Clinical trial NCT06190691
Conditions: Healthy Hepatic Insufficiency
Sponsor: Eli Lilly and Company
Start date: 2020-12-18; Completion date: 2021-12-30
Enrollment: 36 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 liver function and healthy participants. The side effects and tolerability of pirtobrutinib will also be evaluated. Participation could last about 46 days.

Detailed description:

Arms: arm 1: Participants received a single dose of Pirtobrutinib 200 milligrams (mg) administered orally on Day 1. arm 2: Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. arm 3: Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. arm 4: Participants 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-JZNF Version 2.0
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Pharmacokinetic Study of
LOXO-305 Administered to Fasted Hepatically Impaired Male and Female Subjects and Fasted Matched-control
Healthy Subjects
NCT06190691
Approval Date: 07-Oct-2020


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, 
T oler a nce, a n d P h ar m ac o ki netic St u d y of L O X O -3 0 5 A d mi nistere d t o 
F aste d He p atic all y I m p aire d M ale a n d Fe m ale S u bjects a n d F aste d 
M atc he d -c o ntr ol He alt h y S u bjects  
Pr ot oc ol Stat us: Fi nal 
Pr ot oc ol Date: 0 7 Oct o ber 2 0 2 0  
Pr ot oc ol Versi o n: 2. 0 
I n vesti gati o nal Me dici nal Pr o d uct: L O X O-3 0 5  
Pr ot oc ol Refere nce N u m ber: L O X O -B T K -2 0 0 1 2 
C o va nce St u d y N u m ber: 8 4 1 9 6 9 1  
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.  
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  
7 0 1 Gate wa y B o ule var d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0  
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 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 2  of 6 9  
 
 
 
S P O N S O R A P P R O V A L  
 
I ha ve rea d t he pr ot oc ol a n d a p pr o ve it: 
 
 
 
 
 
0 7 - O c t - 2 0  |  1 3 : 4 0 : 4 5  P D T  
Date  
P P D


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 3 of 69 
 
 
 
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 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 4  of 6 9  
 
 
 
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 
7 0 1 Gate wa y B o ule var d, S uite 4 2 0  
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
U S A  
Tel ( mai n): 
 
S p o ns or’s  St u d y  C o ntact  
 
 
L o x o O nc ol o g y, I nc.  
Tel ( m o bile): 
 
Tel (alter nati ve c o ntact): 
 
E ma il: 
 
C o va nce  Me dical  M o nit or  
 
 
C o va nce Cli nical Researc h U nit, I nc.  
3 4 0 2 Ki ns ma n B o ule var d  
Ma dis o n, Wisc o nsi n 5 3 7 0 4 
U S A  
Tel ( office): 
 
Tel (alter nati ve): 
 
E ma il: 
 
S p o ns or’s  Me dical  C o ntact  
 
C o ns ulti n g t o L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
E ma il: 
 
Seri o us A d verse E ve nt ( S A E) 
Re p orti n g  
E ma il: S A EI nta ke @c o va nce.c o m 
 
 
Bi oa nal ytical  La b orat or y  
Alt uras A nal ytics,  I nc. 
1 3 2 4 Alt uras Dri ve  
M osc o w, I da h o 8 3 8 4 3 
U S A  
Tel ( mai n): 
 
E ma il: 
 
Statisticia n  
 
C o va nce  
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E ma il: 
 
Pr ot oc ol  Me dical  Writer  
 
C o va nce  
Tel: 
 
E ma il: 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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P P D
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Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 5 of 69 
 
 
 
SYNOPSIS 
 
Study Title 
 
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and 
Pharmacokinetic Study of LOXO-305 Administered to Fasted Hepatically 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 hepatic 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 hepatic 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 mild, moderate, or severe impaired hepatic 
function and healthy subjects with normal hepatic function. Hepatic function will be 
classified based on the Child-Pugh (CP) classification of hepatic impairment. 
 
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up 
to 8 subjects with mild impairment, up to 8 subjects with moderate impairment, and up to 8 
subjects with severe impairment, per CP classification – assessed at Screening and verified at 
Check-in [Day -1]) and 8 to 24 subjects with normal hepatic function are enrolled, with the 
goal of having at least 6 subjects from each hepatic impairment group per CP classification 
and at least 6 subjects with normal hepatic function complete the study. Hepatically impaired 
subjects will be assigned to groups according to CP scores at Check-in (Day -1) to ensure 
stability of hepatic impairment and subject safety, as determined by the Investigator (or 
designee). Subjects will be enrolled within the following groups based on their CP score at 
Screening and Check-in (Day -1) as judged by the Investigator (or designee), Covance 
Medical Monitor, and Sponsor: 
 
• Group 1: Matched-control healthy subjects with normal hepatic function; 
• Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15); 
A parallel-design strategy will be adopted for the hepatic impairment groups, with interim 
reviews of safety data after the first 2 subjects from Group 2 (mild hepatic impairment 
subjects) and Group 3 (moderate hepatic impairment subjects) and matched-control healthy 
subjects are enrolled and have completed all study-related assessments including the follow- 
up phone call. The safety data will include adverse events (AEs) and serious AEs (SAEs), 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 6 of 69 
 
 
 
vital signs, physical examinations, electrocardiograms (ECGs), and clinical laboratory 
evaluations. Enrollment and dosing for remaining subjects in any group may occur after the 
interim data for that group are reviewed and the Covance Medical Monitor, Investigator (or 
designee), and Sponsor agree it is safe to proceed with dosing. If available, PK data and 
matched-control healthy subject data may also be used during the interim review. 
 
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 hepatic 
impairment subject(s). Should another hepatic 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 hepatic 
impairment group. Each subject with normal hepatic function may be matched with up to 1 
subject within each hepatic impairment group. 
 
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. 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 Informed Consent Form [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: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 7 of 69 
 
 
 
Number of Subjects 
 
A total of up to 24 subjects with hepatic impairment (up to 8 subjects with mild impairment, 
up to 8 subjects with moderate impairment, and up to 8 subjects with severe impairment, per 
CP classification) and approximately 8 to 24 matched-control healthy subjects with normal 
hepatic function will be enrolled in the study with the goal of having at least 6 subjects from 
each hepatic impairment group per CP classification and at least 6 subjects with normal 
hepatic function complete the study. Of these hepatic impairment subjects enrolled per CP 
category, enrollment will also aim to have at least 4 subjects meet severe hepatic impairment 
criteria per the National Cancer Institute's Organ Dysfunction Working Group (NCI-ODWG) 
classification, at least 4 subjects meet moderate hepatic impairment criteria per NCI-ODWG 
classification, and at least 4 subjects meet mild hepatic impairment criteria per NCI-ODWG 
classification. Subjects who withdraw or drop out of the study may be replaced if deemed 
necessary by the Sponsor. 
 
Main Criteria for Inclusion 
 
Male subjects and female subjects of nonchildbearing 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 hepatic impairment, based on medical history, physical examination findings, 
vital sign measurements, ECG, and clinical laboratory evaluations at Screening and 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 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 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. 
 
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: 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 8 of 69 
 
 
 
Serial PK blood samples for the analysis of plasma concentrations of LOXO-305 will be 
collected from predose through 168 hours postdose. 
 
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), 
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 (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 Vd/F 
(Vz/F,u). 
 
Safety: 
 
Safety will be monitored with AE inquiries, clinical laboratory evaluations, vital sign 
measurements, ECGs, and physical examinations. 
 
Statistical Methods 
 
The primary analysis planned for this study is to evaluate the PK of LOXO-305 after a single 
dose in subjects with mild, moderate, or severe hepatic impairment, compared to subjects 
with normal hepatic function. To evaluate the effect of hepatic function group on the PK of a 
single dose of LOXO-305, paired t-tests will be performed for each hepatic impairment group 
(by CP classification) versus the normal group with respect to 1-to-1 matching. 
 
In addition, an analysis of covariance (ANCOVA) will be performed on the natural log (ln)- 
transformed AUC0-t, AUC0-inf, and Cmax. The ANCOVA model will contain a categorical 
factor of population for subjects with varied-degree hepatic impairment (severe, moderate, 
and mild by CP classification) and healthy matched-control subjects, a categorical covariate 
(sex), and continuous covariates (age and BMI). Ratios of least squares means and 90% 
confidence intervals will be calculated using the exponentiation of the difference between 
hepatic 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 
natural log (ln)-transformed unbound AUC0-t, unbound AUC0-inf, and unbound Cmax. Similar 
ANCOVA analysis will be applied for evaluating the effect of hepatic function group by 
NCI-ODWG classification. 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 9 of 69 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................ 1 
SPONSOR APPROVAL .......................................................................................................... 2 
INVESTIGATOR AGREEMENT ............................................................................................ 3 
STUDY IDENTIFICATION .................................................................................................... 4 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS .......................................................................................................... 9 
LIST OF TABLES AND FIGURES ....................................................................................... 11 
LIST OF ABBREVIATIONS ................................................................................................. 12 
1. 
INTRODUCTION .......................................................................................................... 15 
1.1. Background ............................................................................................................... 15 
1.2. Nonclinical Pharmacokinetics and Toxicology ........................................................ 15 
1.3. Potential for Drug-drug Interactions ......................................................................... 17 
1.4. Summary of Clinical Experience .............................................................................. 18 
1.4.1. 
Safety .......................................................................................................... 18 
1.4.2. 
Pharmacokinetics ........................................................................................ 19 
1.5. Study Rationale ......................................................................................................... 21 
1.6. Risk Assessment ....................................................................................................... 22 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................ 23 
2.1. Objectives ................................................................................................................. 23 
2.1.1. 
Primary Objective ....................................................................................... 23 
2.1.2. 
Secondary Objective ................................................................................... 23 
2.2. Endpoints .................................................................................................................. 23 
2.2.1. 
Primary Endpoints ....................................................................................... 23 
2.2.2. 
Secondary Endpoints................................................................................... 23 
3. 
INVESTIGATIONAL PLAN ......................................................................................... 24 
3.1. Overall Study Design and Plan ................................................................................. 24 
3.2. Child-Pugh Classification ......................................................................................... 26 
3.3. NCI-ODWG Classification ....................................................................................... 26 
3.4. Discussion of Study Design ...................................................................................... 27 
3.5. Selection of Doses in the Study ................................................................................ 27 
4. 
SELECTION OF STUDY POPULATION .................................................................... 28 
4.1. Screening Procedures ................................................................................................ 28 
4.2. Check-in Procedures (Day -1) .................................................................................. 29 
4.3. Inclusion Criteria ...................................................................................................... 29 
4.4. Exclusion Criteria ..................................................................................................... 32 
4.5. Subject Number and Identification ........................................................................... 36 
4.6. Removal of Subjects from Study Participation ......................................................... 37 
4.7. Matching Process ...................................................................................................... 38 
5. 
STUDY TREATMENTS ................................................................................................ 39 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 10 of 69 
 
 
5.1. Description, Storage, Packaging, and Labeling ........................................................ 39 
5.2. Study Treatment Administration .............................................................................. 39 
5.3. Randomization .......................................................................................................... 40 
5.4. Blinding .................................................................................................................... 40 
5.5. Treatment Compliance .............................................................................................. 40 
5.6. Drug Accountability ................................................................................................. 40 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ............................... 41 
6.1. Concomitant Therapies ............................................................................................. 41 
6.2. Diet, Fluid, and Activity Control .............................................................................. 41 
7. 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 43 
7.1. Pharmacokinetic Assessments .................................................................................. 43 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ....................... 43 
7.1.2. 
Analytical Methodology ............................................................................. 43 
7.2. Safety and Tolerability Assessments ........................................................................ 43 
7.2.1. 
Adverse Events ........................................................................................... 43 
7.2.2. 
Clinical Laboratory Evaluations ................................................................. 44 
7.2.3. 
Vital Signs ................................................................................................... 45 
7.2.4. 
12-lead Electrocardiogram .......................................................................... 45 
7.2.5. 
Physical Examination .................................................................................. 45 
8. 
SAMPLE SIZE AND DATA ANALYSIS ..................................................................... 47 
8.1. Determination of Sample Size .................................................................................. 47 
8.2. Interim Analysis ........................................................................................................ 47 
8.3. Analysis Populations ................................................................................................ 47 
8.3.1. 
Study Populations ....................................................................................... 47 
8.4. Pharmacokinetic Analysis ........................................................................................ 48 
8.4.1. 
Descriptive Analysis ................................................................................... 49 
8.4.2. 
Statistical Methodology .............................................................................. 49 
8.5. Safety Analysis ......................................................................................................... 49 
8.6. Data Handling and Record Keeping ......................................................................... 50 
8.7. Quality Control and Quality Assurance .................................................................... 50 
9. 
ADMINISTRATIVE ASPECTS .................................................................................... 51 
9.1. Change in Protocol ................................................................................................... 51 
9.2. Site Initiation Visit/Investigator Meeting ................................................................. 51 
9.3. Disclosure ................................................................................................................. 51 
9.4. Monitoring ................................................................................................................ 51 
9.5. Institutional Review Board ....................................................................................... 51 
9.6. Informed Consent ..................................................................................................... 52 
9.7. Records ..................................................................................................................... 52 
9.8. Reference to Declaration of Helsinki/Basic Principles ............................................. 52 
9.9. Financing and Insurance ........................................................................................... 53 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 1 1  of 6 9  
 
 
1 0.  R E F E R E N C E S  ............................................................................................................... 5 4  
1 1.  A P P E N DI C E S  ................................................................................................................ 5 6  
A p pe n di x 1: A d verse E ve nt Re p orti n g  .............................................................................. 5 7  
A p pe n di x 2: Cli nical  La b orat or y  E val uati o ns  .................................................................... 6 1  
A p pe n di x 3: T otal  Bl o o d V ol u me  ...................................................................................... 6 2  
A p pe n di x 4: Sc he d ule of  Assess me nts  .............................................................................. 6 3  
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  ................................................. 6 7  
 
 
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 0  
Ta ble 2: P har mac o ki netic of L O X O -3 0 5 F oll o wi n g a Si n gle 2 0 0 -m g D ose 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, C ycle 1 Da y 1)  
a n d Healt h y S u bjects  ( St u d y L O X O -B T K -2 0 0 1 4)  ............................................. 2 1  
Ta ble 3: C hil d -P u g h Assess me nt of  He patic  F u ncti o n  ..................................................... 2 6  
Ta ble 4: Nati o nal Ca ncer I nstit ute -Or ga n D ysf u ncti o n W or ki n g Gr o u p f or He patic 
D ysf u ncti o n  Criteria  ........................................................................................... 2 7  
Ta ble 5: S u bject Gr o u p a n d N u m ber  of  S u bjects  .............................................................. 3 7  
Ta ble 6:  St u d y  Dr u gs  ........................................................................................................ 3 9  
 
Fi g ure 2: St u d y  Desi g n  Sc he matic  .................................................................................... 2 5  
C CI


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 12 of 69 
 
 
 
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 
bpm 
beats per minute 
BSEP 
bile salt exporter pump 
BTK 
Bruton’s tyrosine kinase 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
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 
CP 
Child-Pugh 
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 
EMA 
European Medicines Agency 
EOS 
End of Study 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 13 of 69 
 
 
 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
fu 
fraction unbound 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HRT 
hormone-replacement therapy 
IB 
Investigator’s Brochure 
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 
NCI-ODWG 
National Cancer Institute-Organ Dysfunction Working Group 
NHL 
non-Hodgkin lymphoma 
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 
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 
TEAE 
treatment-emergent adverse event 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 14 of 69 
 
 
 
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 


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 15 of 69 
 
 
 
1. INTRODUCTION 
 
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product (IMP), LOXO-305.1 
1.1. 
Background 
 
LOXO-305 (also known as LY3527727) is a selective inhibitor of the Bruton’s tyrosine 
kinase (BTK) being developed by Loxo Oncology. LOXO-305 is distinct from the approved 
BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) in several important ways 
including on the basis of its selectivity, favorable absorption, distribution, metabolism, and 
excretion properties, and non-covalent binding mode.2 The non-covalent binding mode of 
LOXO-305 is unaffected by BTK C481 substitutions, a common mechanism of drug 
resistance described for all available covalent inhibitors.3,4,5,6,7 These features enable 
LOXO-305 dosed orally at 100 mg and higher once daily (QD) to achieve pharmacokinetic 
(PK) exposures that exceed the concentration required for 90% inhibition (IC90) of BTK-wild 
type and BTK C481 at trough and thus deliver tonic BTK target inhibition throughout the 
dosing period, regardless of the intrinsic rate of BTK turnover. LOXO-305 is also a highly 
selective molecule, with more than 300-fold more selectivity for BTK versus 370 other 
kinases tested and no significant inhibition of non-kinase off-targets at 1 μM, thus limiting 
the potential for off-target mediated toxicities. Collectively, these unique properties of 
LOXO-305 are expected to deliver more potent, continuous, and selective inhibition of BTK 
in a variety of settings, potentially resulting in increased efficacy. Of note, the activity of 
LOXO-305 in diverse preclinical model systems supports this underlying hypothesis.2 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate 
binding site of the BTK competitively, with no evidence of irreversible binding. 
 
1.2. 
Nonclinical Pharmacokinetics and Toxicology 
 
LOXO-305 had high permeability in vitro, but low aqueous solubility. To reduce the 
variability in oral absorption, a spray-dried dispersion (SDD) tablet formulation was 
developed that showed consistent oral bioavailability of approximately 50% in rats and 80% 
in dogs. The bioavailability of the SDD formulation was also not dependent on feeding state 
in dogs. 
 
As is common in rodents, oral exposure of LOXO-305 was consistently much higher in 
female rats than in males given the same dose of LOXO-305. The sex difference was also 
apparent after intravenous (IV) administration of LOXO-305. There was no difference in the 
PK of LOXO-305 between sexes of dog, and none is expected in other non-rodent species, 
including humans. 
 
The volume of distribution (Vz) of LOXO-305 ranged from approximately 2 L/kg in the dog 
to 5 L/kg in the male rat, which indicates that LOXO-305 distributes into tissues. LOXO-305 
had protein binding of approximately 95% in human plasma. A somewhat lower extent of 
binding (approximately 82% to 92%) was observed across mouse, rat, rabbit, and dog. 
 
LOXO-305 was metabolized slowly by human microsomal fractions and hepatocytes. The 
low rates of metabolism in both these human in vitro systems suggest that LOXO-305 will 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 1 6  of 6 9  
 
 
 
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 biti o n 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 Μ, 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 ( Cma 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 Cma 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 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.  
 
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. A d diti o nall y, i n d o gs 
treate d f or 1 5 wee ks, t w o 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 
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 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 1 7  of 6 9  
 
 
 
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 t o 
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  
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. 
 
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 rat 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 ( 5 0 % i n hi bit or y c o nce ntrati 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 
p ol y pe pti de 1 B 1 ( O A T P 1 B 1), or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 3 ( O A T P 1 B 3), 
or ga nic cati o n tra ns p orter ( O C T) 1, O C T 2, O A T 3, a n d bile salt e x p orter p u m p ( B S E P).  
C CI
C CI
C CI
C CI


Protocol 
Covance Study: 8419691 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20012 
Protocol Version 2.0, 07 October 2020 
Page 18 of 69 
 
 
 
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 09 April 2020, safety data were available from 172 treated patients, with 300 mg QD as 
the highest dose administered (Section 1.4.1). As of 30 March 2020 (data cutoff date), PK 
data were available from 107 patients (Section 1.4.2). 
 
LOXO-305 was recently investigated in 1 study in healthy volunteers (LOXO-BTK-20014). 
LOXO-BTK-20014 is a pilot food-effect cross-over study evaluating the effects of food and a 
proton-pump inhibitor (omeprazole) on the PK of LOXO-305 where 10 healthy volunteers 
were given 200 mg of LOXO-305 on 3 separate days, each followed by a washout period. 
Two additional studies are ongoing in healthy volunteers (LOXO-BTK-20006 and LOXO- 
BTK-20017). LOXO-BTK-20006 is a drug-drug interaction 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 single ascending dose 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. 
 
1.4.1. 
Safety 
 
As of 09 April 2020, 172 patients were treated in the first-in-human study 
(LOXO-BTK-18001) and received LOXO-305 at doses ranging from 25 mg QD to 300 mg 
QD. A full summary of treatment-emergent adverse events (TEAEs) for patients in this study 
is provided in the LOXO-305 IB and the Investigator is directed to the safety information 
described in that document.1 
Overall, TEAEs were reported in 123 of 172 treated patients in the safety population and 
were mild or moderate severity (Grade 1 or 2) in 89 of 123 (51.7%) patients and were 
Grade 3 or 4 in severity in 33 of 123 (19.2%) patients. The most frequently reported TEAEs 
occurring in ≥ 10% of patients were fatigue (12.8% total, 7.0% related) and diarrhea (10.5% 
total, 6.4% related). The most frequently reported drug-related TEAEs (those in > 5% of 
patients) were fatigue (7.0%), diarrhea (6.4%), and contusion (5.2%). All other drug-related 
TEAEs occurred in < 5% of patients each. The most frequently reported Grade ≥ 3 TEAEs 
included neutropenia (4.1% total; 2.9% related), neutrophil count decreased (2.3% total; 1.2% 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 1 9  of 6 9  
 
 
 
relate d), a ne mia ( 1. 7 % t otal; 0. 6 % relate d), fati g ue, le u k oc yt osis, a n d platelet c o u nt 
decrease d (eac h 1. 2 % t otal; eac h 0. 6 % relate d), a n d h y p o kale mia ( 1. 2 % t otal; n o ne relate d).  
 
Fi ve patie nts ( 2. 9 % of all 1 7 2 patie nts treate d) disc o nti n ue d L O X O -3 0 5 beca use of T E A Es; 
2 of t he 5 patie nts ( 1. 2 % of all patie nts treate d) disc o nti n ue d L O X O -3 0 5 beca use of a 
treat me nt-relate d e ve nt. O ne of t hese patie nts wit h ma ntle cell l y m p h o ma treate d i n t he 
1 0 0 -m g Q D gr o u p disc o nti n ue d d ue t o Gra de 3 le u k oc yt osis c o nsi dere d relate d t o st u d y dr u g. 
St u d y t hera p y was hel d f or res ol uti o n of le u k oc yt osis a n d t he patie nt s u bse q ue ntl y pr o gresse d 
a n d st u d y t hera p y was n ot res u me d; t he e ve nt of le u k oc yt osis was rec or de d as 
rec o vere d/res ol ve d. T he sec o n d patie nt treate d i n t he 1 5 0-m g Q D gr o u p disc o nti n ue d d ue t o 
Gra de 2 m yal gia; t he m yal gia was o n g oi n g. T he patie nt ha d pre vi o usl y recei ve d i br uti ni b, 
w hic h was disc o nti n ue d after 3 m o nt hs of treat me nt f or A Es.  
A t otal of 5 deat hs ha ve bee n re p orte d f or patie nts treate d i n t his st u d y, L O X O -B T K -1 8 0 0 1. 
N o deat hs were c o nsi dere d relate d t o L O X O -3 0 5.  
 
Fr o m A E data re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n 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, all T E A Es ( hea dac he, na usea, a n d v o miti n g) were Gra de 1 i n 
se verit y a n d c o nsi dere d relate d t o L O X O-3 0 5. All 3 e ve nts were re p orte d b y 1 s u bject a n d 
res ol ve d wit hi n 1 t o 1. 5 da ys ( data o n file at t he ti me of pr ot oc ol de vel o p me nt). Fr o m 
preli mi nar y A E data re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n i n healt h y v ol u nteers i n 
t he L O X O-B T K -2 0 0 0 6 st u d y, all T E A Es (i nter mitte nt belc hi n g, bl oati n g, i nsect bite, 
a p ht h o us ulcer, na usea, i nter mitte nt diarr hea [ x 2], m uscle t witc h) were Gra de 1 i n se verit y 
a n d bl oati n g, i nter mitte nt diarr hea a n d i nter mitte nt belc hi n g were c o nsi dere d relate d t o 
L O X O -3 0 5. All 7 A Es were re p orte d b y 3 s u bjects a n d all e ve nts res ol ve d pri or t o E n d of 
Treat me nt ( E O T; data o n file at t he ti me of pr ot oc ol de vel o p me nt). Fr o m preli mi nar y A E 
data re p orte d f oll o wi n g L O X O -3 0 5 a d mi nistrati o n i n healt h y v ol u nteers i n C o h ort 1 of t he 
L O X O -B T K -2 0 0 1 7 st u d y, t here was o ne T E A E ( hea dac he), o bser ve d i n t he 3 0 0 m g  
L O X O -3 0 5 C o h ort , w hic h was Gra de 1 i n se verit y a n d c o nsi dere d relate d t o L O X O -3 0 5. T he 
e ve nt res ol ve d wit hi n 2 h o urs ( data o n file at t he ti me of pr ot oc ol de vel o p me nt).  
 
T o date, t here ha ve bee n n o cli nicall y si g nifica nt a b n or mal fi n di n gs i n vital si g ns a n d E C G 
data i n t he st u dies i n vesti gati n g L O X O -3 0 5 c o n d ucte d i n healt h y v ol u nteers.  
 
1. 4. 2.  
P h ar m ac o ki netics  
 
As of 3 0 Marc h 2 0 2 0, P K data were a vaila ble fr o m 1 0 7 patie nts e nr olle d i n  
L O X O -B T K -1 8 0 0 1. 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 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 t he 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. F oll o wi n g a d mi nistrati o n of d oses of 1 0 0 m g Q D hi g her, 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 
 of B T K i n vitr o  
(Fi g ure 1 ). 
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 2 0  of 6 9  
 
 
 
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)  
 
 
 
 
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 -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) 
T 1/ 2  
( h) 
Ge o me a n 
( % 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  
3 0 0 m g Q D  
A b bre viati o ns: A U C 0 -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; C ma x = ma xi m u m dr u g c o nce ntrati 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; % C V = c oefficie nt of variati o n i n perce nt; T 1/ 2 = half -life; tma x = ti me of ma xi mal plas ma 
c o nce ntrati o n.  
a N = 5; b N = 8; c N = 1 8; d N = 1 6; e N = 2 0; f N = 1 6; g N = 1 5  
Data c ut off date: Marc h 3 0, 2 0 2 0.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0  
0  
 
0  
2  
4  
6  
8  
0  
Ti m e ( h)  
 
 
 
 
2  
4  
6  
8  
Ti m e ( h)  
 
Data c ut off date: Marc h 3 0, 2 0 2 0.  
 
Si n gle d oses of 2 0 0 m g L O X O -3 0 5 were i n vesti gate d i n a st u d y i n healt h y v ol u nteers 
( L O X O-B T K -2 0 0 1 4, Pil ot F o o d Effect st u d y) i n w hic h t he P K was deter mi ne d. F oll o wi n g a  
 
2 5 m g  ( N = 5) 
5 0 m g  ( N = 6) 
1 0 0 m g  ( N = 1 0) 
1 5 0 m g  ( N = 2 0) 
2 0 0 m g  ( N = 2 9) 
2 5 0 m g  ( N = 2 4) 
3 0 0 m g  ( N = 1 8) 
 
2 5 m g  ( N = 5) 
5 0 m g  ( N = 6) 
1 0 0 m g ( N = 9)  
1 5 0 m g  ( N = 2 0) 
2 0 0 m g  ( N = 2 4) 
2 5 0 m g  ( N = 2 5) 
3 0 0 m g  ( N = 1 6) 
M e a n C o n c e ntr ati o n ( n g/ m L)  
M e a n C o n c e nt ati o n ( n g/ m L)  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 2 1  of 6 9  
 
 
 
si n gle d ose of 2 0 0 m g L O X O-3 0 5 t o patie nts or healt h y s u bjects, A U C fr o m 0 t o 8 h o urs was 
si milar bet wee n t he t w o gr o u ps a n d C ma x was a p pr o xi matel y  
 hi g her i n healt h y s u bjects, 
as s h o w n i n t he ta ble bel o w ( data o n file at t he ti me of pr ot oc ol de vel o p me nt).  
 
T a ble 2: P h ar m ac o ki netic of L O X O -3 0 5 F oll o wi n g a Si n gle 2 0 0 -m g D ose 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, C ycle 1 D a y 1) a n d He alt h y 
S u bjects ( St u d y L O X O -B T K -2 0 0 1 4)  
 
 
P ar a meter  
He alt h y V ol u nteers a  
C a ncer P atie nts b  
Ge o metric Me a n  
C V  
n  
Ge o metric Me a n  
C V  
n  
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 0 t o 8 h o urs; C V =c oefficie nt of variati o n; 
C ma x = ma xi m u m c o nce ntrati o n; n = n u m ber of s u bjects.  
a L O X O-B T X -2 0 0 1 4, 2 0 0 m g si n gle d ose, faste d 
b L O X O -B T K -1 8 0 0 1, 2 0 0 m g si n gle d ose, faste d  
 
I n healt h y v ol u nteers, t he ge o metric mea n si n gle-d ose C ma x of a p pr o xi matel y 5 4 5 0 n g/ m L 
f oll o wi n g a 2 0 0-m g si n gle d ose is 
 bel o w t he N O E L (i n rat, 
) f or 
micr o n uclei i n d ucti o n.  
 
1. 5.  
St u d y  R ati o n ale  
 
Li ver disease ca n ca use alterati o ns i n dr u g dis p ositi o n a n d P K. S uc h alterati o ns ca n re d uce 
t he cleara nce of dr u gs eli mi nate d b y he patic meta b olis m or biliar y e xcreti o n a n d affect 
plas ma pr otei n bi n di n g, w hic h i n t ur n c o ul d i nfl ue nce t he pr ocesses of a bs or pti o n, 
distri b uti o n, a n d eli mi nati o n. Res ults fr o m t his st u d y will pr o vi de i nf or mati o n o n t he safet y, 
t olera bilit y, a n d e x p os ure of L O X O-3 0 5 i n partici pa nts wit h he patic i m pair me nt a n d 
partici pa nts wit h n or mal he patic f u ncti o n.  
 
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 he patic i m pair me nt. T he c urre nt st u d y will be carrie d o ut i n 
s u bjects wit h he patic i m pair me nt acc or di n g t o 3 differe nt C hil d-P u g h ( C P) cate g ories 9 ,1 0  
( mil d, m o derate, a n d se vere i m pair me nt) a n d als o i n matc he d-c o ntr ol healt h y s u bjects. Of 
t hese he patic i m pair me nt s u bjects e nr olle d per C P cate g or y, e nr oll me nt will als o ai m t o ha ve 
at least 4 s u bjects meet se vere he patic i m pair me nt criteria per Nati o nal Ca ncer I nstit ute's 
Or ga n D ysf u ncti o n W or ki n g Gr o u p ( N CI -O D W G) classificati o n, at least 4 s u bjects meet 
m o derate he patic i m pair me nt criteria per N CI -O D W G classificati o n, a n d at least 4 s u bjects 
meet mil d he patic i m pair me nt criteria per N CI -O D W G classificati o n. 1 1  
T here are se veral met h o ds use d t o cate g orize t he se verit y of he patic i m pair me nt. Des pite its 
i m perfecti o ns, t he C P classificati o n is t he m ost wi del y use d a n d is a n acce pta ble met h o d 
s u p p orte d b y re g ulat or y a ge ncies (i ncl u di n g t he U nite d States F o o d a n d Dr u g A d mi nistrati o n 
[ F D A] a n d t he E ur o pea n Me dici nes A ge nc y [ E M A]). F urt her data a nal ysis will be perf or me d 
usi n g N CI -O D W G classificati o n f or he patic d ysf u ncti o n (see Secti o n 8 ).1 1  T he F D A a n d 
E M A G ui deli nes rec o m me n d t hat t he “ n u m ber of s u bjects e nr olle d s h o ul d be s ufficie nt t o 
detect cli nicall y rele va nt P K differe nces.” I n t he c urre nt st u d y, u p t o 8 s u bjects wit h mil d  
C CI
C CI
C CI
C CI


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hepatic impairment, up to 8 subjects with moderate hepatic impairment, up to 8 subjects with 
severe hepatic impairment, and 8 to 24 healthy subjects with normal hepatic function will be 
enrolled. The PK and safety profiles between each hepatic impairment group and their 
matching (age, sex, and body mass index [BMI]) healthy subjects will be compared. 
 
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 single ascending dose 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. 
 
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 electrocardiogram (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 hepatic 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 hepatic 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 
• 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) 
• 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 fraction 
unbound (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 mild, moderate, or severe impaired hepatic 
function and healthy subjects with normal hepatic function. Hepatic function will be 
classified based on the CP classification of hepatic impairment (Table 3).9,10 
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up 
to 8 subjects with mild impairment, up to 8 subjects with moderate impairment, and up to 8 
subjects with severe impairment, per CP classification – assessed at Screening and verified at 
Check-in [Day -1]) and 8 to 24 subjects with normal hepatic function are enrolled, with the 
goal of having at least 6 subjects from each hepatic impairment group per CP classification 
and at least 6 subjects with normal hepatic function complete the study. Hepatically impaired 
subjects will be assigned to groups according to CP scores at Check-in (Day -1) to ensure 
stability of hepatic impairment and subject safety, as determined by the Investigator [or 
designee]. Subjects will be enrolled within the following groups based on their CP score at 
Screening and Check-in (Day -1) as judged by the Investigator (or designee), Covance 
Medical Monitor, and Sponsor: 
 
• Group 1: Matched-control healthy subjects with normal hepatic function; 
• Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15). 
A parallel-design strategy will be adopted for the hepatic impairment groups, with interim 
reviews (as detailed in Section 8.2) of the safety data after the first 2 subjects from Group 2 
(mild hepatic impairment subjects) and Group 3 (moderate hepatic impairment subjects) and 
matched-control healthy subjects are enrolled and have completed all study-related 
assessments including the follow-up phone call. 
 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by 
age (± 10 years), BMI (± 20%), and sex to the completed hepatic impairment subject(s). 
Should another hepatic 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 hepatic impairment 
group. Each subject with normal hepatic function may be matched with up to 1 subject within 
each hepatic impairment group. 
 
The schematic of the study design is displayed in Figure 2.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 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. 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 approximately 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 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. For instructions regarding food and water intake, refer to Section 6.2. 
Pharmacokinetic samples will be obtained through 168 hours postdose. 
 
Figure 2: 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 serious AEs (SAEs) will be collected beginning at informed consent. 
Adverse events will be reported throughout the study (ie, from signing of the ICF until End of 
Study [EOS], or until 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 


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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. 
Child-Pugh Classification 
Per FDA Guidance12 hepatic impairment will be classified as mild, moderate, or severe using 
the CP System (Table 3),9,10 and the parameters to determine the CP class for each subject 
with hepatic impairment will be collected at Screening and Check-in (Day -1). Further data 
analysis will be performed using NCI-ODWG classification (see Section 8). 
 
Table 3: Child-Pugh Assessment of Hepatic Function 
 
Points Scored for Observed Findings 
1 
2 
3 
Hepatic encephalopathy gradea 
0 
1 or 2c 
3 or 4c 
Ascitesb 
Absent 
Slight 
Moderate 
Serum bilirubin, mg/dL (µmol/L) 
< 2 (< 34) 
2 to 3 (34 to 50) 
> 3 (> 50) 
Serum albumin, g/dL (g/L) 
> 3.5 (> 35) 
2.8 to 3.5 (28 to 35) 
< 2.8 (< 28) 
International normalized ratio 
< 1.7 
1.7 to 2.3 
> 2.3 
Chronic Hepatic Impairment is classified into Child-Pugh (CP) class A to C, employing the added score of the 5 parameters 
in the table above. 
Mild Impairment (CP-A): 5 or 6 points; Moderate Impairment (CP-B): 7 to 9 points; Severe Impairment (CP-C): 10 to 15 
points. 
a In this study, hepatic encephalopathy is graded according to the following criteria: 
• 
Grade 0: normal consciousness, personality, neurological examination, or normal electroencephalogram; 
• 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, or 5 cycles per second waves; 
• 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, or slow triphasic waves; 
• 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, or slower waves; 
• 
Grade 4: unarousable coma, no personality/behavior, decerebrate, or slow 2 to 3 cycles per second delta activity. 
b Ascites is graded according to the following criteria: 
• 
Absent: No ascites is detectable by manual examination or by ultrasound investigation, if ultrasound investigation 
is performed; 
• 
Slight: Ascites palpitation doubtful, but ascites measurable by ultrasound investigation, if performed; 
• 
Moderate: Ascites detectable by palpitation and by ultrasound investigation, if performed; 
• 
Severe: Necessity of paracentesis; does not respond to medication treatment. 
c A subject with hepatic encephalopathy of Grade 2 or above would not be admitted into the study. 
 
3.3. 
NCI-ODWG Classification 
Subjects will also be classified according to NCI-ODWG criteria (Table 4).11 Of these hepatic 
impairment subjects enrolled per CP classification, enrollment will also aim to have at least 4 
subjects meet severe hepatic impairment criteria per NCI-ODWG classification, at least 4 
subjects meet moderate hepatic impairment criteria per NCI-ODWG classification, and at 
least 4 subjects meet mild hepatic impairment criteria per NCI-ODWG classification. 


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Table 4: National Cancer Institute-Organ Dysfunction Working Group for Hepatic 
Dysfunction Criteria 
 
NCI-ODWG Criteria 
Hepatic Impairment 
Total Bilirubin 
AST 
Normal 
≤ULN 
≤ULN 
Mild 
> ULN to 1.5 x ULN 
>ULN 
Moderate 
>1.5 to 3 x ULN 
Any 
Severe 
> 3 – 10 x ULN 
Any 
Abbreviations: AST = aspartate aminotransferase; NCI-ODWG = National Cancer Institute-Organ Dysfunction 
Working Group; ULN = upper limit of normal. 
 
3.4. 
Discussion of Study Design 
 
A single-dose, parallel design is the standard design to investigate the PK of a drug in 
subjects with hepatic impairment. A parallel design is required to include subjects with 
hepatic impairment and matched-control healthy subjects with normal hepatic function. A 
single dose level of 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 hepatic function will be enrolled in this study 
to serve as a reference group for interpretation of the results. Patients with a range of hepatic 
impairment will be included to enhance the ability to detect and characterize the effects of 
hepatic function on the PK of LOXO-305. 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. 
 
Preclinical and clinical data suggest that LOXO-305 is likely to be well tolerated in healthy 
human subjects. However, liver disease can cause alterations in drug disposition, reducing the 
clearance of drugs eliminated by hepatic metabolism or biliary excretion and affect plasma 
protein binding, which in turn could influence the processes of distribution and elimination. 
Therefore, in this study, a cautious approach will be adopted, where the first 2 subjects from 
Group 2 (mild hepatic impairment subjects) and Group 3 (moderate hepatic impairment 
subjects) and matched-control healthy subjects may be dosed concurrently, followed by an 
interim review of the safety and PK data (if available) before dosing is resumed for the 
remaining subjects in any (all) group(s) (see Section 8.2). 
3.5. 
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. 
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 
 
Up to 8 subjects will be enrolled into each hepatic impairment treatment group to have at 
least 6 subjects from each group complete the study. Up to 24 subjects will be enrolled into 
the matched-control healthy subject group to have at least 6 healthy subjects matched to each 
hepatic impairment treatment group complete the study. Healthy control subjects will be 
matched demographically to hepatically 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. Child-Pugh class score (subjects with hepatic impairment only) 
4. NCI-ODWG class score (subjects with hepatic impairment only) 
5. Demographic data 
6. Medical history (including review of medication[s]) 
7. Height, weight, and BMI 
8. Complete physical examination (Section 7.2.5) 
9. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
10. 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) 
11. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
12. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
13. Screens for hepatitis C virus (HCV) antibody (healthy matched-control subjects only), 
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 equivalent 
(Appendix 2) 
14. Hemoglobin A1c (HbA1c) test (Appendix 2) 
15. Screen for selected drugs of abuse, including cotinine (healthy matched-control 
subjects only) and alcohol (breath or urine test [Appendix 2]) 
16. Estimated glomerular filtration rate (eGFR; Appendix 2) 
17. Serum pregnancy test (for female subjects only; Appendix 2) 
18. Follicle-stimulating hormone (FSH) test (for post-menopausal female subjects only; 
Appendix 2) 


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19. 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. Child-Pugh class score (subjects with hepatic impairment only) 
3. NCI-ODWG class score (subjects with hepatic impairment only) 
4. Interim medical history, including concomitant medication(s) 
5. Weight and BMI 
6. Abbreviated 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 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. Screen for COVID-19 via PCR or equivalent (Appendix 2) 
12. Screen for selected drugs of abuse, including cotinine (healthy matched-control 
subjects only) and alcohol (breath or urine test [Appendix 2]) 
13. eGFR (Appendix 2) 
14. Serum pregnancy test (for female subjects only; Appendix 2) 
15. 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. 
 
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 
hepatic 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 levels consistent with post-menopausal status per the laboratory’s 
reference ranges. All female subjects must have a negative qualitative serum 
pregnancy test (serum human chorionic gonadotropin; serum quantitative human 
chorionic gonadotropin tests may be used for confirmation as needed) at Screening 
and Check-in (Day -1). Female subjects are required to refrain from donation of ova 
from Check-in (Day -1) until 6 months after Day 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 
salpingectomy, bilateral oophorectomy, or confirmed tubal 
occlusion more than 6 months prior to Day 1 for male partner); 
or 
4. be post-menopausal with amenorrhea for at least 1 year prior to 
Day 1 and FSH serum levels consistent with post-menopausal 
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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 hepatic impairment in 
sex, age (± 10 years), and BMI (± 20%). Note: Each matched-control healthy subject 
may be matched with up to 1 subject within each hepatic impairment group. 
Additional inclusion criteria for subjects with hepatic impairment 
9. Considered to have mild, moderate, or severe hepatic impairment (of any etiology) 
that has been clinically stable (no acute episodes of illness due to deterioration in 
hepatic 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 hepatic impairment, subjects must have a 
CP score of 5 to 6 (mild), 7 to 9 (moderate), or 10 to 15 (severe), with known medical 
history of liver disease (with or without a known history of alcohol abuse). 
10. Currently on a stable medication regimen, defined as not starting new drug(s) or 
significantly changing drug dosage(s) within 14 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 Covance Medical Monitor, Investigator (or 
designee) and Sponsor. 
11. Non-hepatic abnormal laboratory values must be not clinically significant, as judged 
by the Investigator (or designee), Covance Medical Monitor, and Sponsor. 
12. Anemia secondary to hepatic disease will be acceptable if hemoglobin is ≥ 8 g/dL and 
anemia symptoms are not clinically significant. Must have ≥ 35,000 platelets. 


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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 
Covance Medical Monitor, Investigator (or designee), and/or Sponsor: 
a. pancreatitis 
b. peptic ulcer disease 
c. intestinal malabsorption 
d. gastric reduction surgery 
e. history or presence of clinically significant cardiovascular disease: 
i. Myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to Day 1 
ii. Symptomatic angina pectoris within 6 months prior to Day 1 
iii. New York Heart Association Class ≥ 2 congestive heart failure within 6 
months prior to Day 1 
iv. Congenital prolonged QT syndrome 
v. Ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
vi. Arrhythmia (excluding benign sinus arrhythmia) or history of 
arrhythmia requiring medical intervention 
vii. Ventricular dysfunction or risk factors for Torsades de Pointes (eg, 
heart failure, cardiomyopathy, family history of Long QT Syndrome) 
viii. Clinically significant screening ECG abnormalities including, but not 
limited to, 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, 
hernia repair, and cholecystectomy will be allowed. Bariatric surgery 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 exclusion criteria #23, #24, #25, #26, 
#36, and #37 below) at Screening or Check-in (Day -1). Rechecks of clinically 
significant abnormal clinical laboratory results (excluding those further defined in 
exclusion criteria #23, #24, #25, #26, #36, and #37 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. 


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5. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Screening and/or Check-in (Day -1). 
6. Positive serologic test for HbsAg, HBV IgM core antibody, or HIV antibody at 
Screening. Subjects who are positive for HBV IgM by antibody will require 
confirmation by PCR before enrollment to detect presence of active virus. Subjects 
who are HBV PCR positive or for whom a PCR is unable to be obtained will not be 
eligible. 
7. Positive PCR test (or equivalent) for COVID-19 at Screening or Check-in (Day -1). 
Further details regarding COVID-19 testing (including procedures for subjects who 
test positive at any time throughout CRU confinement) are specified in a separate 
document. 
8. 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. 
9. Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours 
prior to Check-in (Day -1) and through EOT or ET. 
10. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
11. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
12. Participation in any other investigational study drug trial involving administration of 
any investigational drug in the past 30 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1. 
13. Use or intention to use any prescription or over-the-counter medications (including 
but not limited to any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers [including herbal products such as St. John’s wort], strong P-glycoprotein 
(P-gp) inhibitors, proton pump inhibitors, antacids, H2-receptor antagonists and drugs 
that prolong QT/QTc interval, 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 hepatically impaired, needed to stabilize the subject’s underlying medical 
condition (or concurrent baseline conditions) and deemed acceptable Medical 
Monitor, Investigator (or designee), and Sponsor, and provided that the subject has 
been on a stable dose for a minimum of 14 days prior to Day 1. 
14. History of a major surgical procedure within 30 days prior to Screening. 
15. 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. 
16. Poor peripheral venous access. 
17. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
18. Receipt of blood products within 2 months prior to Check-in (Day -1). 


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19. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
Additional exclusion criteria for matched-control healthy subjects: 
20. 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. 
21. ECG findings deemed abnormal by the Investigator (or designee) at Screening, 
Check-in (Day -1), or prior to dosing on Day 1. 
22. 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 beats per minute (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. 
23. Abnormal liver function tests (LFTs), as defined by aspartate aminotransferase, 
alanine aminotransferase, and serum (total and direct) bilirubin, as well as amylase 
and lipase above the upper limit of the normal range at Screening or Check-in 
(Day -1). Rechecks of LFTs, amylase, and lipase above the upper limit of the normal 
range that are not clinically significant (as determined by the Investigator [or 
designee]) will be permitted up to 2 times during Screening and Check-in (Day -1) to 
confirm eligibility for study participation if the values fall within normal ranges. 
24. eGFR < 90 mL/minute/1.73m2 calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation at Screening or Check-in (Day -1). 
Rechecks of out-of-range eGFR values that are not clinically significant (as 
determined by the Investigator [or designee]) will be permitted up to 2 times during 
Screening and Check-in (Day -1) to confirm eligibility for study participation if the 
values fall within the range stated above. 
25. 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. 


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26. Hemoglobin, below the lower limit of normal range at Screening or Check-in 
(Day -1). Rechecks of hemoglobin below the lower limit of 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 are stable or normalizing. 
27. Known ongoing alcohol and/or drug abuse within 2 years prior to Screening, or 
evidence of such abuse as indicated by the laboratory assays for drugs of abuse 
(including cotinine and alcohol) conducted during Screening and/or at Check-in 
(Day -1). Tests for drugs of abuse (including cotinine and alcohol) must be negative at 
both Screening and Check-in (Day -1). 
28. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. 
29. Significant history or clinical manifestation of any allergic, dermatological, biliary, 
hepatic, gastrointestinal, renal, metabolic, hematological, pulmonary, cardiovascular 
(including any prior history of cardiomyopathy or cardiac failure), neurological, or 
psychiatric disorder (as determined by the Investigator [or designee]). Note: subjects 
with a history of appendectomy and/or hernia repairs will be acceptable. 
30. History of diabetes mellitus; HbA1c ≥ 6.5%. 
31. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
32. Has completed or withdrawn from any other study investigating LOXO-305 and have 
previously received the investigational product within the last 30 days. 
33. Positive serologic test for HCV antibody at Screening. Subjects who are positive for 
HCV by antibody will require confirmation by PCR before enrollment to detect 
presence of active virus. Subjects who are HCV PCR positive or for whom a PCR is 
unable to be obtained will not be eligible. 
Additional exclusion criteria for subjects with hepatic impairment: 
34. QTcF value of > 450 msec for subjects with mild or moderate hepatic impairment or 
> 470 msec for subjects with severe hepatic 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. 
35. 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. Heart rate < 50 or > 99 bpm 
c. Systolic BP < 90 or > 150 mmHg 
d. Diastolic BP < 40 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 


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Investigator [or designee], based on the age and hepatic 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 values fall within the ranges referenced 
above. 
36. eGFR of < 90 mL/minute/1.73m2 calculated using the CKD-EPI equation at 
Screening or Check-in (Day -1) for subjects with mild or moderate hepatic 
impairment or eGFR of < 60 mL/minute/1.73m2 calculated using the CKD-EPI 
equation at Screening or Check-in (Day -1) for subjects with severe hepatic 
impairment. Rechecks of out-of-range eGFR values that are not clinically significant 
(as determined by the Investigator [or designee]) will be permitted up to 2 times 
during Screening and Check-in (Day -1) to confirm eligibility for study participation 
if the values fall within the range stated above. 
37. Values outside the normal ranges for creatine kinase, LFTs, amylase, and lipase may 
be acceptable as consistent with the subject’s hepatic condition (if stable for 1 month 
prior to Screening), and if the Investigator (or designee) and Sponsor feel that the 
results are not clinically significant (based on age and hepatic impairment status). 
38. Known ongoing alcohol and/or drug abuse within 1 month prior to Screening, or 
evidence of such abuse as indicated by the laboratory assays for drugs of abuse 
(including alcohol) conducted during Screening and/or at Check-in (Day -1). Tests for 
drugs of abuse (aside from cotinine) must be negative at both Screening and Check-in 
(Day -1) unless the positive drug screen is considered to be due to the use of a 
prescription drug which is approved by the Covance Medical Monitor, Investigator 
(or designee), and Sponsor. 
39. 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. 
40. 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), Covance Medical Monitor, and Sponsor. 
41. History of cancer within the past 5 years (except localized basal cell, squamous, or in 
situ cancer of the skin). 
42. Has a portal systemic shunt. 
43. Has required new medication for hepatic encephalopathy within the 6 months prior to 
Check-in (Day -1). 
44. 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 hepatic function (Table 5) 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 
will consist of 6 digits in which the first set of 3 digits will identify the CRU and the second 
set of 3 digits will identify the subject (eg, 001-101). 


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Subject numbers will be used on all study documentation. 
 
Group 1: Matched-control healthy subjects: 001-100 through 001-199 
Group 2: Subjects with mild hepatic impairment: 001-200 through 001-299 
Group 3: Subjects with moderate hepatic impairment: 001-300 through 001-399 
Group 4: Subjects with severe hepatic impairment: 001-400 through 001-499. 
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 5: Subject Group and Number of Subjects 
 
Group 
Description of Hepatic Functiona 
N 
1 
Matched Normal Hepatic Function 
8 to 24 
2 
Mild Hepatic Impairment 
8 
3 
Moderate Hepatic Impairment 
8 
4 
Severe Hepatic Impairment 
8 
a Hepatic function determined using the Child-Pugh assessment (Section 3.2). 
 
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 
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. 


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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 hepatically impaired subjects (age 
[± 10 years], BMI [± 20%], and sex). An individual matched-control healthy subject may be 
matched with up to 1 subject within each hepatic impairment group (ie, to a maximum of 
3 hepatically 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 6). 
 
Table 6: Study Drugs 
 
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(s). 
 
The tablets containing 100 mg LOXO-305 will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificate of Analysis. It will be provided in 
high-density polyethylene bottles and stored according to the instructions on the label. 
Study drugs will be stored at the CRU in a location that is locked with restricted access. 
The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drugs will be stored in accordance with the labeling. The 
study drugs will be transferred from bulk supplies into the subject’s dose container by 
qualified CRU employees. Each unit dose container will be appropriately labeled. 
 
5.2. 
Study Treatment Administration 
 
Subjects will receive 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 
for at least 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. 
 
Each unit dose will be prepared by qualified CRU staff. Each unit dose container will be 
appropriately labeled. 
 
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be consistently administered the appropriate 
dose at a specific time, the exact dose time of subjects may be staggered to obviate the need 
to have all subjects on precisely the same study schedule. For each dose, the subject’s actual 
dose time will be recorded in the source documents and transcribed into the eCRF. 


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Subjects will be instructed not to crush, split, or chew the study drugs. 
 
Subjects will not lay supine for 4 hours following LOXO-305 dose administration, except as 
necessitated by the occurrence of an AE(s) and/or study procedure(s). 
 
5.3. 
Randomization 
 
This is a non-randomized study. The study has a fixed treatment sequence. 
 
5.4. 
Blinding 
 
This is an open-label study. 
 
5.5. 
Treatment Compliance 
 
The following measures will be employed to ensure treatment compliance: 
 
• All doses will be administered under the supervision of suitably qualified CRU staff. 
• Immediately after oral dose administration, a visual inspection of the mouth and 
hands will be performed for each subject. 
• At each dose preparation occasion, a predose and postdose inventory of LOXO-305 
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 and over-the-counter medications 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 hepatically impaired, needed to stabilize the subject’s underlying medical 
condition (or concurrent baseline conditions) as described below. This includes but is not 
limited to: moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers (including 
herbal products such as St. John’s wort), strong P-glycoprotein (P-gp) inhibitors, proton 
pump inhibitors, antacids, H2-receptor antagonists, and drugs that prolong QT/QTc interval, 
natural or herbal supplements, and HRT. 
 
For hepatically 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 14 days prior to Day 1. Hepatically 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. Hepatically 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. 
 
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 LOXO-305 plasma levels, protein binding, and potential 
analysis of metabolites 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 
and protein binding will be recorded on the eCRF. 
 
Processing, storage, and shipping instructions for these PK blood samples and protein binding 
samples will be provided in a separate Laboratory Manual. The number of blood samples and 
total blood volume required for PK testing and protein binding 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 unbound fraction 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 measurements, and at an appropriate time for all other days). Subjects will 
also be encouraged to voluntarily report AEs occurring at any other time through the EOS. 
 
Adverse events, whether volunteered, identified by the subject’s responses to HDYF? 
Inquiries, or noted on physical examination, ECG, vital sign measurements, or clinical 
laboratory evaluations, will be recorded throughout the study (ie, from signing of the ICF 
until EOS [or ET if the subject discontinues from the study and does not complete a 
follow-up phone call]), either as subject medical history (if the event is reported as beginning 
prior to signing of the ICF or if the event occurs prior to study drug administration on Day 1 
and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs 
(if the event occurs after signing of the ICF but prior to study drug administration on Day 1 
and is assessed as related to study procedures by the Investigator [or designee], or if the event 
occurs after study drug administration on Day 1 through EOT or ET regardless of relationship 
to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by 
the Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be reported. 
 
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up phone call, all subjects must be followed until EOS. Subjects with AEs that are 
assessed as related to study drug by the Investigator (or designee) that 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 
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 (healthy matched-control subjects only), HbsAg, HBV IgM core 
antibody, and HIV antibody will be performed at Screening. 
 
Testing for COVID-19 via PCR or equivalent will be performed at the timepoints specified in 
Appendix 4. Testing for COVID-19 may also be conducted periodically during the subject’s 
CRU confinement, at the discretion of the Investigator (or designee). Further details 
regarding COVID-19 testing (including procedures for subjects who test positive at any time 
throughout CRU confinement) are specified in a separate document. 
 
A urine drug screen for selected drugs of abuse (including cotinine [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 pregnancy test (female subjects 
only [serum quantitative may be used for confirmation if needed]) and an FSH test 
(post-menopausal female subjects only) will be performed at the timepoints specified in 
Appendix 4. 
 
The number of blood samples and total blood volume required for clinical laboratory 
evaluations 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. 
 
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). 


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Abbreviated physical examinations will evaluate general appearance and the following body 
systems/organs: dermatological; pulmonary; cardiovascular; abdominal; and neurological. 
 
The physical examination at Screening will include hepatic encephalopathy and ascites 
evaluations for the CP assessment. 


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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
 
A total of up to 24 subjects with hepatic impairment (up to 8 subjects from each hepatic 
impairment group, per CP classification) and approximately 8 to 24 matched-control healthy 
subjects with normal hepatic function will be enrolled in the study with the goal of having at 
least 6 subjects from each hepatic impairment group per CP classification and at least 6 
subjects with normal hepatic function complete the study. Of these hepatic impairment 
subjects enrolled per CP category, enrollment will also aim to have at least 4 subjects meet 
severe hepatic impairment criteria per NCI-ODWG classification, at least 4 subjects meet 
moderate hepatic impairment criteria per NCI-ODWG classification, and at least 4 subjects 
meet mild hepatic impairment criteria per NCI-ODWG classification. 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 hepatic function. 
 
8.2. 
Interim Analysis 
 
Interim reviews of safety data will be conducted after the first 2 subjects from Group 2 (mild 
hepatic impairment subjects) and Group 3 (moderate hepatic impairment subjects) and 
matched-control healthy subjects are enrolled and have completed all study-related 
assessments including the follow-up phone call. The safety data will include AEs and SAEs, 
vital signs, physical examinations, ECGs, and clinical laboratory evaluations. Enrollment and 
dosing for remaining subjects in any group may occur after the interim data for that group are 
reviewed and the Covance Medical Monitor, Investigator (or designee), and Sponsor agree it 
is safe to proceed with dosing. 
 
Each interim review will be a teleconference between the Covance Medical Monitor, 
Investigator (or designee), and/or Sponsor to discuss safety data. 
 
If available, PK data and matched-control healthy subject data may also be used during the 
interim review. 
 
8.3. 
Analysis Populations 
8.3.1. 
Study 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 time to 
maximum concentration. The impact of protocol deviations on PK population will be 
evaluated on a case-by-case basis. 
 
The Safety Population will consist of all subjects who have received at least 1 dose of study 
drug. Subjects will be classified into groups based on actual treatment received. 


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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 
area under the concentration-time curve (AUC) from hour 0 to 
the last measurable concentration, calculated using the linear 
trapezoidal rule for increasing and decreasing concentrations 
AUC0-inf 
AUC from hour 0 extrapolated to infinity, calculated using the 
formula: 
 
AUC0-inf  = AUC0-t  + Ct
 
λz 
 
where Ct is the last measurable concentration and Z is the 
apparent terminal elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC 
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 (ln)(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 
Additionally, the number of points used to estimate Z will be presented in a listing. 
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 Vd/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.). 


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Other parameters may be added as appropriate. Final PK parameters reported will be detailed 
in the Statistical Analysis Plan (SAP). 
 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analysis will be performed using SAS Version 9.4 or greater. More details on the analyses 
will be included in the SAP. 
 
8.4.1. 
Descriptive Analysis 
 
Plasma concentrations and PK parameters will be summarized separately by CP and 
NCI-ODWG hepatic 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 protein binding will be 
tabulated separately by CP and NCI-ODWG hepatic function group. 
 
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 mild, moderate, or severe hepatic impairment, compared to subjects 
with normal hepatic function. To evaluate the effect of hepatic function group on the PK of a 
single dose of LOXO-305, paired t-tests will be performed for each hepatic impairment group 
(by CP classification) versus the normal group with respect to 1-to-1 matching. 
 
In addition, an analysis of covariance (ANCOVA) will be performed on the natural log (ln)- 
transformed AUC0-t, AUC0-inf, and Cmax. The ANCOVA model will contain a categorical 
factor of population for subjects with varied-degree hepatic impairment (severe, moderate, 
and mild by CP classification) and healthy matched-control subjects, a categorical covariate 
(sex), and continuous covariates (age and BMI). Ratios of least squares means and 90% 
confidence intervals (CIs) will be calculated using the exponentiation of the difference 
between hepatic 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 natural log (ln)-transformed unbound AUC0-t, unbound AUC0-inf, and unbound Cmax. The 
specific procedures will be documented in the SAP. Similar ANCOVA analysis will be 
applied for evaluating the effect of hepatic function group by NCI-ODWG classification. 
 
8.5. 
Safety Analysis 
 
All safety assessments, including AEs and SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and 12-lead ECGs, will be 
tabulated and summarized where possible, using descriptive methodology by hepatic function 
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 22.1 (or higher). The incidence of AEs 
for each hepatic function (matched-control healthy subjects, mild, moderate, and severe) will 
be presented by severity and by relationship to study drug as determined by the Investigator 


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or designee (Appendix 1 for AE reporting). All TEAEs will be summarized by system-organ 
class and preferred term, with a breakdown by hepatic function. 
 
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 client-provided specifications. 
The final datasets structure will be verified using Web Submission Data Manager®, while the 
dataset content will be peer reviewed by an independent programmer. 
 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will 
be peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by 
the Covance scientific team during the dry run and data review meetings. 
 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
 
8.7. 
Quality Control and Quality Assurance 
 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per client request, and as applicable, according to the contract 
between Covance and the Sponsor. 


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9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator (or designee). 
 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator (or designee), and the IRB (see Form 
FDA 1572). 
 
9.2. 
Site Initiation Visit/Investigator Meeting 
 
Prior to the start of the clinical study, the representative(s) of the Sponsor and/or Covance 
will meet with the Investigator (or designee) and appropriate CRU staff to familiarize the 
Investigator (or designee) and CRU staff with the materials necessary for conducting the 
clinical study. 
 
9.3. 
Disclosure 
 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, oral 
presentations, abstracts) by the Investigator (or designee) or their representative(s), shall 
require prior notification and review, within a reasonable timeframe, by the Sponsor, and 
cannot be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of 
the Sponsor’s intellectual property rights. 
 
9.4. 
Monitoring 
 
Covance (on behalf of the Sponsor) will designate Study Monitors who will be responsible 
for monitoring this clinical trial. Covance’s Study Monitors 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), Applications for FDA Approval to Market a New Drug (21 CFR 314), and 
Radioactive Drugs for Certain Research Uses (21 CFR 361.1), as appropriate. As such, these 
sections of US Title 21 CFR, along with the applicable International Council for 
Harmonisation (ICH) Guidelines, are commonly known as Good Clinical Practices, 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 3.1). 2020. 
 
2. Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, Rothenberg SM, et al. A next 
generation reversible BTK Inhibitor, for overcoming acquired resistance to irreversible 
BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18. 
 
3. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK 
with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 
4;369(1):32–42. 
 
4. Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol. 2017 May 1;35(13):1437–43. 
 
5. Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to 
acalabrutinib in CLL is mediated primarily by BTK mutations. 2019;134(Supplement_1). 
 
6. Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022–35. 
 
7. Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017 
04;129(18):2519–25. 
 
8. Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, Haruna M, et al. QT 
PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT 
Interval Prolongation by Human Pharmaceuticals [Internet]. Journal of pharmacological 
sciences. 2005 [cited 2020 Jun 10]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/16493187/ 
 
9. CG C, JG T. Surgery and Portal Hypertension [Internet]. Major problems in clinical 
surgery. 1964 [cited 2020 Jun 26]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/4950264/ 
 
10. Rn P, Im M-L, Jl D, Mc P, R W. Transection of the Oesophagus for Bleeding 
Oesophageal Varices [Internet]. The British journal of surgery. 1973 [cited 2020 Jun 26]. 
Available from: https://pubmed.ncbi.nlm.nih.gov/4541913/ 
 
11. Patel H, Egorin MJ, Remick SC, Mulkerin D, Takimoto CHM, Doroshow JH, et al. 
Comparison of Child-Pugh (CP) criteria and NCI organ dysfunction working group 
(NCI-ODWG) criteria for hepatic dysfunction (HD): Implications for chemotherapy 
dosing. JCO. 2004 Jul 15;22(14_suppl):6051–6051. 
 
12. Food and Drug Administration. Guidance for Industry: Pharmacokinetics in Patients with 
Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling [Internet]. Food and Drug Administration; 2003. Available from: 


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http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc 
es/ucm072123.pdf 


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


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


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treatment and the contraceptive method, in addition to the pregnancy the drug interaction 
should also be captured as a separate AE. 
 
Definition of Serious Adverse Events 
 
An SAE (by 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 (IB) or if it is not 
listed at the specificity or severity that has been observed for an unapproved investigational 
medicinal product (IMP). 
 
Reporting 
 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of the 
drug and represent events that are assessed as serious, related, and unexpected. Food and 
Drug Administration-reportable AEs will be reported by the CRU to the Sponsor and the 
responsible 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 
Creatinine 
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) 
count 
WBC differential (percent 
and absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Hemoglobin A1cb 
Thyroid-stimulating hormoneb 
Estimated glomerular filtration ratea,d 
SARS-CoV-2 (COVID-19) test 
Coagulation Parameters: 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Human immunodeficiency virus 
antibody 
Hepatitis B surface antigen 
Hepatitis B virus immunoglobulin M 
core antibodyf 
Hepatitis C virus antibody (healthy 
matched-control subjects only)f 
For Female Subjects only: 
Pregnancy test (serum qualitative, 
serum quantitative may be used for 
confirmation if needed)c 
Follicle-stimulating hormone 
(post-menopausal female subjects 
only)b 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity 
Protein 
Urobilinogen 
Microscopic examination 
including bacteria, casts, 
crystals, epithelial cells, 
RBCs, and WBCs (if protein, 
leukocyte esterase, nitrite, or 
blood is positive) 
Urine Drug Screen:a 
Including but not limited to the 
following: 
Alcohol (ethanol)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. Subjects who are positive for hepatitis B virus (HBV) immunoglobulin M or hepatitis C virus (HCV) by antibody will 
require confirmation by polymerase chain reaction (PCR) before enrollment to detect presence of active virus. Subjects 
who are HBV or HCV PCR positive or for whom a PCR is unable to be obtained will not be eligible. 


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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 
5 
5 
20 
20 
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: 
157 mL 
a Estimated glomerular filtration rate will be assessed as part of the clinical chemistry sample. 
 
Note: Although the total maximum volume to be analyzed is anticipated to be approximately 
157 mL, due to the variability in sampling requirements at different laboratories, the total 
volume of blood collected from each subject may vary. 


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Appendix 4: Schedule of Assessments 


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 6 4  of 6 9  
 
 
 
 
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 u  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 w  
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  
 
 
 
 
 
C P Cl ass Sc ore b  
X  
X  
 
 
 
 
N CI -O D W G Cl ass Sc ore b  
X  
X  
 
 
 
 
Me dic al Hist or y  
X  
X c 
 
 
 
 
Hei g ht/ Wei g ht/ B MI  
X d  
X d  
 
 
 
 
P h ysic al E x a mi n ati o n e 
X  
X  
 
 
X  
 
1 2 -Le a d E C G f 
X  
X  
X  
 
X  
 
Vit al Si g ns g  
X h,i  
X h,i  
X i 
X  
X h,i  
 
H D Y F ? I n q uir y j 
X  
X  
X  
X  
X  
X  
A Es/ S A Es k  
X  
X  
X  
X  
X  
X  
L O X O -3 0 5 D ose l 
 
 
X  
 
 
 
Cli nic al L a b or at or y E v al u ati o ns o  
X  
X  
 
X v  
X v  
 
C O VI D -1 9 Test p  
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 q  
X  
X  
 
 
 
 
Pri or a n d C o nc o mit a nt Me dic ati o ns r 
X  
X  
X  
X  
X  
X  
Ser u m Pre g n a nc y Test s 
X  
X  
 
X v  
X v  
 
F S H Test t 
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 P = C hil d -P u g h; 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 T er 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; N CI -O D W G = Nati o nal Ca ncer I nstit ute –  Or ga n D ysf u ncti o n W or ki n g 
Gr o u p; P K = p har mac o ki netic; 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.  S u bjects wit h he patic i m pair me nt o nl y. C hil d -P u g h a n d N CI -O D W G sc ores will be calc ulate d at Scree ni n g a n d C hec k -i n ( Da y -1); he paticall y i m paire d s u bjects will be assi g ne d t o gr o u ps 
acc or di n g t o C P sc ores at C hec k -i n ( Da y -1) t o e ns ure sta bilit y of he patic i m pair me nt a n d s u bject safet y, as deter mi ne d b y t he I n vesti gat or ( or  desi g nee).  
c. I nteri m me dical hist or y o nl y.  
C CI


Pr ot oc ol  
C o va nce St u d y: 8 4 1 9 6 9 1  
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 2  
Pr ot oc ol Versi o n 2. 0, 0 7 Oct o ber 2 0 2 0  
Pa ge 6 5  of 6 9  
 
 
 
d.  Hei g ht c ollecte d at Scree ni n g o nl y, b o d y mass i n de x base d o n Scree ni n g  hei g ht.  
e. 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).  
f. 1 2 -lea d E C Gs  will  be  o btai ne d at  Scree ni n g, C hec k -i n, Da y  1 ( pre d ose  a n d 2 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 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.  
g.  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 a n d C hec k -i n ( Da y 1), Da y 1 ( pre d ose a n d 2 h o urs p ost d ose), 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, v ital 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. B P 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 b ject 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.  
h.  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, Da y -1, a n d at E O T ( Da y 8) or  E T.  
i. 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, 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 ure 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. 
j. A n  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.  
k.  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.  
l. 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 at least 2 h o urs  p ost d ose.  
o.  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 uri nal ysis ( 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 o f 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 p erf 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. 
p.  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  e q ui vale nt.  
q.  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. 
r. 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 he patic 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.  
s. Fe male s u bjects  o nl y.  
t. P ost -me n o pa usal fe male s u bjects  o nl y.  
C CI


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u. 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 serum pregnancy test results (female subjects only) 
are to be available for review by the Investigator (or designee) prior to subject release from the CRU at the EOT visit and prior to subject release from the CRU at the ET visit if available. 
v. Clinical laboratory evaluations and serum pregnancy test (female subjects only) will be performed on the day prior to subject release from the CRU (Day 7) if the subject completes the study 
(EOT). Clinical laboratory evaluations and serum pregnancy test (female subjects only) will be performed on the day of subject release from the CRU if the subject terminates early (ET). 
w. To be conducted 7 days (± 2 days) following EOT 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. 


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Appendix 5: Protocol Amendment Summary of Changes 
Protocol Version 2.0 (dated 7th October 2020) incorporated the following changes in Protocol 
Version 1.0 (dated 7th August 2020): 
• Additional data from non-clinical studies with LOXO-305 has been added to 
Section 1.2, Nonclinical Pharmacokinetics and Toxicology. 
• Additional data from clinical studies with LOXO-305 has been added to Section 1.4, 
Summary of Clinical Experience, Section 1.4.1, Safety, and Section 1.6, Risk 
Assessment. 
• The Protocol has been updated to allow glucose tablets to be administered as needed 
for treatment of hypoglycaemia during the study as a safety precaution. 
• The number of subjects aimed to be enrolled into each National Cancer Institute's 
Organ Dysfunction Working Group (NCI-ODWG) classification for hepatic 
impairment has been clarified throughout the Protocol from a minimum of 4 subjects 
with mild and moderate hepatic impairment by NCI-ODWG classification, to at least 
4 subjects meeting moderate hepatic impairment criteria per NCI-ODWG 
classification, and at least 4 subjects meeting mild hepatic impairment criteria per 
NCI-ODWG classification. 
• Table 4, National Cancer Institute-Organ Dysfunction Working Group for Hepatic 
Dysfunction Criteria has been corrected such that the criteria for mild hepatic 
impairment and severe hepatic impairment are consistent with the criteria used in the 
publication cited in the Protocol. 
• The requirements for hepatitis C virus antibody testing have been clarified throughout 
the Protocol to state that this will be conducted in healthy matched-control subjects 
only to be consistent with Section 4.1, Screening Procedures, #13. 
• The requirements for hepatitis B virus testing have been clarified throughout the 
Protocol to state that it will be performed using an immunoglobulin M (IgM) core 
antibody test. 
• The requirements for oral temperature measurements to be taken have been revised 
throughout the Protocol, to allow any type of temperature measurements to be taken 
to provide flexibility to study sites. 
• The duration of contraceptive requirements for male subjects without documentation 
of sterilization has been clarified to state that male subjects must follow 1 of the 
contraception methods listed under inclusion criterion #5b from Day 1 through 6 
months after Day 1. 
• The contraceptive requirements for sexual intercourse between male subjects with 
female partners who are pregnant or breastfeeding has been clarified to state that this 
should be avoided from Check-in (Day -1) through 6 months after Day 1, unless the 
male subject uses a condom with spermicide. 
• Inclusion criterion #12 has been amended to reduce the acceptable hemoglobin level 
from ≥ 9 g/dL to ≥ 8 g/dL for subjects who have anemia secondary to hepatic disease, 
where anemia symptoms are not clinically significant. This criterion has been updated 


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to more accurately reflect the range typically seen in a hepatic impairment population, 
without impacting subject safety. 
• Exclusion criterion #4 has been revised to allow clinically significant (as determined 
by the Investigator [or designee]) abnormal clinical laboratory results (excluding 
those further defined in exclusion criteria #23, #24, #25, #26, #36, and #37) to be 
repeated 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. This 
change has been made to account for transient abnormal results. 
• Exclusion criteria #8 and #9 and Section 6.2, Diet, Fluid, and Activity Control have 
been updated to remove the Investigator (or designee) and Sponsor discretion for 
inclusion of subjects who consume grapefruit/grapefruit juice, Seville oranges or its 
juice or alcohol or caffeine-containing foods or beverages within the specified time 
prior to Check-in (Day -1). This has been amended as consumption of any of the 
noted items in the specified time prior to Check-in (Day -1) would not be permitted in 
any circumstance. 
• Exclusion criterion #13 and Section 6.1, Concomitant Therapies has been updated to 
include strong P-glycoprotein inhibitors, proton pump inhibitors, antacids, and 
H2-receptor antagonists in the list of specified restricted over-the-counter and 
prescription medications to provide further guidance to the sites. 
• The duration of the restriction for prescription and over-the-counter medication prior 
to Day 1 in Exclusion criterion #13, Section 6.1, Concomitant Therapies, and 
Appendix 4, Schedule of Assessments, footnote r has been amended to 14 days or 5 
half-lives (whichever is longer) prior to Day 1 to account for medications that may 
have a prolonged half-life. 
• Exclusion criterion #16 ‘Estimated glomerular filtration rate (eGFR) of <50 mL/min 
at Screening or Check-in (Day -1) using the Modification of Diet in Renal Disease 
formula’, has been replaced with exclusion criteria #24 (healthy subjects) and #36 
(hepatic impairment subjects only). Exclusion criteria #24 and #36 specify that the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation will be 
used to calculate eGFR, and per Food and Drug Administration (FDA) 
recommendation, healthy subjects with an eGFR < 90 mL/minute/1.73m2 , mild and 
moderate hepatically impaired subjects with an eGFR of < 90 mL/minute/1.73m2, and 
severe hepatically impaired subjects with an eGFR of < 60 mL/minute/1.73m2 at 
Screening and Check-in (Day -1) will be excluded. Rechecks of out-of-range eGFR 
values that are not clinically significant (as determined by the Investigator [or 
designee]) will be permitted up to 2 times during Screening and Check-in (Day -1) to 
confirm eligibility for study participation if the values fall within the range stated 
above. Appendix 2, Clinical Laboratory Evaluations has been amended to state that 
the CKD-EPI equation will be used to calculate eGFR. 
• The exclusion of subjects for white blood cell count and platelet count below the 
lower limit of normal range at Screening and Check-in (Day -1) has been removed 
from exclusion criterion #26. Instead, subjects with clinically significant (as 
determined by the Investigator [or designee]) abnormal white blood cell count and 
platelet count (that do not fall within normal ranges or do not stabilize upon repeat 
assessment) will be excluded per exclusion criterion #4. 


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• Exclusion criteria #20, #22, #23, #25, #26, #34, and #35 have been updated to allow 
out of the specified range values that are not clinically significant (as determined by 
the Investigator [or designee]) to be permitted to be repeated up to 2 times during 
Screening, Check-in (Day -1), and predose on Day 1 (where applicable) to confirm 
eligibility for study. This change has been made to account for transient abnormal 
results. 
• Exclusion criterion #32 has been clarified to state the duration of time in which the 
subject should not have previously received the investigational product is within the 
last 30 days. 
• The limit for QT interval corrected for heart rate using Fridericia’s method (QTcF) in 
exclusion criterion #34 has been revised to > 450 msec for subjects with mild or 
moderate hepatic impairment or > 470 msec for subjects with severe hepatic 
impairment at Screening, Check-in (Day -1), or predose on Day 1 per FDA 
recommendation. 
• Exclusion criterion #35 has been updated to clarify that out-of-range vital signs 
parameters judged as non-clinically significant will be based on hepatic impairment 
status and subject age. 
• Exclusion criterion #37 has been updated to clarify that the decision to deem creatine 
kinase, liver function tests, amylase, and lipase values clinically significant will be 
based on hepatic impairment status as well as age. 
• Section 4.5, Subject Number and Identification has been clarified to include guidance 
on the numbering of subjects by hepatic function group (the second set of digits). 
• Clarification that water will be restricted for 1-hour predose and 1-hour postdose, with 
the exception of water administered for dose administration has been provided. 
• An analysis of covariance statistical analysis has been added to Section 8.4.2, 
Statistical Methodology for natural log (ln)-transformed unbound AUC0-t, unbound 
AUC0-inf, and unbound Cmax per FDA recommendation. 
• Appendix 4, Schedule of Assessments, footnote o has been clarified to specify the 
measurement timepoint postdose for clinical laboratory evaluations. 
• Appendix 4, Schedule of Assessments, footnotes f, g, and i, have been clarified to 
specify the measurement timepoint postdose and the allowed measurement window 
for 12-lead electrocardiograms, vital signs, and oxygen saturation. 
• 12-lead ECGs are required to be assessed at Screening, Check-in (Day -1), and 
predose on Day 1 according to exclusion criterion #22 of the Protocol. Appendix 4, 
Schedule of Assessments, erroneously omitted a 12-lead ECG assessment predose on 
Day 1 and has been revised to include this. 
 
Minor updates: 
 
• The amendment/version number and date were updated throughout the protocol. 
• Typographical errors and formatting errors were corrected, and minor clarifications 
and corrections were made, as necessary. 
• The synopsis was updated to be consistent with the changes made to the body text. 

SAP_001.pdf: 
Statistical Analysis Plan J2N-OX-JZNF Version 1.0
An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Pharmacokinetic Study of 
LOXO-305 Administered to Fasted Hepatically Impaired Male and Female Subjects and Fasted Matched-control 
Healthy Subjects
NCT06190691
Approval Date: 22-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 Hepatically Impaired Male and Female Subjects and Fasted 
Matched-control Healthy Subjects  
SAP Status: Sponsor Final 
SAP Version: 1.0  
SAP Date: 22MAR2021  
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20012 
Covance Study: 8419691  
Sponsor:  
Study Site:  
Loxo Oncology, Inc.  
Multiple Sites 
A wholly owned subsidiary of Eli Lilly and 
Company  
701 Gateway Boulevard, Suite 420  
South San Francisco, California 94080 
USA  
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: 8419691 
Protocol Reference: LOXO-BTK-20012 
Sponsor Final, Version 1.0, 22MAR2021 
Page 2 of 22 
ST-AD-031 Version 01 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................. 1 
TABLE OF CONTENTS ............................................................................................................ 2 
LIST OF ABBREVIATIONS ..................................................................................................... 4 
1. INTRODUCTION .................................................................................................................. 6 
2. STUDY OBJECTIVES ........................................................................................................... 6 
2.1. Primary Objective ............................................................................................................ 6 
2.2. Secondary Objective ........................................................................................................ 6 
3. STUDY ENDPOINTS ............................................................................................................ 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN ................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ......................................................................................... 9 
6. STUDY TREATMENT AND HEPATIC FUNCTION GROUPS ........................................ 11 
7. DEFINITIONS OF POPULATIONS ................................................................................... 12 
7.1. All Subjects Population .................................................................................................. 12 
7.2. Safety Population ........................................................................................................... 12 
7.3. Pharmacokinetic Population .......................................................................................... 12 
8. STATISTICAL METHODOLOGY ...................................................................................... 12 
8.1. General ........................................................................................................................... 12 
8.1.1. Calculation of the Summary Statistics .................................................................... 13 
8.1.2. Repeat and Unscheduled Readings ......................................................................... 13 
8.1.3. Definitions of Baseline and Change from Baseline ................................................ 14 
8.2. Subject Disposition and Population Assignment ........................................................... 14 
8.3. Screening Demographics and Baseline Characteristics ................................................. 14 
8.4. Prior and Concomitant Medication ................................................................................ 14 
8.5. Pharmacokinetic Assessments ....................................................................................... 15 
8.5.1. Pharmacokinetic Analysis ....................................................................................... 15 
8.5.2. Presentation of Pharmacokinetic Data .................................................................... 17 
8.5.3. Pharmacokinetic Statistical Methodology ............................................................... 18 
8.6. Safety and Tolerability Assessments .............................................................................. 20 
8.6.1. Adverse Events ........................................................................................................ 20 


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8.6.2. Clinical Laboratory Parameters ............................................................................... 21 
8.6.3. Vital Signs Parameters ............................................................................................. 21 
8.6.4. 12-lead Electrocardiogram Parameters ................................................................... 22 
8.6.5. Other Assessments ................................................................................................... 22 
8.6.6. Safety and Tolerability Statistical Methodology ..................................................... 22 
9. INTERIM ANALYSES ........................................................................................................ 22 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES .......... 22 
11. REFERENCES ................................................................................................................... 23 
12. APPENDICES .................................................................................................................... 24 


SAP  
CONFIDENTIAL 
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Protocol Reference: LOXO-BTK-20012 
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Page 4 of 22 
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 
BMI  
body mass index 
BLQ  
below the limit of quantification  
CDISC  
Clinical Data Interchange Standards Consortium  
CL/F  
apparent systemic clearance  
CL/F,u  
unbound apparent systemic clearance  
CI  
confidence interval  
Cmax  
maximum observed plasma concentration  
Cmax,u  
unbound maximum observed plasma concentration 
CP  
Child-Pugh  
CRU  
Clinical Research Unit  
CSR  
clinical study report  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV  
coefficient of variation  


SAP  
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Covance Study: 8419691 
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Page 5 of 22 
ST-AD-031 Version 01 
ECG 
electrocardiogram  
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 
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  
MedDRA  
Medical Dictionary for Regulatory Activities  
MRTinf  
mean residence time extrapolated to infinity  
NC  
not calculated  
NCI-ODWG  
National Cancer Institute-Organ Dysfunction Working Group  
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  
SAE  
serious adverse event  
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   


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ST-AD-031 Version 01 
1. INTRODUCTION
This SAP has been developed after review of the clinical study protocol (Final Version 2.0 
dated 07 October 2020) and electronic case report form.   
This SAP describes the planned analysis of the pharmacokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented in 
the clinical study report (CSR) is provided in the accompanying TFL shells document.   
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP must 
be finalized prior to the lock of the clinical database for this study. When the SAP and TFL 
shells are approved, they will serve as the template for this study’s CSR.   
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.   
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials and 
ICH E3 guideline Structure and Content of Clinical Study Reports.1,2   
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES
2.1. Primary Objective 
The primary objective of the study is to evaluate the PK profile of LOXO-305 in subjects with 
impaired hepatic 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 hepatic 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)


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Covance Study: 8419691  
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ST-AD-031 Version 01  
● time to maximum observed plasma concentration (tmax)  
● 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 extrapolated to infinity (MRTinf).  
In addition, a single blood sample will be collected predose to determine the fraction unbound 
(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), performing 
physical examinations and clinical laboratory evaluations, measuring vital signs, and 
recording electrocardiogram (ECGs).  
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 mild, moderate, or severe impaired hepatic 
function and healthy subjects with normal hepatic function. Hepatic function will be 
classified based on the Child-Pugh (CP) classification of hepatic impairment.   
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up 
to 8 subjects with mild impairment, up to 8 subjects with moderate impairment, and up to 8 
subjects with severe impairment, per CP classification – assessed at Screening and verified at 
Check-in [Day -1]) and 8 to 24 subjects with normal hepatic function are enrolled, with the 
goal of having at least 6 subjects from each hepatic impairment group per CP classification 
and at least 6 subjects with normal hepatic function complete the study. Hepatically impaired 
subjects will be assigned to groups according to CP scores at Check-in (Day -1) to ensure 
stability of hepatic impairment and subject safety, as determined by the Investigator [or 
designee]. Subjects will be enrolled within the following groups based on their CP score at 


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CONFIDENTIAL  
Covance Study: 8419691  
Protocol Reference: LOXO-BTK-20012  
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Page 8 of 22  
  
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Screening and Check-in (Day -1) as judged by the Investigator (or designee), Covance 
Medical Monitor, and Sponsor:   
● Group 1: Matched-control healthy subjects with normal hepatic function;  
● Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); ● 
Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
● Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15).  
A parallel-design strategy will be adopted for the hepatic impairment groups, with interim 
reviews of the safety data after the first 2 subjects from Group 2 (mild hepatic impairment 
subjects) and Group 3 (moderate hepatic impairment subjects) and matched-control healthy 
subjects are enrolled and have completed all study-related assessments including the followup 
phone call.   
A schematic of the study design is presented in Figure 1.   
Figure 1:  Study Design   
  
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   
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 hepatic 
impairment subject(s). Should another hepatic 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 hepatic 
impairment group. Each subject with normal hepatic function may be matched with up to 1 
subject within each hepatic 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 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  


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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. 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 
approximately 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 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. PK samples will be obtained through 168 hours postdose.  
In this study, physical examinations, 12-lead ECGs, vital sign measurements, How Do You 
Feel? inquiries, clinical chemistry panel, coagulation parameters, hematology panel, 
urinalysis, and recording of concomitant medications will be performed at specified times 
during the study.  
AEs and serious AEs (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 hepatic impairment (up to 8 subjects from each hepatic 
impairment group, per CP classification) and approximately 8 to 24 matched-control healthy 
subjects with normal hepatic function will be enrolled in the study with the goal of having at 
least 6 subjects from each hepatic impairment group per CP classification and at least 6 
subjects with normal hepatic function complete the study. Of these hepatic impairment 
subjects enrolled per CP category, enrollment will also aim to have at least 4 subjects meet 
severe hepatic impairment criteria per National Cancer Institute-Organ Dysfunction Working 
Group (NCI-ODWG) classification, at least 4 subjects meet moderate hepatic impairment 
criteria per NCI-ODWG classification, and at least 4 subjects meet mild hepatic impairment 


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criteria per NCI-ODWG classification. 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 hepatic function.  


 
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Total Bilirubin:  ≤ULN   
Normal  
6. STUDY TREATMENT AND HEPATIC FUNCTION GROUPS  
The planned treatment administered for all subjects will be 200 mg LOXO-305.  
The hepatic function group names and ordering to be used in the TFLs are presented in Table 
1 and Table 2.   
Table 1:  Presentation of Hepatic Function Groups in TFLs by CP classification (Safety 
and PK)  
Hepatic Function Group  
Child-Pugh  
Classification  
Abbreviation  
Order in TFLs  
Normal Hepatic Function  
NA*  
Normal  
1  
Mild Hepatic Impairment  
5 or 6 points (Class 
A)  
Mild  
2  
Moderate Hepatic Impairment  
7 to 9 points  (Class 
B)  
Moderate  
3  
Severe Hepatic Impairment  
10 to 15 points  
(Class C)  
Severe  
4  
*Only subjects with hepatic impairment will have CP scores calculated at screening and Day -1. Hepatically 
impaired subjects will be assigned to groups according to CP scores at Check in (Day -1)  
All hepatic function groups described above are the planned groups. The TFLs will reflect the 
actual hepatic function groups dosed based upon their CP score unless otherwise stated.    
Table 2:   Presentation of Hepatic Function Groups in TFLs by NCI-ODWG 
classification (PK)  
NCI-ODWG Classification  Abbreviation  Order in 
Hepatic Function Group  
TFLs  
Normal Hepatic Function  
AST: ≤ULN *  
1  
Mild Hepatic Impairment  
Total Bilirubin: > ULN to 1.5 x ULN  
AST: >ULN  
Mild  
2  
Moderate Hepatic Impairment  
Total Bilirubin: >1.5 to 3 x ULN  
AST: Any  
Moderate  
3  
Severe Hepatic Impairment  
Total Bilirubin: > 3 – 10 x ULN  AST: 
Any   
Severe  
4  
Abbreviations: AST = aspartate aminotransferase; NCI-ODWG = National Cancer Institute-Organ Dysfunction 
Working Group; ULN = upper limit of normal.  
*Only subjects with hepatic impairment will have NCI-ODWG scores calculated at screening and Day -1.  
Hepatically impaired subjects will be assigned to groups according to NCI-ODWG scores at Check in (Day -1)  
  
  


 
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7. DEFINITIONS OF POPULATIONS   
Any protocol deviations, including those related to COVID-19, will be considered prior to 
database lock for their importance and taken into consideration when assigning subjects to 
populations.   
7.1. All Subjects Population   
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.   
7.2. Safety Population   
The safety population will consist of all subjects who have received 1 dose of study drug. 
Subjects will be classified into hepatic function groups based on their CP score.  
7.3. Pharmacokinetic Population   
The PK population will consist of all subjects who have received a dose of LOXO-305, have 
at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times median tmax. The impact 
of protocol deviations on PK population will be evaluated on a case-by-case basis.   
8. STATISTICAL METHODOLOGY   
8.1. General   
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the 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.   


 
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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 
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 signs measurements and ECG data only, any predose value recorded in addition to 
the original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the original 
value will be defined as an unscheduled value. For all other data types (eg, laboratory 


 
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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 8.1.3).  
8.1.3. Definitions of Baseline and Change from Baseline   
Baseline value is defined as the last non-missing measurement before administration of 
LOXO-305.   
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.   
A summary table by hepatic function group, CP score and NCI-ODWG separately will be 
provided, based on the all subjects population.   
8.3. Screening Demographics and Baseline Characteristics   
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and BMI will be listed. The CP score will be listed and summarized. 
NCI-ODWG classification will be listed and summarized.   
A summary table by hepatic function group will be provided, based on the safety population.    
8.4. Prior and Concomitant Medication   
Prior medication will be defined as medication that ends prior to the 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.   


 
S A P  
C O N FI D E N TI A L  
 
C o va nce St u d y: 8 4 1 9 6 9 1  
Pr ot oc ol Refere nce: L O X O -B T K - 2 0 0 1 2  
 
S p o ns or Fi nal, Versi o n 1. 0, 2 2 M A R 2 0 2 1  
Pa ge 1 5 of 2 2  
 
  
S T -A D -0 3 1 Versi o n 0 1  
Pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he Worl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O Dr u g) Gl o bal, F or mat B 3, Versi o n Se pte m ber 2 0 2 0. Pri or a n d c o nc o mita nt 
me dicati o ns will be liste d.    
8. 5.  P h ar m ac o ki netic Assess me nts   
8. 5. 1.  P h ar m ac o ki netic A n al ysis   
T he f oll o wi n g P K para meters will be deter mi ne d w here p ossi ble fr o m t he plas ma 
c o nce ntrati o ns of L O X O- 3 0 5 usi n g n o nc o m part me ntal met h o ds i n vali date d s oft ware 
pr o gra m P h oe ni x Wi n N o nli n ( Certara, Versi o n 8. 1 or hi g her):  
P ar a meter  
U nits a  
Defi niti o n  
A U C 0-t  
h * n g/ m L   
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o t he last 
meas ura ble c o nce ntrati o n (t last)b  
A U C 0- i nf  
h * n g/ m L   
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d 
t o i nfi nit yc  
% A U C
e xtra p  
%   
perce nta ge e xtra p olati o n f or A U C 0- i nf  
C ma x   
n g/ m L   
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
tma x   
h   
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n  
λ Z   
1/ h   
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  
t1/ 2  
h   
a p pare nt ter mi nal eli mi nati o n half -life  
C L/ F  
L/ h   
a p pare nt s yste mic cleara nce   
V z/ F  
L   
a p pare nt v ol u me of distri b uti o n at t he ter mi nal p hase  
M R T
i nf  
h  
mea n resi de nce ti me e xtra p olate d t o i nfi nit y  
a U nits are base d o n c o nce ntrati o n u nits ( pr o vi de d b y t he bi oa nal ytical la b or preferre d u nits f or prese ntati o n of P K 
para meters) a n d d ose u nits use d i n t he st u d y. b Area u n der t he c o nce ntrati o n -ti me c ur ve will be calc ulate d usi n g t he li near 
tra pez oi dal r ule f or i ncreasi n g a n d decreasi n g c o nce ntrati o ns c Base d o n t he last o bser ve d q ua ntifia ble c o nce ntrati o n  
T he u n b o u n d fracti o n (f u) i n plas ma, e x presse d as a deci mal, will be calc ulate d fr o m pr otei n 
bi n di n g c o nce ntrati o n data as t he u n b o u n d dr u g c o nce ntrati o n di vi de d b y t he t otal dr u g 
c o nce ntrati o n i n plas ma. T he f u val ue deter mi ne d f or eac h s u bject will be use d t o calc ulate 
t he f oll o wi n g u n b o u n d L O X O- 3 0 5 P K para meters f or eac h i n di vi d ual s u bject:   
C ma x, u     
U n b o u n d C ma x , calc ulate d as Cma x *f u  
A U C 0- t, u  
U n b o u n d A U C 0-t, calc ulate d as A U C0-t*f u  
A U C 0- i nf, u  
U n b o u n d A U C 0- i nf, calc ulate d as A U C0- i nf*f u  
C L/ F, u   
U n b o u n d C L/ F, calc ulate d as D ose/ A U C 0- i nf, u  
V z/ F,u   
U n b o u n d V z/ F, calc ulate d as C L/ F,u/Z   
A d diti o nal P K para meters ma y be deter mi ne d w here a p pr o priate.  
T he P K a nal ysis will be carrie d o ut w here p ossi ble usi n g act ual bl o o d sa m pli n g ti mes 
p ost d ose. If a n act ual ti me is missi n g, t he sa m ple c o nce ntrati o n res ult will be treate d as 
missi n g u nless t here is scie ntific j ustificati o n t o i ncl u de t he res ult usi n g t he  n o mi nal ti me.   


 
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The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. If 
Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax.  
8.5.1.1. 
Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life  
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations.  
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-inf, t1/2, CL/F, and Vz/F, 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  
1/h  
apparent terminal elimination rate constant  
λz Upper  
h  
end of exponential fit  
λz Lower  
h  
start of exponential fit  
λz N  
NA  
number of data points included in the log-linear regression  
λz Span Ratio  
NA  
time period over which λz was determined as a ratio of t1/2  
R2-adj  
NA  
adjusted coefficient for determination of exponential fit  
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR.  
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.   
If AUC0-inf cannot be determined reliably for all subjects, an alternative AUC measure, such 
as AUC to a fixed time point or AUC0-t, may be used in the statistical analysis.  


 
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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 will 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.  
● 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.  


 
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● 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 hepatic function group and time postdose will be provided for plasma 
PK concentrations using CP and NCI-ODWG classifications separately. 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 hepatic function groups will be provided for all PK parameters, with the 
exception of diagnostic regression-related PK parameters using CP and NCI-ODWG 
classifications separately. 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 and unbound PK parameters. Excluded subjects will 
be listed in the PK parameter tables, but will be excluded from the statistical analysis and 
summary statistics and noted as such in the tables.  
In addition, summary statistics for protein binding will be tabulated separately by CP and 
NCI-ODWG hepatic function group.  
8.5.3.1. Statistical Analysis   
The primary analysis planned for this study is to evaluate the PK of LOXO-305 after a single 
dose in subjects with mild, moderate, or severe hepatic impairment, compared to subjects 
with normal hepatic function. To evaluate the effect of hepatic function group on the PK of a 
single dose of LOXO-305, paired t-tests will be performed for each hepatic impairment group 
(by CP classification) versus the normal group with respect to 1-to-1 matching on the natural 
log (ln)-transformed AUC0-t, AUC0-inf, and Cmax. 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 hepatic 
impairment group and the matching normal group.  


 
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CCI 
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 hepatic impairment (severe, moderate, and mild by 
CP classification) and healthy matched-control 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 hepatic function cohort least 
squares means from the ANCOVA analyses on the ln-transformed AUC0-t, AUC0-inf, and Cmax 
with the normal group as reference. In addition, an ANCOVA will be performed on the 
lntransformed unbound AUC0-t, unbound AUC0-inf, and unbound Cmax. Similar ANCOVA 
analysis will be applied for evaluating the effect of hepatic function group by NCI-ODWG 
classification.   
CCI 
Additionally, a scatterplot of the ln-transformed PK parameters (AUC0-t, AUC0-inf, and Cmax) 
and corresponding unbound PK parameters versus screening/baseline Child-Pugh total score 
and its individual components will 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  
  


 
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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.   
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 hepatic 
function group   
● TEAEs by severity and hepatic function group   
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by hepatic function group   
● Treatment-related TEAEs by severity and hepatic 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 hepatic function group   
● Preferred term and hepatic 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.   


 
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● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, 
the minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of dosing is 01MAY2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).   
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019  
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).   
● For the calculation of summary statistics: If 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 
hepatic 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, 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 hepatic function group and timepoint.   


 
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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 hepatic function group and timepoint. QTcF values that are > 
450 msec and increase from baseline > 30 msec will be flagged in the data listing.    
8.6.5. Other Assessments   
Medical history and physical examination will be listed. Any physical examination 
abnormalities reported will also be flagged as clinically significant or not clinically 
significant as indicated.   
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.   
8.6.6. Safety and Tolerability Statistical Methodology   
No inferential statistical analyses are planned.    
9. INTERIM ANALYSES   
Interim reviews of safety data will be conducted after the first 2 subjects from Group 2 (mild 
hepatic impairment subjects) and Group 3 (moderate hepatic impairment subjects) and 
matched-control healthy subjects are enrolled and have completed all study-related 
assessments including the follow-up phone call. The safety data will include AEs and SAEs, 
vital signs, physical examinations, ECGs, and clinical laboratory evaluations. Enrollment and 
dosing for remaining subjects in any group may occur after the interim data for that group are 
reviewed and the Covance Medical Monitor, Investigator (or designee), and Sponsor agree it 
is safe to proceed with dosing.  
Each interim review will be a teleconference between the Covance Medical Monitor, 
Investigator (or designee), and/or Sponsor to discuss safety data.  
If available, PK data and matched-control healthy subject data may also be used during the 
interim review.   
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES   
There were no significant changes from the protocol-specified analyses.   


 
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11. REFERENCES   
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 5 
February 1998.   
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.   
   
 


 
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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  
  
  


 
 
   
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