Clinical trial NCT05134337
Conditions: Healthy Volunteers
Sponsor: Loxo Oncology, Inc.
Start date: 2020-02-12; Completion date: 2020-10-30
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to learn about how itraconazole and rifampin affect LOXO-305 in healthy participants. Participation could last about 8 weeks.

Detailed description:

Arms: arm 1: * Day 1: a single oral dose of 200 milligrams (mg) LOXO-305 was administered.
* Day 8: oral doses of 200 mg itraconazole was administered twice daily.
* Days 9 to 18: single oral dose of 200 mg itraconazole was administered once daily, and on Day 12 it was co-administered with a single oral dose of 200 mg LOXO-305. arm 2: * Day 1: a single oral dose of 200 mg LOXO-305 was administered.
* Days 8 to 23: oral dose of 600 mg rifampin was administered once daily, and on Days 8 \& 17, it was co-administered with a single oral dose of 200 mg LOXO-305.
Interventions: intervention 1: LOXO-305 intervention 2: Itraconazole intervention 3: Rifampin
Intervention descriptions: intervention 1: Oral LOXO-305 intervention 2: Oral itraconazole intervention 3: Oral rifampin

Protocol documents:
Prot_000.pdf: 
Protocol LOXO-BTK-20006 (J2N-OX-JZNC) Version 1
A Phase 1, Open Label, Two-part, Fixed-sequence Drug Interaction Study to 
Investigate the Effect of Strong CYP3A4 Inhibitor (Itraconazole) and 
CYP3A4 Inducer (Rifampin) on the Pharmacokinetics of LOXO 305 in 
Healthy Adult Subjects
NCT05134337
Approval date: 14-Jan-2020


TI T L E P A G E 
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Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 6 of 60 
SYNOPSIS 
Study Title 
A Phase 1, Open-label, Two-part, Fixed-sequence Drug Interaction Study to Investigate the 
Effect of Strong CYP3A4 Inhibitor (Itraconazole) and CYP3A4 Inducer (Rifampin) on the 
Pharmacokinetics of LOXO-305 in Healthy Adult Subjects 
Objectives 
The primary objectives of the study are: 
 to assess the impact of multiple oral doses of itraconazole (a strong cytochrome P450 
[CYP]3A4 and P-glycoprotein [P-gp] inhibitor) on the single oral dose 
pharmacokinetics (PK) of LOXO-305 in healthy adult subjects; 
 to assess the effect of multiple oral doses of rifampin (strong CYP3A4 inducer) on the 
single oral dose PK of LOXO-305 in healthy adult subjects; 
 to assess the effect of a single oral dose of rifampin on the single oral dose PK of 
LOXO-305 in healthy adult subjects. 
The secondary objectives of the study are: 
 to assess the safety and tolerability of a single oral dose of LOXO-305 when 
administered alone and co-administered with multiple oral doses of itraconazole; 
 to assess the safety and tolerability of a single oral dose of LOXO-305 when 
administered alone and co-administered with single and multiple oral doses of 
rifampin. 
Study Design 
This is a Phase 1, 2-part study. Each part will be conducted as an open-label, 2-period, 
fixed-sequence study. Following completion of the sentinel subjects in Part 1, the study parts 
may be conducted concurrently. 
In Part 1, a single oral dose of 200 mg LOXO-305 will be administered in the morning on 
Day 1 of Period 1, following a fast of at least 10 hours prior to and 4 hours after dosing. 
Blood samples for PK analysis of LOXO-305 alone will be taken up to 168 hours postdose on 
Day 1. In Period 2, multiple oral doses of 200 mg itraconazole will be administered twice 
daily (BID) on Day 8, and once daily (QD) from Day 9 until Day 18 inclusive (for a total of 
11 consecutive days). and co-administered with a single oral dose of 200 mg LOXO-305 on 
Day 12 under fasted conditions. On Day 8, when itraconazole is administered BID, the 
morning dose will be administered alone at the actual time of the Day 1 LOXO-305 dose 
(± 1 hour), approximately 30 minutes after starting a standard breakfast, and the evening dose 
will be administered approximately 10 (±1) hours after the morning dose, approximately 
30 minutes after starting a standard evening meal. All meals should be entirely consumed 
within 30 minutes. On Days 9 to 11 and Days 13 to 18, the QD dose of itraconazole will be 
administered alone at the actual time of the Day 1 LOXO-305 dose (± 1 hour), approximately 
30 minutes after the start of a standard breakfast, which should be entirely consumed within 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 7 of 60 
30 minutes. On Day 12, a single oral dose of 200 mg LOXO-305 and a single oral dose of 
200 mg itraconazole will be co-administered in the morning, following a fast of at least 
10 hours prior to and 4 hours after dosing with LOXO-305 and itraconazole. Blood samples 
for PK analysis of LOXO-305 in the presence of itraconazole will be taken up to 168 hours 
postdose of the LOXO-305 dose on Day 12. 
In Part 2, a single oral dose of 200 mg LOXO-305 will be administered on Day 1 of Period 1 
following a fast of at least 10 hours prior to and 4 hours after dosing. Blood samples for PK 
analysis of LOXO-305 alone will be taken up to 168 hours postdose on Day 1. In Period 2, 
multiple oral doses of 600 mg rifampin will be administered QD from Day 8 until Day 23 
inclusive (for a total of 16 consecutive days). On Days 8 and 17, a single oral dose of 600 mg 
rifampin will be co-administered with a single oral dose of 200 mg LOXO-305 in the 
morning following a fast of at least 10 hours prior to and 4 hours after dosing with 
LOXO-305 and rifampin. On Days 9 to 16 and 18 to 23, the dose of rifampin will be 
administered alone at the actual time of the Day 1 LOXO-305 dose (± 1 hour), following a 
fast of at least 8 hours prior to and 2 hours after dosing. Blood samples for PK analysis of 
LOXO-305 in the presence of rifampin will be taken up to 24 hours after the LOXO-305 dose 
on Day 8 and up to 168 hours after the LOXO-305 dose on Day 17. 
Urine samples will be collected on Days 8, 11, 15, and 17 of Part 2 (and may be stored for 
future potential assessment of 6β-hydroxycortisol and free cortisol concentrations to evaluate 
the level of CYP3A enzyme induction and/or for further exploratory analysis). 
In Part 1, there will be a washout period of 7 days between the dose of LOXO-305 on Day 1 
(Period 1) and the first dose of itraconazole on Day 8 (Period 2). 
In Part 2, there will be a washout period of 7 days between the dose of LOXO-305 on Day 1 
(Period 1) and the first dose of rifampin and dose of LOXO-305 on Day 8 (Period 2). 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 19 in Part 1 or Day 24 in Part 2, following 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. 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
In this study, physical examinations, 12-lead electrocardiograms (ECGs), vital signs, How Do 
You Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation parameters, CK, 
complete blood count (CBC), 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. Adverse 
events will be reported throughout the study (ie, from signing of the Informed Consent Form 
[ICF] until End of Study [EOS], or until ET if the subject discontinues from the study and 
does not complete a follow-up phone call), either as subject medical history (if the event is 
reported as beginning prior to signing of the ICF or if the event occurs prior to study drug 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 8 of 60 
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 
24 healthy adult male and female subjects (women of non-childbearing potential only); 
12 subjects in Part 1 and 12 subjects in Part 2 to ensure that 20 subjects complete the study. 
This is a phase 1 study and the sample size is not based upon any formal power calculations 
but is consistent with previous studies of a similar design. 
Each subject will participate in either Part 1 or Part 2, but not both. 
Every attempt will be made to enroll at least 3 subjects of each sex in the study. 
If subjects are withdrawn by the Investigator (or designee) or voluntarily withdraw 
prematurely from the study, replacement subjects may be enrolled only if deemed necessary 
by the Sponsor. 
Main Criteria for Inclusion 
Male subjects and female subjects of non-childbearing potential, between 18 and 55 years of 
age, inclusive, at Screening, and within body mass index (BMI) range 18.0 to 32.0 kg/m2, 
inclusive. Subjects will be in good general health, based on medical history, physical 
examination findings, vital signs, 12-lead electrocardiogram (ECG), or clinical laboratory 
tests at Screening and/or Check-in (Day -1), as determined by the Investigator (or designee). 
Investigational Medicinal Products, Dose, and Mode of Administration 
LOXO-305 will be supplied by the Sponsor as 100-mg tablets for oral administration. 
Itraconazole will be supplied by Covance as 100-mg capsules for oral administration. 
Rifampin will be supplied by Covance as 300-mg capsules for oral administration 
Part 1 (CYP3A4 and P-gp Inhibitor): 
 Day 1 (Period 1): single oral dose of 200 mg LOXO-305 (2 × 100-mg tablets) 
following a fast of at least 10 hours prior to and 4 hours after the LOXO-305 dose; 
 Day 8 (Period 2): BID dose of 200 mg (2 × 100-mg capsules) itraconazole; the 
morning dose administered alone at the actual time of the Day 1 LOXO-305 dose 
(± 1 hour), approximately 30 minutes after starting a standard breakfast, and the 
evening dose administered approximately 10 (±1) hours after the morning dose, 
approximately 30 minutes after starting a standard evening meal. All meals should be 
entirely consumed within 30 minutes; 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 9 of 60 
 Days 9 to 11 and Days 13 to 18 (Period 2): QD oral doses of 200 mg itraconazole 
administered at the actual time of the Day 1 LOXO-305 dose (± 1 hour), 
approximately 30 minutes after the start of a standard breakfast, which should be 
entirely consumed within 30 minutes; 
 Day 12 (Period 2): single oral dose of 200 mg LOXO-305 and single oral dose of 
200 mg itraconazole co-administered in the morning following a fast of at least 
10 hours prior to and 4 hours after dosing. 
Part 2 (CYP3A4 Inducer): 
 Day 1 (Period 1): single oral dose of 200 mg LOXO-305 (2 × 100-mg tablets) 
following a fast of at least 10 hours prior to and 4 hours after the LOXO-305 dose; 
 Days 8 and 17 (Period 2): single oral dose of 200 mg LOXO-305 and single oral dose 
of 600 mg rifampin (2 × 300-mg capsules) co-administered in the morning following 
a fast of at least 10 hours prior to and 4 hours after dosing; 
 Days 9 to 16 and Days 18 to 23 (Period 2): QD oral doses of 600 mg rifampin 
administered at the actual time of the Day 1 LOXO-305 dose (± 1 hour) following a 
fast of at least 8 hours prior to and 2 hours after the rifampin dose. 
All study drugs will be administered with approximately 240 mL of water. An additional 
100 mL of water may be administered if needed. 
In Part 1, there will be a washout period of 7 days between the dose of LOXO-305 on Day 1 
(Period 1) and the first dose of itraconazole on Day 8 (Period 2). 
In Part 2, there will be a washout period of 7 days between the dose of LOXO-305 on Day 1 
(Period 1) and the first dose of rifampin and dose of LOXO-305 on Day 8 (Period 2). 
Duration of Subject Participation in the Study: 
Planned Study Conduct Duration: approximately 90 days. 
Screening Period: 
Planned Enrollment/Screening Duration: up to 28 days (Day -29 to Day -2). 
Length of Confinement: 
Part 1: a total of 20 days (19 nights), from the time of Check-in (Day -1) through the 
168-hour (post-Day 12) PK blood draw and EOT assessments (Day 19). 
Part 2: a total of 25 days (24 nights), from the time of Check-in (Day -1) through the 
168-hour (post-Day 17) PK blood draw and EOT assessments (Day 24). 
Follow-up Phone Call (End of Study [EOS]): 7 days (± 2 days) after EOT or ET. 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 10 of 60 
Criteria for Evaluation: 
Pharmacokinetics: 
In Part 1, serial PK blood samples for the analysis of plasma concentrations of LOXO-305 
will be collected from predose through 168 hours postdose following administration of 
LOXO-305 alone on Day 1 (Period 1) and with itraconazole on Day 12 (Period 2). In Part 2, 
serial PK blood samples for the analysis of plasma concentrations of LOXO-305 will be 
collected from predose through 24 hours postdose following administration of LOXO-305 
and rifampin on Day 8 (Period 2) and from predose through 168 hours postdose following 
administration of LOXO-305 alone on Day 1 (Period 1) and with rifampin on Day 17 
(Period 2). 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): area under the concentration-time curve from 
Hour 0 to 24 hours postdose, as calculated by the linear trapezoidal method (for Day 1 and 
Day 8 of Part 2 PK only [AUC0-24]), 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-inf), extrapolation for area under the concentration-time curve 
(%AUCextrap), maximum observed plasma concentration (Cmax), time to maximum observed 
concentration (tmax), apparent terminal elimination rate constant (λZ), apparent systemic 
clearance (CL/F), apparent first order terminal elimination rate constant (Kel) 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 (eg, 3 or more non-zero plasma concentrations [Kel]), and 
apparent terminal elimination half-life (t½). 
No value for Kel, AUC0-inf, CL/F, or t½ will be reported for cases that do not exhibit a 
terminal log linear phase in the concentration-time profile. The PK sampling to 24 hours on 
Day 8 in Part 2 may not be sufficient for calculation of several Kel-dependent PK parameters. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive timepoints with 
quantifiable concentrations. 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. 
Safety: 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory tests, measuring vital signs, and 12-lead ECGs. 
Statistical Methods 
Pharmacokinetics: 
A mixed effect model including treatment as a fixed effect and subject as a random effect will 
be used to analyze the natural log (ln)-transformed PK parameters (AUC0-t, AUC0-inf, and 
Cmax). The ratios and their 90% confidence intervals (CIs) of the PK parameter for each 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 11 of 60 
treatment comparison will be constructed using the exponentiation of the difference and the 
CIs from the mixed effect model. 
Safety: 
All safety assessments, including AEs and SAEs, vital signs measurements, clinical 
laboratory results, physical examination results, concomitant medications, and 12-lead ECGs 
will be tabulated and summarized where possible, using descriptive methodology, as needed, 
by timepoint. Unless otherwise specified, baseline value is defined as the last non-missing 
measurement before administration of LOXO-305 in each period. No formal statistical 
analyses are planned for the safety data. All safety data will be listed by subject. 
Additional details on the analyses will be included in the Statistical Analysis Plan (SAP). 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 12 of 60 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF TABLES ...................................................................................................................14 
LIST OF ABBREVIATIONS ..................................................................................................15 
1. 
INTRODUCTION ...........................................................................................................17 
1.1.  Background ................................................................................................................17 
1.2.  Non-clinical Pharmacokinetics ..................................................................................17 
1.3.  Potential for Drug-drug Interactions ..........................................................................18 
1.4.  Summary of Clinical Experience ...............................................................................18 
1.4.1. 
Safety ...........................................................................................................18 
1.4.2. 
Pharmacokinetics .........................................................................................19 
1.5.  Study Rationale ..........................................................................................................19 
1.6.  Benefit-risk Assessment ............................................................................................20 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................20 
2.1.  Objectives ..................................................................................................................20 
2.2.  Endpoints ...................................................................................................................21 
3. 
INVESTIGATIONAL PLAN ..........................................................................................22 
3.1.  Overall Study Design and Plan ..................................................................................22 
3.1.1. 
Part 1 – Itraconazole (CYP3A4 and P-gp Inhibitor) ....................................22 
3.1.2. 
Part 2 – Rifampin (CYP3A4 Inducer) .........................................................23 
3.1.3. 
Overall..........................................................................................................23 
3.2.  Discussion of Study Design .......................................................................................24 
3.3.  Selection of Doses in the Study .................................................................................25 
4. 
SELECTION OF STUDY POPULATION .....................................................................27 
4.1.  Screening Procedures .................................................................................................27 
4.2.  Check-in Procedures (Day -1) ...................................................................................27 
4.3.  Inclusion Criteria .......................................................................................................28 
4.4.  Exclusion Criteria ......................................................................................................29 
4.5.  Subject Number and Identification ............................................................................32 
4.6.  Removal of Subjects from Study Participation .........................................................33 
5. 
STUDY TREATMENTS .................................................................................................33 
5.1.  Description, Storage, Packaging, and Labeling .........................................................33 
5.2.  Study Treatment Administration ...............................................................................34 
5.3.  Randomization ...........................................................................................................35 


Protocol 
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Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 13 of 60 
5.4.  Blinding .....................................................................................................................35 
5.5.  Treatment Compliance ...............................................................................................35 
5.6.  Drug Accountability ..................................................................................................36 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................36 
6.1.  Concomitant Therapies ..............................................................................................36 
6.2.  Diet, Fluid, and Activity Control ...............................................................................37 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................37 
7.1.  Pharmacokinetic Assessments ...................................................................................37 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................37 
7.1.2. 
Analytical Methodology ..............................................................................37 
7.2.  Safety and Tolerability Assessments .........................................................................38 
7.2.1. 
Adverse Events ............................................................................................38 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................39 
7.2.3. 
Vital Signs ....................................................................................................39 
7.2.4. 
12-lead Electrocardiogram ...........................................................................40 
7.2.5. 
Physical Examination...................................................................................40 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................40 
8.1.  Determination of Sample Size ...................................................................................40 
8.2.  Analysis Populations .................................................................................................40 
8.2.1. 
Study Populations ........................................................................................40 
8.3.  Pharmacokinetic Analysis .........................................................................................41 
8.3.1. 
Descriptive Analysis ....................................................................................42 
8.3.2. 
Statistical Methodology ...............................................................................42 
8.4.  Safety Analysis ..........................................................................................................42 
8.5.  Data Handling and Record Keeping ..........................................................................42 
8.6.  Quality Control and Quality Assurance .....................................................................43 
9. 
ADMINISTRATIVE ASPECTS .....................................................................................43 
9.1.  Change in Protocol ....................................................................................................43 
9.2.  Site Initiation Visit/Investigator Meeting ..................................................................43 
9.3.  Disclosure ..................................................................................................................43 
9.4.  Monitoring .................................................................................................................43 
9.5.  Institutional Review Board ........................................................................................44 
9.6.  Informed Consent ......................................................................................................44 
9.7.  Records ......................................................................................................................44 
9.8.  Reference to Declaration of Helsinki/Basic Principles .............................................45 
9.9.  Financing and Insurance ............................................................................................45 
10.  REFERENCES ................................................................................................................45 
11.  APPENDICES .................................................................................................................47 
Appendix 1: Adverse Event Reporting ...............................................................................48 
Appendix 2: Clinical Laboratory Evaluations .....................................................................52 


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Appendix 3: Total Blood Volume .......................................................................................53 
Appendix 4: Schedule of Assessments ...............................................................................54 
 
LIST OF TABLES 
Table 1: Preliminary Pharmacokinetic Parameters of LOXO-305 in Patients with 
Cancer (Study LOXO-BTK-18001) ....................................................................19 
Table 2: Study Drug – Part 1 .............................................................................................34 
Table 3: Study Drug – Part 2 .............................................................................................34 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
%AUCextrap 
extrapolation for area under the concentration-time curve 
ADL 
Activities of Daily Living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose 
AUC0-inf 
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 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BTK 
Bruton’s tyrosine kinase 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval(s) 
CK 
creatine kinase 
CL/F 
apparent systemic clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction(s) 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 


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IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
Kel 
apparent first order terminal elimination rate constant 
LFT 
liver function test(s) 
ln 
natural log 
LS 
least squared 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MZL 
marginal zone lymphoma 
NHL 
non-Hodgkin lymphoma 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell(s) 
SAE 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed concentration 
TSH 
thyroid-stimulating hormone 
UA 
urinalysis 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WM 
Waldenstrom’s macroglobulinemia 
λZ 
apparent terminal elimination rate constant 


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1. INTRODUCTION 
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product (IMP).1 
1.1. 
Background 
LOXO-305 (also known as LY3527727) is a selective inhibitor of the Bruton’s tyrosine 
kinase (BTK) being developed by Loxo Oncology. In enzyme and cellular assays, 
LOXO-305 potently inhibits wildtype BTK and the BTK C481S-acquired resistance mutation 
which results from a serine substitution at position 481. This inhibitory activity correlated 
with significant inhibition of growth of BTK-dependent human lymphoma cell lines. C481S 
mutations (and other substitutions of this cysteine residue) are clinically important because 
they may explain more than half the cases of acquired resistance to commercially available 
covalent BTK inhibitors in patients with chronic lymphocytic leukemia (CLL), and have also 
been identified in Waldenstrom’s macroglobulinemia (WM), and mantle cell lymphoma 
(MCL) patients.2–5 LOXO-305 was at least 300-fold more selective for BTK than for 98% of 
370 other kinases tested in a large in vitro screen, and at least 70-fold more selective for BTK 
than for 98% of 180 non-BTK kinases screened in live human peripheral blood mononuclear 
cells. 
Irreversible BTK inhibitors like ibrutinib and acalabrutinib have transformed the treatment 
landscape of several BTK-dependent B-cell malignancies, including CLL, WM, MCL, and 
marginal zone lymphoma (MZL). However, the efficacy of these agents in the long-term is 
limited by the development of mutations in BTK, most commonly through BTK C481 
substitution mutations that prevent covalent binding and inactivation of BTK by irreversible 
inhibitors. Additionally, half of patients who discontinue ibrutinib therapy have adverse 
events which are attributed to off-target effects and limit long-term use of ibrutinib. 
Therefore, a more potent and selective inhibitor of BTK with activity against BTK-wildtype 
and C481 mutant BTK may provide clinical benefit to patients with B-cell malignancies 
where treatment with irreversible BTK inhibitors has failed. 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate (ATP) 
binding site of the BTK kinase competitively and has single digit nanomolar activity against 
BTK-wildtype and C481S. There is no evidence of covalent or irreversible binding. Loxo 
Oncology is initiating the clinical development of LOXO-305 for the treatment of patients 
with previously treated CLL/small lymphocytic lymphoma (SLL), WM, MCL, MZL, and 
other B-cell non-Hodgkin lymphoma (NHL). 
1.2. 
Non-clinical Pharmacokinetics 
In non-clinical studies, LOXO-305 was metabolized slowly by human microsomal fractions 
and hepatocytes. The low rates of metabolism in both these human in vitro systems suggest 
that LOXO-305 will have low clearance in humans. In vitro data with cloned expressed 
cytochrome P450 (CYP) enzymes and human liver microsomes indicate that CYP3A4 is the 
primary enzyme that metabolizes LOXO-305. 
There was very little metabolism of LOXO-305 in human hepatocytes and the only 
metabolite detected was a glucuronide of LOXO-305. The glucuronide formed by the human 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 1 9 6 6 6 
Pr ot oc ol Refere nce: L O X O- B T K- 2 0 0 0 6 
Pr ot oc ol Versi o n 1, 1 4 Ja n uar y 2 0 2 0 
Pa ge 1 8 of 6 0 
he pat oc ytes was als o f or me d b y rat a n d d o g he pat oc ytes, s u p p ort i n g t he use of rat a n d d o g f or 
n o n-cli nical safet y assess me nt. 
Re nal cleara nce of L O X O- 3 0 5 i n mal e a n d fe male rats was ne gli gi ble. N o re nal cleara nce 
data are a vaila ble i n ot her s peci es, b ut t his pat h wa y is ofte n c o nser ve d acr oss s pecies a n d 
t heref ore, n o re nal cleara nce is e x pecte d i n h u ma ns. 
1. 3.  
P ote nti al f or Dr u g- dr u g I nter acti o ns 
L O X O- 3 0 5 s h o we d n o detecta ble i n hi biti o n ( 5 0 % i n hi bit or y c o nce n trati o n [I C5 0] >   μ M) 
of C Y P 1 A 2, C Y P 2 B 6, a n d C Y P 2 D 6 a n d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, 
a n d C Y P 3 A 4, wit h I C 5 0 val ues ra n gi n g fr o m  
 μ M i n h u ma n li ver micr os o mes a n d 
he pat oc ytes. After pr e-i nc u bati o n of micr os o mes or he pat oc ytes wit h L O X O- 3 0 5, t he 
i n hi bit or y p ote nc y of L O X O- 3 0 5 f or C Y P 2 C 8 a n d C Y P 3 A 4 was i ncrease d, s u g gesti n g t he 
p ote ntial f or ti me- de pe n de nt i n hi biti o n of C Y P 2 C 8 or C Y P 3 A 4. 
L O X O- 3 0 5 is a s u bstrate f o r P- gl yc o pr otei n ( P- g p). 
L O X O- 3 0 5 s h o we d little or n o i n h i biti o n of C Y P 1 A 2, C Y P 2 B 6, C Y P 2C 9, C Y P 2 C 1 9, or 
C Y P 2 D 6 i n vitr o, b ut a p pears t o b e a wea k ti me- de pe n de nt i n hi bi t or of C Y P 2 C 8 a n d 
C Y P 3 A 4. 
1. 4.  
S u m m ar y of Cli nic al E x perie nce 
L O X O- 3 0 5 is c urre ntl y bei n g st u die d i n a n o n g oi n g gl o bal P hase 1/ 2 first-i n- h u ma n st u d y, 
L O X O- B T K- 1 8 0 0 1, i n patie nts wit h pre vi o usl y treate d C L L/ S L L or N H L. T he starti n g d ose 
of L O X O- 3 0 5 was 2 5 m g o nce dail y ( Q D). 
As of 2 7 Se pte m ber 2 0 1 9 ( data c ut o ff date), safet y data were a vaila ble fr o m 2 8 treate d 
patie nts, wit h 2 0 0 m g Q D as t he hi g hest d ose a d mi nistere d ( Secti o n 1. 4. 1 ). As of 
2 5 Oct o ber 2 0 1 9, Da y 8 of C ycle 1 p har m ac o ki netic ( P K) data wer e a vaila ble fr o m 
2 5 patie nts ( Secti o n 1. 4. 2 ). 
1. 4. 1.  
S afet y 
As of 2 7 Se pte m ber 2 0 1 9, 2 7 ( 9 6. 4 %) of t he 2 8 patie nts were c o n ti n ui n g treat me nt; 1 patie nt 
i n t he 2 5 m g Q D c o h ort disc o nti n ued treat me nt d ue t o pr o gressi v e disease a n d wit h dre w 
c o nse nt. 
O verall, 2 2 ( 7 8. 6 %) patie nts e x perie nce d at least 1 treat me nt-e mer ge nt a d verse e ve nt 
( T E A E), re gar dless of relati o ns hi p t o st u d y dr u g. Treat me nt-e mer ge nt a d verse e ve nts were 
c o de d acc or di n g t o t he Me dical Dic ti o nar y f or Re g ulat or y Acti vities ( Me d D R A) s yste m 
or ga n class ( S O C) a n d preferre d t er m ( P T). Acr oss t he 2 5 m g t o 2 0 0- m g Q D d ose ra n ge, t he 
m ost fre q ue ntl y re p orte d T E A Es  ( > 1 0 % of patie nts), re gar dless of relati o ns hi p t o st u d y dr u g, 
were fati g ue ( 2 5. 0 %), diarr hea ( 1 7. 9 %), a ne mia ( 1 4. 3 %), art hral gia ( 1 0. 7 %), bac k pai n 
( 1 0. 7 %), i ncrease d bl o o d biliru bi n ( 1 0. 7 %), c o nt usi o n ( 1 0. 7 %), a n d mac ul o- pa p ular ras h 
( 1 0. 7 %). 
As of t he date c ut off of 2 7 Se pte m ber 2 0 1 9, m ost T E A Es were mil d or m o derate ( Gra de 1 
or 2) i n se verit y. Gra de 3 T E A Es ha ve bee n re p orte d i n 2 patie n ts t o date ( 1 wit h ne utr o pe nia 
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 1 9 6 6 6 
Pr ot oc ol Refere nce: L O X O- B T K- 2 0 0 0 6 
Pr ot oc ol Versi o n 1, 1 4 Ja n uar y 2 0 2 0 
Pa ge 1 9 of 6 0 
a n d 1 wit h le u k oc yt osis, t he latter als o re p orte d as a seri o us a d verse e ve nt [ S A E]). B ot h of 
t hese were j u d ge d b y t he I n vesti gator t o be relate d t o t he st u d y dr u g. 
1. 4. 2.  
P h ar m ac o ki netics 
As of 2 5 Oct o ber 2 0 1 9, preli mi nar y stea d y-state P K data ( Da y 8 of C ycle 1) were a vaila ble 
fr o m 2 5 patie nts e nr olle d i n L O X O- B T K- 1 8 0 0 1. T hese data de m o nstrate t hat L O X O- 3 0 5 is 
a bs or be d after oral a d mi nistrat i o n wit h a me dia n ti me t o ma xi m um o bser ve d c o nce ntrati o n 
(tma x ) of a p pr o xi matel y 2 h o urs a n d l o w cleara nce (Ta ble 1 ). 
Alt h o u g h t he plas ma half-life c o ul d n ot be calc ulate d wit h cert ai nt y beca use of t he li mite d 
sa m pli n g i nter val ( 0 t o 8 h o urs), it a p pears t o be a p pr o xi mately 1 8 h o urs. Stea d y-state P K 
para meters of L O X O- 3 0 5 i n t hese  ca ncer patie nts are prese nte d i n Ta ble 1 . F oll o wi n g 
a d mi nistrati o n of t he 1 0 0 m g Q D, 1 5 0 m g Q D, or 2 0 0 m g Q D, mea n u n b o u n d tr o u g h plas ma 
le vels of L O X O- 3 0 5 e xcee de d t he c o nce ntrati o n re q uire d f or 9 0 % i n hi biti o n (I C9 0) of t he 
C 4 8 1 S m uta nt of B T K i n vitr o. 
T a ble 1: Preli mi n ar y P h ar m ac o k i netic P ar a meters of L O X O- 3 0 5 i n P atie nts wit h 
C a ncer ( St u d y L O X O- B T K- 1 8 0 0 1) 
D ose ( m g)  
N 
C m a x  
( n g/ m L) 
tm a x  
( h) 
A U C 0- 2 4 
( n g‧ h/ m L) 
C L/ F 
( L/ h) 
t½  
( h) 
2 5 m g ( Q D) 
5 0 m g ( Q D) 
1 0 0 m g ( Q D) 
1 5 0 m g ( Q D) 
2 0 0 m g ( Q D) 
A b bre viati o ns: A U C 0- 2 4 = area u n der t he c o nce ntratio n-ti me c ur ve fr o m H o ur 0 t o 2 4 h o urs p ost d ose; C L/ F = a p pare nt oral 
cleara nce; C ma x  = ma xi m u m o bser ve d plas ma c o nce ntrati o n, C V = c oefficie nt of variati o n; N = n u m be r of patie nts; 
Q D = o nce dail y; t ½  = a p pare nt ter mi nal eli mi nati o n half-life; tma x  = ti me t o ma xi m u m o bser ve d c o nce ntrati o n. 
Mea n ( C V %) data are prese nte d f or C
ma x , A U C0- 2 4, C L/ F, a n d t½ ; me dia n ( mi ni m u m- ma xi m u m) data are prese nte d f or tma x . 
Data c ut off date: 2 5 Oct o ber 2 0 1 9. 
1. 5.  
St u d y R ati o n ale 
T he o bjecti ve of dr u g- dr u g i nter acti o n ( D DI) st u dies is t o dete r mi ne w het her p ote ntial 
i nteracti o ns bet wee n a n i n vesti gati o nal dr u g a n d ot her dr u gs e x ist. Dr u g- dr u g i nteracti o n 
st u dies ha ve a n i m p orta nt r ole i n dr u g de vel o p me nt, 6 a n d t his st u d y is bei n g perf or me d as 
part of t he de vel o p me nt pr o gra m f or L O X O- 3 0 5. 
I n n o n-cli nical st u dies, L O X O- 3 0 5 was meta b olize d sl o wl y b y h u m a n micr os o mal fracti o ns 
a n d he pat oc ytes. T he l o w rates of meta b olis m i n b ot h t hese h u ma n i n vitr o s yste ms s u g gest 
t hat L O X O- 3 0 5 will ha ve l o w cleara nce i n h u ma ns. I n vitr o data wit h cl o ne d e x presse d C Y P 
e nz y mes a n d h u ma n li ver micr os o me s i n dicate t hat C Y P 3 A 4 is t he pri mar y e nz y me t hat 
meta b olizes L O X O- 3 0 5. It is als o a  s u bstrate f or direct gl uc ur oni dati o n a n d P- g p. Gi ve n t he 
t he oretical p ote ntial f or C Y P 3 A4 i n hi bit ors or i n d ucers t o alte r t he P K of L O X O- 3 0 5, a 
cli nical dr u g i nter acti o n st u d y is warra nte d t o deter mi ne t he e xte nt of a n y i nteracti o n. T his 
st u d y is desi g ne d t o deter mi ne t he effect of C Y P 3 A 4 a n d P- g p i n hi biti o n b y itrac o naz ole a n d 
C Y P 3 A 4 i n d ucti o n a n d P- g p i n hi biti o n b y rifa m pi n o n t he P K of L O X O- 3 0 5. Itrac o naz ole is 
a str o n g C Y P 3 A 4 a n d P- g p i n hi bit o r c o m m o nl y use d as a pr ot ot y pical C Y P 3 A 4 i n hi bit or i n 
D DI st u dies. Li ke wise, rifa m pi n is a str o n g C Y P 3 A 4 i n d ucer a n d is c o m m o nl y use d as a 
C CI


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prototypical CYP3A4 inducer in DDI studies.6 Rifampin has also been shown to be an 
effective inhibitor of P-gp in the gut when administered as an acute single dose. 
1.6. 
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. The 
dose of LOXO-305 administered in this study is not anticipated to induce any potential risk to 
subjects participating in this study as it is a single dose which does not exceed the highest 
dose safely administered in first in human studies.1 More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with LOXO-305 may be 
found in the IB.1 
The doses of itraconazole and rifampin administered in this study are not anticipated to 
induce any potential risk or benefit to subjects participating in this study, as they are multiple 
doses administered according to the dosing recommendations in the full prescribing 
information for itraconazole and rifampin.7,8 
The potential risk of participating in this study is well managed by the study set-up and is 
considered negligible. The safety monitoring practices employed will include AE reporting, 
vital signs, 12-lead electrocardiogram (ECG), clinical laboratory evaluations, and physical 
examinations, and are considered adequate to protect the subjects’ safety. 
As this is the first time LOXO-305 is to be administered with a CYP3A4 inhibitor in healthy 
adult males and females of non-childbearing potential, Part 1 will include a sentinel group for 
safety purposes. This sentinel group will be composed of 3 subjects. Following completion of 
the sentinel cohort, the Investigator and Sponsor will review all pertinent safety and 
tolerability data (and PK data, if available) from the sentinel cohort before proceeding to dose 
the remaining 9 subjects in the second cohort in Part 1 and subjects in Part 2. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objectives of the study are: 
 to assess the impact of multiple oral doses of itraconazole (a strong CYP3A4 and P-gp 
inhibitor) on the single oral dose PK of LOXO-305 in healthy adult subjects; 
 to assess the effect of multiple oral doses of rifampin (strong CYP3A4 inducer) on the 
single oral dose PK of LOXO-305 in healthy adult subjects; 
 to assess the effect of a single oral dose of rifampin on the single oral dose PK of 
LOXO-305 in healthy adult subjects. 


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The secondary objectives of the study are: 
 to assess the safety and tolerability of a single oral dose of LOXO-305 when 
administered alone and co-administered with multiple oral doses of itraconazole; 
 to assess the safety and tolerability of a single oral dose of LOXO-305 when 
administered alone and co-administered with single and multiple oral doses of 
rifampin. 
2.2. 
Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): 
 area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal method (for Day 1 and Day 8 of Part 2 PK only 
[AUC0-24]) 
 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-inf) 
 extrapolation for area under the concentration-time curve (%AUCextrap) 
 maximum observed plasma concentration (Cmax) 
 time to maximum observed concentration (tmax) 
 apparent terminal elimination rate constant (λZ) 
 apparent systemic clearance (CL/F) 
 apparent first order terminal elimination rate constant (Kel) 
 apparent terminal elimination half-life (t½). 
A mixed effect model including treatment as a fixed effect and subject as a random effect will 
be used to analyze the natural log (ln)-transformed PK parameters (AUC0-t, AUC0-inf, and 
Cmax), using the appropriate statistical procedure. 
No value for Kel, AUC0-inf, CL/F, or t½ will be reported for cases that do not exhibit a 
terminal log linear phase in the concentration-time profile. The PK sampling to 24 hours on 
Day 8 in Part 2 may not be sufficient for calculation of several Kel-dependent PK parameters. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive timepoints with 
quantifiable concentrations. 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory tests, measuring vital signs, and 12-lead ECGs. 


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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 1, 2-part study. Each part will be conducted as an open-label, 2-period, 
fixed-sequence study. Following completion of the sentinel subjects in Part 1, the study parts 
may be conducted concurrently. 
3.1.1. 
Part 1 – Itraconazole (CYP3A4 and P-gp Inhibitor) 
In Part 1, Period 1, a single oral dose of 200 mg LOXO-305 will be administered in the 
morning of Day 1, following a fast of at least 10 hours prior to and 4 hours after dosing with 
LOXO-305. Blood samples for PK analysis of LOXO-305 in the absence of itraconazole will 
be taken up to 168 hours postdose of LOXO-305 on Day 1. 
In Part 1, Period 2, multiple oral doses of 200 mg itraconazole will be administered twice 
daily (BID) on Day 8, and QD from Day 9 until Day 18 inclusive (for a total of 
11 consecutive days) and co-administered with a single oral dose of 200 mg LOXO-305 on 
Day 12 under fasted conditions. On Day 8, when itraconazole is administered BID, the 
morning dose will be administered alone at the actual time of the Day 1 LOXO-305 dose 
(± 1 hour), approximately 30 minutes after starting a standard breakfast, and the evening dose 
will be administered approximately 10 (±1) hours after the morning dose, approximately 
30 minutes after starting a standard evening meal. All meals should be entirely consumed 
within 30 minutes. On Days 9 to 11 and Days 13 to 18, the QD dose of itraconazole will be 
administered alone at the actual time of the Day 1 LOXO-305 dose (± 1 hour), approximately 
30 minutes after the start of a standard breakfast, which should be entirely consumed within 
30 minutes. On Day 12, a single oral dose of 200 mg LOXO-305 and a single oral dose of 
200 mg itraconazole will be co-administered in the morning, following a fast of at least 
10 hours prior to and 4 hours after dosing with LOXO-305 and itraconazole. Blood samples 
for PK analysis of LOXO-305 in the presence of itraconazole will be taken up to 168 hours 
postdose of the LOXO-305 dose on Day 12. 
There will be a washout period of 7 days between the dose of LOXO-305 on Day 1 (Period 1) 
and the first dose of itraconazole on Day 8 (Period 2). 
Part 1 will be divided into 2 cohorts; a sentinel cohort will comprise 3 subjects and the 
second cohort will comprise 9 subjects, for a total of 12 subjects. 
Following completion of the sentinel cohort, the Investigator and Sponsor will review all 
pertinent safety and tolerability data (and PK data, if available) from the sentinel cohort 
before proceeding to dose the remaining 9 subjects in the second cohort in Part 1 of subjects 
in Part 2. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 19 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 


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subjects who received at least 1 dose of study drug (including subjects who are terminated 
early) 7 days (± 2 days) after EOT or ET. 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
3.1.2. 
Part 2 – Rifampin (CYP3A4 Inducer) 
In Part 2, Period 1, a single oral dose of 200 mg LOXO-305 will be administered on Day 1, 
following a fast of at least 10 hours prior to and 4 hours after dosing with LOXO-305. Blood 
samples for PK analysis of LOXO-305 in the absence of rifampin will be taken up to 
168 hours postdose of LOXO-305 on Day 1. 
In Part 2, Period 2, multiple oral doses of 600 mg rifampin will be administered QD from 
Day 8 until Day 23 inclusive (for a total of 16 consecutive days) and co-administered with a 
single oral dose of 200 mg LOXO-305 on Days 8 and 17. On Days 8 and 17, a single oral 
dose of 200 mg LOXO-305 and a single oral dose of 600 mg rifampin will be 
co-administered in the morning following a fast of at least 10 hours prior to and 4 hours after 
dosing with LOXO-305 and rifampin. On Days 9 to 16 and Days 18 to 23, the dose of 
rifampin will be administered alone at the actual time of the Day 1 LOXO-305 dose 
(± 1 hour), following a fast of at least 8 hours prior to and 2 hours after dosing with rifampin. 
Blood samples for PK analysis of LOXO-305 in the presence of rifampin will be taken up to 
24 hours postdose of LOXO-305 on Day 8 and up to 168 hours postdose of LOXO-305 on 
Day 17. 
Urine samples will be collected on Days 8, 11, 15, and 17 of Part 2 only (and may be stored 
for future potential assessment of 6β-hydroxycortisol and free cortisol concentrations to 
evaluate the level of CYP3A enzyme induction and/or for further exploratory analysis). 
There will be a washout period of 7 days between the dose of LOXO-305 on Day 1 (Period 1) 
and the first dose of rifampin and dose of LOXO-305 on Day 8 (Period 2). 
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 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 EOT on 
Day 24 upon completion of all PK and safety assessments or 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. 
3.1.3. 
Overall 
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, physical examinations, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) 
inquiries, clinical chemistry panel, coagulation parameters, creatine kinase (CK), complete 
blood count (CBC), urinalysis (UA; Appendix 2) and recording of concomitant medications 
will be performed at specified times during the study (for specific timepoints and details on 


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each study variable, refer to Appendix 4). Adverse events and SAEs will be collected 
beginning at informed consent. Adverse events will be reported throughout the study (ie, 
from signing of the 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. 
In Part 1, blood samples for LOXO-305 PK analysis will be obtained from predose through 
168 hours postdose after LOXO-305 is administered alone on Day 1 (Period 1) and with 
itraconazole on Day 12 (Period 2). In Part 2, blood samples for LOXO-305 PK analysis will 
be obtained from predose through 168 hours postdose after LOXO-305 is administered on 
alone on Day 1 (Period 1) and with rifampin Day 17 (Period 2), and through 24 hours after 
LOXO-305 is administered with rifampin on Day 8 (Period 2). 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 
Overall 
Data from in vitro studies with cloned expressed CYP enzymes and human liver microsomes 
indicate that CYP3A4 is the primary enzyme that metabolizes LOXO-305. Furthermore, 
LOXO-305 is a substrate for P-gp, thus rendering LOXO-305 susceptible to DDI when 
co-administered with inhibitors or inducers of CYP3A4 and/or P-gp. 
The fixed single-sequence design used in this study is typical for interaction studies where a 
relatively small number of subjects are required, because it allows intra-subject comparisons. 
This study will be open-label because the study endpoints are not considered subjective. 
Multiple doses of itraconazole and rifampin will allow the DDI effect(s) of both study drugs 
on LOXO-305 to be assessed at steady-state, therefore the maximal inhibition or induction 
effect on CYP3A4 and P-gp will be achieved. 
Conducting the study in healthy adult subjects mitigates the potential confounding effects of 
the disease state and concomitant medications. 
Part 1 – Itraconazole (CYP3A4 and P-gp Inhibitor) 
In Part 1, the effects of multiple oral doses of itraconazole (a strong CYP3A4 and P-gp 
inhibitor) on the PK of LOXO-305 will be investigated. Itraconazole is a well-characterized, 
competitive, strong inhibitor of CYP3A4 and a potent inhibitor of P-gp; thus it was selected 
for this study as per recommendations in the Food and Drug Administration (FDA) Guidance 
for Drug Interaction Studies.6 Itraconazole capsules, when administered alone (ie, Days 8 


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to 11, and Days 13 to 18), will be administered under fed conditions (ie, approximately 
30 minutes after the start of a standard meal [breakfast or evening meal]) to enhance oral 
absorption and ensure that adequate plasma concentrations are attained for maximal 
inhibitory effect on CYP3A4 at steady-state. When co-administered with LOXO-305; 
however, both drugs will be administered in the fasted state, as the effect of food on the PK 
of LOXO-305 has not yet been fully evaluated. As this will be the first time LOXO-305 will 
be administered with a CYP3A4 inhibitor in healthy adult males and females of 
non-childbearing potential, Part 1 will include a sentinel cohort for safety purposes. This 
sentinel cohort will comprise 3 subjects. Following completion of the sentinel cohort, the 
Investigator and Sponsor will review all pertinent safety and tolerability data (and PK data, if 
available) from the sentinel cohort before proceeding to dose the remaining 9 subjects in the 
second cohort in Part 1 and subjects in Part 2. 
Part 2 – Rifampin (CYP3A4 Inducer and P-gp Inhibitor) 
In Part 2, the effects of multiple oral doses of rifampin (a strong CYP3A4 inducer) on the PK 
of LOXO-305 will be investigated. Rifampin, administered as multiple doses, has been 
selected as a CYP3A4 inducer for this study, in accordance with recommendations in the 
FDA Guidance for Drug Interaction Studies.6 
In addition, the effects of single oral doses of rifampin on the PK of LOXO-305 will be 
investigated. Rifampin has been shown to be an effective inhibitor of P-gp in the gut when 
administered as an acute single dose. As such, on Day 8, a single dose of rifampin and 
LOXO-305 will be co-administered to evaluate the effect of P-gp inhibition on the PK of 
LOXO-305. Once daily dosing of rifampin from Days 8 to 23 will be adequate to attain 
maximal CYP3A4 enzyme induction.9 In Part 2, all study drugs will be administered in the 
fasted state (ie, following a fast of at least 10 hours prior to and 4 hours after dosing when 
co-administered with LOXO-305, and a fast of at least 8 hours prior to and 2 hours after 
dosing when rifampin is administered alone in Part 2, as absorption of rifampin is reduced 
when administered with food).8 
3.3. 
Selection of Doses in the Study 
LOXO-305 
Single oral doses of 200 mg LOXO-305 on Days 1 and 12 in Part 1, and Days 1, 8, and 17 in 
Part 2 will be evaluated as this is the anticipated therapeutic dose level. The selected dose 
level is a conservative safe dose when an increase in exposure is anticipated in the presence 
of CYP3A4 inhibitor or inducer and P-gp inhibitor, and will meet the objectives of the study. 
Doses of LOXO-305 from 25 mg QD to 200 mg QD have been evaluated in a Phase 1/2 
first-in-human study in patients with previously treated chronic CLL/SLL or NHL with 
ongoing dose escalation above 200 mg QD as approved by the study’s Safety Review 
Committee. The available data demonstrate that LOXO-305 appears safe and well tolerated at 
these doses. At all evaluated doses, including doses above 200 mg QD, no dose-limiting 
toxicities have been identified in humans.1 
Itraconazole 
The clinical dose of itraconazole is 200 mg administered once BID and then QD. In this 
study, itraconazole will be dosed BID for 1 day (Day 8) and then QD for 10 days (ie, Days 9 
to 18), with LOXO-305 co-administered on the fifth day after the start of itraconazole dosing 


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(ie, Day 12). Although itraconazole reaches steady-state at approximately 15 days QD 
dosing, BID dosing on Day 8 (ie, a loading dose on the first day of dosing) helps to achieve 
steady-state within 5 days of dosing, allowing co-administration of LOXO-305 and 
itraconazole on Day 12. Similar dosing schemes have been used in previously reported DDI 
studies and have demonstrated sufficient inhibition of CYP3A enzymes with 5 days of QD 
dosing.10 To maintain the same level of inhibition, itraconazole will be administered until 
Day 18. 
As itraconazole capsules should be administered with a full meal to maximize its absorption, 
on Days 9 to 11 and 13 to 18, the dose of itraconazole will be administered alone at the actual 
time of the Day 1 LOXO-305 dose (± 1 hour), approximately 30 minutes after the start of a 
standard breakfast to maximize the inhibition potential. On Day 8, when itraconazole is 
administered BID, the morning dose will be administered alone at the actual time of the 
Day 1 LOXO-305 dose (± 1 hour), approximately 30 minutes after starting a standard 
breakfast, and the evening dose will be administered approximately 10 (±1) hours after the 
morning dose, approximately 30 minutes after starting a standard evening meal. All meals 
should be entirely consumed within 30 minutes. On Day 12, to assess the DDI under the most 
sensitive conditions, both itraconazole and LOXO-305 will be administered in the fasted state 
(ie, following a fast of at least 10 hours prior to and 4 hours after dosing with itraconazole 
and LOXO-305). 
Rifampin 
The dose of rifampin selected for this study is 600 mg QD, which is the commonly used 
clinical dose level. Rifampin will be dosed QD for 16 days (ie, Days 8 to 23), with 
LOXO-305 co-administered on the first and tenth day after the start of rifampin dosing (ie, 
Days 8 and 17, respectively). As per literature, an acute dose of rifampin inhibits 
P-gp-mediated transport while chronic dosing strongly induces CYP3A enzymes and P-gp.11 
Therefore, the acute (transporter) effect of a single dose of rifampin on the single-dose PK of 
LOXO-305 will be assessed to maximize the ability to observe small differences in PK. 
Sampling up to 24 hours will be sufficient to evaluate the inhibitory effects as P-gp acts 
mostly in the gut (absorption/distribution phases). Rifampin dosing alone will then be 
continued QD to assess its induction potential on LOXO-305. The half-life of rifampin is 
approximately 3 hours following a 600-mg oral dose;8 however, the time required to produce 
maximum enzyme induction is substantially longer for the synthesis of new enzymes. The 
timeframe from maximum induction by rifampin has been estimated at a minimum of 5 days 
of 600-mg QD dosing.9 In most DDI studies, oral rifampin is typically administered as a 
600-mg QD dose for 4 to 18 days.12 Dosing will continue until Day 23 to maintain induction 
throughout the PK sampling time. 
As absorption of rifampin is reduced when administered with food, on Days 8 and 17, a 
single oral dose of 200 mg LOXO-305 and a single oral dose of 600 mg rifampin will be 
administered following a fast of at least 10 hours prior to and 4 hours after dosing. On Days 9 
to 16 and Days 18 to 23, rifampin will be administered alone following a fast of at least 
8 hours prior to and 2 hours after dosing with rifampin. 


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4. SELECTION OF STUDY 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. Inclusion/exclusion criteria 
2. Informed consent 
3. Demographic data 
4. Medical history (including review of medication[s]) 
5. Height, weight, and body mass index (BMI) 
6. Complete physical examination (Section 7.2.5) 
7. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
8. Vital signs (including oral temperature, respiratory rate, and supine blood pressure 
[BP] and pulse rate [measured after the subject has been supine for at least 5 minutes]; 
Section 7.2.3) 
9. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
10. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, CK, CBC, and UA; Appendix 2) 
11. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), 
and human immunodeficiency virus (HIV) antibody (Appendix 2) 
12. Hemoglobin A1c (HbA1c) test (Appendix 2) 
13. Screen for selected drugs of abuse, including cotinine and an alcohol breath test 
(Appendix 2) 
14. Serum pregnancy test (for female subjects only; Appendix 2) 
15. Follicle-stimulating hormone (FSH) test (for post-menopausal female subjects only; 
Appendix 2) 
16. Thyroid-stimulating hormone (TSH) test (Appendix 2) 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
1. Review of inclusion/exclusion criteria 
2. Interim medical history, including concomitant medication(s) 
3. Weight and BMI 
4. Abbreviated physical examination (Section 7.2.5) 


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5. 12-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4) 
6. Vital signs (including oral temperature, respiratory rate, and supine BP and pulse rate 
[measured after the subject has been supine for at least 5 minutes]; Section 7.2.3) 
7. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.2.1) 
8. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, CK, CBC, and UA; Appendix 2) 
9. Screen for selected drugs of abuse, including cotinine and an alcohol breath test 
(Appendix 2) 
10. Serum pregnancy test (for female subjects only; Appendix 2) 
11. 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; #1, Section 4.2). 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 non-childbearing potential, between 18 and 55 years of age, 
inclusive, at Screening. 
2. Within BMI range 18.0 to 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, or clinical laboratory 
evaluations (Appendix 4) at Screening and/or Check-in (Day -1) as assessed by the 
Investigator (or designee). 
4. Female subjects of non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy, or confirmed tubal occlusion more than 6 months prior to study drug 
administration) or post-menopausal (defined as at least 12 months post-cessation of 
menses without an alternative medical cause). Post-menopausal status will be 
confirmed with a screening serum FSH level ≥ 40 mIU/mL. All female subjects must 
have a negative qualitative serum pregnancy test (serum human chorionic 
gonadotropin; serum quantitative human chorionic gonadotropin tests may be used for 
confirmation as needed) at Screening and Check-in (Day -1). 


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5. Male subjects who are capable of fathering a child must agree to use 1 of the 
following methods of contraception from the time of the dose administration through 
6 months after the last dose of LOXO-305 administration: 
a. Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in 
(Day -1). If documentation is not available, male subjects must follow 1 of the 
contraception methods below: 
i. Male condom with spermicide, or 
ii. A male subject must ensure that their female partner meets 1 of the 
following criteria: 
1. intrauterine device (IUD) (hormonal IUD; eg, Mirena®). 
Copper IUDs are acceptable (eg, ParaGard®); 
2. established use of oral, implanted, transdermal, intravaginal, or 
hormonal method of contraception associated with inhibition of 
ovulation; or 
3. bilateral tubal ligation; or 
4. be post-menopausal with amenorrhea for at least 1 year prior to 
dosing and FSH serum levels consistent with post-menopausal 
status. 
Male subjects who practice true abstinence because of a lifestyle choice (ie, do not 
become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence by a female partner (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. If a male subject is abstinent at the time of signing the ICF 
but becomes sexually active 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 19-night stay for subjects 
participating in Part 1 or 24-night stay for subjects participating in Part 2 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: 
a. oral body temperature > 37.5°C; 
b. pulse rate < 50 or > 99 beats per minute (bpm); 
c. systolic BP < 89 or > 139 mmHg; 
d. diastolic BP < 50 or > 89 mmHg. 
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 pulse rate and BP values 
will be permitted up to 2 times to confirm eligibility for study participation. Subjects 
may be eligible for participation in the study based on rechecked pulse rate 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) 


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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 physical examination at Screening and/or Check-in (Day -1). 
5. Abnormal liver function tests (LFTs), as defined by aspartate aminotransferase (AST), 
alanine aminotransferase (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 (Day -1). 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 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation. 
8. Positive serologic test for HBsAg, HCV, or 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). Alcohol breath 
tests must be negative at both Screening and 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) and Sponsor. 
12. Positive urine screen for drugs of abuse at Screening or Check-in (Day -1). 
13. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET. 
14. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
15. 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). 
16. Use or intention to use any prescription or over-the-counter medications (including 
but not limited to any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers, strong P-gp inhibitors, proton pump inhibitors, antacids, H2-receptor 
antagonists, and drugs that prolong QT/QTc interval, herbal products, natural or 


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herbal supplements, and hormone-replacement therapy [HRT]) 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. 
17. History of a major surgical procedure within 30 days prior to Screening. 
18. 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. 
19. 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-305. 
20. Poor peripheral venous access. 
21. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
22. Receipt of blood products within 2 months prior to Check-in (Day -1). 
23. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. 
24. 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). 
Note: subjects with a history of uncomplicated cholecystectomy, appendectomy 
and/or hernia repairs will be acceptable. 
25. History of diabetes mellitus; HbA1c ≥ 6.5%. 
26. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
27. Have previously completed or withdrawn from any other study investigating 
LOXO-305, and have previously received the investigational product. 
28. 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. 
29. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
4.5. 
Subject Number and Identification 
Subject numbers 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 in Part 1, 
the second set of 3 digits will begin with 1 (eg 001-101), for subjects in Part 2, the second set 
of 3 digits will begin with a 2 (eg 001-201). If subjects are withdrawn by the Investigator (or 
designee) or voluntarily withdraw prematurely from the study, replacement subjects will be 
enrolled only if deemed necessary by the Sponsor. If necessary, as determined by the 


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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 200 to the last 
3 digits of the subject number for the subject they are replacing (eg, Subject Number 001-301 
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 non-permitted concomitant medication that might 
affect subject safety or study assessments/objectives, etc. Notification of withdrawal will 
immediately be made to the Study Monitor. In case of withdrawal, efforts will be made to 
perform all 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. 
In the event that the study is terminated early, the Sponsor or its designee will provide 
specific guidance to the CRU regarding the EOS procedures. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study drug (Table 2 for Part 1 and Table 3 for Part 2). 


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Table 2: Study Drug – Part 1 
Study Drug 
LOXO-305 
Itraconazole 
Form 
Tablet 
Capsule 
Strength 
100 mg 
100 mg 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Catalent San Diego or Lonza Pharma & Biotech 
Mylan Pharmaceuticals Inc. 
Note: specific manufacturer and purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug. 
Table 3: Study Drug – Part 2 
Study Drug 
LOXO-305 
Rifampin 
Form 
Tablet 
Capsule 
Strength 
100 mg 
300 mg 
Supplier 
Loxo Oncology, Inc. 
Covance 
Manufacturer 
Catalent San Diego or Lonza Pharma & Biotech 
Lannett Company Inc. 
Note: specific manufacturer and purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug. 
The tablets containing 100 mg LOXO-305 will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificate of Analysis. It will be provided in 
high-density polyethylene bottles and stored according to the instructions on the label. 
The capsules containing 100 mg of itraconazole and 300 mg of rifampin will be supplied by 
the site, along with the lot numbers. Both the itraconazole and rifampin will be provided in 
high-density polyethylene bottles and stored according to the instructions on the label. 
Study drugs will be stored at the CRU in a location that is locked with restricted access. 
The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drugs will be stored in accordance with the labeling. The 
study drugs will be transferred from bulk supplies into the subject’s dose container by 
qualified CRU employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
In Part 1, Period 1, a single oral dose of 200 mg LOXO-305 will be administered on Day 1, 
following a fast of at least 10 hours prior to and 4 hours after dosing with LOXO-305. In 
Part 1, Period 2, multiple oral doses of 200 mg itraconazole will be administered BID on 
Day 8, and QD from Day 9 until Day 18 inclusive (for a total of 11 consecutive days) and 
co-administered with a single oral dose of 200 mg LOXO-305 on Day 12 under fasted 
conditions. On Day 8, when itraconazole is administered BID, the morning dose will be 
administered alone at the actual time of the Day 1 LOXO-305 dose (± 1 hour), approximately 
30 minutes after starting a standard breakfast, and the evening dose will be administered 
approximately 10 (±1) hours after the morning dose, approximately 30 minutes after starting 
a standard evening meal. All meals should be entirely consumed within 30 minutes. On 
Days 9 to 11 and Days 13 to 18, the QD dose of itraconazole will be administered alone at the 


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actual time of the Day 1 LOXO-305 dose (± 1 hour), approximately 30 minutes after the start 
of a standard breakfast, which should be entirely consumed within 30 minutes. On Day 12, a 
single oral dose of 200 mg LOXO-305 and a single oral dose of 200 mg itraconazole will be 
co-administered in the morning following a fast of at least 10 hours prior to and 4 hours after 
dosing with LOXO-305 and itraconazole. 
In Part 2, Period 1, a single oral dose of 200 mg LOXO-305 will be administered on Day 1, 
following a fast of at least 10 hours prior to and 4 hours after dosing with LOXO-305. In 
Part 2, Period 2, multiple oral doses of 600 mg rifampin will be administered QD from Day 8 
until Day 23 inclusive (for a total of 16 consecutive days) and co-administered with a single 
oral dose of 200 mg LOXO-305 on Days 8 and 17. On Days 8 and 17, a single oral dose of 
200 mg LOXO-305 and a single oral dose of 600 mg rifampin will be co-administered in the 
morning following a fast of at least 10 hours prior to and 4 hours after dosing with 
LOXO-305 and rifampin. On Days 9 to 16 and Days 18 to 23, the dose of rifampin will be 
administered alone at the actual time of the Day 1 LOXO-305 dose (± 1 hour), following a 
fast of at least 8 hours prior to and 2 hours after dosing with rifampin. 
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 subjects. Although the 
timing of events requires that each subject will be consistently administered the appropriate 
dose at a specific time, the exact dose time of subjects may be staggered to obviate the need 
to have all subjects on precisely the same study schedule. For each dose, the subject’s actual 
dose time will be recorded in the source documents and transcribed into the eCRF. 
Subjects will be instructed not to crush, split, or chew the study drugs. 
Subjects will not lay supine for 4 hours following LOXO-305 dose administration, except as 
necessitated by the occurrence of an AE(s) and/or study procedure(s). 
5.3. 
Randomization 
This is a non-randomized study. The study has a fixed treatment sequence. 
5.4. 
Blinding 
This is an open-label study. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
 All doses will be administered under the supervision of suitably qualified CRU staff. 
 Immediately after dose administration, a visual inspection of the mouth and hands will 
be performed for each subject. 


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 At each dose preparation occasion, a predose and postdose inventory of LOXO-305, 
itraconazole, and rifampin will be performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-305 
tablets, itraconazole capsules, and rifampin capsules received. In addition, an accurate drug 
disposition record will be kept, specifying the amount dispensed to each subject and the date 
of dispensing. This drug accountability record will be available for inspection at any time. At 
the completion of the study, the original drug accountability record will be available for 
review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused LOXO-305 tablets will be disposed of by the CRU, 
following the Sponsor’s written/emailed instructions. Itraconazole and rifampin capsules will 
be disposed of by the CRU in accordance with the CRU’s standard operating procedures. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Paracetamol/acetaminophen (maximum of 2 g/day for up to 3 consecutive days) is an 
acceptable concomitant medication. 
Subjects will refrain from use of any prescription or nonprescription medications/products 
during the study until EOT or ET, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent. 
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 HRT, herbal products, natural 
or herbal supplements, except for paracetamol/acetaminophen as referenced above) 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 (with the 
exception of itraconazole and rifampin administered for the purposes of this study/in 
accordance with the protocol), strong P-gp inhibitors, proton pump inhibitors, antacids, 
H2-receptor antagonists, 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 
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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, should not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
While confined at the CRU, subjects will receive a standard diet at scheduled times that do 
not conflict with other study-related activities. 
Dietary requirement in relation to dosing are described in Section 3.1 and Section 5.2. 
7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for PK analysis of LOXO-305 plasma levels 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 samples will be provided in 
a separate Laboratory Manual. The number of blood samples and total blood volume required 
for PK testing is presented in Appendix 3. 
7.1.2. 
Analytical Methodology 
Concentrations of LOXO-305 in plasma (Part 1 and Part 2) and potentially 
6β-hydroxycortisol and free cortisol concentrations (Part 2 only) in urine to evaluate the level 
of CYP3A enzyme induction (if determined to be necessary) will be determined using a 
validated bioanalytical method. Specifics of the bioanalytical methods will be provided in a 
separate document. 
Urine samples may be stored for future potential assessment of 6β-hydroxycortisol and free 
cortisol concentrations to evaluate the level of CYP3A enzyme induction and/or for further 
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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 
 PK blood sampling 
 vital signs assessments 
 12-lead ECGs 
 blood and urine samples for clinical laboratories 
 physical examination. 
7.2.1. 
Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes 
in your health status since Screening/since you were last asked?” at the timepoints specified 
in Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in [Day -1], at each 
postdose vital 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. 
Adverse events, whether volunteered, identified by the subject’s responses to HDYF? 
inquiries, or noted on physical examination, 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 


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levels, as judged by the Investigator or designee and confirmed by the Sponsor. The 
Investigator (or designee) should use appropriate judgment in ordering additional tests as 
necessary to monitor the resolution of events. The Sponsor may request that additional safety 
tests be performed. 
Subjects will receive a follow-up phone call 7 days (± 2 days) after EOT or ET to determine 
if any SAE or drug-related AE has occurred since the EOT or ET visit. 
At all times, a subject may be required to remain at the CRU for longer at the discretion of 
the Investigator (or designee). 
Any event that meets the criteria of a suspected unexpected serious adverse reaction 
(SUSAR) will be reported to the Institutional Review Board (IRB)/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-305 for 
expected adverse reactions. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours], coagulation 
parameters, CK, CBC, TSH, HbA1c [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 (female subjects only [serum quantitative may be used for 
confirmation if needed]) and an FSH test (post-menopausal female subjects only) will be 
performed at the timepoints specified in Appendix 4. 
The number of blood samples and total blood volume required for clinical laboratory 
evaluations is presented in Appendix 3. A list of the specific evaluations is in Appendix 2. 
7.2.3. 
Vital Signs 
Vital signs (including oral temperature, respiratory rate, and supine BP, and pulse rate) will 
be obtained at the timepoints specified in Appendix 4. 
Blood pressure and pulse rate measurements should be performed using the same arm for 
each reading and measurements should be taken after the subject has been resting in the 
supine position for at least 5 minutes. 
When vital 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. 


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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 in Appendix 4. The QT interval will be corrected for heart rate by Fridericia’s 
(QTcF = QT/[RR]1/3) formula. 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to and as 
close as possible to the scheduled blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated physical examination will be performed at the timepoints specified 
in Appendix 4. Complete physical examinations will evaluate general appearance and the 
following body systems/organs: dermatological; head and eyes; ears, nose, mouth, and throat; 
pulmonary; cardiovascular; abdominal; lymphatic; musculoskeletal/extremities; and 
neurological. Weight and height will be reported (height only reported during Screening). 
Abbreviated physical examinations 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 
Twenty-four healthy adult male and female subjects (women of non-childbearing potential 
only); 12 subjects in Part 1 and 12 subjects in Part 2 to ensure that 20 subjects complete the 
study. This is a phase 1 study and the sample size is not based upon any formal power 
calculations but is consistent with previous studies of a similar design. 
Each subject will participate in either Part 1 or Part 2, but not both. 
Every attempt will be made to enroll at least 3 subjects of each sex in the study. 
8.2. 
Analysis Populations 
8.2.1. 
Study Populations 
The PK Population will consist of all subjects who have received a dose of LOXO-305, have 
at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times median time to 
maximum concentration. 
The Safety Population will consist of all subjects who have received at least 1 dose of study 
drug. Subjects will be classified into groups based on actual treatment received. 


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8.3. 
Pharmacokinetic Analysis 
In Part 1, serial PK blood samples for the analysis of plasma concentrations of LOXO-305 
will be collected from predose through 168 hours postdose following administration of 
LOXO-305 alone on Day 1 (Period 1) and with itraconazole on Day 12 (Period 2). In Part 2, 
serial PK blood samples for the analysis of plasma concentrations of LOXO-305 will be 
collected from predose through 24 hours postdose following administration of LOXO-305 
and rifampin on Day 8 (Period 2) and from predose through 168 hours postdose following 
administration of LOXO-305 alone on Day 1 (Period 1) and with rifampin on Day 17 
(Period 2). 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-305 (as appropriate): 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal method (for Day 1 and Day 8 of Part 2 PK 
only) 
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for 
increasing and decreasing concentrations 
AUC0-inf 
AUC extrapolated to infinity, calculated using the formula: 
 
 
AUC0-inf = 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 plasma concentration 
tmax 
 
time to maximum observed concentration 
λZ 
apparent terminal elimination rate constant, where Z is the magnitude of the 
slope of the linear regression of the log concentration versus time profile 
during the terminal phase 
CL/F  
apparent systemic clearance 
t½ 
apparent terminal elimination half-life (whenever possible), where 
t½ = ln(2)/λZ 
Kel 
apparent first-order terminal elimination rate constant 
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 8.1 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. 


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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). 
8.3.2. 
Statistical Methodology 
The primary analysis planned for this study is a mixed effect model that includes treatment as 
a fixed effect and subject as a random effect. The analysis will be performed on the 
ln-transformed PK parameters (AUC0-t, AUC0-inf, and Cmax) and include calculation of least 
squared (LS) means and the difference between treatment LS means, as well as their 
corresponding 90% confidence intervals (CIs). The ratios and their 90% CIs of the PK 
parameter for each treatment comparison will be constructed using the exponentiation of the 
difference and the CIs from the mixed effect model. 
8.4. 
Safety Analysis 
All safety assessments, including AEs and SAEs, vital signs measurements, clinical 
laboratory results, physical examination results, concomitant medications, and 12-lead ECGs, 
will be tabulated and summarized where possible, using descriptive methodology, as needed, 
by timepoint. Unless otherwise specified, baseline value is defined as the last non-missing 
measurement before administration of LOXO-305 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 (WHO Drug 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 (Appendix 1 
for AE reporting). All TEAEs will be summarized by SOC and PT, using 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. 


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The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will 
be peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by 
the Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.6. 
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 


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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. 
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). 


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All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the CRU archives. 
9.8. 
Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the US 
CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), Applications for FDA Approval to Market a New Drug (21 CFR 314), and 
Radioactive Drugs for Certain Research Uses (21 CFR 361.1), as appropriate. As such, these 
sections of US Title 21 CFR, along with the applicable International Council for 
Harmonisation (ICH) Guidelines, are commonly known as Good Clinical Practices (GCP), 
which are consistent with the Declaration of Helsinki. 
9.9. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
10. REFERENCES 
1.  Loxo Oncology, Inc. LOXO-305 – Investigator’s Brochure (Version 2). 18 November 
2019. 
2.  Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022–35. 
3.  Woyach JA, Furman RR, Liu T-M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance 
mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 
12;370(24):2286–94. 
4.  Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol. 2017 May 1;35(13):1437–43. 
5.  Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017 
04;129(18):2519–25. 
6.  Food and Drug Administration. Guidance for Industry: Drug Interaction Studies - Study 
design, data analysis, and implications for dosing and labeling. Draft Guidance [Internet]. 
Food and Drug Administration; 2006. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm292362.pdf 
7.  Itraconazole capsules by Mylan Pharmaceuticals Inc. Full prescribing information 
(electronic monograph) published on the DailyMed website (document revised 9/2019). 


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 46 of 60 
8.  Rifampin capsules by Lannett Company Inc. Full prescribing monograph information 
(electronic monograph) published on the DailyMed website (document revised 9/2019). 
9.  Tran JQ, Kovacs SJ, McIntosh TS, Davis HM, Martin DE. Morning spot and 24-hour 
urinary 6 beta-hydroxycortisol to cortisol ratios: intraindividual variability and 
correlation under basal conditions and conditions of CYP 3A4 induction. J Clin 
Pharmacol. 1999 May;39(5):487–94. 
10.  Yoshizato T, Kotegawa T, Imai H, Tsutsumi K, Imanaga J, Ohyama T, et al. Itraconazole 
and domperidone: a placebo-controlled drug interaction study. Eur J Clin Pharmacol. 
2012 Sep;68(9):1287–94. 
11.  Shumaker RC, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effect of rifampicin 
on the pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014 
Sep;34(9):651–9. 
12.  Templeton IE, Houston JB, Galetin A. Predictive utility of in vitro rifampin induction 
data generated in fresh and cryopreserved human hepatocytes, Fa2N-4, and HepaRG 
cells. Drug Metab Dispos. 2011 Oct;39(10):1921–9. 


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11. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy adult subject, whether or not considered drug-related by 
the Investigator (or designee). A treatment-emergent adverse event (TEAE) is an AE that 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: An event that puts the patient at 
immediate risk of death 
 
Grade 5 Death related to AE. 
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 
5 options for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option. 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 


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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
 
NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship 
and another cause (eg, concomitant drugs, therapies, complications, comorbidities) 
is suspected. 
 
RELATED = The time course between administration of investigational product 
and the occurrence or worsening of the AE is consistent with a causal relationship 
and no other cause (eg, concomitant drugs, therapies, complications, comorbidities) 
can be identified. 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through End of Study (EOS) or Early Termination (ET; if the subject 
discontinues from the study and does not complete a follow-up phone call) and for up to 
90 days after study drug administration should be reported by the Investigator (or designee) 
via email to Covance or the Sponsor’s Clinical Safety Representative within 24 hours of 
being notified. Covance or the Sponsor’s Clinical Safety Representative will then forward the 
Pregnancy Form to the Investigator for completion. 
email: SAEIntake@Covance.com 
A subject becoming pregnant while on study drug will immediately be withdrawn from the 
study and ET study procedures will be performed. The subject or partner should be followed 
by the Investigator until completion of the pregnancy. If the pregnancy ends for any reason 
before the anticipated date, the Investigator should notify Covance or 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 adverse event (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 Clinical Research Unit (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 Covance or the Sponsor’s Clinical Safety Representative via email. 
All pregnancies should be recorded on the AE electronic Case Report Form (eCRF; as 
appropriate), in addition to completion of the required pregnancy forms. If the Investigator 
suspects that a pregnancy was the result of an interaction between the study treatment and the 
contraceptive method, in addition to the pregnancy the drug interaction should also be 
captured as a separate AE. 


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Definition of Serious Adverse Events 
An SAE (by Food and Drug Administration [FDA] definition) is any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience (ie, one that places the subject, in the 
view of the Investigator [or designee], at immediate risk of death); 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect; 
 
An important medical event that may require medical or surgical intervention to 
prevent one of the above outcomes. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed 
in the Reference Safety Information section of the Investigator’s Brochure (IB) or if it is not 
listed at the specificity or severity that has been observed for an unapproved investigational 
medicinal product (IMP). 
Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of the 
drug and represent events that are assessed as serious, related, and unexpected. Food and 
Drug Administration-reportable AEs will be reported by the CRU to the Sponsor and the 
responsible Institutional Review Board (IRB). Final determination of whether an event 
represents a suspected unexpected serious adverse reaction (SUSAR) will be the 
responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or 
reported, and within 24 hours of any SAE (regardless of whether the event is assessed as 
related or unrelated to study drug) being first recognized or reported, Covance or the 
Sponsor’s Clinical Safety Representative will be notified by the Investigator or designee in 
writing using the following email address: 
email: SAEIntake@Covance.com 
To report the SAE, the completed report form should be sent by email to Covance or the 
Sponsor’s Clinical Safety Representative within 24 hours of awareness. Incoming reports are 
reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 


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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 (CBC):
Other Tests: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase 
(AST) 
Bilirubin (direct and total) 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase (CK) 
Creatinine 
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (percent and 
absolute): 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Hemoglobin A1c (HbA1c)b 
Thyroid-stimulating hormone 
(TSH)b 
Coagulation Parameters: 
Activated partial thrombin time 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Human immunodeficiency virus 
(HIV) antibody 
Hepatitis B surface antigen 
(HBsAg) 
Hepatitis C virus (HCV) 
antibody 
For Female Subjects only: 
Pregnancy test (serum 
qualitative, serum quantitative 
may be used for confirmation if 
needed)c 
Follicle-stimulating hormone 
(post-menopausal female 
subjects only)b 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity  
Protein 
Urobilinogen 
Microscopic examination 
including bacteria, casts, 
crystals, epithelial cells, RBCs, 
and WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Estimated creatinine clearancea 
Urine Drug Screen:a 
Including but not limited to the 
following: 
Alcohol (ethanol) (breath test) 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine (metabolite)  
Methadone 
Opiates 
Phencyclidine 
Cotinine 
a. Performed at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Performed at Screening, Check-in (Day -1), and End of Treatment (EOT)/Early Termination (ET) only. 


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Appendix 3: Total Blood Volume 
Part 1: Itraconazole (CYP3A4 and P-gp Inhibitor) 
The following blood volumes will be withdrawn for each subject participating in Part 1: 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 350 mL in Part 1. 
Part 2 – Rifampin (CYP3A4 Inducer) 
The following blood volumes will be withdrawn for each subject participating in Part 2: 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 410 mL in Part 2.
Assessment 
Approximate Blood 
Volume per Sample 
(mL) 
Maximum 
Number of Blood 
Samples 
Approximate 
Total Volume 
(mL) 
Serology 
4.0 
1 
4.0 
Hemoglobin A1c (HbA1c) 
4.0 
1 
4.0 
Primary pharmacokinetic (PK) sampling 
4.0 
40 
160.0 
Clinical laboratory tests: 
    Complete blood count (CBC) 
    Clinical chemistry 
    Coagulation parameters 
 
4.0 
4.0 
3.0 
 
7 
7 
7 
 
28.0 
28.0 
21.0 
Serum pregnancy test (female subjects 
only) 
4.0 
3 
12.0 
Serum follicle-stimulating hormone (FSH; 
post-menopausal female subjects only) 
4.0 
1 
4.0 
Thyroid-stimulating hormone (TSH) 
4.0 
1 
4.0 
Total: 
265.0 mL 
Assessment 
Approximate Blood 
Volume per Sample 
(mL) 
Maximum 
Number of Blood 
Samples 
Approximate 
Total Volume 
(mL) 
Serology 
4.0 
1 
4.0 
Hemoglobin A1c (HbA1c) 
4.0 
1 
4.0 
Primary pharmacokinetic (PK) sampling 
4.0 
53 
212.0 
Clinical laboratory tests: 
    Complete blood count (CBC) 
    Clinical chemistry 
    Coagulation parameters 
 
4.0 
4.0 
3.0 
 
8 
8 
8 
 
32.0 
32.0 
24.0 
Serum pregnancy test (female subjects 
only) 
4.0 
3 
12.0 
Serum follicle-stimulating hormone (FSH; 
post-menopausal female subjects only) 
4.0 
1 
4.0 
Thyroid-stimulating hormone (TSH) 
4.0 
1 
4.0 
Total: 
328.0 mL 


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Page 54 of 60 
Appendix 4: Schedule of Assessments


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 1 9 6 6 6  
Pr ot oc ol Refere nce: L O X O- B T K- 2 0 0 0 6 
Pr ot oc ol Versi o n 1, 1 4 Ja n uar y 2 0 2 0 
Pa ge 5 5 of 6 0 
P art 1 – Itr ac o n az ole ( C Y P 3 A 4 a n d P- g p I n hi bit or) 
St u d y Pr oce d ures a
Scree ni n g 
( D a ys - 2 9 
t o - 2) 
C hec k-i n
( D a y - 1) 
Peri o d 1 
Peri o d 2 
Cli nic 
Disc h ar ge/
E O T 
( D a y 1 9) or 
E T r 
F oll o w- u p 
P h o ne C all 
( E O S) 
1  
2  
3  
4  
5  
6  
7  
8  
9  1 0  1 1  1 2 1 3 1 4 1 5 1 6 1 7 1 8
7 ( ± 2) d a ys 
p ost E O T or 
E T s 
C o nfi ne d t o t he C R U  
  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
 
I ncl usi o n/ E xcl usi o n 
Criteria 
X 
 
X  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
I nf or me d C o nse nt 
 
X  
  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
De m o gra p hics 
 
X  
  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
Me dical Hist or y  
X  
X
b  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
Hei g ht/ Wei g ht/ B MI  
X  
X c  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
P h ysical 
E xa mi nati o n d 
X 
 
X  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
X  
 
1 2-lea d E C G e  
X  
X  
X 
   
X 
     
X    
  
  X    
  X    
  
  
X  
 
Vital Si g ns f  
X  
X  
X 
   
X 
     
X    
  
  X    
  X    
  
  
X  
 
H D Y F? I n q uir y g  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X 
A Es/ S A Es h  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X 
L O X O- 3 0 5 D osi n g i  
  
 
 
X 
 
 
 
 
 
 
       
X 
   
 
 
 
  
  
 
Itrac o naz ole D osi n gj  
  
  
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
  
 
 
 
  
 
Cli nical La b orat or y 
E val uati o ns l 
X  
X  
  
  
  
X  
  
  
X  
  
  
  
X  
  
  
  
X  
  
  
  
X  
 
He patitis a n d HI V 
Scree n 
X  
  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
H b A 1c Test m  
 
X  
  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
Dr u g Scree n n 
 
X 
 
X  
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
  
  
 
C CI
C CI


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Study Proceduresa
Screening 
(Days -29 
to -2) 
Check-in
(Day -1) 
Period 1 
Period 2 
Clinic 
Discharge/
EOT 
(Day 19) or 
ETr 
Follow-up 
Phone Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12
13
14
15
16
17
18
7 (±2) days 
post EOT or 
ETs 
Prior and 
Concomitant 
Medicationso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy 
Testp 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FSH Testq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; BP = blood pressure; CBC = complete blood count; CK = creatine kinase; CRU = Clinical Research Unit; 
ECG = electrocardiogram; EOS = End of Study; EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; HDYF? = How Do You Feel?; HIV = human 
immunodeficiency virus; ICF = Informed Consent Form; PK = pharmacokinetic; SAE = serious adverse event; TSH = thyroid-stimulating hormone; UA = urinalysis. 
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 physical examination will be performed at Screening. An abbreviated physical examination will be performed at Check-in (Day -1) and at EOT (Day 19). 
e. 12-lead ECGs 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 (predose and 2 hours after LOXO-305 dosing), Day 4 (ie, 72 hours after LOXO-305 dosing on Day 1), Day 8 (ie, 168 hours after LOXO-305 dosing on Day 1), 
Day 12 (before LOXO-305 and itraconazole dosing), Day 15 (ie, 72 hours after LOXO-305 and itraconazole dosing on Day 12), and at EOT/Day 19 (168 hours after LOXO-305 and 
itraconazole dosing on Day 12). 
f. Vital signs measurements (oral temperature, respiratory rate, and supine BP and pulse rate) will be obtained at Screening and Day -1, Day 1 (predose and 2 hours after LOXO-305 dosing), 
Day 4 (ie, 72 hours after LOXO-305 dosing on Day 1), Day 8 (ie, 168 hours after LOXO-305 dosing on Day 1), Day 12 (before LOXO-305 and itraconazole dosing), Day 15 (ie, 72 hours 
after LOXO-305 and itraconazole dosing on Day 12), and at EOT/Day 19 (168 hours after LOXO-305 and itraconazole dosing on Day 12). Vital signs measurements should be carried out 
prior to and as close as possible to having blood drawn. Blood pressure and pulse rate 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 will be 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. Adverse events and SAEs will be collected beginning at informed consent. Adverse events 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 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 1 9 6 6 6  
Pr ot oc ol Refere nce: L O X O- B T K- 2 0 0 0 6 
Pr ot oc ol Versi o n 1, 1 4 Ja n uar y 2 0 2 0 
Pa ge 5 7 of 6 0 
Da y 1 t hr o u g h E O T or E T re gar dle ss of relati o ns hi p t o st u d y dr ug). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o  st u d y dr u g are t o be rec or de d. All S A Es t hat de vel o p fr o m 
t he ti me of I C F si g nin g u ntil E O S ( or  E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete  a f oll o w- u p p h o ne call) are t o be re p orte d. 
i. O n Da y 1, L O X O- 3 0 5 will be a d mi n istere d i n t he m or ni n g f oll o wi ng a fast of at least 1 0 h o urs pr i or t o a n d 4 h o urs after t he L OX O- 3 0 5 d ose. O n Da y 1 2, L O X O- 3 0 5 will be c o-a d mi nistere d 
wit h itrac o naz ole i n t he m or ni n g f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g wit h L O X O- 3 0 5 a n d itrac o naz ole. 
j. O n Da y 8, BI D d oses of itrac o naz o le will be a d mi nistere d. O n Days 9 t o 1 8 (i ncl usi ve), Q D d oses  of itrac o naz ole will be a d mi nistere d. O n Da y 1 2, itrac o naz ole will be c o-a d mi nistere d wit h 
L O X O- 3 0 5 i n t he m or ni n g f oll o wi n g a fast of at least 1 0 h o urs p ri or t o a n d 4 h o urs after d osin g wit h L O X O- 3 0 5 a n d itrac o naz ole. O n Da y 8, w he n itrac o naz ole w ill is a d mi nistere d BI D, t he 
m or ni n g d ose will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 L O X O- 3 0 5 d ose ( ± 1 h o ur),  a p pr o xi matel y 3 0 mi n utes after starti n g a sta n dar d brea kfast, a n d t he e ve ni n g d ose will 
be a d mi nistere d a p pr o xi matel y 1 0 ( ± 1) h o urs after t he m or ni n g d ose, a p pr o xi matel y 3 0 mi n utes after starti n g a sta n dar d e ve ni n g  meal. O n Da ys 9 t o 1 1 a n d Days 1 3 t o 1 8, t he Q D d ose of 
itrac o naz ole will be a d mi nistere d al o ne at t he act ual ti me of the Da y 1 L O X O- 3 0 5 d ose ( ± 1 h o ur),  a p pr o xi matel y 3 0 mi n utes after t he start of a sta n dar d bre a kfast. All meals s h o ul d be 
e ntirel y c o ns u me d wit hi n 3 0 mi n utes. 
 
l. Cli nical c he mistr y pa nel i ncl u di n g C K (faste d at least 8 h o urs) , c oa g ulati o n para meters, C B C, an d U A will be perf or me d at Scre e ni n g, C hec k-i n ( Da y - 1), Da ys 4 a n d 7, a n d Da ys 1 1 a n d 1 5 
( bef ore itrac o naz ole d osi n g), a n d at E O T ( Da y 1 9) or E T. 
m.  He m o gl o bi n A 1c test perf o r me d at Scree ni n g o nl y. 
n.  Alc o h ol breat h test a n d dr u gs of a b use uri ne test, i ncl u di n g c oti ni ne. Res ults fr o m t he alc o h ol an d dr u g tests will be use d t o  deter mi ne s u bject eli gi bilit y per t he i ncl usi o n/e xcl usi o n crit eria. 
o.  Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de d be gi n ni n g at i nf or me d c o nse nt . I n a d diti o n, all I n vesti gat or-a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 3 0 da ys pri or t o 
st u d y dr u g a d mi nistrati o n f or prescri pti o n me dicati o ns, a n d 1 4 da ys pri or t o st u d y dr u g a d mi nistrati o n f or n o n- prescri pti o n me dicati o ns, will be rec o r de d o n t he s u bject’s electr o nic Case 
Re p ort F or m. 
p.  Fe male s u bjects o nl y. 
q.  P ost- me n o pa usal fe m ale s u bjects o nl y. 
r. E O T is defi ne d as w he n t he s u bject is release d fr o m t he C R U f ol l o wi n g c o m pleti o n of all assess me nts t hr o u g h Da y 1 9. E T is defi ne d as w he n t he s u bject is release d fr o m t he C R U if t he 
s u bject ter mi nates t he st u d y earl y. Vital si g ns, E C G, a n d safety la b orat or y res ults f or cli nic al c he mistr y, he mat ol o g y, c oa g ul ati o n, a n d U A are t o be a vaila ble f or re vie w b y t he I n vesti gat o r or 
desi g nee pri or t o s u bject release fr o m t he C R U at t he E O T or E T visit. 
s. T o be perf or me d 7 da ys ( ± 2 da ys) f oll o wi n g E O T or E T. E O S is d efi ne d as w he n t he C R U c o ntact s t he s u bject b y a f oll o w- u p p h o ne call 7 da ys ( ± 2 da ys) after t he E O T visit or E T visit t o 
deter mi ne if a n y S A E or st u d y dr u g-relate d A E has occ urre d si nc e t he E O T or E T visi t. All s u bjects w h o recei ve d L O X O- 3 0 5 (i ncl u di n g s u bjects w h o are ter mi nat e d earl y) will be c o ntacte d. 
C CIC CI


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 1 9 6 6 6  
Pr ot oc ol Refere nce: L O X O- B T K- 2 0 0 0 6 
Pr ot oc ol Versi o n 1, 1 4 Ja n uar y 2 0 2 0 
Pa ge 5 8 of 6 0 
P art 2 – Rif a m pi n ( C Y P 3 A 4 I n d ucer) 
St u d y Pr oce d ures a
Scree ni n g 
( D a ys - 2 9 
t o - 2) 
C hec k-i n
( D a y - 1)
Peri o d 1 
Peri o d 2 
Cli nic 
Disc h ar ge/
E O T 
( D a y 2 4) 
or E T s 
F oll o w- u p 
P h o ne C all 
( E O S) 
1  2  3  4  5  6  7  8  9  1 0 1 1 1 2  1 3  1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3
7 ( ± 2) d a ys 
p ost E O T 
or E T t 
C o nfi ne d t o t he 
C R U 
  
X  
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
X
X
X
X  
X  
 
I ncl usi o n/ E xcl usi o n 
Criteria 
X 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
I nf or me d C o nse nt 
 
X  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
De m o gra p hics 
 
X  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
Me dical Hist or y  
X  
X
b  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
Hei g ht/ Wei g ht/ B MI  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
P h ysical 
E xa mi nati o n d 
X 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
1 2-lea d E C G e 
 
X 
 
X 
 
X
 
 
X
 
 
 
X
 
 
X
 
 
 
 
 
X
 
 
X
 
 
 
 
X  
 
Vital Si g ns f 
 
X 
 
X 
 
X
 
 
X
 
 
 
X
 
 
X
 
 
 
 
 
X
 
 
X
 
 
 
 
X  
 
H D Y F? I n q uir y g  
X  
X  
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
X
X
X
X  
X  
X 
A Es/ S A Es h  
X  
X  
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
X
X
X
X  
X  
X 
L O X O- 3 0 5 D osi n g i
  
 
 
X
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
X
 
 
 
 
 
  
  
 
Rifa m pi n D osi n g j  
  
  
 
 
 
 
 
 
 
X
X
X
X
X 
X 
X
X
X
X
X
X
X
X
X
X  
  
 
 
 
  
 
C CI
C CI


Protocol 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Protocol Version 1, 14 January 2020 
Page 59 of 60 
Study Proceduresa
Screening 
(Days -29 
to -2) 
Check-in
(Day -1)
Period 1 
Period 2 
Clinic 
Discharge/
EOT 
(Day 24) 
or ETs 
Follow-up 
Phone Call 
(EOS) 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
7 (±2) days 
post EOT 
or ETt 
Urine Samples for 
6β-hydroxycortisol 
and Free Cortisol 
Concentrationsl 
 
 
 
 
 
 
 
 
 
X
 
 
X
 
 
 
X
 
X
 
 
 
 
 
 
 
 
Clinical Laboratory 
Evaluationsm 
X 
X 
 
 
 
X
 
 
X
 
 
 
X
 
 
 
 
X
 
 
 
X
 
 
 
X 
 
Hepatitis and HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 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
X
X
X
X
X
X
X
X
X
X 
X 
Serum Pregnancy 
Testq 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FSH Testr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; CK = creatine kinase; CRU = Clinical Research Unit; ECG = electrocardiogram; EOS = End of Study; 
EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HDYF? = How Do You Feel?; HIV = human immunodeficiency virus; 
ICF = Informed Consent Form; PK = pharmacokinetic; QD = once daily; SAE = serious adverse event; TSH = thyroid-stimulating hormone; UA = urinalysis. 
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 physical examination will be performed at Screening. An abbreviated physical examination will be performed at Check-in (Day -1) and at EOT (Day 24). 
e. 12-lead ECGs 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 (predose and 2 hours postdose after LOXO-305 dosing), Day 4 (72 hours after LOXO-305 dosing), Day 8 (168 hours after LOXO-305 dosing and predose of 


Pr ot oc ol 
C O N FI D E N TI A L 
C o va nce St u d y: 8 4 1 9 6 6 6  
Pr ot oc ol Refere nce: L O X O- B T K- 2 0 0 0 6 
Pr ot oc ol Versi o n 1, 1 4 Ja n uar y 2 0 2 0 
Pa ge 6 0 of 6 0 
L O X O- 3 0 5 a n d rifa m pi n d osi n g), D a y 1 1 ( 7 2 h o urs after L O X O- 3 0 5 a n d rifa m pi n d osi n g). Da y 1 7 ( p re d ose of L O X O- 3 0 5 a n d rifa m pi n d osi n g), Da y 2 0 ( 7 2 h o urs after L O X O- 3 0 5 a n d 
rifa m pi n d osi n g), a n d at E O T ( 16 8 h o urs p ost d ose [ie, Da y 2 4] of L O X O- 3 0 5 a n d rifa m pi n d osi n g). 
f. Vital si g ns meas ure me nts ( oral te m perat ure, res pirat or y rate, a n d s u pi ne B P a n d p ulse rate) w ill be o btai ne d at Scree ni n g a n d Da y - 1, Da y 1 ( pre d ose a n d 2 h o urs after L O X O- 3 0 5 d osi n g), 
Da y 4 ( 7 2 h o urs after L O X O- 3 0 5 d os i n g), Da y 8 ( 1 6 8 h o urs p ost d ose ( L O X O- 3 0 5 d osi n g a n d pre d ose of L O X O- 3 0 5 a n d rifa m pi n d osi n g), Da y 1 1 ( 7 2 h o urs after L O X O- 3 0 5 a n d rifa m pi n 
d osi n g). Da y 1 7 ( pre d ose of L O X O- 3 0 5 a n d rifa m pi n d osi n g), Da y 2 0 ( 7 2 h o urs after L O X O- 3 0 5 a n d ri fa m pi n d osi n g), a n d at E O T ( 16 8 h o urs p ost d ose [ie, Da y 2 4] of L O X O- 3 0 5 a n d 
rifa m pi n d osi n g). Vital si g ns meas ure me nts s h o ul d be carrie d o ut pri or t o a n d as cl ose as p ossible t o ha vi n g bl o o d dra w n. Bl o o d press ure a n d p ulse rate will be meas ure d usi n g t he sa me ar m 
f or eac h rea di n g after t he s u bject has bee n s u pi ne f or at least 5 mi n utes. 
g.  A n H D Y F? i n q uir y will b e perf or me d at Scree n i n g (after t he I C F is si g ne d), at C hec k-i n ( Da y - 1), at eac h p ost d ose vital si g ns assess me nt, a n d at a n a p pr o priate ti me f or all ot her da ys. 
h.  A d verse e ve nts a n d S A Es will be c ollecte d be gi n ni n g at i nf or me d  c o nse nt. A d verse e ve nts will be rec or de d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F u ntil E O S, or u ntil E T if t he 
s u bject disc o nti n ues fr o m t he stu d y a n d d oes n ot c o m plete a f ol l o w- u p p h o ne call), eit her as s u bject me dical histor y (if t he e ve nt is re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if  t he 
e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is  assesse d as n ot relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee]) or as A Es (if t h e e ve nt occ urs after si g ni n g o f t he 
I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d b y t he I n vesti gat or [ or desi g nee]) as relate d t o st u d y pr oce d ures, or if t he e ve nt occ urs a fter st u d y dr u g a d mi nistrati o n o n 
Da y 1 t hr o u g h E O T or E T re gar dle ss of relati o ns hi p t o st u d y dr ug). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o  st u d y dr u g are t o be rec or de d. All S A Es t hat de vel o p fr o m 
t he ti me of I C F si g nin g u ntil E O S ( or  E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete  a f oll o w- u p p h o ne call) are t o be re p orte d. 
i. O n Da y 1, L O X O- 3 0 5 will be a d mi n istere d i n t he m or ni n g f oll o wi ng a fast of at least 1 0 h o urs pr i or t o a n d 4 h o urs after t he L OX O- 3 0 5 d ose. O n Da ys 8 a n d 1 7, L O X O- 3 0 5 will be 
c o-a d mi nistere d wit h rifa m pi n i n  t he m or ni n g f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g wit h L O X O- 3 0 5 a n d rifa m pi n. 
j. O n Da ys 8 t o 2 3 (i ncl usi ve), Q D d oses of rifa m pi n will be a d mi n istere d. O n Da ys 8 a n d 1 7, rifa m pin will be c o-a d mi nistere d wit h L O X O- 3 0 5 i n t he m or ni n g f oll o wi n g a fast of at least 
1 0 h o urs pri or  t o a n d 4 h o urs after d osi n g wit h L O X O- 3 0 5 a n d rifa m pi n. O n Da ys 9 t o 1 6 a n d Da ys 1 8 t o 2 3, t he d ose of rifa m pi n  will be a d mi nistere d al o ne at t he act ual ti me of t he Da y 1 
L O X O- 3 0 5 d ose ( ± 1 h o ur), f oll o wi n g a fast of at least 8 h o urs pri or t o a n d 2 h o urs after d osi n g. 
 
l. Uri ne sa m ples will be c ollecte d o n t he m or ni n gs of Da ys 8, 1 1, 1 5, a n d 1 7 a n d ma y be st ore d f or  f ut ure p ote ntial assess me nt of 6 β- h y dr o x yc ortis ol a n d free c ortis ol c o nce ntratio ns t o e val uat e 
t he le vel of C Y P 3 A enz y me i n d ucti o n. 
m.  Cli nical c he mistr y pa nel i ncl u di n g C K (faste d at least 8 h o urs) , c oa g ulati o n para meters, C B C, an d U A will be perf or me d at Scre e ni n g, C hec k-i n ( Da y - 1), Da ys 4 a n d 7, a n d Da ys 1 1, 1 6, 
a n d 2 0 ( bef ore rifa m pi n d osi n g), a n d at E O T ( Da y 2 4) or E T. 
n.  He m o gl o bi n A 1c test perf o r me d at Scree ni n g o nl y. 
o.  Alc o h ol breat h test a n d dr u gs of a b use uri ne test, i ncl u di n g c oti ni ne. Res ults fr o m t he alc o h ol an d dr u g tests will be use d t o  deter mi ne s u bject eli gi bilit y per t he i ncl usi o n/e xcl usi o n crit eria. 
p.  Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de d be gi n ni n g at i nf or me d c o nse nt . I n a d diti o n, all I n vesti gat or-a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 3 0 da ys pri or t o 
st u d y dr u g a d mi nistrati o n f or prescri pti o n me dicati o ns, a n d 1 4 da ys pri or t o st u d y dr u g a d mi nistrati o n f or n o n- prescri pti o n me dicati o ns, will be rec o r de d o n t he s u bject’s electr o nic Case 
Re p ort F or m. 
q.  Fe male s u bjects o nl y. 
r. P ost- me n o pa usal fe m ale s u bjects o nl y. 
s. E O T is defi ne d as w he n t he s u bject is release d fr o m t he C R U f ol l o wi n g c o m pleti o n of all assess me nts t hr o u g h Da y 2 4. E T is defi ne d as w he n t he s u bject is release d fr o m t he C R U if t he 
s u bject ter mi nates t he st u d y earl y. Vital si g ns, E C G, a n d safet y la b orat or y res ults f or cli nic al c he mistr y, he mat ol o g y, c oa g ul ati o n, a n d U A are t o be a vaila ble f or re vie w b y t he I n vesti gat o r or 
desi g nee pri or t o s u bject release fr o m t he C R U at t he E O T or E T visit. 
t. T o be perf or me d 7 da ys ( ± 2 da ys) f oll o wi n g E O T or E T. E O S is d efi ne d as w he n t he C R U c o ntact s t he s u bject b y a f oll o w- u p p h o ne call 7 da ys ( ± 2 da ys) after t he E O T visit or E T visit t o 
deter mi ne if a n y S A E or st u d y dr u g-relate d A E has occ urre d si nc e t he E O T or E T visi t. All s u bjects w h o recei ve d L O X O- 3 0 5 (i ncl u di n g s u bjects w h o are ter mi nat e d earl y) will be c o ntacte d. 
C CIC CI

SAP_001.pdf: 
Statistical Analysis Plan LOXO-BTK-20006 (J2N-OX-JZNC) Version 1.0 
A Phase 1, Open Label, Two-part, Fixed-sequence Drug Interaction Study to 
Investigate the Effect of Strong CYP3A4 Inhibitor (Itraconazole) and CYP3A4 
Inducer (Rifampin) on the Pharmacokinetics of LOXO 305 in Healthy Adult 
Subjects
NCT05134337
Approval date: 05-Jun-2020


TITLE PAGE 
Statistical Analysis Plan 
A Phase 1, Open-label, Two-part, Fixed-sequence Drug Interaction Study 
to Investigate the Effect of Strong CYP3A4 Inhibitor (Itraconazole) and 
CYP3A4 Inducer (Rifampin) on the Pharmacokinetics of LOXO-305 in 
Healthy Adult Subjects 
SAP Status: Sponsor Final 
SAP Version: 1 
SAP Date: 05JUNE2020 
Investigational Product: LOXO-305 
Protocol Reference: LOXO-BTK-20006 
Covance Study: 8419666 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company  
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Principal Investigator: 
Lawrence Galitz, MD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


SAP 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Sponsor Final, Version 1, 05JUNE2020   
 
2 of 23 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1. Primary Objectives .......................................................................................................... 6 
2.2. Secondary Objectives ...................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 7 
4.1. Part 1 – Itraconazole (CYP3A4 and P-gp Inhibitor) ....................................................... 7 
4.2. Part 2 – Rifampin (CYP3A4 Inducer) ............................................................................. 8 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 10 
6. STUDY TREATMENTS ..................................................................................................... 10 
7. DEFINITIONS OF POPULATIONS .................................................................................. 11 
7.1. All Subjects Population ................................................................................................. 11 
7.2. Safety Population .......................................................................................................... 11 
7.3. Pharmacokinetic Population ......................................................................................... 11 
8. STATISTICAL METHODOLOGY .................................................................................... 11 
8.1. General .......................................................................................................................... 11 
8.1.1. Calculation of the Summary Statistics ................................................................... 12 
8.1.2. Repeat and Unscheduled Readings  ....................................................................... 12 
8.1.3. Definitions of Baseline and Change from Baseline ............................................... 13 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Screening Demographics and Baseline Characteristics ................................................ 13 
8.4. Prior and Concomitant Medication ............................................................................... 14 
8.5. Pharmacokinetic Assessments ...................................................................................... 14 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 14 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 16 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 17 
8.6. Safety and Tolerability Assessments ............................................................................ 19 
8.6.1. Adverse Events ....................................................................................................... 19 
8.6.2. Clinical Laboratory Parameters .............................................................................. 20 


SAP 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Sponsor Final, Version 1, 05JUNE2020   
 
3 of 23 
8.6.3. Vital Signs Parameters ........................................................................................... 21 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 21 
8.6.5. Other Assessments ................................................................................................. 21 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 21 
9. INTERIM ANALYSES ....................................................................................................... 21 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 22 
11. REFERENCES .................................................................................................................. 22 
12. APPENDICES ................................................................................................................... 23 


SAP 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Sponsor Final, Version 1, 05JUNE2020   
 
4 of 23 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ADaM 
analysis data model 
AE 
adverse event 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours 
postdose 
AUC0-inf 
AUC extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
extrapolated to infinity 
BID 
twice daily 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent systemic clearance  
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
Electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
GLSM 
geometric least squares mean 
GMR 
geometric mean ratio 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
λz 
apparent terminal elimination rate constant 
LLOQ 
lower limit of quantification 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
not calculated 


SAP 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Sponsor Final, Version 1, 05JUNE2020   
 
5 of 23 
NR 
no result 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
apparent terminal elimination half-life  
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time to maximum observed concentration 
WHODrug 
World Health Organization Drug Dictionary  


SAP 
CONFIDENTIAL 
Covance Study: 8419666 
Protocol Reference: LOXO-BTK-20006 
Sponsor Final, Version 1, 05JUNE2020   
 
6 of 23 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1 
dated 14 January 2020) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK), and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Loxo Oncology, Inc. A limited amount of information about this 
study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Loxo Oncology, Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
2.1. Primary Objectives 
The primary objectives of this study are: 
● To assess the impact of multiple oral doses of itraconazole (a strong cytochrome P450 
[CYP]3A4 and P-glycoprotein [P-gp] inhibitor) on the single oral dose 
pharmacokinetics (PK) of LOXO-305 in healthy adult subjects. 
● To assess the effect of multiple oral doses of rifampin (strong CYP3A4 inducer) on 
the single oral dose PK of LOXO-305 in healthy adult subjects. 
● To assess the effect of a single oral dose of rifampin on the single oral dose PK of 
LOXO-305 in healthy adult subjects.  
2.2. Secondary Objectives 
The secondary objectives of this study are: 
● To assess the safety and tolerability of a single oral dose of LOXO-305 when 
administered alone and co-administered with multiple oral doses of itraconazole. 


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● To assess the safety and tolerability of a single oral dose of LOXO-305 when 
administered alone and co-administered with single and multiple oral doses of 
rifampin. 
3. STUDY ENDPOINTS  
The following PK parameters will be calculated whenever possible, based on the plasma 
concentration of LOXO-305 (as appropriate): 
● Area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal method (for Day 1 and Day 8 of Part 2 PK only 
[AUC0-24]) 
● 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-inf) 
● Extrapolation for area under the concentration-time curve (%AUCextrap) 
● Maximum observed plasma concentration (Cmax) 
● Time to maximum observed concentration (tmax) 
● Apparent terminal elimination rate constant (λZ also known as Kel)  
● Apparent systemic clearance (CL/F) 
● Apparent terminal elimination half-life (t1/2) 
Safety and tolerability will be assessed by monitoring adverse events (AEs), performing 
physical examinations and clinical laboratory tests, measuring vital signs, and 12-lead 
electrocardiograms (ECGs).  
4. STUDY DESIGN  
This is a Phase 1, 2-part study. Each part will be conducted as an open-label, 2-period, 
fixed-sequence study. Following completion of the sentinel subjects in Part 1, the study parts 
may be conducted concurrently. Each subject will participate in either Part 1 or Part 2, but not 
both.  
4.1. Part 1 – Itraconazole (CYP3A4 and P-gp Inhibitor) 
In Part 1, Period 1, a single oral dose of 200 mg LOXO-305 will be administered in the 
morning of Day 1, following a fast of at least 10 hours prior to and 4 hours after dosing with 
LOXO-305. Blood samples for PK analysis of LOXO-305 in the absence of itraconazole will 
be taken up to 168 hours postdose of LOXO-305 on Day 1.  
In Part 1, Period 2, multiple oral doses of 200 mg itraconazole will be administered twice 
daily (BID) on Day 8, and once daily (QD) from Day 9 until Day 18 inclusive (for a total of 


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11 consecutive days) and co-administered with a single oral dose of 200 mg LOXO-305 on 
Day 12 under fasted conditions. On Day 8, when itraconazole is administered BID, the 
morning dose will be administered alone at the actual time of the Day 1 LOXO-305 dose 
(± 1 hour), approximately 30 minutes after starting a standard breakfast, and the evening dose 
will be administered approximately 10 (±1) hours after the morning dose, approximately 
30 minutes after starting a standard evening meal. All meals should be entirely consumed 
within 30 minutes. On Days 9 to 11 and Days 13 to 18, the QD dose of itraconazole will be 
administered alone at the actual time of the Day 1 LOXO-305 dose (± 1 hour), approximately 
30 minutes after the start of a standard breakfast, which should be entirely consumed within 
30 minutes. On Day 12, a single oral dose of 200 mg LOXO-305 and a single oral dose of 
200 mg itraconazole will be co-administered in the morning, following a fast of at least 
10 hours prior to and 4 hours after dosing with LOXO-305 and itraconazole. Blood samples 
for PK analysis of LOXO-305 in the presence of itraconazole will be taken up to 168 hours 
postdose of the LOXO-305 dose on Day 12.  
There will be a washout period of 7 days between the dose of LOXO-305 on Day 1 (Period 1) 
and the first dose of itraconazole on Day 8 (Period 2). 
Part 1 will be divided into 2 cohorts; a sentinel cohort will comprise 3 subjects and the 
second cohort will comprise 9 subjects, for a total of 12 subjects. 
Following completion of the sentinel cohort, the Investigator and Sponsor will review all 
pertinent safety and tolerability data (and PK data, if available) from the sentinel cohort 
before proceeding to dose the remaining 9 subjects in the second cohort in Part 1 of subjects 
in Part 2. 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 19 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. 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
4.2. Part 2 – Rifampin (CYP3A4 Inducer) 
In Part 2, Period 1, a single oral dose of 200 mg LOXO-305 will be administered on Day 1, 
following a fast of at least 10 hours prior to and 4 hours after dosing with LOXO-305. Blood 
samples for PK analysis of LOXO-305 in the absence of rifampin will be taken up to 
168 hours postdose of LOXO-305 on Day 1. 
In Part 2, Period 2, multiple oral doses of 600 mg rifampin will be administered QD from 
Day 8 until Day 23 inclusive (for a total of 16 consecutive days) and co-administered with a 
single oral dose of 200 mg LOXO-305 on Days 8 and 17. On Days 8 and 17, a single oral 
dose of 200 mg LOXO-305 and a single oral dose of 600 mg rifampin will be 
co-administered in the morning following a fast of at least 10 hours prior to and 4 hours after 


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dosing with LOXO-305 and rifampin. On Days 9 to 16 and Days 18 to 23, the dose of 
rifampin will be administered alone at the actual time of the Day 1 LOXO-305 dose 
(± 1 hour), following a fast of at least 8 hours prior to and 2 hours after dosing with rifampin. 
Blood samples for PK analysis of LOXO-305 in the presence of rifampin will be taken up to 
24 hours postdose of LOXO-305 on Day 8 and up to 168 hours postdose of LOXO-305 on 
Day 17.  
Urine samples will be collected on Days 8, 11, 15, and 17 of Part 2 only (and stored for future 
potential assessment of 6β-hydroxycortisol and free cortisol concentrations to evaluate the 
level of CYP3A enzyme induction and/or for further exploratory analysis).  
There will be a washout period of 7 days between the dose of LOXO-305 on Day 1 (Period 1) 
and the first dose of rifampin and dose of LOXO-305 on Day 8 (Period 2).  
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 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 EOT on 
Day 24 upon completion of all PK and safety assessments or 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. 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
4.3 Overall 
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, physical examinations, 12-lead ECGs, vital signs, How Do You Feel? inquiries, 
clinical chemistry panel, coagulation parameters, creatine kinase, complete blood count, 
urinalysis and recording of concomitant medications will be performed at specified times 
during the study. The AEs and serious adverse events (SAEs) will be collected beginning at 
informed consent. The AEs will be reported throughout the study (ie, from signing of the ICF 
until End of Study [EOS], or until ET if the subject discontinues from the study and does not 
complete a follow-up phone call), either as subject medical history (if the event is reported as 
beginning prior to signing of the ICF or if the event occurs prior to study drug administration 
on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) 
or as AEs (if the event occurs after signing of the ICF but prior to study drug administration 
on Day 1 and is assessed as related to study procedures by the Investigator [or designee], or if 
the event occurs after study drug administration on Day 1 through EOT or ET regardless of 
relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to 
study drug by the Investigator (or designee) are to be reported. All SAEs that develop from 
the time of ICF signing until EOS (or ET, if the subject discontinues from the study and does 
not complete a follow-up phone call) are to be reported. Study completion is defined as the 
time of the last subject’s follow-up phone call.  


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5. SAMPLE SIZE JUSTIFICATION  
Twenty-four healthy adult male and female subjects (women of non-childbearing potential 
only); 12 subjects in Part 1 and 12 subjects in Part 2 to ensure that 20 subjects complete the 
study. This is a phase 1 study and the sample size is not based upon any formal power 
calculations but is consistent with previous studies of a similar design.  
Each subject will participate in either Part 1 or Part 2, but not both. Part 1 will be divided into 
2 cohorts; a sentinel cohort will comprise 3 subjects and the second cohort will comprise 9 
subjects, for a total of 12 subjects.  
Every attempt will be made to enroll at least 3 subjects of each sex in the study.  
6. STUDY TREATMENTS  
The study treatment sequence names and ordering to be used in the TFLs are presented in 
Table 1. 
Table 1: 
Presentation of Study Treatment Sequences in TFLs  
Part 
Study Treatment Sequence 
Order in 
TFLs 
1 
LOXO-305 alone/LOXO-305 and itraconazole 
1 
2 
LOXO-305 alone/LOXO-305 and rifampin once  /LOXO-305 and rifampin 
QD 
2 
The study treatment names, and ordering to be used in the TFLs are presented in Table 2 ,  
Table 3. Presentation of Study Treatments in TFLs – Part 1 Non AE and PK Outputs 
Study Treatment 
Order in TFLs 
200 mg LOXO-305 Alone 
1 
200 mg LOXO-305 + 200 mg itraconazole QD 
2 
 
Table 4 and Table 4. 
 
Table 2: 
Presentation of Study Treatments in TFLs – Part 1 AE Outputs 
Study Treatment 
Order in TFLs 
200 mg LOXO-305 Alone 
1 
200 mg itraconazole Alone 
2 
200 mg LOXO-305 + 200 mg itraconazole QD 
3 


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Table 3. 
 Presentation of Study Treatments in TFLs – Part 1 Non AE and PK 
Outputs 
Study Treatment 
Order in TFLs 
200 mg LOXO-305 Alone 
1 
200 mg LOXO-305 + 200 mg itraconazole QD 
2 
 
Table 4: 
Presentation of Study Treatments in TFLs – Part 2 
Study Treatment 
Order in TFLs 
200 mg LOXO-305 Alone 
1 
200 mg LOXO-305 + 600 mg rifampin once 
2 
200 mg LOXO-305 + 600 mg rifampin QD 
3 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received.  
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations.  
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(LOXO-305). Subjects will be classified into groups based on actual treatment received.  
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of LOXO-305, have 
at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter can be 
computed. A subject may be excluded from the PK summary statistics and statistical analysis 
if the subject has an AE of vomiting that occurs at or before 2 times the median tmax. 
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 


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if they completed all protocol-specified procedures and assessments for the end-of-treatment 
visit. Any subject who discontinued the study will be identified accordingly in the listings. 
Summaries and statistical analyses will include the subjects assigned to the relevant 
population based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline.  
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not 
be calculated, with the exception of n, minimum, and maximum.  
● As ET data is not associated with any scheduled timepoint, it will be excluded from 
all calculations of summary statistics.  
● Post dose repeats and unscheduled assessments will not be included in calculation of 
summary statistics.  
For categorical data the following rules will be applied:  
● If the categories of a parameter are ordered (eg, AE severity), all categories between 
the possible minimum and maximum categories will be included, even if n = 0 for a 
given category. If the categories are not ordered (eg, race), only those categories for 
which there is at least 1 subject represented will be included.  
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is 
missing. This will ensure that the population size totals are consistent across different 
parameters.  


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8.1.2. Repeat and Unscheduled Readings  
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value.  
The original scheduled value will be used in all calculations post dose. In the event of any 
repeats or unscheduled measurements taken pre-dose the values will be considered when 
determining the baseline value for each period. 
Post dose repeats, unscheduled assessments, and ET measurements will be excluded from all 
calculations, with the exception of the baseline derivation (see Section 8.1.3). 
8.1.3. Definitions of Baseline and Change from Baseline  
Baseline value is defined as the last non missing measurement before administration of 
LOXO-305 in each treatment period.  
Part 1 
In general, baseline for Part 1 refers to the pre-dose value collected on Day 1 period 1 and 
Day 12. For laboratory tests, baseline is the value collected on Day -1 period 1 and Day 11 
period 2. 
Part 2  
In general, baseline for Part 2 refers to the pre-dose value collected on Day 1 period 1, Day 8 
period 2 and Day 17 Period 2. 
If the date/time of the value is incomplete or missing, it will be excluded from the baseline 
calculation, unless the incomplete date/time indicates the value was recorded prior to dosing 
of LOXO-305 in each period.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects.  
See Section 8.1.2 for more detail on handling repeat and unscheduled readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment sequence will be provided, based on the all subjects 
population.  


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8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment sequence will be provided, based on the safety population.  
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose of LOXO-305. 
Concomitant medication will be defined as medication that starts during or after the first dose 
or starts but does not end prior to the first dose.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2019. Prior and concomitant 
medications will be listed.  
8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of LOXO-305 using non-compartmental methods performed using Phoenix 
WinNonlin (Certara USA, Inc.) version 8.1 or higher: 
Parameter Definition 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose, as 
calculated by the linear trapezoidal rule for increasing and decreasing 
concentrations (for Day 1 and Day 8 of Part 2 PK only) 
 
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for 
increasing and decreasing concentrations 
AUC0-inf 
AUC extrapolated to infinity, calculated using the formula: 
AUC0-inf = AUC0-t + 
z
t
λ
C
 
where Ct is the last measurable concentration and Z is the apparent terminal 
elimination rate constant 
%AUCextrap percentage extrapolation for AUC0-inf (except for Part 2 Day 8) 
Cmax 
maximum observed plasma concentration 
tmax 
time to maximum observed plasma 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; additionally, the number of points used to estimate 
λz will be presented in a listing (wherever possible)  
t1/2 
apparent terminal elimination half-life (whenever possible),  
where t1/2 = natural log (ln)(2)/Z 
CL/F 
apparent systemic clearance (except for Part 2 Day 8) 


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Additional PK parameters may be determined where appropriate. The number of points used 
to estimate Z, the lower and upper points used in estimation, Z span ratio, and the adjusted 
coefficient for determination of exponential fit (R2 adjusted) will be presented in a listing. 
The PK analysis will, where possible, be carried out using actual postdose times recorded in 
the raw data. If actual times are missing, nominal times may be used with sponsor approval.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
No value for Z, AUC0-inf, CL/F, or t½ will be reported for cases that do not exhibit a terminal 
log linear phase in the concentration-time profile. The PK sampling to 24 hours on Day 8 in 
Part 2 may not be sufficient for calculation of several Z-dependent PK parameters. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive timepoints with 
quantifiable concentrations. 
Cmax and tmax will be obtained directly from the plasma concentration-time profiles. For 
multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported if possible.  
8.5.1.1. Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
Concentration values that are below the limit of quantification (BLQ) will be set to zero, with 
defined exceptions as follows; 
● Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
● If there are late positive concentration values following 2 BLQ concentration values 
in the apparent terminal phase, these values will be evaluated. If these values are 
considered to be anomalous, they will be set to missing. 
● If an entire concentration-time profile is BLQ, the profile will be excluded from the 
PK analysis. 
● If a Period 1 predose concentration is missing, it may be set to 0 (for PK analysis 
only) by default within the Phoenix WinNonlin software. Handling of missing 
predose values in Period 2 will be assessed on a case by case basis. 
8.5.1.2. Criteria for the Calculation of an Apparent Terminal Elimination Rate 
Constant and Half-Life 
8.5.1.2.1. Number of Data Points 
At least 3 data points will be included in the regression analysis and preferably should not 
include Cmax. 


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8.5.1.2.2. Goodness of Fit 
When assessing terminal elimination phases, the adjusted coefficient of determination for 
exponential fit (R2 adjusted) value will be used as a measure of the goodness of fit of the data 
points to the determined line.  
Regression-based parameters (eg, AUC0-inf, λz, t1/2, and CL/F) will only be calculated if the R2 
adjusted value of the regression line is greater than or equal to 0.7. 
8.5.1.2.3. Period of Estimation 
The time period used for the estimation of apparent terminal elimination rate constant, where 
possible, will be over at least 2 half lives.  
Where the terminal elimination rate constant is estimated over a time period of less than 2 
half-lives, it will be flagged in the data listings at the discretion of the Pharmacokineticist, 
and the robustness of the value should be discussed in the CSR.  
8.5.1.3. Calculation of AUC 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with at 
least one of these concentrations following Cmax. 
For any partial AUC determination (eg, AUC0-24), nominal time will generally be used for the 
end of the interval. Actual times for partial AUC intervals may be used at the discretion of the 
pharmacokineticist.  
AUC0-inf values where the percentage extrapolation is less than 20% will be reported. 
AUC0-inf values where the percentage extrapolation is between 20 to 30% will be flagged, and 
included in the summary statistics and statistical analysis, whilst AUC0-inf values where the 
percentage extrapolation is greater than 30% will be reported but excluded from summary 
statistics and statistical analysis.   
8.5.1.4. Anomalous Values 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
the CSR. 
Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
Subjects with positive predose values greater than 5% of Cmax may be excluded from the 
summary statistics and statistical analysis at the discretion of the Pharmacokineticist.  


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8.5.2. Presentation of Pharmacokinetic Data 
8.5.2.1. Presentation Pharmacokinetic Plasma Drug Concentration Data 
The following rules will be applied if there are values that are BLQ or if there are missing 
values (eg, no result [NR]) in plasma concentration data series to be summarized. 
● For the calculation of summary statistics, BLQ values will be set to zero. 
● If an embedded BLQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics. 
● Where there is NR, these will be set to missing. 
● If there are less than 3 values in the data series, only the minimum, maximum and N 
will be presented. The other summary statistics will be denoted as not calculated 
(NC). BLQ is considered a value. 
● If all the values are BLQ, then the arithmetic mean, arithmetic standard deviation 
(SD), median, minimum and maximum will be presented as zero, and the geometric 
mean and geometric coefficient of variation (CV) will be denoted as NC. 
● If the value of the arithmetic mean or median is below the LLOQ, these values will be 
presented as zero and the geometric mean and geometric CV will be denoted as NC. 
8.5.2.2. Presentation Pharmacokinetic Parameters 
For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables, mean (+ SD) figures, overlaying individual figures, and individual figures 
by treatment and time postdose will be provided for plasma PK concentrations. All PK 
concentration figures will be produced on both linear and semi-logarithmic scales, with the 
exception of figures across all days, which will be produced on the linear scale only. The 
+SD bars will only be displayed on the linear scale.   
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Summary statistics (n, Mean, SD, CV%, 
minimum, median, maximum, geometric mean [Geom Mean] and geometric CV% [Geom 
CV%]) will be calculated for plasma LOXO-305 PK parameters. Excluded subjects will be 
listed in the PK parameter tables, but will be excluded from the summary statistics and noted 
as such in the tables. 


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8.5.3.1. Statistical Analyses 
A statistical analysis will be conducted to investigate the drug-drug interaction on the PK of 
LOXO-305 for AUC0-24 ,AUC0-t, AUC0-inf, and Cmax . The comparisons of interest are: 
Study Part 1:  
To access the impact of multiple oral doses of itraconazole on the single oral dose PK of 
LOXO-305 (AUC0-t, AUC0-inf, and Cmax)  
● 200 mg itraconazole co-administered with 200 mg LOXO-305 (test treatment) vs 200 
mg LOXO-305 alone (reference treatment).  
Study Part 2:  
To assess the effect of multiple oral doses of rifampin (strong CYP3A4 inducer) on the 
single oral dose PK of LOXO-305 (AUC0-t, AUC0-inf, and Cmax) in healthy adult subjects 
● 600 mg rifampin QD co-administered with 200 mg LOXO-305 (test treatment, Day 17) 
vs 200 mg LOXO-305 alone (reference treatment) 
To assess the effect of a single oral dose of rifampin on the single oral dose PK of LOXO-
305 (AUC0-24, and Cmax)  
● 600 mg rifampin once co-administered with 200 mg LOXO-305 (test treatment, Day 
8) vs 200 mg LOXO-305 alone (reference treatment) 
 
The ln-transformed3 PK parameters (AUC0-24, AUC0-t, AUC0-inf, and Cmax) will be analyzed 
using a mixed model.4 The model will include actual treatment as fixed effect, and subject as 
a random effect.  
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test and reference treatments, and corresponding 90% 
confidence interval (CI) will be calculated; these values will then be exponentiated to give the 
geometric least squares mean (GLSM), geometric mean ratios (GMR), and corresponding 
90% CI.  
Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
  by parcat1n parcat1 paramn param; 
  class trtan usubjid; 
  model lpk = trtan / cl residual ddfm = kr; 
  lsmeans trtan / cl pdiff = control('1') alpha = 0.1; 
  random intercept / subject = usubjid;  


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  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.1. All AEs will be assigned severity grade using National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose.  
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment (LOXO-305 or itraconazole or rifampin), as determined by the investigator.  
For Part 1 of this study, the assignment of TEAEs to the associated treatments will be as 
follows: 
● A TEAE occurring during or after Day 1 dosing and prior to Day 8 dosing will be 
assigned to 200 mg LOXO-305  
● A TEAE occurring during or after Day 8 dosing and prior to Day 12 dosing will be 
assigned to 200 mg itraconazole  
● A TEAE occurring during or after Day 12 dosing will be assigned to 200 mg 
LOXO-305 and/or 200 mg itraconazole 
For Part 2 of this study, the assignment of TEAEs to the associated treatments will be as 
follows: 
● A TEAE occurring during or after Day 1 dosing and prior to Day 8 dosing will be 
assigned to 200 mg LOXO-305  
● A TEAE occurring during or after Day 8 dosing will be assigned to 200 mg LOXO-
305 and/or 600 mg rifampin 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last dose for TEAEs only.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, and leading to discontinuation) by treatment  
● TEAEs by severity and treatment  


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● Treatment-related TEAEs (overall, serious, and leading to discontinuation) by 
treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
● System organ class, preferred term, day of onset, and treatment  
For the AE data the following rules will apply:  
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time 
or the end date/time indicates an AE started prior to the first dose.  
● For the derivation of treatment-related TEAE status: If the study treatment 
relationship for a TEAE is missing, a TEAE will be assumed to be a treatment-related 
TEAE.  
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, 
the minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of the last dose is 01MAY2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).  
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).  
● For the calculation of summary statistics: If the severity of a TEAE is missing, a 
TEAE will be counted under the maximum severity possible, up to Grade 4 in the 
absence of a fatal outcome.   
● For the calculation of summary statistics: If a subject experienced multiple TEAEs 
with the same preferred term for the same treatment, this will be counted as 1 TEAE 
for that treatment under the maximum severity recorded.  


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8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters, with changes from baseline, will be listed; any value 
outside the clinical reference range will be flagged, and whether the out of range value was 
deemed clinically significant or not clinically significant will be indicated. Separate listings 
will be provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range.  
The observed results and change from baseline for clinical chemistry, complete blood count, 
and coagulation parameters will be summarized descriptively by study part and timepoint. 
Boxplots of the observed values will also be provided.    
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to 0 whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters  
All vital signs parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated  
The observed results and change from baseline for all vital signs parameters will be 
summarized descriptively by treatment and timepoint. Boxplots of the observed values will 
also be provided.  
.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged, and whether the out of range value was deemed 
clinically significant or not clinically significant will be indicated.  
The observed results and change from baseline for all 12-lead ECG parameters will be 
summarized descriptively by treatment group and timepoint. Boxplots of the observed values 
will also be provided. QTcF values that are > 450 msec and increase from baseline > 30 msec 
will be flagged in the data listing.  
8.6.5. Other Assessments  
Medical history and physical examination will be listed.  Any physical examination 
abnormalities reported will also be flagged as clinically significant or not clinically 
significant as indicated.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  


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8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.   
9. INTERIM ANALYSES  
No interim analyses are planned.  
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
4. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
5. 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(6):657-680. 


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12. APPENDICES 
Appendix 1: 
Document History 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
NA = not applicable