An Open-Label, Fixed-Sequence Study to Evaluate the Effect of Multiple Doses of LOXO-292 on the Single Dose Pharmacokinetics of Midazolam in Healthy Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol Amendment J2G-OX-JZJR (2) 
An Open-Label, Fixed-Sequence Study to Evaluate the Effect of Multiple Doses of 
LOXO-292 on the Single Dose Pharmacokinetics of Midazolam in Healthy Adult Subjects
NCT05338476 
Approval Date: 30-Jul-2018 

Page 1 
Clinical Protocol 
An Open-Label, Fixed-Sequence Study to Evaluate the Effect of Multiple Doses of 
LOXO-292 on the Single Dose Pharmacokinetics of Midazolam in Healthy Adult 
Subjects 
Celerion Project No.: CA24334 
Sponsor Project No.: LOXO-RET-18017 
US IND No.: 133193 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Loxo Oncology, Inc. 
and/or Celerion. Any viewing or disclosure of such information that is not authorized in 
writing by Loxo Oncology, Inc. and/or Celerion is strictly prohibited. Such information may 
be used solely for the purpose of reviewing or performing this study. 

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CONFIDENTIAL  
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 7 
Pharmacokinetic and Statistical 
Analyses 
 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
and/or 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.: +1 402 476-2811 
Fax: +1 402 939-0428 
 

CONFIDENTIAL  
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 8 
4 
TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY ............................................................................. 2 
2 PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ......................... 4 
3 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................ 6 
4 TABLE OF CONTENTS ................................................................................................. 8 
5 SYNOPSIS ....................................................................................................................... 11 
6 STUDY EVENTS FLOW CHART ............................................................................... 13 
7 ABBREVIATIONS ......................................................................................................... 18 
8 INTRODUCTION........................................................................................................... 21 
8.1 
Background ............................................................................................................. 21 
8.1.1 
LOXO-292 ................................................................................................ 21 
8.1.2 
Midazolam ................................................................................................ 23 
8.2 
Rationale .................................................................................................................. 23 
8.2.1 
Rationale for this Study and Study Design ............................................... 23 
8.2.2 
Rationale for the Dose Selection and Dose Regimen ............................... 24 
8.2.3 
Rationale for Primary Endpoints .............................................................. 24 
8.3 
Risks and/or Benefits to Subjects ............................................................................ 24 
9 OBJECTIVES AND ENDPOINTS ............................................................................... 26 
9.1 
Objectives ................................................................................................................ 26 
9.2 
Endpoints ................................................................................................................. 26 
10 STUDY DESIGN ............................................................................................................. 27 
10.1 Overall Study Design and Plan ............................................................................... 27 
10.1.1 
Confinement, Return Visits, and Follow-Up ............................................ 27 
10.1.2 
End of Study Definition ............................................................................ 27 
11 STUDY POPULATION ................................................................................................. 28 
11.1 Inclusion Criteria ..................................................................................................... 28 
11.2 Exclusion Criteria .................................................................................................... 29 
11.3 Early Termination of Subjects from the Study ........................................................ 31 
11.4 Study Restrictions ................................................................................................... 31 
11.4.1 
Prohibitions and Concomitant Medication ............................................... 31 
11.4.2 
Meals ......................................................................................................... 32 
11.4.3 
Activity ..................................................................................................... 33 
12 TREATMENTS............................................................................................................... 34 
12.1 Treatments Administered ........................................................................................ 34 
12.2 Dose Modification ................................................................................................... 34 

CONFIDENTIAL  
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 9 
12.3 Method of Treatment Assignment ........................................................................... 34 
12.4 Blinding ................................................................................................................... 35 
12.5 Treatment Compliance ............................................................................................ 35 
13 STUDY ASSESSMENTS AND PROCEDURES ......................................................... 36 
13.1 Screening ................................................................................................................. 36 
13.2 Safety Assessments ................................................................................................. 36 
13.2.1 
Physical Examination................................................................................ 36 
13.2.2 
Vital Signs ................................................................................................. 36 
13.2.3 
ECG Monitoring ....................................................................................... 37 
13.2.4 
Pulse Oximetry.......................................................................................... 37 
13.2.5 
Body Weight ............................................................................................. 37 
13.2.6 
Clinical Laboratory Tests .......................................................................... 38 
13.2.7 
Adverse Events ......................................................................................... 39 
13.2.7.1 Adverse Event Definition ......................................................... 39 
13.2.7.2 Monitoring ............................................................................... 39 
13.2.7.3 Reporting .................................................................................. 39 
13.2.7.4 Serious Adverse Event ............................................................. 40 
13.3 Pharmacokinetic Assessments ................................................................................. 41 
13.3.1 
Blood Sampling and Processing ............................................................... 41 
13.3.2 
Pharmacokinetic Parameters ..................................................................... 42 
13.3.3 
Analytical Method .................................................................................... 43 
13.4 Blood Volume Drawn for Study Assessments ........................................................ 43 
14 STATISTICAL CONSIDERATIONS .......................................................................... 44 
14.1 Sample Size Determination ..................................................................................... 44 
14.2 Population for Analyses .......................................................................................... 44 
14.3 Statistical Analyses ................................................................................................. 44 
14.3.1 
Pharmacokinetic Analyses ........................................................................ 44 
14.3.1.1 Descriptive Statistics ................................................................ 44 
14.3.1.2 Analysis of Variance ................................................................ 44 
14.3.1.3 Steady State Analysis (Period 2 only) ...................................... 45 
14.3.1.4 Ratios and Confidence Intervals .............................................. 45 
14.3.2 
Safety Analyses ......................................................................................... 45 
15 STUDY ADMINISTRATION ....................................................................................... 46 
15.1 Ethics ....................................................................................................................... 46 
15.1.1 
Institutional Review Board ....................................................................... 46 
15.1.2 
Ethical Conduct of the Study .................................................................... 46 
15.1.3 
Subject Information and Consent.............................................................. 46 

CONFIDENTIAL  
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 10 
15.2 Termination of the Study ......................................................................................... 46 
15.3 Data Quality Assurance ........................................................................................... 46 
15.4 Direct Access to Source Data/Documents .............................................................. 47 
15.5 Drug Supplies, Packaging and Labeling ................................................................. 47 
15.6 Data Handling and Record Keeping ........................................................................ 47 
15.7 Report Format ......................................................................................................... 48 
15.8 Publication Policy ................................................................................................... 48 
16 REFERENCES ................................................................................................................ 49 
 
LIST OF TABLES 
Table 1: 
Blood Volume during the Study .................................................................... 43 
 

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CONFIDENTIAL  
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 12 
LOXO-292, whichever comes last) to determine if any adverse 
event (AE) has occurred since the last study visit.  
Number of Subjects: 
Sixteen (16), healthy, adult male and female (women of non-
childbearing potential only) subjects will be enrolled. Every 
attempt will be made to enroll at least 3 subjects of each sex. 
Dosage, Dosage Form, 
Route, and Dose 
Regimen: 
Treatment A (Period 1): 2 mg midazolam (1 mL of 2 mg/mL 
syrup) administered at Hour 0 on Day 1. 
Treatment B (Period 2): 160 mg LOXO-292 (2 x 80 mg capsules) 
administered BID, approximately every 
12 hours, for 10 consecutive days 
(within ± 1 hour of dosing time on 
Day 1) with 2 mg midazolam (1 mL of 
2 mg/mL syrup) coadministered on the 
morning of Day 10. 
All study drugs will be administered orally with approximately 
240 mL of room temperature water. When LOXO-292 and 
midazolam are administered concurrently, only 240 mL of room 
temperature water will be administered for both drugs. 
Key Assessments: 
Pharmacokinetics: 
The following PK parameters will be calculated for midazolam 
and 1-OH-midazolam in plasma, as appropriate, in Period 1, 
Day 1 and Period 2, Day 10: AUC0-t, AUC0-inf, AUC%extrap, 
Cmax, Tmax, Kel, t½, CL/F (midazolam only), and Vz/F 
(midazolam only). 
The following PK parameters will be calculated for LOXO-292 
in plasma, as appropriate, in Period 2, Day 1, Day 9, and Day 10 
(following morning dosing): AUC0-12, AUCtau, Cmax, 
Cmax,ss, Ctrough, Tmax, Tmax,ss, and CL,ss/F. 
An analysis of variance (ANOVA) will be performed on the 
midazolam and 1-OH-midazolam natural log (ln)-transformed 
AUC0-t, AUC0-inf, and Cmax, using the appropriate statistical 
procedure. 
Safety: 
Safety will be monitored through 12-lead electrocardiograms 
(ECGs), physical examination, vital sign measurements, pulse 
oximetry, clinical laboratory tests, and AEs. Incidence of AEs 
and number of subjects with AE will be tabulated and summary 
statistics for the 12-lead ECGs, vital signs, and clinical 
laboratory tests may be computed and provided, as deemed 
clinically appropriate. 
 

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CCI

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 14 
Period 1 footnotes: 
a: 
For details on Procedures, refer to Section 13. 
b: 
Within 28 days prior to the first study drug administration (i.e., midazolam). 
c: 
There will be a washout period of 48 hours days between midazolam dose in Period 1 and the first LOXO-292 dose in Period 2. Subjects are confined to 
the CRU from C-I through EOS or ET, including throughout the washout period. 
d: 
Subjects will be admitted to the CRU in Period 1, Day -1, at the time indicated by the CRU.  
e: 
The 16-hour postdose in Period 1, Day 1, will be either on Day 1 or Day 2, depending on the time of dosing on Day 1. 
f: 
Symptom-driven physical examination may be performed at other times, at the PI’s or designee’s discretion. 
g: 
To be performed within 24 hours prior to dosing. 
h: 
A baseline oxygen saturation reading will be performed prior to midazolam dosing and will be monitored continuously with a pulse oximeter for 
approximately 6 hours postdose (with the exception of restroom use), with readings taken at approximately the scheduled time points. 
i: 
Prior to dosing. 
j: 
Samples for serum chemistry will be obtained following a fast of at least 12 hours at screening and at check-in; at other scheduled times, serum chemistry 
tests will be performed after at least an 8-hour fast. However, in case of dropouts or rechecks, subjects may not have fasted for 12 or 8 hours prior to the 
time that the serum chemistry sample is taken. 
 
Abbreviations: ♀ = Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, Coag = coagulation, ConMeds = Concomitant 
medication, 
CRU = Clinical 
research 
unit, 
ECG = Electrocardiogram, 
FSH = Follicle-stimulating 
hormone, 
Hem = Hematology, 
HIV = Human 
immunodeficiency virus, HR = Heart rate, PI = Principal Investigator, PMP = Postmenopausal, Preg = Pregnancy, RR = Respiratory rate, Scr = Screening, 
T = Temperature, UA = Urinalysis.  
 
 
 

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CCI
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CCI
CCI

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 17 
Period 2 footnotes: 
a: 
For details on Procedures, refer to Section 13. 
b: 
There will be a washout period of 48 hours days between midazolam dose in Period 1 and the first LOXO-292 dose in Period 2. Subjects are confined to 
the CRU from C-I through EOS or ET, including throughout the washout period. 
c: 
To be performed within 24 hours prior to dosing  
d: 
Symptom-driven physical examination may be performed at other times, at the PI’s or designee’s discretion.  
e: 
Samples for serum chemistry will be obtained following a fast of at least 12 hours at screening and at check-in; at other scheduled times, serum chemistry 
tests will be performed after at least an 8-hour fast. However, in case of dropouts or rechecks, subjects may not have fasted for 12 or 8 hours prior to the 
time that the serum chemistry sample is taken. 
f: 
Prior to dosing.  
g: 
A baseline oxygen saturation reading will be performed prior to midazolam dosing and will be monitored continuously with a pulse oximeter for 
approximately 6 hours postdose (with the exception of restroom use), with readings taken at approximately the scheduled time points. 
h: 
The 16-hour postdose in Period 2, Day 10, will be either on Day 9 or Day 10, depending on the time of dosing on Day 10. 
i: 
To be performed at the end of study, in Period 2, Day 11, or prior to early termination from the study. 
j: 
The CRU will attempt to contact all subjects who received at least one dose of study drug (including subjects who terminate the study early) using their 
standard procedures approximately 7 days after the last study drug administration to determine if any AE has occurred since the last study visit. 
 
Abbreviations: ♀ = Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, Coag = coagulation, ConMeds = Concomitant 
medication, CRU = Clinical research unit, ECG = Electrocardiogram, EOS or ET = End-of-Study or early termination, FU = Follow-up, Hem = Hematology, 
HR = Heart rate, PI = Principal Investigator, PMP = Postmenopausal, Preg = Pregnancy, RR = Respiratory rate, T = Temperature, UA = Urinalysis.  
 

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CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 18 
7 
ABBREVIATIONS 
~ 
Approximately  
μM 
Micromolar 
1-OH-midazolam 
1-hydroxymidazolam 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC%extrap 
Percent of AUC0-inf extrapolated  
AUC0-t 
Area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration (t) 
AUCtau 
Area under the concentration-time curve during a dosing 
interval (tau), at steady state 
AUC0-inf 
Area under the concentration-time curve, from time 0 
extrapolated to infinity 
BID 
Twice daily 
bpm 
Beats per minute 
BMI 
Body mass index 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F 
Apparent total plasma clearance after oral (extravascular) 
administration 
Cm 
Centimeter 
Cmax 
Maximum observed concentration  
Cmax,ss 
Maximum observed concentration at steady-state. 
CRF 
Case report form 
CRU 
Clinical Research Unit 
Ctrough 
Concentration observed at the end of the dosing interval 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 19 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HCl 
Hydrochloride 
HCV 
Hepatitis C virus 
hERG 
Human ether-a-go-go related gene 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Inhibitory concentration at 50% 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
Kel 
Apparent terminal elimination rate constant 
kg 
Kilogram 
LSMs 
Least-squares means 
m2 
Meters squared 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
mRNA 
Messenger ribonucleic acid 
msec 
Millisecond 
No. 
Number 
oz 
Ounces 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 20 
QA 
Quality Assurance 
QTc 
Corrected value of the interval between the Q and T waves on the 
electrocardiogram tracing 
RET 
Rearranged during transfection 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse events  
Tmax 
Time to reach maximum observed concentration 
Tmax,ss 
Time to reach maximum observed concentration at steady-state 
t½ 
Apparent terminal elimination half-life 
US 
United States 
USA 
United States of America 
Vz/F 
Apparent volume of distribution during the terminal elimination 
phase after oral (extravascular) administration 
WHO 
World Health Organization 
 

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CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 22 
LOXO-292 was not mutagenic in the GLP bacterial mutation assay. LOXO-292 was not 
found to be phototoxic when evaluated in an in vitro neutral red uptake phototoxicity assay. 
Based on preclinical pharmacology experiments with human cancer cells in vitro and in 
murine xenograft models, meaningful inhibition of RET in tumors is expected to be 
achievable with oral dosing regimens ≥ 40 mg/day. 
Based on the nonclinical profile, including results from animal toxicology studies, theoretical 
risks of human exposure to LOXO-292 include the following: loss of appetite, decrease in 
body weight, increase in total white blood cells, neutrophils, and monocytes, decrease in 
albumin, increase in globulin, decreased albumin:globulin ratio, decrease in total protein, 
increased body temperature, lethargy, increase in cholesterol and triglycerides, increase in 
phosphorus, changes in taste sensation and/or development of xerostomia, gastrointestinal 
symptoms/signs: nausea, vomiting, loose stools, abdominal discomfort, decreases in red cell 
mass (red blood cell, hemoglobin, hematocrit) and reticulocytes, decrease in platelets, 
increases in liver function tests (alkaline phosphatase, aspartate aminotransferase, and alanine 
aminotransferase). 
LOXO-292 has been given orally and intravenously to mice, rats, dogs, minipigs, and 
monkey. LOXO-292 was absorbed and bioavailable in all species tested. Solubility studies 
and pharmacokinetic studies suggest that the pharmacokinetic exposure of LOXO-292 may 
be reduced by proton pump inhibitors and other antacids. LOXO-292 appears to be 
metabolized primarily by CYP3A4, but at therapeutically relevant exposures, it is not 
anticipated to inhibit or induce drug-metabolizing enzymes. LOXO-292 is also a substrate for 
the Breast Cancer Resistance Protein. 
Refer to the Investigator’s Brochure for detailed background information on LOXO-292 
(Investigator’s Brochure 2018). 
Clinical 
LOXO-292 is currently being studied in an ongoing global Phase 1 first in human Study 
LOXO-RET-17001 in patients with advanced solid tumors including RET fusion-positive 
NSCLC, RET-mutant MTC, and other tumors with increased RET activity. The starting dose 
of LOXO-292 was 20 mg once daily. As of a January 5, 2018 data cut-off date, safety data 
was available from 57 patients with 160 mg BID as the highest dose administered. As of the 
January 5, 2018, no dose-limiting toxicities have been reported. Treatment-emergent adverse 
events (TEAEs) occurring in ≥ 10% of patients were: fatigue (16%), diarrhea (16%), and 
dyspnea (12%). The majority of TEAEs were Grades 1 or 2 and no ≥ Grade 3 TEAEs were 
related to study drug. Three subjects have died during the study, and no deaths have been 
attributed to study drug. 
Loxo Oncology has also initiated 3 IRB-approved, FDA-allowed single patient protocols 
(LOXO-RET-17002, LOXO-RET-17003, and LOXO-RET-17004) to provide access to 
LOXO-292 for patients with clinical need not meeting eligibility criteria for the ongoing 
clinical studies. As of January 5, 2018, no TEAEs have been attributed to study drug for 
these patients. 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 23 
As of February 9, 2018, PK data were available from patients (from the LOXO-RET-17001 
study). LOXO-292 is absorbed after oral administration with a time to maximum 
concentration (Tmax) of approximately 2 hours. Although the pharmacokinetic sampling of 
LOXO-292 was not long enough to adequately characterize AUC0-inf, the half-life was 
estimated to be at least 12 hours or longer. Low concentrations of LOXO-292 were recovered 
as unchanged drug in urine indicating that the kidney contributes to overall clearance. 
8.1.2 
Midazolam 
Midazolam is a relatively short-acting benzodiazepine central nervous system depressant that 
has sedative, anxiolytic, amnesic, and hypnotic effects. Benzodiazepine pharmacological 
properties appear to result from reversible interactions with major inhibitory central nervous 
system neurotransmitter gamma-amino butyric acid. Midazolam is available as syrup for oral 
administration and a solution for administration intramuscularly or intravenously (Full 
Prescribing information of midazolam syrup, 2017). 
Midazolam is rapidly absorbed after oral administration. Following oral administration of 
midazolam in healthy subjects, the mean Tmax of midazolam ranges from 0.17 to 2.65 hours 
and the half-life is approximately (~)4 hours. In adult and pediatric patients older than 1 year, 
~ 97% of midazolam binds to plasma albumin. Midazolam is primarily metabolized in the 
liver and intestines by CYP3A to its pharmacologically active metabolite, 1-OH-midazolam, 
followed by glucuronidation of the metabolite, which is then excreted in urine. The median 
Tmax of the active metabolite 1-OH-midazolam is 0.75 hour, with a half-life of ~ 6 hours 
(Celerion in-house data). Midazolam is also metabolized to two other minor metabolites: 
4-hydroxymidazolam (~3% of the dose) and 1, 4-dihydroximidazolam (about 1% of the 
dose) that are excreted in small amount in the urine as conjugates (Full Prescribing 
information of midazolam syrup, 2017). 
Midazolam is a pregnancy category D drug (Full Prescribing information of midazolam 
syrup, 2017).  
8.2 
Rationale 
8.2.1 Rationale for this Study and Study Design 
Metabolic routes of elimination, including most of those occurring through the CYP family 
of enzymes, can be inhibited or induced by concomitant drug treatment. Changes arising 
from metabolic DDI can be significant, and contribute to increases or decreases in the blood 
and tissue concentrations of the parent drug or active metabolite. Increased concentrations of 
a parent drug or its active metabolite can alter the safety and efficacy profile of a drug.  
Data from in vitro studies indicate that LOXO-292 is a weak, time-dependent inhibition of 
CYP3A4, although at a therapeutically relevant unbound plasma concentration 
(e.g., 0.03 μM), the rate of inactivation of CYP3A4 is small relative to its rate of 
regeneration. In data from human hepatocytes showed weak, concentration-dependent 
induction from LOXO-292 (0.03-100 μM) of CYP1A2, CYP2B6, and CYP3A4 messenger 
ribonucleic acid (mRNA), however at LOXO-292 concentrations of 3 μM or lower, induction 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 24 
of CYP1A2, CYP2B6, and CYP3A4 mRNA and enzymatic activity was less than 20% the 
level of their respective positive controls omeprazole, phenobarbital, and rifampin.  
Based on in vitro data, it is anticipated that LOXO-292 may inhibit or induce CYP3A 
enzymes. This study will therefore be conducted to evaluate the potential effect of 
LOXO-292 on CYP3A4 enzyme in vivo. Midazolam selection as a substrate is based on 
previous widespread use as a suitable established marker of CYP3A activity and it is 
recommended to be used as a CYP3A sensitive probe by the FDA (FDA, 2017). 
A fixed-sequence design has been selected. This design will reduce the study duration and 
will ensure similar CYP baseline levels in the start of each period. The washout period 
between the midazolam dosing is considered sufficient to prevent carryover effects of the 
preceding treatment as it is greater than 10 half-lives of midazolam, if the half-life is up to 
4 hours in duration.  
8.2.2 Rationale for the Dose Selection and Dose Regimen 
LOXO-292: A single dose of 160 mg LOXO-292 was selected because it is a dose that has 
been given twice daily to cancer patients and preliminary safety and PK data show that this 
dose is likely at or near a recommended Phase 2 dose for further study in cancer patients. A 
single dose of 160 mg should provide sufficient levels of LOXO-292 to assess the PK 
properties being investigated. As of January 5, 2018 data cut-off date, safety data were 
available from 57 patients with doses up to 160 mg BID (320 mg/day). As of this date, no 
dose-limiting toxicities have been reported, however the effect of food and gastric pH has not 
been explored. 
Midazolam: Sedation is a potential side effect of midazolam use. However, the 2 mg dose 
selected for use in this study is substantially lower than the doses typically required for 
effective sedation (0.5 mg/kg to a maximum of 20 mg-midazolam hydrochloride [HCl] 
syrup) and is a relatively low therapeutic dose in adults. In a number of DDI studies with 
CYP3A4 inhibitors, a 2 mg dose of midazolam has been used (Adams, 2005; 
Majumdar, 2003). Furthermore, a 2 mg midazolam dose was well tolerated without 
significant sedation in previous Celerion studies conducted in a similar adult population with 
a similar study design. Thus, the oral 2 mg dose in this study is expected to be safe and well 
tolerated. 
8.2.3 Rationale for Primary Endpoints 
The primary PK endpoints will include midazolam and 1-OH-midazolam AUC0-t, 
AUC0-inf, and Cmax, as these parameters describe the exposure of midazolam and are 
thought to be the most relevant PK parameters for the purpose of evaluating an interaction. 
8.3 
Risks and/or Benefits to Subjects 
The dose of LOXO-292 administered in this study is not anticipated to induce any potential 
risk or benefit to subjects participating in this study as it does not exceed the highest daily 
total dose safely administered in first in human studies (Investigator’s Brochure 2018). 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 25 
The dose of midazolam administered in this study is not anticipated to result in any potential 
risk to subjects participating in the study as it is a single dose administered according to the 
dosing recommendations found in the full prescribing information for midazolam HCl 
(syrup) (Full Prescribing information of midazolam syrup, 2017). 
The safety monitoring practices employed by this protocol (i.e., 12-lead ECG, vital signs, 
pulse oximetry, clinical laboratory tests, AE questioning, and physical examination) are 
adequate to protect the subjects’ safety. 
There will be no direct health benefit for study participants from receipt of study drug. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at screening and during the study.

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 26 
9 
OBJECTIVES AND ENDPOINTS 
9.1 
Objectives 
Primary: 
To investigate the effect of multiple-dose LOXO-292 on the single-dose PK of midazolam, a 
sensitive CYP3A substrate, in healthy adult subjects. 
Secondary: 
1) To evaluate the single-dose PK of LOXO-292 administered alone and the multiple-dose PK 
of LOXO-292 with and without coadministration of midazolam in healthy adult subjects. 
2) To determine the safety and tolerability of multiple-dose LOXO-292 alone and when 
coadministered with a single-dose of midazolam in healthy adult subjects. 
9.2 
Endpoints 
Pharmacokinetics: 
The primary PK endpoints for midazolam and 1-OH-midazolam will include, as appropriate, 
AUC0-t, AUC0-inf, AUC%extrap, Cmax, Tmax, Kel, t½, CL/F (midazolam only), and Vz/F 
(midazolam only).  
The secondary PK endpoints for LOXO-292 will include, as appropriate, AUC0-12, AUCtau, 
Cmax, Cmax,ss, Ctrough, Tmax, Tmax,ss, and CL,ss/F. 
Safety: 
Safety endpoints will include 12-lead ECGs, physical examinations, pulse oximetry, vital 
signs, clinical laboratory tests, and AEs. 

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CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 28 
11 STUDY POPULATION 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to enrollment. The Sponsor will provide approval of subjects for enrolment prior to 
dosing. 
11.1 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study: 
1. Healthy, adult, male or female (of non-childbearing potential only), 18-55 years of age, 
inclusive, at screening. 
2. Continuous non-smoker who has not used tobacco- and/or nicotine-containing products for 
at least 3 months prior to the first dosing and throughout the study, based on subject self-
reporting. 
3. Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kg/m2 at screening and have a minimum weight 
of at least 50 kg at screening.  
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the PI or designee, and as confirmed 
by the Sponsor. Liver function tests (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP]), and serum (total and direct) 
bilirubin, as well as amylase and lipase, must be within the upper limit of normal for the 
laboratory used by the clinical site at screening and check-in (Day -1 Period 1). Rechecks 
of the liver function tests (ALT, AST, and ALP) and serum (total and direct) bilirubin, as 
well as amylase and lipase will be permitted up to two times to confirm subject eligibility. 
Subjects may be eligible for participation in the study based on rechecked values if the PI 
(or designee), with agreement from the Sponsor, feels that the results are not clinically 
significant, and will not impact study conduct. 
5. A female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dosing: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status. 
6. A non-vasectomized, male subject must agree to use a condom with spermicide or abstain 
from sexual intercourse during the study until 6 months after the last dosing. (No 
restrictions are required for a vasectomized male provided his vasectomy has been 

CONFIDENTIAL 
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Page 29 
performed 4 months or more prior to the first dosing of study drug. A male who has been 
vasectomized less than 4 months prior to study first dosing must follow the same 
restrictions as a non-vasectomized male). 
7. If male, must agree not to donate sperm from the first dosing until 6 months after the last 
dosing. 
8. Understands the study procedures in the informed consent form (ICF), and be willing and 
able to comply with the protocol. 
11.2 Exclusion Criteria 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the PI or designee, and as confirmed by the Sponsor. 
3. History of any illness that, in the opinion of the PI or designee, and as confirmed by the 
Sponsor, might confound the results of the study or poses an additional risk to the subject 
by their participation in the study. 
4. History of gastritis, gastrointestinal tract, or hepatic disorder or other clinical condition that 
might, in the opinion of the PI or designee, and as confirmed by the Sponsor, affect the 
absorption, distribution, biotransformation, or excretion of LOXO-292 or midazolam.  
5. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
dosing.  
6. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or 
related compounds, or inactive ingredients. 
7. History or presence of: 
• liver disease, 
• diabetes,  
• pancreatitis, 
• peptic ulcer disease,  
• intestinal malabsorption,  
• gastric reduction surgery,  
• history or presence of clinically significant cardiovascular disease: 
o myocardial infarction or cerebrovascular thromboembolism within 6 months prior 
to first dosing 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 30 
o symptomatic angina pectoris 
o New York Heart Association Class ≥2 congestive heart failure 
o congenital prolonged QT syndrome  
o ventricular pre-excitation syndrome (Wolff-Parkinson White syndrome) 
o arrhythmia or history of arrhythmia requiring medical intervention  
o ventricular dysfunction or risk factors for Torsades de Pointes (e.g., heart failure, 
cardiomyopathy, family history of Long QT Syndrome) 
o significant screening ECG abnormalities: 
 Left bundle-branch block 
 Second degree atrioventricular (AV) block, type 2, or third degree AV block 
 QTcF interval is >450 msec 
 ECG findings deemed abnormal with clinical significance by the PI or 
designee at screening and prior to Period 1, Day 1 dosing. 
8. Female subjects of childbearing potential.  
9. Female subjects with a positive pregnancy test or who are lactating. 
10. Positive urine drug or alcohol results at screening or check-in. 
11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg) or hepatitis C virus (HCV). 
12. Seated blood pressure is less than 90/50 mmHg or greater than 139/89 mmHg at screening 
and prior to Period 1, Day 1 dosing. Rechecks of blood pressure values will be permitted 
up to two times to confirm eligibility for study participation. Subjects may be eligible for 
participation in the study based on rechecked values if the PI (or designee), with agreement 
from the Sponsor, feels that the results are not clinically significant, and will not impact 
study conduct. 
13. Seated heart rate is lower than 50 bpm or higher than 99 bpm at screening and prior to 
Period 1, Day 1 dosing. Rechecks of heart rate values will be permitted up to two times to 
confirm eligibility for study participation. Subjects may be eligible for participation in the 
study based on rechecked values if the PI (or designee), with agreement from the Sponsor, 
feels that the results are not clinically significant, and will not impact study conduct. 
14. Estimated creatinine clearance <90 mL/min at screening or prior to Period 1, Day 1 dosing. 
15. Unable to refrain from or anticipates the use of: 
• Any drug, including prescription and non-prescription medications, herbal remedies, or 
vitamin supplements for 14 days prior to the first dosing and throughout the study. 

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After first dosing, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the PI or designee. 
• Any drugs known to be significant inducers of CYP3A enzymes and/or P-gp, including 
St. John’s Wort, for 28 days prior to the first dosing and throughout the study. 
Appropriate sources (e.g., Flockhart TableTM) will be consulted to confirm lack of 
PK/pharmacodynamics interaction with study drug. 
16. Has been on a diet incompatible with the on-study diet, in the opinion of the PI or designee, 
and as confirmed by the Sponsor, within the 30 days prior to the first dosing and 
throughout the study. 
17. Donation of blood or significant blood loss within 56 days prior to the first dosing. 
18. Plasma donation within 7 days prior to the first dosing. 
19. Participation in another clinical study within 30 days prior to the first dosing. The 30-day 
window will be derived from the date of the last blood collection or dosing, whichever is 
later, in the previous study to Period 1, Day 1 of the current study. 
11.3 Early Termination of Subjects from the Study 
Subjects are free to withdraw from the study at any time for any reason.  
In addition, subjects may be withdrawn from the study by the PI or designee for the following 
reasons: 
• AEs. 
• Difficulties in blood collection. 
• Positive pregnancy test. 
• Positive urine drug and alcohol test. 
A subject may be withdrawn by the PI, designee, or the Sponsor if either considers enrollment 
of the subject into the study is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons. Prompt notification to the Sponsor of withdrawal of any subject 
should be provided. 
Subjects who withdraw from the study will undergo early termination from the study 
procedures as outlined in the Study Events Flow Chart (Section 6).  
11.4 Study Restrictions 
11.4.1 Prohibitions and Concomitant Medication 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 

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• Xanthines/Caffeine: 24 hours prior to first dosing and throughout the study (small 
amounts of caffeine derived from normal foodstuffs e.g., 250 mL/8 oz./1 cup 
decaffeinated coffee or other decaffeinated beverage, per day, with the exception of 
espresso; 45 g/1.5 oz. chocolate bar, per day, would not be considered a deviation to 
this restriction); 
• Alcohol: 48 hours prior to first dosing and throughout the study; 
• Grapefruit/Seville orange and their juices: 14 days prior to first dosing and throughout 
the study; 
• Other Fruit Juice: 72 hours prior to first dosing and throughout the study; 
• Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts, mustard), and charbroiled meats: 7 days prior to first 
dosing and throughout the study. 
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 11.2. 
After first dosing, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the PI or designee.  
If deviations occur, the PI or designee in consultation with the Sponsor if needed will decide on 
a case-by-case basis whether the subject may continue participation in the study. 
All medications (including vitamins and herbal supplements) taken by subjects during the 
course of the study will be recorded. 
Use of any tobacco- and/or nicotine-containing products will be prohibited throughout the 
study. 
11.4.2 Meals 
Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour 
after each study drug administration, but will be allowed ad libitum at all other times. Other 
fluids may be given as part of meals and snacks but will be restricted at all other times 
throughout the confinement period. 
In Period 1, Day 1, subjects will fast overnight for at least 10 hours prior to study drug 
administration and will continue to fast for at least 4 hours postdose. 
In Period 2, Days 1 to 9 and evening dose on Day 10, subjects will fast for at least 2 hours prior 
to each dose (morning and evening) and will continue the fast for at least 1 hour postdose.  
In Period 2, Day 10, subjects will fast overnight for at least 10 hours prior to study drug 
administration and will continue to fast for at least 4 hours postdose.  
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all 
food and drink except water between meals and snacks. 

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Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each period. 
11.4.3 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours post morning dose, 
except when they are seated, supine, or semi-reclined for study procedures. However, should 
AEs occur at any time, subjects may be placed in an appropriate position or will be permitted 
to lie down on their right side. 
There is no specific restriction of activity after dosing in the evening doses. 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of 
the study. 
 
 

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12 TREATMENTS 
12.1 Treatments Administered 
LOXO-292 will be supplied as 80 mg capsules. 
Midazolam will be supplied as midazolam HCl 2 mg/mL syrup, equivalent to 2 mg of 
midazolam.  
Treatments are described as follows: 
Treatment A (Period 1): 
2 mg midazolam (1 mL of 2 mg/mL syrup) administered at Hour 0 
on Day 1. 
Treatment B (Period 2): 
160 mg LOXO-292 (2 x 80 mg capsules) administered BID, 
approximately every 12 hours, for 10 consecutive days (within 
± 1 hour of dosing time on Day 1) with 2 mg midazolam (1 mL of 
2 mg/mL syrup) coadministered on the morning of Day 10. 
Each dose of LOXO-292 and midazolam will be administered orally with 240 mL of room 
temperature water. When LOXO-292 and midazolam are administered concurrently, only 
240 mL of room temperature water will be administered for both drugs. The dose of 
midazolam in Period 1, Day 1 and the coadministered morning doses of LOXO-292 and 
midazolam in Period 2, Day 10 will be preceded by an overnight fast of at least 10 hours. All 
other doses will be preceded by a 2-hour fast. 
Subjects will be instructed not to crush, split, or chew LOXO-292. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period.  
The exact clock time of dosing will be recorded. 
12.2 Dose Modification 
The dose and administration of the study drugs to any subject may not be modified. If 
necessary a subject must be discontinued for the reasons described in Section 11.3. 
12.3 Method of Treatment Assignment 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of the first dosing, different from the screening 
number, and will receive the corresponding product.  
Subjects will receive each treatment on one occasion. The sequence to be used will be AB.  
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 001).  

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12.4 Blinding 
This is an open-label study.  
12.5 Treatment Compliance  
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the subjects 
have swallowed the study drug.  
For LOXO-292 only, once a subject has finished the dosing water, the qualified designee will 
use a flashlight and a tongue depressor to check the subject’s mouth. Subjects’ hands will also 
be verified to ensure that the LOXO-292 was ingested. 

CONFIDENTIAL 
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13 STUDY ASSESSMENTS AND PROCEDURES 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be performed 
at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI or designee and/or the Sponsor for 
reasons related to subject safety. 
For this study, the blood collection for midazolam, 1-OH-midazolam, and LOXO-292 is the 
critical parameter and needs to be collected as close to the exact time point as possible. All 
other procedures should be completed as close to the prescribed/scheduled time as possible, but 
can be performed prior or after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
13.1 Screening 
Within 28 days prior to the first dosing, medical history and demographic data, including 
name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI (kg/m2) and history of 
tobacco use will be reported. Each subject will have a physical examination, vital sign 
measurements (heart rate, blood pressure, temperature, and respiratory rate), 12-lead ECG, and 
the laboratory tests of hematological, hepatic and renal function and additional tests as noted in 
Section 13.2.6. 
13.2 Safety Assessments 
13.2.1 Physical Examination 
Full and abbreviated physical examination will be performed as outlined in the Study Events 
Flow Chart (Section 6).  
An abbreviated physical examination will include at the minimum, examination of respiratory, 
cardiovascular, and gastrointestinal systems, with the option for further examination of 
additional systems as necessary based on reported symptoms/AEs.  
Symptom-driven physical examinations may be performed at other times, if deemed necessary 
by the PI or designee.  
13.2.2 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, will 
be measured as outlined in the Study Events Flow Chart (Section 6). Additional vital signs may 
be taken at any other times, if deemed necessary. 
Blood pressure, heart rate, and respiratory rate measurements will be performed with subjects 
in a seated position, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g. nausea, dizziness) or if deemed necessary by the PI or designee. 

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Blood pressure, heart rate, and respiratory rate will be measured within 24 hours prior to Day 1 
dosing in each period for the predose time point. At all other predose time points, blood 
pressure and heart rate will be measured within 2 hours prior to dosing. When scheduled 
postdose, vital signs will be performed within approximately 15 minutes of the scheduled time 
point.  
13.2.3 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Section 6). 
Additional ECGs may be taken at any other times, if deemed necessary by the PI or designee. 
ECGs will be performed with subjects in a supine position. All ECG tracings will be reviewed 
by the PI or designee. 
ECGs will be measured within 24 hours prior to Day 1 dosing in each period for the predose 
time point. At all other predose time points, ECGs will be collected within 2 hours prior to 
dosing. When scheduled postdose, ECGs will be performed within approximately 20 minutes 
of the scheduled time point. 
13.2.4 Pulse Oximetry 
Each subject will have a baseline pulse oximetry reading done prior to midazolam 
administration and will be monitored continuously for approximately 6 hours with a pulse 
oximeter (oxygen levels as saturation [%]) with readings taken at scheduled timepoints as 
outlined in the Study Events Flow Chart (Section 6). 
Where the time of monitoring coincides with a blood sampling time point, the reading will be 
taken approximately 15 minutes prior to the scheduled time point. Readings may be taken at 
other times, if deemed necessary by the PI or designee. 
Any oxygen saturation reading deemed clinically significant by the PI will be documented. 
13.2.5 Body Weight 
Body weight (kg) will be reported as outlined in the Study Events Flow Chart (Section 6).  

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13.2.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart (Section 6). 
In addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI or designee.  
Hematology 
 
Serum Chemistry* 
• 
Hemoglobin 
• 
Hematocrit  
• 
Total and differential leukocyte count 
• 
Red blood cell count 
• 
Platelet count 
 
 
Coagulation 
• 
Prothrombin 
Time/International 
normalized ratio 
• 
Activated partial thromboplastin time 
 
 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
ALP 
• 
AST 
• 
ALT 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Magnesium 
• 
Chloride 
• 
Glucose (fasting) 
• 
Creatinine** 
• 
Cholesterol 
• 
Triglycerides 
• 
Phosphorus 
• 
Creatine kinase 
• 
Amylase 
• 
Lipase 
 
Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein*** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood*** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase*** 
 
• 
HIV test 
• 
HBsAg 
• 
HCV 
• 
Urine drug screen 
 
Opiates 
 
Opioids 
(methadone, 
oxycodone, 
and 
fentanyl) 
 
Amphetamines  
 
Barbiturates  
 
Benzodiazepines  
 
Cocaine  
 
Cannabinoids  
• 
Urine alcohol screen 
• 
Serum pregnancy test  
(for females only) 
• 
FSH (for postmenopausal females only) 
• 
Thyroid stimulating hormone 
 
* 
Samples for serum chemistry will be obtained following a fast of at least 12 hours at screening and at 
check-in; at other scheduled times, serum chemistry tests will be performed after at least an 8 hour fast. 
However, in case of dropouts or rechecks, subjects may not have fasted for 12 or 8 hours prior to the 
time that the serum chemistry sample is taken. 
** At screening and prior to Period 1, Day 1 dosing, creatinine clearance will be calculated using the 
Cockcroft-Gault formula. 
*** If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination 
(for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 

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13.2.7 Adverse Events  
13.2.7.1 
Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
13.2.7.2 
Monitoring 
Subjects will be monitored from screening (signing of informed consent) and throughout the 
study for adverse reactions to the study drugs and/or procedures. Prior to release, subjects will 
be asked how they are feeling. At the follow-up, subjects will be queried with an open-ended 
question such as: ‘How have you been feeling since your last visit?’ 
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test 
value(s) will be evaluated by the PI or designee and treated and/or followed up until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the PI or designee 
and confirmed by the Sponsor.  
Treatment of serious adverse events (SAEs) will be performed by a physician, either at 
Celerion or at a nearby hospital emergency room. Where appropriate, medical test(s) and/or 
examination(s) will be performed to document resolution of event(s). Outcome may be 
classified as resolved, improved, unchanged, worse, fatal, or unknown (lost to follow-up). 
13.2.7.3 
Reporting 
All AEs that occurred during this clinical study will be recorded. The start of the AE reporting 
for a subject will be the signing of informed consent for this study. Between the time of 
informed consent and with the first dose of study drug, only AEs (non-serious and serious) 
assessed as related to study procedures should be reported. All other events should be reported 
as medical history. After the first dose of study drug, all AEs (serious and non-serious, related 
and unrelated) should be reported. Unless a subject withdraws consent for follow-up, all 
subjects must be followed until the end of the AE reporting period at 7 days after the last study 
drug administration (midazolam or LOXO-292, whichever comes last) or when any ongoing 
drug-related AEs and/or SAEs have resolved or become stable. The PI should use appropriate 
judgment in ordering additional tests as necessary to monitor the resolution of events. The 
Sponsor may request that certain AEs be followed longer and/or additional safety tests be 
performed. SAEs which occur after the reporting period has ended must be reported only if 
they are considered by the PI to be related to study drug (or study procedure). 

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The PI should use appropriate judgment in ordering additional tests as necessary to monitor the 
resolution of events. The Sponsor may request that certain AEs be followed longer and/or 
additional safety tests be performed.  
The PI or designee will review each event and assess its relationship to drug treatment (yes 
[related] or no [unrelated]). Each sign or symptom reported will be graded on the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 toxicity grading scale.  
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on the following general guideline (NCI 
CTCAE 27 Nov 2017): 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A Semi-colon indicates ‘or’ within the description of the grade. 
Note: Activities of Daily Living (ADL) 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
13.2.7.4 
Serious Adverse Event 
If any AEs are serious, as defined by the FDA Code of Federal Regulations (CFR), Title 21, 
special procedures will be followed. All SAEs will be reported to the Sponsor or designee via 
fax or e-mail within 24 hours of first awareness of the event, whether or not the serious 
event(s) are deemed drug-related. All serious event reporting will adhere to 21 CFR 312.32 for 
Investigational New Drugs (IND) and to the Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE, dated December 2012. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes: Death, a life-threatening AE, inpatient 

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Page 41 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity 
or disability, or a congenital anomaly/birth defect. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI (or 
designee) or Sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
All SAEs occurring from the signing of consent through 7 days after the last dose of study drug 
(midazolam or LOXO-292, whichever comes last) must be reported on a SAE Report Form 
provided by LOXO Oncology and sent by fax or e-mail to the Sponsor listed in Section 3 
within 24 hours of first awareness of the event. 
When using the SAE efax (+ 1 203 643-2013) a cover page including study identification 
number and study drug product (i.e., LOXO-292) is required. Alternatively, an email can be 
sent to safety@loxooncology.com. 
The PI is not obligated to actively seek information regarding the occurrence of new SAEs 
beginning after the 7-day post last dose period. However, if the PI learns of such an SAE, and 
that event is deemed associated with the use of study drug, he/she should promptly document 
and report the event. 
The PI will be requested to supply detailed information as well as follow-up regarding the 
SAE. Although not considered an AE per se, the Sponsor must be notified of any subject or 
subject’s partner who becomes pregnant during the study at any time between the start of 
screening until 90 days after the last administration of study drug. 
13.3 Pharmacokinetic Assessments 
13.3.1 Blood Sampling and Processing 
For all subjects, blood samples for the determination of midazolam, 1-OH-midazolam, and 
LOXO-292 will be collected at scheduled time points as delineated in the Study Events Flow 
Chart (Section 6). 
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately. 

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13.3.2 Pharmacokinetic Parameters 
PK parameters for plasma midazolam and 1-OH-midazolam in Period 1, Day 1, and Period 2, 
Day 10, will be calculated as follows, as appropriate: 
 
AUC0-t: 
 
The area under the concentration-time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method. 
AUC0-inf: 
The area under the concentration-time curve from time 0 extrapolated to 
infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of 
the last measurable plasma concentration to the elimination rate 
constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated, represented as 
(1 - AUC0-t/AUC0-inf)*100. 
CL/F: 
Apparent total plasma clearance after oral (extravascular) 
administration, calculated as Dose/AUC0-inf (midazolam only). 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than one 
time point, Tmax is defined as the first time point with this value. 
Kel: 
Apparent first-order terminal elimination rate constant calculated from a 
semi-log plot of the plasma concentration versus time curve. The 
parameter will be calculated by linear least-squares regression analysis 
using the maximum number of points in the terminal log-linear phase 
(e.g., three or more non-zero plasma concentrations). 
t½: 
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel. 
Vz/F: 
Apparent volume of distribution during the terminal elimination phase 
after oral (extravascular) administration, calculated as (Dose/AUC0-
inf) x Kel (midazolam only). 
PK parameters for plasma LOXO-292 in Period 2, Day 1, Day 9, and Day 10 will be calculated 
as follows, as appropriate (note that the 16- and 24-hour PK sample in Period 2, Day 10 will be 
reported in descriptive statistics only and will not be included in the PK parameters 
computation): 
AUC0-12: 
The area under the concentration-time curve, from time 0 to the 12 hour 
timepoint, as calculated by the linear trapezoidal method (Day 1). 
AUCtau: 
The area under the concentration-time curve during a dosing 
interval (tau) at steady state (Days 9 and 10). 
CL,ss/F: 
Apparent total plasma clearance after oral (extravascular) 
administration, calculated as Dose/AUCtau (Days 9 and 10). 

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CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 44 
14 STATISTICAL CONSIDERATIONS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
14.1 Sample Size Determination 
Based on in vitro data, it is anticipated that LOXO-292 may inhibit or induce CYP3A enzymes 
and therefore affect midazolam PK profile. Sixteen (16) subjects are considered sufficient to 
evaluate the magnitude of this interaction. 
14.2 Population for Analyses 
PK Population: Plasma samples from all subjects will be assayed even if the subjects do not 
complete the study. All subjects who comply sufficiently with the protocol and display an 
evaluable PK profile (e.g., exposure to treatment, availability of measurements and absence of 
major protocol violations) will be included in the statistical analyses.  
Safety Population: All subjects who received at least one dose of either of the study drugs will 
be included in the safety evaluations. 
14.3 Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by Celerion 
and agreed upon with the Sponsor. This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoints definition and/or its 
analysis will also be reflected in a protocol amendment. Additional statistical analyses other 
than those described in this section may be performed if deemed appropriate.  
14.3.1 Pharmacokinetic Analyses 
14.3.1.1 
Descriptive Statistics 
Values will be calculated for the plasma concentrations and the PK parameters listed in 
Section 13.3.1 for midazolam, 1-OH-midazolam, and LOXO-292 using appropriate summary 
statistics to be fully outlined in the SAP.  
14.3.1.2 
Analysis of Variance 
An ANOVA will be performed on the ln-transformed AUC0-t, AUC0-inf, and Cmax of 
midazolam and 1-OH-midazolam. The ANOVA model will include treatment as fixed effect 
and subject as the random effect. Each ANOVA will include calculation of least-squares means 
(LSMs), the difference between treatment LSMs, and the standard error associated with this 
difference. The above statistical analyses will be done using the appropriate statistical 
procedure. 

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CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 46 
15 STUDY ADMINISTRATION 
15.1 Ethics 
15.1.1 Institutional Review Board  
This protocol will be reviewed by the Advarra IRB, and the study will not start until the IRB 
has approved the protocol or a modification thereof. The IRB is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The IRB is compliant to International Council on 
Harmonisation (ICH) guidelines, and may be reached at: 
Advarra IRB  
6940 Columbia Gateway Drive, Suite 110 
Columbia, Maryland 21046, USA 
Tel.: +1 410 884-2900 
15.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration of 
Helsinki, GCP, and the ICH harmonized tripartite guideline regarding GCP (E6 Consolidated 
Guidance, April 1996). 
15.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date 
an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
15.2 Termination of the Study 
Celerion reserves the right to terminate the study in the interest of subject welfare. 
Sponsor reserves the right to suspend or terminate the study at any time. 
15.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant to 
the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, GCP and GLP requirements as well as applicable 
regulatory requirements and local laws, rules and regulations relating to the conduct of the 
clinical study. 

CONFIDENTIAL 
CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 47 
The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit 
checks are then performed for appropriate databases as a validation routine using SAS® or 
comparable statistical program to check for missing data, data inconsistencies, data ranges, etc. 
Corrections are made prior to database lock. 
15.4 Direct Access to Source Data/Documents 
Celerion will ensure that the Sponsor, IRB, and inspection by domestic and foreign regulatory 
authorities will have direct access to all study-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event that other 
study-related monitoring should be done by other parties, they will be required to sign a 
confidentiality agreement prior to any monitoring and auditing. 
15.5 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of the LOXO-292 capsules to allow completion 
of this study. Celerion will provide sufficient quantities of midazolam to allow completion of 
the study. The lot numbers and expiration dates (where available) of the study drugs supplied 
will be recorded in the final report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be retained by Celerion, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. Any remaining supplies that 
were purchased by Celerion will be destroyed. If no supplies remain, this fact will be 
documented in the pharmacy product accountability records. 
15.6 Data Handling and Record Keeping 
Celerion standard CRFs will be supplied. CRFs are printed off directly from the database. Each 
CRF is reviewed and signed by the PI. 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Celerion until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period however if required by the applicable regulatory requirements 
or by an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
PI/Institution as to when these documents no longer need to be retained. 

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CA24334 (LOXO-RET-18017), Final Protocol, Amendment 2 30Jul2018 
 
Page 48 
15.7 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports).  
15.8 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 

CONFIDENTIAL 
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Page 49 
16 REFERENCES 
Adams M. et al. Oxymorphone extended release does not affect CYP2C9 or CYP3A6 
metabolic pathways. J Clin Pharmacol. 2005;45:337-45. 
Chow SC and Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 
Marcel Dekker Inc., New York, 1992. 
Food and Drug Administration. Guidance for Industry: Drug Interaction Studies – Study 
Design, Data Analysis, Implications for Dosing, and Clinical Implications (Draft Guidance 
October 2017) published on the website 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.ht
m. 
LOXO-292. Investigator’s Brochure. Loxo Oncology, Inc. Version 3.0. 05-Apr-2018. 
Midazolam hydrochloride syrup (West-Ward Pharmaceuticals Corp), full prescribing 
information (electronic monograph) document revised: April 2017. Available at: 
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a833c24b-6dca-44d7-a0d6-
20012fa1ea77&type=display  
Majumdar AK. et al Effects of aprepitant on cytochrome P450 3A4 activity using midazolam 
as a probe. Clin Pharmacol Ther. 2003;74(2):150-6. 
National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), 
Revised: Nov-2017 (v5.0). Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf. 
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach 
for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 
1987;15:657-80.