An Open-Label, 3-Period, Fixed Sequence Study to Evaluate the Effect of an H2 Antagonist and a Proton Pump Inhibitor on the Single Dose Pharmacokinetics of LOXO-292 in Healthy Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Clinical Study Protocol Version 1.0 J2G-OX-JZJL 
 
An Open-Label, 3-Period, Fixed Sequence Study to Evaluate the Effect of an H2 Antagonist and a 
Proton Pump Inhibitor on the Single Dose Pharmacokinetics of LOXO-292 in Healthy Adult Subjects 
NCT05338502 
Approval Date: 20-June-2019 

Clinical Study Report 
CONFIDENTIAL 
Covance Study: 8412056 
Sponsor Reference: LOXO-RET-19075 
  
16.1. Study Information 
16.1.1. 
Protocol and Amendments 
 
Final
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Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
Page 1 of 53 
TITLE PAGE 
Protocol 
An Open-Label, 3-Period, Fixed Sequence Study to Evaluate the Effect of an 
H2 Antagonist and a Proton Pump Inhibitor on the Single Dose 
Pharmacokinetics of LOXO-292 in Healthy Adult Subjects 
Protocol Status: Final 
Original Final Protocol Date: 20 June 2019 
Protocol Version: 1 
Investigational Product: LOXO-292 
Protocol Reference Number: LOXO-RET-19075 
Covance Study Number: 8412-056 
IND Number: 133193 
for 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
by 
Covance Early Clinical Services 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
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Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019 
Page 2 of 53 
STUDY IDENTIFICATION 
Sponsor 
Loxo Oncology, Inc. 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
(650) 989-8051 (Main Telephone No.)
Sponsor’s Study Contact 
Sponsor’s Medical Contact 
Bioanalytical Laboratory 
Protocol Medical Writer 
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PPD
PPD
PPD
PPD

Protocol 
Covance Study 8412-056 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-19075 
PRINCIPAL INVESTIGATOR AND SPONSOR- SIGNATORIES 
An Open-Label, 3--Period, Fixed Sequence Study to Evaluate the Effect of an 
112 Antagonist and a Proton Pump Inhibitor on the Single Dose 
Pharmacokinetics of LOX0-292 in Healthy Adult Subjects 
SPONSOR: 
Loxo Oncology, Inc. 
70 l Gateway Boulevard, Suite 420 
South San Francisco, California 94080, USA 
SPONSOR'S 
REPRESENTATIVE: 
Protocol Final: 20 June 2019 
Page 3 of 53 
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PPD
PPD
PPD
PPD

Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
Page 4 of 53 
SYNOPSIS 
Title of study: An Open-Label, 3-Period, Fixed Sequence Study to Evaluate the Effect of an H2 
Antagonist and a Proton Pump Inhibitor on the Single Dose Pharmacokinetics of LOXO-292 in 
Healthy Adult Subjects 
Objectives:  
The objectives of this study are:  
Primary: 
• 
To assess the effect of multiple doses of an H2 antagonist (ranitidine) administered with a 
single dose of LOXO-292 on the pharmacokinetics (PK) of LOXO-292 under fasted 
conditions in healthy adult subjects. 
• 
To assess the effect of multiple doses of a proton pump inhibitor (PPI) (omeprazole) 
administered with a single dose of LOXO-292 on the PK of LOXO-292 given with a 
low-fat meal in healthy adult subjects. 
Secondary: 
• 
To determine the safety and tolerability of a single dose of LOXO-292 under fasted 
conditions alone, in combination with an H2 antagonist (ranitidine) under fasted conditions, 
and in combination with a PPI (omeprazole) given with a low-fat meal in healthy adult 
subjects. 
Study design: 
This is an open label, 3-period, fixed sequence study. 
 
In Period 1, a single oral dose of LOXO-292 will be administered under fasted conditions. On 
Day 1 of Period 1, a single oral dose of 160 mg of LOXO-292 will be administered following a fast 
of 10 hours prior to and 4 hours after the LOXO-292 dose. Blood samples for LOXO-292 PK 
analysis will be taken for 168 hours after the LOXO-292 dose on Day 1. 
 
In Period 2, multiple oral doses of ranitidine will be administered twice daily from Day 8 until 
Day 18 inclusively (for a total of 11 consecutive days) and administered with a single oral dose of 
LOXO-292 on Day 12 under fasted conditions. On Day 12, a single oral dose of 160 mg of 
LOXO-292 will be administered following a fast of 10 hours prior to and 4 hours after the 
LOXO-292 dose. On Day 12, ranitidine will be administered 2 hours (± 10 minutes) after the 
LOXO-292 dose. On Days 8 - 11 and 13 - 18, the morning dose of ranitidine will be administered 
(with breakfast) approximately 2 hours (± 1 hour) after the planned or actual time of the Day 12 
LOXO-292 dose and the evening dose of ranitidine will be administered (with a light meal/snack) 
approximately 10 hours (± 1 hour) prior to the planned or actual time of the Day 12 LOXO-292 
dose. Blood samples for LOXO-292 PK analysis will be taken for 168 hours after the LOXO-292 
dose on Day 12.  
 
In Period 3, multiple oral doses of omeprazole will be administered once daily from Day 19 until 
Day 29 inclusively (for a total of 11 consecutive days) and administered with a single oral dose of 
LOXO-292 on Day 23 with a low-fat meal. On Day 23, omeprazole and a single oral dose of 
160 mg of LOXO-292 will be coadministered within 30 minutes of the start of a low-fat meal, 
which will be entirely consumed within 30 minutes. On Days 19 - 22 and 24 - 29, omeprazole will 
be administered following a fast of 2 hours prior to and 1 hour after the omeprazole dose (Note: 
omeprazole will be administered at approximately the actual time of the Day 12 LOXO-292 
dosing). Blood samples for LOXO-292 PK analysis will be taken for 168 hours after the 
LOXO-292 dose on Day 23. 
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Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
Page 5 of 53 
There will be a washout period of 7 days between the LOXO-292 dose in Period 1 and the first dose 
of ranitidine in Period 2 and between the LOXO-292 dose in Period 2 and the first dose of 
omeprazole in Period 3.  
 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor.  
 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of Treatment 
(EOT) on Day 30 upon completion of all PK and safety assessments or Early Termination (ET) if 
the subject discontinues. A follow-up phone call will occur for all subjects who received at least 
1 dose of study drug (including subjects who are terminated study early) 7 days (± 2 days) after 
EOT or ET. 
 
In this study, physical examinations (PEs), 12-lead electrocardiograms (ECGs), vital signs, How Do 
You Feel? inquiries, clinical chemistry panel, coagulation parameters, complete blood count (CBC), 
and urinalysis (UA; Appendix 2) and concomitant medication recording will be performed at 
Screening and at specified times during the study (for specific timepoints and details on each study 
variable, refer to Appendix 4). Adverse events (AEs) and serious adverse events (SAEs) will be 
collected beginning at informed consent. AEs will be reported throughout the study (ie, from 
signing of the Informed Consent Form [ICF] until End of Study [EOS], or until ET if the subject 
discontinues from the study and does not complete a follow-up phone call), either as subject 
medical history (if the event is reported as beginning prior to signing of the ICF or if the event 
occurs prior to study drug administration on Day 1 and is assessed as not related to study 
procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the ICF 
but prior to study drug administration on Day 1 and is assessed as related to study procedures by the 
Investigator [or designee], or if the event occurs after study drug administration on Day 1 through 
EOT or ET regardless of relationship to study drug). From EOT or ET through EOS, only AEs 
assessed as related to study drug by the Investigator (or designee) are to be reported. All SAEs that 
develop from the time of ICF signing until EOS (or ET, if the subject discontinues from the study 
and does not complete a follow-up phone call) are to be reported. 
 
Study Completion is defined as the time of the last subject’s follow-up phone call. 
Number of subjects: 
Twenty healthy, adult, male and female subjects (women of nonchildbearing potential only) are 
considered sufficient to assess the effect of multiple doses of an H2 antagonist (under fasted 
conditions) or a PPI (given with a low-fat meal) on the PK of LOXO-292. 
 
Every attempt will be made to enroll at least 3 subjects of each sex in the study. 
 
Subjects who withdraw or drop out of the study may be replaced if deemed necessary by the 
Sponsor. 
Diagnosis and main criteria for inclusion: 
Male subjects and female subjects of nonchildbearing potential, between 18 and 55 years of age, 
inclusive, at Screening, and within body mass index (BMI) range 18.5 to 32.0 kg/m2, inclusive. 
Subjects will be in good general health, based on medical history, PE findings, vital signs, ECG, 
and clinical laboratory tests at Screening and Check-in (Day -1), as determined by the Investigator 
(or designee). 
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Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
Page 6 of 53 
Investigational products, dose, and mode of administration: 
LOXO-292 will be supplied by Loxo Oncology as 80 mg capsules for oral administration. 
Ranitidine will be supplied by Covance as 150 mg tablets for oral administration. Omeprazole will 
be supplied by Covance as 40 mg capsules for oral administration 
 
Period 1: Subjects will be administered 160 mg LOXO-292 (2 x 80 mg capsules) on Day 1 
administered under fasted conditions. 
 
Period 2: Subjects will be administered 150 mg of rantidine twice daily from Day 8 of through 
Day 18, inclusive, administered with 160 mg LOXO-292 on Day 12 under fasted conditions.  
 
Period 3: Subjects will be administered 40 mg of omeprazole once daily from Day 19 through 
Day 29, inclusive, administered with 160 mg LOXO-292 on Day 23 with a low-fat meal.  
Duration of subject participation in the study: 
Planned Enrollment/Screening Duration: up to 28 days (Day -29 to Day -2). 
 
Length of Confinement: a total of 31 days (30 nights), from the time of Check-in (Day -1) through 
the 168-hour PK blood draw and end of study assessments (Day 30). 
 
Follow-up Phone Call: 7 days (± 2 days) after EOT or ET. 
 
Planned Study Conduct Duration: approximately 60 days 
Criteria for evaluation: 
Pharmacokinetics: 
Serial PK blood samples for the analysis of plasma LOXO-292 concentrations will be collected 
from predose through 168 hours postdose.  
 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-292 (as appropriate): area under the concentration-time curve from Hour 0 
to the last measurable concentration (AUC0-t), area under the concentration time curve extrapolated 
to infinity (AUC0-∞), extrapolation for area under the concentration time curve (%AUCextrap), 
maximum plasma concentration (Cmax), time to maximum observed concentration (tmax), elimination 
rate constant (λZ), apparent systemic clearance (CL/F), and apparent terminal elimination half-life 
(t½). 
 
An analysis of variance (ANOVA) will be performed on the natural log (ln)transformed AUC0-t, 
AUC0-∞, and Cmax, using the appropriate statistical procedure. 
 
Safety: 
Safety will be monitored through 12-lead ECGs, PEs, concomitant medications, vital sign 
measurements, clinical laboratory tests, and AEs. 
 
 
 
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CCI

Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019 
Page 7 of 53 
Statistical methods: 
Pharmacokinetics:  
The primary analysis planned for this study is an analysis of variance (ANOVA) model that 
includes treatment as a fixed-effect and subject as a random-effect. 
 
 
 
 
 
  
Safety:  
All safety assessments, including AEs and SAEs, vital signs measurements, clinical laboratory 
results, PE results, concomitant medications, and ECG interpretations, will be tabulated and 
summarized where possible, using descriptive methodology, as needed, by timepoint. Unless 
otherwise specified, baseline value is defined as the last nonmissing measurement before 
administration of LOXO-292 in each period. No formal statistical analyses are planned for the 
safety data. 
More details on the analyses will be included in the Statistical Analysis Plan (SAP). 
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CCI

Protocol 
CONFIDENTIAL 
Covance Study 8412-056 
Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
Page 8 of 53 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STUDY IDENTIFICATION ...........................................................................................................2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ............................................3 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES AND FIGURES..............................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
1. 
INTRODUCTION ......................................................................................................15 
1.1. 
Background .................................................................................................................15 
1.2. 
Summary of Nonclinical Studies ................................................................................15 
1.3. 
Summary of Clinical Studies ......................................................................................16 
1.4. 
Study Rationale ...........................................................................................................18 
1.5. 
Benefit-risk Assessment .............................................................................................18 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................19 
2.1. 
Objectives ...................................................................................................................19 
2.2. 
Endpoints ....................................................................................................................19 
3. 
INVESTIGATIONAL PLAN .....................................................................................20 
3.1. 
Overall Study Design and Plan ...................................................................................20 
3.2. 
Discussion of Study Design ........................................................................................21 
3.3. 
Selection of Doses in the Study ..................................................................................22 
4. 
SELECTION OF STUDY POPULATION ................................................................22 
4.1. 
Screening Procedures ..................................................................................................22 
4.2. 
Check-in Procedures (Day -1) ....................................................................................23 
4.3. 
Inclusion Criteria ........................................................................................................24 
4.4. 
Exclusion Criteria .......................................................................................................25 
4.5. 
Subject Number and Identification .............................................................................29 
4.6. 
Removal of Subjects from Study Participation ..........................................................29 
5. 
STUDY TREATMENTS............................................................................................30 
5.1. 
Description, Storage, Packaging, and Labeling ..........................................................30 
5.2. 
Study Treatment Administration ................................................................................31 
5.3. 
Randomization ............................................................................................................32 
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Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
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5.4. 
Blinding ......................................................................................................................32 
5.5. 
Treatment Compliance ................................................................................................32 
5.6. 
Drug Accountability ...................................................................................................32 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ...........................33 
6.1. 
Concomitant Therapies ...............................................................................................33 
6.2. 
Diet, Fluid, and Activity Control ................................................................................33 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................34 
7.1. 
Pharmacokinetic Assessments ....................................................................................34 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing .......................................34 
7.1.2. 
Analytical Methodology .............................................................................................34 
7.2. 
Safety and Tolerability Assessments ..........................................................................35 
7.2.1. 
Adverse Events ...........................................................................................................35 
7.2.2. 
Clinical Laboratory Evaluations .................................................................................36 
7.2.3. 
Vital Signs ..................................................................................................................36 
7.2.4. 
12-Lead Electrocardiogram ........................................................................................36 
7.2.5. 
Physical Examination .................................................................................................37 
8. 
SAMPLE SIZE AND DATA ANALYSIS.................................................................37 
8.1. 
Determination of Sample Size. ...................................................................................37 
8.2. 
Analysis Populations ..................................................................................................37 
8.2.1. 
Study Populations .......................................................................................................37 
8.3. 
Pharmacokinetic Analysis ..........................................................................................37 
8.3.1. 
Descriptive Analysis ...................................................................................................38 
8.3.2. 
Analysis of Variance (ANOVA) ................................................................................39 
8.4. 
Safety Analysis ...........................................................................................................39 
8.5. 
Data Handling and Record Keeping ...........................................................................39 
8.6. 
Quality Control and Quality Assurance ......................................................................40 
9. 
ADMINISTRATIVE ASPECTS ................................................................................40 
9.1. 
Change in Protocol .....................................................................................................40 
9.2. 
Site Initiation Visit/Investigator Meeting ...................................................................40 
9.3. 
Disclosure ...................................................................................................................40 
9.4. 
Monitoring ..................................................................................................................40 
9.5. 
Institutional Review Board .........................................................................................41 
9.6. 
Informed Consent .......................................................................................................41 
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Protocol Final: 20 June 2019  
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9.7. 
Records .......................................................................................................................41 
9.8. 
Reference to Declaration of Helsinki/Basic Principles ..............................................42 
9.9. 
Financing and Insurance .............................................................................................42 
10. 
REFERENCES ...........................................................................................................43 
11. 
APPENDICES ............................................................................................................44 
Appendix 1: Adverse Event Reporting ..........................................................................................45 
Appendix 2: Clinical Laboratory Evaluations ...............................................................................49 
Appendix 3: Total Blood Volume..................................................................................................50 
Appendix 4: Schedule of Assessments ..........................................................................................51 
 
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Protocol 
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Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
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LIST OF TABLES AND FIGURES 
Table 1 
Study Drug – Period 1 ................................................................................................30 
Table 2 
Study Drug – Period 2 ................................................................................................30 
Table 3 
Study Drug – Period 3 ................................................................................................30 
 
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Protocol 
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Protocol Reference: LOXO-RET-19075 
Protocol Final: 20 June 2019  
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATU 
temporary authorization use 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last measurable 
concentration 
AV 
atrioventricular 
BMI 
body mass index 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination  
FDA 
Food and Drug Administration 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
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Protocol Final: 20 June 2019  
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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HDYF? 
How do you feel? 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IC50 
50% inhibitory concentration 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board  
IUD 
intrauterine device 
λZ 
apparent terminal elimination rate constant 
LFT 
liver function test 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCR 
polymerase chain reaction 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve  
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell 
RET 
rearranged during transfection 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SPP 
single-patient protocols 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax  
time to maximum observed concentration 
UA 
urinalysis 
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Protocol 
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Protocol Final: 20 June 2019  
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Abbreviation 
Definition 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
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Protocol 
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1. INTRODUCTION 
Refer to the current Investigator’s Brochure (IB)1 for detailed information concerning the 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
the investigational medicinal product. 
1.1. 
Background 
LOXO-292 is a small molecule and 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. 
1.2. 
Summary of Nonclinical Studies 
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 
electrocardiogram [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. 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. In the 3-month repeated-dose study, an increase in QTc interval was noted 
in female minipigs administered 5 mg/kg/day of LOXO-292, but the degree of the increase was 
small (approximately 7 to 12%). These low magnitude QTc changes were potentially 
LOXO-292-related but were not considered adverse. 
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. 
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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, lymphoid 
tissues, physeal cartilage, and testes; while the gastrointestinal tract and ovaries were target 
tissues in minipig. Other target tissues identified in the rat included: multi-tissue mineralization, 
incisor teeth, lung, Brunner’s gland, vagina, and possibly liver. Assessment of doses associated 
with moribundity/death revealed a steep dose response curve for both species. LOXO-292 was 
not mutagenic in the GLP bacterial mutation assay and was not clastogenic in the in vivo 
micronucleus assay. LOXO-292 was not found to be phototoxic when evaluated in an in vitro 
neutral red uptake phototoxicity assay. LOXO-292 is a developmental toxicant and is 
embryolethal. 
In repeated dose toxicity studies in Sprague-Dawley Rats, minor changes suggestive of hepatic 
effects were higher alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in 
males (≥ 20 mg/kg/day) and females (≥ 50 mg/kg/day), higher aspartate aminotransferase (AST) 
levels in those receiving the high-dose (both sexes), and a higher cholesterol concentration in 
males (≥ 20 mg/kg/day). Reversible, LOXO-292-related decreases in liver and thymus weights 
occurred in males at 75 and 45 mg/kg/day, respectively. None of these minor changes were 
correlated to any liver findings microscopically, suggesting minor functional alterations of the 
liver rather than overt hepatocellular injury. ALP levels were also increased in Göttingen 
minipigs administered 5 or 12 mg/kg/day in repeated dose toxicity studies; however, this change 
had no associated clinical or microscopic findings and was considered not adverse. 
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, 
hemoglobin, hematocrit) and reticulocytes, decrease in platelets, increases in liver function tests 
(LFTs; ALP, AST, and ALT), possible pancreas injury, possible QTc prolongation, possible 
decreased testicular weight, possible increased vaginal mucous and altered 
menstruation/ovulation 
Refer to the current IB1 for detailed background information on LOXO-292. 
1.3. 
Summary of Clinical Studies 
LOXO-292 is currently being studied in an ongoing global Phase 1/2 first in human Study 
LOXO-RET-17001 in patients with advanced solid tumors including RET fusion-positive 
non-small cell lung cancer, RET-mutant medullary thyroid cancer, and other tumors with 
increased RET activity. The starting dose of LOXO-292 was 20 mg once daily. 
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Single doses of 320 mg, 640 mg, and 720 mg have been administered to healthy volunteers in the 
ongoing Study LOXO-RET-18057. Interim safety and tolerability analysis showed that all dose 
levels were well-tolerated and there were no Grade ≥ 3 toxicities up to the maximum dose level 
tested (720 mg). 
As of a March 30, 2019 data cut-off date, safety data was available from 422 patients with 
240 mg twice daily as the highest dose administered.  
During dose escalation, 2 dose-limiting toxicities (DLTs) were reported, both at the 240 mg 
twice daily dose level: 1 DLT of Grade 3 tumor lysis syndrome and 1 DLT of Grade 3 
thrombocytopenia. The remaining 4 patients treated at this dose level cleared the 28-day 
DLT window and continued on study. The dosage of 160 mg twice daily was selected as the 
recommended Phase 2 dose (RP2D) based on safety data (N = 82) and preliminary efficacy data 
(N = 64 evaluable) for patients treated at doses from 20 mg once daily through 240 mg twice 
daily.2,3,4  
Across 9 dose levels ranging from 20 mg once daily to 240 mg twice daily in these 422 patients, 
treatment-emergent adverse events (TEAEs) occurring in ≥ 15% patients were: dry mouth 
(30.8% total; 25.1% related), diarrhea (27.7% total; 12.8% related), hypertension (27.3% total; 
16.8% related), fatigue (22.3% total; 14.5% related), constipation (21.8% total; 10.0% related), 
AST increased (21.6% total; 15.6% related), ALT increased (20.4% total; 15.4% related), 
headache (18.7% total; 6.9% related), nausea (18.0% total; 6.6% related), edema peripheral 
(17.3% total; 9.5% related), and blood creatinine increased (14.9% total; 7.3% related). 
A total of 205 (48.6%) patients across all dose levels experienced ≥ Grade 3 TEAEs. TEAEs of 
≥ Grade 3 that were considered to be related to study drug were reported in 95 (22.5%) patients 
across all dose levels. The most common Grade ≥ 3 TEAEs included hypertension (12.3%; 7.1% 
related), ALT increased (6.2%; 4.7% related), AST increased (4.7%; 3.1% related), 
hyponatremia (4.3%; 0.2% related), ECG QT prolonged (2.8%; 2.1% related), dyspnea and 
lymphopenia (each 2.6%; 0% and 0.9% related, respectively), diarrhea and thrombocytopenia 
(each 2.1%; 0.7% and 1.7% related, respectively). All other Grade ≥ 3 TEAEs occurred in less 
than 2% of patients overall.  
Sixteen patients have died within 28 days of the last dose of study drug, and no deaths have been 
attributed to study drug. 
As of April 15, 2019, pharmacokinetic (PK) data were available from 335 patients. LOXO-292 is 
absorbed after oral administration with a median time to maximum observed concentration (tmax) 
of approximately 2 hours.  
As of March 30, 2019, Loxo Oncology initiated 40 single-patient protocols (SPPs), Special 
Access Scheme, Compassionate Use, or Temporary Authorization Use (ATU) cases to provide 
access to LOXO-292 for patients with clinical need not meeting eligibility criteria for the 
ongoing clinical study. For the SPPs, Special Access Scheme, Compassionate Use, or ATU 
cases, only serious adverse events (SAEs) are required to be reported. To date, there have been 
39 SAEs reported in 15 of the patients participating in SPPs, of which 3 have been reported as 
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serious adverse reactions (SARs) which were submitted as Suspected Unexpected Serious 
Adverse Reactions (SUSARs). 
Preliminary PK data available from completed studies (LOXO-RET-18014 and 
LOXO-RET-18015) in healthy subjects indicate that LOXO-292 has an estimated apparent 
terminal elimination half-life (t½) of approximately 24 hours after a single dose. 
Refer to the current IB1 for detailed and updated background clinical study information on 
LOXO-292. 
1.4. 
Study Rationale 
LOXO-292 has pH-dependent solubility and its PK can be affected by agents that modify gastric 
pH such as proton pump inhibitors (eg, omeprazole). Under fasted conditions, following a single 
dose of 160 mg LOXO-292 administered to 20 omeprazole-treated healthy volunteers, the area 
under the concentration-time curve (AUC) and Cmax of LOXO-292 were approximately 69% to 
88% lower than following administration of LOXO-292 under fasted conditions without 
omeprazole. The effect of an H2 antagonist on the PK of LOXO-292 has not been tested. 
In contrast to omeprazole, which is an irreversible inhibitor of gastric acid secretion, ranitidine 
has a shorter duration of action. This study will test the effect of ranitidine when given 10 hours 
before and 2 hours after the dose of LOXO-292. 
The effect of omeprazole on the PK of LOXO-292 is reduced or eliminated when LOXO-292 is 
given with a high-calorie, high-fat meal. The AUC of LOXO-292 following administration of a 
single dose of 160 mg with a high-calorie, high-fat meal to 20 omeprazole-treated healthy 
volunteers was approximately 2% higher than following 160 mg LOXO-292 given under fasted 
conditions without omeprazole, although Cmax was approximately 49% lower. Therefore, during 
Period 3, LOXO-292 will be administered with a low-fat meal.  
To determine if the effect of agents that modify gastric pH on the PK of LOXO-292 can be 
reduced by various antacid dosing regimens, this study will evaluate the effect of multiple doses 
of an H2 antagonist (ranitidine) administered with a single dose of LOXO-292 administered 
under fasted conditions and the effect of multiple-doses of a proton pump inhibitor (PPI) 
(omeprazole) administered with a single dose of LOXO-292 given with a low-fat meal on the PK 
of LOXO-292 in healthy adult subjects. 
1.5. 
Benefit-risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment of 
their medical status) from participating in the study.  
The risks of participation are primarily those associated with adverse reactions to the study 
treatments, although there may also be some discomfort from collection of blood samples and 
other study procedures. More information about the known and expected benefits, risks, and 
reasonably anticipated AEs associated with LOXO-292 may be found in the current IB.1  
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The dose of ranitidine administered in this study is not anticipated to induce any significant 
potential risk or benefit to subjects participating in this study, as the multiple doses are 
administered according to the dosing recommendations found in the full prescribing information 
for ranitidine.5  
The dose of omeprazole administered in this study is not anticipated to induce any significant 
potential risk or benefit to subjects participating in this study, as the multiple doses are 
administered according to the dosing recommendations found in the full prescribing information 
for omeprazole.6  
The safety monitoring practices employed by this protocol (ie, 12-lead electrocardiogram [ECG], 
vital signs, clinical laboratory tests, AE questioning, and physical examinations [PEs]) are 
adequate to protect the subjects’ safety. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The objectives of this study are:  
Primary: 
• 
To assess the effect of multiple doses of an H2 antagonist (ranitidine) administered with 
a single dose of LOXO-292 on the PK of LOXO-292 under fasted conditions in healthy 
adult subjects. 
• 
To assess the effect of multiple doses of a PPI (omeprazole) administered with a single 
dose of LOXO-292 on the PK of LOXO-292 given with a low-fat meal in healthy adult 
subjects. 
Secondary: 
• 
To determine the safety and tolerability of a single dose of LOXO-292 under fasted 
conditions alone, in combination with an H2 antagonist (ranitidine) under fasted 
conditions, and in combination with a PPI (omeprazole) given with a low-fat meal in 
healthy adult subjects. 
2.2. 
Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-292 (as appropriate): area under the concentration-time curve from 
Hour 0 to the last measurable concentration (AUC0-t), area under the concentration time curve 
extrapolated to infinity (AUC0-∞), extrapolation for area under the concentration time curve 
(%AUCextrap), maximum plasma concentration (Cmax), tmax, elimination rate constant (λZ), 
apparent systemic clearance (CL/F), and apparent terminal elimination half-life (t½). 
Safety and tolerability will be assessed by monitoring AEs, performing PEs and clinical 
laboratory tests, measuring vital signs, and recording ECGs. 
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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is an open label, 3-period, fixed sequence study. 
In Period 1, a single oral dose of LOXO-292 will be administered under fasted conditions. On 
Day 1 of Period 1, a single oral dose of 160 mg of LOXO-292 will be administered following a 
fast of 10 hours prior to and 4 hours after the LOXO-292 dose. Blood samples for LOXO-292 
PK analysis will be taken for 168 hours after the LOXO-292 dose on Day 1. 
In Period 2, multiple oral doses of ranitidine will be administered twice daily from Day 8 until 
Day 18 inclusively (for a total of 11 consecutive days) and administered with a single oral dose 
of LOXO-292 on Day 12 under fasted conditions. On Day 12, a single oral dose of 160 mg of 
LOXO-292 will be administered following a fast of 10 hours prior to and 4 hours after the 
LOXO-292 dose. On Day 12, ranitidine will be administered 2 hours (± 10 minutes) after the 
LOXO-292 dose. On Days 8-11 and 13-18, the morning dose of ranitidine will be administered 
(with breakfast) approximately 2 hours (± 1 hour) after the planned or actual time of the Day 12 
LOXO-292 dose and the evening dose of ranitidine will be administered (with a light 
meal/snack) approximately 10 hours (± 1 hour) prior to the planned or actual time of the Day 12 
LOXO-292 dose. Blood samples for LOXO-292 PK analysis will be taken for 168 hours after the 
LOXO-292 dose on Day 12.  
In Period 3, multiple oral doses of omeprazole will be administered once daily from Day 19 until 
Day 29 inclusively (for a total of 11 consecutive days) and administered with a single oral dose 
of LOXO-292 on Day 23 with a low-fat meal. On Day 23, omeprazole and a single oral dose of 
160 mg of LOXO-292 will be coadministered within 30 minutes of the start of a low-fat meal, 
which will be entirely consumed within 30 minutes. On Days 19 - 22 and 24 - 29, omeprazole 
will be administered following a fast of 2 hours prior to and 1 hour after the omeprazole dose 
(Note: omeprazole will be administered at approximately the actual time of the Day 12 
LOXO-292 dosing). Blood samples for LOXO-292 PK analysis will be taken for 168 hours after 
the LOXO-292 dose on Day 23. 
There will be a washout period of 7 days between the LOXO-292 dose in Period 1 and the first 
dose of ranitidine in Period 2 and a washout period of 7 days between the LOXO-292 dose in 
Period 2 and the first dose of omeprazole in Period 3.  
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor.  
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of Treatment 
(EOT) on Day 30 upon completion of all PK and safety assessments or Early Termination (ET) if 
the subject discontinues. A follow-up phone call will occur for all subjects who received at least 
1 dose of study drug (including subjects who are terminated early) 7 days (± 2 days) after EOT 
or ET. 
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The start of the study is defined as the date the first subject who is enrolled in the study signs an 
Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects who are 
assigned a dose of study drug; this definition excludes screen failure subjects.  
In this study, PEs, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) inquiries, clinical 
chemistry panel, coagulation parameters, complete blood count (CBC), and urinalysis (UA; 
Appendix 2) and recording of concomitant medications will be performed at specified times 
during the study (for specific timepoints and details on each study variable, refer to Appendix 4). 
AEs and SAEs will be collected beginning at informed consent. AEs will be reported throughout 
the study (ie, from signing of the ICF until End of Study [EOS], or until ET if the subject 
discontinues from the study and does not complete a follow-up phone call), either as subject 
medical history (if the event is reported as beginning prior to signing of the ICF or if the event 
occurs prior to study drug administration on Day 1 and is assessed as not related to study 
procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the 
ICF but prior to study drug administration on Day 1 and is assessed as related to study 
procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From EOT 
or ET through EOS, only AEs assessed as related to study drug by the Investigator (or designee) 
are to be reported. All SAEs that develop from the time of ICF signing until EOS (or ET, if the 
subject discontinues from the study and does not complete a follow-up phone call) are to be 
reported.  
Blood samples for LOXO-292 PK analysis will be obtained in each period through 168 hours 
following LOXO-292 administration. A study flow chart is presented in Appendix 4. Study 
completion is defined as the time of the last subject’s follow-up phone call. 
3.2. 
Discussion of Study Design 
This study will evaluate the effect of multiple doses of an H2 antagonist (ranitidine) administered 
under fasted conditions and the effect of effect of multiple-doses of a PPI (omeprazole) given 
with a low-fat meal on the PK of LOXO-292 in healthy adult subjects. 
Gastric pH can alter the absorption of acidic and basic drugs and nonclinical study results 
indicate that LOXO-292 may be sensitive to gastric pH. The Food and Drug Administration 
(FDA) has recently published a review on the topic and has encouraged studies to address the 
effects of coadministration of gastric pH modifiers on oral exposure.7 Thus, a PPI and an H2 
antagonist were chosen to be studied.  
Subjects will participate in 3 periods in a fixed sequence. The washout period of 7 days between 
LOXO-292 doses is considered sufficient to prevent carryover effects of the treatments. 
However, as omeprazole may have a prolong effect on acid secretion due to the irreversible 
nature of omeprazole binding to H+/K+ ATPase pump, the omeprazole treatment portion will be 
conducted only in Period 3 to ensure the effect of a PPI with a low-fat meal can be assessed 
without confounding factors. 
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3.3. 
Selection of Doses in the Study 
LOXO-292 
An oral dose has been selected for this study because this is the intended clinical route of 
administration. The dose of 160 mg of LOXO-292 was selected based on clinical study results 
and its observed PK profile. The 160 mg dose is expected to ensure sufficient quantifiable 
plasma concentrations of LOXO-292 for determination of systemic PK exposure. In a Phase 1/2 
clinical study in cancer patients (LOXO-RET-17001), 160 mg of LOXO-292 dosed twice daily 
has been evaluated and has been selected for further testing in a larger number of cancer patients 
to evaluate its safety and efficacy.  
Omeprazole: 
A dose of 40 mg omeprazole daily is within the recommended dose as prescribed in the labeling. 
In addition, multiple doses for 4 consecutive days prior to LOXO-292 administration will ensure 
maximum inhibition of acid secretion by omeprazole, because the inhibitory effect of 
omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after 
4 days.  
Ranitidine: 
A dose of 150 mg ranitidine twice daily is within the recommended dose as prescribed in the 
labeling. In addition, multiple doses for 4 consecutive days prior to LOXO-292 administration 
will mimic real-life scenarios of patients taking H2 antagonists in the intended patient 
population.  
4. SELECTION OF STUDY POPULATION 
The study will be conducted in healthy subjects. As per the recommendations of the FDA in the 
draft guidance on clinical drug interaction studies,8 drug interaction studies can be carried out in 
healthy volunteers assuming that findings in healthy subjects can be used to predict findings in 
the intended patient population.  
4.1. 
Screening Procedures 
The following screening procedures will be performed for all potential subjects at a visit 
conducted within 28 days of study entry (ie, prior to Check-in [Day -1]): 
1. Informed consent 
2. Demographic data 
3. Medical history 
4. Inclusion/exclusion criteria 
5. Height, weight, and body mass index (BMI) 
6. Complete PE (Section 7.2.5) 
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7. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), and 
human immunodeficiency virus (HIV) antibody (Appendix 2) 
8. Screen for selected drugs of abuse (including cotinine) and an alcohol breath test 
(Appendix 2) 
9. Twelve-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
10. Vital signs (including oral temperature, respiratory rate, and supine blood pressure [BP] 
and heart rate [HR; measured after the subject has been supine for at least 5 minutes]) 
(Section 7.2.3) 
11. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, creatine kinase (CK), CBC, and UA; Appendix 2) 
12. Hemoglobin A1c test (Appendix 2) 
13. Thyroid stimulating hormone (TSH) test (Appendix 2) 
14. How Do You Feel? inquiry and AE and concomitant medication evaluations 
(Section 7.2.1) 
15. Serum pregnancy test (for females only; Appendix 2) 
16. Follicle-stimulating hormone (FSH) test (for postmenopausal females only; Appendix 2) 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
1. AEs 
2. Interim medical history 
3. Weight and BMI 
4. Abbreviated PE (Section 7.2.5) 
5. Review of inclusion/exclusion criteria 
6. Screen for selected drugs of abuse (including cotinine) and an alcohol breath test 
(Appendix 2) 
7. Twelve-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
8. Vital signs (including oral temperature, respiratory rate, and supine BP and HR 
[measured after the subject has been supine for at least 5 minutes]) (Section 7.2.3) 
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9. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], including CK, coagulation parameters, CBC, and UA; Appendix 2) 
10. TSH test (Appendix 2) 
11. How Do You Feel? inquiry and concomitant medication evaluations (Section 7.2.1) 
12. Serum pregnancy test (for females only; Appendix 2) 
13. Follicle-stimulating hormone (FSH) test (for postmenopausal females only; Appendix 2) 
14. Compliance with concomitant medications and exclusionary restrictions (Section 6) 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Day -1 (as appropriate; Section 4). In addition, continued compliance with 
concomitant medication and other restrictions will be verified. 
The Sponsor will review medical history and all screening evaluations for potential subjects prior 
to enrollment. Prior to dosing, the Sponsor will provide approval of subjects selected for 
enrollment by the Investigator (or designee). 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria apply 
will be eligible to be enrolled into the study. Safety evaluations may be repeated at the discretion 
of the Investigator (or designee) or Sponsor. 
4.3. 
Inclusion Criteria 
Subjects who meet the following criteria at Screening and Check-in (Day -1), unless otherwise 
specified, may be included in the study: 
1. Males, and females of nonchildbearing potential, between 18 and 55 years of age, 
inclusive, at Screening 
2. Within BMI range 18.5 to 32.0 kg/m2, inclusive 
3. In good health, determined by no clinically significant findings from medical history, PE, 
12-lead ECG, vital signs measurements, or clinical laboratory evaluations (Appendix 4) 
at Screening or Check-in as assessed by the Investigator (or designee) 
4. Females of nonchildbearing potential, defined as being permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or confirmed tubal 
occlusion more than 6 months prior to study drug administration) or postmenopausal 
(defined as at least 12 months postcessation of menses without an alternative medical 
cause). Postmenopausal status will be confirmed with a screening serum FSH level 
≥ 40 mIU/mL. All females must have a negative qualitative serum pregnancy test (serum 
human chorionic gonadotropin) at Screening and Check-in (Day -1) 
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5. 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 of LOXO-292 administration: 
• 
Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, male subjects must follow one of the 
contraception methods below: 
o Male condom with spermicide, and 
o For a female partner of male study participant: 
- 
Intrauterine device (IUD) (hormonal IUD; eg, Mirena®). Copper 
IUDs are acceptable (eg, ParaGard®); 
- 
Established use of oral, implanted, transdermal, intravaginal, or 
hormonal method of contraception associated with inhibition of 
ovulation; or 
- 
Bilateral tubal ligation. 
Males who practice true abstinence because of a lifestyle choice (ie, do not become 
abstinent just for the purpose of study participation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the ICF but becomes 
sexually active through EOS, he must agree to use contraception as described above.  
For male subjects, sexual intercourse with female partners who are pregnant, or 
breastfeeding should be avoided. Male subjects are required to refrain from donation of 
sperm from Check-in (Day -1) until 6 months after administration of study drug. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements 
do not apply. 
6. Able to understand and provide written informed consent 
7. Able to comply with all study procedures, including the 30-night stay at the CRU and 
follow-up phone call 
4.4. 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. History or presence of any of the following, deemed clinically significant by the 
Investigator (or designee), and/or Sponsor: 
a. liver disease 
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b. pancreatitis 
c. peptic ulcer disease 
d. intestinal malabsorption 
e. gastric reduction surgery  
f. history or presence of clinically significant cardiovascular disease: 
i. Myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to the first dose administration (Day 1) 
ii. Symptomatic angina pectoris within 6 months prior to the first dose 
administration (Day 1) 
iii. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to the first dose administration (Day 1) 
iv. Congenital prolonged QT syndrome 
v. Ventricular pre-excitation syndrome (Wolff-Parkinson White syndrome) 
vi. Arrhythmia (excluding benign sinus arrhythmia) or history of arrhythmia 
requiring medical intervention 
vii. Ventricular dysfunction or risk factors for Torsades de Pointes (eg, heart 
failure, cardiomyopathy, family history of Long QT Syndrome) 
viii. Significant screening ECG abnormalities:   
1. Left bundle branch block 
2. Second degree atrioventricular (AV) block, type 2, or third-degree 
AV block 
3. QT interval corrected for heart rate using Fridericia’s method 
(QTcF) is > 450 msec 
2. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
• 
Oral body temperature > 37.5°C 
• 
Heart rate < 50 or > 99 bpm 
• 
Systolic BP < 89 or > 139 mmHg 
• 
Diastolic BP < 50 or > 89 mmHg 
For these parameters, out-of-range values that are not clinically significant (as determined 
by the Investigator or designee) may be repeated twice during Screening, Check-in 
(Day -1), and predose on Day 1. Note: Rechecks of HR and BP values will be permitted 
up to 2 times to confirm eligibility for study participation. Subjects may be eligible for 
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participation in the study based on rechecked HR and/or BP values if the values fall 
within the ranges stated above. 
3. Abnormal laboratory values (CBC, UA, clinical chemistry panel [fasted at least 8 hours], 
excluding those further defined in exclusion criteria 5, 6, and 7 below) determined to be 
clinically significant by the Investigator (or designee), and Sponsor at Screening and/or 
Check-in (Day -1) as confirmed by repeat assessment 
4. Clinically significant abnormality, as determined by the Investigator (or designee), from 
PE at Screening and/or Check-in (Day -1) 
5. Abnormal LFTs, as defined by AST, ALT, and serum (total and direct) bilirubin, as well 
as amylase and lipase above the upper limit of the normal range at Screening or Check-in. 
Rechecks of LFTs, amylase, and lipase will be permitted up to 2 times to confirm 
eligibility for study participation if the values fall within normal ranges. 
6. Any clinically significant deviations from normal ranges in CK unless approved by the 
Investigator (or designee) and Sponsor. Rechecks of CK will be permitted up to 2 times 
to confirm eligibility for study participation if the out of range values are stable or 
trending down and the Investigator (or designee) and the Sponsor deem that the results 
are not clinically significant and will not impact study conduct. 
7. Estimated creatinine clearance ≤ 90 mL/minute at Screening or Check-in (Day -1) 
calculated using the Cockcroft-Gault equation 
8. Positive serologic test for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV) antibody at Screening. Subjects who are 
positive for hepatitis B virus, HCV, or HIV by antibody will require confirmation by 
polymerase chain reaction (PCR) before enrollment to detect presence of active virus. 
Subjects who are PCR positive or for whom a PCR is unable to be obtained will not be 
eligible. 
9. Subjects with known ongoing alcohol and/or drug abuse within 2 years prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays and alcohol 
breath tests conducted during Screening and/or at Check-in (Day -1) 
10. Consumption of grapefruit/grapefruit juice or Seville oranges or its juice within 7 days 
prior to Check-in (Day -1) and through EOT or ET 
11. Consumption of alcohol or caffeine containing foods or beverages within 72 hours prior 
to Check-in (Day -1) and through EOT or ET, unless deemed acceptable by the 
Investigator (or designee) 
12. Positive alcohol breath test result at Screening or Check-in (Day -1) 
13. Positive urine screen for drugs of abuse at Screening or Check-in (Day -1) 
14. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET 
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15. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee) 
16. Participation in any other investigational study drug trial involving administration of any 
investigational drug in the past 30 days or 5 half-lives (if known), whichever is longer, 
prior to the first dose administration (Day 1) 
17. Use or intention to use any prescription or over-the-counter medications (including but 
not limited to any moderate or strong cytochrome P450 (CYP)3A4 and/or CYP3A5 
inhibitors or inducers, strong P-gp inhibitors, proton pump inhibitors [with the exception 
of omeprazole administered for the purposes of this study/in accordance with the 
Protocol], antacids, H2-receptor antagonists [with the exception of ranitidine 
administered for the purposes of this study/in accordance with the Protocol], and drugs 
that prolong QT/QTc interval, herbal products, natural or herbal supplements) within 
14 days prior to the first dose administration (Day 1) and through EOT or ET, unless 
deemed acceptable by the Investigator (or designee) and Sponsor 
18. History of a major surgical procedure within 30 days prior to Screening 
19. History or presence, upon clinical evaluation, of any illness that, in the opinion of the 
Investigator, would interfere with the ability to provide informed consent or comply with 
study instructions, or that might confound the interpretation of the study results, or put 
the subject at undue risk 
20. History of gastritis, gastrointestinal tract, or hepatic disorder or other clinical condition 
that might, in the opinion of the Investigator or designee, and as confirmed by the 
Sponsor, affect the absorption, distribution, biotransformation, or excretion of 
LOXO-292 
21. Poor peripheral venous access 
22. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening 
23. Receipt of blood products within 2 months prior to Check-in (Day -1) 
24. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET 
25. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, biliary, renal, hematological, pulmonary, cardiovascular (including any prior 
history of cardiomyopathy or cardiac failure), gastrointestinal, neurological, or 
psychiatric disorder (as determined by the Investigator), or cancer within the past 5 years 
(except localized basal cell, squamous, or in situ cancer of the skin) 
26. History of diabetes mellitus; hemoglobin A1c ≥ 6.5% 
27. History of congenital nonhemolytic hyperbilirubinemia (eg, Gilbert’s syndrome) 
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28. Have previously completed or withdrawn from any other study investigating LOXO-292, 
and have previously received the investigational product 
29. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator 
(or designee), and as confirmed by the Sponsor, within the 30 days prior to the first 
dosing and through EOT or ET 
30. Subjects who, in the opinion of the Investigator (or designee), should not participate in 
this study 
4.5. 
Subject Number and Identification 
Subject number will consist of 6 digits in which the first set of 3 digits will identify the site and 
the second set of 3 digits will identify the subject (eg, 001-101). For subjects who are withdrawn 
by the Investigator (or designee) or who voluntarily withdraw prematurely from the study, 
replacement subjects will be enrolled only if deemed necessary by the Sponsor. If necessary, as 
determined by the Sponsor, subjects who fail to complete the treatment or have insufficient PK 
data may be replaced. Replacement subjects will be assigned a subject number by adding 100 to 
the last 3 digits of the subject number for the subject they are replacing (eg, Subject 
Number 001-201 replaces Subject Number 001-101).  
4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue the 
study. Subjects may be withdrawn because of the following: change in compliance with 
inclusion/exclusion criterion that is clinically relevant and affects subject safety, occurrence of 
AEs, occurrence of pregnancy, intake of nonpermitted concomitant medication that might affect 
subject safety or study assessments/objectives, etc. Notification of withdrawal will immediately 
be made to the Study Monitor. In case of withdrawal, efforts will be made to perform all final 
study day assessments (Appendix 4). The date the subject is withdrawn from the study and the 
reason for withdrawal will be recorded on the subject’s electronic Case Report Form (eCRF). All 
withdrawn subjects with AEs that are assessed as related to study drug and which are ongoing at 
ET may continue to be followed until the symptoms or value(s) return to normal, or acceptable 
levels, as judged by the Investigator (or designee) and confirmed by the Sponsor.  
The entire study may be discontinued at the discretion of the Investigator (or designee) or 
Sponsor, based on the occurrence of the following: 
• 
Adverse events unknown to date with respect to their nature, severity, and/or duration; 
• 
Increased frequency and/or severity and/or duration of known AEs; 
• 
Medical or ethical reasons affecting the continued performance of the study; 
• 
Difficulties in the recruitment of subjects; 
• 
Cancellation of drug development. 
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In the event that the study is terminated early, the Sponsor or its designee will provide specific 
guidance to the CRU regarding the end of study procedures. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate quantities of 
the study drug for Period 1 (Table 1) Period 2 (Table 2), and Period 3 (Table 3). 
Table 1 
Study Drug – Period 1 
Study Drug 
LOXO-292 
Form 
Capsulea 
Strength 
80 mg 
Supplier 
Loxo Oncology, Inc. 
Manufacturer 
Avista Pharma Solutions, Inc. 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug. 
Table 2 
Study Drug – Period 2 
Study Drug 
LOXO-292 
Ranitidine 
Form 
Capsulea 
Tablet 
Strength 
80 mg 
150 mg 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Avista Pharma Solutions, Inc. 
Ajanta Pharma Limited 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug. 
Table 3 
Study Drug – Period 3 
Study Drug 
LOXO-292 
Omeprazole 
Form 
Capsulea 
40 mg 
Strength 
80 mg 
capsule 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Avista Pharma Solutions, Inc. 
Sandoz Inc 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug. 
The capsules containing 80 mg LOXO-292 will be supplied by the Sponsor (or designee), along 
with the batch/lot numbers and Certificate of Analysis. It will be provided in high density 
polyethylene bottles and stored according to the instructions on the label. 
Study drugs will be stored at the CRU in a location that is locked with restricted access. 
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The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drugs will be stored in accordance with the labeling. The study 
drugs will be transferred from bulk supplies into the subject’s dose container by qualified CRU 
employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
LOXO-292 will be supplied by Loxo Oncology as 80 mg capsules for oral administration. 
Ranitidine will be supplied by Covance as 150 mg tablets for oral administration. Omeprazole 
will be supplied by Covance as 40 mg delayed-release capsules for oral administration. 
In Period 1, a single oral dose of LOXO-292 will be administered under fasted conditions. On 
Day 1 of Period 1, a single oral dose of 160 mg of LOXO-292 will be administered following a 
fast of 10 hours prior to and 4 hours after the LOXO-292 dose. Blood samples for LOXO-292 
PK analysis will be taken for 168 hours after the LOXO-292 dose on Day 1. 
In Period 2, multiple oral doses of ranitidine will be administered twice daily from Day 8 until 
Day 18 inclusively (for a total of 11 consecutive days) and administered with a single oral dose 
of LOXO-292 on Day 12 under fasted conditions. On Day 12, a single oral dose of 160 mg of 
LOXO-292 will be administered following a fast of 10 hours prior to and 4 hours after the 
LOXO-292 dose. On Day 12, ranitidine will be administered 2 hours (± 10 minutes) after the 
LOXO-292 dose. On Days 8 - 11 and 13 - 18, the morning dose of ranitidine will be 
administered (with breakfast) approximately 2 hours (± 1 hour) after the planned or actual time 
of the Day 12 LOXO-292 dose and the evening dose of ranitidine will be administered (with a 
light meal/snack) approximately 10 hours (± 1 hour) prior to the planned or actual time of the 
Day 12 LOXO-292 dose. Blood samples for LOXO-292 PK analysis will be taken for 168 hours 
after the LOXO-292 dose on Day 12.  
In Period 3, multiple oral doses of omeprazole will be administered once daily from Day 19 until 
Day 29 inclusively (for a total of 11 consecutive days) and administered with a single oral dose 
of LOXO-292 on Day 23 with a low-fat meal. On Day 23, omeprazole and a single oral dose of 
160 mg of LOXO-292 will be coadministered within 30 minutes of the start of a low-fat meal, 
which will be entirely consumed within 30 minutes. On Days 19 - 22 and 24 - 29, omeprazole 
will be administered following a fast of 2 hours prior to and 1 hour after the omeprazole dose 
(Note: omeprazole will be administered at approximately the actual time of the Day 12 
LOXO-292 dosing). Blood samples for LOXO-292 PK analysis will be taken for 168 hours after 
the LOXO-292 dose on Day 23. 
All study drugs will be administered orally with approximately 240 mL of water. An additional 
100 mL of water may be administered if needed. 
Each unit dose will be prepared by qualified clinical staff. Each unit dose container will be 
appropriately labeled. 
Appropriate unit dose(s), as described above, will be administered to consecutively numbered 
subjects. Although the timing of events requires that each subject will be consistently 
administered the appropriate dose at a specific time, the exact dose time of consecutive subjects 
may be staggered to obviate the need to have all subjects on precisely the same study schedule. 
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For each dose, the subject’s actual dose time will be recorded in the source documents and 
transcribed into the eCRF. 
Subjects will be instructed not to crush, split, or chew the study drugs. 
Subjects will not lay supine for 4 hours following LOXO-292 dose administration, except as 
necessitated by the occurrence of an AE(s) and/or study procedure(s). 
5.3. 
Randomization 
This is an open-label study. 
5.4. 
Blinding 
This is an open-label study. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• 
All doses will be administered under the supervision of suitably qualified CRU staff. 
• 
Immediately after dose administration, visual inspection of the mouth and hands will be 
performed for each subject. 
• 
At each dosing occasion, a predose and postdose inventory of LOXO-292, omeprazole 
and ranitidine will be performed as appropriate. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-292 
capsules, omeprazole capsules, and ranitidine tablets received. In addition, an accurate drug 
disposition record will be kept, specifying the amount dispensed to each subject and the date of 
dispensing. This drug accountability record will be available for inspection at any time. At the 
completion of the study, the original drug accountability record will be available for review by 
the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused assembled 
unit doses will be retained until completion of the study. 
At the completion of the study, all unused LOXO-292 capsules will be returned to the Sponsor or 
disposed of by the CRU, per the Sponsor’s written instructions. Omeprazole capsules and 
ranitidine tablets will be disposed of by the CRU in accordance with the CRUs standard 
operating procedures. 
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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurs within 5 half-lives (if known) or 30 days, whichever is 
longer, prior to dose administration (Day 1). 
All prescription and over-the-counter medications (including, herbal products, natural or herbal 
supplements) are prohibited for 14 days prior to dose administration (Day 1) and through EOT or 
ET, unless deemed acceptable by the Investigator (or designee), and Sponsor. This includes but 
is not limited to: Moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers, strong 
P-gp inhibitors, proton pump inhibitors (with the exception of omeprazole administered for the 
purposes of this study/in accordance with the protocol), antacids, H2-receptor antagonists (with 
the exception of ranitidine administered for the purposes of this study/in accordance with the 
protocol), and drugs that prolong QT/QTc interval. 
Any medication taken by a subject during the course of the study, including details of its dosage, 
administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without prior 
approval of the Investigator (or designee), and Sponsor, unless its use is deemed necessary in a 
medical emergency. In this case, the use of the concomitant medication will be reported as soon 
as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
Subjects are required to refrain from use of tobacco, smoking cessation products, and nicotine-
containing products within 3 months prior to Screening through EOT or ET.  
Consumption of foods or beverages containing grapefruit/grapefruit juice or Seville oranges or 
its juice within 7 days prior to Check-in (Day -1) and through EOT or ET will not be allowed 
unless deemed acceptable by the Investigator (or designee), and Sponsor. 
Consumption of alcohol- or caffeine-containing foods or beverages within 72 hours prior to 
Check-in (Day -1) and through EOT or ET will not be allowed unless deemed acceptable by the 
Investigator (or designee), and Sponsor. 
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and during 
the period of confinement at the CRU and will otherwise maintain their normal level of physical 
activity through EOT or ET (ie, will not begin a new exercise program or participate in any 
unusually strenuous physical exertion). 
While confined at the CRU, subjects will receive a standardized diet at scheduled times that do 
not conflict with other study-related activities. 
In Period 1, a single oral dose of LOXO-292 will be administered under fasted conditions. On 
Day 1 of Period 1, a single oral dose of 160 mg of LOXO-292 will be administered following a 
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fast of 10 hours prior to and 4 hours after the LOXO-292 dose. Blood samples for LOXO-292 
PK analysis will be taken for 168 hours after the LOXO-292 dose on Day 1. 
In Period 2, multiple oral doses of ranitidine will be administered twice daily from Day 8 until 
Day 18 inclusively (for a total of 11 consecutive days) and administered with a single oral dose 
of LOXO-292 on Day 12 under fasted conditions. On Day 12, a single oral dose of 160 mg of 
LOXO-292 will be administered following a fast of 10 hours prior to and 4 hours after the 
LOXO-292 dose. On Day 12, ranitidine will be administered 2 hours (± 10 minutes) after the 
LOXO-292 dose. On Days 8 - 11 and 13 - 18, the morning dose of ranitidine will be 
administered (with breakfast) approximately 2 hours (± 1 hour) after the planned or actual time 
of the Day 12 LOXO-292 dose and the evening dose of ranitidine will be administered (with a 
light meal/snack) approximately 10 hours (± 1 hour) prior to the planned or actual time of the 
Day 12 LOXO-292 dose. Blood samples for LOXO-292 PK analysis will be taken for 168 hours 
after the LOXO-292 dose on Day 12.  
In Period 3, multiple oral doses of omeprazole will be administered once daily from Day 19 until 
Day 29 inclusively (for a total of 11 consecutive days) and administered with a single oral dose 
of LOXO-292 on Day 23 with a low-fat meal. On Day 23, omeprazole and a single oral dose of 
160 mg of LOXO-292 will be coadministered within 30 minutes of the start of a low-fat meal, 
which will be entirely consumed within 30 minutes. On Days 19 - 22 and 24 - 29, omeprazole 
will be administered following a fast of 2 hours prior to and 1 hour after the omeprazole dose 
(Note: omeprazole will be administered at approximately the actual time of the Day 12 
LOXO-292 dosing). Blood samples for LOXO-292 PK analysis will be taken for 168 hours after 
the LOXO-292 dose on Day 23. 
7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for PK analysis of LOXO-292 plasma levels will be collected at the timepoints 
specified in Appendix 4. The exact time of the study drug administration and the actual time of 
blood sampling for PK analysis will be recorded on the eCRF. 
Processing, storage, and shipping instructions for these PK blood will be provided in a separate 
Laboratory Manual. The number of blood samples and total blood volume required for PK 
testing and protein binding is presented in Appendix 3. 
7.1.2. 
Analytical Methodology 
Concentrations of LOXO-292 in plasma will be determined using a validated bioanalytical 
method. Specifics of the bioanalytical methods will be provided in a separate document.  
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7.2. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee) or Sponsor.  
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
any other procedures to be performed at the same timepoint. The order of priority for scheduling 
procedures around a timepoint is (in descending order of priority): 
• 
Dosing 
• 
Pharmacokinetic blood sampling 
• 
Vital signs assessments 
• 
ECG 
• 
Blood and urine samples for clinical laboratories 
• 
PE 
7.2.1. 
Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a nonleading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 
Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in (Day -1), at each postdose 
vital signs assessment, and at an appropriate time for all other days). Subjects will also be 
encouraged to voluntarily report AEs occurring at any other time through the EOS. 
AEs, whether volunteered, identified by the subject’s responses to HDYF? inquiries, or noted on 
PE, ECG, vital signs assessments, or laboratory tests, will be recorded throughout the study (ie, 
from signing of the ICF until EOS [or ET if the subject discontinues from the study and does not 
complete a follow-up phone call]), either as subject medical history (if the event is reported as 
beginning prior to signing of the ICF or if the event occurs prior to study drug administration on 
Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as 
AEs (if the event occurs after signing of the ICF but prior to study drug administration on Day 1 
and is assessed as related to study procedures by the Investigator [or designee], or if the event 
occurs after study drug administration on Day 1 through EOT or ET regardless of relationship to 
study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by the 
Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF signing 
until EOS (or ET, if the subject discontinues from the study and does not complete a follow-up 
phone call) are to be reported.  
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up phone call, all subjects must be followed until EOS. Subjects with AEs that are 
assessed as related to study drug by the Investigator (or designee) which are ongoing at EOS may 
continue to be followed until the symptoms or value(s) return to normal, or acceptable levels, as 
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judged by the Investigator or designee and confirmed by the Sponsor. The Investigator (or 
designee) should use appropriate judgment in ordering additional tests as necessary to monitor 
the resolution of events. The Sponsor may request that additional safety tests be performed.  
Subjects will receive a follow-up phone call 7 days (± 2 days) after EOT or ET to determine if 
any AE has occurred since the EOT or ET visit.  
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
Investigator (or designee). 
Any event that meets the criteria of a SUSAR will be reported to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) according to CRU policy by the Investigator (or 
designee) and to regulatory authorities by the Sponsor (or Sponsor designee) according to 
regulatory authority requirements. Refer to Reference Safety Information in the current IB1 for 
LOXO-292 for expected adverse reactions. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours], coagulation 
parameters, CBC, TSH, hemoglobin A1c [Screening only], and UA) will be collected at the 
timepoints specified in Appendix 4. 
Screens for HCV antibody, HBsAg, and HIV antibody will be performed at Screening. A urine 
drug screen for selected drugs of abuse (including cotinine) and an alcohol breath test will be 
performed at Screening and repeated at Check-in (Day -1) for all subjects. A serum qualitative 
pregnancy test (females only) and an FSH test (postmenopausal females only) will be performed 
at the timepoints specified in Appendix 4.  
The number of blood samples and total blood volume required for clinical laboratory evaluations 
is presented in Appendix 3. A list of the specific evaluation is in Appendix 2. 
7.2.3. 
Vital Signs 
Vital signs (including oral temperature, respiratory rate, and supine BP and HR) will be obtained 
at the timepoints specified in Appendix 4. 
Blood pressure and HR measurements should be performed using the same arm for each reading 
and measurements should be taken after the subject has been resting in the supine position for at 
least 5 minutes.  
When vital signs assessments are scheduled at the same time as blood draws, the blood draws 
will be obtained at the scheduled timepoint, and the vital signs will be obtained prior to and as 
close as possible to the scheduled blood draw. 
7.2.4. 
12-Lead Electrocardiogram 
A 12-lead ECG (including PR, RR, QRS, and QT interval parameters) will be obtained after the 
subject has been resting for at least 10 minutes in the supine position at the timepoints specified 
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in Appendix 4. The QT interval will be corrected for HR by Fridericia’s (QTcF = QT/[RR]1/3) 
formula. 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to and as close 
as possible to the scheduled blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated PE will be performed at the timepoints specified in Appendix 4. 
Complete PEs will evaluate general appearance and the following body systems/organs: 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; lymphatic; musculoskeletal/extremities; and neurological. Weight and height will be 
reported (height only reported during Screening). 
Abbreviated PEs will evaluate general appearance and the following body systems/organs: 
dermatological; pulmonary; cardiovascular; abdominal; and neurological. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size. 
 
 
 
8.2. 
Analysis Populations 
8.2.1. 
Study Populations 
The PK Population will consist of all subjects who have received a dose of LOXO-292, have at 
least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. 
The Safety Population will consist of all subjects who have received at least 1 dose of study 
drug. Subjects will be classified into groups based on actual treatment received. 
8.3. 
Pharmacokinetic Analysis 
Serial PK blood samples for the analysis of plasma LOXO-292 concentrations will be collected 
from predose through 168 hours postdose.  
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Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-292 (as appropriate):  
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the 
last measurable concentration, calculated using the linear 
trapezoidal rule for increasing and decreasing concentrations 
AUC0-∞ 
AUC extrapolated to infinity, calculated using the formula: 
 
 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
 
 
where Ct is the last measurable concentration and λZ is the apparent 
terminal elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
λZ 
apparent terminal elimination rate constant, where λZ is the 
magnitude of the slope of the linear regression of the log 
concentration versus-time profile during the terminal phase 
CL/F 
apparent systemic clearance 
t½ 
apparent terminal elimination half-life (whenever possible), where 
t½ = natural log (ln)(2)/ λZ 
Additionally, the number of points used to estimate λZ will be presented in a listing. 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 6.4 or higher (Certara USA Inc.). 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the Statistical Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical analysis 
will be performed using SAS Version 9.3 or greater. More details on the analyses will be 
included in the SAP.  
8.3.1. 
Descriptive Analysis 
Plasma concentrations and PK parameters will be summarized with descriptive statistics 
(number, arithmetic mean, standard deviation, coefficient of variation [CV%], geometric mean, 
geometric CV%, median, minimum, and maximum). 
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8.3.2. 
Analysis of Variance (ANOVA) 
The primary analysis planned for this study is an ANOVA model that includes treatment as a 
fixed-effect and subject as a random-effect. 
 
 
  
8.4. 
Safety Analysis 
All safety assessments, including AEs and SAEs, vital signs measurements, clinical laboratory 
results, PE results, concomitant medications, and ECG interpretations, will be tabulated and 
summarized where possible, using descriptive methodology, as needed, by timepoint. Unless 
otherwise specified, baseline value is defined as the last nonmissing measurement before 
administration of LOXO-292 in each period. No formal statistical analyses are planned for the 
safety data. All safety data will be listed by subject. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHODrug Global B3, 01 March 2019). The incidence of AEs will be presented by 
severity and by relationship to study drug as determined by the Investigator (see Appendix 1 for 
AE reporting). All TEAEs will be summarized by system organ class and preferred term, using 
Medical Dictionary for Regulatory Activities (MedDRA Version 22.0).  
8.5. 
Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a CRU staff member authorized to make the 
change. Changes will be made by striking a single line through erroneous data and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not apparent, 
a brief explanation for the change will be written adjacent to the change by the clinician. 
The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the CRU and verified by the Study Monitor. Data will 
then be reviewed by the data management group to resolve any outstanding issues. Listings will 
be generated after the database is cleaned by data management and will be reviewed by the 
Covance scientific team. The eCRF and ancillary data will be converted into final SAS® datasets 
following Study Data Tabulation Model or client-provided specifications. The final datasets 
structure will be verified using Web Submission Data Manager®, while the dataset content will 
be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will be 
peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by the 
Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
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8.6. 
Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance standard operating 
procedures or per client request and as applicable, according to the contract between Covance 
and the Sponsor. 
9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator (or designee). 
There will be no alterations in the protocol affecting subject safety without the express written 
approval of the Sponsor, Investigator (or designee), and the IRB (see Form FDA 1572). 
9.2. 
Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator (or designee) and appropriate clinical staff to familiarize the Investigator (or 
designee) and clinical staff with the materials necessary for conducting the clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information collected/documented 
during the study, will be regarded as confidential. The Investigator (or designee) agrees not to 
disclose such information in any way without prior written permission from the Sponsor. 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, oral 
presentations, abstracts) by the Investigator (or designee) or their representative(s), shall require 
prior notification and review, within a reasonable timeframe, by the Sponsor, and cannot be 
made in violation of the Sponsor’s confidentiality restrictions or to the detriment of the 
Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate a Study Monitor who will be responsible for monitoring this clinical 
trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and source 
documentation completion and retention, and accurate study drug accountability. To this end, the 
Sponsor’s Study Monitor will visit the CRU at suitable intervals and be in frequent contact 
through verbal and written communication. It is essential that the Sponsor’s Study Monitor has 
access to all documents (related to the study and the individual participants) at any time these are 
requested. In turn, the Sponsor’s Study Monitor will adhere to all requirements for subject 
confidentiality as outlined in the ICF. The Investigator (or designee) and Investigator’s staff will 
be expected to cooperate with the Sponsor’s Study Monitor, to be available during a portion of 
the monitoring visit to answer questions, and to provide any missing information. 
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9.5. 
Institutional Review Board 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
advertisement, ICF, and other information provided to subjects will be reviewed and approved 
by the IRB. The Sponsor will supply relevant material for the Investigator (or designee) to 
submit to the IRB for the protocol’s review and approval. Verification of the IRB unconditional 
approval of the protocol and the written ICF statement will be transmitted to the Investigator (or 
designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol amendments 
and of serious and unexpected AEs. Approval for protocol amendments will be transmitted in 
writing to the Investigator (or designee). If requested, the Investigator (or designee) will permit 
audits by the IRB and regulatory inspections by providing direct access to source 
data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate intervals 
(not to exceed 1 year) and a Study Progress Report following the completion, termination, or 
discontinuation of the Investigator’s (or designee’s) participation in the study. 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the protocol) 
by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can withdraw 
from the study at any time. In accordance with 21 CFR 50, the informed consent process shall be 
documented by the use of a written ICF approved by the IRB and signed by the subject prior to 
protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
9.7. 
Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each eCRF will 
be retained by the Investigator (or designee). All source documents, records, and reports will be 
retained by the CRU in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the CRU archives. 
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9.8. 
Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the US CFR 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), Applications for FDA Approval to Market a New Drug (21 CFR 314), and 
Radioactive Drugs for Certain Research Uses (21 CFR 361.1), as appropriate. As such, these 
sections of US Title 21 CFR, along with the applicable International Council for Harmonisation 
Guidelines, are commonly known as Good Clinical Practices, which are consistent with the 
Declaration of Helsinki. 
9.9. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
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Page 43 of 53 
10. REFERENCES
1.
Loxo Oncology, Inc. LOXO-292 – Investigator’s Brochure (Version 5.0). 05 June 
2019.
2.
Drilon, A, Subbiah, V, Oxnard G, et al. A phase 1 study of LOXO-292, a potent 
and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin 
Oncol 2018;36(suppl): abstr 102.
3.
Oxnard G, Subbiah V, Park K, et al. Clinical activity of LOXO-292, a highly 
selective RET inhibitor, in patients with RET fusion + non-small cell lung cancer. J 
Thoracic Oncol 1018;13(10):S349-50.
4.
Wirth LJ, Cabanillas ME, Sherman EJ, et al. Clinical activity of LOXO-292, a 
highly selective RET inhibitor, in patients with RET-altered thyroid cancers: an 
update from ASCO 2018. 88th Meeting of the American Thyroid Association, 3-7 
Oct 2018.
5.
Ranitidine - ranitidine tablets [package insert]. Bridgewater, NJ: Amneal 
Pharmaceuticals LLC; 2016.
6.
Omeprazole – omeprazole capsule delayed release [package insert]. Princeton, NJ: 
Sandoz Inc; 2018.
7.
Zhang L, Wu F, Lee SC, et al. pH-dependent drug-drug interactions for weak base 
drugs: potential implications for new drug development. Clin Pharmacol Ther 
2014;96:266-77.
8.
Food and Drug Administration: Center for Drug Evaluation and Research (CDER). 
Guidance for Industry: Clinical Drug Interaction Studies (Oct 2017). 
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11. APPENDICES 
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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy subject, whether or not considered drug related by the 
Investigator (or designee). A treatment-emergent AE is an AE that is reported after a dose of 
study drug. 
The following are all AEs: 
• 
Unfavorable changes in general condition; 
• 
Subjective or objective signs/symptoms; 
• 
Concomitant diseases or accidents; 
• 
Clinically relevant adverse changes in laboratory parameters observed in a subject 
during a clinical study. 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant by 
the Investigator or designee), and accidents observed in the context of a clinical trial, irrespective 
of a possible causal relationship with the administration of the trial substance.  
Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• 
Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• 
Grade 2 Moderate: Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*  
• 
Grade 3 Severe or medically significant but not immediately life threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**  
• 
Grade 4 Life-threatening consequences: Urgent intervention indicated 
• 
Grade 5 Death related to AE 
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 
5 options for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option.  
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
• 
NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (eg, concomitant drugs, therapies, complications, comorbidities) is 
suspected; 
• 
RELATED = The time course between administration of investigational product and 
the occurrence or worsening of the AE is consistent with a causal relationship and no 
other cause (eg, concomitant drugs, therapies, complications, comorbidities) can be 
identified. 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through EOS or ET (if the subject discontinues from the study and does not 
complete a follow-up phone call) and for up to 90 days after study drug administration should be 
reported by the Investigator (or designee) via eFax to the Sponsor’s clinical safety representative 
within 24 hours of being notified. The Sponsor’s safety representative will then forward the 
Pregnancy Form to the Investigator for completion. 
eFax: +1 (203) 643-2013 
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. The subject or partner should be 
followed by the Investigator until completion of the pregnancy. If the pregnancy ends for any 
reason before the anticipated date, the Investigator should notify the Sponsor’s clinical safety 
representative. At the completion of the pregnancy, the Investigator will document the outcome 
of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as a serious AE (SAE; ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an 
SAE. 
Male subjects will be instructed to notify the Investigator immediately if they discover their 
sexual partner is pregnant. In this instance, the partner must provide written consent before 
pregnancy information can be collected. When a CRU becomes aware that the female partner of 
a male subject is pregnant, they are to contact the Investigator immediately (within 24 hours of 
the CRU staff becoming aware of the event) in addition to notifying the Sponsor’s safety 
representative via eFax. 
All pregnancies should be recorded on the AE eCRF, in addition to completion of the required 
pregnancy forms. If the Investigator suspects that a pregnancy was the result of an interaction 
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between the study treatment and the contraceptive method, in addition to the pregnancy the drug 
interaction should also be captured as a separate AE. 
Definition of Serious Adverse Events 
An SAE (by FDA definition) is any adverse drug experience occurring at any dose that results in 
any of the following outcomes: 
• 
Death; 
• 
A life-threatening adverse drug experience (ie, one that places the subject, in the view 
of the Investigator [or designee], at immediate risk of death); 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant disability/incapacity; 
• 
A congenital anomaly/birth defect; 
• 
An important medical event that may require medical or surgical intervention to 
prevent one of the above outcomes. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed in 
the Reference Safety Information section of the IB or if it is not listed at the specificity or 
severity that has been observed for an unapproved investigational medicinal product. 
Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of the 
drug and represent events that are assessed as serious, related, and unexpected. Food and Drug 
Administration-reportable AEs will be reported by the CRU to the Sponsor and the responsible 
Institutional Review Board (IRB). Final determination of whether an event represents a SUSAR 
will be the responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or reported, 
and within 24 hours of any SAE (regardless of whether the event is assessed as related or 
unrelated to study drug) being first recognized or reported, the Sponsor’s clinical safety 
representative will be notified by the Investigator or designee in writing (eg, facsimile) using the 
following eFax number or email: 
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eFax: +1 (203) 643-2013 
email: safety@loxooncology.com 
To report the SAE, the completed report form should be sent by eFax to the Sponsor’s clinical 
safety representative within 24 hours of awareness. Incoming reports are reviewed during normal 
business hours. Additional reporting instructions and the SAE Report Form are provided in the 
Study Manual.  
The IRB will be notified of any FDA-reportable AE within the timeframe required by the IRB. 
The IRB Serious and Unexpected Adverse Experience Submission Form will be completed and 
submitted with the copy of the written confirmation or summary of the AE. 
 
 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel (Fasted): 
Complete Blood Count: 
Other Tests: 
Alanine aminotransferase 
Hematocrit 
Hemoglobin A1c 
Thyroid-stimulating hormone 
 
Albumin 
Hemoglobin 
Alkaline phosphatase 
Mean corpuscular hemoglobin 
Amylase 
Aspartate aminotransferase 
Mean corpuscular hemoglobin 
concentration 
Bilirubin (direct and total) 
Mean corpuscular volume 
Blood urea nitrogen  
Platelet count 
Coagulation Parameters: 
Calcium 
Red blood cell (RBC) count 
Activated partial thrombin time 
Chloride 
RBC distribution width 
Partial thromboplastin time 
Cholesterol 
Creatine kinase 
Creatinine  
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium  
Sodium 
Total protein  
Triglycerides  
Uric acid 
White blood cell (WBC) count  
WBC differential (percent and 
absolute):  
Prothrombin time 
International normalized ratio 
 
Basophils 
Eosinophils  
Lymphocytes  
Monocytes 
Neutrophils 
Serology: 
Human immunodeficiency virus 
antibody  
Hepatitis B surface antigen 
Hepatitis C virus antibody  
 
Urine Drug Screen: 
 
Urinalysis: 
 
For Female Subjects only: 
Including but not limited to the 
following:  
Alcohol (ethanol) (breath test) 
Amphetamines 
Barbiturates 
Benzodiazepines 
Bilirubin  
Color and appearance  
Glucose  
Ketones  
Leukocyte esterase  
Nitrite 
Pregnancy test (serum qualitative) 
Follicle-stimulating hormone 
(postmenopausal females only) 
Cannabinoids  
Cocaine (metabolite)  
Methadone  
Opiates  
Phencyclidine  
Cotinine  
Occult blood  
pH and specific gravity  
Protein  
Urobilinogen  
Microscopic examination including 
bacteria, casts, crystals, epithelial 
cells, RBCs, and WBCs (if protein, 
leukocyte esterase, nitrite, or blood 
is positive) 
Estimated Creatinine Clearance 
 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Purpose 
Approximate Blood 
Volume per Sample (mL) 
Maximum Number 
of Blood Samples 
Approximate Total 
Volume (mL) 
Serology 
4 
1 
4 
Hemoglobin A1c  
4 
1 
4 
Primary Pharmacokinetic 
(PK) Sampling 
4 
60 
240 
Clinical Laboratory Tests: 
Complete Blood Count 
Clinical Chemistry 
Coagulation Parameters 
 
4 
4 
3 
 
10 
10 
10 
 
40 
40 
30 
Serum Pregnancy Test 
(females only) 
4 
3 
12 
Serum Follicle-stimulating 
Hormone Test 
(postmenopausal females 
only) 
4 
2 
8 
Thyroid-stimulating Hormone 
4 
2 
8 
Total: 
386 mL 
 
 
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Appendix 4: Schedule of Assessments 
Study Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in  
(Day -1) 
Period 1 
Period 2 
Period 3 
Follow-up Phone 
Call (EOS) 
Day  
1 
Day  
2 
Day 
7 
Day 
8 
Day 
11 
Day 
12 
Day 
13 
Day 
18 
Day 
19 
Day 
22 
Day 
23 
Day 
24 
Clinic 
Discharge/
EOT Day 
30 or ETs 
7 (±2) days post 
EOT or ETt 
Confined to the CRU 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
12-Lead ECGe 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Vital Signsf 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
HDYF? Inquiryg 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LOXO-292 Dosingi 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Ranitidine Dosingj 
 
 
 
 
 
X (Days 8 to 18, inclusive) 
 
 
 
 
 
 
Omeprazole Dosingk 
 
 
 
 
 
 
 
 
 
 
X (Days 19 to 29, inclusive) 
 
Primary PK Blood 
Samplesl 
 
 
X (Days 1-8) 
 
X (Days 12-19) 
 
X (Days 23-29) 
 
Clinical Laboratory 
Evaluationsm 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin A1c Testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screeno 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medicationsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testq 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Follicle-Stimulating 
Hormone Testr 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid-Stimulating 
Hormone Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; CK = creatine kinase; CRU = Clinical Research Unit; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; 
ET = early termination; HDYF? = How Do You Feel?; HIV = human immunodeficiency virus; ICF = Informed Consent Form; PE = physical examination; PK = pharmacokinetic; 
SAE = serious adverse event. 
a. For details on study procedures, see Section 7. 
b Interim medical history only. 
c Weight and BMI (based on Screening height) only. 
d A complete PE will be performed at Screening and EOT (or ET). An abbreviated PE will be performed at Check-in (Day -1) and 1 hour postdose on Days 1, 12, and 23 (1 hour post 
LOXO-292 dose).  
e Electrocardiograms will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the scheduled blood draws 
at Screening and Day -1, Day 1 (before LOXO-292 dosing), Day 2, Day 8 (before ranitidine dosing), Day 12 (before LOXO-292 dosing), Day 13, Day 19 (before omeprazole dosing), Day 23 
(before LOXO-292 dosing), Day 24, and EOT (or ET). 
f Vital signs measurements (oral temperature, respiratory rate, and supine blood pressure and heart rate) will be obtained Screening and Day -1, Day 1 (before LOXO-292 dosing), Day 2, Day 8 
(before ranitidine dosing), Day 12 (before LOXO-292 dosing), Day 13, Day 19 (before omeprazole dosing), Day 23 (before LOXO-292 dosing), Day 24, and EOT (or ET). Vital signs 
measurements should be carried out prior to and as close as possible to having blood drawn. Blood pressure and HR will be measured using the same arm for each reading after the subject has 
been supine for at least 5 minutes. 
g An HDYF? inquiry performed at Screening (after the ICF is signed), at Check-in (Day -1), at each postdose vital signs assessment, and at an appropriate time for all other days. 
h AEs and SAEs will be collected beginning at informed consent. AEs will be recorded throughout the study (ie, from signing of the ICF until EOS, or until ET if the subject discontinues from 
the study and does not complete a follow-up phone call), either as subject medical history (if the event is reported as beginning prior to signing of the ICF or if the event occurs prior to study 
drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the ICF but prior to study drug 
administration on Day 1 and is assessed by the Investigator [or designee]) as related to study procedures, or if the event occurs after study drug administration on Day 1 through EOT or ET 
regardless of relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug are to be recorded. All SAEs that develop from the time of ICF signing 
until EOS (or ET if the subject discontinues from the study and does not complete a follow-up phone call) are to be reported. 
i LOXO-292 will be administered in the morning of Days 1 and 12, following a fast of 10 hours prior to and 4 hours after the LOXO-292 dose. On Day 23, LOXO-292 will be coadministered 
with omeprazole within 30 minutes of the start of a low-fat meal which will be entirely consumed within 30 minutes.  
j On Day 12, ranitidine will be administered 2 hours (± 10 minutes) after the LOXO-292 dose. On Days 8 - 11 and 13 - 18, the morning dose of ranitidine will be administered (with breakfast) 
approximately 2 hours (± 1 hour) after the planned or actual time of the Day 12 LOXO-292 dose and the evening dose of ranitidine will be administered (with a light meal/snack) 
approximately 10 hours (± 1 hour) prior to the planned or actual time of the Day 12 LOXO-292 dose. 
k On Day 23, omeprazole and a single oral dose of 160 mg of LOXO-292 will be coadministered within 30 minutes of the start of a low-fat meal, which will be entirely consumed within 
30 minutes. On Days 19-22 and 24-29, omeprazole will be administered following a fast of 2 hours prior to and 1 hour after the omeprazole dose (Note: omeprazole will be administered at 
approximately the actual time of the Day 12 LOXO-292 dosing). 
l Primary PK blood samples will be collected prior to dosing (within 30 minutes) and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours after LOXO-292 
administration on Days 1, 12, and 23 for Periods 1, 2, and 3, respectively. The allowed sampling window for PK blood samples will be the following: within 15 minutes prior to dosing for the 
predose sample timepoint; ± 5 minutes for sampling timepoints within the first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 minutes for the sampling 
timepoints ranging from 48 to 168 hours. 
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m Clinical chemistry panel including CK (fasted at least 8 hours), coagulation parameters, complete blood count, and urinalysis will be performed at Screening, Check-in (Day -1), and Days 2, 
7, 11 (before ranitidine dosing), 13, 18 (before ranitidine dosing), 22 (before omeprazole dosing), and 24; and at EOT (Day 30) or ET. 
n Hemoglobin A1c test performed at Screening only.  
o Alcohol breath test and drugs of abuse urine test, including cotinine. Results from the alcohol and drug tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
p Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 30 days prior to 
study drug administration for prescription medications, and 14 days prior to study drug administration for nonprescription medications, will be recorded on the subject’s electronic Case Report 
Form. 
q Female subjects only. 
r Postmenopausal female subjects only. 
s EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 30. ET is defined as when the subject is released from the CRU if the 
subject terminates the study early. Vital sign, ECG, and safety laboratory results for serum chemistry, hematology, coagulation, and urinalysis are to be available for review by the Investigator 
or designee prior to subject release from the CRU at the EOT or ET visit. 
t To be performed 7 days (± 2 days) following EOT or ET. EOS is defined as when the CRU contacts the subject by a follow-up phone call 7 days (± 2 days) after the EOT visit or ET visit to 
determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-292 (including subjects who are terminated early) will be contacted. 
 
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Clinical Protocol 
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CONFIDENTIAL 
Protocol LOXO-RET-19075 
 
 
Final, 10 Jul 2019 
Page 1 of 4 
 
Letter of Administrative Change (LOAC) No. 2 
An Open-Label, 3-Period, Fixed Sequence Study to Evaluate the Effect of an 
H2 Antagonist and a Proton Pump Inhibitor on the Single Dose 
Pharmacokinetics of LOXO-292 in Healthy Adult Subjects 
Protocol Date: 20 June 2019 
Letter of Administrative Change (LOAC) Effective Date:  10 July 2019 
 
Sponsor Reference Number: LOXO-RET-19075 
Covance Study Number: 8412-056 
IND Number: 133193 
 
Description of Changes: 
The purpose of this LOAC is to amend the text in Section 12.1, Inclusion Criteria, Sub-Section 
12.1.1, All Subjects of the Protocol (dated 20 Jun 2019) to include bilateral tubal libgation as an 
acceptable form of sterilization for female study participants. 
Section 12.1, Inclusion Criteria, Sub-Section, 12.1.1 All Subjects of the Protocol will be revised 
as follows: 
Females of nonchildbearing potential, defined as being permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal ligation or 
confirmed tubal occlusion more than 6 months prior to study drug administration) or 
postmenopausal (defined as at least 12 months postcessation of menses without an alternative 
medical cause). Postmenopausal status will be confirmed with a screening serum FSH level 
≥ 40 mIU/mL. All females must have a negative qualitative serum pregnancy test (serum 
human chorionic gonadotropin) at Screening and Check-in (Day -1) 
 
 
 
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PPD

Clinical Protocol 
Covance Study 8412-056 
CONFIDENTIAL 
Protocol LOXO-RET-19075 
 
 
Final, 10 Jul 2019 
Page 2 of 4 
 
 
Reason for Changes: 
Bilateral tubal libgation was erroneously not listed as an acceptable form of sterilization for 
female study participants Section 12.1, Inclusion Criteria, Sub-Section 12.1.1, All Subjects, in 
the Protocol dated 20 June 2019.
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PPD

Clinical Protocol 
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CONFIDENTIAL 
Protocol LOXO-RET-19075 
 
 
Final, 10 Jul 2019 
Page 4 of 4 
 
SPONSOR AGREEMENT 
 
 
 
 
 
Date 
10-Jul-19 | 13:42:21 PDT
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PPD

Clinical Protocol 
Covance Study 8412-056 
CONFIDENTIAL 
Protocol LOXO-RET-19075 
 
 
Final, 24 June 2019 
Page 1 of 4 
 
Letter of Administrative Change (LOAC) No. 1 
An Open-Label, 3-Period, Fixed Sequence Study to Evaluate the Effect of an 
H2 Antagonist and a Proton Pump Inhibitor on the Single Dose 
Pharmacokinetics of LOXO-292 in Healthy Adult Subjects 
Protocol Date: 20 June 2019 
Letter of Administrative Change (LOAC) Effective Date:  24 June 2019 
 
Sponsor Reference Number: LOXO-RET-19075 
Covance Study Number: 8412-056 
IND Number: 133193 
 
 
 
Description of Changes: 
The purpose of this LOAC is to revise the name of the manufacturer of ranitidine included in 
Table 2 of Section 5.1, Description, Storage, Packaging, and Labeling, of the Protocol, dated 20 
Jun 2019. 
Table 2 of Section 5.1, Description, Storage, Packaging, and Labeling will be revised as 
follows: 
Table 1 Study Drug – Period 2 
Study Drug 
LOXO-292 
Ranitidine 
Form 
Capsulea 
Tablet 
Strength 
80 mg 
150 mg 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Avista Pharma Solutions, Inc. 
Amneal Pharmaceuticals, LLC. 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug. 
 
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Clinical Protocol 
Covance Study 8412-056 
CONFIDENTIAL 
Protocol LOXO-RET-19075 
 
 
Final, 24 June 2019 
Page 2 of 4 
 
Reason for Changes: 
Table 2 of Section 5.1, Description, Storage, Packaging, and Labeling lists the manufacturer of 
ranitidine 150 mg tablets as Ajanta Pharma Limited.  The manufacturer of ranitidine 150 mg 
tablets to be used in this study is Amneal Pharmaceuticals, LLC. 
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Page 61 of 62
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Clinical Protocol 
Covance Study 8412-056 
CONFIDENTIAL 
Protocol LOXO-RET-19075 
 
 
Final, 24 June 2019 
Page 4 of 4 
 
SPONSOR AGREEMENT 
 
 
 
 
 
Date 
24-Jun-19 | 09:45:53 PDT
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