Tolerability Assessments ............................................................................ 18 
8.6.1. Adverse Events ....................................................................................................... 18 
8.6.2. Clinical Laboratory Parameters .............................................................................. 20 


SAP 
CONFIDENTIAL 
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Protocol Reference: LOXO-BTK-20013 
Sponsor Final, Version 1.0, 08MAR2021 
Page 3 of 23 
 
ST-AD-031 Version 01 
8.6.3. Vital Signs Parameters ........................................................................................... 20 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
8.6.5. Other Assessments ................................................................................................. 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 21 
9. INTERIM ANALYSES ....................................................................................................... 21 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 21 
11. REFERENCES .................................................................................................................. 21 
12. APPENDICES ................................................................................................................... 23 


SAP 
CONFIDENTIAL 
Covance Study: 8419692 
Protocol Reference: LOXO-BTK-20013 
Sponsor Final, Version 1.0, 08MAR2021 
Page 4 of 23 
 
ST-AD-031 Version 01 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).   
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
extrapolated to infinity 
ADaM 
analysis data model 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AUC 
area under the concentration-time curve  
AUC0-inf 
area under the concentration-time curve from hour 0 extrapolated to 
infinity 
AUC0-inf,u 
unbound area under the concentration-time curve from hour 0 
extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
AUC0-t,u 
unbound area under the concentration-time curve from hour 0 to the last 
measurable concentration 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CI 
confidence interval 
CL/F 
apparent systemic clearance 
CL/F,u 
unbound apparent systemic clearance 
Cmax 
maximum observed plasma concentration 
Cmax,u 
unbound maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
fu 
unbound fraction 
Geom CV 
geometric CV 
Geom Mean 
geometric mean 
ICF 
Informed Consent Form 


SAP 
CONFIDENTIAL 
Covance Study: 8419692 
Protocol Reference: LOXO-BTK-20013 
Sponsor Final, Version 1.0, 08MAR2021 
Page 5 of 23 
 
ST-AD-031 Version 01 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
λz 
apparent terminal elimination rate constant 
λZ Lower 
start of exponential fit 
λZ N 
number of data points included in the log-linear regression 
λZ Span Ratio 
time period over which λZ was determined as a ratio of t1/2 
λZ Upper 
end of exponential fit 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTinf 
mean residence time based on area under the concentration-time curve 
from time 0 extrapolated to infinity 
NC 
not calculated 
NR 
not reported 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R2-adj 
adjusted coefficient for determination of exponential fit 
COVID-19  
SARS-CoV-2 
SAE 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
apparent plasma terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time to maximum observed plasma concentration 
Vz/F 
apparent volume of distribution at the terminal phase 
Vz/F,u 
unbound apparent volume of distribution at the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
 


SAP 
CONFIDENTIAL 
Covance Study: 8419692 
Protocol Reference: LOXO-BTK-20013 
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Page 6 of 23 
 
ST-AD-031 Version 01 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 2.0 
dated 17 February 2021) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
2.1. Primary Objective 
The primary objective of the study is to evaluate the PK profile of LOXO-305 in subjects 
with impaired renal function compared to matched-control healthy subjects. 
2.2. Secondary Objective 
The secondary objective of the study is to evaluate safety and tolerability of LOXO-305 in 
subjects with impaired renal function and matched-control healthy subjects. 
3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305: 
 maximum observed plasma concentration (Cmax) 
 time to maximum observed plasma concentration (tmax) 


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 area under the concentration-time curve (AUC) from hour 0 to the last measurable 
concentration (AUC0-t)  
 area under the concentration-time curve from hour 0 extrapolated to infinity 
(AUC0-inf) 
 percentage extrapolation for AUC0-inf (%AUCextrap) 
 apparent terminal elimination rate constant (λz) 
 apparent plasma terminal elimination half-life (t1/2) 
 apparent systemic clearance (CL/F) 
 apparent volume of distribution at the terminal phase (Vz/F) 
  mean residence time based on AUC0-inf (MRTinf). 
In addition, a single blood sample will be collected predose to determine the unbound 
fraction (fu) of LOXO-305 in plasma and, whenever possible, the following PK parameters 
will be calculated for unbound LOXO-305 using fu: unbound Cmax (Cmax, u), unbound AUC0-t 
(AUC0-t,u), unbound AUC0-inf (AUC0-inf,u), unbound CL/F (CL/F,u), and unbound Vz/F 
(Vz/F,u). 
3.2. Secondary Endpoints 
Safety and tolerability will be assessed by monitoring adverse events (AEs) and concomitant 
medications, performing physical examinations and clinical laboratory evaluations, 
measuring vital signs, and performing 12-lead electrocardiograms electrocardiogram (ECGs). 
These safety and tolerability endpoints are deemed adequate to detect any safety signals. 
4. STUDY DESIGN  
This study is an open-label, nonrandomized, multi-center, single-dose, parallel-group study to 
determine the PK, safety, and tolerability of LOXO-305 administered orally at a dose of 
200 mg to fasted adult males and females with impaired renal function and healthy subjects 
with normal renal function. Renal function will be classified based on the baseline estimated 
glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) study equation outlined in Table 1.  
Table 1: 
The CKD-EPI Equation3 to be used for eGFR Estimation 
Sex and race 
Serum creatinine (mg/dL) 
Equation 
Female 
Black 
≤ 0.7 
eGRF = 166 × (Scr/0.7)-0.329 × (0.993)Age 
> 0.7 
eGRF = 166 × (Scr/0.7)-1.209 × (0.993)Age 
Male 
Black 
≤ 0.9 
eGRF = 163 × (Scr/0.9)-0.411 × (0.993)Age 
> 0.9 
eGRF = 163 × (Scr/0.9)-1.209 × (0.993)Age 
Female 
White or other 
≤ 0.7 
eGRF = 144 × (Scr/0.7)-0.329 × (0.993)Age 
> 0.7 
eGRF = 144 × (Scr/0.7)-1.209 × (0.993)Age 
Male 
≤ 0.9 
eGRF = 141 × (Scr/0.9)-0.411 × (0.993)Age 


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White or other 
> 0.9 
eGRF = 141 × (Scr/0.9)-1.209 × (0.993)Age 
Baseline eGFR will be obtained for all subjects (ie, subjects with renal impairment and 
matched-control healthy subjects) by taking the mean of the eGFR obtained from Screening 
and from historical values obtained within a 3-month period from Screening. If no historical 
eGFR value is available, a second Screening eGFR sample will be taken during the Screening 
period (≥ 14 days apart) and the mean of the 2 values will be used as the baseline eGFR for 
group assignment. Individual eGFR values recorded for each measurement contributing to the 
subject mean baseline value must fall within the specified eGFR ranges for each group (ie, 
matched-control healthy subjects and subjects with severe renal impairment [and subjects 
with mild and/or moderate renal impairment, if they are enrolled]) to categorize subjects’ 
renal impairment status. The eGFR based on CKD-EPI equation will be repeated at Check-in 
(Day -1) to confirm renal impairment status. For matched-control healthy subjects, a single 
assessment of actual creatinine clearance computed over a 24-hour urine collection may be 
used in place of the eGFR (based on the CKD-EPI equation), at the Investigator’s (or 
designee’s) discretion. 
Subjects with severe renal impairment (Group 4), and matched-control healthy subjects with 
normal renal function (Group 1) will begin enrolling in the study first. Subjects will be 
recruited so that up to 8 subjects with severe renal impairment and up to 8 subjects with 
normal renal function are enrolled, with the goal of having at least 6 subjects with severe 
renal impairment and at least 6 matched-control healthy subjects complete the study.  
Subjects will be enrolled within the following groups based on their eGFR values calculated 
using the CKD-EPI equation at Screening and repeated at Check-in (Day -1) as judged by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor: 
● Group 1: Matched-control healthy subjects with normal renal function (eGFR: 
≥ 90 mL/min/1.73 m2) 
● Group 4: Subjects with severe renal impairment (eGFR: < 30 mL/min/1.73 m2) 
Continuous review of the safety data and PK data (if available) from up to 8 subjects with 
severe renal impairment and up to 8 matched-control healthy subjects with normal renal 
function will be conducted after these subjects have completed all study-related assessments 
through 72 hours (approximately 3 half-lives) postdose, at a minimum. The safety data will 
include AEs and serious AEs (SAEs), vital signs, physical examinations, ECGs, and clinical 
laboratory evaluations. 
Following continuous review of the safety data and PK data from up to 8 subjects with severe 
renal impairment (Group 4) and up to 8 matched-control healthy subjects with normal renal 
function (Group 1), subjects with mild renal impairment (Group 2) and/or moderate renal 
impairment in (Group 3) may be enrolled if deemed necessary by the Sponsor. If no clinically 
relevant effect on PK is observed in subjects in Group 1 and Group 4, enrollment of subjects 
in Group 2 and/or Group 3 will not occur.  
If the Sponsor deems it necessary to enroll subjects with mild and/or moderate renal 
impairment, subjects will be recruited so that up to 8 subjects with mild renal impairment, up 


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to 8 subjects with moderate renal impairment, and up to an additional 16 matched-control 
healthy subjects with normal renal function may be enrolled, with the goal of having at least 
6 subjects with mild renal impairment and at least 6 subjects with moderate renal impairment 
and their matched-control healthy subjects complete the study. Enrollment and dosing for 
subjects in Group 2 and/or Group 3 may only occur after the safety and PK data for subject(s) 
in Group 1 and Group 4 through a minimum of 72 hours postdose are reviewed and the 
Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed 
with dosing.  
Subjects will be enrolled within the following groups based on their eGFR values calculated 
using the CKD-EPI equation at Screening and repeated at Check-in (Day -1) as judged by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor:  
● Group 2: Subjects with mild renal impairment (60 ≤ eGFR < 90 mL/min/1.73 m2)  
● Group 3: Subjects with moderate renal impairment (30 ≤ eGFR < 60 mL/min/1.73 m2)  
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by 
age (± 10 years), body mass index (BMI; ± 20%), and sex to the completed renal impairment 
subject(s). Should another renal impairment subject be identified with whom an already 
enrolled healthy subject is demographically matched, the healthy subject may also be 
matched with that impaired subject as long as the impaired subject is in a different renal 
impairment group. Each subject with normal renal function may be matched with up to 1 
subject within each renal impairment group.  
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned a dose of study drug; this definition excludes screen failure subjects. 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and will be admitted to the Clinical Research Unit (CRU) on Day -1 
(Check-in). Subjects who are determined to be screen failures are permitted to be re-screened 
if the Investigator (or designee), with agreement from the Covance Medical Monitor and the 
Sponsor, feels that the subject may meet eligibility criteria upon re-screen. Re-screened 
subjects will be provided a new subject number.  
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 8 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. Subjects will be dosed on Day 1. A follow-up 
phone call will occur for all subjects who received a dose of study drug (including subjects 
who are terminated early) 7 days (± 2 days) after EOT or ET. The duration of participation is 
expected to be up to 46 days (Screening through follow-up phone call).  
On the morning of Day 1, after at least an 8-hour fast, a single oral dose of 
200 mg LOXO-305 will be administered with approximately 240 mL of water. No food will 
be allowed for up to 2 hours postdose. Glucose tablets may be administered as needed for 


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treatment of hypoglycemia in renally impaired subjects with diabetes. PK samples will be 
obtained through 168 hours postdose. 
A schematic of the study design is presented in Figure 1.  
Figure 1: Study Design 
 
ICF = informed consent form; PK = Pharmacokinetics  
Note: Single oral dose of LOXO-305 at 200 mg administered orally after at least an 8-hour fast. 
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistry panel, coagulation parameters, hematology panel, 
urinalysis, and recording of concomitant medications will be performed at specified times 
during the study.  
AEs and SAEs will be collected beginning at informed consent. AEs will be reported 
throughout the study (ie, from signing of the ICF until End of Study [EOS], or until ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as 
subject medical history (if the event is reported as beginning prior to signing of the ICF or if 
the event occurs prior to study drug administration on Day 1 and is assessed as not related to 
study procedures by the Investigator [or designee]) or as AEs (if the event occurs after 
signing of the ICF but prior to study drug administration on Day 1 and is assessed as related 
to study procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From 
EOT or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a follow-up phone 
call) are to be reported.  
Study completion is defined as the time of the last subject’s follow-up. 
5. SAMPLE SIZE JUSTIFICATION  
A total of up to 24 subjects with renal impairment (up to 8 subjects with severe impairment, 
and, if necessary, up to 8 subjects with moderate impairment, and/or up to 8 subjects with 
mild impairment, per eGFR using the CKD-EPI equation) and approximately 8 to 24 
matched-control healthy subjects with normal renal function will be enrolled in the study 
with the goal of having at least 6 subjects from each renal impairment group enrolled in the 
study and at least 6 subjects with normal renal function complete the study. The sample size 
chosen for this study was based upon precedent set by other PK studies of similar nature and 


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was not based on power calculations to detect statistically significant differences among 
groups. This number is considered a sufficient sample size to evaluate the PK of LOXO-305 
under various degrees of renal function.  
6. STUDY TREATMENT AND RENAL FUNCTION GROUPS 
The planned treatment administered for all subjects will be 200 mg LOXO-305. 
The renal function group names and ordering to be used in the TFLs are presented in Table 2.  
Table 2: 
Presentation of Renal Function Groups in TFLs  
Renal Function Group 
Abbreviation 
Order in TFLs 
Normal Renal Function 
Normal 
1 
Mild Renal Impairment 
Mild 
2 
Moderate Renal Impairment 
Moderate 
3 
Severe Renal Impairment 
Severe 
4 
All renal function groups described above are the planned groups. If the mild and moderate 
renal impairment groups are not enrolled, the subsequent order of the severe group will be 
amended. The TFLs will reflect the actual renal function groups dosed based upon their 
eGFR using the CKD-EPI equation.   
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those related to SARS-CoV-2 (COVID-19), will be 
considered prior to database lock for their importance and taken into consideration when 
assigning subjects to populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The Safety Population will include all subjects who received 1 dose of study drug. Subjects 
will be classified into renal function groups based off of their baseline eGFR value using the 
CKD-EPI equation.  
7.3. Pharmacokinetic Population  
The PK Population will include all subjects who received a dose of LOXO-305, have at least 
1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be computed. 
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times median tmax. The impact of 
protocol deviations on the PK population will be evaluated on a case-by-case basis.  


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8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the EOS visit. Any 
subject who discontinued the study will be identified accordingly in the listings. Summaries 
and statistical analyses will include the subjects assigned to the relevant population based on 
data type.   
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 3.1.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.   
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, and any parameter 
derivations.   
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
 Missing values will not be imputed, unless specifically stated otherwise.  
 Unrounded data will be used in the calculation of summary statistics.  
 If the number of subjects with valid observations (n) <3, summary statistics will not 
be calculated, with the exception of n, minimum, and maximum.   
 As ET data is not associated with any scheduled timepoint, it will be excluded from 
all calculations of summary statistics.  
 Postdose repeats and unscheduled assessments will not be included in calculations 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 


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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 Readings  
For vital sign measurements and 12-lead ECG data only, any predose value recorded in 
addition to the original value or a postdose value recorded within 15 minutes of the original 
value will be defined as a repeat value; any postdose value recorded more than 15 minutes 
after the original value will be defined as an unscheduled value. For all other data types (eg, 
laboratory 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.  
Post dose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations, with the exception of the baseline derivation (see Section 0). 
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.  
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.   
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.  


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A summary table by renal function group 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 BMI will be listed.  
A summary table by renal function group will be provided, based on the safety population.  
The eGFR data will be listed and summarized. 
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the dose of LOXO-305. 
Concomitant medication will be defined as medication that starts during or after the dose of 
LOXO-305 or starts but does not end prior to the dose of LOXO-305.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2020 (or later if upversioned 
during the study). Prior and concomitant medications will be listed.   
8.5. Pharmacokinetic Assessments   
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of LOXO-305 using noncompartmental methods in validated software 
program Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUC0-t 
h*ng/mL 
area under the concentration-time curve from hour 0 to the last 
measurable concentration (tlast)b 
AUC0-inf 
h*ng/mL 
area under the concentration-time curve from time 0 extrapolated 
to infinityc 
%AUCextrap 
% 
percentage extrapolation for AUC0-inf 
Cmax 
ng/mL 
maximum observed plasma concentration 
tmax 
h 
time to maximum observed plasma concentration 
λz 
1/h 
apparent terminal elimination rate constant 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent systemic clearance  
Vz/F 
L 
apparent volume of distribution at the terminal phase 
MRTinf 
h 
mean residence time (based on AUC0-inf) 
fu 
-- 
unbound fraction 
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. 


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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 
The unbound fraction (fu) in plasma, expressed as a decimal, will be calculated from protein 
binding concentration data as the unbound drug concentration divided by the total drug 
concentration in plasma. The fu value determined for each subject will be used to calculate 
the following unbound LOXO-305 PK parameters for each individual subject:  
Cmax,u  
Unbound Cmax, calculated as Cmax*fu 
AUC0-t,u 
Unbound AUC0-t, calculated as AUC0-t*fu 
AUC0-inf,u 
Unbound AUC0-inf, calculated as AUC0-inf*fu 
CL/F,u  
Unbound CL/F, calculated as Dose/AUC0-inf,u 
Vz/F,u  
Unbound Vz/F, calculated as CL/F,u/Z 
Additional PK parameters may be determined where appropriate. 
The PK analysis will be carried out where possible using actual blood sampling times 
postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time.  
The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax. 
8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The 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, Vz/F, and MRTinf) 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 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 


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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. 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should follow Cmax.  
AUC0-inf values where the percentage extrapolation is less than 30% will be reported. 
AUC0-inf values where the percentage extrapolation is greater than 30% will be listed but 
excluded from descriptive statistics and statistical analysis.  
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rules apply with special situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it may be set to 0 by default within 
Phoenix WinNonlin. 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
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. 


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● 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). 
For PK parameters the following rule will apply: 
● For the calculation of summary statistics of PK parameters, all not reported (NR) and 
not calculated (NC) values in a data series will be set to missing. 
● The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
● Geometric mean and CV will not be calculated for tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by renal function and time postdose will be provided for plasma PK 
concentrations. All PK concentration figures will be produced on both linear and semi-
logarithmic scales. The +SD bars will only be displayed on the linear scale.  
Summary tables by renal function 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. A Figure of individual PK 
parameters (AUC0-t, AUC0-inf, and Cmax) and corresponding unbound PK paramaters and 
corresponding geometric mean of PK parameters figures by renal function will be provided. 
Excluded subjects will be listed in the PK parameter tables, but will be excluded from the 
statistical analysis and summary statistics and noted as such in the tables. 
The primary analysis planned for this study is to evaluate the PK of LOXO-305 after a single 
dose in subjects with renal impairment compared to subjects with normal renal function.  
Paired t-tests will be performed to assess the differences in PK parameters (AUC0-t, AUC0-inf, 
and Cmax) and corresponding unbound PK parameters between each renal impairment group 
versus the corresponding matched-control healthy group with respect to 1 to 1 matching. The 
analysis will be based on the natural log (ln)-transformed PK parameters. Geometric mean 
ratios and their corresponding 90% confidence intervals (CIs) will be calculated using the 
exponentiation of the mean difference and the CIs obtained for the difference in mean 
between each renal impairment group and the matching healthy control group.  
Paired t-test Analysis: 
proc ttest data = <data in> alpha=0.1; 
  by parcat1 paramn paramcd; 
  paired logaval&test.*logaval&ref.; 
  ods output statistics = <data out>;   
  ods output ttests = <data out>; 


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run; 
In addition, an analysis of covariance (ANCOVA) will be performed on the ln-transformed 
AUC0-t, AUC0-inf, and Cmax. The ANCOVA model will contain a categorical factor of 
population for subjects with varied-degree renal impairment (severe, moderate, and mild) and 
matched-control healthy subjects, a categorical covariate (sex), and continuous covariates 
(age and BMI). Ratios of least squares means (LSM) and 90% CIs will be calculated using 
the exponentiation of the difference between renal function cohort LSM from the ANCOVA 
analyses on the ln-transformed AUC0-t, AUC0-inf, and Cmax. In addition, an ANCOVA will be 
performed on the ln-transformed AUC0-t,u, AUC0-inf,u, and Cmax,u.  
ANCOVA Analysis: 
proc mixed data = <data in>; 
  by parcat1 paramn paramcd; 
  class &renimp sex; 
  model laval = &renimp sex age bmi / alpha=0.1 cl outp=pred residual   
  ddfm=kr; 
  lsmeans &renimp / cl pdiff=control('1') alpha=0.1; 
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
The relationship between LOXO-305 PK parameters (ie, Cmax and AUC) and measures of 
renal function (such as eGFR and creatinine clearance) may be explored using a linear 
regression approach or other methods. The effect of covariates such as age, BMI, and sex 
may be investigated. 
Additionally, a scatterplot of the ln-transformed PK parameters (AUC0-t, AUC0-inf, and Cmax) 
and corresponding unbound PK paramaters versus eGFR be produced. The linear regression 
will be included on the plot, along with two-sided 90% confidence bands for the linear 
regression line. The Spearman rank correlation coefficient will also be calculated.. 
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 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 LOXO-305 dosing, or starts prior to LOXO-305 dosing and increases in severity after 
LOXO-305 dosing.   
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment (LOXO-305), as determined by the investigator.  


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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 for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by renal 
function group  
● TEAEs by severity and renal function group  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by renal function group  
● Treatment-related TEAEs by severity and renal function group  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and renal function group  
● Preferred term and renal function group  
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.  
● 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).  


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● 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. 
The observed results and change from baseline for clinical chemistry, hematology, and 
coagulation parameters, with changes from baseline will be summarized descriptively by 
renal function group and timepoint.   
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, and calculation of summary statistics, <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 results will be summarized 
descriptively by renal function group and timepoint.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated.   
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by renal function group and timepoint. For the mild renal 
impairment, moderate renal impairment and Healthy subjects QTcF values that are > 
450 msec and increase from baseline > 30 msec will be flagged in the data listing. For severe 
renal impairment subjects 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.  


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8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.   
9. INTERIM ANALYSES  
Subjects with renal impairment assessed as severe, along with matched-control healthy 
subjects, will begin enrolling in the study first. Continuous review of the safety data and PK 
data (if available) from up to 8 subjects with severe renal impairment and up to 8 matched-
control healthy subjects with normal renal function will be conducted after these subjects 
have completed all study-related assessments through 72 hours (approximately 3 half-lives) 
postdose, at a minimum. The safety data will include AEs and SAEs, vital signs, physical 
examinations, ECGs, and clinical laboratory evaluations. 
If a clinically relevant difference is observed in the PK of subject(s) with severe renal 
impairment compared to matched-control healthy subjects during continuous review of the 
safety and PK data, then subjects with renal impairment assessed as mild (60 ≤ eGFR 
< 90 mL/min/1.73 m2) and/or moderate (30 ≤ eGFR < 60 mL/min/1.73 m2), along with 
additional matched-control healthy subjects (if needed) will be enrolled, to determine the 
extent of the effect of varying severities of renal impairment on the PK of LOXO-305. 
Enrollment of subjects with mild and/or moderate renal impairment will only be initiated if 
deemed necessary by the Sponsor following the continuous review of safety and PK data 
from severe renal impairment subjects and their matched-control healthy subjects. If no 
clinically relevant effect on PK is observed, enrollment of mild and/or moderate subjects will 
not occur. 
Enrollment and dosing for remaining subjects in Group 2 and/or Group 3 may only occur 
after the data for Group 1 and Group 4 are reviewed and the Covance Medical Monitor, 
Investigator (or designee), and Sponsor agree it is safe to proceed with dosing. 
Subjects will be recruited for Group 2 and/or Group 3 so that up to 8 subjects with mild renal 
impairment, up to 8 subjects with moderate renal impairment, and up to an additional 
16 matched-control healthy subjects with normal renal function may be enrolled, with the 
goal of having at least 6 subjects with mild renal impairment and at least 6 subjects with 
moderate renal impairment and their matched-control healthy subjects complete the study. 
Teleconferences will occur as needed between the Covance Medical Monitor, Investigator (or 
designee), and Sponsor to discuss PK, safety, and tolerability data.  
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  


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2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Levey A, Stevens L, Schmid C, Zhang Y, Castro A, Feldman H, et al. A new equation to 
estimate glomerular filtration rate. Ann intern med. 2009;150(9): 604-12. 


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


08-Mar-21 | 14:05:00 PST
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