Clinical trial NCT05338515
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2019-02-12; Completion date: 2019-03-26
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to determine how safe and how well tolerated selpercatinib is when given as oral doses to healthy participants. The study will also assess how fast selpercatinib gets into the blood stream and how long it takes the body to remove it. The study will last up to about 6 weeks, inclusive of screening period.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 320 mg selpercatinib on Day 1, preceded by an overnight fast of at least 10 hours, followed by a fast from food (not including water) for at least 4 hours post dose. arm 2: Participants received a single oral dose of 640 mg selpercatinib on Day 1, preceded by an overnight fast of at least 10 hours, followed by a fast from food (not including water) for at least 4 hours post dose. arm 3: Participants received a single oral dose of 720 mg selpercatinib on Day 1, preceded by an overnight fast of at least 10 hours, followed by a fast from food (not including water) for at least 4 hours post dose.
Interventions: intervention 1: Selpercatinib
Intervention descriptions: intervention 1: Administered orally.

Protocol documents:
Prot_000.pdf: 
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 
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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 
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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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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
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 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
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 
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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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CA27486 (LOXO-RET-18057), Final Protocol, 25Jan2019 
 
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. 
 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
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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 
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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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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. 
LOXO-RET-18057; CA27486; 16.1.1 Protocol and Protocol Amendments
54

SAP_001.pdf: 
Statistical Analysis Plan 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: 03-Apr-2019


16.1.9 
Documentation of Statistical Methods 
16.1.9.1 
Statistical Analysis Plan 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
1
-
a........._ 
celerion 
Translating Science to 
Medicine 


Statistical Analysis Plan 
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of LOXO-292 in Healthy Adult Subjects
Protocol No: LOXO-RET-18057 
Final Protocol Date: 25 January 2019 
Compound Name: LOXO-292 
Celerion Project CA27486 
Final Version 1.0 
Date: 03 April 2019 
Loxo Oncology, Inc. 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080, USA 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
And 
100 Alexis-Nihon Boulevard, Suite 360, 
Montreal, QC, H4M 2N8, Canada 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
2


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, C1inica1 Study Report No. CA27486 
Statistical Analysis Plan Signature Page 
Compound Name: LOXO-292 
Protocol: LOXO-RET-18057 
Study Title: A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, 
and Pharrnacokine6cs of LOXO-292 in Healthy Adult Subjects 
Issue Date: 03 April 2019 
Signature: 
Signature: 
p 
Date: 
Pl 
n.D. 
Senior Biostatistician I, Data Management and Biometrics 
Celerion, Pl 
USA 
Date: 
Pharmacokinetic Scientist, Clinical Pharmacology and Phannacometrics, 
Data Management and Biometrics 
Celerion, Pl 
, Canada 
03-Apr- 19 I 13 : 31:39 PDT 
Date: -------
1"B~f8fii§~ve mis document 
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'{jning J ime4/3/2019!1,31:33P,MEDJ_ 
. 
C i·r 
. US'A 
. xo ncolo!!v. lnc., :soutll :san !'ranc1sco, a 11on11a, 
1AED9C4257704079AF581F022F7FF518 
Sratistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 2 of88 
3 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 3 of 88 
Table of Contents 
1. INTRODUCTION ..............................................................................................................5 
2. OBJECTIVES AND ENDPOINTS ....................................................................................5 
2.1 Objectives ..................................................................................................................5 
2.2 Endpoints ..................................................................................................................5 
3. STUDY DESIGN ...............................................................................................................6 
4. ANALYSIS POPULATIONS ............................................................................................7 
4.1 Analysis Populations .................................................................................................7 
4.2 Preliminary Data and Interim Analysis .....................................................................7 
5. TREATMENT DESCRIPTIONS .......................................................................................7 
6. PHARMACOKINETIC ANALYSIS .................................................................................8 
6.1 Measurements and Collection Schedule ...................................................................8 
6.2 Bioanalytical Method for LOXO-292 .......................................................................9 
6.3 Investigational Product and PK Analyte Information of LOXO-292 .......................9 
6.4 Pharmacokinetic Concentrations ...............................................................................9 
6.5 Noncompartmental Pharmacokinetic Analysis and Parameter Calculation 
for LOXO-292 ...........................................................................................................9 
6.6 Data Summarization and Presentation ....................................................................11 
6.7 Statistical Analysis of PK Parameters .....................................................................12 
7. SAFETY ...........................................................................................................................13 
7.1 Subject Discontinuation ..........................................................................................14 
7.2 Demographics .........................................................................................................14 
7.3 Adverse Events........................................................................................................14 
7.4 Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation, 
and Urinalysis) ........................................................................................................16 
7.5 Vital Signs (Blood Pressure, Heart Rate, and Temperature) ..................................17 
7.6 ECG (Heart Rate, PR, QRS, QT, and QTcF [QT with Fridericia 
correction]) ..............................................................................................................18 
7.7 Concomitant Medications .......................................................................................19 
7.8 Physical Examination ..............................................................................................19 
8. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS ................19 
9. SUMMARY TABLES AND FIGURES ..........................................................................19 
9.1 In-text Summary Tables and Figures ......................................................................19 
9.2 Section 14 Summary Tables and Figures ................................................................20 
9.3 Section 16 Data Listings .........................................................................................23 
10. TABLE AND FIGURE SHELLS .....................................................................................26 
10.1 In-text Summary Tables Shells ...............................................................................27 
10.2 Figures Shells ..........................................................................................................34 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 4 of 88 
10.3 Section 14 Summary Tables Shells .........................................................................44 
11. LISTING SHELLS ...........................................................................................................63 
 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
1. INTRODUCTION 
The following statistical analysis plan (SAP) provides the framework for the 
summarization of the data from this study. The SAP may change due to unforeseen 
circumstances. Any changes made from the planned analysis within protocol, after 
the unblinding, or locking of the database will be documented in the clinical study 
rep01t (CSR). The section refened to as Table Shells within this SAP describes the 
traceability of the tables, figures, and listings (TFLs) back to the data. Note that the 
header for this page will be the one used for the main body of the CSR. 
Any additional exploratory analyses not addressed within this SAP and/or driven by 
the data, or requested by Loxo Oncology, Inc., will be considered out of scope and 
will be described in the CSR as needed. 
2. OBJECTIVES AND ENDPOINTS 
2.1 
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. 
2.2 
Endpoints 
Safety: 
Safety endpoints will include adverse events (AEs) including the subject incidence, 
number, and severity of treatment-emergent adverse events (TEAEs) following single 
oral doses of LOXO-292 in healthy adult subjects and safety markers for 12-lead 
electrocardiograms (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 VzJF. 
Statistical Analysis Plan, 03 April 2019 
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Page 5 of88 
6 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 6 of 88 
3. STUDY DESIGN  
This will be a Phase I, safety, tolerability, and PK single ascending dose (SAD) study. 
Screening of subjects will occur within 28 days prior to dosing. The study will plan to 
enroll up to 18 healthy, adult male and female (of non-childbearing potential only) 
subjects. Every attempt will be made to enroll at least 1 female in each cohort. 
Up to 3 cohorts will be planned for evaluation, with 6 healthy adult subjects in each 
cohort. 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 Cohort 3 will include 
a sentinel group of 2 subjects who will dose 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 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 
Principal Investigator (PI) and Loxo Oncology, Inc. reviewed all pertinent safety and 
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. Following their 
review, the PI and Loxo Oncology, Inc. will determine that adequate safety and 
tolerability from the previous, lower dose, cohort had been demonstrated to permit 
proceeding to the next cohort. Bioanalytical data, if available, may be used to guide 
the dose escalation decision. Subjects may be replaced at the discretion of the 
Sponsor. 
Subjects will be housed in the clinical research unit (CRU) from Check-in (Day -1), 
at the time indicated by the CRU, until after completion of the 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. 
The CRUs will contact all subjects who received LOXO-292 (including subjects who 
terminate from the study early) at the End of Study (EOS) by a follow up (FU)phone 
call. The EOS/FU phone call will be performed 7 days (± 2 days) after the EOT visit 
or ET visit to determine if any study drug-related adverse event (AE) or serious 
adverse event (SAE) has occurred since the EOT or ET visit. 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
Safety Population 
All subjects who received a dose of study drng will be included in the safety 
evaluations. 
Phumacokinetic Population 
Samples from all subjects will be assayed even if the subjects do not complete the 
study. 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) will be included in the statistical analyses. Data 
for each subject will be included in the summary statistics and statistical comparisons 
of PK parameters with the exceptions described as follows: 
• 
Data from subjects who experience emesis at or before 2 times median Tmax 
for the given treatment during the PK sampling period time course of the 
study for LOXO-292 may be excluded from the summary statistics for the 
given treatment and from the statistical comparison of PK parameters. 
• 
Data from subjects who significantly violate a protocol inclusion or exclusion 
criteria, deviate significantly from the protocol, or have unavailable or 
incomplete data that may influence the PK analysis will be excluded from the 
PK Population. 
Any subject or data excluded from the analysis will be identified, along with the 
reason for exclusion, in the CSR. 
All protocol deviations that occur during the study will be considered prior to 
database lock for their severity/impact and will be taken into consideration when 
subjects are assigned to analysis populations. 
4.2 
Preliminary Data and Interim Analysis 
No interim analysis is planned for this study. 
5. TREATMENT DESCRIPTIONS 
LOXO 292 will be supplied as 80 mg capsules. 
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 instru cted not to crnsh, split, or chew LOXO 292 capsules. 
Statistical Analysis Plan, 03 April 2019 
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Table 5.1 Treatment Descriptions 
Cohort 
Short Description (text, 
tables headers, figures, 
listings, SAS output) 
1 
320 mg 
2 
640mg 
3 
720 mg 
Abbreviated Description 
Administration of 320 mg 
( 4 x 80 mg capsules) 
LOXO-292 on Day 1 
Administration of 640 mg 
(8 x 80 mg capsules) 
LOXO-292 on Day 1 
Administration of 720 mg 
(9 x 80 mg capsules) 
LOXO-292 on Day 1 
Note: additional coh01ts (6 subjects per coh01t) may be emolled if it is deemed appropriate to repeat 
any dose level, or to add an interim dose level(s) (lower than 720 mg), as determined by Loxo 
Oncology, Inc in consultation with the PI, depending on the safety and tolerability results from the 
prior coh01t(s). Dosing will not exceed 720 mg in any subject. The dose increments will be based on a 
review of the safety and (potentially) PK data of previous coho1t s; therefore, the doses listed in this 
table and TFL shells are subject to change. The actual doses used in the study will be depicted in the 
TFLs. 
6. PHARMA CO KINETIC ANALYSIS 
6.1 
Measurements and Collection Schedule 
Blood samples for PK assessment ofLOXO-292 will be taken at the following time 
points on Day 1 for each coh01t: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 
12, 24, 36, 48, 72, 96, 120, 144, and 168 homs postdose. 
All concentration data will be included in the calculation of the individual PK 
parameters, the individual concentration-time plots (based on actual sample times), 
and in the mean concentration-time plots (based on nominal sample times). However, 
if there will be any significant deviations from nominal sample times, some 
concentration data may be excluded from mean concentration-time plots and/or 
additional concentration-time plots of the mean data. All deviations and excluded data 
will be provided and discussed in the CSR. 
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Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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6.2 
Bioanalytical Method for LOXO-292 
Plasma concentrations of LOXO-292 will be determined using a liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) method validated with 
respect to accuracy, precision, linearity, sensitivity, and specificity at Alturas 
Analytics, Inc. (Moscow, Idaho, USA). The analytical range (lower limit of 
quantitation [LLOQ] – upper limit of quantitation [ULOQ]) for LOXO-292 is 1 – 
1000 ng/mL. Samples that contain concentrations greater than 1000 ng/mL may be 
diluted up to 51-fold, if necessary, to be within the quantification range. 
6.3 
Investigational Product and PK Analyte Information of LOXO-292 
LOXO-292 has a molecular weight of approximately 500 g/mol. LOXO-292 will be 
supplied as a powder-in-capsule containing 80 mg of drug substance (freebase) as a 
simple blend with excipients in a hard gelatin capsule.  
6.4 
Pharmacokinetic Concentrations 
Plasma concentrations of LOXO-292 as determined at the collection times and per the 
bioanalytical method described in Section 6.1 and Section 6.2, respectively, will be 
used for the calculation of the plasma LOXO-292 PK parameters. 
6.5 
Noncompartmental Pharmacokinetic Analysis and Parameter Calculation for 
LOXO-292 
The appropriate noncompartmental PK parameters will be calculated from the plasma 
LOXO-292 concentration-time data using Phoenix® WinNonlin® Version 7.0 or 
higher. Actual sample times will be used in the calculations of the PK parameters. 
The calculation of the actual time for LOXO-292 will be in respect to the dose 
administration time of LOXO-292 on Day 1. All PK parameters included in the 
protocol are listed in Table 6.1 below, and are defined as appropriate for study design. 
Table 6.1. Noncompartmental Pharmacokinetic Parameters to be Calculated 
for LOXO-292 
Label to be 
Used in the 
Text, Tables 
and Figures 
Definition 
Method of 
Determination 
AUC0-t 
Area under the concentration-time 
curve, from time 0 to the last 
observed non-zero concentration 
Calculated using the 
Linear Trapezoidal with 
Linear Interpolation 
Method  
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LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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Label to be 
Used in the 
Text, Tables 
and Figures 
Definition 
Method of 
Determination 
AUC0-24 
Area under the concentration-time 
curve from time 0 to 24 hours 
postdose on Day 1. If the 24-hour 
plasma concentration is missing, 
below limit of quantification (BLQ), 
or not reportable, then interpolation or 
extrapolation using the Kel will be 
conducted, as appropriate. If  
extrapolation cannot be performed, 
then this parameter cannot be 
calculated.   
Calculated using the 
Linear Trapezoidal with 
Linear Interpolation 
Method 
AUC0-inf 
Area under the concentration-time 
curve from time 0 extrapolated to 
infinity 
Calculated as  
AUC0-inf = AUC0-t + 
(Clast/Kel) 
where Clast is the last 
observed/measured 
concentration  
AUC%extrap 
Percent of AUC0-inf extrapolated  
Calculated as  
(1-AUC0-t/AUC0-inf) 
*100. 
Cmax 
Maximum observed concentration 
Taken directly from 
bioanalytical data 
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 
Taken from clinical 
database as the 
difference in the time of 
administration and the 
time of the blood draw 
which is associated with 
the Cmax. 
Kel 
Apparent terminal elimination rate 
constant; represents the fraction of 
drug eliminated per unit time  
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  
Calculated as  
0.693/Kel. 
CL/F 
Apparent total plasma clearance after 
oral (extravascular) administration 
Calculated as 
Dose/(AUC0-inf)  
Vz/F 
Apparent volume of distribution 
during the terminal elimination phase 
after oral (extravascular) 
administration 
Calculated as  
Dose/(AUC0-inf x Kel) 
 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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Pharmacokinetic parameters will not be calculated for subjects with fewer than 
3 consecutive postdose time points with quantifiable concentrations. Subjects for 
whom there are insufficient data to calculate the PK parameters will be included in 
the concentration tables only and excluded from the statistical analysis.  
For the calculation of the PK parameters, plasma concentrations BLQ prior to the first 
quantifiable concentration will be set to 0 and plasma concentrations BLQ after the 
first quantifiable concentration will be treated as missing.  
The Kel will be determined using linear regressions composed of least 3 data points. 
The Kel will not be assigned if 1) the terminal elimination phase is not apparent, 2) if 
Tmax is one of the 3 last data points, or 3) if the R2 value is less than 0.75. In cases 
where the Kel interval is not assigned, the values of AUC0-inf, AUC%extrap, t½, 
CL/F, and Vz/F are considered not calculable and will not be reported. Wherever the 
resulting t½ is more than half as long as the sampling interval, the Kel values and 
associated parameters (AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F) may not be 
presented as judged appropriate and in accordance with Celerion SOPs. 
6.6 
Data Summarization and Presentation 
All LOXO-292 PK concentrations and/or PK parameters descriptive statistics will be 
generated using SAS® Version 9.3 or higher. 
The plasma concentrations of LOXO-292 will be listed and summarized by cohort 
and time point for all subjects in the PK Population. Plasma concentrations of 
LOXO-292 will be presented with the same level of precision as received from the 
bioanalytical laboratory. Summary statistics, including sample size (n), arithmetic 
mean (Mean), standard deviation (SD), coefficient of variation (CV%), standard error 
of the mean (SEM), minimum, median, and maximum will be calculated for all 
nominal concentration time points. Excluded subjects will be included in the 
concentration listings, but will be excluded from the summary statistics and noted as 
such in the tables. All BLQ values will be presented as “BLQ” in the concentration 
listings and footnoted accordingly.  
Mean and individual concentration-time profiles will be presented on linear and semi-
log scales. Linear mean plots will be presented with and without SD.  
Plasma LOXO-292 PK parameters will be listed and summarized by cohort for all 
subjects in the PK Population. Pharmacokinetic parameters will be reported to 
3 significant figures for individual parameters, with the exception of Tmax, which 
will be presented with 2 decimal places. Summary statistics (n, arithmetic mean, SD, 
CV%, SEM, minimum, median, maximum, geometric mean [Geom Mean], and 
geometric CV% [Geom CV%]) will be calculated for plasma LOXO-292 PK 
parameters. Excluded subjects will be listed in the PK parameter tables, but will be 
excluded from the summary statistics and noted as such in the tables. 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
The level of precision for each concentration and PK parameter statistic will be 
presented as follows: 
• 
minimum/maximum in same precision as in bioanalytical data and/or 
parameter output, 
• 
mean/median in one more level of precision than minimum/maximum, 
• 
SD/SEM in one more level of precision than mean/median, 
• 
n will be presented as an integer, 
• 
CV% will be presented to the nearest tenth, and 
• 
90% CI will be presented with 2 decimals. 
6.7 
Statistical Analysis of PK Parameters 
If all three cohorts are dosed using different dose levels, dose prop01tionality will be 
evaluated graphically and using a power model. A statistical linear relationship 
between in-transformed LOXO-292 parameters AUC0-t, AUC0-inf, AUC0-24, and 
Cmax and the In-transformed dose will be fitted by using a regression model with ln-
transfonned dose as a covariate. 
Ln(Y) = ~o + ~1 Ln Dose+ t (Model 1) 
where Y represents the PK parameter AUC0-t, A UCO-inf, AUC0-24, and Cmax. 
Dose propo1tionality requires that ~1 = 1 for dose-dependent parameters. 
As a first step, a statistical linear relationship between the ln-transf01med PK 
parameters AUC0-t, AUC0-inf, AUC0-24, and Cmax and the ln-transf01med dose 
will be verified by including a quadratic (ln dose)2 te1m in model. A 5% level of 
significance will be used in sequential testing of the quadratic effect. The statistical 
linear relationship will be concluded if the quadratic te1m is not statistically 
significant at the 0.05 probability level. If the statistical linear relationship is 
established in step 1, a second step will be performed. An estimate of the slope with 
co1Tesponding 90% confidence interval for the quadratic te1m will be obtained from 
the power model. And, a slope around unity indicates the quadratic te1m is found to 
be supported by data; the slope near zero implies the response y is independent of (In 
dose)2. If the quadratic te1m is not suggested from the model in the first step, the 
linear effect in the second step will be evaluated. In the second step, the slope of In 
dose around unit suggests dose-prop01tionality, and the model will be used to 
calculate the 90% Cls for the slope of the ln-transf01med PK parameters AUC0-t, 
AUC0-inf, AUC0-24, and Cmax. 
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Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 13 of 88 
The above assessments of dose proportionality will be performed using the following 
SAS® PROC MIXED code: 
Step 1: To evaluate a quadratic effect: 
PROC MIXED; 
MODEL ln(<PK Parameter>)  =  LDOSE LDOSE*LDOSE / HTYPE=1; 
RUN; 
If the quadratic term is found to be not supported by data in Step 1, and a second step 
will be performed to calculate the 90% CIs for the slope of the ln transformed AUC0-
t, AUC0-inf, AUC0-24, and Cmax parameters. Calculation of the slope and 
associated 90% CI will be performed using the following SAS® PROC MIXED code: 
Step 2: To evaluate a linear effect and to obtain a 90% for the slope parameter: 
PROC MIXED; 
MODEL LPARM = LDOSE / SOLUTION CL ALPHA=0.1 ddfm=kr outp=residuals; 
RUN;  
 
Distributional assumptions underlying the statistical analyses will be assessed by 
visual inspection of residual plots. Normality will be examined by normal probability 
plots, while homogeneity of variance will be assessed by plotting the residuals against 
the predicted values for the model (presented in SAS output). If the assumptions are 
grossly violated then alternative analyses will be performed.  
The following SAS code will be used to plot residuals: 
PROC UNIVARIATE DATA=RESIDUALS PLOT NORMAL; 
VAR RESID; 
HISTOGRAM RESID/NORMAL; 
QQPLOT RESID; 
If data support, plots will be provided showing individual subject values by treatment 
(dose) for each of the PK parameter, together with the predicted PK parameter value 
from the power model. For these plots, individual ln-transformed PK parameter 
values and ln-transformed dose values will be displayed in a scatterplot. The graph 
will display an estimated regression line and 90% CI. The estimated parameters of the 
linear regression (intercept and slope) and their 90% CIs will be included. 
Dose proportionality will be concluded if a statistical linear relationship is 
demonstrated and if the 90% CIs around the slope estimate parameters include the 
value of 1 for dose dependent parameters (AUC0-t, AUC0-inf, AUC0-24, and Cmax).  
7. SAFETY  
No inferential statistics are to be performed for the safety analysis.  
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Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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All clinical safety and tolerability data will be listed by subject and assessment time 
points, including, unscheduled assessments (including rechecks) and early 
termination (ET), chronologically.  
Continuous variables will be summarized using n, mean, SD, minimum, median, and 
maximum. Frequency counts will be reported for categorical data when appropriate.  
The level of precision will be presented as follows: “n” as an integer, 
minimum/maximum in same precision as in the database, mean/median in one more 
precision level than minimum/maximum, and SD in one more precision level than 
mean/median.  
Where individual data points are missing because of dropouts or other reasons, the 
data will be summarized based on reduced denominators. 
When change from baseline is calculated, baseline is the last scheduled assessment 
before dosing in Period 1, including unscheduled assessments, whichever is later. 
Unscheduled assessments and ET measurements taken after first dosing will not be 
used in the summarization. 
Note: The term ‘unscheduled’ assessment used in this SAP also includes recheck 
assessments.  
7.1 
Subject Discontinuation  
Subjects will be summarized by the number of subjects enrolled, completed, and 
discontinued from the study with discontinuation reasons by treatment and overall. 
Discontinuation data will be listed by subject. 
7.2 
Demographics 
Descriptive statistics will be calculated for continuous variables (age, weight, height, 
and body mass index) for study overall. Weight, height and body mass index are 
summarized at screening. Age will be derived from the date of birth to the date of 
dosing in Period 1. Frequency counts will be provided for categorical variables (race, 
ethnicity, and sex) for overall. A by-subject listing will also be provided. 
7.3 
Adverse Events 
All AEs occurring during this clinical trial will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®), Version 21.1.  
Each AE will be graded according to the National Institution of Health’s Common 
Terminology Criteria for Adverse Events (CTCAE, version 5.0) using a 5-point 
severity scale (Grade 1, 2, 3, 4 and 5). Not all grades are appropriate for all AEs. 
Therefore, some AEs may be listed within the CTCAE with fewer than 5 options for 
grade selection. 
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Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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The following clinical descriptions of severity for each AE are based on the following 
general guideline [CTCAE Nov2017]: 
Table 7.3: Adverse Event Severity Level and Description 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention 
indicated; 
limiting 
age-appropriate 
instrumental 
activities of daily living (ADL)*. 
Grade 3  
Severe or medically significant but not immediately life-
threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated. 
Grade 5 
Death related to AE. 
* 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. 
Similarly, the causal relationship of the study drugs to the AE will be described as 
Related or Unrelated to LOXO-292.  
All AEs captured in the database will be listed in by-subject data listings including 
verbatim term, coded term, treatment group, severity grade, relationship to study 
drugs, and action; however, only treatment-emergent AEs (TEAEs) will be 
summarized.  
A TEAE is defined as an undesirable event not present prior to medical treatment, or 
an already present event that worsens either in intensity or frequency following the 
treatment. Each TEAE will be attributed to a treatment based on Investigator (or 
designee) judgment as well as on its onset date and time. If an AE has a change in 
severity grade, the original AE will be given a resolution date and time of the time of 
severity grade increase or decrease and a new AE record will be initiated with the 
new severity grade, and the new AE record will use the resolved date/time of the 
previous record as the onset date/time. If an AE decreases in severity grade, the new 
AE record with less severity will be considered and counted as the same AE event of 
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LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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the previous record with worse severity under the same treatment group in the 
analysis and summary tables. If the severity grade of an AE remains the same, the AE 
will be kept open through to resolution.  
If the onset time of an AE is missing and the onset date is the same as the treatment 
dosing date, then the AE will be considered treatment-emergent. If the onset date of 
an AE is missing, then the AE will be considered treatment-emergent. If the onset 
date of the AE is known to have occurred prior to dosing, then the AE will not be 
treated as a TEAE and will instead be captured as Medical History. 
TEAEs will be tabulated by system organ class and preferred term. Summary tables 
will include the number of subjects reporting the AE and as a percent of the number 
of subjects dosed by treatment and overall. Tables will also be presented by severity 
grade and relationship to study drugs. If a subject experienced the same TEAE more 
than once at a different severity grade for a given treatment, the TEAE will only be 
counted and presented once at the highest severity grade. Similarly, if a subject 
experienced the same TEAE more than once with different assessments of drug 
relationship for a given treatment, only the one considered related to the study drug 
will be counted. 
Should any serious adverse events (SAEs) occur during the study, the SAEs will be 
displayed in a table and a narrative included in the Clinical Study Report. 
7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Coagulation, and 
Urinalysis) 
All clinical laboratory test results will be presented in by-subject data listings. 
However, only serum chemistry, hematology, coagulation and urinalysis values will 
be summarized. 
Hematology, coagulation, serum chemistry and urinalysis tests will be conducted at 
the following time points:   
Table 7.4 Lab Test Time Points 
Study Day 
Screening* 
Day -1 (check-in)*  
Day 2** 
Day 5 
Day 8** * 
 *  performed following a fast of at least 12 hours 
** performed following a fast of at least 8 hours 
*** performed prior to Clinic Discharge/EOT or ET 
 
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LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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Out-of-normal range (OOR) flags will be recorded as follows: high (H) and low (L) 
for numerical results and did-not-match (*) for categorical results. If a value fails the 
reference range, it will automatically be compared to a computer clinically significant 
(CS) range suggested by the PIs (Celerion SOP GSOP.10.1028). If the value falls 
within the computer CS range, it will be noted as “N” for not clinically significant. If 
the value fails (i.e., falls outside of the CS range) the computer CS range, it will be 
flagged with a “Y” which prompts the PI after reviews all laboratory results to 
determine how the OOR value should be followed using 4 Investigator flags: "N", not 
clinically significant, "R", requesting a recheck, "^", checking at the next scheduled 
visit, or "Y", clinically significant. To distinguish the PI flag from the CS range flags, 
the PI flags “N” and “Y” will be presented as “-” and “+” in the data listings, 
respectively. Additionally, a derived flag based on a search of the PI comments for a 
comment of “CS” or “Clinically Significant” will be used. The derived flag will be 
populated with “+” if the positive clinically significant determination is found in the 
comments for cases when the PI flag is populated with a “^” or an “R”. In addition, 
CTCAE, version 5.0 grading (found in NCI CTCAE guidance) will be applied to all 
out of range lab values deemed clinically significant by the Investigator (or designee) 
which are recorded as AEs.  
Out-of-range values and corresponding recheck results will be listed. Other lab results 
within this panel and time point will also be listed for this subject. Results that are 
indicated as CS by the PI (either in the PI flag or in PI comments) will be listed in the 
table.  Out-of-range values laboratory value results which are indicated as CS by PI 
will be reported as AEs.   
For all laboratory values that are numeric, descriptive statistics (n, mean, SD, 
minimum, median, and maximum) will be presented for each laboratory test by 
treatment and time point. Change from baseline will be calculated and summarized 
using the Day -1 check-in value, or in the case of rechecks and unscheduled 
assessments the last non-missing predose measurement prior to dosing of LOXO-292. 
Postdose rechecks, unscheduled assessments, and ET results will not be used for 
calculation of descriptive statistics.  
For each laboratory test, a shift table will be developed comparing the frequency of 
the results at baseline (above normal, normal, or below normal) to postdose results. 
For urinalysis tests, the categories are normal and outside normal. 
All lab results, including unscheduled assessments (including rechecks), will be listed 
by subject. 
7.5 
Vital Signs (Blood Pressure, Heart Rate, and Temperature) 
Vital signs measurements (Blood Pressure [BP], Heart Rate [HR], and Temperature 
[T]) will be taken at the following time points: 
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LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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Table 7.6 Vital Signs Time Points 
Study Day 
Study Hour 
Assessment 
Screening 
  
HR, HR, T† 
Day -1 
Check-in 
HR, BP, T 
Day 1 
0* 
HR, BP, T 
Day 1 
2 
HR, BP 
Day 1 
4 
HR, BP 
Day 1 
24 
HR, BP 
Day 3 
48 
HR, BP 
Day 4 
72 
HR, BP 
Day 5 
96 
HR, BP 
Day 6 
120 
HR, BP 
Day 7 
144 
HR, BP 
Day 8 
168** 
HR, BP, T 
 *  performed within 2 hours prior dosing on Day 1 
** performed prior to Clinic Discharge/EOT or ET 
†HR = heart rate, BP = blood pressure, T = temperature. 
Descriptive statistics will be reported for vital sign measurements (blood pressure and 
heart rate) and change from baseline by treatment and time point. Baseline is Day 1 
predose value, or in the case of unscheduled assessments (including rechecks) is the 
last non-missing predose measurement prior to dosing. Postdose unscheduled 
assessments (including rechecks) and ET results will not be used for calculation of 
descriptive statistics. All vital signs results will be listed by subject. 
7.6 
ECG (Heart Rate, PR, QRS, QT, and QTcF [QT with Fridericia correction]) 
Single 12-lead ECGs measurements will be taken at the following time points:   
Table 7.7: ECG Time Points 
Period Day 
Study Hour 
Screening 
  
Day -1 
Check-in* 
Day 1 
3.5 (Cohorts 2 and 3 only) 
Day 2 
24 
Day 5 
96 
Day 8 
168** 
 *  performed within 24 hours prior dosing on Day 1 
** performed prior to Clinic Discharge/EOT or ET  
 
Descriptive statistics will be reported for ECG parameters and change from baseline 
by treatment and time point. Baseline is Day -1 check-in assessment, or in the case of 
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Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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unscheduled assessments (including rechecks) is the last non-missing predose 
measurement prior to dosing. Postdose unscheduled assessments (including rechecks) 
and  ET results will not be used for calculation of descriptive statistics. All ECG 
interval parameters will be listed by subject and time point of collection with QTcF > 
450 msec and change from baseline > 30 msec flagged. All ECG results will be listed 
by subject. 
7.7 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the WHO 
Dictionary, Version 01-Sep-2018 B3 and listed. 
7.8 
Physical Examination 
A full physical examination will be performed at screening and at Day 8 or upon ET.  
Abbreviated physical examinations will be performed at Check-in (Day -1) and 
1 hour postdose. Symptom-driven physical examinations may be performed at other 
times, at the PI’s or designee’s discretion.  Abnormal findings will be reported as 
medical history or adverse events by the clinical site. Physical examination results 
will be listed by subject and time point.  
8. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS 
The analyses described in this SAP are aligned with those analyses described in the 
protocol.  
9. SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the International Conference on 
Harmonization (ICH) structure but may be renumbered as appropriate during the 
compilation of the tables and figures for the CSR. Note that all summary tables and 
figures will be generated using SAS® Version 9.3 or higher.  
9.1 
In-text Summary Tables and Figures 
The following is a list of table and figure titles that will be included in the text of the 
CSR. Tables and figures will be numbered appropriately during compilation of the 
CSR. 
Section 10: 
Table 10-1 
Subject Disposition (Safety Population) 
Section 11: 
Table 11-1 
Demographic Summary (Safety Population)  
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LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
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Table 11-2 
Summary of Plasma LOXO-292 Pharmacokinetic Parameters 
Following Administration of Single Ascending Doses of LOXO-292 
(Cohorts 1 – 3) (PK Population) 
Table 11-3 
Dose Proportionality Analysis of Plasma LOXO-292 Following 
Administration of Single Ascending Doses of LOXO-292 (Cohorts 1 – 
3) (PK Population)   
Figure 11-1 
Mean Plasma LOXO-292 Concentrations-Time Profiles Following 
Administration of a Single Dose of LOXO-292 (Cohorts 1 – 3) (Linear 
Scale) (PK Population) 
Figure 11-2 
Dose Proportionality of Plasma LOXO-292 AUC0-t Following 
Administration of Single Ascending Doses of LOXO-292 (PK 
Population) (Log Scale) 
Figure 11-3 
Dose Proportionality of Plasma LOXO-292 AUC0-24 Following 
Administration of Single Ascending Doses of LOXO-292 (PK 
Population) (Log Scale) 
Figure 11-4 
Dose Proportionality of Plasma LOXO-292 AUC0-inf Following 
Administration of Single Ascending Doses of LOXO-292 (PK 
Population) (Log Scale) 
Figure 11-5 
Dose Proportionality of Plasma LOXO-292 Cmax Following 
Administration of Single Ascending Doses of LOXO-292 (PK 
Population) (Log Scale) 
Section 12: 
Table 12-1 
Adverse Event Frequency by Treatment - Number of Subjects 
Reporting the Event (% of Subjects Dosed) 
9.2 
Section 14 Summary Tables and Figures 
The following is a list of table and figure titles that will be included in Section 14 of 
the report. Table and figure titles may be renumbered as appropriate during the 
compilation of the report.  
14.1 
Demographic Data Summary Tables  
Table 14.1.1 Summary of Disposition (Safety Population) 
Table 14.1.2 Disposition of Subjects (Safety Population) 
Table 14.1.3 Demographic Summary (Safety Population) 
14.2 
Pharmacokinetic Data Summary Tables and Figures  
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 21 of 88 
14.2.1 Plasma LOXO-292 Tables 
Table 14.2.1.1 Plasma LOXO-292 Concentrations (ng/mL) Following 
Administration of a Single Oral Dose of 320 mg LOXO-292 
(Cohort 1) (PK Population) 
Table 14.2.1.2 Plasma LOXO-292 Concentrations (ng/mL) Following 
Administration of a Single Dose of 640 mg LOXO-292 
(Cohort 2) (PK Population) 
Table 14.2.1.3 Plasma LOXO-292 Concentrations (ng/mL) Following 
Administration of a Single Dose of 720 mg LOXO-292 
(Cohort 3) (PK Population) 
Table 14.2.1.4 Plasma LOXO-292 Pharmacokinetic Parameters Following 
Administration of a Single Dose of 320 mg LOXO-292 
(Cohort 1) (PK Population) 
Table 14.2.1.5 Plasma LOXO-292 Pharmacokinetic Parameters Following 
Administration of a Single Dose of 640 mg LOXO-292 
(Cohort 2) (PK Population) 
Table 14.2.1.6 Plasma LOXO-292 Pharmacokinetic Parameters Following 
Administration of a Single Dose of 720 mg LOXO-292 
(Cohort 3) (PK Population) 
Table 14.2.1.7 Intervals (Hours) Used for Determination of Plasma 
LOXO-292 Kel Values Following Administration of a Single 
Dose of LOXO-292 (Cohorts 1 – 3) (PK Population) 
Table 14.2.1.8 Dose Proportionality Analysis of Plasma LOXO-292 
Following Administration of Single Ascending Doses of 
LOXO-292 (Cohorts 1 – 3) (PK Population) 
14.2.2 Plasma LOXO-292 Figures 
Figure 14.2.2.1 Mean (SD) Plasma LOXO-292 Concentration-Time Profiles 
Following Administration of Single Ascending Doses of 
LOXO-292 (Linear Scale) (PK Population) 
Figure 14.2.2.2 Mean Plasma LOXO-292 Concentration-Time Profiles 
Following Administration of Single Ascending Doses of 
LOXO-292 (Linear Scale) (PK Population) 
Figure 14.2.2.3 Mean Plasma LOXO-292 Concentration-Time Profiles 
Following Administration of Single Ascending Doses of 
LOXO-292 (Semi-Log Scale) (PK Population) 
Figure 14.2.2.4 Dose Proportionality of Plasma LOXO-292 AUC0-t 
Following Administration of Single Ascending Doses of 
LOXO-292 (PK Population) (Log Scale) 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
22


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 22 of 88 
Figure 14.2.2.5 Dose Proportionality of Plasma LOXO-292 AUC0-24 
Following Administration of Single Ascending Doses of 
LOXO-292 (PK Population) (Log Scale) 
Figure 14.2.2.6 Dose Proportionality of Plasma LOXO-292 AUC0-inf 
Following Administration of Single Ascending Doses of 
LOXO-292 (PK Population) (Log Scale) 
Figure 14.2.2.7 Dose Proportionality of Plasma LOXO-292 Cmax Following 
Administration of Single Ascending Doses of LOXO-292 
(PK Population) (Log Scale) 
14.3 
Safety Data Summary Tables  
14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Subjects Reporting Events (% of Subject 
Dosed) (Safety Population) 
Table 14.3.1.2 Treatment-Emergent Adverse Event Frequency by 
Treatment, Severity Grade, and Relationship to Study Drugs 
- Number of Subjects Reporting Events (Safety Population) 
14.3.2 
Listings of Deaths, other Serious and Significant Adverse Events 
Table 14.3.2.1 Serious Adverse Events (Safety Population)  
<If no serious adverse event occurred, a statement ‘There was no serious 
adverse event recorded during the study.’ will be added.> 
14.3.3 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
14.3.4 
Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 Out-of-Range Values and Recheck Results - Serum 
Chemistry (Safety Population) 
Table 14.3.4.2 Out-of-Range Values and Recheck Results – Hematology 
and Coagulation 
Table 14.3.4.3 Out-of-Range Values and Recheck Results – Urinalysis 
Table 14.3.4.4 Clinically Significant Laboratory and Corresponding Results 
(Safety Population) 
14.3.5 
Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 Clinical Laboratory Summary and Change from Baseline – 
Serum Chemistry (Safety Population) 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 23 of 88 
Table 14.3.5.2 Clinical Laboratory Shift from Baseline – Serum Chemistry 
(Safety Population) 
Table 14.3.5.3 Clinical Laboratory Summary and Change from Baseline – 
Hematology (Safety Population) 
Table 14.3.5.4 Clinical Laboratory Shift from Baseline – Hematology 
(Safety Population) 
Table 14.3.5.5 Clinical Laboratory Summary and Change from Baseline – 
Urinalysis (Safety Population) 
Table 14.3.5.6 Clinical Laboratory Shift from Baseline – Urinalysis (Safety 
Population) 
Table 14.3.5.7 Vital Sign Summary and Change from Baseline (Safety 
Population)  
Table 14.3.5.8 12-Lead Electrocardiogram Summary and Change from 
Baseline (Safety Population) 
9.3 
Section 16 Data Listings 
Note: Virology test results (Hepatitis and HIV) that are provided by the clinical 
laboratory will not be presented in subject data listings and will not be included in the 
database transfer. 
Data listings are numbered following the ICH structure but may be renumbered as 
appropriate during the compilation of the TFLs for the CSR. The following is a list of 
appendix numbers and titles that will be included as data listings: 
16.1 
Study Information 
Appendix 16.1.9 
Statistical Methods 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1 
Subject Discontinuation (Safety Population) 
16.2.2 
Protocol Deviations 
Appendix 16.2.2 
Protocol Deviations 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 24 of 88 
16.2.3 
Subjects Excluded from <Pharmacokinetic/Efficacy> Analysis 
Appendix 16.2.3 
Subjects Excluded from <Pharmacokinetic/Efficacy> 
Analysis 
<Note: Appendices 16.2.2 and 16.2.3 are generated in MS Word for inclusion 
in the study report.> 
16.2.4 
Demographic Data 
Appendix 16.2.4.1 
Demographics (Safety Population) 
Appendix 16.2.4.2 
Updated Informed Consent (Safety Population) 
Appendix 16.2.4.3 
Physical Examination (Safety Population) 
Appendix 16.2.4.4 
Medical and Surgical History (Safety Population) 
16.2.5 
Compliance and/or Drug Concentration Data 
Appendix 16.2.5.1.1 Inclusion Criteria   
Appendix 16.2.5.1.2 Exclusion Criteria 
Appendix 16.2.5.2 
Subject Eligibility (Safety Population) 
Appendix 16.2.5.3 
Check-in Criteria and Responses (Safety Population) 
Appendix 16.2.5.4.1 Test Compound Description (Safety Population) 
Appendix 16.2.5.4.2 Test Compound Administration Times (Safety 
Population) 
Appendix 16.2.5.5 
Blood Draw Times (Safety Population) 
Appendix 16.2.5.6 
Meal Times (Safety Population) 
Appendix 16.2.5.7 
Concomitant Medications (Safety Population) 
16.2.6 
Individual Pharmacokinetic Response Data 
Appendix 16.2.6.1 
Individual Plasma LOXO-292 Concentrations Versus 
Time Profiles Following Administration of a Single 
Dose of 320 mg LOXO-292 for Subject X (Cohort 1) 
(Linear and Semi-Log Scale)  
Appendix 16.2.6.2 
Individual Plasma LOXO-292 Concentrations Versus 
Time Profiles Following Administration of a Single 
Dose of 640 mg LOXO-292 for Subject X (Cohort 2) 
(Linear and Semi-Log Scale) 
Appendix 16.2.6.3 
Individual Plasma LOXO-292 Concentrations Versus 
Time Profiles Following Administration of a Single 
Dose of 720 mg LOXO-292 for Subject X (Cohort 3) 
(Linear and Semi-Log Scale) 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
25


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 25 of 88 
16.2.7 
Adverse Events Listings 
Appendix 16.2.7.1 
Adverse Events (I of II) (Safety Population) 
Appendix 16.2.7.2 
Adverse Events (II of II) (Safety Population) 
Appendix 16.2.7.3 
Adverse Event Non-Drug Therapy (Safety Population) 
Appendix 16.2.7.4 
Adverse Event Preferred Term Classification (Safety 
Population) 
16.2.8 
Listings of Individual Laboratory Measurements and Other 
Safety Observations 
Appendix 16.2.8.1.1 Clinical Laboratory Report - Serum Chemistry (Safety 
Population)  
Appendix 16.2.8.1.2 Clinical Laboratory Report - Hematology (Safety 
Population) 
Appendix 16.2.8.1.3 Clinical Laboratory Report - Urinalysis (Safety 
Population) 
Appendix 16.2.8.1.4 Clinical Laboratory Report - Urine Drug Screening 
(Safety Population) 
Appendix 16.2.8.1.5 Clinical Laboratory Report - Other (Safety Population) 
Appendix 16.2.8.1.6 Clinical Laboratory Report - Comments (Safety 
Population) 
Appendix 16.2.8.2 
Vital Signs (Safety Population) 
Appendix 16.2.8.3 
12-Lead Electrocardiogram (Safety Population) 
Appendix 16.2.8.4 
Phone Call (Safety Population) 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
26


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 26 of 88 
10. TABLE AND FIGURE SHELLS  
The following table shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the tables and figures that will be presented and included in the final CSR. Unless 
otherwise noted, all in-text tables will be presented in Times New Roman font size 8 
and post-text tables in Courier New size font 9. These tables will be generated 
according to the ADaM Model 2.1 and ADaM implementation guide 1.1.   
  
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
27


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
10.1 
In-text Summary Tables Shells 
Table 10-1 
Summary of Disposition (Safety Population) 
Disposition 
320mg 
640mg 
F.nrolled 
XX: (100%) 
XX: (100%) 
Completed Study 
XX(XX%) 
XX(XX%) 
Discontinued Early 
XX(XX%) 
XX(XX%) 
<Reason!> 
XX(XX%) 
XX(XX%) 
<Reason2> 
XX(XX%) 
XX(XX%) 
320 mg LOX0-292: Administration of320 mg (4 x 80 mg capsules) LOXO-292 on Day 1 
640 mg LOXO-292: Administration of 320 mg (8 x 80 mg capsules) LOX0-292 on Day 1 
720 mg LOX0-292: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1 
Source: Table 14 .1.1.1 
Program: /CAXXXXX/sas_prg/stsas/intext/t_disp.sas DDMMMYYYY HH:MM 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
720mg 
XX: (100%) 
XX(XX%) 
XX(XX%) 
XX(XX%) 
XX(XX%) 
Overnll 
XX:(100%) 
XX(XX%) 
XX(XX%) 
XX(XX%) 
XX(XX%) 
Page 27 of88 
28 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
Table 11-1 
Demographic Summary (Safety Population) 
Trait 
320mg 
640mg 
Sex 
Male 
XX(XXo/o) 
XX(XXo/o) 
Female 
XX(XX%) 
XX(XX%) 
Race 
Asian 
XX(XXo/o) 
XX(XXo/o) 
Black or African 
XX(XXo/o) 
XX(XXo/o) 
American 
White 
:XX(XX%) 
:XX(XX%) 
Ethnicity 
Hispanic or Latino 
XX(XXo/o) 
XX(XXo/o) 
Not Hispanic or Latino 
XX(XXo/o) 
XX(XXo/o) 
Age• (yr) 
n 
xx 
xx 
Mean 
xx.xx 
xx.xx 
SD 
xx.xxx 
xx.xxx 
Minimum 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
Maximum 
xx.xx 
xx.xx 
Height (cm) 
n 
xx 
xx 
Mean 
xxx.x 
xxx.x 
SD 
x.xx 
x.xx 
Minimum 
XXX 
XXX 
Median 
xxx.x 
xxx.x 
Maximum 
XXX 
XXX 
320 mgLOXO-292: Administration of320 mg (4 x 80 mg capsules) LOXO-292 on Day l 
640 mg LOXO-292: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day l 
720 mg LOXO-292: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day l 
• Age is calculated from the date of first dosing. 
BMI = Body mass index 
Source: Table 14.l.l.3 
Program: /CAXXXXX/sas _prg/stsas/intexttest/t demsas DDMMMYYYY HH:MM 
720mg 
Study Overall 
XX(XXo/o) 
XX(XXo/o) 
XX(XX%) 
XX(XX%) 
XX(XXo/o) 
XX(XXo/o) 
XX(XXo/o) 
XX(XXo/o) 
:XX(XX%) 
:XX(XXo/o) 
XX(XXo/o) 
XX(XX%) 
XX(XXo/o) 
XX(XXo/o) 
xx 
xx 
xx.xx 
xx.xx 
xx.xxx 
xx.xxx 
xx.xx 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.xx 
xx 
xx 
xxx.x 
xxx.x 
x.xx 
x.xx 
XXX 
XXX 
xxx.x 
xxx.x 
XXX 
XXX 
Programmer Note: Weight (kg) and BMI (kg/m2) will also be summarized in the table 
above. 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 28 of88 
29 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Table 11-2 will be in the following fo1mat: 
Table 11-2 Summaiy of Plasma LOXO-292 Phai·macokinetic Pai·ameters Following Administration of Single Ascending Doses of 
LOXO-292 (Coho1ts 1 - 3) (PK Population) 
Pharmacokinetic 
Parnmeters 
320 mg 
640 mg 
720mg 
Paraml (units) 
XXX.X (XX.X) [n=xx] 
XXX.X (XX.X) [u=xx] 
XXX.X (XX.X) [u=xx] 
Paratn2 (units) 
XXX.X (XX.X) [u=xx] 
XXX.X (XX.X) [u=xx] 
XXX.X (XX.X) [u=xx] 
Param3 (units) 
XXX.X (XX.X) [n=xx] 
XXX.X (XX.X) [u=xx] 
XXX.X (XX.X) [n=xx] 
Param4 (units) 
xxx.x (XX.x) [ n=xx l 
xxx.x (XXX) [ u=xx l 
xxx.x (XXX) [ n=xx l 
320 mg LOXO-292: Administration of320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg LOXO-292: Administration of320 mg (8 x 80 mg capsules) LOX0-292 on Day I 
720 mg LOXO-292: Administration of320 mg (9 x 80 mg capsules) LOX0-292 on Day I 
AUCs and Cmax values are presented as geometii c mean and geometric CV%. 
Tmax values are presented as median (min, max). 
Other parameters are presented as arithmetic mean (± SD). 
Source: Tables 14.2.1.4 through 14.2.1.6 
Statistical Analysis Plan, 03 April 2019 
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Page 29 of88 
30 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Notes for Generating the Actual Table: 
Presentati on of Data: 
• 
The foll owi ng PK paramet ers wi ll be presented i n the foll owi ng order and wi t h following uni ts: AUC0-24 (ng*hr / mL), AUCO--t (ng*hr / mL), 
AUCO-inf (ng*hr/ mL), AUC%extrap (%) , Qnax (ng/ mL), Tmax (hr) , Kel (1/ hr), t ½ (hr) , CL/ F (L/ hr), and Vz/ F (L) 
• 
n wi l l be presented as an int eger (wi th no decimal) ; 
• 
Surrrnary statisti cs wi l l be presented wi th same preci sion as defined i n post-text shel l s 
Celerian Note: Per study design needs, the following changes are made to this table relative to Celerian's standard shell: 
1. Add the thi rd treatment column to thi s table and update title 
Program: 
/ CAXXXXX/ sas_prg/pksas/ i ntext- pk- tabl es. sas 
D~ 
HH:M-IJ 
Program: 
/ CAXXXXX/ sas_prg/ pksas/ adam_i nt ext_pkparam. sas 
DDJI.M1YYYY 
HH: M-IJ 
Statistical Analysis Plan, 03 April 2019 
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Page 30 of88 
31 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Table 11-3 will be in the following fo1mat: 
Table 11-3 Dose Proportionality Analysis of Plasma LOXO-292 Following Administration of Single Ascending Doses of LOXO-292 
(Coho1ts 1 - 3) (PK Population) 
Phal'macokinetic 
Estimate of Slope (b) 
Standal'd erl'Ol' 
90% Confidence Interval 
Parameters 
for Slope 
paraml 
x.xxxx 
x.xxxx 
x.xxxx -x.xxxx 
param2 
x.xxxx 
x.xxxx 
x.xxxx -x.xxxx 
oaram3 
x.xxxx 
x.xxxx 
x.xxxx -x.xxxx 
param4 
x.xxxx 
x.xxxx 
x.xxxx -x.xxxx 
Parameters were h1-trnnsfonned ptior to analysis. 
The following statistical model using PROC MIXED of SAS was used to test dose propo1tionality: 
Parameter = a + Dose"b which was equivalent to hl(Parameter) = hl(a) + b[h1(Dose)] 
Dose proportionality is not rejected if the 90% CI for b contains I . 
Som-ce: Table 14.2.1.6 
Statistical Analysis Plan, 03 April 2019 
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Page 31 of88 
32 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Notes for Generating the Actual Table: 
PK Paraneters are AUC0- 24, AUCO- t, AUCO-inf , and Qnax 
Pl ease use the f ootnot e below: 
Paranet ers =re l n- transforned prior to analysi s . 
The foll owi ng stati stical model using PROC MIXED of SAS was used t o test dose proporti onali ty: Paramet er = a * DoseAb which was 
equi valent t o l n (Paramet er) = l n(a ) + b [ln(Dose)] 
Dose proporti onali ty is not rejected i f t he 90% CI f or b contains 1. 
Presentation of Dat a: 
Slq:e will be presented t o 4 decimal places 
Standard error will be presented to 4 decimal pl aces 
90% CI wi l l be presented t o 4 decimal pl aces 
Pr ogr a m: 
/ CAXXXXX/ sas_ p r g / pksas/ doseprop- mixed. sas 
DDMMMYYYY 
HH:MM 
Statistical Analysis Plan, 03 April 2019 
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Page 32 of88 
33 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
Table 12-1 
Treatment-Emergent Adverse Event Frequency by Treatment -
Number of Subjects Reporting the Event (% of Subjects Dosed) (Safety 
Population) 
Treatment 
Adverse Events* 
320 mg 
640 mg 
720mg 
Overnll 
NU11lber of Subjects Dosed 
:XX(100%) 
:XX(100%) 
:XX(100%) 
:XX (100%) 
NU11lber of Subjects With TEAFs 
:XX(XX%) 
:XX(XX%) 
:XX(XX%) 
:XX(XX%) 
NU11lber of Subjects Without 1EAEs 
:XX(XX%) 
:XX(XX%) 
:XX(XX%) 
:XX(XX%) 
System Organ Class 1 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
Preferred Tenn 1 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
Preferred Tenn 2 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
System Organ Class 2 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
X ( X"/o) 
Preferred Tenn 1 
X ( X"/o) 
X(Xo/o) 
X(Xo/o) 
X ( X"/o) 
Preferred Tenn 2 
X(Xo/o) 
X(Xo/o) 
X(Xo/o) 
X ( X"/o) 
320 mg LOX0-292: Administrationof320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg LOX0-292: Administrationof320 mg (8 x 80 mg capsules) LOX0-292 on Day 1 
720 mg LOX0-292: Administrationof320 mg (9 x 80 mg capsules) LOX0-292 on Day 1 
* Adverse events are coded using MedDRA® Version 21. l by System Organ Class and Preferred Tenn. 
1EAE = Treatment-emergent Adverse event 
Although a subject may have had 2 or more clinical adverse experiences, the subject is counted only once within a category. 
The same subject may appear in different categories. 
For an AE with multiple changes in severity, a new record with severity less or equal to its maxinll111l severity will not be 
included in the adverse event summary tables. 
Source: Table 14.3.1.1 
Pro<>rnm: /CAXXXXX/sas or!!/stsas/intexttest/t ae.sas DDMMMYYYY HH:MM 
Programmer Note: S01t by decreasing frequency of system organ class and by prefeITed term 
within a system organ class of Overall column. 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 33 of88 
34 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 34 of 88 
10.2 
Figures Shells 
Figures 11-1 and 14.2.2.2 will be in the following format: 
 
Figure 11-1 
Mean Plasma LOXO-292 Concentrations-Time Profiles Following Administration of Single Ascending Doses of 
LOXO-292 (Cohorts 1 – 3) (Linear Scale) (PK Population) 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
35
2500 
I\ 
l!l 
2000 
1 
A .g 
.; 
1500 
(.J 
A 
0 u 
A 
2l 
1000 
.E:> 
(3---------£] Treatment A: XX mg drug name 
" - - 0 
Treatment B: YY mg drug name 
7> Treatment C: ZZ mg drng name 
--- -G - - -- - ----- - ------- -- - 0 
0 
48 
96 
144 
192 
240 
288 
336 
Hours from Dosing 
Program: /CAXXXXX/sas_J)rg/pksas/adam_meangraph.sas 
DDMMMYYY HH:MM 
Program: /CAXXXXX/sas_J)rg/pksas/meangraph.sas 
DDMMMYYY HH:MM 
384 
432 
480 
528 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
No t es f o r Gener ating the Ac tua l Mean Figure: 
• 
Legend will be "320 mg LOX0-292", "640 rng LOX0-292", and "720 mg LOX0-292" 
• 
Y axis label wi l l be "Pl asma LOX0-292 Concentrati on (ng/ mL) " 
• 
X axi s label wi l l be "Tirre (hr)" 
• 
Add i n footnote: LIDO val ue for LOX0-292 in pl asma is 1.00 ng/ mL 
Progr am: 
/ CAXXXXX/ sas_prg/ pksas/ meangraph.sas 
DIM-MYYYY 
HH:M:11 
Pr ogr am: 
/ CAXXXXX/ sas_ p r g / pksas/ adam_meangraph. sas 
DDMMMYYYY 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
HH: MM 
Page 35 of 88 
36 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 36 of 88 
Figure 14.2.2.1 will be in the following format: 
 
Figure 14.2.2.1 
Mean (SD) Plasma LOXO-292 Concentration-Time Profiles Following Administration of Single Ascending Doses 
of LOXO-292 (Linear Scale) (PK Population) 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
37
3000 
'A 
2500 
I 
,:::: 
0 
·_;:J t g 
u 
,:::: 
0 u 
I\ 
Q) 
.E-l 
0-:: 
2000 
1500 
1000 
500 
G--EJ 
G -
-
El 
0-- ----0 
Treatment A: XX mg dn1g name 
Treatment B: YY mg dn1g name 
Treatment C: ZZ mg dnlg name 
--- - -----
0--qi~-------------------------------------------------
0 
48 
96 
144 
192 
240 
288 
Hours from Dosing 
Treatments B and C are shifted to the right for ease of reading 
336 
Program: /CAXXXXX/sas_prg/pksas/adam_meangraph.sas 
DDMMMYYY HH:MM 
Program: /CAXXXXX/sas_prg/pksas/meangraph.sas 
DDMMMYYY HH:MM 
384 
432 
480 
528 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Notes for Generating the Actual Mean Figure: 
• 
Legend wi l l be "320 mg LOX0-292", "640 rng LOX0-292", and "720 mg LOX0-292" 
• 
Y axis label will be "Pl asma LOX0-292 Concentrati on (ng/ mL)" 
• 
X axis l abel will be "Tirre (hr)" 
• 
Add the followi ng footnote: "640 rng LOX0-292 and 720 rng LOX0-292 are shifted to the right f or ease of reading" 
• 
Add in footnote: LLCQ val ue for LOX0-292 in plasma is 1.00 ng/ mL 
Program: 
/ CAXXXXX/ sas_prg/ pksas/ meangraph.sas 
D~ 
HH:Mvl 
Program: 
/ CAXXXXX/ sas_ p r g / pksas / adam_ meangraph.sas 
DDMMMYYYY 
HH: MM 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 37 of88 
38 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 38 of 88 
Figure 14.2.2.3 will be in the following format: 
 
Figure 14.2.2.3 
Mean Plasma LOXO-292 Concentration-Time Profiles Following Administration of Single Ascending Doses of 
LOXO-292 (Semi-Log Scale) (PK Population) 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
39
10000 
1000 
100 
0 
48 
96 
144 
192 
240 
G-----------EJ 
G -- 0 
0-----<:> 
288 
Hours from Dosing 
Treatment A: XX mg drng name 
Treatment B: YY mg drng name 
Treatment C: ZZ mg drng name 
---0-------------
336 
384 
432 
Program: /CAXXXXX/sas_prg/pksas/adam_meangraph.sas 
DDMMMYYY HH:MM 
Program: /CAXXXXX/sas_prg/pksas/meangraph.sas 
DDMMMYYY HH:MM 
----- -o 
480 
528 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
No t es f o r Gener ating the Ac tua l Mean Figure: 
• 
Legend will be "320 mg LOX0-292", "640 rng LOX0-292", and "720 mg LOX0-292" 
• 
Y axis label wi l l be "Pl asma LOX0-292 Concentrati on (ng/ mL) " 
• 
X axi s label wi l l be "Tirre (hr)" 
• 
Add i n footnote: LIDO val ue for LOX0-292 in pl asma is 1.00 ng/ mL 
Progr am: 
/ CAXXXXX/ sas_prg/ pksas/ meangraph.sas 
DIM-MYYYY 
HH:M:11 
Pr ogr am: 
/ CAXXXXX/ sas_ p r g / pksas/ adam_meangraph. sas 
DDMMMYYYY 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
HH: MM 
Page 39 of 88 
40 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Figures 11-2 through 11-5 and 14.2.2.4 through 14.2.2.7 will be in the following f01mat: 
Figure 11-2 
Dose Proportionality of Plasma LOXO-292 AUC0-t Following Administration of Single Ascending Doses of 
LOXO-292 (PK Population) (Log Scale) 
*** Note: this is not a Celerion standard figure *** 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 40 of 88 
41 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Notes for Generating the Actual Mean Figure: 
• 
Legend wi l l be "320 mg LOX0-292", "640 rng LOX0-292", and "720 mg LOX0-292" 
• 
Y axis label will be "AUC0-24 (ng*hr/ mL), AUC0- t 
(ng*hr/ mL), AUC0-inf (ng*hr/ mL) , and Qnax (ng/ mL)" as appropri ate (Log scale) 
• 
X axis wi ll be "LOX0-292 Dose (rng)" (Log scale) 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 41 of88 
42 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 42 of 88 
Appendix 16.2.6.1 
 
Individual Plasma LOXO-292 Concentration-Time Profiles Following Administration of 
a Single Dose of 320 mg LOXO-292 for Subject X (Cohort 1) (Linear and Semi-Log Scale) 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
43
3000-
2500 -
2000 -
1500-
1000 -
500 -
0 -
0 
48 
96 
144 
0 
48 
96 
144 
Linear Scale 
192 
240 
288 
Hours from Dosing 
Semi-Log Scale 
192 
240 
288 
Hours from Dosing 
BBB Treatment A: XX mg chug name 
e-e-e Treatment B: YY mg chug name 
Treatment C: ZZ mg chug name 
336 
384 
432 
480 
528 
336 
384 
432 
480 
528 
Program: /CAXXXXX/sas__prg/pksas/adam_indgraph.sas 
DDMMMYYY HH:MM 
Program: /CAXXXXX/sas__prg/pksas/indgraph-all.sas 
DDMMMYYY HH:MM 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Rep01t No. CA27486 
Notes for Generating the Actual Individual Figure: 
• 
Use same format for Appendix 16.2.6.1 through 16.2.6.3 
• 
legend will be "320 rrg LOX0-292" for Appendix 16.2. 6. 1 
• 
legend will be "640 rrg LOX0-292" for Appendix 16.2. 6. 2 
• 
legend will be "720 rrg LOX0-292" for Appendix 16.2. 6.3 
• 
Y axis l abel wi l l be "Plasma LOX0-292 Concentrati on (ng/ mL)" 
• 
X axis l abel wil l be "Hours" 
• 
Adi in footnote: LLOQ val ue for LOX0-292 in plasma i s 1. 00 ng/ mL 
Program: 
Program: 
/ CAXXXXX/ sas_prg/ pksas/ indgraph- all.sas 
/ CAXXXXX/ sas_prg/pksas/ adarn_indgraph.sas 
Statistical Analysis Plan, 03 April 2019 
DJ:Ml,1,!YYYY 
HH:MVI 
DI::MMYYYY 
HH: MJI 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 43 of88 
44 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
10.3 
Section 14 Summary Tables Shells 
Tabl e 14 .1. 1 Surrma:ry of Disposi t i on 
Di sposition 
320 rrg 
Enrolled 
X 
Caipl eted 
X 
Di scontinued Earl y 
X 
Feason 1 
X 
Feason 2 
X 
Feason 3 
X 
etc. 
(Safety Popul ati on) 
640 rrg 
X 
X 
X 
X 
X 
X 
Note: 320 rrg: Admini strati on of 320 rrg (4 x 80 rrg capsules) IDX0--292 on Day 1 
640 rrg: Administrati on of 320 rrg (8 x 80 rrg capsules) LOX0--292 on Day 1 
720 rrg : Administrati on of 320 rrg (9 x 80 rrg capsules) LOX0--292 on Day 1 
Program: 
/ CAXXXXX/ sas_p r g / stsas/ tab_PROGRAMNAME . sas 
DDMMMYYYY 
HH: MM 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
720 rrg 
Overall 
X 
xx 
X 
xx 
X 
xx 
X 
xx 
X 
xx 
X 
xx 
Page X of X 
Page 44 of88 
45 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 45 of 88 
 
 
Page X of X 
Table 14.1.2  Disposition of Subjects (Safety Population) 
 
 
                                                                                             Study Completion        
             Subject                                                           ------------------------------------------ 
             Number      Treatment         Dosed            Completed           Status                          Date    
             ------------------------------------------------------------------------------------------------------------ 
             XXX-XXX      XXX mg           Yes              Yes                 Completed Study                 DDMMYYYY 
             XXX-XXX      XXX mg           Yes              No                  Withdrew Consent                DDMMYYYY 
               
 
 
 
Note: 320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
46


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Table 14.1. 3 Derrographic Surrmary (Safety Populati on) 
Tra i t 
320 mg 
Sex 
Male 
X ( XX%) 
Female 
X ( XX%) 
Race 
Asian 
X ( XX%) 
Black or African American 
X ( XX%) 
White 
X ( XX%) 
Ethni ci ty 
Hispani c or Latino 
X ( XX%) 
Not Hispanic or Lati no 
X ( XX%) 
Age* (yr) 
n 
xx 
~an 
xx.x 
SD 
x.xx 
Minirrrum 
xx 
Median 
xx.x 
Maxirrrum 
xx 
Height (an) 
n 
xx 
~an 
xx.x 
SD 
x.xx 
Minirrrum 
xx 
Median 
xx.x 
Maxirrrum 
xx 
Programner Note: Also include wei ght (kg) and BMI (kg/ m2) 
Note : * Age i s calculated f rom the date of first dosing. 
BMI = Body mass index 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg: Admini strati on of 320 mg (8 x 80 mg capsules) LOX0-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOX0-292 on Day 1 
Progr am: 
/ CI\XXXXX/sas_prg/ stsas/tab_PRCGRAMNAME.sas 
D[)M,f.1YYYY 
HH:M-1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
640 mg 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
72 0 mg 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
Page 1 of X 
Study 
Overal l 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X ( XX%) 
X 
X 
( XX%) 
( XX%) 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
Page 46 of88 
47 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 47 of 88 
Tables 14.2.1.1 through 14.2.1.3 will be in the following format:  
 
 Table 14.2.1.1 Plasma LOXO-292 Concentrations (ng/mL) Following Administration of a Single Dose of 320 mg LOXO-292 (Cohort 1) (PK Population)       
 
Subject 
------------------------------- Sample Times (hr) ------------------------------ 
 
Number 
Predose 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
------------------------------------------------------------------------------------------------------ 
X 
BLQ 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
BLQ 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
BLQ 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
------------------------------------------------------------------------------------------------------ 
n 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
CV% 
. 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SEM 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Minimum 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Maximum 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
------------------------------------------------------------------------------------------------------ 
For the calculation of summary statistics, values that are below the limit of quantitation (BLQ) of 1 ng/mL are treated as 0 
before the first quantifiable concentration and as missing elsewhere. 
. = Value missing or not reportable.  
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
48


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 48 of 88 
Notes for Generating the Actual Table: 
 
Presentation of Data: 
Concentrations will be presented to same precision as in bio data.  
Summary statistics presentation with respect to the precision of the bio data: n = integer; Mean and Median +1; SD and SEM +2, Min and Max 
+0, CV% to 1 decimal 
 
Programmer Note:  
PK Time points are: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose.   
 
 
Per study design needs, the following changes are made to this table relative to Celerion standard: 
1. Please remove the <Treatment Sequence> and <Study Period> columns from all tables. 
 
 
Program:  /CAXXXXX/sas_prg/pksas/pk-conc-tables.sas   
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/pk-conc-tables-sig.sas   
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_conc.sas   DDMMMYYYY  HH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
49


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 49 of 88 
Tables 14.2.1.4 through 14.2.1.6 will be in the following format: 
 
Table 14.2.1.4 Plasma LOXO-292 Pharmacokinetic Parameters Following Administration of a Single Dose of 320 mg LOXO-292 (Cohort 1) (PK Population)      
  
                              ---------------------------------- Parameters -------------------------- 
Subject 
param1 
param2 
param3 
param4 
param5 
param6 
Number 
(units) 
(units) 
(units) 
(units) 
(units) 
(units) 
    --------------------------------------------------------------------------------------------------- 
X 
XXX 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
X 
XX.X 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
X 
XXX 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
X 
XX.X 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
X 
XX.X 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
X 
X.XX 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
X 
XXX 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
    --------------------------------------------------------------------------------------------------- 
n 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
XXX.X 
X.XXX 
XXX.X 
XXX.X 
XX.XX 
X.XXXX 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SEM 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
Minimum 
XX.X 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
Median 
XX.XX 
X.XXX 
XXX.X 
XXX.X 
XX.XX 
X.XXXX 
Maximum 
XXX 
X.XX 
XXX 
XXX 
XX.X 
X.XXX 
Geom Mean 
XXX.X 
X.XXX 
XXX.X 
XXX.X 
XX.XX 
X.XXXX 
Geom CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    --------------------------------------------------------------------------------------------------- 
         . = Value missing or not reportable. 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
50


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Notes for Generating the Actual Table: 
Presentati on of Data: 
• 
PK Pararreters will l::e presented i n the following order and with following units: AUC0-24 (ng*hr/ mL), AUCO-t (ng*hr/ mL), AUCO-inf 
(ng*hr/ mL), AUC%extrap (%), Onax (ng/ mL), Tinax (hr) , Kel (1/ hr) , tl/ 2 (hr) , CL/F (L/ hr), and Vz/ F (L) 
• 
n wi l l l::e presented as an integer (wi th no decimal ); 
• 
Paraneter values f or exposure based parameters (i.e. AUCs, Cmax, Vz/ F, and CL/ F) wi l l be presented with, at maximum, the precision of 
the bio data, and, at minimum, 3 s i gnifi cant f i gures (to l::e determined by the PKist once bio data are recei ved) . Surrmary statistics 
for exposure pararreter s will l::e presented as: 1-ean, 1-edian, and Gean 1-ean+l; SD and SEM +2, Min and Max +0. 
• 
Val ues for time-based pararreters (i .e . Tmax and tl/ 2) wi l l be presented with 2 decimal s . Surrmary statistics for tine-based parameters 
will l::e presented as: 1-ean, Median, and Gean Mean +1; SD +2, Min and Max +0. 
• 
Val ues for rate constants (i .e. Kel ) wi l l l::e presented wi t h 3 s i gnifi cant figures. Surmary stati stics for Kel wil l l::e presented as: 
1-ean, Median, and Gean Mean +1; SD and SEM +2, Min and Max +0. 
• 
CV% and Gean CV% for all pararreters wi ll l::e presented with 1 decimal 
Per study design needs, the following changes are made to this table relative to Celerion standard: 
1 . 
Pl ease remove the "Treatnent Sequence" and "Study Peri od" col umns. 
Progr am: 
/ CAXXXXX/ sas_prg/ pksas/ pk-tables .sas 
D!MfflYYY 
HH:t-M 
Pr ogram: 
/ CAXXXXX/ sas_ p r g / pksas/ adam_pkparam . sas 
DDMMMYYYY 
HH:MM 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 50 of88 
51 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Table 14.2.1.7 will be in the following format: 
Table 14.2. 1.7 Intei:vals (Hours) Used for Determination of Plasma IDX0-292 Kel Values Folla,.,ing Adninistrati on of a Singl e Dose of IDX0-292 
(Cohorts 1 - 3) (PK Population) 
Subject 
Nu!ter 
Treatrrent 
Interval 
R2 
n 
X 
X 
xx.x - xx.x 
x.xxx 
X 
X 
X 
xx.x - xx.x 
x.xxx 
X 
X 
X 
xx.x - xx.x 
x.xxx 
X 
X 
X 
xx.x - xx.x 
x.xxx 
X 
X 
X 
xx.x - xx.x 
x.xxx 
X 
X 
X 
xx.x - xx.x 
x.xxx 
X 
320 m:i-: Administrati on of 320 m:i- (4 x 80 mg capsules) IDX0-292 on Day 1 
640 m:i-: Administrati on of 640 m:i- (8 x 80 mg capsules) IDX0-292 on Day 1 
720 mg: Adnini strati on of 720 mg (9 x 80 ITT:)" capsules) LOX0-292 on Day 1 
R2 = Coeffi cient of determination 
n = Number of points used in Kel calculation 
. = Kel val ue not reportable. 
Notes for Generating the Actual Table: 
Presentat i on of Data: 
I ntei:val start and stop times wi l l be presented t o 1 decimal or 3 sig figures min; 
R2 wil l be presented to 3 decimals; 
n wi l l be presented as an integer (with no decimal ) 
Progr am: 
Program: 
/ CAXXXXX/sas_prg/ pksas/ kel-tables- parallel. sas 
/ CAXXXXX/ sas_ p r g / pksas/ adam_ kel . sas 
Statistical Analysis Plan, 03 April 2019 
DDJIMl1YYYY 
HH: M-1 
DDMMMYYYY 
HH:MM 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 51 of88 
52 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Table 14.2.1.8 will be in the following format: 
Table 14.2.1.8 Dose Proportionality Analysi s of Plasrra IDX0-292 Folla-1ing Adninistration of Singl e Ascending Doses of IDX0-292 (Cohorts 1 - 3) (PK 
Population) 
Phannacokinetic 
Estimate of Slope 
Parameters 
Paraml 
Param2 
Param3 
Presentation of Data: 
Slope will be presented to 4 decimal places 
Standard error will be presented to 4 decimal pl aces 
90% CI will be presented to 4 decimal places 
Statistical Analysis Plan, 03 April 2019 
(b) 
x.xxxx 
x.xxxx 
x.xxxx 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Standard 
Error 
x.xxxx 
x.xxxx 
x.xxxx 
90% Confidence Interval 
for Sl ope 
x.xxxx - x.xxxx 
x.xxxx - x.xxxx 
x.xxxx - x.xxxx 
Page 52 of88 
53 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 53 of 88 
Notes for Generating the Actual Table: 
 
Programmers Note: 
PK Parameters are AUC0-24, AUC0-t, AUC0-inf, and Cmax 
 
Please use the footnote below: 
Parameters were ln-transformed prior to analysis.        
The following statistical model using PROC MIXED of SAS was used to test dose proportionality: Parameter = a * Dose^b which was 
equivalent to ln(Parameter) = ln(a) + b[ln(Dose)] 
Dose proportionality is not rejected if the 90% CI for b contains 1. 
 
 
 
Program:  /CAXXXXX/sas_prg/pksas/doseprop-mixed.sas   
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_dosepropmixed.sas   
DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
54


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 54 of 88 
Page 1 of X 
 
Table 14.3.1.1  Treatment-emergent Adverse Event Frequency by Treatment – Number of Subjects Reporting Events (% of Subject Dosed) (Safety 
Population) 
 
TE Adverse Event*                                      320 mg              640 mg              720 mg        Overall 
 -------------------------------------------------------------------------------------------------------------------- 
 Number of Subjects Dosed                              X (100%)            X (100%)            X (100%)       X(100%) 
 Number of Subjects with TE Adverse Events             X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
 Number of Subjects without TE Adverse Events          X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
 -------------------------------------------------------------------------------------------------------------------- 
 Nervous system disorders                              X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Dizziness                                           X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Headache                                            X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Presyncope                                          X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
 Respiratory, thoracic and mediastinal disorders       X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Dry throat                                          X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Oropharyngeal pain                                  X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Sinus congestion                                    X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
   Sneezing                                            X  (XX%)            X  (XX%)            X  (XX%)       X (XX%) 
etc.                                                                                                                 
 -------------------------------------------------------------------------------------------------------------------- 
Note:  * Adverse events are classified according to MedDRA Version 21.1 by System Organ Class and Preferred Term. 
       TE = Treatment-emergent  
For an AE with multiple changes in severity, a new record with severity less or equal to its maximum severity will not be included in 
the adverse event summary tables. 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
Programmer Note: Sort by decreasing frequency of system organ class and by preferred term within a system organ class of Overall column. 
For each subject, please sort the AEs with same verbatim and preferred term by onset date/time. For any pair (e.g., AE_S1, AE_S2) of these 
AEs (for same subject, same verbatim and preferred term), if the onset date/time of AE_S2 = resolved date/time of AE_S1 and the grade of 
AE_S2 < the grade level of AE_S1, then mark the AE_S2 with a flag like EVAUL_FLG =”N”.  Then, for AE analysis (summary tables), please 
exclude the ones with EVAUL_FLG =”N”. Won’t repeat this comment again.  
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
55


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 55 of 88 
 
Page 1 of 1 
 
Table 14.3.1.2  Treatment-Emergent Adverse Event Frequency by Treatment, Severity Grade, and Relationship to Study Drugs - Number of 
Subjects Reporting Events (Safety Population) 
 
                                          Number of               Severity Grade        Relationship to Study Drug    
                                              Subjects with     --------------------------  --------------------------  - 
           TE Adverse Event*  Treatment       Adverse Events    1    2    3     4     5      Related      Not Related     
           ---------------------------------------------------------------------------------------------------------- --- 
           Dizziness          320 mg                X           X    X    X     X     X         X             X           
           Dry eye            640 mg                X           X    X    X     X     X         X             X           
           Dry mouth          XXX mg                X           X    X    X     X     X         X             X           
                                                    X           X    X    X     X     X         X             X           
           Dry throat         XXX mg                X           X    X    X     X     X         X             X           
           Ear pain           XXX mg                X           X    X    X     X     X         X             X           
           Fatigue            XXX mg                X           X    X    X     X     X         X             X           
           ---------------------------------------------------------------------------------------------------------- --- 
           Treatment 320 mg                        XX           X    X    X     X     X         X             X           
           Treatment 640 mg                        XX           X    X    X     X     X         X             X           
           Treatment 720 mg                        XX           X    X    X     X     X         X             X           
           Overall                                 XX           X    X    X     X     X         X             X           
           ---------------------------------------------------------------------------------------------------------- --- 
 
Note:  * Adverse events are classified according to MedDRA Version 21.1 by System Organ Class and Preferred Term.  
       TE = Treatment-emergent; AE = Adverse event 
       Severity Grade: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant but not immediately life- 
       threatening; Grade 4 = Life-threatening consequences; Grade 5 = Death related to AE.  
       AEs are graded according to NCI CTCAE version 5.0 grading scale. Not all grades are appropriate for all AEs, therefore some AEs  
       are listed in the CTCAE with fewer than 5 options for grade selection. 
       If a TEAE decreased in severity grade, the new TEAE record with less severity was counted as the same TEAE event of the previous 
       record with worse severity under the same treatment group. 
       When a subject experienced the same TEAE at more than one level of severity during a treatment period, only the most severe one  
       was counted.  
       When a subject experienced the same TEAE at more than one level of drug relationship during a treatment period, only the one  
       related to study drugs was counted. 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
56


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 56 of 88 
 
Page X of X 
 
Table 14.3.2.1 Serious Adverse Events (Safety Population) 
 
                                                Onset/Resolution                                                      Other                
Subject                   Adverse   PT*/       --------------------           Severity                                Action               
Number   Treatment  TE?^   Event    SOC        Day  Date       Time    Freq*  Grade      Ser*  Outcome     Action     Taken   Relationship 
------------------------------------------------------------------------------------------------------------------------------------------ 
XXX-XXX   640 mg    Yes    XXXXXXX  XXXXXXX/   XX/  DDMMMYYYY/ XX:XX/  Inter.   X        NS    Recovered   XXXXXXXXX  None    XXXXXXXXX/   
                                    XXXXXXXX   XX   DDMMMYYYY  XX:XX                           or resolved XXXXXXXXX  XXXX    XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
Note:  * Adverse events are classified according to MedDRA Version 21.1 by System Organ Class and Preferred Term. 
       TE = Treatment-emergent; PT = Preferred Term; SOC = System Organ Class, Onset day is relative to Period 1 Day 1. 
       Freq* represents Frequency:  SI = Single Episode, Inter. = Intermittent, Cont. = Continuous   
       Ser* represents Serious:  NS = Not Serious 
       Severity/Intensity: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant but not immediately  
       life-threatening; Grade 4 = Life-threatening consequences; Grade 5 = Death related to AE 
       AEs are graded according to NCI CTCAE version 5.0 grading scale. Not all grades are appropriate for all AEs, therefore some AEs are  
       listed in the CTCAE with fewer than 5 options for grade selection. 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1 
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
Programmer Note: if there are no serious adverse events reported, there will be just one table (Table 14.3.2.1) with the statement “There 
was no serious adverse event recorded during the study.” 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
57


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Tables 14.3.4.1-14.3.4.3 will have the following f01mat. 
Table 14.3. 4.1 Out- of- Range Values and Recheck Resul ts - Serum Chemistry 
Parameterl Parameter2 
Subject 
Age$/ 
Study 
< Range> 
< Range> 
Number 
Treatment 
Sex 
Period 
Day 
Hour 
Date 
(Unit) 
(Uni t ) 
xxx-xxx 
XXX mg 
XX/ M 
Screen 
XX HN 
xx 
1 
-x 
Check- in DI:M-'MYYYY 
xx 
xx 
1 
X 
X 
DI:M-'MYYYY 
xx 
xx 
X 
X 
DI:M-'MYYYY 
xx 
xx 
X 
X 
XX LY-
XX IN 
Page 1 of X 
(Safety Population) 
Parameter3 
Parameter4 Parameters 
< Range> 
< Range> 
< Range> 
(Unit) 
(Unit) 
(Uni t ) 
xx 
xx 
XX HN 
xx 
xx 
xx 
xx 
XXHN 
xx 
xx 
xx 
xx 
xx 
XX LY-
xx 
Programrer Note: Replace Parameterl , 2 etc. with actual l ab tests in the study. Sort unscheduled assessment and earl y tenn chronol ogicall y 
with other scheduled assessments and rechecks. 
Recheck should be sorted with the scheduled time point the recheck is for. 
Arrange al phabetical ly by lab test name. 
Note: 
$ Age is calculated from the date of first dosing 
Abnormal flag: H = Above Reference Range, L = Below Reference Range 
Corrputer Clinical signifi cance: N = Not Cl inicall y Significant, Y = Cli nical l y Si gni f i cant 
PI I nterpretation: - = Not Clinically Si gnificant, R = Tobe Rechecked, A = Wil l be Retested at a Later Event 
320 mg: Admini stration of 320 mg (4 x 80 mg capsules) LOX0--292 on Day 1 
640 mg: Admini stration of 320 mg (8 x 80 mg capsules) LOX0--292 on Day 1 
720 mg: Admini stration of 320 mg (9 x 80 mg capsules) LOX0--292 on Day 1 
Program: 
/ CAXXXXX/ sas_prg/ stsas/ tab_ PROGRAMNAME . sas 
DDMMMYYYY 
HH:MM 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 57 of88 
58 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Table 14 .3. 4.4 Clinically Si gnificant Laboratory and CorresJX)nding Results (Safety Population) 
Subject 
Age$/ Study 
Number 
Treatrrent 
Sex 
Per i od 
Day 
Hour Date 
Tine 
Departrrent 
Test 
Result 
Reference 
XXX- XXX 
XXX mg 
XX/ X 
X 
X 
x.xx DDJ\MfYYYY 
HH:1'41: SS Serum Chemistry Cholester ol 
XXX 
X - X 
X xx.xx 
DDJ\MfYYYY 
HH:1'41: SS Serum Chemistry Cholester ol 
XXX 
HYR+ 
X - X 
X xx.xx 
DDJ\MfYYYY 
HH:1'41: SS Serum Chemistry Cholesterol 
XXX 
HY-
X - X 
X xx.xx 
DDJ\MfYYYY 
HH:1'41:SS Serum Chemistry Cholester ol 
XXX 
HN 
X - X 
Page 1 of X 
Range 
Uni t 
mg/ dL 
mg/ dL 
mg/ dL 
mg/ dL 
Programrer Note: All tine JX)ints for a subject/ test with at least one value deerred as CS by t he PI will be presented in this table. 
If there were no CS values as deerred by PI (i.e., no "CS" or "Clini cally Signifi cant" in the PI flag or conment field in 
t he laboratory dataset), then this table will contai n onl y the staterrent: "There were no laboratory values deerred 
clinically significant by t he PI i n the study." 
Note: 
$ Age is calculated from the date of first dosing 
H = Above Reference Range, L = Below Reference Range 
Canputer: N = Not Clini cal ly Si gnifi cant, Y = Cl ini call y Significant 
PI Interpretation: -
= Not Clinically Si gnificant, R = To be Rechecked, 
A 
= Will be Retested at a Later Event 
320 mg: Adninistrati on of 320 mg (4 x 80 mg capsules) LOX0--292 on Day 1 
640 mg: Adninistration of 320 mg (8 x 80 mg capsules) LOX0--292 on Day 1 
720 mg: Adninistrati on of 320 mg (9 x 80 mg capsules) LOX0--292 on Day 1 
Program 
/CAXXXXX/ECR/sas_prg/ stsas/ tab/ PRCGRAMNAME.sas DIM1MYYYY 
HH:!lt1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 58 of88 
59 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 59 of 88 
Tables 14.3.5.1, 14.3.5.3, and 14.3.5.5 will have the following format.  
 
Page 1 of X 
 
Table 14.3.5.1  Clinical Laboratory Summary and Change from Baseline - Serum Chemistry (Safety Population) 
 
                                                               Treatment            Change From Baseline 
                                          Time                    --------------------------     --------------------------- 
 Laboratory Test (unit)   Normal Range#   Point       Statistic   320 mg    640 mg    720 mg     320 mg    640 mg    720 mg  
 --------------------------------------------------------------------------------------------------------------------------- 
 Parameter1 (unit)        XX – XX         Day -1      n               XX        XX                                           
                                                      Mean         XX.XX     XX.XX                                           
                                                      SD           X.XXX     X.XXX                                           
                                                      Minimum       XX.X      XX.X                                           
                                                      Median       XX.XX     XX.XX                                           
                                                      Maximum       XX.X      XX.X                                           
 
                                          Day 2       n               XX        XX        XX         XX        XX        XX  
                                                      Mean         XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                      SD           X.XXX     X.XXX     X.XXX      X.XXX     X.XXX     X.XXX  
                                                      Minimum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
                                                      Median       XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                      Maximum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
 
                                          Day 5       n               XX        XX        XX         XX        XX        XX  
                                                      Mean         XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                      SD           X.XXX     X.XXX     X.XXX      X.XXX     X.XXX     X.XXX  
                                                      Minimum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
                                                      Median       XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                      Maximum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
 
<Programmer note: Similar for remaining laboratory tests. Also need to add Day 8 time point. Sort alphabetically by lab test name.> 
 
Note:  # Lowest of the lower ranges and highest of the higher ranges are used. Refer to Appendix 16.1.10.1 for the breakdown.  
       Baseline is Day -1 check-in and is the last non-missing predose measurement prior to dosing, including rechecks and unscheduled 
       assessments.  
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
60


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 60 of 88 
Tables 14.3.5.2, 14.3.5.4, and 14.3.5.6 will have the following format.  
Page 1 of X 
 
Table 14.3.5.2  Clinical Laboratory Shift from Baseline - Serum Chemistry (Safety Population) 
 
                                             Baseline L         Baseline N         Baseline H     
                                         ------------------  -----------------  ----------------- 
                                              Postdose            Postdose           Postdose 
      Laboratory                  Time   ------------------  -----------------   ---------------- 
      Test (units)   Treatment    Point     L    N     H        L    N    H        L    N    H 
      ------------------------------------------------------------------------------------------- 
      Testname(unit)  XXX mg      Day 2     X    XX    X        X   XX    X        X    XX   X   
 
                                  Day 5     X    XX    X        X   XX    X        X    XX   X   
 
                                  Day 8     X    XX    X        X   XX    X        X    XX   X   
 
 
 
<Programmer note: Similar for remaining laboratory tests. Use N = Within Normal Range, O = Outside Normal Range for 
urinalysis shift table.> 
 
Note:  N = Within Normal Range, L = Below Normal Range, H= Above Normal Range. 
Baseline is Day -1 check-in and is the last non-missing predose measurement prior to dosing of LOXO-292, including rechecks and 
unscheduled assessments.  
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/tab_programname.sas  DDMMMYYYY  HH:MM    
  
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
61


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 61 of 88 
Page 1 of X 
 
Table 14.3.5.7  Vital Sign Summary and Change from Baseline (Safety Population) 
 
                                                            Treatment            Change From Baseline 
             Vital sign         Time                           --------------------------     --------------------------- 
             Paramater (unit)   Point              Statistic   320 mg    640 mg    720 mg     320 mg    640 mg    720 mg  
             ------------------------------------------------------------------------------------------------------------ 
             Parameter1 (unit)  Day -1 Check-in    n               XX        XX                                           
                                                   Mean         XX.XX     XX.XX                                           
                                                   SD           X.XXX     X.XXX                                           
                                                   Minimum       XX.X      XX.X                                           
                                                   Median       XX.XX     XX.XX                                           
                                                   Maximum       XX.X      XX.X                                           
 
                                Day 1 Predose      n               XX        XX                                           
                                                   Mean         XX.XX     XX.XX                                           
                                                   SD           X.XXX     X.XXX                                           
                                                   Minimum       XX.X      XX.X                                           
                                                   Median       XX.XX     XX.XX                                           
                                                   Maximum       XX.X      XX.X                                           
 
                                Day 1 Hour 2       n               XX        XX        XX         XX        XX        XX  
                                                   Mean         XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                   SD           X.XXX     X.XXX     X.XXX      X.XXX     X.XXX     X.XXX  
                                                   Minimum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
                                                   Median       XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                   Maximum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
 
 
<Programmer note: Similar for remaining vital sign parameters. Also need to add additional time points: Day 1 Hour 4, 
Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, and Day 8.  
 
Note:  Baseline is Day 1 predose and is the last non-missing predose measurement prior to dosing, including rechecks and unscheduled 
       assessments.> 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
  
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
62


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 62 of 88 
 
Page 1 of X 
 
Table 14.3.5.8  12-Lead Electrocardiogram Summary and Change from Baseline (Safety Population) 
 
                                                            Treatment            Change From Baseline 
                                       Time                    --------------------------     --------------------------- 
             ECG Paramater (unit)      Point       Statistic   320 mg    640 mg    720 mg     320 mg    640 mg    720 mg  
             ------------------------------------------------------------------------------------------------------------ 
             Parameter1 (unit)         Day -1      n               XX        XX                                           
                                                   Mean         XX.XX     XX.XX                                           
                                                   SD           X.XXX     X.XXX                                           
                                                   Minimum       XX.X      XX.X                                           
                                                   Median       XX.XX     XX.XX                                           
                                                   Maximum       XX.X      XX.X                                           
 
                                       Day 2       n               XX        XX        XX         XX        XX        XX  
                                                   Mean         XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                   SD           X.XXX     X.XXX     X.XXX      X.XXX     X.XXX     X.XXX  
                                                   Minimum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
                                                   Median       XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                   Maximum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
 
                                       Day 5       n               XX        XX        XX         XX        XX        XX  
                                                   Mean         XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                   SD           X.XXX     X.XXX     X.XXX      X.XXX     X.XXX     X.XXX  
                                                   Minimum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
                                                   Median       XX.XX     XX.XX     XX.XX      XX.XX     XX.XX     XX.XX  
                                                   Maximum       XX.X      XX.X      XX.X       XX.X      XX.X      XX.X  
 
<Programmer note: Similar for remaining ECG parameters. Also need to add Day 8 time point.> 
 
Note:  Baseline is Day -1 check-in assessment and is the last non-missing predose measurement prior to dosing, including rechecks and 
unscheduled assessments. 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
Program:  /CAXXXXX/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
63


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 63 of 88 
11. LISTING SHELLS 
The following listing shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the listings that will be presented and included in the final CSR. These listings will 
be generated off of the Celerion SDTM Tabulation Model 1.4 mapped in accordance 
with SDTM Implementation Guide 3.2. All listings will be presented in Courier New 
size font 9.  
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
64


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 64 of 88 
Page 1 of X 
 
Appendix 16.1.10.1  Clinical Laboratory Reference Ranges 
 
                  Laboratory Group           Test Name                     Sex         Age Category  Normal Range    Unit      
                  ------------------------------------------------------------------------------------------------------------ 
                  Serum Chemistry            Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
 
                  Hematology                 Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
                                             Test Name                     XXXXXX      XX            XX – XX         units 
 
 
 
 
 
 
 
 
<Programmer note: Sort alphabetically by lab test name within each lab group.> 
 
 
 
 
 
 
 
 
 
 
<similar for remaining Laboratory Groups and Test Names> 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
65


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 65 of 88 
Page 1 of X 
 
Appendix 16.2.1  Subject Discontinuation (Safety Population) 
 
                                          Subject     Study              Completed  
                               Treatment  Number      Period    Date      Study?    Primary Discontinuation Reason 
                               ----------------------------------------------------------------------------------- 
                               XXX mg     XXX-XXX     Post   DDMMMYYYY     YES    
                               XXX mg     XXX-XXX     Post   DDMMMYYYY     YES    
                               XXX mg     XXX-XXX     Post   DDMMMYYYY     YES    
                               XXX mg     XXX-XXX     Post   DDMMMYYYY     NO       Adverse Event           
                               XXX mg     XXX-XXX     Post   DDMMMYYYY     YES    
                               XXX mg     XXX-XXX     Post   DDMMMYYYY     YES    
 
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
66


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendix 16. 2. 4. 1 
Deroographi cs (Safety Populati on) 
Subject 
Date of 
Age* 
Treatment 
Number 
Bi rth 
(yrs) 
Sex 
Race 
Ethni city 
XXX mg 
XXX- XXX 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
XXX mg 
XXX- XXX 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
XXX mg 
xxx-xxx 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
XXX mg 
xxx-xxx 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
XXX mg 
XXX- XXX 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
XXX mg 
XXX- XXX 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
XXX mg 
xxx-xxx 
DDtlM1YYYY 
xx 
AAAAAA 
AMAAAAA 
AAAAAAMAA 
Note: 
* Age i s cal culated form the date of first dosing. 
320 mg: Admini stration of 320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg: Admini strati on of 320 mg (8 x 80 mg capsules) LOX0-292 on Day 1 
720 mg: Admini strati on of 320 mg (9 x 80 mg capsul es) LOX0-292 on Day 1 
Progr am: 
/ CAXXXXX/ sas_pr g/ st sas/ l i s_PRCGRAMNAME. sas DDt-M1YYYY 
HH: M'1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
He i ght 
Wei ght 
(an) 
(kg) 
XXX 
xx.xx 
XXX 
xx.xx 
XXX 
xx.xx 
XXX 
xx.xx 
XXX 
xx.xx 
XXX 
xx.xx 
XXX 
xx.xx 
Body Mass 
Inforrred 
Index 
Consent 
(kg/rn"2) 
Dat e 
xx.xx 
DIM-t,1YYYY 
xx.xx 
DIM-t,1YYYY 
xx.xx 
DIM-t,1YYYY 
xx.xx 
DIM-t,1YYYY 
xx.xx 
DIM-t,1YYYY 
xx.xx 
DIM-t,1YYYY 
xx.xx 
DIM-t,1YYYY 
Page 1 of X 
I nforrred 
Consent 
Versi on Date 
DIM-t,1YYYY 
DIM-t,1YYYY 
DIM-t,1YYYY 
DIM-t,1YYYY 
DIM-t,1YYYY 
DIM-t,1YYYY 
DIM-t,1YYYY 
Page 66 of 88 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendix 16.2.4.2 Updated Inf ormed Consent (Safety Populat i on) 
Subject 
Date Subject Signed 
Informed Re-Consent 
Treatment 
Number 
Informed Re-Consent 
Version Date 
XXX mg 
xxx- xxx 
lliMMfYYY 
DJ:M,MYYYY 
XXX mg 
xxx- xxx 
ffiM:l1MYYYY 
DJ:M,MYYYY 
XXX mg 
xxx- xxx 
ffiM:l1MYYYY 
DDM--'MYYYY 
XXX mg 
XXX- XXX 
ffiM:l1MYYYY 
DDM--'MYYYY 
XXX mg 
xxx- xxx 
ffiM:l1MYYYY 
DDM--'MYYYY 
XXX mg 
xxx- xxx 
lliMMfYYY 
DDM--'MYYYY 
XXX mg 
xxx- xxx 
D£l!lfJMYYYY 
DIJMl1MYYYY 
Note: 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg: Administration of 320 mg (8 x 80 mg capsules) WX0-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsul es) WX0-292 on Day 1 
Progr am: 
/ CAXXXXX/ sas_prg/ stsas/ lis_PROSRAMNAME. sas DDM-11YYYY 
HH: M-1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Reason for 
Re-Consent 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 68 of 88 
Page 1 of X 
 
Appendix 16.2.4.3  Physical Examination (Safety Population) 
 
           Subject                           Study       Study                Body                 Answer or                     
           Number    Treatment    Period     Day         Hour      Date       System               Result           Comment 
           --------------------------------------------------------------------------------------------------------------------- 
           XXX-XXX    XXX mg      Screen                           DDMMMYYYY  Was PE performed?    Yes        
                                                                              General              Normal     
                                                                              HEENT                Normal     
                                                                              < >                  < > 
 
                                  1           -1         Check-in  DDMMMYYYY  Was PE performed?    Yes 
                                                                              HEENT                Unchanged  
                                                                              < >                  < > 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 69 of 88 
Page 1 of X 
 
Appendix 16.2.4.4  Medical and Surgical History (Safety Population) 
 
                                                                                   Date 
               Subject    Any      Study                                   ----------------------                                         
  Treatment    Number   History?   Period      Category    Body system       Start         End         Ongoing?   Condition or Events     
  --------------------------------------------------------------------------------------------------------------------------------------- 
    XXX mg     XXX-XXX    XXX      Screen      Medical     XXXXXXXXXXX       DDMMMYYYY    DDMMMYYYY    YES        XXXXXXX XXXXXX XXXXXXXX 
                                               Surgical                      DDMMMYYYY    DDMMMYYYY            
 
    XXX mg     XXX-XXX    XXX      Screen      Medical     XXXXXXXXXXX       DDMMMYYYY    DDMMMYYYY    NO      
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 70 of 88 
 
Page 1 of X 
 
Appendix 16.2.5.1.1  Inclusion Criteria 
 
   1.  Healthy, adult, male or female (of non-childbearing potential only), 18-55 years of age, inclusive, at screening.   
   2.  < >  
   3.  < >  
   4.  < >  
   5.  < >  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
71


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendix 16.2 .5. 1 .2 Exclus i on Criteria 
1. 
Is mentall y of l egally incapacitated or has s i gni f i cant erroti onal probl ems at the t ime of t he screeni ng visit or expected 
during the conduct of the study. 
2. 
< > 
3. 
< > 
4. 
< > 
5. 
< > 
6. 
< > 
7. 
< > 
Progr am: 
/CAXXXXX/sas_prg/st sas/li s_PROGRAMNAME. sas DDt-M-1YYYY 
HH:M-1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 1 of X 
Page 71 of88 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Ap:i:endix 16.2.5.2 Subject Eligibility (Safety Population) 
Subject 
Study 
Treatment 
Number 
Peri od 
XXX mg 
XXX mg 
XXX- XXX 
Screen 
XXX- XXX 
Screen 
Did subject meet 
all eligibility criteria? 
YES 
NO 
Note: 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOX0-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOX0-292 on Day 1 
Progr am: 
/ CAXXXXX/ sas_prg/ stsas/ l i s_PRCGRAMNAME. sas Dot-M-1YYYY 
HH: M"1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
<this column is 
only presented i f 
data is present> 
Page 1 of X 
Page 72 of88 
73 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
A~ndix 16.2. 5. 3. 1 Check- i n Criteria 
1. 
Di d t he Subject report any study restri ction vi ol ations since the last study visit? 
Program: 
/ CAXXXXX/ sas_prg/ stsas/ l i s_PRCGRAMNAME. sas DDM-MYYYY 
HH: M1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 1 of 1 
Page 73 of88 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 74 of 88 
Page 1 of X 
 
Appendix 16.2.5.3.2  Check-in Responses (Safety Population) 
 
 
                      Subject  Study                                                                         
         Treatment    Number   Period Day  Hour       Date       Time      Check-in Criteria      Specify               
         -------------------------------------------------------------------------------------------------------------------- 
           XXX mg     XXX-XXX   1      X   Check-in   DDMMMYYYY  hh:mm      YES                   <this column prints       
                                                                                                   only if data is present> 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 75 of 88 
Page 1 of X 
 
Appendix 16.2.5.4.1  Test Compound Description 
 
                         Compound                                                      Form            Route    
                         -------------------------------------------------------------------------------------- 
                         XXXXXXXXXXXXXX                                                < >             XXXX     
 
                         XXXXXXXXXXXXXX                                                < >             XXXX     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 76 of 88 
Page 1 of X 
 
Appendix 16.2.5.4.2  Test Compound Administration Times (Safety Population) 
 
                   Subject  Study               Start      Start                                                                 
     Treatment     Number   Period  Day  Hour   Date       Time     Compound            Dosage    Comments                       
     --------------------------------------------------------------------------------------------------------------------------- 
       XXX mg      XXX-XXX    1      X   0     DDMMMYYYY  HH:MM:SS  XXXXXXXXX             < >     <Only populate if there are    
                                                                                                   comments present in the data> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
77


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendix 16.2.5.5 PK Blood Draw Times (Safety Population) 
Subject 
Study 
Actual 
Number 
Treatrrent 
Period 
Day 
Hour 
Date 
Time 
xxx-xxx 
XXX mg 
1 
1 
-x.xx 
DDJVM-1YYYY 
X:XX:XX 
xx.xx DDJVM-1YYYY 
X:XX:XX 
xx.xx 
DDJVM-1YYYY 
X:XX:XX 
xx.xx 
DDJVM-1YYYY 
XX:XX:XX 
xx.xx DDJVM-1YYYY 
XX:XX:XX 
xx.xx DDJVM-1YYYY 
XX:XX:XX 
xx.xx DDJVM-1YYYY 
XX:XX:XX 
xx.xx DDJVM-1YYYY 
XX:XX:XX 
xx.xx 
DDJVM-1YYYY 
XX:XX:XX 
2 
xx.xx 
DDJVM-1YYYY 
X:XX:XX 
xx.xx DDJVM-1YYYY 
X:XX:XX 
xx.xx DDJVM-1YYYY 
XX:XX:XX 
3 
xx.xx 
DDJVM-1YYYY 
X:XX:XX 
Note: 
320 mg: Administration of 320 mg (4 x 80 mg capsules) LOX0-292 on Day 1 
640 mg: Admini stration of 320 mg (8 x 80 mg capsules) LOX0-292 on Day 1 
720 mg: Admini strati on of 320 mg (9 x 80 mg capsules) LOX0-292 on Day 1 
Program: 
/ CAXXXXX/ sas_prg/stsas/ l i s_PROGRAMNAME. sas DDJVM-1YYYY 
HH:M-1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Bioassay 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
xxxxxxxxxxx 
Ccmrents 
Page 1 of X 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 78 of 88 
Page 1 of X 
 
Appendix 16.2.5.6  Meal Times (Safety Population) 
  
            Subject              Study                                               Start     Stop                              
            Number   Treatment   Period   Day   Hour   Event         Date            Time      Time        Comments              
            -------------------------------------------------------------------------------------------------------------------- 
            XXX-XXX   XXX mg       1       -X  -XX.XX  LUNCH      DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                               -XX.XX  DINNER     DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                               -XX.XX  SNACK      DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                            X   XX.XX  LUNCH      DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                               -XX.XX  DINNER     DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                               -XX.XX  SNACK      DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                            X   XX.XX  BREAKFAST  DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                               -XX.XX  LUNCH      DDMMMYYYY         XX:XX:XX  XX:XX:XX   
                                               -XX.XX  DINNER     DDMMMYYYY         XX:XX:XX  XX:XX:XX   
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 79 of 88 
Page 1 of X 
 
Appendix 16.2.5.7  Prior and Concomitant Medications (Safety Population) 
 
                                                                                                                     AE No 
Subject   Treat-  Any    Prior to  Medication                                Start           Stop           Indi-   (If Due  Continuing  
Number    ment    Med^?  Study?   (WHO* Term)   Dosage   Route     Frequency Day/Date/Time   Day/Date/Time  cation   to AE)  Medication? 
---------------------------------------------------------------------------------------------------------------------------------------- 
XXX-XXX     X     No              None                                                                                                   
XXX-XXX     X     Yes    Yes      ACETAMINOPHEN 620 mg   BY MOUTH  AS NEEDED XX/DDMMMYYYY/   XX/DDMMYYYY/   XXXXX    XXX     YES         
                                 (ACETAMINOPHEN)                             HH:MM           HH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Concomitant medications are coded with WHO Dictionary Version 01SEP2018. 
       ^ Med = Medication; UNK = Unknown 
       Prior medication was medication taken prior to study drug administration. 
       Start and stop day is relative to Period 1 Day 1. 
       320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 80 of 88 
Page 1 of X 
 
 
Appendix 16.2.7.1  Adverse Events (I of II) (Safety Population) 
 
                                                Time from                                                   
                                                Last Dose                Onset                   Resolved          Duration  
  Subject                     Adverse Event/   ----------       ----------------------  ------------------------   ---------- 
  Number    Treatment  TE?^   Preferred Term*   (DD:HH:MM)      Day    Date       Time   Day    Date       Time   (DD:HH:MM) 
  --------------------------------------------------------------------------------------------------------------------------- 
  XXX-XXX    XXX mg    None                                                                            
 
  XXX-XXX    XXX mg    Yes    XXXXXXXXXXXXX/     XX:XX:XX       XX     DDMMMYYYY  X:XX   XX     DDMMMYYYY  X:XX    XX:XX:XX  
                              XXXXXXXXXX       
 
                       No     XXXXXXXXXXXXX/     XX:XX:XX       XX     DDMMMYYYY  X:XX   XX     DDMMMYYYY  X:XX    XX:XX:XX 
                              XXXXXXXXXX       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Adverse events are classified according to MedDRA Version 21.1 by System Organ Class and Preferred Term. 
       ^ TE = Treatment-emergent, Onset and resolved day is relative to Period 1 Day 1. 
       320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
81


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendix 16.2. 7. 2 Adverse Events (I I of I I ) (Safety Popul ation) 
Onset 
other 
Subject 
Adverse 
Action 
Number 
Treatrrent 
Event 
Day 
Date 
Tirre 
Freq" Severi ty Ser* Out cane 
Action 
Taken 
XXX- XXX 
XXX rrg 
None 
xxx- xxx 
XXX rrg 
xxxxxxx xx 
D!X-M'1YYYY XX:XX Inter. Grade 1 
NO 
Resol ved 
Dose Not 
None 
Changed 
Relationship t o 
Study Drug 
Note: 
Ser* = Seri ous; Freq* represents Frequency: 
SI = Si ngle Epi sode, Inter. = Intermit tent, Cont . = Cont i nuous 
Severi ty/ Intensi ty: Grade 1 = Mil d; Grade 2 = Moderate; Grade 3 = Severe or rredically signifi cant but not i.Irrrediately 
life-threatening; Grade 4 = Li fe -threatening consequences; Grade 5 = Death related to AE 
Page 1 of X 
AEs are graded according to NCI CTCAE versi on 5.0 grading scale. Not all grades are appropr i ate for all AEs, therefore sorre AEs are 
l isted in t he CTCAE with fewer than 5 options for grade selection. 
320 rrg: Administration of 320 mg (4 x 80 mg capsules) LOX0--292 on Day 1 
640 mg: Administrati on of 320 mg (8 x 80 mg capsules) LOX0--292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOX0--292 on Day 1 
Program: 
/CAXXXXX/ sas_prg/ stsas/ lis_PROGRAMNAME. sas DDM-MYYYY 
fill: M'1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 81 of88 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 82 of 88 
Page 1 of X 
 
Appendix 16.2.7.3  Adverse Event Non-Drug Therapy (Safety Population) 
 
                                                    Onset                   Resolved                    Therapy                 
          Subject               Adverse    ----------------------  ------------------------  ---------------------------------- 
          Number   Treatment    Event      Day    Date       Time   Day    Date       Time    Date     Time   Description       
          --------------------------------------------------------------------------------------------------------------------- 
          XXX-XXX   XXX mg      DRY LIPS   XX     DDMMMYYYY  X:XX   XX     DDMMMYYYY  X:XX   DDMMMYYYY XX:XX  PETROLEUM JELLY   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Onset and resolved day is relative to Period 1 Day 1. 
       320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 83 of 88 
Page 1 of X 
 
Appendix 16.2.7.4  Adverse Event Preferred Term Classification (Safety Population) 
 
                                                                                                                Onset         
   Subject                Adverse                                                                      ---------------------- 
   Number    Treatment    Event                        Preferred Term*         Body System             Day    Date       Time 
   -------------------------------------------------------------------------------------------------------------------------- 
   XXX-XXX    XXX mg      XXXXXXX XXXXX XXXX XXXXXX    XXXXXXXXXX XXXXXXX      XXXXXXXXXXXXXXXXXXXXX   XX     DDMMMYYYY  X:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Adverse events are classified to MedDRA Version 21.1 by System Organ Class and Preferred Term. 
       Onset day is relative to Period 1 Day 1. 
       320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
84


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendices 16.2.8.1.2-16.2.8.1.5 will have the following format. 
Appendix 16. 2. 8.1.1 Clini cal Laboratory Report - Serum Chemistry (Safety Populati on) 
Pararreterl 
Parameter2 
Pararreter 3 
Pararreter4 
Subject 
A~$/ 
Study 
< Range> 
< Range> 
< Range> 
< Range> 
Cohort Number 
Sex 
Period 
Day 
Hour 
Date 
(Unit) 
(Unit) 
(Unit) 
(Unit) 
X 
XXX- XXX 
XX/M 
Screen 
DDM-MYYYY 
XX HN 
xx 
xx 
xx 
1 
- X 
Check- i n 
DIM-MYYYY 
xx 
xx 
xx 
xx 
X 
0 
DIM-MYYYY 
xx 
xx 
xx 
XXHN 
X 
0 
DIJt.M.1YYYY 
xx 
xx 
xx 
xx 
X 
0 
DIM-MYYYY 
XX LY-
XX LN 
xx 
XX LY-
Page 1 of X 
PararreterS 
< Range> 
(Unit) 
XXHN 
xx 
xx 
xx 
xx 
Prograrrrrer Note: Replace Pararreter l , 2 etc. wi t h actual l ab tests in the study. Sort unscheduled assessrrent and early tenn chronol ogicall y 
wi t h ot her scheduled assessnents and rechecks. 
Recheck should be sorted wi th t he schedul ed tine poi nt the recheck is for. 
Arrange al phabeti call y by l ab t est narre. 
Note: 
$ Age i s calculated f rom the date of first dosi ng . 
H = Above Reference Range, L = Below Reference Range 
Conputer Cl ini cal Signif i cance: N = Not Cl inically Signi ficant, Y = Cl i nical l y Si gnificant 
PI Interpretation: - = Not Clini cally Significant, R = Tobe Rechecked, A = Wil l be Retested at a Later Event 
320 mq: Administration of 320 mq (4 x 80 mq capsules) LOX0-292 on Day 1 
640 mq: Admini strati on of 320 mq (8 x 80 mq capsul es) LOX0-292 on Day 1 
720 mq: Admini strati on of 320 mq (9 x 80 mq capsul es) LOX0-292 on Day 1 
Progr am: 
/CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME. sas DD~ 
HH:M-1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 84 of88 
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 85 of 88 
Page 1 of X 
 
Appendix 16.2.8.1.6  Clinical Laboratory Report - Comments (Safety Population) 
 
    Subject              Study                                                                                                            
    Number   Treatment   Period     Day     Hour    Date    Department      Test           Result       Unit      Comment                 
    ------------------------------------------------------------------------------------------------------------------------------------- 
    XXX-XXX   XXX mg       X         X     -X.X   DDMMMYYYY Other Tests     Fibrinogen     XXX          mg/dL     Not significant in the  
                                                                                                                  context of this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 86 of 88 
Page 1 of X 
 
Appendix 16.2.8.2  Vital Signs (Safety Population) 
 
                                                             Blood Pressure (mmHg)  Heart  Temper-                         
Subject   Treat-  Study                                      ---------------------- rate   ature   Weight            
Number    ment    Period Day  Hour          Date      Time   Test  Arm  Sys/Dia     (bpm)   (°C)   (kg)    Comments  
-------------------------------------------------------------------------------------------------------------------- 
XXX-XXX   XXX mg  Screen                 DDMMMYYYY  X:XX:XX                                        XXX.X             
                                         DDMMMYYYY  X:XX:XX SUPX Right  XXX/ XX      XX    XX.X                      
                    1    -X   Check-in   DDMMMYYYY XX:XX:XX                                        XXX.X             
                                         DDMMMYYYY XX:XX:XX SUPX Right  XXX/ XX      XX                              
                          X   X.X        DDMMMYYYY XX:XX:XX SUPX Right                                               
                              X.X        DDMMMYYYY XX:XX:XX SUPX Right                                               
                              X.X        DDMMMYYYY  X:XX:XX SUPX Right  XXX/ XX      XX                              
                              X.X        DDMMMYYYY  X:XX:XX SUPX Right  XXX/ XX      XX                              
                              X.X        DDMMMYYYY  X:XX:XX SUPX Right  XXX/ XX      XX                              
                                R        DDMMMYYYY XX:XX:XX SUPX Right  XXX/ XX      XX                              
                              X.X        DDMMMYYYY XX:XX:XX SUPX Right                                               
 
 
 
 
 
 
 
 
 
Programmer note: Sort unscheduled assessment and early term chronologically with other scheduled assessments and rechecks.  Recheck should 
be sorted with the scheduled time point the recheck is for. 
 
 
 
 
Note:  SUPX = X-minute supine, R = Recheck Value, Sys/Dia = Systolic/Diastolic 
       320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
87


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
Appendix 16. 2.8. 3 
12-Iead El ectrocardiogram (Safety Popul ation) 
Heart 
Subject 
Study 
Rate 
PR 
QRS 
Number 
Treat.Trent 
Peri od 
Day 
Hour 
Date 
Tine 
Result 
(bpm) 
(msec) (msec) 
XXX- XXX 
XXX mg 
Screen 
D[l,IM>1YYYY 
X:XX:XX 
NORMAL 
xx 
xxx.x 
xx.x 
1 
- 1 
Check- in 
DJ:M.MYYYY X:XX:XX 
NORMAL 
xx 
xxx.x xx.x 
x.xx 
DJ:M.MYYYY 
X:XX:XX 
NORMAL 
xx 
xxx.x xx.x 
X 
x.xx 
DJ:M.MYYYY X:XX:XX 
NORMAL 
xx 
xxx.x xx.x 
x.xx 
DDM>MYYYY 
X:XX:XX 
NORMAL 
xx 
xxx.x xx.x 
X 
x.xx 
DDM>MYYYY 
X:XX:XX 
NORMAL 
xx 
xxx.x xx.x 
X 
x.xx 
DDM>MYYYY 
X:XX:XX 
NORMAL 
xx 
xxx.x xx.x 
Page 1 of X 
QT 
QTcF* 
(msec) (msec) 
Cam-ents 
xxx.x xxx.x 
xxx.x xxx.x 
xxx.x xxx.x 
xxx.x xxx.x 
xxx.x xxx.x 
xxx.x xxx.x # 
xxx.x xxx.x@ 
Programrer note: Sort unscheduled assessment and early term chronol ogi cal ly with other scheduled assessments and rechecks . 
Recheck should 
be sorted with t he scheduled tine point the recheck i s for. 
Note: 
NCS = Abnormal , Not Clinically Signi ficant 
QrcF* = QT corrected for heart rate using Fri derici a's correction. 
# = QrcF > 450, @ = QTcF change from baseline greater than 30 msec 
320 mg: Adninistrati on of 320 mg (4 x 80 mg capsules) WX0-292 on Day 1 
640 mg: Administrati on of 320 mg (8 x 80 mg capsules) WX0-292 on Day 1 
720 mg: Administration of 320 mg (9 x 80 mg capsules) WX0-292 on Day 1 
Program: 
/ CAXXXXX/sas_prg/ stsas/lis_PROGRAMNAME. sas DDM:'-t1YYYY 
HH: M-1 
Statistical Analysis Plan, 03 April 2019 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods 
Page 87 of 88 
88 


Loxo Oncology, Inc. 
LOXO-292, LOXO-RET-18057 
Celerion, Clinical Study Report No. CA27486 
 
Statistical Analysis Plan, 03 April 2019 
Page 88 of 88 
Page 1 of X 
 
Appendix 16.2.8.4  Phone Call (Safety Population) 
 
          Subject               Study                                                                                     
          Number    Treatment   Period     Day    Phone Call Completed?        Date      Time         If no, reason       
          --------------------------------------------------------------------------------------------------------------- 
          XXX-XXX    XXX mg       X         X         Yes/No                 DDMMMYYYY   HH:MM        Wrong number        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  320 mg: Administration of 320 mg (4 x 80 mg capsules) LOXO-292 on Day 1  
640 mg: Administration of 320 mg (8 x 80 mg capsules) LOXO-292 on Day 1  
720 mg: Administration of 320 mg (9 x 80 mg capsules) LOXO-292 on Day 1  
 
 
 
 
 
 
 
Program:  /CAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
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16.1.9.2 
Statistical Outputs 
 
 
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                                                                                                                       Page 1 of 2 
                                   Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter AUC0-24 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LAUC24 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      3 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.3375 
 
 
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                                                                                                                       Page 2 of 2 
                                   Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter AUC0-24 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            26.2 
                                                   AIC (smaller is better)          28.2 
                                                   AICC (smaller is better)         28.5 
                                                   BIC (smaller is better)          28.9 
 
 
                                                       Type 1 Tests of Fixed Effects 
 
                                                              Num     Den 
                                              Effect           DF      DF    F Value    Pr > F 
 
                                              LDOSE             1      15       2.60    0.1279 
                                              LDOSE*LDOSE       1      15       0.09    0.7681 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-24 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LAUC24 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      2 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.3183 
 
 
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                                                                                                                       Page 2 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-24 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            30.8 
                                                   AIC (smaller is better)          32.8 
                                                   AICC (smaller is better)         33.1 
                                                   BIC (smaller is better)          33.6 
 
 
                                                         Solution for Fixed Effects 
 
                                              Standard 
                     Effect       Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
                     Intercept      6.3992      2.3343      16       2.74      0.0145       0.1      2.3238     10.4746 
                     LDOSE          0.6169      0.3717      16       1.66      0.1165       0.1    -0.03208      1.2658 
 
 
                                                       Type 3 Tests of Fixed Effects 
 
                                                             Num     Den 
                                               Effect         DF      DF    F Value    Pr > F 
 
                                               LDOSE           1      16       2.75    0.1165 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-24 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                                           Lower       Upper 
                                               Parameter    Estimate       Limit       Limit 
 
                                               Intercept      6.3992      2.3238     10.4746 
                                               Slope          0.6169    -0.03208      1.2658 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 2 
                                   Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter AUC0-t 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LAUCLST 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      3 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.2431 
 
 
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                                                                                                                       Page 2 of 2 
                                   Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter AUC0-t 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            21.3 
                                                   AIC (smaller is better)          23.3 
                                                   AICC (smaller is better)         23.6 
                                                   BIC (smaller is better)          24.0 
 
 
                                                       Type 1 Tests of Fixed Effects 
 
                                                              Num     Den 
                                              Effect           DF      DF    F Value    Pr > F 
 
                                              LDOSE             1      15       3.38    0.0859 
                                              LDOSE*LDOSE       1      15       0.18    0.6797 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 3 
                                         Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-t 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LAUCLST 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      2 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.2306 
 
 
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                                                                                                                       Page 2 of 3 
                                         Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-t 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            25.7 
                                                   AIC (smaller is better)          27.7 
                                                   AICC (smaller is better)         27.9 
                                                   BIC (smaller is better)          28.4 
 
 
                                                         Solution for Fixed Effects 
 
                                              Standard 
                     Effect       Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
                     Intercept      7.0351      1.9866      16       3.54      0.0027       0.1      3.5667     10.5035 
                     LDOSE          0.5970      0.3163      16       1.89      0.0774       0.1     0.04475      1.1493 
 
 
                                                       Type 3 Tests of Fixed Effects 
 
                                                             Num     Den 
                                               Effect         DF      DF    F Value    Pr > F 
 
                                               LDOSE           1      16       3.56    0.0774 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                         Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-t 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                                           Lower       Upper 
                                               Parameter    Estimate       Limit       Limit 
 
                                               Intercept      7.0351      3.5667     10.5035 
                                               Slope          0.5970     0.04475      1.1493 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 2 
                                  Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter AUC0-inf 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LAUCIFO 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      3 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.2437 
 
 
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                                                                                                                       Page 2 of 2 
                                  Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter AUC0-inf 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            21.3 
                                                   AIC (smaller is better)          23.3 
                                                   AICC (smaller is better)         23.6 
                                                   BIC (smaller is better)          24.0 
 
 
                                                       Type 1 Tests of Fixed Effects 
 
                                                              Num     Den 
                                              Effect           DF      DF    F Value    Pr > F 
 
                                              LDOSE             1      15       3.39    0.0854 
                                              LDOSE*LDOSE       1      15       0.18    0.6790 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-inf 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LAUCIFO 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      2 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.2312 
 
 
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                                                                                                                       Page 2 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-inf 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            25.7 
                                                   AIC (smaller is better)          27.7 
                                                   AICC (smaller is better)         28.0 
                                                   BIC (smaller is better)          28.5 
 
 
                                                         Solution for Fixed Effects 
 
                                              Standard 
                     Effect       Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
                     Intercept      7.0292      1.9893      16       3.53      0.0028       0.1      3.5561     10.5023 
                     LDOSE          0.5990      0.3168      16       1.89      0.0769       0.1     0.04592      1.1520 
 
 
                                                       Type 3 Tests of Fixed Effects 
 
                                                             Num     Den 
                                               Effect         DF      DF    F Value    Pr > F 
 
                                               LDOSE           1      16       3.58    0.0769 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-inf 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                                           Lower       Upper 
                                               Parameter    Estimate       Limit       Limit 
 
                                               Intercept      7.0292      3.5561     10.5023 
                                               Slope          0.5990     0.04592      1.1520 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 2 
                                    Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter Cmax 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LCMAX 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      3 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.3736 
 
 
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                                                                                                                       Page 2 of 2 
                                    Dose Proportionality Analysis for Plasma LOXO-292 PK Parameter Cmax 
                                                       for Table 14.2.1.8 (Quadratic) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            27.7 
                                                   AIC (smaller is better)          29.7 
                                                   AICC (smaller is better)         30.1 
                                                   BIC (smaller is better)          30.5 
 
 
                                                       Type 1 Tests of Fixed Effects 
 
                                                              Num     Den 
                                              Effect           DF      DF    F Value    Pr > F 
 
                                              LDOSE             1      15       2.12    0.1662 
                                              LDOSE*LDOSE       1      15       0.02    0.8827 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 3 
                                          Dose Proportionality Analysis for Plasma LOXO-292 - Cmax 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                             Model Information 
 
                                           Data Set                     WORK.TOTAL 
                                           Dependent Variable           LCMAX 
                                           Covariance Structure         Diagonal 
                                           Estimation Method            REML 
                                           Residual Variance Method     Profile 
                                           Fixed Effects SE Method      Model-Based 
                                           Degrees of Freedom Method    Residual 
 
 
                                                                Dimensions 
 
                                                    Covariance Parameters             1 
                                                    Columns in X                      2 
                                                    Columns in Z                      0 
                                                    Subjects                          1 
                                                    Max Obs Per Subject              18 
 
 
                                                          Number of Observations 
 
                                                Number of Observations Read              18 
                                                Number of Observations Used              18 
                                                Number of Observations Not Used           0 
 
 
                                                           Covariance Parameter 
                                                                 Estimates 
 
                                                           Cov Parm     Estimate 
 
                                                           Residual       0.3508 
 
 
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                                                                                                                       Page 2 of 3 
                                          Dose Proportionality Analysis for Plasma LOXO-292 - Cmax 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                            The Mixed Procedure 
 
                                                              Fit Statistics 
 
                                                   -2 Res Log Likelihood            32.4 
                                                   AIC (smaller is better)          34.4 
                                                   AICC (smaller is better)         34.7 
                                                   BIC (smaller is better)          35.1 
 
 
                                                         Solution for Fixed Effects 
 
                                              Standard 
                     Effect       Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
                     Intercept      4.3482      2.4504      16       1.77      0.0950       0.1     0.07012      8.6262 
                     LDOSE          0.5860      0.3902      16       1.50      0.1526       0.1    -0.09519      1.2673 
 
 
                                                       Type 3 Tests of Fixed Effects 
 
                                                             Num     Den 
                                               Effect         DF      DF    F Value    Pr > F 
 
                                               LDOSE           1      16       2.26    0.1526 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                          Dose Proportionality Analysis for Plasma LOXO-292 - Cmax 
                                                        for Table 14.2.1.8 (Linear) 
 
                                                                           Lower       Upper 
                                               Parameter    Estimate       Limit       Limit 
 
                                               Intercept      4.3482     0.07012      8.6262 
                                               Slope          0.5860    -0.09519      1.2673 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 1 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-t 
                                                           for Figure 14.2.2.7 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                 Number of Observations Read          18 
                                                 Number of Observations Used          18 
 
 
                                                           Analysis of Variance 
 
                                                                  Sum of           Mean 
                              Source                   DF        Squares         Square    F Value    Pr > F 
 
                              Model                     1        0.82125        0.82125       3.56    0.0774 
                              Error                    16        3.68893        0.23056 
                              Corrected Total          17        4.51018 
 
 
                                           Root MSE              0.48016    R-Square     0.1821 
                                           Dependent Mean       10.77842    Adj R-Sq     0.1310 
                                           Coeff Var             4.45487 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 2 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-t 
                                                           for Figure 14.2.2.7 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                           Parameter Estimates 
 
                                                                         Parameter       Standard 
                  Variable     Label                             DF       Estimate          Error    t Value    Pr > |t| 
 
                  Intercept    Intercept                          1        7.03512        1.98661       3.54      0.0027 
                  LDOSE        Log Value of Actual Treatment      1        0.59705        0.31635       1.89      0.0774 
                               Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                        Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-t 
                                                           for Figure 14.2.2.7 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                            Output Statistics 
 
                                    Dependent    Predicted       Std Error 
                             Obs     Variable        Value    Mean Predict        90% CL Predict         Residual 
 
                               1      10.4651      10.4791          0.1948       9.5744      11.3838      -0.0140 
                               2      11.1581      10.4791          0.1948       9.5744      11.3838       0.6791 
                               3      10.9136      10.4791          0.1948       9.5744      11.3838       0.4345 
                               4       9.5716      10.4791          0.1948       9.5744      11.3838      -0.9075 
                               5      10.2653      10.4791          0.1948       9.5744      11.3838      -0.2138 
                               6      10.5566      10.4791          0.1948       9.5744      11.3838       0.0775 
                               7      10.8621      10.8929          0.1284      10.0252      11.7607      -0.0308 
                               8      11.4083      10.8929          0.1284      10.0252      11.7607       0.5154 
                               9      10.5419      10.8929          0.1284      10.0252      11.7607      -0.3511 
                              10      11.2988      10.8929          0.1284      10.0252      11.7607       0.4059 
                              11      10.3294      10.8929          0.1284      10.0252      11.7607      -0.5635 
                              12      10.5328      10.8929          0.1284      10.0252      11.7607      -0.3601 
                              13      10.5899      10.9633          0.1497      10.0852      11.8413      -0.3733 
                              14      10.5752      10.9633          0.1497      10.0852      11.8413      -0.3881 
                              15      11.7530      10.9633          0.1497      10.0852      11.8413       0.7898 
                              16      11.0174      10.9633          0.1497      10.0852      11.8413       0.0541 
                              17      11.4140      10.9633          0.1497      10.0852      11.8413       0.4508 
                              18      10.7584      10.9633          0.1497      10.0852      11.8413      -0.2049 
 
 
                                               Sum of Residuals                           0 
                                               Sum of Squared Residuals             3.68893 
                                               Predicted Residual SS (PRESS)        4.77330 
 
 
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                                                                                                                       Page 1 of 3 
                                       Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-24 
                                                           for Figure 14.2.2.8 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                 Number of Observations Read          18 
                                                 Number of Observations Used          18 
 
 
                                                           Analysis of Variance 
 
                                                                  Sum of           Mean 
                              Source                   DF        Squares         Square    F Value    Pr > F 
 
                              Model                     1        0.87671        0.87671       2.75    0.1165 
                              Error                    16        5.09307        0.31832 
                              Corrected Total          17        5.96979 
 
 
                                           Root MSE              0.56420    R-Square     0.1469 
                                           Dependent Mean       10.26685    Adj R-Sq     0.0935 
                                           Coeff Var             5.49532 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 2 of 3 
                                       Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-24 
                                                           for Figure 14.2.2.8 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                           Parameter Estimates 
 
                                                                         Parameter       Standard 
                  Variable     Label                             DF       Estimate          Error    t Value    Pr > |t| 
 
                  Intercept    Intercept                          1        6.39921        2.33428       2.74      0.0145 
                  LDOSE        Log Value of Actual Treatment      1        0.61688        0.37171       1.66      0.1165 
                               Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                       Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-24 
                                                           for Figure 14.2.2.8 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                            Output Statistics 
 
                                    Dependent    Predicted       Std Error 
                             Obs     Variable        Value    Mean Predict        90% CL Predict         Residual 
 
                               1       9.8894       9.9576          0.2289       8.8945      11.0206      -0.0681 
                               2      10.6905       9.9576          0.2289       8.8945      11.0206       0.7329 
                               3      10.5971       9.9576          0.2289       8.8945      11.0206       0.6396 
                               4       8.9243       9.9576          0.2289       8.8945      11.0206      -1.0333 
                               5       9.3860       9.9576          0.2289       8.8945      11.0206      -0.5716 
                               6      10.3050       9.9576          0.2289       8.8945      11.0206       0.3474 
                               7      10.3395      10.3852          0.1509       9.3655      11.4048      -0.0456 
                               8      11.0223      10.3852          0.1509       9.3655      11.4048       0.6371 
                               9      10.0003      10.3852          0.1509       9.3655      11.4048      -0.3848 
                              10      10.7864      10.3852          0.1509       9.3655      11.4048       0.4012 
                              11       9.8830      10.3852          0.1509       9.3655      11.4048      -0.5022 
                              12       9.9566      10.3852          0.1509       9.3655      11.4048      -0.4286 
                              13       9.9191      10.4578          0.1759       9.4261      11.4896      -0.5387 
                              14      10.0936      10.4578          0.1759       9.4261      11.4896      -0.3642 
                              15      11.3690      10.4578          0.1759       9.4261      11.4896       0.9112 
                              16      10.5137      10.4578          0.1759       9.4261      11.4896       0.0559 
                              17      10.8764      10.4578          0.1759       9.4261      11.4896       0.4186 
                              18      10.2511      10.4578          0.1759       9.4261      11.4896      -0.2067 
 
 
                                               Sum of Residuals                           0 
                                               Sum of Squared Residuals             5.09307 
                                               Predicted Residual SS (PRESS)        6.67982 
 
 
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                                                                                                                       Page 1 of 3 
                                       Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-inf 
                                                           for Figure 14.2.2.9 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                 Number of Observations Read          18 
                                                 Number of Observations Used          18 
 
 
                                                           Analysis of Variance 
 
                                                                  Sum of           Mean 
                              Source                   DF        Squares         Square    F Value    Pr > F 
 
                              Model                     1        0.82655        0.82655       3.58    0.0769 
                              Error                    16        3.69893        0.23118 
                              Corrected Total          17        4.52548 
 
 
                                           Root MSE              0.48082    R-Square     0.1826 
                                           Dependent Mean       10.78453    Adj R-Sq     0.1316 
                                           Coeff Var             4.45838 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 2 of 3 
                                       Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-inf 
                                                           for Figure 14.2.2.9 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                           Parameter Estimates 
 
                                                                         Parameter       Standard 
                  Variable     Label                             DF       Estimate          Error    t Value    Pr > |t| 
 
                  Intercept    Intercept                          1        7.02918        1.98930       3.53      0.0028 
                  LDOSE        Log Value of Actual Treatment      1        0.59897        0.31677       1.89      0.0769 
                               Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                       Dose Proportionality Analysis for Plasma LOXO-292 - AUC0-inf 
                                                           for Figure 14.2.2.9 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                            Output Statistics 
 
                                    Dependent    Predicted       Std Error 
                             Obs     Variable        Value    Mean Predict        90% CL Predict         Residual 
 
                               1      10.4696      10.4842          0.1951       9.5783      11.3902      -0.0147 
                               2      11.1650      10.4842          0.1951       9.5783      11.3902       0.6808 
                               3      10.9144      10.4842          0.1951       9.5783      11.3902       0.4302 
                               4       9.5750      10.4842          0.1951       9.5783      11.3902      -0.9092 
                               5      10.2787      10.4842          0.1951       9.5783      11.3902      -0.2056 
                               6      10.5587      10.4842          0.1951       9.5783      11.3902       0.0745 
                               7      10.8661      10.8994          0.1286      10.0305      11.7684      -0.0333 
                               8      11.4174      10.8994          0.1286      10.0305      11.7684       0.5180 
                               9      10.5468      10.8994          0.1286      10.0305      11.7684      -0.3527 
                              10      11.3095      10.8994          0.1286      10.0305      11.7684       0.4101 
                              11      10.3349      10.8994          0.1286      10.0305      11.7684      -0.5645 
                              12      10.5363      10.8994          0.1286      10.0305      11.7684      -0.3631 
                              13      10.6012      10.9700          0.1499      10.0907      11.8492      -0.3688 
                              14      10.5779      10.9700          0.1499      10.0907      11.8492      -0.3921 
                              15      11.7593      10.9700          0.1499      10.0907      11.8492       0.7894 
                              16      11.0231      10.9700          0.1499      10.0907      11.8492       0.0532 
                              17      11.4232      10.9700          0.1499      10.0907      11.8492       0.4532 
                              18      10.7646      10.9700          0.1499      10.0907      11.8492      -0.2054 
 
 
                                               Sum of Residuals                           0 
                                               Sum of Squared Residuals             3.69893 
                                               Predicted Residual SS (PRESS)        4.78441 
 
 
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                                                                                                                       Page 1 of 3 
                                         Dose Proportionality Analysis for Plasma LOXO-292 - Cmax 
                                                           for Figure 14.2.2.10 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                 Number of Observations Read          18 
                                                 Number of Observations Used          18 
 
 
                                                           Analysis of Variance 
 
                                                                  Sum of           Mean 
                              Source                   DF        Squares         Square    F Value    Pr > F 
 
                              Model                     1        0.79125        0.79125       2.26    0.1526 
                              Error                    16        5.61220        0.35076 
                              Corrected Total          17        6.40345 
 
 
                                           Root MSE              0.59225    R-Square     0.1236 
                                           Dependent Mean        8.02245    Adj R-Sq     0.0688 
                                           Coeff Var             7.38243 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 2 of 3 
                                         Dose Proportionality Analysis for Plasma LOXO-292 - Cmax 
                                                           for Figure 14.2.2.10 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                           Parameter Estimates 
 
                                                                         Parameter       Standard 
                  Variable     Label                             DF       Estimate          Error    t Value    Pr > |t| 
 
                  Intercept    Intercept                          1        4.34816        2.45036       1.77      0.0950 
                  LDOSE        Log Value of Actual Treatment      1        0.58604        0.39019       1.50      0.1526 
                               Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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                                                                                                                       Page 3 of 3 
                                         Dose Proportionality Analysis for Plasma LOXO-292 - Cmax 
                                                           for Figure 14.2.2.10 
 
                                                              Model: MODEL1 
                                                 Dependent Variable: AVAL Analysis Value 
 
                                                            Output Statistics 
 
                                    Dependent    Predicted       Std Error 
                             Obs     Variable        Value    Mean Predict        90% CL Predict         Residual 
 
                               1       7.3715       7.7286          0.2403       6.6127       8.8445      -0.3571 
                               2       8.4764       7.7286          0.2403       6.6127       8.8445       0.7477 
                               3       8.4805       7.7286          0.2403       6.6127       8.8445       0.7519 
                               4       6.7405       7.7286          0.2403       6.6127       8.8445      -0.9881 
                               5       7.0901       7.7286          0.2403       6.6127       8.8445      -0.6386 
                               6       8.2375       7.7286          0.2403       6.6127       8.8445       0.5088 
                               7       8.1519       8.1348          0.1584       7.0645       9.2052       0.0171 
                               8       8.7499       8.1348          0.1584       7.0645       9.2052       0.6150 
                               9       7.8861       8.1348          0.1584       7.0645       9.2052      -0.2488 
                              10       8.6827       8.1348          0.1584       7.0645       9.2052       0.5479 
                              11       7.7187       8.1348          0.1584       7.0645       9.2052      -0.4162 
                              12       7.4501       8.1348          0.1584       7.0645       9.2052      -0.6848 
                              13       7.8120       8.2039          0.1846       7.1208       9.2869      -0.3919 
                              14       7.9725       8.2039          0.1846       7.1208       9.2869      -0.2314 
                              15       9.2301       8.2039          0.1846       7.1208       9.2869       1.0263 
                              16       8.1017       8.2039          0.1846       7.1208       9.2869      -0.1022 
                              17       8.2865       8.2039          0.1846       7.1208       9.2869       0.0826 
                              18       7.9655       8.2039          0.1846       7.1208       9.2869      -0.2383 
 
 
                                               Sum of Residuals                           0 
                                               Sum of Squared Residuals             5.61220 
                                               Predicted Residual SS (PRESS)        7.38988 
 
 
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16.1.9.3 
Normality Assessments 
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Normality Assessment for Plasma LOXO-292 - AUC0-24 for Table 14.2.1.8 
 
Variable:  Resid  
(Residual) 
 
Moments 
N 
18 Sum Weights 
18 
Mean 
0 Sum Observations 
0 
Std Deviation 
0.54735048 Variance 
0.29959255 
Skewness 
0.03401098 Kurtosis 
-0.9501699 
Uncorrected SS 5.09307327 Corrected SS 
5.09307327 
Coeff Variation 
. Std Error Mean 
0.12901174 
 
 
Basic Statistical Measures 
Location 
Variability 
Mean 
0.00000 Std Deviation 
0.54735 
Median -0.05687 Variance 
0.29959 
Mode 
. Range 
1.94447 
 
 Interquartile Range 0.84716 
 
 
Tests for Location: Mu0=0 
Test 
Statistic 
p Value 
Student's t 
t 
0 Pr > |t| 
1.0000 
Sign 
M 
-1 Pr >= |M| 0.8145 
Signed Rank S 
0.5 Pr >= |S| 
1.0000 
 
 
Tests for Normality 
Test 
Statistic 
p Value 
Shapiro-Wilk 
W 
0.956817 Pr < W 
0.5415 
Kolmogorov-Smirnov D 
0.136012 Pr > D 
>0.1500 
Cramer-von Mises 
W-Sq 0.058553 Pr > W-Sq 
>0.2500 
Anderson-Darling 
A-Sq 
0.354958 Pr > A-Sq 
>0.2500 
 
 
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Quantiles (Definition 5) 
Quantile 
Estimate 
100% Max 
0.911191 
99% 
0.911191 
95% 
0.911191 
90% 
0.732887 
75% Q3 
0.418596 
50% Median 
-0.056869 
25% Q1 
-0.428560 
10% 
-0.571557 
5% 
-1.033276 
1% 
-1.033276 
0% Min 
-1.033276 
 
 
Extreme Observations 
Lowest 
Highest 
Value Obs 
Value Obs 
-1.033276 
4 0.418596 
17 
-0.571557 
5 0.637136 
8 
-0.538749 
13 0.639577 
3 
-0.502206 
11 0.732887 
2 
-0.428560 
12 0.911191 
15 
 
 
         Stem Leaf                     #             Boxplot                                   Normal Probability Plot                 
            0 6679                     4                |                   0.75+                                 * +*+*++++*             
            0 1344                     4             +--+--+                    |                         ++*+**+*++                      
           -0 444210                   6             *-----*               -0.25+                ++*+**+** *                            
           -0 655                      3                |                       |       +++++*+*+ *                                        
           -1 0                        1                |                  -1.25++++++++*                                                  
              ----+----+----+----+                                               
+----+----+----+----+----+----+----+----+----+----+        
                                                                                     -2        -1         0        +1        +2             
                                                                                                                                            
                                                                                                                                            
 
 
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Normality Assessment for Plasma LOXO-292 - AUC0-24 for Table 14.2.1.8 
 
 
 
 
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30 
25 
20 
"i= 
(J.) 
15 
(J.) 
P-.. 
10 
5 
0 
-1.0 
-0.6 
-0.2 
0.2 
0.6 
1.0 
Residual 
Program: /CA27486/sas _JJrg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 


  
 
Normality Assessment for Plasma LOXO-292 - AUC0-24 for Table 14.2.1.8 
 
Fitted Normal Distribution for Resid (Residual) 
 
Parameters for Normal 
Distribution 
Parameter Symbol Estimate 
Mean 
Mu 
0 
Std Dev 
Sigma 
0.54735 
 
 
Goodness-of-Fit Tests for Normal Distribution 
Test 
Statistic 
p Value 
Kolmogorov-Smirnov D 
0.13601194 Pr > D 
>0.150 
Cramer-von Mises 
W-Sq 0.05855315 Pr > W-Sq 
>0.250 
Anderson-Darling 
A-Sq 
0.35495841 Pr > A-Sq 
>0.250 
 
 
Quantiles for Normal 
Distribution 
Percent 
Quantile 
Observed Estimated 
1.0 
-1.03328 
-1.27333 
5.0 
-1.03328 
-0.90031 
10.0 
-0.57156 
-0.70146 
25.0 
-0.42856 
-0.36918 
50.0 
-0.05687 
0.00000 
75.0 
0.41860 
0.36918 
90.0 
0.73289 
0.70146 
95.0 
0.91119 
0.90031 
99.0 
0.91119 
1.27333 
 
 
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Normality Assessment for Plasma LOXO-292 - AUC0-24 for Table 14.2.1.8 
 
 
 
 
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1.0 
0.5 
0 
-0.5 
-1.0 
-1.5 '-,---------~---------~--------~----------r" 
-2 
-1 
0 
2 
Normal Quantiles 
Program: /CA27486/sas _JJrg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 


  
 
Normality Assessment for Plasma LOXO-292 - AUC0-t for Table 14.2.1.8 
 
Variable:  Resid  
(Residual) 
 
Moments 
N 
18 Sum Weights 
18 
Mean 
0 Sum Observations 
0 
Std Deviation 
0.46582814 Variance 
0.21699586 
Skewness 
0.02529015 Kurtosis 
-0.7048472 
Uncorrected SS 3.68892959 Corrected SS 
3.68892959 
Coeff Variation 
. Std Error Mean 
0.10979675 
 
 
Basic Statistical Measures 
Location 
Variability 
Mean 
0.00000 Std Deviation 
0.46583 
Median -0.02241 Variance 
0.21700 
Mode 
. Range 
1.69726 
 
 Interquartile Range 0.79460 
 
 
Tests for Location: Mu0=0 
Test 
Statistic 
p Value 
Student's t 
t 
0 Pr > |t| 
1.0000 
Sign 
M 
-1 Pr >= |M| 0.8145 
Signed Rank S 
4.5 Pr >= |S| 
0.8650 
 
 
Tests for Normality 
Test 
Statistic 
p Value 
Shapiro-Wilk 
W 
0.963641 Pr < W 
0.6731 
Kolmogorov-Smirnov D 
0.14155 Pr > D 
>0.1500 
Cramer-von Mises 
W-Sq 
0.05408 Pr > W-Sq 
>0.2500 
Anderson-Darling 
A-Sq 
0.323198 Pr > A-Sq 
>0.2500 
 
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Quantiles (Definition 5) 
Quantile 
Estimate 
100% Max 
0.7897647 
99% 
0.7897647 
95% 
0.7897647 
90% 
0.6790547 
75% Q3 
0.4344805 
50% Median 
-0.0224074 
25% Q1 
-0.3601238 
10% 
-0.5634883 
5% 
-0.9074926 
1% 
-0.9074926 
0% Min 
-0.9074926 
 
 
Extreme Observations 
Lowest 
Highest 
Value Obs 
Value Obs 
-0.907493 
4 0.434481 
3 
-0.563488 
11 0.450776 
17 
-0.388061 
14 0.515411 
8 
-0.373340 
13 0.679055 
2 
-0.360124 
12 0.789765 
15 
 
 
         Stem Leaf                     #             Boxplot                                   Normal Probability Plot                 
            6 89                       2                |                    0.7+                                      *++++*               
            4 1352                     4             +-----+                    |                              * **++*+                   
            2                                        |     |                    |                              ++++                         
            0 58                       2             |  +  |                    |                         ++*+*                             
           -0 31                       2             *-----*                -0.1+                     +++* *                              
           -2 976510                   6             +-----+                    |              *  **+** *                                 
           -4 6                        1                |                       |            *++++                                          
           -6                                           |                       |        +++++                                              
           -8 1                        1                |                   -0.9+    +++*                                                   
              ----+----+----+----+                                               
+----+----+----+----+----+----+----+----+----+----+        
          Multiply Stem.Leaf by 10**-1                                               -2        -1         0        +1        +2         
                                                                                                                                            
                                                                                                                                            
 
 
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Normality Assessment for Plasma LOXO-292 - AUC0-t for Table 14.2.1.8 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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40 
35 
30 
25 
....., 
i:::: 
Q.) 
u 20 
...... 
Q.) 
P-.. 
15 
10 
5 
0 
-0.8 
-0.4 
0 
0.4 
0.8 
Residual 
Program: /CA27486/sas _prg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 


  
 
Normality Assessment for Plasma LOXO-292 - AUC0-t for Table 14.2.1.8 
 
Fitted Normal Distribution for Resid (Residual) 
 
Parameters for Normal 
Distribution 
Parameter Symbol Estimate 
Mean 
Mu 
0 
Std Dev 
Sigma 
0.465828 
 
 
Goodness-of-Fit Tests for Normal Distribution 
Test 
Statistic 
p Value 
Kolmogorov-Smirnov D 
0.14154968 Pr > D 
>0.150 
Cramer-von Mises 
W-Sq 0.05408010 Pr > W-Sq 
>0.250 
Anderson-Darling 
A-Sq 
0.32319805 Pr > A-Sq 
>0.250 
 
 
Quantiles for Normal 
Distribution 
Percent 
Quantile 
Observed Estimated 
1.0 
-0.90749 
-1.08368 
5.0 
-0.90749 
-0.76622 
10.0 
-0.56349 
-0.59698 
25.0 
-0.36012 
-0.31420 
50.0 
-0.02241 
0.00000 
75.0 
0.43448 
0.31420 
90.0 
0.67905 
0.59698 
95.0 
0.78976 
0.76622 
99.0 
0.78976 
1.08368 
 
 
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Normality Assessment for Plasma LOXO-292 - AUC0-t for Table 14.2.1.8 
 
 
 
 
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1.00 
0.75 
0.50 
+ 
0.25 
;::l 
"d 
0 
·uJ 
(J.) 
-0.25 
-0.50 
-0.75 
-1.00 
-2 
-1 
0 
1 
2 
Normal Quantiles 
Program: /CA27486/sas _JJrg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 


  
 
Normality Assessment for Plasma LOXO-292 - AUC0-inf for Table 14.2.1.8 
 
Variable:  Resid  
(Residual) 
 
Moments 
N 
18 Sum Weights 
18 
Mean 
0 Sum Observations 
0 
Std Deviation 
0.46645909 Variance 
0.21758408 
Skewness 
0.02449645 Kurtosis 
-0.7030042 
Uncorrected SS 3.69892938 Corrected SS 
3.69892938 
Coeff Variation 
. Std Error Mean 
0.10994546 
 
 
Basic Statistical Measures 
Location 
Variability 
Mean 
0.00000 Std Deviation 
0.46646 
Median -0.02399 Variance 
0.21758 
Mode 
. Range 
1.69857 
 
 Interquartile Range 0.79328 
 
 
Tests for Location: Mu0=0 
Test 
Statistic 
p Value 
Student's t 
t 
0 Pr > |t| 
1.0000 
Sign 
M 
-1 Pr >= |M| 0.8145 
Signed Rank S 
4.5 Pr >= |S| 
0.8650 
 
 
Tests for Normality 
Test 
Statistic 
p Value 
Shapiro-Wilk 
W 
0.963429 Pr < W 
0.6689 
Kolmogorov-Smirnov D 
0.143674 Pr > D 
>0.1500 
Cramer-von Mises 
W-Sq 0.054387 Pr > W-Sq 
>0.2500 
Anderson-Darling 
A-Sq 
0.324758 Pr > A-Sq 
>0.2500 
 
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Quantiles (Definition 5) 
Quantile 
Estimate 
100% Max 
0.7893745 
99% 
0.7893745 
95% 
0.7893745 
90% 
0.6807874 
75% Q3 
0.4301697 
50% Median 
-0.0239911 
25% Q1 
-0.3631091 
10% 
-0.5645001 
5% 
-0.9091996 
1% 
-0.9091996 
0% Min 
-0.9091996 
 
 
Extreme Observations 
Lowest 
Highest 
Value Obs 
Value Obs 
-0.909200 
4 0.430170 
3 
-0.564500 
11 0.453220 
17 
-0.392096 
14 0.517990 
8 
-0.368800 
13 0.680787 
2 
-0.363109 
12 0.789374 
15 
 
 
         Stem Leaf                     #             Boxplot                                   Normal Probability Plot                 
            6 89                       2                |                    0.7+                                      *++++*               
            4 1352                     4             +-----+                    |                              * **++*+                   
            2                                        |     |                    |                              ++++                         
            0 57                       2             |  +  |                    |                         ++*+*                             
           -0 31                       2             *-----*                -0.1+                     +++* *                              
           -2 976511                   6             +-----+                    |              *  **+** *                                 
           -4 6                        1                |                       |            *++++                                          
           -6                                           |                       |        +++++                                              
           -8 1                        1                |                   -0.9+    +++*                                                   
              ----+----+----+----+                                               
+----+----+----+----+----+----+----+----+----+----+        
          Multiply Stem.Leaf by 10**-1                                               -2        -1         0        +1        +2         
                                                                                                                                            
                                                                                                                                            
 
 
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Normality Assessment for Plasma LOXO-292 - AUC0-inf for Table 14.2.1.8 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
136
40 
35 
30 
25 
....., 
i:::: 
Q.) 
u 20 
...... 
Q.) 
P-.. 
15 
10 
5 
0 
-0.8 
-0.4 
0 
0.4 
0.8 
Residual 
Program: /CA27486/sas _prg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 


  
 
Normality Assessment for Plasma LOXO-292 - AUC0-inf for Table 14.2.1.8 
 
Fitted Normal Distribution for Resid (Residual) 
 
Parameters for Normal 
Distribution 
Parameter Symbol Estimate 
Mean 
Mu 
0 
Std Dev 
Sigma 
0.466459 
 
 
Goodness-of-Fit Tests for Normal Distribution 
Test 
Statistic 
p Value 
Kolmogorov-Smirnov D 
0.14367408 Pr > D 
>0.150 
Cramer-von Mises 
W-Sq 0.05438651 Pr > W-Sq 
>0.250 
Anderson-Darling 
A-Sq 
0.32475804 Pr > A-Sq 
>0.250 
 
 
Quantiles for Normal 
Distribution 
Percent 
Quantile 
Observed Estimated 
1.0 
-0.90920 
-1.08515 
5.0 
-0.90920 
-0.76726 
10.0 
-0.56450 
-0.59779 
25.0 
-0.36311 
-0.31462 
50.0 
-0.02399 
0.00000 
75.0 
0.43017 
0.31462 
90.0 
0.68079 
0.59779 
95.0 
0.78937 
0.76726 
99.0 
0.78937 
1.08515 
 
 
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Normality Assessment for Plasma LOXO-292 - AUC0-inf for Table 14.2.1.8 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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1.00 
0.75 
0.50 
0.25 
;::l 
"d 
0 
·uJ 
(J.) 
-0.25 
-0.50 
-0.75 
-1.00 
-2 
-1 
0 
1 
2 
Normal Quantiles 
Program: /CA27486/sas _JJrg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 


  
 
Normality Assessment for Plasma LOXO-292 - Cmax for Table 14.2.1.8 
 
Variable:  Resid  
(Residual) 
 
Moments 
N 
18 Sum Weights 
18 
Mean 
0 Sum Observations 
0 
Std Deviation 
0.57456894 Variance 
0.33012946 
Skewness 
0.23968228 Kurtosis 
-0.950472 
Uncorrected SS 5.61220085 Corrected SS 
5.61220085 
Coeff Variation 
. Std Error Mean 
0.1354272 
 
 
Basic Statistical Measures 
Location 
Variability 
Mean 
0.00000 Std Deviation 
0.57457 
Median -0.16680 Variance 
0.33013 
Mode 
. Range 
2.01438 
 
 Interquartile Range 0.93976 
 
 
Tests for Location: Mu0=0 
Test 
Statistic 
p Value 
Student's t 
t 
0 Pr > |t| 
1.0000 
Sign 
M 
-1 Pr >= |M| 0.8145 
Signed Rank S 
-0.5 Pr >= |S| 
1.0000 
 
 
Tests for Normality 
Test 
Statistic 
p Value 
Shapiro-Wilk 
W 
0.950454 Pr < W 
0.4322 
Kolmogorov-Smirnov D 
0.156434 Pr > D 
>0.1500 
Cramer-von Mises 
W-Sq 0.078884 Pr > W-Sq 
0.2084 
Anderson-Darling 
A-Sq 
0.433324 Pr > A-Sq 
>0.2500 
 
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Quantiles (Definition 5) 
Quantile 
Estimate 
100% Max 
1.026269 
99% 
1.026269 
95% 
1.026269 
90% 
0.751894 
75% Q3 
0.547859 
50% Median 
-0.166802 
25% Q1 
-0.391901 
10% 
-0.684769 
5% 
-0.988116 
1% 
-0.988116 
0% Min 
-0.988116 
 
 
Extreme Observations 
Lowest 
Highest 
Value Obs 
Value Obs 
-0.988116 
4 0.547859 
10 
-0.684769 
12 0.615043 
8 
-0.638559 
5 0.747736 
2 
-0.416163 
11 0.751894 
3 
-0.391901 
13 1.026269 
15 
 
 
         Stem Leaf                     #             Boxplot                                   Normal Probability Plot                 
            1 0                        1                |                   1.25+                                           *+++++++       
            0 55678                    5             +-----+                    |                              * **++*+*++++             
            0 01                       2             |  +  |                    |                         ++*+*++++                        
           -0 4442221                  7             *-----*                    |                 **+**+** *                             
           -0 76                       2                |                       |       *++++*+*++                                         
           -1 0                        1                |                  -1.25+++++++++                                                  
              ----+----+----+----+                                               
+----+----+----+----+----+----+----+----+----+----+        
                                                                                     -2        -1         0        +1        +2             
                                                                                                                                            
                                                                                                                                            
 
 
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Normality Assessment for Plasma LOXO-292 - Cmax for Table 14.2.1.8 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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35 
30 
25 
"'i:: 20 
Q.) 
Q.) 
P-.. 
15 
10 
5 
0 
-1.0 
-0.5 
0 
Residual 
0.5 
Program: /CA27486/sas _prg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22 
1.0 


  
 
Normality Assessment for Plasma LOXO-292 - Cmax for Table 14.2.1.8 
 
Fitted Normal Distribution for Resid (Residual) 
 
Parameters for Normal 
Distribution 
Parameter Symbol Estimate 
Mean 
Mu 
0 
Std Dev 
Sigma 
0.574569 
 
 
Goodness-of-Fit Tests for Normal Distribution 
Test 
Statistic 
p Value 
Kolmogorov-Smirnov D 
0.15643424 Pr > D 
>0.150 
Cramer-von Mises 
W-Sq 0.07888421 Pr > W-Sq 
0.208 
Anderson-Darling 
A-Sq 
0.43332377 Pr > A-Sq 
>0.250 
 
 
Quantiles for Normal 
Distribution 
Percent 
Quantile 
Observed Estimated 
1.0 
-0.98812 
-1.33665 
5.0 
-0.98812 
-0.94508 
10.0 
-0.68477 
-0.73634 
25.0 
-0.39190 
-0.38754 
50.0 
-0.16680 
0.00000 
75.0 
0.54786 
0.38754 
90.0 
0.75189 
0.73634 
95.0 
1.02627 
0.94508 
99.0 
1.02627 
1.33665 
 
 
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Normality Assessment for Plasma LOXO-292 - Cmax for Table 14.2.1.8 
 
 
 
 
LOXO-RET-18057; CA27486; 16.1.9 Documentation of Statistical Methods
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1.5 
1.0 
0.5 
;::l 
"d 
"ul 
(J.) 
0 
+ 
+ 
+ 
-0.5 
-1.0 '-,---------~---------~--------~---------," 
-2 
-1 
0 
2 
Normal Quantiles 
Program: /CA27486/sas _JJrg/pksas/adam _ doseprop-mixed.sas 19JUN2019 4:22