A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LOXO-292 in Healthy Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol J2G-OX-JZJF 
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics 
of LOXO-292 in Healthy Adult Subjects
NCT05338515
Approval date: 25-Jan-2019

16.
Appendices
16.1 
Study Information
16.1.1 
Protocol and Protocol Amendments
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
1
. 
' 
celerion 
Translating Science to 
Medicine 

T,-anslating Soience a;o 
Medicine 
Protocol Clarification Letter for Celerion Study No.: CA27486 
Loxo 011cology, Jnc. Project No.: LOXO-RET-18057 
Date of Final J>rotocol: 25-Jan-2019 
Date of Protocol Clarification Letter: 25-Feb-2019 
A Phase I. Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharruacokine ·cs of 
.!:.?X0-:?11.'.!!!!!lthy_A-d-u-l_t_s_u«b_J_'c_cts __________ , _____ ~----------· 
Per the final protocol, and as per Section l3.2.3, additional 12-lead electrocardiogram (ECGs) m y be taken at 
any ether time(s), if deemed necessary by the Principal Investigator (Pl) or designee. As per equest of the 
Sponsor and PI, an additional safety ECG is to be performed at 3.5 hours post.dose on Day I for 11 subjects in 
Cohort 2 and Cohort 3. The event timing 1s to coincide with the anticipated maximum concen tion (Cmax) 
following a single dose of LOXO-292. 
Therefore, the below sections should read as follows: 
Section 6 Study Events Flow Chart 
A check mark should be added in the safety 12-lead ECG row on Day 1 at 3.5 hours (for Cohorts and 3 only). 
Section 13.2.3 ECG Monitoring 
Paragraph 3 of Section 13.2.3 is modified a,; follows (updates in bold) 
ECGs will be measured at Screening, at Check-in (Day-1), Day J (Hour 3.5), Days 2 and 5 pos ose, and at 
the EOT or ET (CRU discharge). ECGs will be obtained prior to and as close as possible to 
e scheduled 
blood draws if scheduled at the same time. 
The final protocol. 25-•Jan-2019 was not amended to incorporate these changes, therefore, t is protocol 
Pl 
cifi.ca,t.fooJet.tws heiJ.}.a_wtltt,;;,,.i. ____ _ 
(riDocuSigned by: 
11:'1~
---· Name•P I 
I 
Pl 
J ~~-d11hJ)pprove this document 
Pl 
~~3BJ6~:~b~ AM EST 
Pl 
B79BAD69CBA 
(Pl 
!.tvID, CPI 
Principal Ilwestigator 
Cderion 
22-24 Lisburn Road, Belfast, Northern Ireland 
Tel: 0044 (0) 2890554040 • Fax: 0044 (0) 2890554141 
Pl 
Date 
25-Feb- 19 I 07 :58:12 
ST 
Date 
Date 
age 1 of 1 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
2 

Page 1 
Clinical Protocol 
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of LOXO-292 in Healthy Adult Subjects 
Celerion Project No.: CA27486 
Sponsor Project No.: LOXO-RET-18057 
US IND No.: 133193 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Loxo Oncology, Inc. 
and/or Celerion. Any viewing or disclosure of such information that is not authorized in 
writing by Loxo Oncology, Inc. and/or Celerion is strictly prohibited. Such information may 
be used solely for the purpose of reviewing or performing this study. 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
3
celerion 
Translating Science to 
Medicine 

CONFIDENTIAL 
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
1 
PROTOCOL REVISION HISTORY 
1
25 January 2019 
byPI ------
I Final Protocol 
Page 2 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
4 

CONFIDENTIAL 
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
2 
PRINCIPAL INVESTIGATOR AND SPONSOR - SIGNATORIES 
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of LOXO-292 in Healthy Adult Subjects 
SPONSOR: 
SPONSOR'S 
REPRESENTATIVE: 
Loxo Oncology, Inc. 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080, USA 
~=="""=='_,MD, PhD 
Pl 
o Loxo Oncology, Inc. 
Mobile Pl 
E-maiI:PI 
(E:DocuS1qned bv: 
U.gnajili@.Jame: ___ 
_ 
25-Jan-19 I 09:57:18 PST 
Date 
L
Signing Reason: I approve this document 
Signing Time 1/25/2019 12:57:1 5 PM EST 
01A6C830EC5145848DE60879BAD69CBA 
Page 3 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
5 

CONFIDENTIAL 
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of LOX0-292 in Healthy Adult Subjects 
CLINICAL SITE AND CELERION PRINCIPAL INVESTIGATOR 
Pl 
Tel.:~P;;;;I ===== 
Fax: Pl _____ 
____. 
Pl 
Signature r 
I 
Printed Name 
Pl 
Page 4 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
6 

CONFIDENTIAL 
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact Information 
for Serious Adverse Event 
Reporting 
Medical Monitor 
Additional Sponsor Contact 
Protocol Author 
Certified Clinical Laboratory 
Bioanalytical Laboratory for 
LOX0-292 
efax: +l 203 643-2013 
E-mail: safety@loxooncology.com 
~Pl===::--'~iD, PhD 
Pl 
o Loxo Oncology, Inc. 
Mobile: 
E-mail: Pl 
Pl 
Pl 
, Clinical Operations 
Loxo Oncology, Inc. 
Tel.: Pl 
E-mail: Pl 
Pl 
PhD 
Semor Scientist, Protocol and Medical Writer 
Celerion 
I 
Pl 
Pl 
freland 
Tel.: Pl 
Fax: PI 
E-mail: Pl 
Celerion 
2420 West Baseline Road 
Tempe, Arizona 85283, USA 
Contact: 
Tel.: Pl 
ext. Pl 
Fax:PI 
-~ 
Alturas Analytics, Inc. 
Alturas Technology Park 
1324 Alturas Drive 
Moscow, Idaho 83843, USA 
Tel.: + 1 208 883-3400 
Page 5 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
7 

CONFIDENTIAL  
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
Page 6 
Pharmacokinetic and Statistical 
Analyses 
 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
and/or 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.: +1 402 476-2811 
Fax: +1 402 939-0428 
 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
Page 7 
4 
TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY ............................................................................. 2 
2 PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ......................... 3 
3 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................ 5 
4 TABLE OF CONTENTS ................................................................................................. 7 
5 SYNOPSIS ....................................................................................................................... 10 
6 STUDY EVENTS FLOW CHART ............................................................................... 14 
7 ABBREVIATIONS ......................................................................................................... 17 
8 INTRODUCTION........................................................................................................... 20 
8.1 
Background ............................................................................................................. 20 
8.1.1 
LOXO-292 ................................................................................................ 20 
8.2 
Rationale .................................................................................................................. 22 
8.2.1 
Rationale for this Study and Study Design ............................................... 22 
8.2.2 
Rationale for the Dose Selection and Dose Regimen ............................... 22 
8.2.3 
Rationale for Primary Endpoints .............................................................. 23 
8.3 
Risks and/or Benefits to Subjects ............................................................................ 24 
9 OBJECTIVES AND ENDPOINTS ............................................................................... 25 
9.1 
Objectives ................................................................................................................ 25 
9.2 
Endpoints ................................................................................................................. 25 
10 STUDY DESIGN ............................................................................................................. 26 
10.1 Overall Study Design and Plan ............................................................................... 26 
10.1.1 
Confinement, Return Visits, and Follow-Up ............................................ 26 
10.1.2 
End of Study Definition ............................................................................ 27 
11 STUDY POPULATION ................................................................................................. 28 
11.1 Inclusion Criteria ..................................................................................................... 28 
11.2 Exclusion Criteria .................................................................................................... 29 
11.3 Early Termination of Subjects from the Study ........................................................ 32 
11.4 Study Restrictions ................................................................................................... 32 
11.4.1 
Prohibitions and Concomitant Medication ............................................... 32 
11.4.2 
Meals ......................................................................................................... 33 
11.4.3 
Activity ..................................................................................................... 34 
12 TREATMENTS............................................................................................................... 35 
12.1 Treatments Administered ........................................................................................ 35 
12.2 Dose Modification ................................................................................................... 35 
12.3 Method of Treatment Assignment ........................................................................... 35 
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Page 8 
12.4 Blinding ................................................................................................................... 36 
12.4.1 
Dose Escalation Criteria and Stopping Rules ........................................... 36 
12.5 Treatment Compliance ............................................................................................ 37 
13 STUDY ASSESSMENTS AND PROCEDURES ......................................................... 38 
13.1 Screening ................................................................................................................. 38 
13.2 Safety Assessments ................................................................................................. 38 
13.2.1 
Physical Examination................................................................................ 38 
13.2.2 
Vital Signs ................................................................................................. 38 
13.2.3 
ECG Monitoring ....................................................................................... 39 
13.2.4 
Body Weight ............................................................................................. 39 
13.2.5 
Clinical Laboratory Tests .......................................................................... 39 
13.2.6 
Adverse Events ......................................................................................... 40 
13.2.6.1 Adverse Event Definition ......................................................... 40 
13.2.6.2 Monitoring ............................................................................... 40 
13.2.6.3 Reporting .................................................................................. 41 
13.2.6.4 Serious Adverse Event ............................................................. 42 
13.3 Pharmacokinetic Assessments ................................................................................. 43 
13.3.1 
Blood Sampling and Processing ............................................................... 43 
13.3.2 
Future Analyses ........................................................................................ 44 
13.3.3 
Pharmacokinetic Parameters ..................................................................... 44 
13.3.4 
Analytical Method .................................................................................... 45 
13.4 Blood Volume Drawn for Study Assessments ........................................................ 46 
14 STATISTICAL CONSIDERATIONS .......................................................................... 47 
14.1 Sample Size Determination ..................................................................................... 47 
14.2 Population for Analyses .......................................................................................... 47 
14.3 Statistical Analyses ................................................................................................. 47 
14.3.1 
Safety Analyses ......................................................................................... 47 
14.3.2 
Pharmacokinetic Analyses ........................................................................ 48 
14.3.2.1 Descriptive Statistics ................................................................ 48 
15 STUDY ADMINISTRATION ....................................................................................... 49 
15.1 Ethics ....................................................................................................................... 49 
15.1.1 
Institutional Review Board ....................................................................... 49 
15.1.2 
Ethical Conduct of the Study .................................................................... 49 
15.1.3 
Subject Information and Consent.............................................................. 49 
15.1.4 
Confidentiality .......................................................................................... 49 
15.2 Termination of the Study ......................................................................................... 50 
15.3 Data Quality Assurance ........................................................................................... 50 
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Page 9 
15.4 Direct Access to Source Data/Documents .............................................................. 50 
15.5 Drug Supplies, Packaging and Labeling ................................................................. 50 
15.6 Data Handling and Record Keeping ........................................................................ 50 
15.7 Report Format ......................................................................................................... 51 
15.8 Publication Policy ................................................................................................... 51 
16 REFERENCES ................................................................................................................ 52 
 
LIST OF TABLES 
Table 1: 
Maximum concentration (Cmax) values following single dose 
LOXO-292 (160 mg) administered under fasting conditions ........................ 23 
Table 2: 
Blood Volume during the Study .................................................................... 46 
 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
Page 10 
5 
SYNOPSIS 
Compound: 
LOXO-292 
Clinical Indication: 
Cancer 
Study Phase and Type: 
Phase 1 – Single ascending dose (SAD), safety, and tolerability.  
Study Objectives: 
Primary: 
To assess the safety and tolerability of single oral doses of 
LOXO-292 when administered to healthy adult subjects. 
Secondary: 
To assess the pharmacokinetics (PK) of single oral doses of 
LOXO-292 when administered to healthy adult subjects. 
Summary of Study 
Design: 
This is a Phase I, safety, tolerability, and PK SAD study.   
Up to 3 cohorts are planned for evaluation. In each cohort, 
6 healthy adult subjects are planned for evaluation. Subjects will 
participate in only one cohort. In each cohort, subjects will receive 
a single oral dose of LOXO-292 on Day 1. Cohort 2 and possibly 
Cohort 3 will include a sentinel group of 2 subjects who will be 
dosed at least 48 hours before the remaining 4 subjects. Blood 
samples will be collected for the PK assessment of LOXO-292 in 
plasma for 168 hours postdose. 
Safety and tolerability will be assessed through End of Treatment 
(EOT) or Early Termination (ET) by monitoring adverse events 
(AEs), performing physical examinations, and clinical laboratory 
tests, measuring vital signs, and recording electrocardiograms 
(ECGs).  
Dose escalation to a higher dose level (i.e., next cohort) will not 
take place until the PI and the Sponsor have reviewed all pertinent 
safety/tolerability data (e.g., physical examinations, ECGs, vital 
signs, clinical laboratory tests, and AEs) through a minimum of 
48 hours (Day 3) postdose for Cohort 1 and through a minimum of 
120 hours postdose (Day 5) for Cohort 2 and have determined that 
adequate safety and tolerability from the previous, lower dose, 
cohort has been demonstrated to permit proceeding to the next 
cohort. Bioanalytical data, if available, may be used to guide the 
dose-escalation decision. 
The clinical research unit (CRU) will contact all subjects who 
received LOXO-292 (including subjects who terminate from the 
study early [ET]) at the End of Study (EOS, as defined in the 
Study Events Flowchart, Section 6) by a follow up phone call 
(FU). The EOS/FU phone call will be performed 7 days (± 2 days) 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
12

CONFIDENTIAL 
Number of Subjects: 
Dosage, Dosage F01m, 
Route, and Dose 
Regimen: 
Dose 
Escalation/Stopping 
Criteria 
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
after EOT or ET ( as defined in the Study Events Flowchati, 
Section 6) to detennine if any serious adverse event (SAE) or 
study drng AE has occmTed since EOT or ET. 
Tue study is planned to emoll up to 18 healthy, adult male and 
female ( of non-childbea1ing potential only) subjects (up to 3 
coh01is with 6 subjects in each coho1t). Eve1y attempt will be 
made to emoll at least 1 female in each coho1i. 
Planned dose levels will be as follows: 
Coholi 1: 
320 mg LOXO-292 (4 x 80 mg capsules) on 
Day 1 
Coh01i 2: 
'.S 640 mg LOXO-292 ('.S 8 x 80 mg capsules) on 
Dayl 
Coholi 3: 
'.S 720 mg ('.S 9 x 80 mg capsules) LOXO-292 on 
(Optional) 
Day 1 
Additional cohorts ( 6 subjects per coho1t) may be emolled if it is 
deemed appropriate to repeat any dose level, or to add an interim 
dose level or levels (lower than 720 mg), as determined by the 
Sponsor in consultation with the PI, depending on the safety and 
tolerability results from the prior coh01i(s). Dosing will not exceed 
720 mg in any subject. 
All study drngs will be administered orally after an overnight fast 
with approximately 240 mL of water. Additional water in 
increments of 50 mL up to a maximum of 100 mL may be 
administered if needed by the subject. 
The decision to proceed to the next higher dose administration will 
be made following the review of all peliinent safety/tolerability 
data ( e.g., physical examinations, ECGs, vital signs, clinical 
laboratory tests, and AEs) from all subjects through a minimum of 
48 hours (Day 3) postdose for Coho1t 1 and through a minimum of 
120 hours postdose (Day 5) for Coholi 2. Dose escalation to the 
next dose level (i.e., next coho1t) will not take place until the PI 
and the Sponsor have dete1mined that adequate safety and 
tolerability from the previous, lower dose, coholi has been 
demonstrated to permit proceeding to the next cohort 
Together they will make one of the following determinations: 
1. To continue with the study as planned. 
Page 11 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
13 

CONFIDENTIAL 
CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
2. To continue with the study and add additional safety 
evaluations to subsequent coh01ts. 
3. fu the event of the following occunence: 
One (1) or more subject(s) at a given dose level experiences a 
drng related Common Tenninology Criteria for Adverse 
Events (CTCAE) grade~ 3 toxicity, which is deemed 
clinically significant by the PI or designee with agreement 
from the Sponsor, a decision will be made as follows: 
• 
Continue with the study by repeating the CUITent dose; 
• 
Adjust to an inte1mediate dose between the cmrent dose 
and the next planned dose; 
• 
Adjust to an inte1mediate dose between the cmrent dose 
and the previous lower dose; 
• 
Dose administration may be pe1mitted to continue as 
deemed by PI, in agreement with the Sponsor, where the 
safety parameter assessed does not pose a subject safety 
risk based on safety knowledge from prior LOXO-292 
studies. 
4. fu the event of the following occUITence: 
Two (2) or more subjects in a dose level experience a drng 
related CTCAE grade 
3 toxicity, which are deemed clinically 
significant by the PI or designee with agreement from the 
Sponsor, a decision will be made as follows: 
• 
Dose administration may be pe1mitted to continue as 
planned if deemed acceptable by PI, in agreement with the 
Sponsor, where the safety parameter assessed does not 
pose a subject safety risk based on safety knowledge from 
prior LOXO-292 studies; 
• 
Evaluate an alternative dose level; 
• 
The study may be terminated with no additional dose 
administration to any subjects. 
5. One (1) or more subject(s) in a dose level has a drng related 
SAE, a decision will be made as follows: 
• 
Evaluate an alternative dose level; 
• 
The study will be terminated with no additional dose 
administration to any subjects in any coh01t. 
Bioanalytical data may be used, if available, to guide 
dose-escalation decisions or for selection of an alternate dose for 
evaluation, and/or to confum the sampling schedule. 
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LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments 
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Page 13 
A sufficient period of time will be allowed between Day 3 of 
Cohort 1 and the dose of the next cohort and between Day 5 of 
Cohort 2 and the dose of the next cohort in order for the PI and the 
Sponsor to adequately review the safety and tolerability data from 
the prior cohort. 
Key Assessments: 
Safety: 
All safety assessments, including AEs and SAEs, vital sign 
measurements, clinical laboratory results, physical examination 
results, concomitant medications, and ECG interpretations, will be 
tabulated and summarized where possible, using descriptive 
methodology by treatment and time point. 
Pharmacokinetics: 
The following PK parameters will be calculated for LOXO-292 in 
plasma, as appropriate: AUC0-t, AUC0-24, AUC0-inf, 
AUC%extrap, CL/F, Cmax, Tmax, Kel, t½, and Vz/F. 
Future analysis in plasma for metabolite(s) formation may be 
conducted. 
 
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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
Page 14 
6 
STUDY EVENTS FLOW CHART 
Study Procedure a 
Scr b 
Study Days 
FU/ 
EOS e 
Days → 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
Clinic Discharge/ 
EOT or ET d 
Hours → 
C-I c 
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
12 
24 
36 
48 
72 
96 
120 
144 
168 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviated Physical 
Examination f 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead Safety ECG g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Vital Signs (HR and BP) h 
X 
X 
X i 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs (T) 
X 
X 
X i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hem, Serum Chem j, Coag, 
and UA  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X j 
 
 
 
X 
 
 
X 
 
Thyroid Stimulating 
Hormone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Preg Test (♀ only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum FSH (PMP ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Cotinine 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring k 
X 
X 
ConMeds Monitoring 
X 
X 
Study Drug Administration 
/ PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOXO-292 Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for LOXO-292 l 
 
 
X m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
Page 15 
Study Procedure a 
Scr b 
Study Days 
FU/ 
EOS e 
Days → 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
Clinic Discharge/ 
EOT or ET d 
Hours → 
C-I c 
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
12 
24 
36 
48 
72 
96 
120 
144 
168 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU n 
 
X 
 
Visit  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes: 
a: 
For details on Procedures, refer to Section 13. 
b: 
Within 28 days prior to LOXO-292 administration. 
c: 
Subjects will be admitted to the CRU at C-I (Day -1), at the time indicated by the CRU.  
d: 
To be performed at EOT or at ET. 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 signs, ECGs, clinical safety laboratory results for serum chemistry, hematology, 
coagulation, and urinalysis, and AEs are to be available for review by the PI or designee prior to subject release from the CRU at EOT or ET. 
e:  
To be performed 7 days (± 2 days) following EOT or ET. End of Study (EOS) is defined as when the CRU contacts the subject by phone call 7 days (± 2 days) after EOT or 
ET to determine if any SAE or study drug related AE has occurred since EOT or ET. All subjects who received LOXO-292 (including subjects who terminate the study 
early) will be contacted.  
f: 
Symptom-driven physical examination(s) may be performed at other times, at the PI’s or designee’s discretion. Scheduled abbreviated physical examinations will include, 
at a minimum, examination of respiratory, cardiovascular, and gastrointestinal systems, with the option for further examination of additional systems as necessary based on 
reported symptoms/AEs. 
g: 
Subjects are to be supine for at least 10 minutes prior to ECG assessment. ECGs will be obtained prior to and as close as possible to the scheduled blood draws if scheduled 
at the same time. 
h:  
Vital signs (HR and BP) will be obtained at Screening, C-I (Day -1), predose, and at 2 hours (± 10 minutes) and 4 hours (± 10 minutes) postdose on Day 1, and once daily 
through EOT (or ET). Vital sign measurements should be carried out prior to and as close as possible to having blood drawn. BP and HR will be measured using the same 
arm for each reading.  Subjects are to be supine for at least 5 minutes prior to vital signs assessments.  
i: 
To be performed within 2 hours prior to dosing on Day 1. 
j: 
Samples for serum chemistry will be obtained following a fast of at least 12 hours at Screening and at C-I (Day -1); at other scheduled times, serum chemistry tests will be 
performed after at least an 8-hour fast. However, in case of dropouts or rechecks, subjects may not have fasted for 12 or 8 hours prior to the time that the serum chemistry 
sample is taken. The Day 2 scheduled laboratory assessment must be obtained under fasting conditions. 
k: 
AEs and SAEs will be recorded beginning at informed consent. AEs will be recorded throughout the study (i.e., from signing of the ICF until EOS or ET if the subject 
discontinues from the study and does not complete a follow up 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 PI [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 PI [or designee], or if the event occurs after study 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
17
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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
Page 16 
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 PI (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 call) are to be reported. 
l:  
The sampling windows for PK blood samples will be as follows: within 30 minutes prior to dosing for the predose sample time point; ± 5 minutes for sampling time points 
within the first 12 hours; ± 30 minutes for sampling time points > 12 hours ≤ 36 hours; and ± 60 minutes for the sampling time points from ≥ 48 to ≤ 168 hours.  
m: 
To be performed prior to dosing. 
n: 
Subjects will be confined to the CRU until the completion of 168-hour blood draw and EOT procedures or until completion of ET procedures. 
 
Abbreviations: ♀ = Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, Coag = coagulation, ConMeds = Concomitant medication, 
CRU = Clinical research unit, ECG = Electrocardiogram, EOS = End of Study, EOT = End of Treatment, ET = Early termination, FSH = Follicle-stimulating hormone, 
FU = Follow up, Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart rate, ICF= Informed consent form, PI = Principal Investigator, PMP = Postmenopausal, 
Preg = Pregnancy, PK = Pharmacokinetic, SAE = Serious adverse event, Scr = Screening, T = Temperature, UA = Urinalysis.  
 
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7 
ABBREVIATIONS 
μM 
Micromolar 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-24 
The area under the concentration-time curve, from time 0 to 
Hour 24 
AUC%extrap 
Percent of AUC0-inf extrapolated  
AUC0-t 
Area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration (t) 
AUC0-inf 
Area under the concentration-time curve, from time 0 
extrapolated to infinity 
AV 
Atrioventricular  
BP 
Blood pressure 
BID 
Twice daily 
bpm 
Beats per minute 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CL/F 
Apparent total plasma clearance after oral (extravascular) 
administration 
Cmax 
Maximum observed concentration  
CRF 
Case report form 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FU 
Follow up 
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g 
gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
hERG 
Human ether-a-go-go related gene 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
Inhibitory concentration at 50% 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine device  
Kel 
Apparent terminal elimination rate constant 
kg 
Kilogram 
LFT 
Liver function test 
m2 
Meter squared 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
NCI 
National Cancer Institute  
ng 
Nanogram 
No. 
Number 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QTc 
Corrected value of the interval between the Q and T waves on the 
electrocardiogram tracing 
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RBC 
Red blood cell 
RET 
Rearranged during transfection 
RSI 
Reference Safety Information  
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse events  
Tmax 
Time to reach maximum observed concentration 
t½ 
Apparent terminal elimination half-life 
US 
United States 
USA 
United States of America 
Vz/F 
Apparent volume of distribution during the terminal elimination 
phase after oral (extravascular) administration 
WBC 
White blood cell 
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8 
INTRODUCTION 
8.1 
Background 
8.1.1 
LOXO-292 
LOXO-292 is small molecule and a selective inhibitor of the rearranged during transfection 
(RET) receptor tyrosine kinase designed to competitively block the adenosine triphosphate 
binding site of the kinase. LOXO-292 was at least 250-fold more selective for RET than for 
98% of 329 other kinases tested in a large in vitro screen. Consistent with such a high degree 
of selectivity, LOXO-292 caused significant cytotoxicity in human cancer cell lines that 
harbored endogenous, clinically relevant RET gene alterations but was much less cytotoxic 
against human cancer cell lines without RET alterations. Potent and selective inhibition of 
RET may provide clinical benefit to subjects with malignancies due to oncogenic alterations 
in RET or with other mechanisms of increased RET activity. 
Nonclinical 
Cardiac safety of LOXO-292 was evaluated in a Good Laboratory Practice (GLP) in vitro 
assay for human ether-a-go-go related gene (hERG) activity, in a GLP in vivo study in 
conscious telemetry-instrumented minipigs, and in a GLP 28-day repeat-dose toxicology 
study (with ECG monitoring) in minipigs. LOXO-292 had a 50% inhibitory concentration 
(IC50) value of 1.1 μM in the GLP hERG assay, which is approximately 14- and 6-fold higher 
than the predicted maximum unbound concentration at the dose of 80 mg and 160 mg 
respectively twice daily (BID). There were no LOXO-292-related changes in any 
cardiovascular endpoints including QT interval corrected for heart rate (QTc) at doses up to 
12 mg/kg in the safety pharmacology cardiovascular study in conscious minipigs. 
Furthermore, there were no LOXO-292-related ECG changes in the 28-day repeat-dose 
toxicity study in minipigs at the high dose of 12 mg/kg. Together, these data indicate that 
LOXO-292 has a low risk of inducing delayed ventricular repolarization, prolongation of the 
QTc interval, and unstable arrhythmias. 
Administration of LOXO-292 at single doses up to 45 mg/kg in male rats had no effect on 
respiratory function. 
Potential effects of LOXO-292 on the central nervous system were evaluated as part of the 
GLP 28-day repeat-dose study in rats, in functional observational battery tests and locomotor 
activity assessments. Findings were limited to animals receiving the high dose on week 4 of 
the dosing phase, and were attributed to poor general body condition and weight changes 
associated with LOXO-292 administration rather than specific neurological effects. 
Additionally, no microscopic abnormalities in neuronal tissues were found. 
In toxicology studies of LOXO-292 that were conducted in the rat and minipig, the primary 
pathologic findings for both species were in the tongue, pancreas, bone marrow and 
lymphoid tissues; while the gastrointestinal tract and ovaries were target tissues in minipig. 
Other target tissues identified in the rat included: multi-tissue mineralization, physeal 
cartilage, incisor teeth, lung, Brunner’s gland, and possibly liver. Assessment of doses 
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associated with moribundity/death revealed a steep dose response curve for both species. 
LOXO-292 was not mutagenic in the GLP bacterial mutation assay. When evaluated in two 
in vitro assays, LOXO-292 was not genotoxic. LOXO-292 was not found to be phototoxic 
when evaluated in an in vitro neutral red uptake phototoxicity assay. 
Based on preclinical pharmacology experiments with human cancer cells in vitro and in 
murine xenograft models, meaningful inhibition of RET in tumors is expected to be 
achievable with oral dosing regimens ≥ 40 mg/day. 
Based on the nonclinical profile, including results from animal toxicology studies, theoretical 
risks of human exposure to LOXO-292 include the following: loss of appetite, decrease in 
body weight, increase in total white blood cells, neutrophils, and monocytes, decrease in 
albumin, increase in globulin, decreased albumin:globulin ratio, decrease in total protein, 
increased body temperature, lethargy, increase in cholesterol and triglycerides, increase in 
phosphorus, changes in taste sensation and/or development of xerostomia, gastrointestinal 
symptoms/signs: nausea, vomiting, loose stools, abdominal discomfort, decreases in red cell 
mass (red blood cell [RBC], hemoglobin, hematocrit) and reticulocytes, decrease in platelets, 
increases in liver function tests (alkaline phosphatase, aspartate aminotransferase, and alanine 
aminotransferase) and possible pancreas injury. 
LOXO-292 has been given orally and intravenously to mice, rats, dogs, minipigs, and 
monkey. LOXO-292 was absorbed and bioavailable in all species tested. Solubility studies 
and pharmacokinetic studies suggest that the pharmacokinetic exposure of LOXO-292 may 
be reduced by proton pump inhibitors and other antacids. LOXO-292 appears to be 
metabolized primarily by cytochrome p450 (CYP)3A4, but at therapeutically relevant 
exposures, it is not anticipated to inhibit or induce drug-metabolizing enzymes. LOXO-292 is 
also a substrate for BCRP. 
Refer to the Investigator’s Brochure (IB) for detailed background information on LOXO-292 
(Investigator’s Brochure, Version 4, October 2018). 
Clinical 
LOXO-292 is currently being studied in an ongoing global Phase 1/2 (Study LOXO-
RET-17001) in patients with advanced solid tumors including RET fusion-positive NSCLC, 
RET-mutant medullary thyroid carcinoma, and other tumors with increased RET activity. 
The starting dose of LOXO-292 was 20 mg once daily.  
As of a July 19, 2018 data cut-off date, safety data was available from 153 patients with 
240 mg BID as the highest dose administered. As of this date, two dose-limiting toxicities 
(DLTs) of tumor lysis syndrome and Grade 3 thrombocytopenia at the 240 mg BID dose 
level have been reported. The most frequently reported treatment-emergent adverse events 
(TEAEs; [> 10% of patients]), were dry mouth (20.3%; 14.4% related), diarrhea (15.7%; 
7.2% related), fatigue (15.7%; 11.8% related), constipation (12.4%; 2.6% related), headache 
(11.1%; 3.3% related), and hypertension (10.5%; 3.9% related). Regarding TEAEs, 8 patients 
experienced ≥ Grade 3 TEAEs that were judged by the Investigator as related to study drug. 
Three (3) patients have died within 28 days of their last dose of study drug and no deaths 
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have been attributed to study drug. A small number of patients have experienced Grade 3 or 
higher liver function test (LFT) abnormalities, considered related to the study drug, occurring 
between 20 - 56 days after starting LOXO-292. These changes were asymptomatic and 
resolved with dose interruption. LOXO-292 was resumed at a lower dose following 
normalization of the LFTs.   
As of August 24 2018, PK data were available from 141 patients (from the global Phase 1/2 
study). LOXO-292 is absorbed after oral administration with a median time to maximum 
concentration (Tmax) of approximately 2 hours. Although the PK sampling of LOXO-292 
was not long enough to adequately characterize AUC0-inf, the half-life appears to be 
20 hours. Low concentrations of LOXO-292 were recovered as unchanged drug in urine 
indicating that the kidney contributes to overall clearance. 
As of September 14, 2018, Loxo Oncology has initiated 16 single patient protocols, Special 
Access Scheme, or Temporary Authorization Use cases to provide access to LOXO-292 for 
patients with clinical need not meeting eligibility criteria for the ongoing global Phase 1/2 
study. To date, no TEAEs have been attributed to study drug for these patients. 
Preliminary PK data available from ongoing studies (LOXO-RET-18014 and 
LOXO-RET-18015) being conducted in healthy subjects indicate that LOXO-292 has an 
estimated terminal t½ of approximately 24 hours after a single dose.  
8.2 
Rationale 
8.2.1 Rationale for this Study and Study Design 
When developing new drugs for clinical indications, it is necessary to collect data on the 
safety, tolerability, and PK in order to support further development of the compound as a 
useful clinical candidate and determine dose levels and dose intervals for subsequent studies. 
This study will assess the safety, tolerability, and PK of LOXO-292 in healthy subjects at 
higher dose levels than previously administrated in this population so as to ascertain the 
therapeutic and supratherapeutic exposures of LOXO-292 for the upcoming thorough QT 
study.  
8.2.2 Rationale for the Dose Selection and Dose Regimen 
Single doses of 160 mg are currently being investigated in 2 studies in healthy volunteers in 
which Cmax have been preliminarily determined. LOXO-RET-18014 is a drug-drug 
interaction study evaluating the effects of itraconazole and rifampin on the PK of 
LOXO-292. In LOXO-RET-18015 the effects of food and of a proton-pump inhibitor 
(omeprazole) are being evaluated on the PK of LOXO-292. Preliminary Cmax data was 
reported for LOXO-292 following each study part and data when LOXO-292 was 
administered alone under fasted conditions in these studies are presented in Table 1 (Data on 
file at the time of protocol development).  
 
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Table 1: Maximum concentration (Cmax) values following single dose LOXO-292 
(160 mg) administered under fasting conditions 
LOXO-292 Study Number 
Part 
Sample Size (n) 
Cmax* (ng/mL) 
LOXO-RET-18014 
1 
12 
1656 ± 626 ng/mL 
LOXO-RET-18014 
2 
12 
1458 ± 626 ng/mL 
LOXO-RET-18015 
1 
20 
2223 ± 685 ng/mL 
*Arithmetic mean (AM) ± standard deviation (SD) 
Cmax = Maximum concentration (preliminary data), mL = milliliter, ng = nanogram 
   
Single doses of greater than 160 mg have not been given to healthy subjects and the data 
from Table 1 suggest the single-dose Cmax average value following dose level of 160 mg 
LOXO-292 is approximately 1800 ng/mL.  
In a dose-exposure analysis in cancer patients who received doses of 20 mg once daily to 
240 mg BID in the ongoing Phase 1/2 LOXO-RET-17001 Study, the CL/F of LOXO-292 
decreased with increasing dose strength leading to greater than proportional increases in 
LOXO-292 exposure with increases in LOXO-292 doses. The steady-state Cmax of 
LOXO-292 in cancer patients treated with 160 mg BID, the currently recommended Phase 2 
dose and dose planned for commercialization, is 3320 ± 1220 ng/mL (n=65, Investigator’s 
Brochure, Version 4, October 2018). Based on the data from a single dose of 160 mg when 
administered to healthy subjects, the Cmax of a single dose of 320 mg (the dose selected for 
Cohort 1) is expected to be twice as high as from 160 mg i.e., approximately 3600 ng/mL, 
representing the therapeutic Cmax value expected in patients. The dose of 640 mg was 
selected for Cohort 2 as with linear PK, it is anticipated to produce a Cmax of approximately 
6640 ng/mL, which is approximately twice as high as the Cmax seen in cancer patients 
treated with 160 mg BID LOXO-292 and would be considered the supratherapeutic exposure 
target. 
All AEs reported following LOXO-292 administration in LOXO-RET-18014 were ≤ Grade 2 
in severity and not considered related to LOXO-292. The majority of AEs reported in 
LOXO-RET-18015 were ≤ Grade 2 in severity. There was one Grade 3 event of 
hypertriglyceridemia reported during the study and considered treatment related. Other 
LOXO-292 related events in this study included Grade 1 increased alkaline phosphatase 
(ALP), Grade 2 increased serum amylase, Grade 1 increased alanine aminotransferase 
(ALT), Grade 1 increased aspartate aminotransferase (AST), and Grade 1 dyspepsia (Data on 
file at the time of protocol development).     
8.2.3 Rationale for Primary Endpoints 
The primary endpoint of this study is to assess the safety and tolerability of LOXO-292. 
LOXO-292 has already been administered to healthy subjects (LOXO-RET-18014 and 
LOXO-RET-18015) at a single dose level of 160 mg. As a dose-exposure analysis in cancer 
patients (LOXO-RET-17001) indicated that a reduction in clearance led to greater than 
proportional increases in LOXO-292 exposure with increases in LOXO-292 doses, this study 
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will investigate the safety and tolerability of higher doses (i.e., potential therapeutic and 
supratherapeutic doses) of LOXO-292 when administered to healthy subjects. Ascending 
doses up to and possibly including 720 mg will be investigated. The safety endpoints in the 
study are deemed adequate to detect any safety signals when these higher doses of 
LOXO-292 are administered to healthy subjects.   
8.3 
Risks and/or Benefits to Subjects 
The doses of LOXO-292 administered in this study are not anticipated to induce any 
significant risk or benefit to subjects participating in this study. The dose escalation 
procedures and safety monitoring practices employed by this protocol (i.e., 12-lead ECG, 
vital signs, clinical laboratory tests, AE monitoring, and physical examination) are adequate 
to protect the subjects’ safety. 
There will be no direct health benefit for study participants from receipt of study drug. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at Screening and during the study.
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9 
OBJECTIVES AND ENDPOINTS 
9.1 
Objectives 
Primary: 
To assess the safety and tolerability of single oral doses of LOXO-292 when administered to 
healthy adult subjects. 
Secondary: 
To assess the PK of single oral doses of LOXO-292 when administered to healthy adult 
subjects. 
9.2 
Endpoints 
Safety: 
Safety endpoints will include AEs including the subject incidence, number, and severity of 
TEAEs following single oral doses of LOXO-292 in healthy adult subjects and safety markers 
for 12-lead ECGs, physical examinations, vital signs, and clinical laboratory tests. 
Pharmacokinetics: 
The plasma PK endpoints will include AUC0-t, AUC0-24, AUC0-inf, AUC%extrap, CL/F, 
Cmax, Tmax, Kel, t½, and Vz/F. 
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10 STUDY DESIGN 
10.1 Overall Study Design and Plan 
This is a Phase I, safety, tolerability, and PK SAD study.   
Screening of subjects will occur within 28 days prior to dosing. 
The study is planned to enrol up to 18 healthy, adult male and female (of non-childbearing 
potential only) subjects. Every attempt will be made to enrol at least 1 female in each cohort. 
Up to 3 cohorts are planned for evaluation.  In each cohort, 6 healthy adult subjects are planned 
for evaluation. Subjects will participate in only one cohort. In each cohort, subjects will receive 
a single oral dose of LOXO-292 on Day 1. Cohort 2 and possibly Cohort 3 will include a 
sentinel group of 2 subjects who will be dosed at least 48 hours before the remaining 
4 subjects. Blood samples will be collected for the PK assessment of LOXO-292 in plasma for 
168 hours postdose. 
Safety and tolerability will be assessed through EOT or ET by monitoring AEs, performing 
physical examinations, and clinical laboratory tests, measuring vital signs, and recording 
ECGs.  
Dose escalation to a higher dose level (i.e., next cohort) will not take place until the PI and the 
Sponsor have reviewed all pertinent safety/tolerability data (e.g., physical examinations, ECGs, 
vital signs, clinical laboratory tests, and AEs) through a minimum of 48 hours (Day 3) postdose 
for Cohort 1 and through a minimum of 120 hours postdose (Day 5) for Cohort 2 and have 
determined that adequate safety and tolerability from the previous, lower dose, cohort has been 
demonstrated to permit proceeding to the next cohort. Bioanalytical data, if available, may be 
used to guide the dose-escalation decision. 
Timing of all study procedures are indicated in the Study Events Flow Chart (Section 6). 
Subjects may be replaced at the discretion of the Sponsor. 
10.1.1 Confinement, Return Visits, and Follow-Up 
Subjects will be housed in the CRU through EOT or ET beginning on Day -1, at the time 
indicated by the CRU, until after completion of study procedures on Day 8 (EOT) or ET study 
procedures. EOT is defined as the day on which the subject is released from the CRU, 
following all study procedures (see Study Events Flow Chart, Section 6). Vital signs, ECG, 
clinical safety laboratory results, and AEs are to be available for review by the PI or designee 
prior to release from the CRU at EOT or ET. At all times, a subject may be required to remain 
at the CRU for longer at the discretion of the PI or designee and/or Sponsor.  
The CRU will contact all subjects who received LOXO-292 (including subjects who terminate 
from the study early [ET]) at the EOS (as defined in the Study Events Flowchart, Section 6) 
by a follow up phone call (FU). The EOS/FU phone call will be performed 7 days (± 2 days) 
after EOT or ET (as defined in the Study Events Flowchart, Section 6) to determine if any SAE 
or study drug related AE has occurred since EOT or ET. 
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10.1.2 End of Study Definition 
End of Study (EOS) is defined as the day on which the subject completes the follow up phone 
call (Study Events Flow Chart, Section 6). 
 
Study completion applies to the clinical conduct of the study overall (i.e., last subject’s 
Follow-up phone call). 
 
 
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11 STUDYPOPULATION 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to emollment. The Sponsor will provide approval of subjects for emollment prior to 
dosing. 
11.1 Inclusion Crite.-ia 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study: 
1. Healthy, adult, male or female ( of non-childbearing potential only), 18-5 5 years of age, 
inclusive, at Screening. 
2. Continuous non-smoker who has not used tobacco- and/or nicotine-containing products for 
at least 3 months prior to dosing and through EOT or ET. 
3. Body mass index (BMD 
18.0 and:=:; 32.0 kg/m2 at Screening and have a minimum weight 
of at least 50 kg at Screening. 
4. Medically healthy with no clinically significant medical histo1y, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the PI or designee, and as confirmed 
by the Sponsor. Liver function tests (ALT and AST), semm (total and direct) bilimbin, 
amylase and lipase, and tests for hemoglobin, white blood cells (WBCs), and neutrophils 
must be within the upper limit of n01mal for the laborat01y used by the clinical site at 
Screening and Check-in (Day -I). Rechecks of the liver function tests (ALT and AST), 
sernm (total and direct) bilirnbin, amylase and lipase, and tests for hemoglobin, WBCs, and 
neutrophils will be permitted up to two times to confnm subject eligibility. Subjects may be 
eligible for paiticipation in the study based on rechecked values if the PI (or designee), 
with agreement from the Sponsor, feels that the results are not clinically significant, and 
will not impact study conduct. 
5. A female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to dosing: 
• 
hysteroscopic sterilization; 
• 
bilateral tubal ligation or bilateral salpingectomy; 
• 
hysterectomy; 
• 
bilateral oophorectomy; 
or be postmenopausal with amenoIThea for at least I yeai· prior to dosing and 
follicle-stimulating ho1mone (FSH) semm levels consistent with postmenopausal status. 
6. Males who are capable of fathering a child must agree to use one of the following methods 
of contraception from the time of the dose administration through 6 months after the last 
dose: 
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Male subjects will be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, male subjects must follow the contraception methods 
below: 
a. Male condom with spermicide, and 
b. For a female partner of male study participant: 
l .Intrnuterine device (IUD) (ho1monal IUD; e.g., Mirena®). Copper IUDs 
are acceptable (e.g., ParaGard®); 
2.Established use of oral, implanted, transde1mal, or hmm onal method of 
contraception associated with inhibition of ovulation; or 
3.Bilateral tubal ligation. 
Males who practice tru e abstinence because of a lifestyle choice (i.e., do not become 
abstinent just for the purpose of study pa1t icipation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (e.g., calendar, ovulation, 
symptothe1m al, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the info1med consent 
fo1m (ICF) but becomes sexually active during the study, he must agree to use 
contraception as described above. 
Male subjects should ensure that condoms with spe1micide are used from the time of the 
study drng administr·ation until 6 months after the last dose of study drng when having 
intercourse with female pa1tners who are pregnant or breast feeding. Male subjects are 
required to refrain from donation of spe1m from Check-in (Day -1) until 6 months after the 
last dose of study mug. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do 
not apply. 
Males who have been sterilized, must have confirmed documentation of surgical success 
7. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol. 
11.2 Exclusion Criteria 
Subjects must not be emolled in the study if they meet any of the following criteria: 
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
Screening visit or expected dming the conduct of the study. 
2. History or presence of clinically significant medical or psychiatr·ic condition or disease in 
the opinion of the PI or designee, and as confirmed by the Sponsor. 
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3. History of any illness that, in the opinion of the PI or designee, and as confnmed by the 
Sponsor, might confound the results of the study or poses an additional risk to the subject 
by their pa1ticipation in the study. 
4. History of gastritis, gastrointestinal tract, or hepatic disorder or other clinical condition that 
might, in the opinion of the PI or designee, and as confnmed by the Sponsor, affect the 
absorption, distribution, biotransformation, or excretion of LOXO-292. 
5. History or presence of alcoholism or drng abuse within the past 2 years prior to dosing. 
6. History or presence of hypersensitivity or idiosyncratic reaction to the study dmgs or 
related compounds, or inactive ingredients. 
7. History or presence of: 
• 
liver disease, 
• 
pancreatitis, 
• 
peptic ulcer disease, 
• 
intestinal malabsorption, 
• 
gastric reduction surgery, 
• 
history or presence of clinically significant cardiovascular disease: 
o myocardial infarction or cerebrovascular thromboembolism within 6 months prior 
to dosing 
o symptomatic angina pectolis 
o New York Heart Association Class ~2 congestive heart failure 
o congenital prolonged QT syndrome 
o ventricular pre-excitation syndrome (Wolff-Parkinson White syndrome) 
o anhythmia or history of anhythmia requiring medical intervention 
o ventricular dysfunction or risk factors for Torsades de Pointes (e.g., hea1t failure, 
cardiomyopathy, family history of Long QT Syndrome) 
o significant screening ECG abnormalities: 
left bundle-branch block 
second degree atrioventricular (AV) block, type 2, or third-degree AV block 
Frederica conected QTc (QTcF) interval is >450 msec 
ECG :findings deemed abnormal with clinical significance by the PI or 
designee at Screening and prior to dosing. 
8. Female subjects of childbearing potential. 
9. Female subjects with a positive pregnancy test or who ar·e lactating. 
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10. Positive urine chug or alcohol results at Screening or Check-in (Day -1). 
11. Positive urine cotinine test at Screening or Check-in (Day-1). 
12. Positive results at Screening for human immunodeficiency vims (HIV), hepatitis B surface 
antigen (HBsAg) or hepatitis C vims (HCV). Subjects who are positive for hepatitis B 
vims, HCV, or HIV by antibody will require confirmation by polymerase chain reaction 
(PCR) before emollment to detect presence of active vims. Subjects who are PCR positive 
will not be eligible. 
13. Subjects with at-rest (i.e., supine for at least 5 minutes) diastolic BP of <50 or >89 mmHg 
and/or supine systolic BP of <89 or >139 mmHg at Screening, Check-in (Day -1), and prior 
to dosing. Rechecks of blood pressure values will be permitted up to two times to confirm 
eligibility for study pa1ticipation. Subjects may be eligible for participation in the study 
based on rechecked values if the PI (or designee), with agreement from the Sponsor, feels 
that the results are not clinically significant, and will not impact study conduct. 
14. Supine heart rate is lower than 45 bpm or higher than 99 bpm at Screening, Check-in 
(Day -1 ), and prior to dosing. Rechecks of heart rate values will be permitted up to two 
times to confirm eligibility for study pa1ticipation. Subjects may be eligible for 
participation in the study based on rechecked values if the PI ( or designee ), with agreement 
from the Sponsor, feels that the results are not clinically significant, and will not impact 
study conduct. 
15. Estimated creatinine clearance <90 mL/min at Screening or Check-in (Day -1). 
16. Unable to refrain from or anticipates the use of any dmg, including prescription and 
non-prescription medications, herbal remedies, or natural or vitamin supplements for 
14 days prior to dosing and through EOT or ET, unless allowed by the PI (or designee), 
with agreement from the Sponsor. Hormone replacement therapy (HR T) is not permitted. 
After dosing, acetaininophen (up to 2 g per 24 hours) may be administered at the discretion 
of the PI or designee. 
17. Unable to refrain from or anticipates the use of any inhibitor or inducer of CYP3A4/ AS or 
of P-gp for 28 days prior to dosing and through EOT or ET. Appropriate sources (e.g., 
Flockha1t Table™) will be consulted to confirm lack of PK interaction with study chug. 
18. Unable to refrain from or anticipates the use of proton pump inhibitors, antacids and 
H2-receptor antagonists for 14 days prior to dosing and through EOT or ET. 
19. Unable to refrain from or anticipates the use of any dmgs that prolongs the QT/QTc 
interval for 14 days prior to dosing and through EOT or ET. 
20. Has been on a diet incompatible with the on-study diet, in the opinion of the PI or designee, 
and as confirmed by the Sponsor, within the 30 days prior to dosing and through EOT or 
ET. 
21. Donation of blood or significant blood loss within 56 days p1ior to dosing. 
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22. Plasma donation within 7 days prior to dosing. 
23. Poor peripheral venous access. 
24. Participation in previous investigational trial with LOXO-292. 
25. StTenuous exercise within 5 days prior to Check-in (Day -1). 
26. Dosing in any other investigational study drng trial involving administration of any 
investigational drng in the past 30 days or 5 half-lives (if known), whichever is longer, 
prior to dosing. 
11.3 Early Termination of Subjects from the Study 
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the PI or designee for the following 
reasons: 
• 
AEs. 
• 
Difficulties in blood collection. 
• 
Positive pregnancy test. 
• 
Positive urine chug and alcohol test. 
A subject may be withch·awn by the PI, designee, or the Sponsor if either considers emollment 
of the subject into the study is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons. Prompt notification to the Sponsor of withch·awal of any subject 
should be provided. 
Subjects who withch·aw from the study will undergo early termination from the study 
procedures as outlined in the Study Events Flow Chaii (Section 6). 
11.4 Study Restrictions 
11.4.1 Prohibitions and Concomitant Medication 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 
• 
Xanthines/Caffeine: 24 hours prior to dosing and through EOT or ET (small amounts of 
caffeine derived from n01mal foodstuffs e.g., 250 mL/8 oz.fl cup decaffeinated coffee 
or other decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. 
chocolate bar, per day, would not be considered a deviation to this restriction); 
• 
Alcohol: 48 hours prior to dosing and through EOT or ET; 
• 
Grapefrnit/Seville orange and their juices: 14 days prior to dosing and through EOT or 
ET; 
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• 
Other Frnit Juice: 72 hours prior to dosing and through EOT or ET; 
Participation in any other investigational study drug ti-ial in which receipt of any investigational 
drng occurs within 5 half-lives (if known) or 30 days, whichever is longer, prior to dose 
administration (Day 1) is prohibited. 
Any prescription or over-the-counter medications (including herbal products, natural or 
vitamin supplements) will be prohibited for at least 14 days prior to dosing through EOT or 
ET, unless allowed by the PI (or designee), with agreement from the Sponsor, as described 
below. 
Any prescription or non-prescription medications that are inhibitors or inducers of CYP3A4 
and CYP3A5 or of P-gp will be prohibited for at least 28 days p1ior to dosing through EOT or 
ET. 
Any proton pump inhibitors, H2-receptor antagonists or antacids will be prohibited for 14 days 
prior to dosing and through EOT or ET. 
Any mu gs that prolong the QT/QTc inte1val will be prohibited for 14 days prior to dosing and 
through EOT or ET. 
From Day -1 through EOT or ET, any concmTent medication including both prescription and 
non-prescription mugs must be discussed with the PI (or designee), and/or Sponsor prior to 
use, unless appropriate medical care necessitates that therapy should begin before the PI ( or 
designee) and/or Sponsor can be consulted. HRT is not pennitted. Following study mug 
adininistration on Day 1, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the PI (or designee). 
If deviations occur, the PI or designee in consultation with the Sponsor if needed will decide on 
a case-by-case basis whether the subject may continue pa1ticipation in the study. 
All medications taken (including vitamins and supplements) by subjects during the course of 
the study will be recorded. 
11.4.2 Meals 
Subjects will fast overnight for at least 10 hours prior to study mug adininistration and will 
continue to fast for at least 4 hours postdose. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all 
food and drink except water between meals and snacks. The Day 2 scheduled laboratory 
assessment must be obtained under fasting conditions (i.e., p1ior to the scheduled standard 
breakfast). 
Each meal and/or snacks se1ved at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each period. 
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11.4.3 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when 
they are supine or semi-reclined for study procedures.  
However, should AEs occur at any time during this period, subjects may be placed in an 
appropriate position or will be permitted to lie down on their right side. 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from 5 days prior to Check-in 
(Day -1) until EOT or ET. 
Subjects will not be permitted to smoke or ingest tobacco or nicotine containing products from 
3 months prior to Screening through the EOT or ET. 
 
 
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12 TREATMENTS 
12.1 Treatments Administered 
LOXO-292 will be supplied as 80 mg capsules.  
Subjects in each cohort will receive a single oral dose of LOXO-292 on Day 1 preceded by an 
overnight fast of at least 10 hours and followed by a fast from food (not including water) for at 
least 4 hour postdose. 
Planned dose levels will be as follows: 
Cohort 1: 
320 mg LOXO-292  (4 x 80 mg capsules) on Day 1 
Cohort 2: 
≤ 640 mg LOXO-292 (≤ 8 x 80 mg capsules) on Day 1 
Cohort 3: 
(Optional) 
≤ 720 mg (≤ 9 x 80 mg capsules) LOXO-292 on Day 1 
Additional cohorts (6 subjects per cohort) may be enrolled if it is deemed appropriate to repeat 
any dose level, or to add an interim dose levels or levels (lower than 720 mg), as determined by 
the Sponsor in consultation with the PI, depending on the safety and tolerability results from 
the prior cohort(s). Dosing will not exceed 720 mg in any subject.  
All study drugs will be administered orally after an overnight fast with approximately 240 mL 
of water. Additional water in increments of 50 mL up to a maximum of 100 mL may be 
administered if needed by the subject. 
Subjects will be instructed not to crush, split, or chew LOXO-292 capsules. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject.  
The exact clock time of dosing will be recorded. 
12.2 Dose Modification 
The dose and administration of the study drug to any subject may not be modified unless as 
otherwise decided in accordance to the dose escalation criteria. If necessary a subject must be 
discontinued for the reasons described in Section 11.3. 
12.3 Method of Treatment Assignment 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique randomization identification number at the time of the dosing, different from the 
screening number.  
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All subjects will receive LOXO-292. 
Subjects may be replaced at the discretion of the Sponsor. 
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 001). 
12.4 Blinding 
This is an open-label study. 
12.4.1 Dose Escalation Criteria and Stopping Rules 
The decision to proceed to the next higher dose administration will be made following the 
review of all pe1tinent safety/tolerability data (e.g., physical examinations, ECGs, vital signs, 
clinical laborato1y tests, and AEs) from all subjects through a minimum of 48 homs (Day 3) 
postdose for Coho1t 1 and through a minimum of 120 homs postdose (Day 5) for Coho1t 2. 
Dose escalation to the next dose level (i.e., next coh01t) will not take place until the PI and the 
Sponsor have determined that adequate safety and tolerability from the previous, lower dose, 
coh01t has been demonstrated to pe1m it proceeding to the next cohort. 
Together they will make one of the following dete1minations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations to subsequent coho1ts. 
3. In the event of the following occunence: 
One (1) or more subject(s) at a given dose level experiences a dmg related CTCAE grade 
2'.: 3 toxicity, which is deemed clinically significant by the PI or designee with agreement 
from the Sponsor, a decision will be made as follows: 
• 
Continue with the study by repeating the ctment dose; 
• 
Adjust to an inte1mediate dose between the cunent dose and the next planned dose; 
• 
Adjust to an inte1mediate dose between the cmrent dose and the previous lower dose; 
• 
Dose administration may be pe1m itted to continue as deemed by PI, in agreement with 
the Sponsor, where the safety parameter assessed does not pose a subject safety risk 
based on safety knowledge from prior LOXO-292 studies. 
4. In the event of the following occunence: 
Two (2) or more subjects in a dose level experience a drng related CTCAE grade 2'.: 3 
toxicity, which are deemed clinically significant by the PI or designee with agreement from 
the Sponsor, a decision will be made as follows: 
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• 
Dose administration may be perm itted to continue as planned if deemed acceptable by 
PI, in agreement with the Sponsor, where the safety parameter assessed does not pose a 
subject safety risk based on safety knowledge from prior LOXO-292 studies; 
• 
Evaluate an alternative dose level; 
• 
The study may be terminated with no additional dose administration to any subjects. 
5. One (1) or more subject(s) in a dose level has a drug related SAE, a decision will be made 
as follows: 
• 
Evaluate an alternative dose level; 
• 
The study will be terminated with no additional dose administration to any subjects in 
any cohort. 
Bioanalytical data may be used, if available, to guide dose-escalation decisions or for selection 
of an alternate dose for evaluation, and/or to confirm the sampling schedule. 
A sufficient period of time will be allowed between Day 3 of Cohort 1 and the dose of the next 
cohort and between Day 5 of Cohort 2 and the dose of the next cohort in order for the PI and 
the Sponsor to adequately review the safety and tolerability data from the prior cohort. 
12.5 Treatment Compliance 
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses of LOXO-292. A mouth check will be performed by the qualified designee to ensure that 
the subjects have swallowed the study drng. Once a subject has finished the dosing water, the 
qualified designee will use a flashlight and a tongue depressor to check the subject's mouth. 
Subjects' hands will also be verified to ensure that the study drng was ingested. 
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13 STUDY ASSESSMENTS AND PROCEDURES 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be performed 
at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI or designee and/or the Sponsor for 
reasons related to subject safety. 
For this study, the blood collection for LOXO-292 is the critical parameter and needs to be 
collected as close to the exact time point as possible and in accordance to the time windows 
provided in the Study Events Flowchart (Section 6).  
The Day 2 scheduled laboratory assessment must be obtained under fasting conditions (i.e., 
prior to the scheduled standard breakfast). 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
13.1 Screening 
Within 28 days prior to dosing, medical history and demographic data, including name, sex, 
age, race, ethnicity, body weight (kg), height (cm), BMI (kg/m2) and history of tobacco use 
will be recorded. Each subject will have a physical examination, vital sign measurements (heart 
rate, blood pressure, and temperature), 12-lead ECG, and the laboratory tests of serum 
chemistry, serology, thyroid stimulating hormone, pregnancy (females), FSH (postmenopausal 
females), hematology, coagulation, amylase, lipase, hemoglobin A1c, hepatic function, and 
urinalysis and additional tests as noted in Section 13.2.5. 
13.2 Safety Assessments 
13.2.1 Physical Examination 
Full physical examinations and abbreviated physical examinations will be performed as 
outlined in the Study Events Flow Chart (Section 6). An abbreviated physical examination 
includes, at the minimum, examination of respiratory, cardiovascular, and gastrointestinal 
systems, with the option for further examination of additional systems as necessary based on 
reported symptoms/AEs. Symptom-driven physical examinations may be performed at other 
times, if deemed necessary by the PI or designee.  
13.2.2 Vital Signs 
Single measurements of body temperature, blood pressure, and heart rate, will be measured as 
outlined in the Study Events Flow Chart (Section 6). Additional vital signs may be taken at any 
other times, if deemed necessary. 
Vital sign measurements should be carried out prior to and as close as possible to having blood 
drawn. Blood pressure and heart rate will be measured using the same arm for each reading. 
Blood pressure, heart rate, and temperature measurements will be performed with subjects in a 
supine position (at least 5 minutes),  
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Blood pressure and heart rate will be measured at Screening, at Check-in (Day -I), at predose 
and at 2 hours ( ± IO minutes) and 4 hours ( ± IO minutes) postdose on Day 1, and once daily on 
each Study Day through EOT or ET (CRU discharge). 
Body temperature will be measured at Screening, at Check-in (Day -I), at predose, and at the 
EOT or ET (CRU discharge). 
13.2.3 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chait (Section 6). 
Additional ECGs may be taken at any other times, if deemed necessary by the PI or designee. 
ECGs will be perfmm ed with subjects in a supine position (at least 10 minutes). All ECG 
tracings will be reviewed by the PI or designee. 
ECGs will be measured at Screening, at Check-in (Day -I), Days 2 and 5 postdose, and at the 
EOT or ET (CRU discharge). ECGs will be obtained p1ior to and as close as possible to the 
scheduled blood draws if scheduled at the same time. 
13.2.4 Body Weight 
Body weight (kg) will be reported as outlined in the Study Events Flow Chait (Section 6). 
13.2.5 Clinical Laborntory Tests 
All tests listed below will be perfo1med as outlined in the Study Events Flow Chait (Section 6). 
In addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI or designee. 
Hematology 
Serum Chemistry* 
• 
Hemoglobin 
• 
Blood Urea Nitrogen 
• 
Hematocrit 
• 
Bilimbin (total and direct) 
• 
RBCcount 
• 
ALP 
• 
Platelet count 
• 
AST 
• 
RBC distribution width 
• 
ALT 
• 
Mean corpuscular hemoglobin 
• 
Albumin 
• 
Mean corpuscular hemoglobin 
• 
Calcium 
concentration 
• 
Iron 
• 
Mean corpuscular volume 
• 
Total Protein 
• 
WBC/leukocyte count 
• 
Uric Acid 
• 
WBC/leukocyte differential (absolute and 
• 
Sodium 
percent) 
• 
Potassium 
• 
Basophils 
• 
Magnesium 
• 
Eosinophils 
• 
Chloride 
• 
Lymphocytes 
• 
Glucose (fasting) 
• 
Monocytes 
• 
Creatine kinase 
• 
Neutrophils 
• 
Creatinine** 
• 
Cholesterol (fasting) 
Coagulation 
• 
Triglycerides (fasting) 
• 
Prothrombin Time/International 
• 
Phosphoms 
nonnalized ratio 
• 
Amylase 
• 
Activated partial thromboplastin time 
• 
Lipase 
• 
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Urinalysis 
• 
pH 
Additional Tests 
• 
HIV test**** 
• 
• 
• • 
• 
• 
• 
• 
• 
• 
Color and appearance 
Specific gravity 
Protein*** 
Glucose 
Ketones 
Bili.rubi.n 
Blood*** 
Nitrite*** 
Urobilinogen 
Leukocyte esterase*** 
• 
HBsAg**** 
• 
HCV**** 
• 
Hemoglobin Al e **** 
• 
Urine drug screen 
Opiates 
Opioids (methadone, oxycodone, and 
fentanyl) 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine metabolite 
Methadone 
Cannabinoids 
Phencyclidine 
• 
Urine cotinine 
• 
Urine alcohol screen 
• 
Semm pregnancy test 
(for females only) 
• 
FSH (for postmenopausal females only)**** 
• 
Thyroid stimulating hormone**** 
Samples for sernm chemistiy will be obtained following a fast of at least 12 hours at Screening and at Check-in 
(Day -1); at other scheduled times, senun chemistly tests will be pe1fonned aft.er at least an 8 hour fast. 
However, in case of dropouts or rechecks, subjects may not have fasted for 12 or 8 hours prior to the ti.me that 
the senun chemistly sample is taken. The Day 2 scheduled laboratory assessment must be obtained tmder 
fasting conditions 
At Screening and Day - 1, creatinine clearance will be calculated using the Cockcroft-Gault formula. 
Ifminalysis is positive for protein, blood, nitiite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be pe1fonned. 
Perfonned at Screening only; subjects who are positive for hepatitis B vi.ms, HCV, or HIV by antibody will 
require continuation by PCR. 
13.2.6 Adve1·se Events 
13.2.6.1 
Adverse Event Definition 
An AE means any untoward medical occmTence associated with the use of a chu g in humans, 
whether or not considered chug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
dmg caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the ch11g and the AE. 
An AE can therefore be any unfavorable and unintended sign (including an abnorm al 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
13.2.6.2 
Monitoring 
Subjects will be monitored from Screening ( signing of informed consent) until EOS ( or ET if 
the subject discontinues and does not complete a follow up call) for adverse reactions to the 
study drugs and/or study procedures. At the EOT or ET visit, subjects will be asked how they 
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Page 41 
are feeling prior to check out from the CRU. During the EOS/follow-up phone call, subjects 
will be queried with an open-ended question such as: ‘How have you been feeling since your 
last visit?’. AEs (whether serious or non-serious), including abnormal laboratory test value(s), 
abnormal vital signs, and ECG abnormalities deemed clinically significant and assessed as 
related to study drug by the PI or designee will be evaluated by the PI or designee and treated 
and/or followed through EOT or ET. AEs which are ongoing at the EOT or ET which are 
assessed as related to study drug by the PI (or designee) will be followed through the EOS. 
AEs which are ongoing at the EOS which are assessed as related to study drug by the PI or 
designee may be continued to be followed until the symptoms or value(s) return to normal, or 
acceptable levels, as judged by the PI or designee and confirmed by the Sponsor.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby hospital 
emergency room. Where appropriate, medical test(s) and/or examination(s) will be performed 
to document resolution of event(s). Outcome may be classified as death related to AE, not 
recovered or not resolved, recovered or resolved, recovered or resolved with sequalae, 
recovering or resolving, or unknown. 
13.2.6.3 
Reporting 
AEs and SAEs will be collected beginning at informed consent. AEs will be recorded 
throughout the study (i.e., from signing of the ICF until EOS or ET if the subject discontinues 
and does not complete a follow up 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 PI [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 PI [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 PI (or designee) are to be reported. All SAEs that develop from the time of 
ICF signing until EOS (or ET, if subject discontinues from the study and does not complete the 
follow up call) are to be reported.    
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow up call, all subjects must be followed until the EOS. AEs which are ongoing at the EOS 
which are assessed as related to study drug may be continued to be followed until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the PI or designee 
and confirmed by the Sponsor. The PI (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.  
The PI or designee will review each AE and assess its relationship to drug treatment (yes 
[related] or no [unrelated]).  
Unrelated The time course between the administration of study drug and the 
occurrence or worsening of the AE rules out a causal relationship and 
another cause is suspected 
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Related 
The time course between administration of study drug and the occurrence or 
worsening of the AE is consistent with a causal relationship and no other 
cause can be identified 
 
Each sign, symptom, or abnormal laboratory value reported as an AE will be graded on the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 toxicity grading scale. Only abnormal clinical laboratory results or other events 
deemed to be clinically significant by the PI or designee will be recorded in the database as 
AEs and will be graded utilizing CTCAE guidelines. 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on the following general guideline (NCI 
CTCAE 27 Nov 2017): 
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 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; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A Semi-colon indicates ‘or’ within the description of the grade. 
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.  
ADL=Activities of Daily Living  
* 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. 
13.2.6.4 
Serious Adverse Event 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Title 21, special procedures will be followed. All SAEs will be 
reported to the Sponsor or designee via fax or e-mail within 24 hours of first awareness of the 
event, whether or not the serious event(s) are deemed drug-related. All serious event reporting 
will adhere to 21 CFR 312.32 for Investigational New Drugs (IND) and to the Guidance for 
Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE, dated 
December 2012. Any event that meets the criteria of a suspected unexpected serious adverse 
reaction (SUSAR) will be reported to the Institutional Review Boards/ Independent ethics 
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committee (IRB/IEC) according to site/CRU policy by the Investigator (or designee) and to 
regulatory authorities by the Sponsor (or Sponsor designee) according to regulatory authority 
requirements. Refer to Reference Safety Information (RSI) in the current IB for expected 
adverse reactions. 
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes: Death, a life-threatening AE, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity 
or disability, or a congenital anomaly/birth defect. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based 
upon 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 the above definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI (or 
designee) or Sponsor, places the patient or subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
All SAEs must be reported on a SAE Report Form provided by Loxo Oncology and sent by fax 
or e-mail to the Sponsor listed in Section 3 within 24 hours of first awareness of the event.  
When using the SAE efax (+ 1 203 643-2013) a cover page including study identification 
number and study drug product (i.e., LOXO-292) is required. Alternatively, an email can be 
sent to safety@loxooncology.com. 
The PI is not obligated to actively seek information regarding the occurrence of new SAEs 
beginning after EOS. However, if the PI learns of such an SAE, and that event is deemed 
associated with the use of study drug, he/she should promptly document and report the event. 
The PI will be requested to supply detailed information as well as follow-up regarding the 
SAE. Although not considered an AE per se, the Sponsor must be notified of any subject or 
subject’s partner who becomes pregnant during the study at any time between Screening until 
90 days after study drug administration on Day 1. 
13.3 Pharmacokinetic Assessments 
13.3.1 Blood Sampling and Processing 
For all subjects, blood samples for the determination of LOXO-292 will be collected at 
scheduled time points as delineated in the Study Events Flow Chart (Section 6). Tubes will be 
identified with a barcode using an appropriate label. 
Instructions for blood sampling, collection, processing, and sample shipment will be provided 
separately. 
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Blood collections performed outside of the sample collection windows as defined in the Study 
Events Flow Chart (Section 6) will be considered deviations. 
13.3.2 Future Analyses 
Any residual plasma from the PK samples may be stored by the Sponsor or Bioanalytical 
facility for up to 5 years following dosing of the last cohort and may be used for future 
analyses of plasma for metabolite(s) formation. Tubes will be identified with a barcode using 
an appropriate label. No diseases/conditions, deoxyribonucleic acid, or ribonucleic acid will be 
the focus of these analyses. The analyses will focus on assessing potential metabolites. Any 
additional research on these samples unspecified by this protocol will require approval from 
the subjects. Samples will not be submitted to a public database.  
The sponsor and contract research organizations involved in the clinical conduct, bioanalytical 
analyses and pharmacokinetics and statistical analysis of the data will have access to the 
samples and/or the data that resulted from the analysis, if performed.  
By signing the ICF, subjects agree to the possible future analysis of these samples; however, at 
any time, the subjects can contact the CRU staff to request destruction of the residual samples 
after the LOXO-292 PK assessments required to meet the primary objective of the study are 
completed.  
13.3.3 Pharmacokinetic Parameters 
PK parameters for plasma LOXO-292 will be calculated as follows, as appropriate: 
 
AUC0-t: 
 
The area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method. 
AUC0-24: 
 
The area under the concentration-time curve, from time 0 to Hour 24, as 
calculated by the linear trapezoidal method. If the 24-hour plasma 
concentration is missing, BLQ or not reportable, then this parameter 
cannot be calculated. 
AUC0-inf: 
The area under the concentration-time curve from time 0 extrapolated to 
infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of 
the last measurable plasma concentration to the elimination rate 
constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated, represented as 
(1 - AUC0-t/AUC0-inf)*100. 
CL/F: 
Apparent total plasma clearance after oral (extravascular) 
administration, calculated as Dose/AUC0-inf. 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than one 
time point, Tmax is defined as the first time point with this value. 
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Kel: 
Apparent first-order terminal elimination rate constant calculated from a 
semi-log plot of the plasma concentration versus time curve. The 
parameter will be calculated by linear least-squares regression analysis 
using the maximum number of points in the terminal log-linear phase 
(e.g., three or more non-zero plasma concentrations). 
t½: 
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel. 
Vz/F: 
Apparent volume of distribution during the terminal elimination phase 
after oral (extravascular) administration, calculated as 
(Dose/AUC0-inf) x Kel. 
No value for Kel, AUC%extrap, AUC0-inf, CL/F, Vz/F, or t½ will be reported for cases that 
do not exhibit a terminal log linear phase in the concentration time profile. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations. 
Individual and mean plasma concentration time curves (both linear and log-linear) will be 
included in the final Clinical Study Report. 
13.3.4 Analytical Method 
Samples will be analyzed for plasma LOXO-292 using validated bioanalytical methods. 
Samples from subjects to be assayed are specified in Section 14.2. 
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13.4 Blood Volume Drawn for Study Assessments 
Table 2: Blood Volume during the Study 
Sample Type 
Number of 
Time Points 
Approximate 
Volume per Time 
Point* (mL) 
Approximate 
Sample Volume 
Over Course of 
Study (mL) 
Screening laboratory safety tests (including 
hematology, serum chemistry, coagulation, 
serology, thyroid stimulating hormone, FSH 
(for postmenopausal female subjects only) and 
serum pregnancy (for female subjects only) 
1 
16 
16 
Screening Hemoglobin A1c 
1 
4 
4 
On-study hematology, serum chemistry, and 
coagulation (and serum pregnancy  [for female 
subjects only] if scheduled at same time) 
4 
16 
64 
Blood for LOXO-292 PK 
21 
4 
84 
Total Blood Volume (mL)  
168* 
* 
Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** 
If additional safety or PK analysis is necessary to obtain sufficient plasma/serum for analysis, additional 
blood may be obtained (up to a maximum of 50 mL). 
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14 STATISTICAL CONSIDERATIONS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
14.1 Sample Size Determination 
The sample size chosen for this study was selected without statistical considerations. It has 
been determined adequate to meet the study objectives. 
14.2 Population for Analyses 
Safety Population: All subjects who received at least one dose of the study drug will be 
included in the safety evaluations. 
PK Population: Plasma samples from all subjects will be assayed even if the subjects do not 
complete the study. PK population will comprise all subjects who comply sufficiently with the 
protocol and display an evaluable PK profile (e.g., exposure to treatment, availability of 
measurements and absence of major protocol violations). 
14.3 Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by Celerion 
and agreed upon with the Sponsor. This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoints definition and/or its 
analysis will also be reflected in a protocol amendment. Additional statistical analyses other 
than those described in this section may be performed if deemed appropriate.  
14.3.1 Safety Analyses 
All safety data will be populated in the individual CRFs. All safety data will be listed by 
subjects. 
Dosing dates and times will be listed by subject. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) and 
summarized by treatment for the number of subjects reporting the TEAE. A by-subject AE data 
listing including verbatim term, coded term, treatment, severity, and relationship to treatment 
will be provided.  
Safety data including ECGs, physical examinations, vital signs assessments, clinical laboratory 
results, will be summarized by treatment and point of time of collection.  
Descriptive statistics using appropriate summary statistics will be calculated for quantitative 
safety data as well as for the difference to baseline, when appropriate.  
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Concomitant medications will be listed by subject and coded using the World Health 
Organization drug dictionary. Medical history will be listed by subject. 
14.3.2 Pharmacokinetic Analyses 
14.3.2.1 
Descriptive Statistics 
Values will be calculated for the plasma concentrations and the PK parameters listed in 
Section 13.3.2 for LOXO-292 using appropriate summary statistics to be fully outlined in the 
SAP.  
Mean and individual LOXO-292 concentration-time profiles will be presented on linear and 
semi-log scales. Any additional PK analysis will be outlined in the SAP. 
Dose proportionality may be assessed using the power model approach, as appropriate. Details 
on this regression analysis will be outlined in the SAP.  
 
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15 STUDY ADMINISTRATION 
15.1 Ethics 
15.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB, and the study will not start until the IRB has 
approved the protocol or a modification thereof. The IRB will be constituted and operate in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56) and will be compliant to The International Council on 
Harmonisation (ICH) guidelines. 
15.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration of 
Helsinki, GCP, and the ICH harmonized tripartite guideline regarding GCP (E6[R2] Good 
Clinical Practice: Integrated Addendum to E6 [R1], Nov 2016). 
15.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date 
an ICF summarizing the discussion prior to Screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
15.1.4 Confidentiality 
All members of the Investigator’s staff have signed confidentiality agreements. By signing this 
protocol, the Investigator and investigational staff will regard all information provided by the 
Sponsor and all information obtained during the course of the study as confidential.  
The Investigator must guarantee the privacy of the subjects taking part in the study. Subjects 
will be identified throughout documentation and evaluation by a unique subject study number. 
Throughout the study, a subject’s source data will only be linked to the Sponsor’s clinical 
study database or documentation via a unique identification number. Any information 
concerning the subjects (clinical notes, identification numbers, etc.) must be kept on file by the 
Investigator who will ensure that it is revealed only to the Sponsor, IRB, or regulatory 
authorities for the purposes of trial monitoring, auditing or official inspections. As required, in 
the case of an event where medical expenses are the responsibility of the Sponsor, personal 
information i.e., full name, social security details etc., may be released to the Sponsor. 
Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information in strictest confidence and in accordance with local data. 
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15.2 Termination of the Study 
Celerion reserves the right to terminate the study in the interest of subject welfare. 
The Sponsor reserves the right to suspend or terminate the study at any time. 
15.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant to 
the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, GCP and GLP requirements as well as applicable 
regulatory requirements and local laws, rules and regulations relating to the conduct of the 
clinical study. 
The Clinical Study Report will be audited by the Celerion QA department and the QA audit 
certificate will be included in the Clinical Study Report. 
Edit checks are then performed for appropriate databases as a validation routine using SAS® or 
comparable statistical program to check for missing data, data inconsistencies, data ranges, etc. 
Corrections are made prior to database lock. 
15.4 Direct Access to Source Data/Documents 
Celerion will ensure that the Sponsor, IRB, and inspection by domestic and foreign regulatory 
authorities will have direct access to all CRUs, source data/documents, and reports for the 
purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event that other 
study-related monitoring should be done by other parties, they will be required to sign a 
confidentiality agreement prior to any monitoring and auditing. 
15.5 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of the LOXO-292 capsules to allow completion 
of this study. The lot numbers and expiration dates (where available) of the study drugs 
supplied will be recorded in the final Clinical Study Report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be retained by the CRU, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies remain, this fact 
will be documented in the pharmacy product accountability records. 
15.6 Data Handling and Record Keeping 
Celerion standard CRFs will be supplied. CRFs are produced and may be printed off from the 
database and made available to the designated study team members.  The CRFs are also stored 
electronically. Each CRF book is reviewed and signed by the PI. The final signed CRFs are 
provided to the Sponsor on CD. 
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All raw data generated in connection with this study, together with the original copy of the 
final Clinical Study Report, will be retained by Celerion until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 5 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform Celerion as to when these documents no longer need to be retained. 
15.7 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final Clinical Study Report will be written according to 
the ICH E3 Guideline (Structure and Content of Clinical Study Reports).  
15.8 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 
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16 REFERENCES 
LOXO-292. Investigator’s Brochure. Loxo Oncology, Inc. Version 4.0. 01-Oct-2018. 
National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), 
Revised: Nov-2017 (v5.0). Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf. 
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