Clinical trial NCT05436912
Conditions: Healthy Hepatic Impairment
Sponsor: Eli Lilly and Company
Start date: 2018-12-10; Completion date: 2019-10-30
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to assess how selpercatinib gets into the blood stream and how long it takes the body to remove it when administered to participants with impaired hepatic function compared to healthy participants. Information about safety and tolerability will be collected. The study will last up to about 7 weeks, inclusive of screening period.

Detailed description:

Arms: arm 1: 160 mg selpercatinib administered orally to healthy participants after at least a 2-hour fast on Day 1. arm 2: 160 mg selpercatinib administered orally to participants with mild hepatic impairment per Child-Pugh \[CP\] classification (CP Class A, score of 5 or 6) after at least a 2-hour fast on Day 1. arm 3: 160 mg selpercatinib administered orally to participants with moderate hepatic impairment per CP classification (CP Class B, score of 7 to 9) after at least a 2-hour fast on Day 1. arm 4: 160 mg Selpercatinib administered orally to participants with severe hepatic impairment per CP classification (CP Class C, score of 10 to 15) after at least a 2-hour fast on Day 1.
Interventions: intervention 1: Selpercatinib
Intervention descriptions: intervention 1: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol J2G-OX-JZJD
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Pharmacokinetic 
Study of LOXO-292 Administered to Fasted Hepatically Impaired Male and Female Subjects and 
Fasted Matched-control Healthy Subjects
NCT05436912
Approval date: 19-Dec-2018


Clinical Study Report 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
16.1. Study Information 
16.1.1. 
Protocol and Amendments 
20 May 2020
Page 1 of 163


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
Protocol 
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, 
and Pharmacokinetic Study of LOX0-292 Administered to Fasted Hepatically 
Impaired Male and Female Subjects and Fasted Matched-control Healthy 
Subjects 
Sponsor: 
Loxo Oncology, Inc. 
Protocol Status: Final 
Amended Protocol Date: 19 December 2018 
Original Final Protocol Date: 15 October 2018 
Protocol Version: 2 
Investigational Product: LOXO-292 
Protocol Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Number: 133193 
Study Site: 
Multiple Sites 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
Sponsor Signato1y: 
Principal Investigator: 
I 
MD, PhD 
Multiple Investigators 
Medical Monitor 
Pl 
to Loxo Oncology, Inc. 
Inf 01mation described herein is confidential and may be disclosed only with the express 
written pe1mission of the Sponsor. 
Protocol Final, 19 December 2018 
Page 1 of76 
Page 2 of 163 


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 2 of 76 
SUMMARY OF AMENDED PROTOCOL CHANGES 
The final protocol LOXO-RET-18022 Version 1, dated 15 October 2018, was amended for the 
following: 
•
To add the term End of Treatment (EOT) and define it as the time of clinic check-out.
Where applicable, subject study restrictions were updated so the duration is through EOT
or Early Termination (ET), rather than End of Study (EOS).
•
To clarify that “Study Completion” applies to the clinical conduct of the study overall
(last subject’s Follow-up phone call) and that “End of Study” applies to each subject for
their individual Follow-up phone call (including for ET subjects), and to update instances
where one of these terms was incorrectly used. Similarly, instances of “during the study”
and “throughout the study” were updated to the appropriate term.
•
To update inclusion criterion 5 regarding contraception, so that subjects must use a male
condom with spermicide and a secondary method, instead of a male condom with
spermicide or another listed method.
•
To add an exclusion criterion prohibiting drugs that may prolong QT/QTc interval within
14 days prior to dose administration and through EOT or ET.
•
To clarify exclusion criteria regarding abnormal laboratory values.
•
To clarify exclusion criteria 13 and 14, and the concomitant medications and concomitant
therapies sections, regarding medication restrictions and prohibited
medications/substances with potential to interact or interfere with the study drug. As part
of these changes, exclusion criterion 13 was split into separate restrictions for healthy
subjects and hepatically impaired subjects, and the exclusion criteria were shifted and
renumbered accordingly.
•
To update exclusion criterion 39 regarding the restriction period for paracentesis from
56 days prior to Check-in (Day -1) to 30 days prior to Screening.
•
To clarify restrictions on consumption of fruit juices such that juices other than grapefruit
and orange are not allowed within 72 hours prior to dose administration and through EOT
or ET.
•
To clarify that there are no restrictions around water consumption during the study.
•
To clarify when adverse events (AEs) should be classified as medical history or as AEs.
•
To clarify that AEs occurring in a subject between EOT or ET and EOS should only be
reported if the event is a serious adverse event or is considered related to study drug.
•
To clarify the timing of the follow-up phone call to subjects from approximately 7 days
after Clinic Discharge to 7 days (± 2 days) after EOT or ET.
Page 3 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 3 of 76 
•
To clarify that for subjects who terminate early and do not have a follow-up call, the AE
reporting period ends at ET.
•
To clarify that a withdrawn subject with an ongoing AE at ET will continue to be
followed only if the AE is considered related to study drug.
•
To clarify the timing requirements for reporting pregnancy in subjects or in the female
partner of a subject.
•
To update the timing window of the predose blood sample for unbound plasma
concentrations of LOXO-292 so that it may be collected within 30 minutes prior to
dosing, rather than within 15 minutes.
•
To update the referenced version of the Investigator’s Brochure to the current version.
The version number, date, and other minor typographical or formatting errors were also updated 
or corrected but do not affect the proposed conduct of the study. 
SUMMARY OF MAJOR CHANGES 
Synopsis – Study design 
Previous text: 
A Follow-up phone call will occur approximately 7 days after Clinic Discharge. 
Now reads: 
A Follow-up phone call will occur 7 days (± 2 days) after EOT or ET. 
Synopsis – Study design 
Previous text: 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) until Clinic 
Discharge on Day 11 upon completion of all PK and safety assessments. A Follow-up phone call 
will occur approximately 7 days after Clinic Discharge. 
On the morning of Day 1, after at least a 2-hour fast, an oral dose of 160 mg LOXO-292 
administered as two 80-mg capsules will be given with 240 mL water. No food will be allowed 
for up to 1 hour postdose. Glucose tablets may be administered as needed for treatment of 
hypoglycemia. 
In this study design, physical examinations (PEs), 12-lead electrocardiograms (ECGs), vital 
signs, How Do You Feel? inquiries, clinical chemistry panel, coagulation parameters, complete 
blood count, and urinalysis will be performed at Screening and at specified times during the 
Page 4 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 4 of 76 
study. All adverse events (AEs) will be recorded throughout the study (ie, from signing of the 
Informed Consent Form until Study Completion), either as subject medical history (if the event 
is reported as occurring prior to signing of the Informed Consent Form [ICF]) or as AEs (if the 
event occurs after administration of LOXO-292). Between the time of ICF signing to 
administration of LOXO-292 only AEs assessed as related to study procedures should be 
reported. All SAEs that develop from he time of ICF signing until Study Completion are to be 
reported. 
Now reads: 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) until EOT on 
Day 11 upon completion of all PK and safety assessments or ET if the subject discontinues. A 
Follow-up phone call will occur 7 days (± 2 days) after EOT or ET. 
On the morning of Day 1, after at least a 2-hour fast, an oral dose of 160 mg LOXO-292 
administered as two 80-mg capsules will be given with 240 mL water. No food will be allowed 
for up to 1 hour postdose. Glucose tablets may be administered as needed for treatment of 
hypoglycemia. 
In this study, physical examinations (PEs), 12-lead electrocardiograms (ECGs), vital signs, How 
Do You Feel? inquiries, clinical chemistry panel, coagulation parameters, complete blood count 
(CBC), and urinalysis (UA; Appendix 2) will be performed at Screening and at specified times 
during the study (for specific timepoints and details on each study variable, refer to Appendix 5). 
Adverse events (AEs) and serious adverse events (SAEs) will be collected beginning at informed 
consent. AEs will be reported throughout the study (ie, from signing of the Informed Consent 
Form [ICF] until End of Study [EOS], or until Early Termination [ET] if the subject discontinues 
from the study and does not complete a follow-up call), either as subject medical history (if the 
event is reported as beginning prior to signing of the ICF or if the event occurs prior to study 
drug administration on Day 1 and is assessed as not related to study procedures by the 
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 End of Treatment [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 call) are to be reported. 
Synopsis – Duration of subject participation in the study 
Previous text: 
Follow-up Phone Call: approximately 7 days after Clinic Discharge. 
Now reads: 
Follow-up Phone Call: 7 days (± 2 days) after EOT or ET. 
Section 3.1. – Overall Study Design and Plan 
Page 5 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 5 of 76 
Previous text: 
A Follow-up phone call will occur approximately 7 days after Clinic Discharge. 
Now reads: 
A Follow-up phone call will occur 7 days (± 2 days) after EOT or ET. 
Section 3.1. – Figure 1  Study Design Schematic 
Previous figure: 
 
New figure: 
 
Section 3.1. – Overall Study Design and Plan 
Previous text: 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) until Clinic 
Discharge on Day 11 upon completion of all PK and safety assessments. A Follow-up phone call 
will occur approximately 7 days after Clinic Discharge.  
On the morning of Day 1, after at least a 2-hour fast, a single oral dose of 160 mg LOXO-292 
will be administered with 240 mL water. No food will be allowed for up to 1 hour postdose. 
Glucose tablets may be administered as needed for treatment of hypoglycemia. For instructions 
regarding food and water intake, please refer to Section 6.2. 
Page 6 of 163
Screening 
Study Treatment (Days -1 to 11) 
Days -29 to -2 
Check-in: 
Day-1 
Dosing: Day 1 
Discharge: 
Day 11 
PK sampling: Days 1 to 11 (0-240 hours postdose) 
Safety assessments: From sign1ng of the tCF to Follow-up phone call 
Screening 
Study Treatment (Days -1 to 11) 
Days -29 to -2 
Check-in: 
Day -1 
Dosing: Day 1 
Discharge: 
Day 11 
PK sampling: Days 1 to 11 (0-240 hours postdose) 
Safety assessments: From signing of the ICF to Follow-up phone call 
Follow-up 
~7 days after 
Discha rge 
Follow-up 
7 (± 2) days 
after Discharge 


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 6 of 76 
In this study design, PEs, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) inquiries, 
clinical chemistry panel, coagulation parameters, complete blood count (CBC), and urinalysis 
(UA; Appendix 2) will be performed at Screening, Check-in (Day -1), and at specified times 
during the study, and/or at Study Completion (for specific timepoints and details on each study 
variable, refer to Appendix 5). All AEs will be recorded throughout the study (ie, from signing of 
the ICF until Study Completion, either as subject medical history (if the event is reported as 
occurring prior to signing of the Informed Consent Form [ICF]) or as AEs (if the event occurs 
after administration of LOXO-292). Between the time of ICF signing to administration of 
LOXO-292 only AEs assessed as related to study procedures should be reported. All SAEs that 
develop from he time of ICF signing until Study Completion are to be reported. 
Now reads: 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) until EOT on 
Day 11 upon completion of all PK and safety assessments or ET if the Subject discontinues. 
A Follow-up phone call will occur 7 days (± 2 days) after EOT or ET.  
On the morning of Day 1, after at least a 2-hour fast, a single oral dose of 160 mg LOXO-292 
will be administered with 240 mL water. No food will be allowed for up to 1 hour postdose. 
Glucose tablets may be administered as needed for treatment of hypoglycemia. For instructions 
regarding food and water intake, please refer to Section 6.2. 
In this study, PEs, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) inquiries, clinical 
chemistry panel, coagulation parameters, complete blood count (CBC), and urinalysis (UA; 
Appendix 2) will be performed at specified times during the study (for specific timepoints and 
details on each study variable, refer to Appendix 5). AEs and serious AEs (SAEs) will be 
collected beginning at informed consent. AEs will be reported throughout the study (ie, from 
signing of the ICF until End of Study [EOS], or until Early Termination [ET] if the subject 
discontinues from the study and does not complete a follow-up call), either as subject medical 
history (if the event is reported as beginning prior to signing of the ICF or if the event occurs 
prior to study drug administration on Day 1 and is assessed as not related to study procedures by 
the 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 End of Treatment [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 call) are to be reported.  
Section 4.3. – Inclusion Criteria 
Previous text: 
5. Males who are capable of fathering a child must agree to use one of the following
methods of contraception from the time of the dose administration through 6 months after
dose administration:
Page 7 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 7 of 76 
• 
Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, male subjects must follow one of the 
contraception methods below: 
o Male condom with spermicide, or  
o For a female partner of male study participant: 
- 
Intrauterine device (IUD) (hormonal IUD; eg, Mirena®). Copper 
IUDs are acceptable (eg, ParaGard®); 
- 
Established use of oral, implanted, transdermal, or hormonal 
method of contraception associated with inhibition of ovulation; or 
- 
Bilateral tubal ligation. 
Males who practice true abstinence because of a lifestyle choice (ie, do not become 
abstinent just for the purpose of study participation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the ICF but becomes 
sexually active during the study, 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 unless condoms with spermicide are used from the time 
of the study drug administration until 6 months after administration of study drug. 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. 
Now reads: 
5. Males who are capable of fathering a child must agree to use one of the following 
methods of contraception from the time of the dose administration through 6 months after 
dose administration: 
• 
Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, male subjects must follow one of the 
contraception methods below: 
o Male condom with spermicide, and 
o For a female partner of male study participant: 
Page 8 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 8 of 76 
- 
Intrauterine device (IUD) (hormonal IUD; eg, Mirena®). Copper 
IUDs are acceptable (eg, ParaGard®); 
- 
Established use of oral, implanted, transdermal, or hormonal 
method of contraception associated with inhibition of ovulation; or 
- 
Bilateral tubal ligation. 
Males who practice true abstinence because of a lifestyle choice (ie, do not become 
abstinent just for the purpose of study participation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the ICF but becomes 
sexually active through EOS, he must agree to use contraception as described above.  
For male subjects, sexual intercourse with female partners who are pregnant or 
breastfeeding should be avoided unless condoms with spermicide are used from the time 
of the study drug administration until 6 months after administration of study drug. 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. 
Section 4.3. – Inclusion Criteria 
Previous text: 
9. Considered to have mild, moderate, or severe hepatic impairment (of any etiology) that 
has been clinically stable (no acute episodes of illness due to deterioration in hepatic 
function) for at least 1 month prior to Screening per the Investigator (or designee), 
Sponsor, and Covance Medical Monitor and are likely to remain stable throughout the 
study. To be classified as having hepatic impairment, subjects must have a CP score of 
5 to 6 (mild), 7 to 9 (moderate), or 10 to 15 (severe), with known medical history of liver 
disease (with or without a known history of alcohol abuse); 
Now reads: 
9. Considered to have mild, moderate, or severe hepatic impairment (of any etiology) that 
has been clinically stable (no acute episodes of illness due to deterioration in hepatic 
function) for at least 1 month prior to Screening per the Investigator (or designee), 
Sponsor, and Covance Medical Monitor and are likely to remain stable through EOS. To 
be classified as having hepatic impairment, subjects must have a CP score of 5 to 6 
(mild), 7 to 9 (moderate), or 10 to 15 (severe), with known medical history of liver 
disease (with or without a known history of alcohol abuse); 
Page 9 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 9 of 76 
Section 4.4. – Exclusion Criteria 
Previous text: 
2. Abnormal laboratory values (clinical chemistry panel [fasted at least 8 hours], excluding 
CK, LFTs, amylase, and lipase as defined below, CBC, and UA) determined to be 
clinically significant by the Investigator (or designee), Covance Medical Monitor, and 
Sponsor at Screening and/or Check-in (Day -1); 
Now reads: 
2. Abnormal laboratory values (CBC, UA, clinical chemistry panel [fasted at least 8 hours], 
excluding those further defined in exclusion criteria 26, 27, and 36 below) determined to 
be clinically significant by the Investigator (or designee), Covance Medical Monitor, and 
Sponsor at Screening and/or Check-in (Day -1); 
Section 4.4. – Exclusion Criteria 
Previous text: 
5. Consumption of grapefruit/grapefruit juice, or Seville oranges from 14 days prior to dose 
administration and throughout the study; 
6. Subjects with known ongoing alcohol and/or drug abuse within 1 month prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays conducted 
during Screening and/or at baseline; 
7. Consumption of alcohol-, citric acid-, or caffeine-containing foods or beverages within 
48 hours prior to Check-in (Day -1) and throughout the study; 
Now reads: 
5. Consumption of grapefruit/grapefruit juice, or Seville oranges from 14 days prior to dose 
administration and through EOT or ET, or consumption of other fruit juices from 
72 hours prior to dose administration and through EOT or ET; 
6. Subjects with known ongoing alcohol and/or drug abuse within 1 month prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays conducted 
during Screening and/or at Check-in (Day -1); 
7. Consumption of alcohol-, citric acid-, or caffeine-containing foods or beverages within 
48 hours prior to Check-in (Day -1) and through EOT or ET; 
Section 4.4. – Exclusion Criteria 
Previous text: 
Page 10 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 10 of 76 
10. Strenuous exercise within 5 days prior to Check-in (Day -1) and throughout the study; 
Now reads: 
10. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET; 
Section 4.4. – Exclusion Criteria 
Previous text: 
13. Use or intention to use any prescription or over-the-counter medications (including 
proton pump inhibitors, herbal products, natural or herbal supplements) within 14 days 
prior to dosing and throughout the study, unless deemed acceptable by Covance Medical 
Monitor, the Investigator (or designee), and Sponsor; 
14. Use or intention to use any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers or strong P-gp inhibitors within 14 days prior to dose administration (Day 1) and 
throughout the study, unless deemed acceptable by Covance Medical Monitor, the 
Investigator (or designee), and Sponsor; 
Now reads: 
13. Use or intention to use any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers, strong P-gp inhibitors, proton pump inhibitors, antacids, or H2-receptor 
antagonists within 14 days prior to dose administration (Day 1) and through EOT or ET, 
unless deemed acceptable by Covance Medical Monitor, the Investigator (or designee), 
and Sponsor; 
14. Use or intention to use any drug that prolongs the QT/QTc interval within 14 days prior 
to dose administration and through EOT or ET; 
23. Use or intention to use any prescription or over-the-counter medications (including herbal 
products, natural or herbal supplements) within 14 days prior to dosing and through EOT 
or ET, unless deemed acceptable by Covance Medical Monitor, the Investigator (or 
designee), and Sponsor; 
33. Use or intention to use any prescription or over-the-counter medications (including herbal 
products, natural or herbal supplements) within 14 days prior to dosing and through EOT 
or ET, unless needed to stabilize the subject’s underlying medical condition (or 
concurrent baseline conditions) and deemed acceptable by the Covance Medical Monitor, 
Investigator (or designee), and Sponsor, and provided that the subject has been on a 
stable dose for a minimum of 30 days prior to study drug administration; 
Section 4.4. – Exclusion Criteria 
Previous text: 
Page 11 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 11 of 76 
25. Abnormal LFTs, as defined by AST, ALT, ALP, 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, unless deemed acceptable by the Investigator (or designee) with prior Sponsor 
approval. 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. Subjects 
may be eligible for participation in the study based on rechecked LFT, amylase, and 
lipase values if the Investigator (or designee), Covance Medical Monitor, and the Sponsor 
deem that the results are not clinically significant and will not impact study conduct; 
Now reads: 
26. Abnormal LFTs, as defined by AST, ALT, and serum (total and direct) bilirubin, as well 
as amylase and lipase above the upper limit of the normal range at Screening or Check-in, 
unless deemed acceptable by the Investigator (or designee) with prior Sponsor approval. 
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. Subjects may be 
eligible for participation in the study based on rechecked LFT, amylase, and lipase values 
if the Investigator (or designee), Covance Medical Monitor, and the Sponsor deem that 
the results are not clinically significant and will not impact study conduct; 
Section 4.4. – Exclusion Criteria 
Previous text: 
27. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and throughout the study. Urine screen for drugs of abuse 
including cotinine and alcohol breath test must be negative at Screening and on Day -1 
(Check-in) of the study unless the positive drug screen is considered to be due to the use 
of a prescription drug which is approved by the Covance Medical Monitor, Investigator 
(or designee), and Sponsor; 
Now reads: 
28. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. Urine screen for drugs of abuse 
including cotinine and alcohol breath test must be negative at Screening and on Day -1 
(Check-in) of the study unless the positive drug screen is considered to be due to the use 
of a prescription drug which is approved by the Covance Medical Monitor, Investigator 
(or designee), and Sponsor; 
Section 4.4. – Exclusion Criteria 
Previous text: 
Page 12 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 12 of 76 
35. Smoking more than 5 cigarettes per day or equivalent (eg, e-vapor cigarette, pipe, cigar, 
chewing tobacco, nicotine patch, nicotine gum) throughout the confinement period of the 
study; unable or being unwilling to refrain from the use of tobacco or nicotine containing 
products for 2 hours prior to dosing and 4 hours after dose administration; 
Now reads: 
37. Smoking more than 5 cigarettes per day or equivalent (eg, e-vapor cigarette, pipe, cigar, 
chewing tobacco, nicotine patch, nicotine gum) throughout the confinement period of the 
study (EOT or ET); unable or being unwilling to refrain from the use of tobacco or 
nicotine containing products for 2 hours prior to dosing and 4 hours after dose 
administration; 
Section 4.4. – Exclusion Criteria 
Previous text: 
39. Recent history of paracentesis (within 56 days prior to Check-in [Day -1]) 
Now reads: 
41. Recent history of paracentesis (within 30 days prior to Screening) 
Section 4.6. – Removal of Subjects from Study Participation 
Previous text: 
All withdrawn subjects will be followed until resolution of all their AEs or until the unresolved 
AEs are judged by the Investigator (or designee) to have stabilized. 
Now reads: 
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. 
Section 5.2. – Study Treatment Administration 
Previous text: 
Each dose of LOXO-292 will be administered orally with approximately 240 mL of room 
temperature water. Doses will be preceded by a fast of at least 2 hours from food (not including 
water) and will be followed by a fast from food (not including water) for at least 1 hour postdose. 
Subjects will restrict their consumption of water for 1 hour prior to dose; at all other times during 
the study, matched-control healthy subjects may consume water ad libitum and hepatically 
impaired subjects may consume water in a manner consistent with their medical condition. 
Page 13 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 13 of 76 
Now reads: 
Each dose of LOXO-292 will be administered orally with approximately 240 mL of room 
temperature water. Doses will be preceded by a fast of at least 2 hours from food (not including 
water) and will be followed by a fast from food (not including water) for at least 1 hour postdose. 
During Clinic confinement in the CRU (Day -1 through EOT or ET), Matched-control healthy 
subjects may consume water ad libitum and hepatically impaired subjects may consume water in 
a manner consistent with their medical condition. 
Section 6.1. – Concomitant Therapies 
Previous text: 
All prescription and over-the-counter medications (including proton pump inhibitors, herbal 
products, natural or herbal supplements) are prohibited for 14 days prior to dose administration 
(Day 1) and throughout the study, unless deemed acceptable by the Covance Medical Monitor, 
Investigator (or designee), and Sponsor or, if the subject is hepatically impaired, needed to 
stabilize the subject’s underlying medical condition (or concurrent baseline conditions) as 
described below. Moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers and strong 
P-gp inhibitors are prohibited for 14 days prior to dose administration (Day 1) and throughout 
the study. 
Now reads: 
All prescription and over-the-counter medications (including, herbal products, natural or herbal 
supplements) are prohibited for 14 days prior to dose administration (Day 1) and through EOT or 
ET, unless deemed acceptable by the Covance Medical Monitor, Investigator (or designee), and 
Sponsor or, if the subject is hepatically impaired, unless needed to stabilize the subject’s 
underlying medical condition (or concurrent baseline conditions) as described below. Moderate 
or strong CYP3A4 and/or CYP3A5 inhibitors or inducers, strong P-gp inhibitors, proton pump 
inhibitors, antacids, and H2-receptor antagonists are prohibited for 14 days prior to dose 
administration (Day 1) and through EOT or ET unless approved by the Covance Medical 
Monitor, Investigator (or designee), and Sponsor. 
Section 6.1. – Concomitant Therapies 
Previous text: 
The use of additional medications is to be avoided from 14 days prior to study drug 
administration until study completion unless required to treat an AE. All concomitant 
medications will be reviewed by the Covance Medical Monitor, Investigator (or designee), and 
Sponsor prior to subject approval. 
Now reads: 
The use of additional medications is to be avoided from 14 days prior to study drug 
administration until EOT or ET unless required to treat an AE. All concomitant medications 
needed to stabilize the subject’s underlying medical condition (or concurrent baseline conditions) 
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Protocol Final, 19 December 2018  
Page 14 of 76 
will be reviewed by the Covance Medical Monitor, Investigator (or designee), and Sponsor prior 
to subject approval. 
Section 6.2. – Diet, Fluid, and Activity Control 
Previous text: 
Matched-control healthy subjects are required to refrain from use of tobacco, smoking cessation 
products, and nicotine-containing products within 3 months prior to Screening and during the 
entire study. Hepatically impaired subjects are required to refrain from the use of tobacco- and 
nicotine-containing products within 2 hours prior to dosing and for 4 hours postdose. 
Consumption of grapefruit, grapefruit juice, or Seville oranges from 14 days prior to dose 
administration (Day 1) and throughout the study will not be allowed unless deemed acceptable 
by the Covance Medical Monitor, Investigator (or designee), and Sponsor. 
Subjects are required to abstain from consuming alcohol-, citric acid-, and caffeine-containing 
foods and beverages for 48 hours prior to Check-in (Day -1) and throughout the study, unless 
deemed acceptable by the Investigator.  
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and during 
the period of confinement at the clinical site and will otherwise maintain their normal level of 
physical activity throughout the entire study (ie, will not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
Now reads: 
Matched-control healthy 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. Hepatically impaired subjects are required to refrain from the use of tobacco- and nicotine-
containing products within 2 hours prior to dosing and for 4 hours postdose. 
Consumption of grapefruit, grapefruit juice, or Seville oranges from 14 days prior to dose 
administration (Day 1) or consumption of other fruit juices from 72 hours prior to dose 
administration and through EOT or ET will not be allowed unless deemed acceptable by the 
Covance Medical Monitor, Investigator (or designee), and Sponsor. 
Subjects are required to abstain from consuming alcohol-, citric acid-, and caffeine-containing 
foods and beverages for 48 hours prior to Check-in (Day -1) and through EOT or ET, unless 
deemed acceptable by the Investigator.  
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and during 
the period of confinement at the clinical site and will otherwise maintain their normal level of 
physical activity through EOT or ET (ie, will not begin a new exercise program or participate in 
any unusually strenuous physical exertion). 
Section 7.2.1. – Adverse Events 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 15 of 76 
Previous text: 
Subjects will be asked a nonleading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 
Appendix 5 (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 during the study. 
All AEs, whether volunteered, identified by the subject’s responses to HDYF? inquiries, or noted 
on PE, ECG, vital signs assessments, or laboratory tests, will be recorded throughout the study 
(ie, from signing of the ICF until Study Completion), either as subject medical history (if the 
event is present  prior to signing of the Informed Consent) or as AEs (if the event occurs after 
administration of LOXO-292). Between the time of ICF signing to administration of LOXO-292 
only AEs assessed as related to study procedures should be reported.  All SAEs that develop 
from the time of ICF signing until Study Completion are to be reported.  Following Clinic 
Discharge, only AEs or SAEs assessed as related to study drug should be reported. 
All AEs (nonserious and serious) should be followed until resolution, return to baseline, 
assessment as stable by the Investigator (or designee), or until the subject withdraws consent or 
is lost to follow-up. 
Subjects will receive a Safety Follow-up phone call approximately 7 days after they are 
discharged from the clinical site to determine if any AE has occurred since the last study visit. 
Now reads: 
Subjects will be asked a nonleading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 
Appendix 5 (ie, at Screening [after the ICF is signed], at Check-in (Day -1), at each postdose 
vital signs assessment, and at an appropriate time for all other days). Subjects will also be 
encouraged to voluntarily report AEs occurring at any other time through the EOS. 
AEs, whether volunteered, identified by the subject’s responses to HDYF? inquiries, or noted on 
PE, ECG, vital signs assessments, or laboratory tests, will be recorded throughout the study (ie, 
from signing of the ICF until EOS [or ET if the subject discontinues from the study and does not 
complete a follow-up 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 
call) are to be reported.  
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up call, all subjects must be followed until EOS. Subjects with AEs that are assessed as 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 16 of 76 
related to study drug by the Investigator (or designee) which are ongoing at EOS may continue to 
be followed until the symptoms or value(s) return to normal, or acceptable levels, as 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 Safety Follow-up phone call 7 days (± 2 days) after EOT or ET to 
determine if any AE has occurred since the EOT or ET visit. 
Section 7.2.5. – Physical Examination 
Previous text: 
A complete or abbreviated PE will be performed at the timepoints specified in Appendix 5. 
Complete PEs will evaluate general appearance and the following body systems/organs: 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; lymphatic; musculoskeletal/extremities; and neurological. Weight and height will be 
recorded (height only recorded during Screening). 
Now reads: 
A complete or abbreviated PE will be performed at the timepoints specified in Appendix 5. 
Complete PEs will evaluate general appearance and the following body systems/organs: 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; lymphatic; musculoskeletal/extremities; and neurological. Weight and height will be 
reported (height only reported during Screening). 
Section 9. – REFERENCES 
Previous text: 
1. Loxo Oncology, Inc. LOXO-292 – Investigator’s Brochure (Version 3.0). 05 April 2018. 
Now reads: 
1. Loxo Oncology, Inc. LOXO-292 – Investigator’s Brochure (Version 4.0). 01 October 2018. 
Appendix 1: Adverse Event Reporting (1.1 Definition of Adverse Events) 
Previous text: 
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. Events occurring 
in the framework of a clinical trial during drug-free and post-treatment periods, under placebo, or 
in a reference group receiving drug or nondrug therapy are also to be designated as AEs. 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 17 of 76 
Now reads: 
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. 
Appendix 1: Adverse Event Reporting (1.3 Pregnancy) 
Previous text: 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed during the study and for up to 90 days after study drug administration should 
be reported by the Investigator (or designee) via eFax to the Sponsor’s clinical safety 
representative within 24 hours of being notified. The Sponsor’s safety representative will then 
forward the Pregnancy Form to the Investigator for completion. 
Now reads: 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through EOS or ET (if the subject discontinues from the study and does not 
complete a follow up call) and for up to 90 days after study drug administration should be 
reported by the Investigator (or designee) via eFax to the Sponsor’s clinical safety representative 
within 24 hours of being notified. The Sponsor’s safety representative will then forward the 
Pregnancy Form to the Investigator for completion. 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 18 of 76 
Appendix 5: Schedule of Assessments 
Previous text: 
Study Procedures 
Screening 
(Days -29 to -2) 
Check-in  
(Day -1) 
 
Day 1 
 
Days 2 to 
10 
Discharge or ET 
Day 11 
Follow-up Phone Call  
~7 days post Discharge 
Confined to the Study Site 
 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Child-Pugh Class Scorea 
X 
X 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
Height/Weight/BMI 
X 
Xc 
 
 
 
 
Physical Examinationd 
X 
X 
X 
 
X 
 
12-Lead ECGe 
X 
X 
 
 
X 
 
Vital Signsf 
X 
X 
X 
X 
X 
 
HDYF? Inquiryg 
X 
X 
X 
X 
X 
X 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
LOXO-292 Dosei 
 
 
X 
 
 
 
Primary PK Blood Samplesj 
 
 
X 
X 
X 
 
Unbound Drug PK Blood Samplek 
 
 
X 
 
 
 
Clinical Laboratory Evaluationsl 
X 
X 
 
X 
X 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
Hemoglobin A1c Testm 
X 
 
 
 
 
 
Drug Screenn 
X 
X 
 
 
 
 
Prior and Concomitant Medicationso 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testp 
X 
X 
 
 
X 
 
Follicle-Stimulating Hormone Testq 
X 
 
 
 
 
 
Thyroid-Stimulating Hormone Test 
X 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; ET = early termination; HDYF? = How Do You Feel?; HIV = human immunodeficiency 
virus; PK = pharmacokinetic; SAE = serious adverse event. 
a Subjects with hepatic impairment only. Child-Pugh (CP) scores will be calculated at Screening and Check-in (Day -1); hepatically impaired subjects will be assigned to groups 
according to CP scores at Check-in (Day -1) to ensure stability of hepatic impairment and subject safety, as determined by the Investigator (or designee). 
b Interim medical history only. 
c Weight and BMI (based on Screening height) only. 
d A complete physical examination (PE) will be performed at Screening and Discharge (or ET). An abbreviated PE will be performed at Check-in (Day -1) and 1 hour postdose on 
Day 1.  
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 19 of 76 
e Electrocardiograms will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the 
scheduled blood draws. 
f Vital signs measurements (oral temperature, respiratory rate, and supine blood pressure and heart rate [HR]) will be obtained at Screening and Check-in (Day -1), predose, at 
2 hours (± 10 minutes) and 4 hours (± 10 minutes) postdose, and at each Study Day through Clinic Discharge (or ET). Vital signs measurements should be carried out prior to and 
as close as possible to having blood drawn. Blood pressure and HR will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. 
g An HDYF? inquiry performed at Screening (after the Informed Consent Form 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 recorded beginning at informed consent. 
i Dose administration is to be given during the morning of Day 1. 
j Primary PK blood samples will be collected prior to dosing (within 30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours 
postdose (Day 11). The allowed sampling window for PK blood samples will be the following: within 15 minutes prior to dosing for the predose sample timepoint; ± 5 minutes 
for sampling timepoints within the first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 minutes for the sampling timepoints ranging from 48 to 
240 hours. 
k For assessment of unbound plasma concentrations of LOXO-292, a blood sample will be collected predose (ie, within 15 minutes prior to dosing). 
l Clinical chemistry panel (fasted at least 8 hours), coagulation parameters, complete blood count, and urinalysis will be performed at Screening, Check-in (Day -1), 24 hours 
postdose (Day 2), Day 5, Day 8, and at Clinic Discharge (Day 11) or ET. 
m Hemoglobin A1c test performed at Screening for subjects with hepatic impairment only.  
n Alcohol breath test and drugs of abuse urine test. Results from the alcohol and drug tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
o Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 
30 days prior to study drug administration for prescription medications, and 14 days prior to study drug administration for nonprescription medications, will be recorded on the 
subject’s electronic Case Report Form. 
p Female subjects only. 
q Postmenopausal female subjects only. 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 20 of 76 
Now reads: 
Study Procedures 
Screening 
(Days -29 to -2) 
Check-in  
(Day -1) 
 
Day 1 
 
Days 2 to 
10 
Clinic 
Discharge/End of 
Treatment 
(EOT) Day 11 or 
Early 
Termination 
(ET) 
Follow-up Phone Call 
(EOS)  
7 (±2) days post EOT or 
ETs 
Confined to the Study Site 
 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Child-Pugh Class Scorea 
X 
X 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
Height/Weight/BMI 
X 
Xc 
 
 
 
 
Physical Examinationd 
X 
X 
X 
 
Xr 
 
12-Lead ECGe 
X 
X 
 
 
Xr 
 
Vital Signsf 
X 
X 
X 
X 
Xr 
 
HDYF? Inquiryg 
X 
X 
X 
X 
Xr 
X 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
LOXO-292 Dosei 
 
 
X 
 
 
 
Primary PK Blood Samplesj 
 
 
X 
X 
Xr 
 
Unbound Drug PK Blood Samplek 
 
 
X 
 
 
 
Clinical Laboratory Evaluationsl 
X 
X 
 
X 
Xr 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
Hemoglobin A1c Testm 
X 
 
 
 
 
 
Drug Screenn 
X 
X 
 
 
 
 
Prior and Concomitant Medicationso 
X 
X 
X 
X 
Xr 
X 
Serum Pregnancy Testp 
X 
X 
 
 
Xr 
 
Follicle-Stimulating Hormone Testq 
X 
 
 
 
 
 
Thyroid-Stimulating Hormone Test 
X 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ET = early termination; HDYF? = How Do 
You Feel?; HIV = human immunodeficiency virus; PK = pharmacokinetic; SAE = serious adverse event. 
a Subjects with hepatic impairment only. Child-Pugh (CP) scores will be calculated at Screening and Check-in (Day -1); hepatically impaired subjects will be assigned to groups 
according to CP scores at Check-in (Day -1) to ensure stability of hepatic impairment and subject safety, as determined by the Investigator (or designee). 
b Interim medical history only. 
c Weight and BMI (based on Screening height) only. 
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Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 21 of 76 
d A complete physical examination (PE) will be performed at Screening and EOT (or ET). An abbreviated PE will be performed at Check-in (Day -1) and 1 hour postdose on Day 
1.  
e Electrocardiograms will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the 
scheduled blood draws. 
f Vital signs measurements (oral temperature, respiratory rate, and supine blood pressure and heart rate [HR]) will be obtained at Screening and Check-in (Day -1), predose, at 
2 hours (± 10 minutes) and 4 hours (± 10 minutes) postdose, and at each Study Day through EOT (or ET). Vital signs measurements should be carried out prior to and as close as 
possible to having blood drawn. Blood pressure and HR will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. 
g An HDYF? inquiry performed at Screening (after the Informed Consent Form is signed), at Check-in (Day -1), at each postdose vital signs assessment, and at an appropriate time 
for all other days. 
h AEs and SAEs will be collected beginning at informed consent.  AEs will be recorded throughout the study (ie, from signing of the Informed Consent Form [ICF] until EOS, or 
until ET if the subject discontinues from the study and does not complete a follow-up call), either as subject medical history (if the event is reported as beginning prior to signing 
of the ICF or if the event occurs prior to study drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the 
event occurs after signing of the ICF but prior to study drug administration on Day 1 and is assessed by the Investigator [or designee]) as related to study procedures, or if the 
event occurs after study drug administration on Day 1 through EOT or ET regardless of relationship to study drug).  From EOT or ET through EOS, only AEs assessed as related 
to study drug are to be recorded.  All SAEs that develop from the time of ICF signing until EOS (or ET if the subject discontinues from the study and does not complete a follow-
up call) are to be reported. 
i Dose administration is to be given during the morning of Day 1. 
j Primary PK blood samples will be collected prior to dosing (within 30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours 
postdose (Day 11). The allowed sampling window for PK blood samples will be the following: within 15 minutes prior to dosing for the predose sample timepoint; ± 5 minutes 
for sampling timepoints within the first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 minutes for the sampling timepoints ranging from 48 to 
240 hours. 
k For assessment of unbound plasma concentrations of LOXO-292, a blood sample will be collected predose (ie, within 30 minutes prior to dosing). 
l Clinical chemistry panel (fasted at least 8 hours), coagulation parameters, complete blood count, and urinalysis will be performed at Screening, Check-in (Day -1), 24 hours 
postdose (Day 2), Day 5, Day 8, and at EOT (Day 11) or ET. 
m Hemoglobin A1c test performed at Screening for subjects with hepatic impairment only.  
n Alcohol breath test and drugs of abuse urine test. Results from the alcohol and drug tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
o Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 
30 days prior to study drug administration for prescription medications, and 14 days prior to study drug administration for nonprescription medications, will be recorded on the 
subject’s electronic Case Report Form. 
p Female subjects only. 
q Postmenopausal female subjects only. 
r EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 11.  ET is defined as when the subject is released from the 
CRU if the subject terminates the study early.  Vital sign, ECG, and safety laboratory results for serum chemistry, hematology, coagulation, and urinalysis are to be available for 
review by the Investigator or designee prior to subject release from the CRU at the EOT or ET visit. 
s To be performed 7 days (± 2 days) following EOT or ET.  End of Study (EOS) is defined as when the CRU contacts the subject by a follow-up phone call 7 days (± 2 days) after 
the EOT visit or ET visit to determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-292 (including subjects who 
terminate the study early) will be contacted. 
 
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Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
n
~ocuSigned by: 
,1J,.n.19IPI 
J ~hbn. 1 approve7nis document 
a};M(l)fil_Wf 121201201a a:o3 03 PM EST 
01A6C830EC5145B48DE60B79BAD69CBA 
Protocol Final, 19 December 2018 
20- Dec-18 I 17 :03:06 PST 
Date 
Page 22 of76 
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Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein._ 
Name, Qualifications 
Principal Investigat01 
Pl 
Protocol Final, 19 December 2018 
-----;I_
PI _ 
_:--
Date 
. 
Page 23 of76 
Page 24 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
[ 
Name, Qualifications 
Principal Investigator 
Protocol Final, 19 December 2018 
Pl 
Date 
Page 23 of76 
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Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
[ 
Name, Qualifications 
Principal Investigator 
Protocol Final, 19 December 2018 
] 
Date 
Page 23 of76 
Page 26 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-l 8022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Pl 
Name, Qualific 
Date 
o .. ~ .c_;_e.oJ •~4 
Pl 
Protocol Final. 19 December 20 I 8 
Page 23 of76 
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Protocol 
Covance Study: 8393612 
CONFIDENTCAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to comluct the study as described herein. 
Name, Qualifications 
Principal fnvestigator 
Pl 
Protocol Final, 19 December 20 I 8 
Date 
Page 23 of76 
Page 28 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Pl 
Name, Qualificationsr l 
Principal Investigator ------
Protocol Final, 19 December 2018 
s 
Page 23 of76 
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Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Pl 
Pl 
Name, Quali 
Date 
Principal ln, 
Protocol Final, 19 December 20 I 8 
Page 23 of76 
Page 30 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
STUDY IDENTIFICATION 
Sponsor 
Sponsor's Study Contact 
Covance Medical Monitor 
Sponsor's Medical Contact 
Bioanalytical Laborat01y 
Protocol Biostatistician 
Protocol Phannacokineticist 
Protocol Final, 19 December 2018 
Loxo Oncology, Inc. 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
(650) 989-8051 (Main Telephone No.) 
Pl 
Clinical Operations 
~---~-~ 
Loxo Oncology, Inc. 
(Mobile Telephone No.) 
(Alternate Contact No.) 
MD 
Clinical Pharmacology 
----------
Covance Clinical Research Unit, Inc. 
I 
(Office Telephone No.) 
=.::;;:====:::.. (Alternate Contact No.) 
to Loxo Oncology, Inc. 
(Mobile Telephone No.) 
~=====.:.----, 
Alturas Analytics, Inc. 
13 24 Alturas Drive 
Moscow, Idaho 83843 
(208) 883-3400 (Main Telephone No.) 
I 
Pl 
MSc 
Covance Early Clinical Biomettics 
Pl 
!(Office Telephone No.) 
Pl 
Pl 
I MS 
---
Medical & Scientific Affairs, 
Clinical Phaimacology Services 
Covance Inc. 
I 
Page 24 of76 
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Protocol 
Covance Study: 8393612 
Protocol Medical Writer 
Protocol Final, 19 December 2018 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
= ====~(O_ffi_1_c_e Telephone No.) 
Covance Medical Writing 
Pl 
(Office Telephone No.) 
Page 25 of 76 
Page 32 of 163 


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
Page 26 of 76 
SYNOPSIS 
Title of study: Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and 
Pharmacokinetic Study of LOXO-292 Administered to Fasted Hepatically Impaired Male and 
Female Subjects and Fasted Matched-control Healthy Subjects 
Objectives:  
The objectives of this study are:  
• 
To evaluate the pharmacokinetic (PK) profile of LOXO-292 in subjects with impaired 
hepatic function compared to matched-control healthy subjects;  
• 
To evaluate safety and tolerability of LOXO-292 in subjects with impaired hepatic function 
and matched-control healthy subjects. 
Study design: 
This study will be an open-label, nonrandomized, multi-center, single-dose, parallel-group, safety, 
tolerability, and PK study of LOXO-292 administered at a dose of 160 mg in fasted 
matched-control healthy males and females with normal hepatic function compared to fasted, 
hepatically impaired subjects. 
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up to 8 
subjects within each of the mild, moderate, and severe impairment groups, per Child-Pugh [CP] 
classification – assessed at Screening and Check-in [Day -1]), and approximately 8 to 16 subjects 
with normal hepatic function are enrolled. Subjects will be enrolled within the following groups 
based on their CP score at Screening and assuming no change in underlying hepatic status at Check-
in (Day -1) as judged by the Investigator (or designee), the Covance Medical Monitor, and the 
Sponsor: 
• 
Group 1: Matched-control healthy subjects with normal hepatic function; 
• 
Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• 
Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• 
Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15). 
A parallel design strategy will be adopted for the hepatic impairment groups, with interim reviews 
of safety data after the first 4 subjects from Group 2 (mild hepatic impairment subjects), the first 
4 subjects from Group 3 (moderate hepatic impairment subjects), and the first 2 subjects from 
Group 4 (severe hepatic impairment subjects) are enrolled and have completed all study-related 
assessments including the Follow-up phone call. Enrollment and dosing for remaining subjects in 
any group may occur after the interim data for that group are reviewed and the Covance Medical 
Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed with dosing. If 
available, PK data and matched-control healthy subject data may also be used during the interim 
review. 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by age 
(± 10 years), body mass index (BMI; ± 20%), and sex to the enrolled hepatic impairment subject(s). 
Should another hepatic impairment subject be identified with whom an already enrolled healthy 
subject is demographically matched, the healthy subject may also be matched with that impaired 
subject as long as the impaired subject is in a different hepatic impairment group. Each subject with 
normal hepatic function may be matched with up to 1 subject within each hepatic impairment 
group. 
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 site on Day -1 (Check-in). Replacement subjects 
may be enrolled only if deemed necessary by the Sponsor.  
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Protocol 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
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Subjects will be confined at the clinical site from the time of Check-in (Day -1) until EOT on 
Day 11 upon completion of all PK and safety assessments or ET if the subject discontinues. A 
Follow-up phone call will occur 7 days (± 2 days) after EOT or ET. 
On the morning of Day 1, after at least a 2-hour fast, an oral dose of 160 mg LOXO-292 
administered as two 80-mg capsules will be given with 240 mL water. No food will be allowed for 
up to 1 hour postdose. Glucose tablets may be administered as needed for treatment of 
hypoglycemia. 
In this study, physical examinations (PEs), 12-lead electrocardiograms (ECGs), vital signs, How Do 
You Feel? inquiries, clinical chemistry panel, coagulation parameters, complete blood count (CBC), 
and urinalysis (UA; Appendix 2) will be performed at Screening and at specified times during the 
study (for specific timepoints and details on each study variable, refer to Appendix 5). Adverse 
events (AEs) and serious adverse events (SAEs) will be collected beginning at informed consent. 
AEs will be reported throughout the study (ie, from signing of the Informed Consent Form [ICF] 
until End of Study [EOS], or until Early Termination [ET] if the subject discontinues from the study 
and does not complete a follow-up call), either as subject medical history (if the event is reported as 
beginning prior to signing of the ICF or if the event occurs prior to study drug administration on 
Day 1 and is assessed as not related to study procedures by the 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 End of Treatment [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 call) are to be reported. 
Study Completion is defined as the time of the last subject’s Follow-up phone call. 
Interim review: 
Interim reviews of safety data will be conducted for each group when the first 4 subjects from 
Group 2 (mild hepatic impairment subjects) are enrolled and have completed the study, when the 
first 4 subjects from Group 3 (moderate hepatic impairment subjects) are enrolled and have 
completed the study, and when the first 2 subjects from Group 4 (severe hepatic impairment 
subjects) are enrolled and have completed the study. These safety data will include AEs and SAEs, 
vital signs, PEs, ECGs, and clinical laboratory tests. If available, PK data and matched-control 
healthy subject data may also be used during the review. Enrollment and dosing for remaining 
subjects in any group may occur after the interim data for that group are reviewed and if the 
Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed with 
dosing. 
Following the interim review of safety data for each group, the dose level may be decreased for the 
remaining subjects in any group pending discussion and agreement between the Covance Medical 
Monitor, Investigator (or designee), and/or Sponsor. If dose is decreased, it will also be decreased 
for the impaired subjects’ respective matched-control healthy subjects. 
Number of subjects: 
A total of up to 24 subjects with hepatic impairment (up to 8 subjects with mild impairment, up to 8 
subjects with moderate impairment, and up to 8 subjects with severe impairment, per CP 
classification) and approximately 8 to 16 matched-control healthy subjects with normal hepatic 
function will be enrolled in the study with the goal of having at least 6 subjects from each hepatic 
impairment group and at least 6 subjects with normal hepatic function complete the study. Subjects 
who withdraw or drop out of the study may be replaced if deemed necessary by the Sponsor. 
Diagnosis and main criteria for inclusion: 
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Protocol 
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Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
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Male subjects and female subjects of nonchildbearing potential, between 18 and 65 years of age, 
inclusive, at Screening, and within BMI range 18.5 to 40.0 kg/m2, inclusive. Subjects will be in 
good general health, except for additional specific inclusion criteria related to subjects with hepatic 
impairment, based on medical history, PE findings, vital signs, ECG, and clinical laboratory tests at 
Screening and Check-in (Day -1), as determined by the Investigator (or designee). 
Investigational products, dose, and mode of administration: 
LOXO-292 will be supplied by Loxo Oncology as 80-mg and 20-mg capsules for oral 
administration. 
Subjects will receive a single dose of LOXO-292, given orally as two 80-mg capsules. If dosing is 
decreased following the interim review of safety data, subjects will be given appropriate doses 
using a combination of 80-mg and 20-mg capsules. 
Duration of subject participation in the study: 
Planned Enrollment/Screening Duration: up to 28 days (Day -29 to Day -2). 
Length of Confinement: a total of 12 days (11 nights), from the time of Check-in (Day -1) through 
the 240-hour PK blood draw and end of study assessments. 
Follow-up Phone Call: 7 days (± 2 days) after EOT or ET. 
Planned Study Conduct Duration: approximately 47 days. 
Criteria for evaluation: 
Pharmacokinetics: 
Serial PK blood samples for the analysis of plasma LOXO-292 concentration levels will be 
collected from predose through 240 hours postdose.  
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-292: maximum observed concentration (Cmax), time to maximum observed 
concentration (tmax), area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), percentage 
extrapolation for AUC (%AUCextrap), apparent terminal elimination rate constant (λz), apparent 
terminal elimination half-life (t1/2), apparent systemic clearance (CL/F), apparent volume of 
distribution during the terminal phase (Vd/F), and mean residence time (MRT).  
In addition, a single blood sample will be collected predose to determine the fraction unbound (fu) 
of LOXO-292 in plasma and, whenever possible, the following PK parameters will be calculated 
for unbound LOXO-292 using fu: unbound Cmax (Cmax,u), unbound AUC0-t (AUC0-t,u), unbound 
AUC0-∞ (AUC0-∞,u), unbound CL/F (CL/F,u), and unbound Vd/F (Vd/F,u).  
Safety: 
Safety and tolerability will be assessed by monitoring AEs, performing PEs and clinical laboratory 
tests (including creatine kinase [CK]), measuring vital signs, and recording ECGs. 
Sample size: 
The sample size chosen for this study was based upon precedent set by other PK studies of similar 
nature and was not based on power calculations to detect statistically significant differences among 
groups.  At least 6 subjects each per hepatic function group are planned to complete the study. This 
is considered a sufficient sample size to evaluate the PK of LOXO-292 under various degrees of 
hepatic function. If necessary, as determined by the Sponsor, subjects who fail to complete the 
treatment or have insufficient PK data may be replaced. 
Statistical methods: 
Pharmacokinetics:  
All subjects who have received a dose of LOXO-292, have at least 1 quantifiable plasma 
concentration, and for whom at least 1 PK parameter can be computed will be included in the PK 
Population. Plasma concentrations and PK parameters will be summarized by hepatic function 
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Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 19 December 2018  
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using descriptive statistics (number, arithmetic mean, standard deviation, coefficient of variation 
[CV%], geometric mean, geometric CV%, median, minimum, and maximum). In addition, 
summary statistics for protein binding will be tabulated by hepatic function group. 
The primary analysis planned for this study is to evaluate the PK of LOXO-292 after a single dose 
in subjects with mild, moderate, or severe hepatic impairment, compared to subjects with normal 
hepatic function. The following statistical methodology will be used, based on 1 to 1 matching: 
The 90% confidence interval of Cmax and AUCs for the ratio between each level of impaired hepatic 
function versus the control group will be presented. Furthermore, if an individual healthy subject is 
matched to 1 subject from any or all hepatic impairment groups, then the primary PK parameters, 
Cmax and AUCs, will be analyzed using the paired t-test to assess the difference between each 
impaired group and the healthy group. The p-value assessing the difference between each impaired 
group and the healthy group will be presented. For cases where 1 to 1 matching between the healthy 
and hepatic impaired groups are not achieved, an analysis of variance will be conducted. The 
specific procedures will be documented in the Statistical Analysis Plan. 
Safety:  
All subjects who receive a dose of LOXO-292 and have at least 1 postdose safety assessment will 
be included in the safety analyses. All safety assessments, including AEs and SAEs, vital signs 
measurements, clinical laboratory (including CK) results, PE results, concomitant medications, and 
ECG interpretations, will be tabulated and summarized where possible, using descriptive 
methodology by hepatic function group and, as needed, by timepoint. No formal statistical analyses 
are planned for the safety data. Interim reviews of safety data are planned for the first 4 subjects 
from Group 2 (mild hepatic impairment subjects), the first 4 subjects from Group 3 (moderate 
hepatic impairment subjects), and the first 2 subjects from Group 4 (severe hepatic impairment 
subjects).  
Page 36 of 163


Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 3 9 3 6 1 2 
Pr ot oc ol Refere nce: L O X O -R E T - 1 8 0 2 2 
Pr ot oc ol Fi nal, 1 9 Dece m ber 2 0 1 8  
Pa ge 3 0 of 7 6 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1 
S U M M A R Y O F A M E N D E D P R O T O C O L C H A N G E S  .......................................................... 2 
S P O N S O R A P P R O V A L  ......................................................................................................... 2 2 
I N V E S TI G A T O R A G R E E M EN T ........................................................................................... 2 3 
S T U D Y I D E N TI FI C A TI O N  ................................................................................................... 2 4 
S Y N O P SI S  ............................................................................................................................... 2 6 
T A B L E O F C O N T E N T S  ......................................................................................................... 3 0 
LI S T O F T A B L E S A N D FI G U R E S ........................................................................................ 3 2 
LI S T O F A B B R E VI A TI O N S .................................................................................................. 3 3  
1.  
I N T R O D U C TI O N ........................................................................................................... 3 5 
1. 1.  
Bac k gr o u n d ............................................................................................................ 3 5  
1. 2.  
S u m mar y of N o ncli nical St u dies ........................................................................... 3 5  
1. 3.  
S u m mar y of Cli nical St u dies  ................................................................................. 3 6 
1. 4.  
St u d y Rati o nale ...................................................................................................... 3 7  
1. 5.  
Be nefit -ris k Assess me nt ......................................................................................... 3 8 
2.  
O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................. 3 8 
2. 1.  
O bjecti ves  .............................................................................................................. 3 8 
2. 2.  
E n d p oi nts ............................................................................................................... 3 8  
3.  
I N V E S TI G A TI O N A L P L A N .......................................................................................... 3 9 
3. 1.  
O verall St u d y Desi g n a n d Pla n .............................................................................. 3 9  
3. 2.  
C hil d -P u g h Classificati o n  ...................................................................................... 4 1 
3. 3.  
Disc ussi o n of St u d y Desi g n ................................................................................... 4 1  
3. 4.  
Selecti o n of D oses i n t he St u d y ............................................................................. 4 2  
4.  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ..................................................................... 4 2 
4. 1.  
Scree ni n g Pr oce d ures ............................................................................................. 4 2  
4. 2.  
C hec k -i n Pr oce d ures ( Da y - 1) ............................................................................... 4 3 
4. 3.  
I ncl usi o n Criteria ................................................................................................... 4 4 
4. 4.  
E xcl usi o n Criteria  .................................................................................................. 4 6 
4. 5.  
S u bject N u m ber a n d I de ntificati o n  ........................................................................ 5 0 
4. 6.  
Re m o val of S u bjects fr o m St u d y Partici pati o n ...................................................... 5 1  
4. 7.  
Matc hi n g Pr ocess  ................................................................................................... 5 2 
5.  
S T U D Y T R E A T M E N T S  ................................................................................................. 5 2 
5. 1.  
Descri pti o n, St ora ge, Pac ka gi n g, a n d La beli n g ..................................................... 5 2  
5. 2.  
St u d y Treat me nt A d mi nistrati o n  ............................................................................ 5 2 
5. 3.  
Ra n d o mizati o n ....................................................................................................... 5 3  
5. 4.  
Bli n di n g.................................................................................................................. 5 3  
5. 5.  
Treat me nt C o m plia nce  ........................................................................................... 5 3 
Pa ge 3 7 of 1 6 3


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Protocol Final, 19 December 2018  
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5.6. 
Drug Accountability...............................................................................................53 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................54 
6.1. 
Concomitant Therapies ..........................................................................................54 
6.2. 
Diet, Fluid, and Activity Control ...........................................................................54 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................55 
7.1. 
Pharmacokinetic Assessments ...............................................................................55 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................55 
7.1.2. 
Analytical Methodology ..............................................................................55 
7.2. 
Safety and Tolerability Assessments .....................................................................56 
7.2.1. 
Adverse Events ............................................................................................56 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................57 
7.2.3. 
Vital Signs ....................................................................................................57 
7.2.4. 
12-Lead Electrocardiogram .........................................................................58 
7.2.5. 
Physical Examination...................................................................................58 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................58 
8.1. 
Determination of Sample Size ...............................................................................58 
8.2. 
Interim Analysis .....................................................................................................58 
8.3. 
Analysis Populations ..............................................................................................59 
8.3.1. 
Study Populations ........................................................................................59 
8.4. 
Pharmacokinetic Analysis ......................................................................................59 
8.5. 
Statistical Analysis of Pharmacokinetic Data ........................................................60 
8.6. 
Statistical Analyses of Safety Data ........................................................................61 
8.7. 
Data Handling and Record Keeping ......................................................................61 
8.8. 
Quality Control and Quality Assurance .................................................................61 
9. 
REFERENCES ................................................................................................................63 
10. APPENDICES .................................................................................................................64 
Appendix 1: Adverse Event Reporting ..............................................................................65 
1.1 
Definition of Adverse Events .................................................................................65 
1.2 
Categorization of Adverse Events .........................................................................65 
1.3 
Pregnancy ...............................................................................................................66 
1.4 
Definition of Serious Adverse Events ....................................................................67 
1.5 
Unexpected Adverse Drug Reaction ......................................................................67 
1.6 
Reporting................................................................................................................67 
Appendix 2: Clinical Laboratory Evaluations ...................................................................69 
Appendix 3: Total Blood Volume ......................................................................................70 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations ............................71 
Appendix 5: Schedule of Assessments ..............................................................................75 
 
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Protocol Final, 19 December 2018  
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LIST OF TABLES AND FIGURES 
Table 1 
Child-Pugh Assessment of Hepatic Function ............................................41 
Table 2 
Subject Group and Number of Subjects.....................................................51 
Table 3 
Study Drug .................................................................................................52 
 
Figure 1 
Study Design Schematic ............................................................................40 
 
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Protocol Final, 19 December 2018  
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
AUC0-∞,u 
unbound 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 
AUC0-t,u 
unbound area under the concentration-time curve from time 0 to the last 
measurable concentration 
AV 
atrioventricular 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CL/F 
apparent systemic clearance 
CL/F,u 
unbound apparent systemic clearance 
Cmax 
maximum observed concentration 
Cmax,u 
unbound maximum observed concentration 
CP 
Child-Pugh 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Evaluation Agency 
FDA 
Food and Drug Administration 
fu 
fraction unbound 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
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Protocol Final, 19 December 2018  
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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IC50 
inhibitory concentration 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board  
IUD 
intrauterine device 
λZ 
apparent terminal elimination rate constant 
LFT 
liver function test 
LSM 
least squares mean 
MRT 
mean residence time 
PCR 
polymerase chain reaction 
PE 
physical examination(s) 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve  
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell 
RET 
rearranged during transfection 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
apparent terminal elimination half-life 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed concentration 
UA 
urinalysis 
Vd/F 
apparent volume of distribution during the terminal phase  
Vd/F,u 
unbound apparent volume of distribution during the terminal phase 
WBC 
white blood cell 
 
 
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Protocol Final, 19 December 2018  
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1. INTRODUCTION 
Refer to the current Investigator’s Brochure (IB)1 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. 
Background 
LOXO-292 is a small molecule and selective inhibitor of the rearranged during transfection 
(RET) receptor tyrosine kinase designed to competitively block the adenosine triphosphate 
binding site of the kinase. LOXO-292 was at least 250-fold more selective for RET than for 98% 
of 329 other kinases tested in a large in vitro screen. Consistent with such a high degree of 
selectivity, LOXO-292 caused significant cytotoxicity in human cancer cell lines that harbored 
endogenous, clinically relevant RET gene alterations but was much less cytotoxic against human 
cancer cell lines without RET alterations. Potent and selective inhibition of RET may provide 
clinical benefit to subjects with malignancies due to oncogenic alterations in RET or with other 
mechanisms of increased RET activity. 
1.2. 
Summary of Nonclinical Studies 
Cardiac safety of LOXO-292 was evaluated in a Good Laboratory Practice (GLP) in vitro assay 
for human ether-a-go-go related gene (hERG) activity, in a GLP in vivo study in conscious 
telemetry-instrumented minipigs, and in a GLP 28-day repeat-dose toxicology study (with 
electrocardiogram [ECG] monitoring) in minipigs. LOXO-292 had a 50% inhibitory 
concentration (IC50) value of 1.1 μM in the GLP hERG assay, which is approximately 14- and 
6-fold higher than the predicted maximum unbound concentration at the dose of 80 mg and 
160 mg respectively twice daily (BID). There were no LOXO-292-related changes in any 
cardiovascular endpoints including QT interval corrected for heart rate (QTc) at doses up to 
12 mg/kg in the safety pharmacology cardiovascular study in conscious minipigs. Furthermore, 
there were no LOXO-292-related ECG changes in the 28-day repeat-dose toxicity study in 
minipigs at the high dose of 12 mg/kg. Together, these data indicate that LOXO-292 has a low 
risk of inducing delayed ventricular repolarization, prolongation of the QTc interval, and 
unstable arrhythmias. 
Administration of LOXO-292 at single doses up to 45 mg/kg in male rats had no effect on 
respiratory function. 
Potential effects of LOXO-292 on the central nervous system were evaluated as part of the 
GLP 28-day repeat-dose study in rats, in functional observational battery tests and locomotor 
activity assessments. Findings were limited to animals receiving the high dose on Week 4 of the 
dosing phase, and were attributed to poor general body condition and weight changes associated 
with LOXO-292 administration rather than specific neurological effects. Additionally, no 
microscopic abnormalities in neuronal tissues were found. 
In toxicology studies of LOXO-292 that were conducted in the rat and minipig, the primary 
pathologic findings for both species were in the tongue, pancreas, bone marrow and lymphoid 
tissues; while the gastrointestinal tract and ovaries were target tissues in minipig. Other target 
tissues identified in the rat included: multi-tissue mineralization, physeal cartilage, incisor teeth, 
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Protocol Final, 19 December 2018  
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lung, Brunner’s gland, and possibly liver. Assessment of doses associated with 
moribundity/death revealed a steep dose response curve for both species. LOXO-292 was not 
mutagenic in the GLP bacterial mutation assay. When evaluated in two in vitro assays, 
LOXO-292 was not genotoxic. LOXO-292 was not found to be phototoxic when evaluated in an 
in vitro neutral red uptake phototoxicity assay. 
In repeated dose toxicity studies in Sprague-Dawley Rats, minor changes suggestive of hepatic 
effects were higher alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in 
males (≥ 20 mg/kg/day) and females (≥ 50 mg/kg/day), higher aspartate aminotransferase (AST) 
levels in those receiving the high-dose (both sexes), and a higher cholesterol concentration in 
males (≥ 20 mg/kg/day). Reversible, LOXO-292-related decreases in liver and thymus weights 
occurred in males at 75 and 45 mg/kg/day, respectively. None of these minor changes were 
correlated to any liver findings microscopically, suggesting minor functional alterations of the 
liver rather than overt hepatocellular injury. ALP levels were also increased in Göttingen 
minipigs administered 5 or 12 mg/kg/day in repeated dose toxicity studies; however, this change 
had no associated clinical or microscopic findings and was considered not adverse. 
Based on preclinical pharmacology experiments with human cancer cells in vitro and in murine 
xenograft models, meaningful inhibition of RET in tumors is expected to be achievable with oral 
dosing regimens ≥ 40 mg/day. 
Based on the nonclinical profile, including results from animal toxicology studies, theoretical 
risks of human exposure to LOXO-292 include the following: loss of appetite, decrease in body 
weight, increase in total white blood cells, neutrophils, and monocytes, decrease in albumin, 
increase in globulin, decreased albumin:globulin ratio, decrease in total protein, increased body 
temperature, lethargy, increase in cholesterol and triglycerides, increase in phosphorus, changes 
in taste sensation and/or development of xerostomia, gastrointestinal symptoms/signs: nausea, 
vomiting, loose stools, abdominal discomfort, decreases in red cell mass (red blood cell, 
hemoglobin, hematocrit) and reticulocytes, decrease in platelets, increases in liver function tests 
(ALP, AST, and ALT). 
LOXO-292 has been given orally and intravenously to mice, rats, dogs, and minipigs. Oral PK 
has also been determined in the monkey. LOXO-292 was absorbed and bioavailable in all 
species tested. Solubility studies and pharmacokinetic studies suggest that the pharmacokinetic 
exposure of LOXO-292 may be reduced by proton pump inhibitors and other antacids. 
LOXO-292 appears to be metabolized primarily by cytochrome p450 (CYP)3A4, but at 
therapeutically relevant exposures, it is not anticipated to inhibit or induce drug-metabolizing 
enzymes. LOXO-292 is also a substrate for the Breast Cancer Resistance Protein. 
Refer to the current IB1 for detailed background information on LOXO-292. 
1.3. 
Summary of Clinical Studies 
LOXO-292 is currently being studied in an ongoing global Phase 1/2 study (Study 
LOXO-RET-17001) in patients with advanced solid tumors including RET fusion-positive 
NSCLC, RET-mutant medullary thyroid carcinoma, and other tumors with increased RET 
activity. The starting dose of LOXO-292 was 20 mg once daily. As of July 19, 2018 data cut-off 
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Protocol Final, 19 December 2018  
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date, safety data was available from 153 patients with 240 mg BID as the highest dose 
administered. As of this date, two dose-limiting toxicities of tumor lysis syndrome and Grade 3 
thrombocytopenia at the 240 mg BID dose level have been reported. The most frequently 
reported treatment-emergent adverse events (TEAEs; > 10% of patients), were dry mouth 
(20.3%; 14.4% related), diarrhea (15.7%; 7.2% related), fatigue (15.7%; 11.8% related), 
constipation (12.4%; 2.6% related), headache (11.1%; 3.3% related), and hypertension (10.5%; 
3.9% related). Regarding TEAEs ≥Grade 3, eight patients experienced Grade 3 TEAEs that were 
judged by the Investigator as related to study drug. Three patients have died within 28 days of 
their last dose of study drug, no deaths have been attributed to study drug. A small number of 
patients have experienced Grade 3 or higher liver function test (LFT) abnormalities, considered 
related to study drug, occurring between 20 to 56 days after starting LOXO-292. These changes 
were asymptomatic and resolved with dose interruption, with LOXO-292 resumed at a lower 
dose following normalization of the LFTs. 
As of August 24, 2018, PK data were available from 141 patients (from the global Phase 1/2 
study). LOXO-292 is absorbed after oral administration with a median time to maximum 
concentration (tmax) of approximately 2 hours. Although the PK sampling of LOXO-292 was not 
long enough to adequately characterize AUC0-∞, the half-life appears to be approximately 
20 hours. Low concentrations of LOXO-292 were recovered as unchanged drug in urine 
indicating that the kidney contributes to overall clearance. 
As of September 14, 2018, Loxo Oncology has initiated 16 single patient protocols, Special 
Access Scheme, or Temporary Authorization Use cases to provide access to LOXO-292 for 
patients with clinical need not meeting eligibility criteria for the ongoing global Phase 1/2 study. 
To date, no TEAEs have been attributed to study drug for these patients. 
Preliminary PK data available from ongoing studies (LOXO-RET-18014 and 
LOXO-RET-18015) being conducted in healthy subjects indicate that LOXO-292 has an 
estimated apparent terminal elimination half-life (t1/2) of approximately 24 hours after a single 
dose. 
Refer to the current IB1 for detailed and updated background clinical study information on 
LOXO-292. 
1.4. 
Study Rationale 
Liver disease can cause alterations in drug disposition and pharmacokinetics (PK). Such 
alterations can reduce the clearance of drugs eliminated by hepatic metabolism or biliary 
excretion and affect plasma protein binding, which in turn could influence the processes of 
absorption, distribution, and elimination. Refer to the IB1 for detailed background information on 
LOXO-292. Results from this study will provide information on the safety, tolerability, and 
exposure of LOXO-292 in participants with hepatic impairment and participants with normal 
hepatic function.  
This study is being conducted to provide information to develop dosing recommendations for 
LOXO-292 in subjects with hepatic impairment. The current study will be carried out in subjects 
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with hepatic impairment according to 3 different Child-Pugh (CP) categories2,3 (mild, moderate, 
and severe impairment) and also in matched-control healthy subjects. 
There are several methods used to categorize the severity of hepatic impairment. Despite its 
imperfections, the CP classification is the most widely used and is an acceptable method 
supported by regulatory agencies (including the United States Food and Drug Administration 
[FDA] and the European Medicines Evaluation Agency [EMA]). The FDA and EMA Guidelines 
recommend that the “number of subjects enrolled should be sufficient to detect clinically 
relevant PK differences.” In the current study, up to 8 subjects with mild hepatic impairment, up 
to 8 subjects with moderate hepatic impairment, up to 8 subjects with severe hepatic impairment, 
and approximately 8 to 16 healthy subjects with normal hepatic function will be enrolled. The 
PK and safety profiles between each hepatic impairment group and their matching (age, sex, and 
body mass index [BMI]) healthy subjects will be compared. 
1.5. 
Benefit-risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment of 
their medical status) from participating in the study. The risks of participation are primarily those 
associated with adverse reactions to the study treatments, although there may also be some 
discomfort from collection of blood samples and other study procedures. More information about 
the known and expected benefits, risks, and reasonably anticipated AEs associated with 
LOXO-292 may be found in the current IB.1  
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The objectives of this study are: 
• To evaluate the PK profile of LOXO-292 in subjects with impaired hepatic function 
compared to matched-control healthy subjects; 
• To evaluate safety and tolerability of LOXO-292 in subjects with impaired hepatic 
function and matched-control healthy subjects. 
2.2. 
Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-292: maximum observed concentration (Cmax), (tmax, area under the 
concentration-time curve (AUC) from Hour 0 to the last measurable concentration (AUC0-t), 
AUC extrapolated to infinity (AUC0-∞), percentage extrapolation for AUC (%AUCextrap), 
apparent terminal elimination rate constant (λz), apparent terminal elimination half-life (t1/2), 
apparent systemic clearance (CL/F), apparent volume of distribution during the terminal phase 
(Vd/F), and mean residence time (MRT).  
In addition, a single blood sample will be collected predose to determine the fraction unbound 
(fu) of LOXO-292 in plasma and, whenever possible, the following PK parameters will be 
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calculated for unbound LOXO-292 using fu: unbound Cmax (Cmax,u), unbound AUC0-t (AUC0-t,u), 
unbound AUC0-∞ (AUC0-∞,u), unbound CL/F (CL/F,u), and unbound Vd/F (Vd/F,u). 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
(PEs) and clinical laboratory tests (including creatine kinase [CK]), measuring vital signs, and 
recording ECGs. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This study is an open-label, nonrandomized, multi-center, single-dose, parallel-group study to 
determine the PK, safety, and tolerability of LOXO-292 administered orally at a dose of 160 mg 
to fasted adult males and females with mild, moderate, or severe impaired hepatic function and 
healthy subjects with normal hepatic function. Hepatic function will be classified based on the 
CP classification of hepatic impairment2,3 (Table 1). 
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up to 8 
subjects with mild impairment, up to 8 subjects with moderate impairment, and up to 8 subjects 
with severe impairment, per CP classification – assessed at Screening and verified at Check-in 
[Day -1]) and approximately 8 to 16 subjects with normal hepatic function are enrolled, with the 
goal of having at least 6 subjects from each hepatic impairment group and at least 6 subjects with 
normal hepatic function complete the study. Subjects will be enrolled within the following 
groups based on their CP score at Screening and Check-in (Day -1) as judged by the Investigator 
(or designee), Covance Medical Monitor, and Sponsor: 
• Group 1: Matched-control healthy subjects with normal hepatic function; 
• Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15); 
A parallel design strategy will be adopted for the hepatic impairment groups. An interim review 
of the safety data will be conducted as detailed in Section 8.2. 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by age 
(± 10 years), BMI (± 20 %), and sex to the completed hepatic impairment subject(s). Should 
another hepatic impairment subject be identified with whom an already enrolled healthy subject 
is demographically matched, the healthy subject may also be matched with that impaired subject 
as long as the impaired subject is in a different hepatic impairment group. Each subject with 
normal hepatic function may be matched with up to 1 subject within each hepatic impairment 
group. 
The schematic of the study design is displayed in Figure 1. 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.  
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Subjects will be confined at the clinical site from the time of Check-in (Day -1) until EOT on 
Day 11 upon completion of all PK and safety assessments or ET if the Subject discontinues. 
A Follow-up phone call will occur 7 days (± 2 days) after EOT or ET.  
On the morning of Day 1, after at least a 2-hour fast, a single oral dose of 160 mg LOXO-292 
will be administered with 240 mL water. No food will be allowed for up to 1 hour postdose. 
Glucose tablets may be administered as needed for treatment of hypoglycemia. For instructions 
regarding food and water intake, please refer to Section 6.2. 
Figure 1 
Study Design Schematic 
 
ICF = Informed Consent Form; PK = pharmacokinetic. 
Note: Single oral dose of LOXO-292 at 160 mg administered orally after at least a 2-hour fast. 
In this study, PEs, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) inquiries, clinical 
chemistry panel, coagulation parameters, complete blood count (CBC), and urinalysis (UA; 
Appendix 2) will be performed at specified times during the study (for specific timepoints and 
details on each study variable, refer to Appendix 5). AEs and serious AEs (SAEs) will be 
collected beginning at informed consent. AEs will be reported throughout the study (ie, from 
signing of the ICF until End of Study [EOS], or until Early Termination [ET] if the subject 
discontinues from the study and does not complete a follow-up call), either as subject medical 
history (if the event is reported as beginning prior to signing of the ICF or if the event occurs 
prior to study drug administration on Day 1 and is assessed as not related to study procedures by 
the 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 End of Treatment [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 call) are to be reported.  
Pharmacokinetic samples will be obtained through 240 hours postdose. A study flow chart is 
presented in Appendix 5. Study Completion is defined as the time of the last subject’s Follow-up 
phone call. 
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Screening 
Study Treatment (Days -1 to 11) 
Days -29 to -2 
Check-in: 
Day -1 
Dosing: Day 1 
Discharge: 
Day 11 
PK sampling: Days 1 to 11 (0-240 hours postdose) 
Safety assessments: From signing of the ICF to Follow-up phone call 
Follow-up 
7 (± 2) days 
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3.2. 
Child-Pugh Classification 
Per FDA Guidance,4 hepatic impairment will be classified as mild, moderate, or severe using the 
CP System2,3 (Table 1), and the parameters to determine the CP class for each subject with 
hepatic impairment will be collected at Screening and Check-in (Day -1). 
Table 1 
Child-Pugh Assessment of Hepatic Function 
 
Points Scored for Observed Findings 
 
1 
2 
3 
Hepatic Encephalopathy gradea 
0 
1 or 2c 
3 or 4c 
Ascitesb 
Absent 
Slight 
Moderate 
Serum bilirubin, mg/dL (µmol/L) 
<2 (<34) 
2 to 3 (34 to 50) 
>3 (>50) 
Serum albumin, g/dL (g/L) 
>3.5 (>35) 
2.8 to 3.5 (28 to 35) 
<2.8 (<28) 
International normalized ratio 
<1.7 
1.7 to 2.3 
>2.3 
Chronic Hepatic Impairment is classified into Child-Pugh (CP) class A to C, employing the added score of the 5 parameters in 
the table above.  
Mild Impairment (CP-A): 5 or 6 points; Moderate Impairment (CP-B): 7 to 9 points; Severe Impairment (CP-C): 10 to 15 points. 
a In this study, hepatic encephalopathy is graded according to the following criteria: 
• 
Grade 0:  normal consciousness, personality, neurological examination, or normal electroencephalogram; 
• 
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, or 5 cycles per second waves; 
• 
Grade 2:  lethargic, time-disoriented, inappropriate, asterixis, ataxia, or slow triphasic waves; 
• 
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, or slower waves; 
• 
Grade 4:  unarousable coma, no personality/behavior, decerebrate, or slow 2 to 3 cycles per second delta activity. 
b Ascites is graded according to the following criteria: 
• 
Absent:  No ascites is detectable by manual examination or by ultrasound investigation, if ultrasound investigation is 
performed; 
• 
Slight:  Ascites palpitation doubtful, but ascites measurable by ultrasound investigation, if performed; 
• 
Moderate:  Ascites detectable by palpitation and by ultrasound investigation, if performed; 
• 
Severe:  Necessity of paracentesis; does not respond to medication treatment. 
c A subject with hepatic encephalopathy of Grade 2 or above would not be admitted into the study. 
3.3. 
Discussion of Study Design 
A single-dose, parallel design is the standard design to investigate the PK of a drug in subjects 
with hepatic impairment. A parallel design is required to include subjects with hepatic 
impairment and matched-control healthy subjects with normal hepatic function. A single dose 
level of LOXO-292 will be used because it has linear PK. The study will be open label because 
study endpoints are objective rather than subjective. 
Based on the PK data from previous studies in healthy subjects, LOXO-292 has an estimated t1/2 
of approximately 24 hours after a single dose (based on current ongoing studies: 
LOXO-RET-18014 and LOXO-RET-18015). Matched-control healthy subjects with normal 
hepatic function will be enrolled in this study to serve as a reference group for interpretation of 
the results. Patients with a range of hepatic impairment will be included to enhance the ability to 
detect and characterize the effects of hepatic function on the PK of LOXO-292. Based on 
nonclinical and clinical data, and the known PK profile of the compound, the duration of the 
treatment period is considered adequate to achieve the study objectives.1 Oral doses were chosen 
because this is the intended clinical route of administration. 
Preclinical and clinical data suggest that LOXO-292 is likely to be well tolerated in healthy 
human subjects and may have an acceptable safety margin. However, studies in animals suggest 
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that the liver may be a potential target of toxicity for this drug. Liver disease can cause 
alterations in drug disposition, reducing the clearance of drugs eliminated by hepatic metabolism 
or biliary excretion and affect plasma protein binding, which in turn could influence the 
processes of distribution and elimination. Therefore, in this study, a cautious approach will be 
adopted, where the first 4 subjects from Group 2 (mild hepatic impairment subjects), the first 
4 subjects from Group 3 (moderate hepatic impairment subjects), and the first 2 subjects from 
Group 4 (severe hepatic impairment subjects) may be dosed concurrently, followed by an interim 
review of the safety data – and possibly PK data – before dosing is resumed for the remaining 
subjects in any (all) group(s) (see Section 8.2). 
3.4. 
Selection of Doses in the Study 
An oral dose has been selected for this study because this is the intended clinical route of 
administration. The dose of 160 mg of LOXO-292 was selected based on clinical study results 
and its observed PK profile. The 160-mg dose is expected to ensure sufficient quantifiable 
plasma concentrations of LOXO-292 for determination of systemic PK exposure. In a Phase 1/2 
clinical study in cancer patients (LOXO-RET-17001), 160 mg of LOXO-292 dosed BID has 
been evaluated and has been selected for further testing in a larger number of cancer patients to 
evaluate its safety and efficacy. Current FDA guidance4 stipulates that a single-dose study may 
be satisfactory where prior evidence indicates that multiple-dose PK is accurately predicted by 
single-dose data for both parent drug and active metabolites (eg, when the drug and active 
metabolites exhibit linear and time-independent PK at the concentrations anticipated in the 
patients to be studied). Thus, the current study will assess the PK of a single dose of 160 mg 
LOXO-292 in healthy and hepatically impaired subjects.  
4.  SELECTION OF STUDY POPULATION 
Up to 8 subjects will be enrolled into each hepatic impairment treatment group to have at least 
6 subjects from each group complete the study. Up to 16 subjects will be enrolled into the 
matched-control healthy subject group to have at least 6 healthy subjects matched to each hepatic 
impairment treatment group complete the study. Healthy control subjects will be matched 
demographically to hepatically impaired subjects as noted in Section 3.1. 
4.1. 
Screening Procedures 
The following screening procedures will be performed for all potential subjects at a visit 
conducted within 28 days of study entry (ie, prior to Check-in [Day -1]): 
1. Informed consent; 
2. Child-Pugh class score (subjects with hepatic impairment only); 
3. Demographic data; 
4. Medical history; 
5. Inclusion/exclusion criteria; 
6. Height, weight, and BMI; 
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7. Complete PE (Section 7.2.5); 
8. Screens for hepatitis C virus (HCV) antibody (for healthy subjects only), hepatitis B 
surface antigen (HBsAg), and human immunodeficiency virus (HIV) antibody 
(Appendix 2);  
9. Screen for selected drugs of abuse, including an alcohol breath test for all subjects and, 
for matched-control healthy subjects only, including cotinine (Appendix 2);  
10. Twelve-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4); 
11. Vital signs (including oral temperature, respiratory rate, and supine blood pressure [BP] 
and heart rate [HR; measured after the subject has been supine for at least 5 minutes]) 
(Section 7.2.3); 
12. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, CK, CBC, and UA; Appendix 2); 
13. Hemoglobin A1c test (subjects with hepatic impairment only);  
14. How Do You Feel? inquiry and AE and concomitant medication evaluations 
(Section 7.2.1); 
15. Serum pregnancy test for females only (Appendix 2); 
16. Follicle-stimulating hormone test (for postmenopausal females only) and 
thyroid-stimulating hormone test (Appendix 2). 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the clinical site and the following procedures will 
be performed: 
1. Child-Pugh class score (subjects with hepatic impairment only); 
2. AEs; 
3. Interim medical history; 
4. Weight; 
5. Abbreviated PE (Section 7.2.5); 
6. Review of inclusion/exclusion criteria; 
7. Screen for selected drugs of abuse, including an alcohol breath test for all subjects and, 
for matched-control healthy subjects only, including cotinine (Appendix 2);  
8. Twelve-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4); 
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9. Vital signs (including oral temperature, respiratory rate, and supine BP and HR
[measured after the subject has been supine for at least 5 minutes]) (Section 7.2.3);
10. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least
8 hours], including CK, coagulation parameters, CBC, and UA; Appendix 2);
11. How Do You Feel? inquiry and concomitant medication evaluations (Section 7.2.1);
12. Serum pregnancy test for females only (Appendix 2);
13. Compliance with concomitant medications and exclusionary restrictions (Section 6).
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Day -1 (as appropriate; Section 5). In addition, continued compliance with 
concomitant medication and other restrictions will be verified. 
The Covance Medical Monitor will review the medical history and all screening evaluations for 
potential subjects prior to enrollment. Prior to dosing, the Sponsor will provide written approval 
of subjects selected for enrollment by the Investigator. 
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), Covance Medical Monitor, 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: 
All subjects: 
1. Males, and females of nonchildbearing potential, between 18 and 65 years of age,
inclusive, at Screening;
2. Within BMI range 18.5 to 40.0 kg/m2, inclusive;
3. In good general health, except for additional specific inclusion criteria related to subjects
with hepatic impairment, based on medical history, PE findings, vital signs, ECG, and
clinical laboratory tests, as determined by the Investigator (or designee);
4. Females of nonchildbearing potential, defined as being permanently sterile (ie, due to
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or confirmed tubal
occlusion more than 6 months prior to study drug administration) or postmenopausal
(defined as at least 12 months postcessation of menses without an alternative medical
cause). Postmenopausal status will be confirmed with a screening serum
follicle-stimulating hormone level within the site laboratory’s range for postmenopausal
status. All females must have a negative qualitative serum pregnancy test (serum human
chorionic gonadotropin) at Screening and Check-in (Day -1);
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5. Males who are capable of fathering a child must agree to use one of the following 
methods of contraception from the time of the dose administration through 6 months after 
dose administration: 
• 
Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, male subjects must follow one of the 
contraception methods below: 
o Male condom with spermicide, and 
o For a female partner of male study participant: 
- 
Intrauterine device (IUD) (hormonal IUD; eg, Mirena®). Copper 
IUDs are acceptable (eg, ParaGard®); 
- 
Established use of oral, implanted, transdermal, or hormonal 
method of contraception associated with inhibition of ovulation; or 
- 
Bilateral tubal ligation. 
Males who practice true abstinence because of a lifestyle choice (ie, do not become 
abstinent just for the purpose of study participation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the ICF but becomes 
sexually active through EOS, he must agree to use contraception as described above.  
For male subjects, sexual intercourse with female partners who are pregnant or 
breastfeeding should be avoided unless condoms with spermicide are used from the time 
of the study drug administration until 6 months after administration of study drug. 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 11-night stay at the clinical site 
and Follow-up phone call; 
Additional inclusion criteria for matched-control healthy subjects only: 
8. Matched to subjects with mild and/or moderate and/or severe hepatic impairment in sex, 
age (± 10 years), and BMI (± 20%). Note: Each matched-control healthy subject may be 
matched with up to 1 subject within each hepatic impairment group; 
Additional inclusion criteria for subjects with hepatic impairment: 
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9. Considered to have mild, moderate, or severe hepatic impairment (of any etiology) that 
has been clinically stable (no acute episodes of illness due to deterioration in hepatic 
function) for at least 1 month prior to Screening per the Investigator (or designee), 
Sponsor, and Covance Medical Monitor and are likely to remain stable through EOS. To 
be classified as having hepatic impairment, subjects must have a CP score of 5 to 6 
(mild), 7 to 9 (moderate), or 10 to 15 (severe), with known medical history of liver 
disease (with or without a known history of alcohol abuse); 
10. Currently on a stable medication regimen, defined as not starting new drug(s) or 
significantly changing drug dosage(s) within 30 days prior to administration of study 
drug. Concomitant medications administered within 30 days prior to dose administration 
must be approved by the Investigator (or designee), Covance Medical Monitor, and 
Sponsor. Subjects must be able to withhold the use of these medications for 2 hours 
predose and 4 hours postdose on the day of study drug administration, unless approved 
by the Covance Medical Monitor, Investigator (or designee) and Sponsor 
11. Non-hepatic abnormal laboratory values must not be clinically relevant, as judged by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor; 
12. Anemia secondary to hepatic disease will be acceptable if hemoglobin is ≥ 8 g/dL and 
anemia symptoms are not clinically significant. Must have ≥ 35,000 platelets. 
4.4. 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
All subjects: 
1. History or presence of any of the following, deemed clinically significant by the Covance 
Medical Monitor, Investigator (or designee), and/or Sponsor: 
a. History or presence of clinically significant cardiovascular disease:  
i. Myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to dose administration 
ii. Symptomatic angina pectoris within 6 months prior to dose administration 
iii. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to dose administration 
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 
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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 
2. Abnormal laboratory values (CBC, UA, clinical chemistry panel [fasted at least 8 hours], 
excluding those further defined in exclusion criteria 26, 27, and 36 below) determined to 
be clinically significant by the Investigator (or designee), Covance Medical Monitor, and 
Sponsor at Screening and/or Check-in (Day -1); 
3. Clinically significant abnormality, as determined by the Investigator (or designee), from 
PE at Screening and/or Check-in (Day -1); 
4. 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 will not be eligible; 
5. Consumption of grapefruit/grapefruit juice, or Seville oranges from 14 days prior to dose 
administration and through EOT or ET, or consumption of other fruit juices from 
72 hours prior to dose administration and through EOT or ET; 
6. Subjects with known ongoing alcohol and/or drug abuse within 1 month prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays conducted 
during Screening and/or at Check-in (Day -1); 
7. Consumption of alcohol-, citric acid-, or caffeine-containing foods or beverages within 
48 hours prior to Check-in (Day -1) and through EOT or ET; 
8. A positive alcohol test result at Screening or Check-in (Day -1);  
9. Positive urine screen for drugs of abuse at Screening or Check-in (Day -1); 
10. Strenuous exercise within 5 days prior to Check-in (Day -1) and through EOT or ET; 
11. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee); 
12. 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 dose administration (Day 1); 
13. Use or intention to use any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers, strong P-gp inhibitors, proton pump inhibitors, antacids, or H2-receptor 
antagonists within 14 days prior to dose administration (Day 1) and through EOT or ET, 
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unless deemed acceptable by Covance Medical Monitor, the Investigator (or designee), 
and Sponsor; 
14. Use or intention to use any drug that prolongs the QT/QTc interval within 14 days prior 
to dose administration and through EOT or ET; 
15. History of a major surgical procedure within 30 days prior to Screening; 
16. 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; 
17. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs except that appendectomy, 
hernia repair, and cholecystectomy will be allowed. Bariatric surgery will not be allowed; 
18. Estimated glomerular filtration rate of <60 mL/min using the Modification of Diet in 
Renal Disease (MDRD) formula; 
19. Subject has required treatment for gastrointestinal bleeding within 6 months prior to 
Check-in (Day -1); 
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); 
Additional exclusion criteria for matched-control healthy subjects: 
23. Use or intention to use any prescription or over-the-counter medications (including herbal 
products, natural or herbal supplements) within 14 days prior to dosing and through EOT 
or ET, unless deemed acceptable by Covance Medical Monitor, the Investigator (or 
designee), and Sponsor; 
24. QT interval corrected for heart rate using Fridericia’s method (QTcF) is > 450 msec;  
25. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
• 
Oral body temperature > 37.5°C; 
• 
Heart rate < 50 or > 99 bpm; 
• 
Systolic BP < 89 or > 139 mmHg; 
• 
Diastolic BP < 50 or > 89 mmHg. 
For these parameters, out-of-range values that are not clinically significant (as determined 
by the Investigator or designee) may be repeated twice during Screening, Check-in 
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(Day -1), and predose on Day 1. Note: Rechecks of HR and BP values will be permitted 
up to 2 times to confirm eligibility for study participation. Subjects may be eligible for 
participation in the study based on rechecked HR and/or BP values if the values fall 
within the ranges stated above or if the Investigator (or designee), Covance Medical 
Monitor, and the Sponsor feel that the results are not clinically significant (based on the 
age) and will not impact study conduct; 
26. Abnormal LFTs, as defined by AST, ALT, and serum (total and direct) bilirubin, as well 
as amylase and lipase above the upper limit of the normal range at Screening or Check-in, 
unless deemed acceptable by the Investigator (or designee) with prior Sponsor approval. 
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. Subjects may be 
eligible for participation in the study based on rechecked LFT, amylase, and lipase values 
if the Investigator (or designee), Covance Medical Monitor, and the Sponsor deem that 
the results are not clinically significant and will not impact study conduct; 
27. Any clinically significant deviations from normal ranges in CK unless approved by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor; 
28. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and through EOT or ET. Urine screen for drugs of abuse 
including cotinine and alcohol breath test must be negative at Screening and on Day -1 
(Check-in) of the study unless the positive drug screen is considered to be due to the use 
of a prescription drug which is approved by the Covance Medical Monitor, Investigator 
(or designee), and Sponsor; 
29. 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);  
30. Positive serologic test for HCV antibody at Screening; 
31. History of diabetes mellitus; 
32. History of congenital nonhemolytic hyperbilirubinemia (eg, Gilbert’s syndrome); 
Additional exclusion criteria for subjects with hepatic impairment: 
33. Use or intention to use any prescription or over-the-counter medications (including herbal 
products, natural or herbal supplements) within 14 days prior to dosing and through EOT 
or ET, unless needed to stabilize the subject’s underlying medical condition (or 
concurrent baseline conditions) and deemed acceptable by the Covance Medical Monitor, 
Investigator (or designee), and Sponsor, and provided that the subject has been on a 
stable dose for a minimum of 30 days prior to study drug administration; 
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34. Subject’s QTcF is > 470 msec;  
35. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
• 
Oral body temperature > 37.5°C; 
• 
Heart rate < 50 or > 99 bpm; 
• 
Systolic BP < 90 or > 150 mmHg; 
• 
Diastolic BP < 40 or > 95 mmHg. 
For these parameters, out-of-range values that are not clinically significant (as determined 
by the Investigator or designee) may be repeated twice during Screening, Check-in 
(Day -1), and predose on Day 1. Note: Rechecks of HR and BP values will be permitted 
up to 2 times to confirm eligibility for study participation. Subjects may be eligible for 
participation in the study based on rechecked HR and/or BP values if values fall within 
the ranges referenced above and the Investigator (or designee), Covance Medical 
Monitor, and the Sponsor feel that the results are not clinically significant (based on the 
age and hepatic impairment status) and will not impact study conduct; 
36. Values outside the normal ranges for CK, LFTs, amylase, and lipase may be acceptable 
as consistent with the subject’s hepatic condition, if stable for 1 month prior to Screening, 
and if the Investigator (or designee) and Sponsor feel that the results are not clinically 
significant (based on subject age) and will not impact study conduct; 
37. Smoking more than 5 cigarettes per day or equivalent (eg, e-vapor cigarette, pipe, cigar, 
chewing tobacco, nicotine patch, nicotine gum) throughout the confinement period of the 
study (EOT or ET); unable or being unwilling to refrain from the use of tobacco or 
nicotine containing products for 2 hours prior to dosing and 4 hours after dose 
administration; 
38. History of unstable diabetes mellitus (as evidenced by hemoglobin A1c ≥ 9.0% at 
Screening). Medications for the treatment of diabetes mellitus must be reviewed and 
approved by the Investigator (or designee), Covance Medical Monitor, and Sponsor; 
39. Subject has a portal systemic shunt; 
40. Subject has required new medication for hepatic encephalopathy within the 6 months 
prior to Check-in (Day -1); 
41. Recent history of paracentesis (within 30 days prior to Screening). 
4.5. 
Subject Number and Identification 
Subjects will be assigned into groups based on their level of hepatic function (Table 2) and will 
be assigned a number by clinical site staff based on the assigned group. Assignment of numbers 
within each group will be in ascending order and no numbers will be omitted. Subject number 
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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). Subject numbers will be used on all study 
documentation. For subjects who are withdrawn by the Investigator (or designee) or who 
voluntarily withdraw prematurely from the study, replacement subjects will be enrolled only if 
deemed necessary by the Sponsor. If necessary, as determined by the Sponsor, subjects who fail 
to complete the treatment or have insufficient PK data may be replaced. Replacement subjects 
will be assigned a subject number by adding 400 to the last 3 digits of the subject number for the 
subject they are replacing (eg, Subject Number 001-501 replaces Subject Number 001-101-105).  
Table 2 
Subject Group and Number of Subjects 
Group 
Description of Hepatic Functiona 
N 
1 
Matched Normal Hepatic Function 
8 to 16 
2 
Mild Hepatic Impairment 
8 
3 
Moderate Hepatic Impairment 
8 
4 
Severe Hepatic Impairment 
8 
a Hepatic function determined using the Child-Pugh assessment (Section 3.2). 
4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue the 
study. Subjects may be withdrawn because of the following: change in compliance with 
inclusion/exclusion criterion that is clinically relevant and affects subject safety, occurrence of 
AEs, occurrence of pregnancy, intake of nonpermitted concomitant medication that might affect 
subject safety or study assessments/objectives, etc. Notification of withdrawal will immediately 
be made to the Study Monitor. In case of withdrawal, efforts will be made to perform all final 
study day assessments (Appendix 5). 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), Sponsor, 
or Covance Medical Monitor 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 investigational sites regarding the end of study procedures. 
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4.7. 
Matching Process 
A matched-control healthy subject will be matched to hepatically impaired subjects (age 
[± 10 years], BMI [± 20%], and sex). An individual matched-control healthy subject may be 
matched with up to 1 subject within each hepatic impairment group (ie, to a maximum of 
3 hepatically impaired subjects across the study [1 mild, 1 moderate, and 1 severe], but to no 
more than 1 subject in each impairment group). A listing of the matched subjects will be 
included in the Clinical Study Report. 
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 3). 
Table 3 
Study Drug 
Study Drug 
LOXO-292 
Forma 
Capsule 
Strength 
20 mgb and 80 mg 
Supplier 
Loxo Oncology, Inc. 
Manufacturer 
Avista Pharma Solutions, Inc. 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the study drug. 
bThe 20-mg dose will only be used if dosing is decreased following the interim review of safety data (Section 8.2). 
The IMP (capsule containing 20 mg [if applicable following interim analysis] or 80 mg 
LOXO-292) will be supplied by the Sponsor (or designee), along with the batch/lot numbers and 
Certificate of Analysis. It will be provided in high density polyethylene bottles and stored 
according to the instructions on the label. 
Study drugs will be stored at the study site 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 drug 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 clinical 
site employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
Subjects will receive a single dose of LOXO-292, given orally as two 80-mg capsules (160 mg 
total dose) orally in the morning on Day 1. The dose of LOXO-292 will be given within 
15 minutes following predose blood sample collection. If dosing is decreased in hepatic subjects 
following the interim review of safety data (Section 8.2), healthy matched-control subjects will 
be dosed at the lower dose in order to provide appropriate matches to hepatically impaired 
subjects. 
Each unit dose will be prepared by qualified clinical staff. Each unit dose container will be 
appropriately labeled. 
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Appropriate unit dose(s), as described above, will be administered to consecutively numbered 
subjects. Although the timing of events requires that each subject will be consistently 
administered the appropriate dose at a specific time, the exact dose time of consecutive subjects 
may be staggered to obviate the need to have all subjects on precisely the same study schedule. 
For each dose, the subject’s actual dose time will be recorded in the source documents and 
transcribed into the eCRF. 
Each dose of LOXO-292 will be administered orally with approximately 240 mL of room 
temperature water. Doses will be preceded by a fast of at least 2 hours from food (not including 
water) and will be followed by a fast from food (not including water) for at least 1 hour postdose. 
During Clinic confinement in the CRU (Day -1 through EOT or ET), Matched-control healthy 
subjects may consume water ad libitum and hepatically impaired subjects may consume water in 
a manner consistent with their medical condition. 
Subjects will not lay supine for 1 hour following dose administration, except as necessitated by 
the occurrence of an AE(s) and/or study procedure(s). 
5.3. 
Randomization 
This is a nonrandomized 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 study site staff. 
• Immediately after dose administration, visual inspection of the mouth and hands will be 
performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of LOXO-292 will be 
performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-292 
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. 
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At the completion of the study, all unused LOXO-292 capsules will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurs within 5 half-lives (if known) or 30 days, whichever is 
longer, prior to dose administration (Day 1). 
All prescription and over-the-counter medications (including, herbal products, natural or herbal 
supplements) are prohibited for 14 days prior to dose administration (Day 1) and through EOT or 
ET, unless deemed acceptable by the Covance Medical Monitor, Investigator (or designee), and 
Sponsor or, if the subject is hepatically impaired, unless needed to stabilize the subject’s 
underlying medical condition (or concurrent baseline conditions) as described below. Moderate 
or strong CYP3A4 and/or CYP3A5 inhibitors or inducers, strong P-gp inhibitors, proton pump 
inhibitors, antacids, and H2-receptor antagonists are prohibited for 14 days prior to dose 
administration (Day 1) and through EOT or ET unless approved by the Covance Medical 
Monitor, Investigator (or designee), and Sponsor. 
For hepatically impaired subjects, the use of prescription and nonprescription medications that 
are needed to stabilize the subject’s underlying medical condition (or concurrent baseline 
conditions) and deemed acceptable by the Covance Medical Monitor, Investigator (or designee) 
and Sponsor are allowed, provided that the subject has been on a stable dose for a minimum of 
30 days prior to study drug administration. Hepatically impaired subjects must be able to 
withhold the use of these medications for 2 hours predose and 4 hours postdose on the day of 
study drug administration, unless approved by the Covance Medical Monitor, Investigator (or 
designee), and Sponsor. Short-term medication adjustments may be made upon consultation with 
the Covance Medical Monitor, Investigator (or designee), and Sponsor per the Medical 
Responsibility Plan. The use of additional medications is to be avoided from 14 days prior to 
study drug administration until EOT or ET unless required to treat an AE. All concomitant 
medications needed to stabilize the subject’s underlying medical condition (or concurrent 
baseline conditions) will be reviewed by the Covance Medical Monitor, Investigator (or 
designee), and Sponsor prior to subject approval. 
Any medication taken by a subject during the course of the study, including details of its dosage, 
administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without prior 
approval of the Covance Medical Monitor, Investigator (or designee), and Sponsor, unless its use 
is deemed necessary in a medical emergency. In this case, the use of the concomitant medication 
will be reported as soon as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
Matched-control healthy 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 
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ET. Hepatically impaired subjects are required to refrain from the use of tobacco- and nicotine-
containing products within 2 hours prior to dosing and for 4 hours postdose. 
Consumption of grapefruit, grapefruit juice, or Seville oranges from 14 days prior to dose 
administration (Day 1) and through EOT or ET or consumption of other fruit juices from 
72 hours prior to dose administration and through EOT or ET will not be allowed unless deemed 
acceptable by the Covance Medical Monitor, Investigator (or designee), and Sponsor. 
Subjects are required to abstain from consuming alcohol-, citric acid-, and caffeine-containing 
foods and beverages for 48 hours prior to Check-in (Day -1) and through EOT or ET, unless 
deemed acceptable by the Investigator.  
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and during 
the period of confinement at the clinical site and will otherwise maintain their normal level of 
physical activity through EOT or ET (ie, will not begin a new exercise program or participate in 
any unusually strenuous physical exertion). 
While confined at the clinical site, subjects will receive a standardized diet at scheduled times 
that do not conflict with other study-related activities. 
Doses of LOXO-292 will be preceded by a fast of at least 2 hours from food (not including 
water) and will be followed by a fast from food (not including water) for at least 1 hour postdose. 
Glucose tablets may be administered as needed for treatment of hypoglycemia. Subjects may 
consume water ad libitum. 
7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for PK analysis of LOXO-292 plasma levels and protein binding and potential 
analysis of metabolites will be collected at the timepoints specified in Appendix 5. The exact 
time of the study drug administration and the actual time of blood sampling for PK analysis and 
protein binding will be recorded on the eCRF. 
Processing, storage, and shipping instructions for these PK blood and protein binding samples 
will be provided in a separate Laboratory Manual. The number of blood samples and total blood 
volume required for PK testing and protein binding is presented in Appendix 3. 
7.1.2. 
Analytical Methodology 
Concentrations of LOXO-292 in plasma will be determined using a validated bioanalytical 
method. Specifics of the bioanalytical methods will be provided in a separate document. The 
concentrations of total and unbound LOXO-292 will be determined in a sample of predose 
plasma fortified with a known concentration of LOXO-292. The unbound fraction will be 
calculated based on total and unbound LOXO-292 levels. Samples of plasma may be analyzed 
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for exploratory analyses of metabolites. If such analyses are conducted, the results will be 
reported separately by the Sponsor. 
7.2. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee), Covance 
Medical Monitor, or Sponsor.  
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
any other procedures to be performed at the same timepoint. The order of priority for scheduling 
procedures around a timepoint is (in descending order of priority): 
• Dosing; 
• Pharmacokinetic blood sampling; 
• Vital signs assessments; 
• Electrocardiograms; 
• 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 nonleading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 
Appendix 5 (ie, at Screening [after the ICF is signed], at Check-in (Day -1), at each postdose 
vital signs assessment, and at an appropriate time for all other days). Subjects will also be 
encouraged to voluntarily report AEs occurring at any other time through the EOS. 
AEs, whether volunteered, identified by the subject’s responses to HDYF? inquiries, or noted on 
PE, ECG, vital signs assessments, or laboratory tests, will be recorded throughout the study (ie, 
from signing of the ICF until EOS [or ET if the subject discontinues from the study and does not 
complete a follow-up 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 
call) are to be reported.  
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Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up call, all subjects must be followed until EOS. Subjects with AEs that are assessed as 
related to study drug by the Investigator (or designee) which are ongoing at EOS may continue to 
be followed until the symptoms or value(s) return to normal, or acceptable levels, as 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 Safety Follow-up phone call 7 days (± 2 days) after EOT or ET to 
determine if any AE has occurred since the EOT or ET visit.  
At all times, a subject may be required to remain at the clinical site for longer at the discretion of 
the Investigator (or designee). 
Any event that meets the criteria of a Suspected Unexpected Serious Adverse Reactions 
(SUSAR) will be reported to the IRB/IEC according to site 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 IB for 
LOXO-292 for expected adverse reactions. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours], coagulation 
parameters, CBC, thyroid-stimulating hormone, hemoglobin A1c [hepatic subjects only], and 
UA) will be collected at the timepoints specified in Appendix 5. 
Screens for HCV antibody, HBsAg, and HIV antibody will be performed at Screening. A drug 
screen for selected drugs of abuse will be performed at Screening and repeated at Check-in 
(Day -1; including an alcohol breath test for all subjects and, for matched-control healthy 
subjects only, including cotinine). A serum qualitative pregnancy test (females only) and a 
follicle-stimulating hormone test (postmenopausal females only) will be performed at the 
timepoints specified in Appendix 5.  
The number of blood samples and total blood volume required for clinical laboratory evaluations 
is presented in Appendix 3. A list of the specific evaluation is in Appendix 2. 
7.2.3. 
Vital Signs 
Vital signs (including oral temperature, respiratory rate, and supine BP and HR) will be obtained 
at the timepoints specified in Appendix 5. 
Blood pressure and HR measurements should be performed using the same arm for each reading 
and measurements should be taken after the subject has been resting in the supine position for at 
least 5 minutes.  
When vital signs assessments are scheduled at the same time as blood draws, the blood draws 
will be obtained at the scheduled timepoint, and the vital signs will be obtained prior to and as 
close as possible to the scheduled blood draw. 
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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 5. The QT interval will be corrected for HR by Fridericia’s (QTcF = QT/[RR]1/3) 
formulae. 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to and as close 
as possible to the scheduled blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated PE will be performed at the timepoints specified in Appendix 5. 
Complete PEs will evaluate general appearance and the following body systems/organs: 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; lymphatic; musculoskeletal/extremities; and neurological. Weight and height will be 
reported (height only reported during Screening). 
The PE at Screening will include hepatic encephalopathy and ascites evaluations for the CP 
assessment. 
Abbreviated PEs will evaluate general appearance and the following body systems/organs: 
dermatological; pulmonary; cardiovascular; abdominal; and neurological. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations to detect statistically significant 
differences among groups. Six subjects each per hepatic function group are planned to complete 
the study. This is considered a sufficient sample size to evaluate the PK of LOXO-292 under 
various degrees of hepatic function. 
8.2. 
Interim Analysis 
Interim reviews of safety data will be conducted for each group when the first 4 subjects from 
Group 2 (mild hepatic impairment subjects) are enrolled and have completed the study, when the 
first 4 subjects from Group 3 (moderate hepatic impairment subjects) are enrolled and have 
completed the study, and when the first 2 subjects from Group 4 (severe hepatic impairment 
subjects), are enrolled and have completed the study. These safety data will include AEs and 
serious AEs (SAEs), vital signs, PEs, ECGs, and clinical laboratory tests. If available, PK data 
and matched-control healthy subject data may also be used during the review. Enrollment and 
dosing for remaining subjects in any group may occur after the interim data for that group are 
reviewed and the Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is 
safe to proceed with dosing. 
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Each interim review will be a teleconference between the Covance Medical Monitor, 
Investigator (or designee), and/or Sponsor to discuss safety data.  
Following the interim review of safety data for a group, the dose level may be decreased for the 
remaining subjects in any group pending discussion and agreement between the Covance 
Medical Monitor, Investigator (or designee), and/or Sponsor. If dosing is decreased, it will also 
be decreased for the impaired subjects’ respective matched-control healthy subjects. 
8.3. 
Analysis Populations 
8.3.1. 
Study Populations 
The PK Population will consist of all subjects who have received a dose of LOXO-292, have at 
least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. 
The Safety Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 postdose safety assessment. 
8.4. 
Pharmacokinetic Analysis 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-292, and according to the model independent approach:5  
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the 
last measurable concentration, calculated using the linear 
trapezoidal rule for increasing and decreasing concentrations 
AUC0-∞ 
AUC extrapolated to infinity, calculated using the formula: 
 
 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
 
 
where Ct is the last measurable concentration and λZ is the 
apparent terminal elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC 
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 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t1/2 = natural log (ln)(2)/λZ 
CL/F 
apparent systemic clearance 
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Vd/F 
apparent volume of distribution during the terminal phase 
MRT 
mean residence time  
fu 
unbound fraction, calculated as unbound concentration divided by 
total concentration 
Additionally, the number of points used to estimate λZ will be presented in a listing. 
The fu value determined for each subject will be used to calculate the following unbound 
LOXO-292 PK parameters for each individual subject:  
Cmax,u 
Unbound Cmax, calculated as Cmax*fu 
AUC0-t,u 
Unbound AUC0-t, calculated as AUC0-t*fu 
AUC0-∞,u 
Unbound AUC0-∞, calculated as AUC0-∞*fu 
CL/F,u 
Unbound CL/F, calculated as Dose/AUC0-∞,u 
Vd/F,u 
Unbound Vd/F, calculated as CL/F,u/λZ 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 6.4 or higher (Certara USA Inc.). 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the Statistical Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. Other data handling 
procedures will be detailed in the SAP. 
8.5. 
Statistical Analysis of Pharmacokinetic Data 
Plasma concentrations and PK parameters will be summarized by hepatic function with 
descriptive statistics (number, arithmetic mean, standard deviation, coefficient of variation 
[CV%], geometric mean, geometric CV%, median, minimum, and maximum). In addition, 
summary statistics for protein binding will be tabulated by hepatic function group. 
The primary analysis planned for this study is to evaluate the PK of LOXO-292 after a single 
dose in subjects with mild, moderate, or severe hepatic impairment, compared to subjects with 
normal hepatic function. The following statistical methodology will be used, based on 1 to 1 
matching: 
An analysis of covariance (ANCOVA) will be performed on the ln transformed AUC0-t, AUC0-∞, 
and Cmax. The ANCOVA model will contain a categorical factor of population for subjects with 
varied degree hepatic impairment (severe, moderate, and mild) and healthy matched control 
subjects, a categorical covariate (sex), and continuous covariates (age and BMI). Ratios of least 
squares means (LSM) and 90% CIs will be calculated using the exponentiation of the difference 
between renal function cohort LSM from the ANCOVA analyses on the ln transformed AUC0-t, 
AUC0-∞, and Cmax. The specific procedures will be documented in the SAP. 
All statistical calculations will be performed using SAS Version 9.3 or greater. 
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8.6. 
Statistical Analyses of Safety Data 
All subjects who received a dose of LOXO-292 and have at least 1 postdose safety assessment 
will be included in the safety analyses. All safety assessments, including AEs and SAEs, vital 
signs measurements, clinical laboratory (including CK) results, PE results, concomitant 
medications, and ECG interpretations, will be tabulated and summarized where possible, using 
descriptive methodology by hepatic function group and, as needed, by timepoint. Unless 
otherwise specified, baseline value is defined as the last nonmissing measurement before 
administration of the study drug. No formal statistical analyses are planned for the safety data. 
The incidence of AEs for each hepatic function will be presented by severity (matched control 
healthy subjects, mild, moderate, and severe) and by relationship to study drug as determined by 
the Investigator (see Appendix 1 for AE reporting). All treatment-emergent AEs will be 
summarized by system organ class and preferred term, with a breakdown by hepatic function, 
using Medical Dictionary for Regulatory Activities. 
8.7. 
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 clinical site 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 clinical site and verified by the Study Monitor. 
Data will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be reviewed 
by the Covance scientific team. The eCRF and ancillary data will be converted into final SAS® 
datasets following Study Data Tabulation Model or client-provided specifications. The final 
datasets structure will be verified using Web Submission Data Manager®, while the dataset 
content will be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will be 
peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by the 
Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.8. 
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. 
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Administrative aspects including regulatory, ethical, and study oversight considerations are 
described in Appendix 4. 
 
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9. REFERENCES 
1. Loxo Oncology, Inc. LOXO-292 – Investigator’s Brochure (Version 4.0). 01 October 2018. 
2. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The Liver and 
Portal Hypertension. Philadelphia, PA: Saunders; 1964:50-64. 
3. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-649. 
4. Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function: Study 
Design, Data Analysis, and Impact on Dosing and Labeling. U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER), May 2003. 
5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York, NY: Marcel Dekker Inc.; 
1982. 
 
 
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10. APPENDICES 
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Appendix 1: Adverse Event Reporting 
1.1 Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy subject, whether or not considered drug related by the 
Investigator (or designee). A treatment-emergent AE is an AE that is reported after a dose of 
study drug. 
The following are all AEs: 
• Unfavorable changes in general condition; 
• Subjective or objective signs/symptoms; 
• Concomitant diseases or accidents; 
• Clinically relevant adverse changes in laboratory parameters observed in a subject during 
a clinical study. 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant by 
the Investigator or designee), and accidents observed in the context of a clinical trial, irrespective 
of a possible causal relationship with the administration of the trial substance.  
1.2 Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2 Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*  
• Grade 3 Severe or medically significant but not immediately life threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**  
• Grade 4 Life-threatening consequences: Urgent intervention indicated 
• Grade 5 Death related to AE 
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 
5 options for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option.  
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
• 
NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (eg, concomitant drugs, therapies, complications, comorbidities) is 
suspected; 
• 
RELATED = The time course between administration of investigational product and the 
occurrence or worsening of the AE is consistent with a causal relationship and no other 
cause (eg, concomitant drugs, therapies, complications, comorbidities) can be identified. 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
 
1.3 Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through EOS or ET (if the subject discontinues from the study and does not 
complete a follow up call) and for up to 90 days after study drug administration should be 
reported by the Investigator (or designee) via eFax to the Sponsor’s clinical safety representative 
within 24 hours of being notified. The Sponsor’s safety representative will then forward the 
Pregnancy Form to the Investigator for completion. 
eFax: +1 (203) 643-2013 
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. The subject or partner should be 
followed by the Investigator until completion of the pregnancy. If the pregnancy ends for any 
reason before the anticipated date, the Investigator should notify the Sponsor’s clinical safety 
representative. At the completion of the pregnancy, the Investigator will document the outcome 
of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as a serious AE (SAE; ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an 
SAE. 
Male subjects will be instructed to notify the Investigator immediately if they discover their 
sexual partner is pregnant. In this instance, the partner must provide written consent before 
pregnancy information can be collected. When a site becomes aware that the female partner of a 
male subject is pregnant, they are to contact the Covance Medical Monitor immediately (within 
24 hours of the site staff becoming aware of the event) in addition to notifying the Sponsor’s 
safety representative via eFax. 
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All pregnancies should be recorded on the AE electronic Case Report Form, 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. 
1.4 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.  
1.5 Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed in 
the Reference Safety Information section of the IB or if it is not listed at the specificity or 
severity that has been observed for an unapproved investigational medicinal product. 
1.6 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 clinical site to the Sponsor, the Covance 
Medical Monitor, and the responsible Institutional Review Board (IRB). Final determination of 
whether an event represents a SUSAR will be the responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or reported, 
and within 24 hours of any SAE (regardless of whether the event is assessed as related or 
unrelated to study drug) being first recognized or reported, the Sponsor’s clinical safety 
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representative will be notified by the Investigator or designee in writing (eg, facsimile) using the 
following eFax number or email: 
eFax: +1 (203) 643-2013 
email: safety@loxooncology.com 
To report the SAE, the completed report form should be sent by eFax to the Sponsor’s clinical 
safety representative within 24 hours of awareness. Incoming reports are reviewed during normal 
business hours. Additional reporting instructions and the SAE Report Form are provided in the 
Study Manual.  
The IRB will be notified of any FDA-reportable AE within the timeframe required by the IRB. 
The IRB Serious and Unexpected Adverse Experience Submission Form will be completed and 
submitted with the copy of the written confirmation or summary of the AE. 
 
 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel (Fasted): 
Complete Blood Count: 
Other Tests: 
Alanine aminotransferase 
Hematocrit 
Hemoglobin A1c (for hepatic 
impairment subjects only) 
Thyroid-stimulating hormone 
 
Albumin 
Hemoglobin 
Alkaline phosphatase 
Mean corpuscular hemoglobin 
Amylase 
Aspartate aminotransferase 
Mean corpuscular hemoglobin 
concentration 
Bilirubin (direct and total) 
Mean corpuscular volume 
Blood urea nitrogen  
Platelet count 
Coagulation Parameters: 
Calcium 
Red blood cell (RBC) count 
Activated partial thrombin time 
Chloride 
RBC distribution width 
Partial thromboplastin time 
Cholesterol 
Creatine kinase 
Creatinine (Renal function will be 
calculated using the MDRD formula) 
Glucose 
Lipase 
Potassium  
Sodium 
Total protein  
Triglycerides  
Uric acid 
White blood cell (WBC) count  
WBC differential (percent and 
absolute):  
Prothrombin time 
International normalized ratio 
 
Basophils 
Eosinophils  
Lymphocytes  
Monocytes 
Neutrophils 
Serology: 
Human immunodeficiency virus 
antibody  
Hepatitis B surface antigen 
Hepatitis C virus antibody  
 
 
 
Drug Screen: 
 
Urinalysis: 
 
For Female Subjects only: 
Including but not limited to the 
following:  
Alcohol (ethanol)  
Amphetamines 
Barbiturates 
Benzodiazepines 
Bilirubin  
Color and appearance  
Glucose  
Ketones  
Leukocyte esterase  
Nitrite 
Pregnancy test (serum qualitative) 
Follicle-stimulating hormone 
(postmenopausal females only) 
Cannabinoids  
Cocaine (metabolite)  
Methadone  
Opiates  
Phencyclidine  
Cotinine (healthy subjects only) 
Occult blood  
pH and specific gravity  
Protein  
Urobilinogen  
Microscopic exam including 
bacteria, casts, crystals, epithelial 
cells, RBCs, and WBCs (if protein, 
leukocyte esterase, nitrite, or blood 
is positive) 
 
 
 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Purpose 
Approximate Blood 
Volume per Sample (mL) 
Maximum Number 
of Blood Samples 
Approximate Total 
Volume (mL) 
Serology 
4 
1 
4 
Hemoglobin A1c (hepatic 
impairment subjects only) 
4 
1 
4 
Primary Pharmacokinetic 
(PK) Sampling 
4 
21 
84 
Unbound Drug PK Sampling 
4 
1 
4 
Clinical Laboratory Tests: 
Complete Blood Count 
Clinical Chemistry 
Coagulation Parameters 
 
4 
4 
3 
 
6 
6 
6 
 
24 
24 
18 
Serum Pregnancy Test 
(females only) 
2 
3 
6 
Serum Follicle-stimulating 
Hormone Test 
(postmenopausal females 
only) 
2 
1 
2 
Thyroid-stimulating hormone 
2 
1 
2 
Total: 
172 mL 
Note: Although the total maximum volume to be analyzed is anticipated to be approximately 
172 mL, due to the variability in sampling requirements at different laboratories, the total volume 
of blood collected from each subject may vary. 
  
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Appendix 4: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an Institutional Review 
Board (IRB) by the Investigator and reviewed and approved by the IRB before the study is 
initiated.  
Any amendments to the protocol will require IRB and regulatory authority (as locally required) 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB. 
• Notifying the IRB of serious AEs or other significant safety findings as required by IRB 
procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects will 
be instructed that they are free to obtain further information from the Investigator (or designee) 
and that their participation is voluntary and they are free to withdraw from the study at any time. 
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Subjects will be given an opportunity to ask questions about the study prior to providing consent 
for participation. 
Following discussion of the study with clinical site personnel, subjects will sign 2 copies of the 
ICF in the presence of a suitably trained member of staff to indicate that they are freely giving 
their informed consent. One copy will be given to the subject, and the other will be maintained in 
the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in eCRFs, 
study-related forms, study reports, or any related publications. Subject and Investigator personal 
data will be treated in compliance with all applicable laws and regulations. In the event the study 
protocol, study report, or study data are included in a public registry, all identifiable information 
from individual subjects or Investigators will be redacted according to applicable laws and 
regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data may 
be examined by Sponsor or Contract Research Organization (CRO [ie, Covance]) auditors or 
other authorized personnel appointed by the Sponsor, by appropriate IRB members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of 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. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
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• The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality checking 
of the data. Predefined agreed risks, monitoring thresholds, quality tolerance thresholds, 
controls, and mitigation plans will be documented in a risk management register. 
Additional details of quality checking to be performed on the data may be included in a 
Data Management Plan.  
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and transmitted 
to Covance electronically, will be integrated with the subject’s eCRF data in accordance with the 
Data Management Plan.  
An eCRF must be completed for each enrolled subject who undergoes any screening procedures, 
according to the eCRF completion instructions. The Sponsor, or CRO, will review the supporting 
source documentation against the data entered into the eCRFs to verify the accuracy of the 
electronic data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data on 
the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical study 
agreement (CSA). Unless otherwise specified in the CSA, the following process will occur: 
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If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and or other presentation 
materials to the Sponsor for review before submission for publication or presentation. The 
Sponsor will have 60 days to respond with any requested revisions, including without limitation, 
the deletion of confidential information. The Investigator will act in good faith upon requested 
revisions, except the Investigator will delete any confidential information from such proposed 
publications. The Investigator will delay submission of such publication or presentation materials 
for up to an additional 90 days in order to have a patent application(s) filed. 
 
 
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Appendix 5: Schedule of Assessments 
Study Procedures 
Screening 
(Days -29 to -2) 
Check-in  
(Day -1) 
 
Day 1 
 
Days 2 to 10 
Clinic 
Discharge/End of 
Treatment (EOT) 
Day 11 or Early 
Termination (ET) 
 
Follow-up Phone Call 
(EOS)  
7 (±2) days post EOT or 
ETs 
Confined to the Study Site 
 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Child-Pugh Class Scorea 
X 
X 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
Height/Weight/BMI 
X 
Xc 
 
 
 
 
Physical Examinationd 
X 
X 
X 
 
Xr 
 
12-Lead ECGe 
X 
X 
 
 
Xr 
 
Vital Signsf 
X 
X 
X 
X 
Xr 
 
HDYF? Inquiryg 
X 
X 
X 
X 
Xr 
X 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
LOXO-292 Dosei 
 
 
X 
 
 
 
Primary PK Blood Samplesj 
 
 
X 
X 
Xr 
 
Unbound Drug PK Blood Samplek 
 
 
X 
 
 
 
Clinical Laboratory Evaluationsl 
X 
X 
 
X 
Xr 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
Hemoglobin A1c Testm 
X 
 
 
 
 
 
Drug Screenn 
X 
X 
 
 
 
 
Prior and Concomitant Medicationso 
X 
X 
X 
X 
Xr 
X 
Serum Pregnancy Testp 
X 
X 
 
 
Xr 
 
Follicle-Stimulating Hormone Testq 
X 
 
 
 
 
 
Thyroid-Stimulating Hormone Test 
X 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ET = early termination; HDYF? = How Do You Feel?; 
HIV = human immunodeficiency virus; PK = pharmacokinetic; SAE = serious adverse event. 
a Subjects with hepatic impairment only. Child-Pugh (CP) scores will be calculated at Screening and Check-in (Day -1); hepatically impaired subjects will be assigned to groups according to CP 
scores at Check-in (Day -1) to ensure stability of hepatic impairment and subject safety, as determined by the Investigator (or designee). 
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b Interim medical history only. 
c Weight and BMI (based on Screening height) only. 
d A complete physical examination (PE) will be performed at Screening and EOT (or ET). An abbreviated PE will be performed at Check-in (Day -1) and 1 hour postdose on Day 1.  
e Electrocardiograms will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the scheduled blood 
draws. 
f Vital signs measurements (oral temperature, respiratory rate, and supine blood pressure and heart rate [HR]) will be obtained at Screening and Check-in (Day -1), predose, at 2 hours 
(± 10 minutes) and 4 hours (± 10 minutes) postdose, and at each Study Day through EOT (or ET). Vital signs measurements should be carried out prior to and as close as possible to having 
blood drawn. Blood pressure and HR will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. 
g An HDYF? inquiry performed at Screening (after the Informed Consent Form is signed), at Check-in (Day -1), at each postdose vital signs assessment, and at an appropriate time for all other 
days. 
h AEs and SAEs will be collected beginning at informed consent.  AEs will be recorded throughout the study (ie, from signing of the Informed Consent Form [ICF] until EOS, or until ET if the 
subject discontinues from the study and does not complete a follow-up call), either as subject medical history (if the event is reported as beginning prior to signing of the ICF or if the event 
occurs prior to study drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the ICF but 
prior to study drug administration on Day 1 and is assessed by the Investigator [or designee]) as related to study procedures, or if the event occurs after study drug administration on Day 1 
through EOT or ET regardless of relationship to study drug).  From EOT or ET through EOS, only AEs assessed as related to study drug are to be recorded.  All SAEs that develop from the 
time of ICF signing until EOS (or ET if the subject discontinues from the study and does not complete a follow-up call) are to be reported. 
i Dose administration is to be given during the morning of Day 1. 
j Primary PK blood samples will be collected prior to dosing (within 30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Day 11). 
The allowed sampling window for PK blood samples will be the following: within 15 minutes prior to dosing for the predose sample timepoint; ± 5 minutes for sampling timepoints within the 
first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 minutes for the sampling timepoints ranging from 48 to 240 hours. 
k For assessment of unbound plasma concentrations of LOXO-292, a blood sample will be collected predose (ie, within 30 minutes prior to dosing). 
l Clinical chemistry panel (fasted at least 8 hours), coagulation parameters, complete blood count, and urinalysis will be performed at Screening, Check-in (Day -1), 24 hours postdose (Day 2), 
Day 5, Day 8, and at EOT (Day 11) or ET. 
m Hemoglobin A1c test performed at Screening for subjects with hepatic impairment only.  
n Alcohol breath test and drugs of abuse urine test. Results from the alcohol and drug tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
o Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 30 days prior to 
study drug administration for prescription medications, and 14 days prior to study drug administration for nonprescription medications, will be recorded on the subject’s electronic Case Report 
Form. 
p Female subjects only. 
q Postmenopausal female subjects only. 
r EOT is defined as when the subject is released from the CRU following completion of all assessments through Day 11.  ET is defined as when the subject is released from the CRU if the 
subject terminates the study early.  Vital sign, ECG, and safety laboratory results for serum chemistry, hematology, coagulation, and urinalysis are to be available for review by the Investigator 
or designee prior to subject release from the CRU at the EOT or ET visit. 
s To be performed 7 days (± 2 days) following EOT or ET.  End of Study (EOS) is defined as when the CRU contacts the subject by a follow-up phone call 7 days (± 2 days) after the EOT visit 
or ET visit to determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received LOXO-292 (including subjects who terminate the study early) 
will be contacted. 
 
Page 83 of 163


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
Protocol 
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, 
and Pharmacokinetic Study of LOX0-292 Administered to Fasted Hepatically 
Impaired Male and Female Subjects and Fasted Matched-control Healthy 
Subjects 
Sponsor: 
Protocol Status: Final Protocol Date: 15 October 2018 
Protocol Version: 1 
Investigational Product: LOXO-292 
Protocol Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Number: 133193 
Study Site: 
Loxo Oncology, Inc. 
Multiple Sites 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
Sponsor Signato1y: 
I 
MD, PhD 
Medical Monitor 
Pl 
to Loxo Oncology, Inc. 
Principal Investigator: 
Multiple Investigators 
Information described herein is confidential and rnay be disclosed only with the express 
written permission of the Sponsor. 
Protocol Final, 15 October 2018 
Page 1 of55 
Page 84 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
rr~ocuSigned by: 
15- 0ct- 18 I 15:00:50 EDT 
IJ 
Signer Name [Pl 
I 
Date 
Protocol Final, 15 October 2018 
Page 2 of55 
Page 85 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
r 
Name, Qualifications 
Principal Investigator 
Protocol Final, 15 October 2018 
Pl 
Date 
Page 3 of55 
Page 86 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
t have read the. protocol and agree to conduct the study as described herein. 
Pl 
Name, Qualifications 
PrincipaJ Investigator 
Protocol Final, 15 October 2018 
Pl 
Date 
Page 3 of55 
Page 87 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Name, Qualifications 
Principal Investigator 
Protocol Final, 15 October 2018 
Date 
Page 3 of55 
Page 88 of 163 


Protocol 
Covance Study: 839361 2 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
1 have read the protocol and agree to conduct the study as described herein. 
Name, Qua 
Princi al ln 
Pl 
Pl 
Protocol Final, 15 October 2018 
r 
Date 
Page 3 of 55 
Page 89 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Name, Qualifications 
Principal Investigator 
Protocol Final, 15 October 2018 
Pl 
Date 
Page 3 of 55 
Page 90 of 163 


Clinical Protocol 
CONFIDENTIAL 
Covance Study 8393612 
Protocol LOXO-RET-18022 
INVESTIGATOR AGREEl\IBNT 
J 
L 
Final, 01 November 2018 
Page 2 of3 
Page 91 of 163 


Protocol 
Covance Study: 8393612 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Name, Qualifia 
Principal lnves 
Pl 
Protocol Final, 15 October 2018 
Pl 
Page 3 of 55 
Page 92 of 163 


Protocol 
Covance Study: 8393612 
Sponsor 
Sponsor's Study Contact 
Covance Medical Monitor 
Sponsor's Medical Contact 
Bioanalytical Laborato1y 
Protocol Biostatistician 
Protocol Phannacokineticist 
Protocol Final, 15 October 2018 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
STUDY IDENTIFICATION 
Loxo Oncology, Inc. 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
(650) 989-8051 (Main Telephone No.) 
Pl 
I 
, Clinical Operations 
Loxo Oncology, Inc. 
01 
(Mobile Telephone No.) 
t""I 
(Alternate Contact No.) 
01 
J 
Pl 
l,MD 
=>I 
I, Clinical Phannacology 
Covance Clinical Research Unit, Inc. 
Pl 
J 
Pl 
I 
Pl 
(Office Telephone No.) 
t""I 
(Alternate Contact No.) 
Pl 
I 
t""I 
l, MD, PhD 
01 
I to Loxo Oncology, Inc. 
t""I 
(Mobile Telephone No.) 
01 
Alturas Analytics, Inc. 
1324 Alturas Dlive 
Moscow, Idaho 83843 
I 
(208) 883-3400 (Main Telephone No.) 
, MS 
Covance Early Clinical Biometrics 
I 
(Office Telephone No.) 
---
, MS 
Medical & Scientific Affairs, 
Clinical Phrumacology Services 
Covance Inc. 
Page 4 of55 
Page 93 of 163 


Protocol 
Covance Study: 8393612 
Protocol Medical Writer 
Protocol Final, 15 October 2018 
CONFIDENTIAL 
Protocol Reference: LOXO-RET-18022 
(Office Telephone No.) 
~ ====:::!......:.-~ 
------
, PhD 
Covance Medical Writing 
I 
(Office Telephone No.) 
Page 5 of55 
Page 94 of 163 


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 6 of 55 
SYNOPSIS 
Title of study: Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and 
Pharmacokinetic Study of LOXO-292 Administered to Fasted Hepatically Impaired Male and 
Female Subjects and Fasted Matched-control Healthy Subjects 
Objectives:  
The objectives of this study are:  
• 
To evaluate the pharmacokinetic (PK) profile of LOXO-292 in subjects with impaired 
hepatic function compared to matched-control healthy subjects;  
• 
To evaluate safety and tolerability of LOXO-292 in subjects with impaired hepatic function 
and matched-control healthy subjects.
Study design: 
This study will be an open-label, nonrandomized, multi-center, single-dose, parallel-group, safety, 
tolerability, and PK study of LOXO-292 administered at a dose of 160 mg in fasted 
matched-control healthy males and females with normal hepatic function compared to fasted, 
hepatically impaired subjects. 
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up to 8 
subjects within each of the mild, moderate, and severe impairment groups, per Child-Pugh [CP] 
classification – assessed at Screening and Check-in [Day -1]), and approximately 8 to 16 subjects 
with normal hepatic function are enrolled. Subjects will be enrolled within the following groups 
based on their CP score at Screening and assuming no change in underlying hepatic status at Check-
in (Day -1) as judged by the Investigator (or designee), the Covance Medical Monitor, and the 
Sponsor: 
• 
Group 1: Matched-control healthy subjects with normal hepatic function; 
• 
Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• 
Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• 
Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15). 
A parallel design strategy will be adopted for the hepatic impairment groups, with interim reviews 
of safety data after the first 4 subjects from Group 2 (mild hepatic impairment subjects), the first 
4 subjects from Group 3 (moderate hepatic impairment subjects), and the first 2 subjects from 
Group 4 (severe hepatic impairment subjects) are enrolled and have completed all study-related 
assessments including the Follow-up phone call. Enrollment and dosing for remaining subjects in 
any group may occur after the interim data for that group are reviewed and the Covance Medical 
Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed with dosing. If 
available, PK data and matched-control healthy subject data may also be used during the interim 
review. 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by age 
(± 10 years), body mass index (BMI; ± 20%), and sex to the enrolled hepatic impairment subject(s). 
Should another hepatic impairment subject be identified with whom an already enrolled healthy 
subject is demographically matched, the healthy subject may also be matched with that impaired 
subject as long as the impaired subject is in a different hepatic impairment group. Each subject with 
normal hepatic function may be matched with up to 1 subject within each hepatic impairment 
group. 
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 site on Day -1 (Check-in). Replacement subjects 
may be enrolled only if deemed necessary by the Sponsor.  
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 7 of 55 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) until Clinic 
Discharge on Day 11 upon completion of all PK and safety assessments. A Follow-up phone call 
will occur approximately 7 days after Clinic Discharge. 
On the morning of Day 1, after at least a 2-hour fast, an oral dose of 160 mg LOXO-292 
administered as two 80-mg capsules will be given with 240 mL water. No food will be allowed for 
up to 1 hour postdose. Glucose tablets may be administered as needed for treatment of 
hypoglycemia. 
In this study design, physical examinations (PEs), 12-lead electrocardiograms (ECGs), vital signs, 
How Do You Feel? inquiries, clinical chemistry panel, coagulation parameters, complete blood 
count, and urinalysis will be performed at Screening and at specified times during the study. All 
adverse events (AEs) will be recorded throughout the study (ie, from signing of the Informed 
Consent Form until Study Completion), either as subject medical history (if the event is reported as 
occurring prior to signing of the Informed Consent Form [ICF]) or as AEs (if the event occurs after 
administration of LOXO-292). Between the time of ICF signing to administration of LOXO-292 
only AEs assessed as related to study procedures should be reported. All SAEs that develop from he 
time of ICF signing until Study Completion are to be reported. 
Study Completion is defined as the time of the last subject’s Follow-up phone call. 
Interim review: 
Interim reviews of safety data will be conducted for each group when the first 4 subjects from 
Group 2 (mild hepatic impairment subjects) are enrolled and have completed the study, when the 
first 4 subjects from Group 3 (moderate hepatic impairment subjects) are enrolled and have 
completed the study, and when the first 2 subjects from Group 4 (severe hepatic impairment 
subjects) are enrolled and have completed the study. These safety data will include AEs and serious 
AEs (SAEs), vital signs, PEs, ECGs, and clinical laboratory tests. If available, PK data and 
matched-control healthy subject data may also be used during the review. Enrollment and dosing 
for remaining subjects in any group may occur after the interim data for that group are reviewed and 
if the Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed 
with dosing. 
Following the interim review of safety data for each group, the dose level may be decreased for the 
remaining subjects in any group pending discussion and agreement between the Covance Medical 
Monitor, Investigator (or designee), and/or Sponsor. If dose is decreased, it will also be decreased 
for the impaired subjects’ respective matched-control healthy subjects. 
Number of subjects: 
A total of up to 24 subjects with hepatic impairment (up to 8 subjects with mild impairment, up to 8 
subjects with moderate impairment, and up to 8 subjects with severe impairment, per CP 
classification) and approximately 8 to 16 matched-control healthy subjects with normal hepatic 
function will be enrolled in the study with the goal of having at least 6 subjects from each hepatic 
impairment group and at least 6 subjects with normal hepatic function complete the study. Subjects 
who withdraw or drop out of the study may be replaced if deemed necessary by the Sponsor. 
Diagnosis and main criteria for inclusion: 
Male subjects and female subjects of nonchildbearing potential, between 18 and 65 years of age, 
inclusive, at Screening, and within BMI range 18.5 to 40.0 kg/m2, inclusive. Subjects will be in 
good general health, except for additional specific inclusion criteria related to subjects with hepatic 
impairment, based on medical history, PE findings, vital signs, ECG, and clinical laboratory tests at 
Screening and Check-in (Day -1), as determined by the Investigator (or designee). 
Investigational products, dose, and mode of administration: 
LOXO-292 will be supplied by Loxo Oncology as 80-mg and 20-mg capsules for oral 
administration. 
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 8 of 55 
Subjects will receive a single dose of LOXO-292, given orally as two 80-mg capsules. If dosing is 
decreased following the interim review of safety data, subjects will be given appropriate doses 
using a combination of 80-mg and 20-mg capsules. 
Duration of subject participation in the study: 
Planned Enrollment/Screening Duration: up to 28 days (Day -29 to Day -2). 
Length of Confinement: a total of 12 days (11 nights), from the time of Check-in (Day -1) through 
the 240-hour PK blood draw and end of study assessments. 
Follow-up Phone Call: approximately 7 days after Clinic Discharge. 
Planned Study Conduct Duration: approximately 47 days. 
Criteria for evaluation: 
Pharmacokinetics: 
Serial PK blood samples for the analysis of plasma LOXO-292 concentration levels will be 
collected from predose through 240 hours postdose.  
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-292: maximum observed concentration (Cmax), time to maximum observed 
concentration (tmax), area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), percentage 
extrapolation for AUC (%AUCextrap), apparent terminal elimination rate constant (λz), apparent 
terminal elimination half-life (t1/2), apparent systemic clearance (CL/F), apparent volume of 
distribution during the terminal phase (Vd/F), and mean residence time (MRT).  
In addition, a single blood sample will be collected predose to determine the fraction unbound (fu) 
of LOXO-292 in plasma and, whenever possible, the following PK parameters will be calculated 
for unbound LOXO-292 using fu: unbound Cmax (Cmax,u), unbound AUC0-t (AUC0-t,u), unbound 
AUC0-∞ (AUC0-∞,u), unbound CL/F (CL/F,u), and unbound Vd/F (Vd/F,u).  
Safety: 
Safety and tolerability will be assessed by monitoring AEs, performing PEs and clinical laboratory 
tests (including creatine kinase [CK]), measuring vital signs, and recording ECGs. 
Sample size: 
The sample size chosen for this study was based upon precedent set by other PK studies of similar 
nature and was not based on power calculations to detect statistically significant differences among 
groups.  At least 6 subjects each per hepatic function group are planned to complete the study. This 
is considered a sufficient sample size to evaluate the PK of LOXO-292 under various degrees of 
hepatic function. If necessary, as determined by the Sponsor, subjects who fail to complete the 
treatment or have insufficient PK data may be replaced. 
Statistical methods: 
Pharmacokinetics:  
All subjects who have received a dose of LOXO-292, have at least 1 quantifiable plasma 
concentration, and for whom at least 1 PK parameter can be computed will be included in the PK 
Population. Plasma concentrations and PK parameters will be summarized by hepatic function 
using descriptive statistics (number, arithmetic mean, standard deviation, coefficient of variation 
[CV%], geometric mean, geometric CV%, median, minimum, and maximum). In addition, 
summary statistics for protein binding will be tabulated by hepatic function group. 
The primary analysis planned for this study is to evaluate the PK of LOXO-292 after a single dose 
in subjects with mild, moderate, or severe hepatic impairment, compared to subjects with normal 
hepatic function. The following statistical methodology will be used, based on 1 to 1 matching: 
The 90% confidence interval of Cmax and AUCs for the ratio between each level of impaired hepatic 
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 9 of 55 
function versus the control group will be presented. Furthermore, if an individual healthy subject is 
matched to 1 subject from any or all hepatic impairment groups, then the primary PK parameters, 
Cmax and AUCs, will be analyzed using the paired t-test to assess the difference between each 
impaired group and the healthy group. The p-value assessing the difference between each impaired 
group and the healthy group will be presented. For cases where 1 to 1 matching between the healthy 
and hepatic impaired groups are not achieved, an analysis of variance will be conducted. The 
specific procedures will be documented in the Statistical Analysis Plan. 
Safety:  
All subjects who receive a dose of LOXO-292 and have at least 1 postdose safety assessment will 
be included in the safety analyses. All safety assessments, including AEs and SAEs, vital signs 
measurements, clinical laboratory (including CK) results, PE results, concomitant medications, and 
ECG interpretations, will be tabulated and summarized where possible, using descriptive 
methodology by hepatic function group and, as needed, by timepoint. No formal statistical analyses 
are planned for the safety data. Interim reviews of safety data are planned for the first 4 subjects 
from Group 2 (mild hepatic impairment subjects), the first 4 subjects from Group 3 (moderate 
hepatic impairment subjects), and the first 2 subjects from Group 4 (severe hepatic impairment 
subjects).  
Page 98 of 163


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 10 of 55 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................10 
LIST OF TABLES AND FIGURES........................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................13 
1. 
INTRODUCTION ...........................................................................................................15 
1.1. 
Background ............................................................................................................15 
1.2. 
Summary of Nonclinical Studies ...........................................................................15 
1.3. 
Summary of Clinical Studies .................................................................................16 
1.4. 
Study Rationale ......................................................................................................17 
1.5. 
Benefit-risk Assessment .........................................................................................18 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................18 
2.1. 
Objectives ..............................................................................................................18 
2.2. 
Endpoints ...............................................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.2. 
Child-Pugh Classification ......................................................................................20 
3.3. 
Discussion of Study Design ...................................................................................21 
3.4. 
Selection of Doses in the Study .............................................................................22 
4. 
SELECTION OF STUDY POPULATION .....................................................................22 
4.1. 
Screening Procedures .............................................................................................22 
4.2. 
Check-in Procedures (Day -1) ...............................................................................23 
4.3. 
Inclusion Criteria ...................................................................................................24 
4.4. 
Exclusion Criteria ..................................................................................................26 
4.5. 
Subject Number and Identification ........................................................................30 
4.6. 
Removal of Subjects from Study Participation ......................................................31 
4.7. 
Matching Process ...................................................................................................31 
5. 
STUDY TREATMENTS .................................................................................................31 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................31 
5.2. 
Study Treatment Administration ............................................................................32 
5.3. 
Randomization .......................................................................................................33 
5.4. 
Blinding..................................................................................................................33 
5.5. 
Treatment Compliance ...........................................................................................33 
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 11 of 55 
5.6. 
Drug Accountability...............................................................................................33 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................33 
6.1. 
Concomitant Therapies ..........................................................................................33 
6.2. 
Diet, Fluid, and Activity Control ...........................................................................34 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................35 
7.1. 
Pharmacokinetic Assessments ...............................................................................35 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................35 
7.1.2. 
Analytical Methodology ..............................................................................35 
7.2. 
Safety and Tolerability Assessments .....................................................................35 
7.2.1. 
Adverse Events ............................................................................................36 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................36 
7.2.3. 
Vital Signs ....................................................................................................37 
7.2.4. 
12-Lead Electrocardiogram .........................................................................37 
7.2.5. 
Physical Examination...................................................................................37 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................38 
8.1. 
Determination of Sample Size ...............................................................................38 
8.2. 
Interim Analysis .....................................................................................................38 
8.3. 
Analysis Populations ..............................................................................................38 
8.3.1. 
Study Populations ........................................................................................38 
8.4. 
Pharmacokinetic Analysis ......................................................................................38 
8.5. 
Statistical Analysis of Pharmacokinetic Data ........................................................40 
8.6. 
Statistical Analyses of Safety Data ........................................................................40 
8.7. 
Data Handling and Record Keeping ......................................................................40 
8.8. 
Quality Control and Quality Assurance .................................................................41 
9. 
REFERENCES ................................................................................................................42 
10. APPENDICES .................................................................................................................43 
Appendix 1: Adverse Event Reporting ..............................................................................44 
1.1 
Definition of Adverse Events .................................................................................44 
1.2 
Categorization of Adverse Events .........................................................................44 
1.3 
Pregnancy ...............................................................................................................45 
1.4 
Definition of Serious Adverse Events ....................................................................46 
1.5 
Unexpected Adverse Drug Experience ..................................................................46 
1.6 
Reporting................................................................................................................46 
Appendix 2: Clinical Laboratory Evaluations ...................................................................48 
Appendix 3: Total Blood Volume ......................................................................................49 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations ............................50 
Appendix 5: Schedule of Assessments ..............................................................................54 
 
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 12 of 55 
LIST OF TABLES AND FIGURES 
Table 1 
Child-Pugh Assessment of Hepatic Function ............................................21 
Table 2 
Subject Group and Number of Subjects.....................................................30 
Table 3 
Study Drug .................................................................................................32 
 
Figure 1 
Study Design Schematic ............................................................................20 
 
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 13 of 55 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
AUC0-∞,u 
unbound 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 
AUC0-t,u 
unbound area under the concentration-time curve from time 0 to the last 
measurable concentration 
AV 
atrioventricular 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CL/F 
apparent systemic clearance 
CL/F,u 
unbound apparent systemic clearance 
Cmax 
maximum observed concentration 
Cmax,u 
unbound maximum observed concentration 
CP 
Child-Pugh 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Evaluation Agency 
FDA 
Food and Drug Administration 
fu 
fraction unbound 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
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Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 14 of 55 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IC50 
inhibitory concentration 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board  
IUD 
intrauterine device 
λZ 
apparent terminal elimination rate constant 
LFT 
liver function test 
LSM 
least squares mean 
MRT 
mean residence time 
PCR 
polymerase chain reaction 
PE 
physical examination(s) 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell 
RET 
rearranged during transfection 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
apparent terminal elimination half-life 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed concentration 
UA 
urinalysis 
Vd/F 
apparent volume of distribution during the terminal phase  
Vd/F,u 
unbound apparent volume of distribution during the terminal phase 
WBC 
white blood cell 
 
 
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Protocol 
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Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 15 of 55 
1. INTRODUCTION 
Refer to the current Investigator’s Brochure (IB)1 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. 
Background 
LOXO-292 is a small molecule and selective inhibitor of the rearranged during transfection 
(RET) receptor tyrosine kinase designed to competitively block the adenosine triphosphate 
binding site of the kinase. LOXO-292 was at least 250-fold more selective for RET than for 98% 
of 329 other kinases tested in a large in vitro screen. Consistent with such a high degree of 
selectivity, LOXO-292 caused significant cytotoxicity in human cancer cell lines that harbored 
endogenous, clinically relevant RET gene alterations but was much less cytotoxic against human 
cancer cell lines without RET alterations. Potent and selective inhibition of RET may provide 
clinical benefit to subjects with malignancies due to oncogenic alterations in RET or with other 
mechanisms of increased RET activity. 
1.2. 
Summary of Nonclinical Studies 
Cardiac safety of LOXO-292 was evaluated in a Good Laboratory Practice (GLP) in vitro assay 
for human ether-a-go-go related gene (hERG) activity, in a GLP in vivo study in conscious 
telemetry-instrumented minipigs, and in a GLP 28-day repeat-dose toxicology study (with 
electrocardiogram [ECG] monitoring) in minipigs. LOXO-292 had a 50% inhibitory 
concentration (IC50) value of 1.1 μM in the GLP hERG assay, which is approximately 14- and 
6-fold higher than the predicted maximum unbound concentration at the dose of 80 mg and 
160 mg respectively twice daily (BID). There were no LOXO-292-related changes in any 
cardiovascular endpoints including QT interval corrected for heart rate (QTc) at doses up to 
12 mg/kg in the safety pharmacology cardiovascular study in conscious minipigs. Furthermore, 
there were no LOXO-292-related ECG changes in the 28-day repeat-dose toxicity study in 
minipigs at the high dose of 12 mg/kg. Together, these data indicate that LOXO-292 has a low 
risk of inducing delayed ventricular repolarization, prolongation of the QTc interval, and 
unstable arrhythmias. 
Administration of LOXO-292 at single doses up to 45 mg/kg in male rats had no effect on 
respiratory function. 
Potential effects of LOXO-292 on the central nervous system were evaluated as part of the 
GLP 28-day repeat-dose study in rats, in functional observational battery tests and locomotor 
activity assessments. Findings were limited to animals receiving the high dose on Week 4 of the 
dosing phase, and were attributed to poor general body condition and weight changes associated 
with LOXO-292 administration rather than specific neurological effects. Additionally, no 
microscopic abnormalities in neuronal tissues were found. 
In toxicology studies of LOXO-292 that were conducted in the rat and minipig, the primary 
pathologic findings for both species were in the tongue, pancreas, bone marrow and lymphoid 
tissues; while the gastrointestinal tract and ovaries were target tissues in minipig. Other target 
tissues identified in the rat included: multi-tissue mineralization, physeal cartilage, incisor teeth, 
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lung, Brunner’s gland, and possibly liver. Assessment of doses associated with 
moribundity/death revealed a steep dose response curve for both species. LOXO-292 was not 
mutagenic in the GLP bacterial mutation assay. When evaluated in two in vitro assays, 
LOXO-292 was not genotoxic. LOXO-292 was not found to be phototoxic when evaluated in an 
in vitro neutral red uptake phototoxicity assay. 
In repeated dose toxicity studies in Sprague-Dawley Rats, minor changes suggestive of hepatic 
effects were higher alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in 
males (≥ 20 mg/kg/day) and females (≥ 50 mg/kg/day), higher aspartate aminotransferase (AST) 
levels in those receiving the high-dose (both sexes), and a higher cholesterol concentration in 
males (≥ 20 mg/kg/day). Reversible, LOXO-292-related decreases in liver and thymus weights 
occurred in males at 75 and 45 mg/kg/day, respectively. None of these minor changes were 
correlated to any liver findings microscopically, suggesting minor functional alterations of the 
liver rather than overt hepatocellular injury. ALP levels were also increased in Göttingen 
minipigs administered 5 or 12 mg/kg/day in repeated dose toxicity studies; however, this change 
had no associated clinical or microscopic findings and was considered not adverse. 
Based on preclinical pharmacology experiments with human cancer cells in vitro and in murine 
xenograft models, meaningful inhibition of RET in tumors is expected to be achievable with oral 
dosing regimens ≥ 40 mg/day. 
Based on the nonclinical profile, including results from animal toxicology studies, theoretical 
risks of human exposure to LOXO-292 include the following: loss of appetite, decrease in body 
weight, increase in total white blood cells, neutrophils, and monocytes, decrease in albumin, 
increase in globulin, decreased albumin:globulin ratio, decrease in total protein, increased body 
temperature, lethargy, increase in cholesterol and triglycerides, increase in phosphorus, changes 
in taste sensation and/or development of xerostomia, gastrointestinal symptoms/signs: nausea, 
vomiting, loose stools, abdominal discomfort, decreases in red cell mass (red blood cell, 
hemoglobin, hematocrit) and reticulocytes, decrease in platelets, increases in liver function tests 
(ALP, AST, and ALT). 
LOXO-292 has been given orally and intravenously to mice, rats, dogs, and minipigs. Oral PK 
has also been determined in the monkey. LOXO-292 was absorbed and bioavailable in all 
species tested. Solubility studies and pharmacokinetic studies suggest that the pharmacokinetic 
exposure of LOXO-292 may be reduced by proton pump inhibitors and other antacids. 
LOXO-292 appears to be metabolized primarily by cytochrome p450 (CYP)3A4, but at 
therapeutically relevant exposures, it is not anticipated to inhibit or induce drug-metabolizing 
enzymes. LOXO-292 is also a substrate for the Breast Cancer Resistance Protein. 
Refer to the current IB1 for detailed background information on LOXO-292. 
1.3. 
Summary of Clinical Studies 
LOXO-292 is currently being studied in an ongoing global Phase 1/2 study (Study 
LOXO-RET-17001) in patients with advanced solid tumors including RET fusion-positive 
NSCLC, RET-mutant medullary thyroid carcinoma, and other tumors with increased RET 
activity. The starting dose of LOXO-292 was 20 mg once daily. As of July 19, 2018 data cut-off 
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date, safety data was available from 153 patients with 240 mg BID as the highest dose 
administered. As of this date, two dose-limiting toxicities of tumor lysis syndrome and Grade 3 
thrombocytopenia at the 240 mg BID dose level have been reported. The most frequently 
reported treatment-emergent adverse events (TEAEs; > 10% of patients), were dry mouth 
(20.3%; 14.4% related), diarrhea (15.7%; 7.2% related), fatigue (15.7%; 11.8% related), 
constipation (12.4%; 2.6% related), headache (11.1%; 3.3% related), and hypertension (10.5%; 
3.9% related). Regarding TEAEs ≥Grade 3, eight patients experienced Grade 3 TEAEs that were 
judged by the Investigator as related to study drug. Three patients have died within 28 days of 
their last dose of study drug, no deaths have been attributed to study drug. A small number of 
patients have experienced Grade 3 or higher liver function test (LFT) abnormalities, considered 
related to study drug, occurring between 20 to 56 days after starting LOXO-292. These changes 
were asymptomatic and resolved with dose interruption, with LOXO-292 resumed at a lower 
dose following normalization of the LFTs. 
As of August 24, 2018, PK data were available from 141 patients (from the global Phase 1/2 
study). LOXO-292 is absorbed after oral administration with a median time to maximum 
concentration (tmax) of approximately 2 hours. Although the PK sampling of LOXO-292 was not 
long enough to adequately characterize AUC0-∞, the half-life appears to be approximately 
20 hours. Low concentrations of LOXO-292 were recovered as unchanged drug in urine 
indicating that the kidney contributes to overall clearance. 
As of September 14, 2018, Loxo Oncology has initiated 16 single patient protocols, Special 
Access Scheme, or Temporary Authorization Use cases to provide access to LOXO-292 for 
patients with clinical need not meeting eligibility criteria for the ongoing global Phase 1/2 study. 
To date, no TEAEs have been attributed to study drug for these patients. 
Preliminary PK data available from ongoing studies (LOXO-RET-18014 and 
LOXO-RET-18015) being conducted in healthy subjects indicate that LOXO-292 has an 
estimated apparent terminal elimination half-life (t1/2) of approximately 24 hours after a single 
dose. 
Refer to the current IB1 for detailed and updated background clinical study information on 
LOXO-292. 
1.4. 
Study Rationale 
Liver disease can cause alterations in drug disposition and pharmacokinetics (PK). Such 
alterations can reduce the clearance of drugs eliminated by hepatic metabolism or biliary 
excretion and affect plasma protein binding, which in turn could influence the processes of 
absorption, distribution, and elimination. Refer to the IB1 for detailed background information on 
LOXO-292. Results from this study will provide information on the safety, tolerability, and 
exposure of LOXO-292 in participants with hepatic impairment and participants with normal 
hepatic function.  
This study is being conducted to provide information to develop dosing recommendations for 
LOXO-292 in subjects with hepatic impairment. The current study will be carried out in subjects 
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with hepatic impairment according to 3 different Child-Pugh (CP) categories2,3 (mild, moderate, 
and severe impairment) and also in matched-control healthy subjects. 
There are several methods used to categorize the severity of hepatic impairment. Despite its 
imperfections, the CP classification is the most widely used and is an acceptable method 
supported by regulatory agencies (including the United States Food and Drug Administration 
[FDA] and the European Medicines Evaluation Agency [EMA]). The FDA and EMA Guidelines 
recommend that the “number of subjects enrolled should be sufficient to detect clinically 
relevant PK differences.” In the current study, up to 8 subjects with mild hepatic impairment, up 
to 8 subjects with moderate hepatic impairment, up to 8 subjects with severe hepatic impairment, 
and approximately 8 to 16 healthy subjects with normal hepatic function will be enrolled. The 
PK and safety profiles between each hepatic impairment group and their matching (age, sex, and 
body mass index [BMI]) healthy subjects will be compared. 
1.5. 
Benefit-risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment of 
their medical status) from participating in the study. The risks of participation are primarily those 
associated with adverse reactions to the study treatments, although there may also be some 
discomfort from collection of blood samples and other study procedures. More information about 
the known and expected benefits, risks, and reasonably anticipated AEs associated with 
LOXO-292 may be found in the current IB.1  
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The objectives of this study are: 
• To evaluate the PK profile of LOXO-292 in subjects with impaired hepatic function 
compared to matched-control healthy subjects; 
• To evaluate safety and tolerability of LOXO-292 in subjects with impaired hepatic 
function and matched-control healthy subjects. 
2.2. 
Endpoints 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of LOXO-292: maximum observed concentration (Cmax), (tmax, area under the 
concentration-time curve (AUC) from Hour 0 to the last measurable concentration (AUC0-t), 
AUC extrapolated to infinity (AUC0-∞), percentage extrapolation for AUC (%AUCextrap), 
apparent terminal elimination rate constant (λz), apparent terminal elimination half-life (t1/2), 
apparent systemic clearance (CL/F), apparent volume of distribution during the terminal phase 
(Vd/F), and mean residence time (MRT).  
In addition, a single blood sample will be collected predose to determine the fraction unbound 
(fu) of LOXO-292 in plasma and, whenever possible, the following PK parameters will be 
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calculated for unbound LOXO-292 using fu: unbound Cmax (Cmax,u), unbound AUC0-t (AUC0-t,u), 
unbound AUC0-∞ (AUC0-∞,u), unbound CL/F (CL/F,u), and unbound Vd/F (Vd/F,u). 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
(PEs) and clinical laboratory tests (including creatine kinase [CK]), measuring vital signs, and 
recording ECGs. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This study is an open-label, nonrandomized, multi-center, single-dose, parallel-group study to 
determine the PK, safety, and tolerability of LOXO-292 administered orally at a dose of 160 mg 
to fasted adult males and females with mild, moderate, or severe impaired hepatic function and 
healthy subjects with normal hepatic function. Hepatic function will be classified based on the 
CP classification of hepatic impairment2,3 (Table 1). 
Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up to 8 
subjects with mild impairment, up to 8 subjects with moderate impairment, and up to 8 subjects 
with severe impairment, per CP classification – assessed at Screening and verified at Check-in 
[Day -1]) and approximately 8 to 16 subjects with normal hepatic function are enrolled, with the 
goal of having at least 6 subjects from each hepatic impairment group and at least 6 subjects with 
normal hepatic function complete the study. Subjects will be enrolled within the following 
groups based on their CP score at Screening and Check-in (Day -1) as judged by the Investigator 
(or designee), Covance Medical Monitor, and Sponsor: 
• Group 1: Matched-control healthy subjects with normal hepatic function; 
• Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15); 
A parallel design strategy will be adopted for the hepatic impairment groups. An interim review 
of the safety data will be conducted as detailed in Section 8.2. 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by age 
(± 10 years), BMI (± 20 %), and sex to the completed hepatic impairment subject(s). Should 
another hepatic impairment subject be identified with whom an already enrolled healthy subject 
is demographically matched, the healthy subject may also be matched with that impaired subject 
as long as the impaired subject is in a different hepatic impairment group. Each subject with 
normal hepatic function may be matched with up to 1 subject within each hepatic impairment 
group. 
The schematic of the study design is displayed in Figure 1. 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.  
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Subjects will be confined at the clinical site from the time of Check-in (Day -1) until Clinic 
Discharge on Day 11 upon completion of all PK and safety assessments. A Follow-up phone call 
will occur approximately 7 days after Clinic Discharge.  
On the morning of Day 1, after at least a 2-hour fast, a single oral dose of 160 mg LOXO-292 
will be administered with 240 mL water. No food will be allowed for up to 1 hour postdose. 
Glucose tablets may be administered as needed for treatment of hypoglycemia. For instructions 
regarding food and water intake, please refer to Section 6.2. 
Figure 1 
Study Design Schematic 
 
ICF = Informed Consent Form; PK = pharmacokinetic. 
Note: Single oral dose of LOXO-292 at 160 mg administered orally after at least a 2-hour fast. 
In this study design, PEs, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) inquiries, 
clinical chemistry panel, coagulation parameters, complete blood count (CBC), and urinalysis 
(UA; Appendix 2) will be performed at Screening, Check-in (Day -1), and at specified times 
during the study, and/or at Study Completion (for specific timepoints and details on each study 
variable, refer to Appendix 5). All AEs will be recorded throughout the study (ie, from signing of 
the ICF until Study Completion, either as subject medical history (if the event is reported as 
occurring prior to signing of the Informed Consent Form [ICF]) or as AEs (if the event occurs 
after administration of LOXO-292). Between the time of ICF signing to administration of 
LOXO-292 only AEs assessed as related to study procedures should be reported. All SAEs that 
develop from he time of ICF signing until Study Completion are to be reported. 
Pharmacokinetic samples will be obtained through 240 hours postdose. A study flow chart is 
presented in Appendix 5.  
Study Completion is defined as the time of the last subject’s Follow-up phone call. 
3.2. 
Child-Pugh Classification 
Per FDA Guidance,4 hepatic impairment will be classified as mild, moderate, or severe using the 
CP System2,3 (Table 1), and the parameters to determine the CP class for each subject with 
hepatic impairment will be collected at Screening and Check-in (Day -1). 
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Screening 
Study Treatment (Days -1 ta 11) 
Days -29 to -2 
Check-in: 
Day-1 
Dosing: Day 1 
Discharge: 
Dayll 
PK sampling: Days 1 to 11 {0-240 hours postdose) 
Safety assessments· From signing of the ICF to Follow-up phone call 
Follow-up 
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Table 1 
Child-Pugh Assessment of Hepatic Function 
 
Points Scored for Observed Findings 
 
1 
2 
3 
Hepatic Encephalopathy gradea 
0 
1 or 2c 
3 or 4c
Ascitesb 
Absent 
Slight 
Moderate 
Serum bilirubin, mg/dL (µmol/L) 
<2 (<34) 
2 to 3 (34 to 50) 
>3 (>50) 
Serum albumin, g/dL (g/L) 
>3.5 (>35) 
2.8 to 3.5 (28 to 35) 
<2.8 (<28) 
International normalized ratio 
<1.7 
1.7 to 2.3 
>2.3 
Chronic Hepatic Impairment is classified into Child-Pugh (CP) class A to C, employing the added score of the 5 parameters in 
the table above.  
Mild Impairment (CP-A): 5 or 6 points; Moderate Impairment (CP-B): 7 to 9 points; Severe Impairment (CP-C): 10 to 15 points. 
a In this study, hepatic encephalopathy is graded according to the following criteria: 
• 
Grade 0:  normal consciousness, personality, neurological examination, or normal electroencephalogram; 
• 
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, or 5 cycles per second waves; 
• 
Grade 2:  lethargic, time-disoriented, inappropriate, asterixis, ataxia, or slow triphasic waves; 
• 
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, or slower waves; 
• 
Grade 4:  unarousable coma, no personality/behavior, decerebrate, or slow 2 to 3 cycles per second delta activity. 
b Ascites is graded according to the following criteria: 
• 
Absent:  No ascites is detectable by manual examination or by ultrasound investigation, if ultrasound investigation is 
performed; 
• 
Slight:  Ascites palpitation doubtful, but ascites measurable by ultrasound investigation, if performed; 
• 
Moderate:  Ascites detectable by palpitation and by ultrasound investigation, if performed; 
• 
Severe:  Necessity of paracentesis; does not respond to medication treatment. 
c A subject with hepatic encephalopathy of Grade 2 or above would not be admitted into the study. 
3.3. 
Discussion of Study Design 
A single-dose, parallel design is the standard design to investigate the PK of a drug in subjects 
with hepatic impairment. A parallel design is required to include subjects with hepatic 
impairment and matched-control healthy subjects with normal hepatic function. A single dose 
level of LOXO-292 will be used because it has linear PK. The study will be open label because 
study endpoints are objective rather than subjective. 
Based on the PK data from previous studies in healthy subjects, LOXO-292 has an estimated t1/2 
of approximately 24 hours after a single dose (based on current ongoing studies: 
LOXO-RET-18014 and LOXO-RET-18015). Matched-control healthy subjects with normal 
hepatic function will be enrolled in this study to serve as a reference group for interpretation of 
the results. Patients with a range of hepatic impairment will be included to enhance the ability to 
detect and characterize the effects of hepatic function on the PK of LOXO-292. Based on 
nonclinical and clinical data, and the known PK profile of the compound, the duration of the 
treatment period is considered adequate to achieve the study objectives.1 Oral doses were chosen 
because this is the intended clinical route of administration. 
Preclinical and clinical data suggest that LOXO-292 is likely to be well tolerated in healthy 
human subjects and may have an acceptable safety margin. However, studies in animals suggest 
that the liver may be a potential target of toxicity for this drug. Liver disease can cause 
alterations in drug disposition, reducing the clearance of drugs eliminated by hepatic metabolism 
or biliary excretion and affect plasma protein binding, which in turn could influence the 
processes of distribution and elimination. Therefore, in this study, a cautious approach will be 
adopted, where the first 4 subjects from Group 2 (mild hepatic impairment subjects), the first 
4 subjects from Group 3 (moderate hepatic impairment subjects), and the first 2 subjects from 
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Group 4 (severe hepatic impairment subjects) may be dosed concurrently, followed by an interim 
review of the safety data – and possibly PK data – before dosing is resumed for the remaining 
subjects in any (all) group(s) (see Section 8.2). 
3.4. 
Selection of Doses in the Study 
An oral dose has been selected for this study because this is the intended clinical route of 
administration. The dose of 160 mg of LOXO-292 was selected based on clinical study results 
and its observed PK profile. The 160-mg dose is expected to ensure sufficient quantifiable 
plasma concentrations of LOXO-292 for determination of systemic PK exposure. In a Phase 1/2 
clinical study in cancer patients (LOXO-RET-17001), 160 mg of LOXO-292 dosed BID has 
been evaluated and has been selected for further testing in a larger number of cancer patients to 
evaluate its safety and efficacy. Current FDA guidance4 stipulates that a single-dose study may 
be satisfactory where prior evidence indicates that multiple-dose PK is accurately predicted by 
single-dose data for both parent drug and active metabolites (eg, when the drug and active 
metabolites exhibit linear and time-independent PK at the concentrations anticipated in the 
patients to be studied). Thus, the current study will assess the PK of a single dose of 160 mg 
LOXO-292 in healthy and hepatically impaired subjects.  
4.  SELECTION OF STUDY POPULATION 
Up to 8 subjects will be enrolled into each hepatic impairment treatment group to have at least 
6 subjects from each group complete the study. Up to 16 subjects will be enrolled into the 
matched-control healthy subject group to have at least 6 healthy subjects matched to each hepatic 
impairment treatment group complete the study. Healthy control subjects will be matched 
demographically to hepatically impaired subjects as noted in Section 3.1. 
4.1. 
Screening Procedures 
The following screening procedures will be performed for all potential subjects at a visit 
conducted within 28 days of study entry (ie, prior to Check-in [Day -1]): 
1. Informed consent; 
2. Child-Pugh class score (subjects with hepatic impairment only); 
3. Demographic data; 
4. Medical history; 
5. Inclusion/exclusion criteria; 
6. Height, weight, and BMI; 
7. Complete PE (Section 7.2.5); 
8. Screens for hepatitis C virus (HCV) antibody (for healthy subjects only), hepatitis B 
surface antigen (HBsAg), and human immunodeficiency virus (HIV) antibody 
(Appendix 2);  
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9. Screen for selected drugs of abuse, including an alcohol breath test for all subjects and, 
for matched-control healthy subjects only, including cotinine (Appendix 2);  
10. Twelve-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4); 
11. Vital signs (including oral temperature, respiratory rate, and supine blood pressure [BP] 
and heart rate [HR; measured after the subject has been supine for at least 5 minutes]) 
(Section 7.2.3); 
12. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, CK, CBC, and UA; Appendix 2); 
13. Hemoglobin A1c test (subjects with hepatic impairment only);  
14. How Do You Feel? inquiry and AE and concomitant medication evaluations 
(Section 7.2.1); 
15. Serum pregnancy test for females only (Appendix 2); 
16. Follicle-stimulating hormone test (for postmenopausal females only) and 
thyroid-stimulating hormone test (Appendix 2). 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the clinical site and the following procedures will 
be performed: 
1. Child-Pugh class score (subjects with hepatic impairment only); 
2. AEs; 
3. Interim medical history; 
4. Weight; 
5. Abbreviated PE (Section 7.2.5); 
6. Review of inclusion/exclusion criteria; 
7. Screen for selected drugs of abuse, including an alcohol breath test for all subjects and, 
for matched-control healthy subjects only, including cotinine (Appendix 2);  
8. Twelve-lead ECG measured after the subject has been resting in the supine position for at 
least 10 minutes (Section 7.2.4); 
9. Vital signs (including oral temperature, respiratory rate, and supine BP and HR 
[measured after the subject has been supine for at least 5 minutes]) (Section 7.2.3); 
10. Clinical laboratory evaluations (Section 7.2.2; clinical chemistry panel [fasted at least 
8 hours], including CK, coagulation parameters, CBC, and UA; Appendix 2);  
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11. How Do You Feel? inquiry and concomitant medication evaluations (Section 7.2.1); 
12. Serum pregnancy test for females only (Appendix 2); 
13. Compliance with concomitant medications and exclusionary restrictions (Section 6). 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Day -1 (as appropriate; Section 5). In addition, continued compliance with 
concomitant medication and other restrictions will be verified. 
The Covance Medical Monitor will review the medical history and all screening evaluations for 
potential subjects prior to enrollment. Prior to dosing, the Sponsor will provide written approval 
of subjects selected for enrollment by the Investigator. 
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), Covance Medical Monitor, 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: 
All subjects: 
1. Males, and females of nonchildbearing potential, between 18 and 65 years of age, 
inclusive, at Screening; 
2. Within BMI range 18.5 to 40.0 kg/m2, inclusive; 
3. In good general health, except for additional specific inclusion criteria related to subjects 
with hepatic impairment, based on medical history, PE findings, vital signs, ECG, and 
clinical laboratory tests, as determined by the Investigator (or designee); 
4. Females of nonchildbearing potential, defined as being permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or confirmed tubal 
occlusion more than 6 months prior to study drug administration) or postmenopausal 
(defined as at least 12 months postcessation of menses without an alternative medical 
cause). Postmenopausal status will be confirmed with a screening serum 
follicle-stimulating hormone level within the site laboratory’s range for postmenopausal 
status. All females must have a negative qualitative serum pregnancy test (serum human 
chorionic gonadotropin) at Screening and Check-in (Day -1); 
5. Males who are capable of fathering a child must agree to use one of the following 
methods of contraception from the time of the dose administration through 6 months after 
dose administration: 
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• 
Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in (Day -1). If 
documentation is not available, male subjects must follow one of the 
contraception methods below: 
o Male condom with spermicide, or  
o For a female partner of male study participant: 
- 
Intrauterine device (IUD) (hormonal IUD; eg, Mirena®). Copper 
IUDs are acceptable (eg, ParaGard®); 
- 
Established use of oral, implanted, transdermal, or hormonal 
method of contraception associated with inhibition of ovulation; or 
- 
Bilateral tubal ligation. 
Males who practice true abstinence because of a lifestyle choice (ie, do not become 
abstinent just for the purpose of study participation) are exempt from contraceptive 
requirements. Periodic abstinence by a female partner (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a male subject is abstinent at the time of signing the ICF but becomes 
sexually active during the study, 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 unless condoms with spermicide are used from the time 
of the study drug administration until 6 months after administration of study drug. 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 11-night stay at the clinical site 
and Follow-up phone call; 
Additional inclusion criteria for matched-control healthy subjects only: 
8. Matched to subjects with mild and/or moderate and/or severe hepatic impairment in sex, 
age (± 10 years), and BMI (± 20%). Note: Each matched-control healthy subject may be 
matched with up to 1 subject within each hepatic impairment group; 
Additional inclusion criteria for subjects with hepatic impairment: 
9. Considered to have mild, moderate, or severe hepatic impairment (of any etiology) that 
has been clinically stable (no acute episodes of illness due to deterioration in hepatic 
function) for at least 1 month prior to Screening per the Investigator (or designee), 
Sponsor, and Covance Medical Monitor and are likely to remain stable throughout the 
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study. To be classified as having hepatic impairment, subjects must have a CP score of 
5 to 6 (mild), 7 to 9 (moderate), or 10 to 15 (severe), with known medical history of liver 
disease (with or without a known history of alcohol abuse); 
10. Currently on a stable medication regimen, defined as not starting new drug(s) or 
significantly changing drug dosage(s) within 30 days prior to administration of study 
drug. Concomitant medications administered within 30 days prior to dose administration 
must be approved by the Investigator (or designee), Covance Medical Monitor, and 
Sponsor. Subjects must be able to withhold the use of these medications for 2 hours 
predose and 4 hours postdose on the day of study drug administration, unless approved 
by the Covance Medical Monitor, Investigator (or designee) and Sponsor 
11. Non-hepatic abnormal laboratory values must not be clinically relevant, as judged by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor; 
12. Anemia secondary to hepatic disease will be acceptable if hemoglobin is ≥ 8 g/dL and 
anemia symptoms are not clinically significant. Must have ≥ 35,000 platelets. 
4.4. 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
All subjects: 
1. History or presence of any of the following, deemed clinically significant by the Covance 
Medical Monitor, Investigator (or designee), and/or Sponsor: 
a. History or presence of clinically significant cardiovascular disease:  
i. Myocardial infarction or cerebrovascular thromboembolism within 
6 months prior to dose administration 
ii. Symptomatic angina pectoris within 6 months prior to dose administration 
iii. New York Heart Association Class ≥ 2 congestive heart failure within 
6 months prior to dose administration 
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 
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2. Second degree atrioventricular (AV) block, type 2, or third degree 
AV block 
2. Abnormal laboratory values (clinical chemistry panel [fasted at least 8 hours], excluding 
CK, LFTs, amylase, and lipase as defined below, CBC, and UA) determined to be 
clinically significant by the Investigator (or designee), Covance Medical Monitor, and 
Sponsor at Screening and/or Check-in (Day -1); 
3. Clinically significant abnormality, as determined by the Investigator (or designee), from 
PE at Screening and/or Check-in (Day -1); 
4. 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 will not be eligible; 
5. Consumption of grapefruit/grapefruit juice, or Seville oranges from 14 days prior to dose 
administration and throughout the study; 
6. Subjects with known ongoing alcohol and/or drug abuse within 1 month prior to 
Screening, or evidence of such abuse as indicated by the laboratory assays conducted 
during Screening and/or at baseline; 
7. Consumption of alcohol-, citric acid-, or caffeine-containing foods or beverages within 
48 hours prior to Check-in (Day -1) and throughout the study; 
8. A positive alcohol test result at Screening or Check-in (Day -1);  
9. Positive urine screen for drugs of abuse at Screening or Check-in (Day -1); 
10. Strenuous exercise within 5 days prior to Check-in (Day -1) and throughout the study; 
11. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee); 
12. 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 dose administration (Day 1); 
13. Use or intention to use any prescription or over-the-counter medications (including 
proton pump inhibitors, herbal products, natural or herbal supplements) within 14 days 
prior to dosing and throughout the study, unless deemed acceptable by Covance Medical 
Monitor, the Investigator (or designee), and Sponsor; 
14. Use or intention to use any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers or strong P-gp inhibitors within 14 days prior to dose administration (Day 1) and 
throughout the study, unless deemed acceptable by Covance Medical Monitor, the 
Investigator (or designee), and Sponsor; 
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15. History of a major surgical procedure within 30 days prior to Screening; 
16. 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; 
17. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs except that appendectomy, 
hernia repair, and cholecystectomy will be allowed. Bariatric surgery will not be allowed; 
18. Estimated glomerular filtration rate of <60 mL/min using the Modification of Diet in 
Renal Disease (MDRD) formula; 
19. Subject has required treatment for gastrointestinal bleeding within 6 months prior to 
Check-in (Day -1); 
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); 
Additional exclusion criteria for matched-control healthy subjects: 
23. QT interval corrected for heart rate using Fridericia’s method (QTcF) is > 450 msec;  
24. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
• 
Oral body temperature > 37.5°C; 
• 
Heart rate < 50 or > 99 bpm; 
• 
Systolic BP < 89 or > 139 mmHg; 
• 
Diastolic BP < 50 or > 89 mmHg. 
For these parameters, out-of-range values that are not clinically significant (as determined 
by the Investigator or designee) may be repeated twice during Screening, Check-in 
(Day -1), and predose on Day 1. Note: Rechecks of HR and BP values will be permitted 
up to 2 times to confirm eligibility for study participation. Subjects may be eligible for 
participation in the study based on rechecked HR and/or BP values if the values fall 
within the ranges stated above or if the Investigator (or designee), Covance Medical 
Monitor, and the Sponsor feel that the results are not clinically significant (based on the 
age) and will not impact study conduct; 
25. Abnormal LFTs, as defined by AST, ALT, ALP, and serum (total and direct) bilirubin, as 
well as amylase and lipase above the upper limit of the normal range at Screening or 
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Check-in, unless deemed acceptable by the Investigator (or designee) with prior Sponsor 
approval. 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. Subjects 
may be eligible for participation in the study based on rechecked LFT, amylase, and 
lipase values if the Investigator (or designee), Covance Medical Monitor, and the Sponsor 
deem that the results are not clinically significant and will not impact study conduct; 
26. Any clinically significant deviations from normal ranges in CK unless approved by the 
Investigator (or designee), Covance Medical Monitor, and Sponsor; 
27. Use of tobacco, smoking cessation products, or products containing nicotine within 
3 months prior to Screening and throughout the study. Urine screen for drugs of abuse 
including cotinine and alcohol breath test must be negative at Screening and on Day -1 
(Check-in) of the study unless the positive drug screen is considered to be due to the use 
of a prescription drug which is approved by the Covance Medical Monitor, Investigator 
(or designee), and Sponsor; 
28. 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);  
29. Positive serologic test for HCV antibody at Screening; 
30. History of diabetes mellitus; 
31. History of congenital nonhemolytic hyperbilirubinemia (eg, Gilbert’s syndrome); 
Additional exclusion criteria for subjects with hepatic impairment: 
32. Subject’s QTcF is > 470 msec;  
33. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital signs at 
Screening, Check-in (Day -1), or prior to dosing on Day 1, including: 
• 
Oral body temperature > 37.5°C; 
• 
Heart rate < 50 or > 99 bpm; 
• 
Systolic BP < 90 or > 150 mmHg; 
• 
Diastolic BP < 40 or > 95 mmHg. 
For these parameters, out-of-range values that are not clinically significant (as determined 
by the Investigator or designee) may be repeated twice during Screening, Check-in 
(Day -1), and predose on Day 1. Note: Rechecks of HR and BP values will be permitted 
up to 2 times to confirm eligibility for study participation. Subjects may be eligible for 
participation in the study based on rechecked HR and/or BP values if values fall within 
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the ranges referenced above and the Investigator (or designee), Covance Medical 
Monitor, and the Sponsor feel that the results are not clinically significant (based on the 
age and hepatic impairment status) and will not impact study conduct; 
34. Values outside the normal ranges for CK, LFTs, amylase, and lipase may be acceptable 
as consistent with the subject’s hepatic condition, if stable for 1 month prior to Screening, 
and if the Investigator (or designee) and Sponsor feel that the results are not clinically 
significant (based on subject age) and will not impact study conduct; 
35. Smoking more than 5 cigarettes per day or equivalent (eg, e-vapor cigarette, pipe, cigar, 
chewing tobacco, nicotine patch, nicotine gum) throughout the confinement period of the 
study; unable or being unwilling to refrain from the use of tobacco or nicotine containing 
products for 2 hours prior to dosing and 4 hours after dose administration; 
36. History of unstable diabetes mellitus (as evidenced by hemoglobin A1c ≥ 9.0% at 
Screening). Medications for the treatment of diabetes mellitus must be reviewed and 
approved by the Investigator (or designee), Covance Medical Monitor, and Sponsor; 
37. Subject has a portal systemic shunt; 
38. Subject has required new medication for hepatic encephalopathy within the 6 months 
prior to Check-in (Day -1); 
39. Recent history of paracentesis (within 56 days prior to Check-in [Day -1]). 
4.5. 
Subject Number and Identification 
Subjects will be assigned into groups based on their level of hepatic function (Table 2) and will 
be assigned a number by clinical site staff based on the assigned group. Assignment of numbers 
within each group will be in ascending order and no numbers will be omitted. Subject number 
will consist of 6 digits in which the first set of 3 digits will identify the site and the second set of 
3 digits will identify the subject (eg, 001-101). Subject numbers will be used on all study 
documentation. For subjects who are withdrawn by the Investigator (or designee) or who 
voluntarily withdraw prematurely from the study, replacement subjects will be enrolled only if 
deemed necessary by the Sponsor. If necessary, as determined by the Sponsor, subjects who fail 
to complete the treatment or have insufficient PK data may be replaced. Replacement subjects 
will be assigned a subject number by adding 400 to the last 3 digits of the subject number for the 
subject they are replacing (eg, Subject Number 001-501 replaces Subject Number 001-101-105).  
Table 2 
Subject Group and Number of Subjects 
Group 
Description of Hepatic Functiona 
N 
1 
Matched Normal Hepatic Function 
8 to 16 
2 
Mild Hepatic Impairment 
8 
3 
Moderate Hepatic Impairment 
8 
4 
Severe Hepatic Impairment 
8 
a Hepatic function determined using the Child-Pugh assessment (Section 3.2). 
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4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue the 
study. Subjects may be withdrawn because of the following: change in compliance with 
inclusion/exclusion criterion that is clinically relevant and affects subject safety, occurrence of 
AEs, occurrence of pregnancy, intake of nonpermitted concomitant medication that might affect 
subject safety or study assessments/objectives, etc. Notification of withdrawal will immediately 
be made to the Study Monitor. In case of withdrawal, efforts will be made to perform all final 
study day assessments (Appendix 5). 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 will be followed until resolution of all their AEs or until the unresolved AEs 
are judged by the Investigator (or designee) to have stabilized. 
The entire study may be discontinued at the discretion of the Investigator (or designee), Sponsor, 
or Covance Medical Monitor 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 investigational sites regarding the end of study procedures. 
4.7. 
Matching Process 
A matched-control healthy subject will be matched to hepatically impaired subjects (age 
[± 10 years], BMI [± 20%], and sex). An individual matched-control healthy subject may be 
matched with up to 1 subject within each hepatic impairment group (ie, to a maximum of 
3 hepatically impaired subjects across the study [1 mild, 1 moderate, and 1 severe], but to no 
more than 1 subject in each impairment group). A listing of the matched subjects will be 
included in the Clinical Study Report. 
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 3). 
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Table 3 
Study Drug 
Study Drug 
LOXO-292
Forma 
Capsule
Strength 
20 mgb and 80 mg
Supplier 
Loxo Oncology, Inc.
Manufacturer 
Avista Pharma Solutions, Inc. 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the study drug. 
bThe 20-mg dose will only be used if dosing is decreased following the interim review of safety data (Section 8.2). 
The IMP (capsule containing 20 mg [if applicable following interim analysis] or 80 mg 
LOXO-292) will be supplied by the Sponsor (or designee), along with the batch/lot numbers and 
Certificate of Analysis. It will be provided in high density polyethylene bottles and stored 
according to the instructions on the label. 
Study drugs will be stored at the study site 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 drug 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 clinical 
site employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
Subjects will receive a single dose of LOXO-292, given orally as two 80-mg capsules (160 mg 
total dose) orally in the morning on Day 1. The dose of LOXO-292 will be given within 
15 minutes following predose blood sample collection. If dosing is decreased in hepatic subjects 
following the interim review of safety data (Section 8.2), healthy matched-control subjects will 
be dosed at the lower dose in order to provide appropriate matches to hepatically impaired 
subjects. 
Each unit dose will be prepared by qualified clinical staff. Each unit dose container will be 
appropriately labeled. 
Appropriate unit dose(s), as described above, will be administered to consecutively numbered 
subjects. Although the timing of events requires that each subject will be consistently 
administered the appropriate dose at a specific time, the exact dose time of consecutive subjects 
may be staggered to obviate the need to have all subjects on precisely the same study schedule. 
For each dose, the subject’s actual dose time will be recorded in the source documents and 
transcribed into the eCRF. 
Each dose of LOXO-292 will be administered orally with approximately 240 mL of room 
temperature water. Doses will be preceded by a fast of at least 2 hours from food (not including 
water) and will be followed by a fast from food (not including water) for at least 1 hour postdose. 
Subjects will restrict their consumption of water for 1 hour prior to dose; at all other times during 
the study, matched-control healthy subjects may consume water ad libitum and hepatically 
impaired subjects may consume water in a manner consistent with their medical condition. 
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Subjects will not lay supine for 1 hour following dose administration, except as necessitated by 
the occurrence of an AE(s) and/or study procedure(s). 
5.3. 
Randomization 
This is a nonrandomized 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 study site staff. 
• Immediately after dose administration, visual inspection of the mouth and hands will be 
performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of LOXO-292 will be 
performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of LOXO-292 
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-292 capsules will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurs within 5 half-lives (if known) or 30 days, whichever is 
longer, prior to dose administration (Day 1). 
All prescription and over-the-counter medications (including proton pump inhibitors, herbal 
products, natural or herbal supplements) are prohibited for 14 days prior to dose administration 
(Day 1) and throughout the study, unless deemed acceptable by the Covance Medical Monitor, 
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Investigator (or designee), and Sponsor or, if the subject is hepatically impaired, needed to 
stabilize the subject’s underlying medical condition (or concurrent baseline conditions) as 
described below. Moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers and strong 
P-gp inhibitors are prohibited for 14 days prior to dose administration (Day 1) and throughout 
the study. 
For hepatically impaired subjects, the use of prescription and nonprescription medications that 
are needed to stabilize the subject’s underlying medical condition (or concurrent baseline 
conditions) and deemed acceptable by the Covance Medical Monitor, Investigator (or designee) 
and Sponsor are allowed, provided that the subject has been on a stable dose for a minimum of 
30 days prior to study drug administration. Hepatically impaired subjects must be able to 
withhold the use of these medications for 2 hours predose and 4 hours postdose on the day of 
study drug administration, unless approved by the Covance Medical Monitor, Investigator (or 
designee), and Sponsor. Short-term medication adjustments may be made upon consultation with 
the Covance Medical Monitor, Investigator (or designee), and Sponsor per the Medical 
Responsibility Plan. The use of additional medications is to be avoided from 14 days prior to 
study drug administration until study completion unless required to treat an AE. All concomitant 
medications will be reviewed by the Covance Medical Monitor, Investigator (or designee), and 
Sponsor prior to subject approval. 
Any medication taken by a subject during the course of the study, including details of its dosage, 
administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without prior 
approval of the Covance Medical Monitor, Investigator (or designee), and Sponsor, unless its use 
is deemed necessary in a medical emergency. In this case, the use of the concomitant medication 
will be reported as soon as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
Matched-control healthy subjects are required to refrain from use of tobacco, smoking cessation 
products, and nicotine-containing products within 3 months prior to Screening and during the 
entire study. Hepatically impaired subjects are required to refrain from the use of tobacco- and 
nicotine-containing products within 2 hours prior to dosing and for 4 hours postdose. 
Consumption of grapefruit, grapefruit juice, or Seville oranges from 14 days prior to dose 
administration (Day 1) and throughout the study will not be allowed unless deemed acceptable 
by the Covance Medical Monitor, Investigator (or designee), and Sponsor. 
Subjects are required to abstain from consuming alcohol-, citric acid-, and caffeine-containing 
foods and beverages for 48 hours prior to Check-in (Day -1) and throughout the study, unless 
deemed acceptable by the Investigator.  
Subjects will refrain from strenuous exercise from 5 days prior to Check-in (Day -1) and during 
the period of confinement at the clinical site and will otherwise maintain their normal level of 
physical activity throughout the entire study (ie, will not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
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While confined at the clinical site, subjects will receive a standardized diet at scheduled times 
that do not conflict with other study-related activities. 
Doses of LOXO-292 will be preceded by a fast of at least 2 hours from food (not including 
water) and will be followed by a fast from food (not including water) for at least 1 hour postdose. 
Glucose tablets may be administered as needed for treatment of hypoglycemia. Subjects may 
consume water ad libitum. 
7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for PK analysis of LOXO-292 plasma levels and protein binding and potential 
analysis of metabolites will be collected at the timepoints specified in Appendix 5. The exact 
time of the study drug administration and the actual time of blood sampling for PK analysis and 
protein binding will be recorded on the eCRF. 
Processing, storage, and shipping instructions for these PK blood and protein binding samples 
will be provided in a separate Laboratory Manual. The number of blood samples and total blood 
volume required for PK testing and protein binding is presented in Appendix 3. 
7.1.2. 
Analytical Methodology 
Concentrations of LOXO-292 in plasma will be determined using a validated bioanalytical 
method. Specifics of the bioanalytical methods will be provided in a separate document. The 
concentrations of total and unbound LOXO-292 will be determined in a sample of predose 
plasma fortified with a known concentration of LOXO-292. The unbound fraction will be 
calculated based on total and unbound LOXO-292 levels. Samples of plasma may be analyzed 
for exploratory analyses of metabolites. If such analyses are conducted, the results will be 
reported separately by the Sponsor. 
7.2. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee), Covance 
Medical Monitor, or Sponsor.  
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
any other procedures to be performed at the same timepoint. The order of priority for scheduling 
procedures around a timepoint is (in descending order of priority): 
• Dosing; 
• Pharmacokinetic blood sampling; 
• Vital signs assessments; 
• Electrocardiograms; 
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• 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 nonleading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 
Appendix 5 (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 during the study. 
All AEs, whether volunteered, identified by the subject’s responses to HDYF? inquiries, or noted 
on PE, ECG, vital signs assessments, or laboratory tests, will be recorded throughout the study 
(ie, from signing of the ICF until Study Completion), either as subject medical history (if the 
event is present  prior to signing of the Informed Consent) or as AEs (if the event occurs after 
administration of LOXO-292). Between the time of ICF signing to administration of LOXO-292 
only AEs assessed as related to study procedures should be reported.  All SAEs that develop 
from the time of ICF signing until Study Completion are to be reported.  Following Clinic 
Discharge, only AEs or SAEs assessed as related to study drug should be reported. 
All AEs (nonserious and serious) should be followed until resolution, return to baseline, 
assessment as stable by the Investigator (or designee), or until the subject withdraws consent or 
is lost to follow-up. 
Subjects will receive a Safety Follow-up phone call approximately 7 days after they are 
discharged from the clinical site to determine if any AE has occurred since the last study visit. 
At all times, a subject may be required to remain at the clinical site for longer at the discretion of 
the Investigator (or designee). 
Any event that meets the criteria of a Suspected Unexpected Serious Adverse Reactions 
(SUSAR) will be reported to the IRB/IEC according to site 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 IB for 
LOXO-292 for expected adverse reactions. 
7.2.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours], coagulation 
parameters, CBC, thyroid-stimulating hormone, hemoglobin A1c [hepatic subjects only], and 
UA) will be collected at the timepoints specified in Appendix 5. 
Screens for HCV antibody, HBsAg, and HIV antibody will be performed at Screening. A drug 
screen for selected drugs of abuse will be performed at Screening and repeated at Check-in 
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(Day -1; including an alcohol breath test for all subjects and, for matched-control healthy 
subjects only, including cotinine). A serum qualitative pregnancy test (females only) and a 
follicle-stimulating hormone test (postmenopausal females only) will be performed at the 
timepoints specified in Appendix 5.  
The number of blood samples and total blood volume required for clinical laboratory evaluations 
is presented in Appendix 3. A list of the specific evaluation is in Appendix 2. 
7.2.3. 
Vital Signs 
Vital signs (including oral temperature, respiratory rate, and supine BP and HR) will be obtained 
at the timepoints specified in Appendix 5. 
Blood pressure and HR measurements should be performed using the same arm for each reading 
and measurements should be taken after the subject has been resting in the supine position for at 
least 5 minutes.  
When vital signs assessments are scheduled at the same time as blood draws, the blood draws 
will be obtained at the scheduled timepoint, and the vital signs will be obtained prior to and as 
close as possible to the scheduled blood draw. 
7.2.4. 
12-Lead Electrocardiogram 
A 12-lead ECG (including PR, RR, QRS, and QT interval parameters) will be obtained after the 
subject has been resting for at least 10 minutes in the supine position at the timepoints specified 
in Appendix 5. The QT interval will be corrected for HR by Fridericia’s (QTcF = QT/[RR]1/3) 
formulae. 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained prior to and as close 
as possible to the scheduled blood draw. 
7.2.5. 
Physical Examination 
A complete or abbreviated PE will be performed at the timepoints specified in Appendix 5. 
Complete PEs will evaluate general appearance and the following body systems/organs: 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; lymphatic; musculoskeletal/extremities; and neurological. Weight and height will be 
recorded (height only recorded during Screening). 
The PE at Screening will include hepatic encephalopathy and ascites evaluations for the CP 
assessment. 
Abbreviated PEs will evaluate general appearance and the following body systems/organs: 
dermatological; pulmonary; cardiovascular; abdominal; and neurological. 
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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations to detect statistically significant 
differences among groups. Six subjects each per hepatic function group are planned to complete 
the study. This is considered a sufficient sample size to evaluate the PK of LOXO-292 under 
various degrees of hepatic function. 
8.2. 
Interim Analysis 
Interim reviews of safety data will be conducted for each group when the first 4 subjects from 
Group 2 (mild hepatic impairment subjects) are enrolled and have completed the study, when the 
first 4 subjects from Group 3 (moderate hepatic impairment subjects) are enrolled and have 
completed the study, and when the first 2 subjects from Group 4 (severe hepatic impairment 
subjects), are enrolled and have completed the study. These safety data will include AEs and 
serious AEs (SAEs), vital signs, PEs, ECGs, and clinical laboratory tests. If available, PK data 
and matched-control healthy subject data may also be used during the review. Enrollment and 
dosing for remaining subjects in any group may occur after the interim data for that group are 
reviewed and the Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is 
safe to proceed with dosing. 
Each interim review will be a teleconference between the Covance Medical Monitor, 
Investigator (or designee), and/or Sponsor to discuss safety data.  
Following the interim review of safety data for a group, the dose level may be decreased for the 
remaining subjects in any group pending discussion and agreement between the Covance 
Medical Monitor, Investigator (or designee), and/or Sponsor. If dosing is decreased, it will also 
be decreased for the impaired subjects’ respective matched-control healthy subjects. 
8.3. 
Analysis Populations 
8.3.1. 
Study Populations 
The PK Population will consist of all subjects who have received a dose of LOXO-292, have at 
least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter can be 
computed. 
The Safety Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 postdose safety assessment. 
8.4. 
Pharmacokinetic Analysis 
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-292, and according to the model independent approach:5  
Cmax 
maximum observed concentration 
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tmax 
time to maximum observed concentration 
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the 
last measurable concentration, calculated using the linear 
trapezoidal rule for increasing and decreasing concentrations 
AUC0-∞ 
AUC extrapolated to infinity, calculated using the formula: 
 
 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
 
 
where Ct is the last measurable concentration and λZ is the 
apparent terminal elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC 
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 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t1/2 = natural log (ln)(2)/λZ 
CL/F 
apparent systemic clearance 
Vd/F 
apparent volume of distribution during the terminal phase 
MRT 
mean residence time  
fu 
unbound fraction, calculated as unbound concentration divided by 
total concentration 
Additionally, the number of points used to estimate λZ will be presented in a listing. 
The fu value determined for each subject will be used to calculate the following unbound 
LOXO-292 PK parameters for each individual subject:  
Cmax,u 
Unbound Cmax, calculated as Cmax*fu 
AUC0-t,u 
Unbound AUC0-t, calculated as AUC0-t*fu 
AUC0-∞,u 
Unbound AUC0-∞, calculated as AUC0-∞*fu 
CL/F,u 
Unbound CL/F, calculated as Dose/AUC0-∞,u 
Vd/F,u 
Unbound Vd/F, calculated as CL/F,u/λZ 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 6.4 or higher (Certara USA Inc.). 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the Statistical Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. Other data handling 
procedures will be detailed in the SAP. 
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8.5. 
Statistical Analysis of Pharmacokinetic Data 
Plasma concentrations and PK parameters will be summarized by hepatic function with 
descriptive statistics (number, arithmetic mean, standard deviation, coefficient of variation 
[CV%], geometric mean, geometric CV%, median, minimum, and maximum). In addition, 
summary statistics for protein binding will be tabulated by hepatic function group. 
The primary analysis planned for this study is to evaluate the PK of LOXO-292 after a single 
dose in subjects with mild, moderate, or severe hepatic impairment, compared to subjects with 
normal hepatic function. The following statistical methodology will be used, based on 1 to 1 
matching: 
An analysis of covariance (ANCOVA) will be performed on the ln transformed AUC0-t, AUC0-∞, 
and Cmax. The ANCOVA model will contain a categorical factor of population for subjects with 
varied degree hepatic impairment (severe, moderate, and mild) and healthy matched control 
subjects, a categorical covariate (sex), and continuous covariates (age and BMI). Ratios of least 
squares means (LSM) and 90% CIs will be calculated using the exponentiation of the difference 
between renal function cohort LSM from the ANCOVA analyses on the ln transformed AUC0-t, 
AUC0-∞, and Cmax. The specific procedures will be documented in the SAP. 
All statistical calculations will be performed using SAS Version 9.3 or greater. 
8.6. 
Statistical Analyses of Safety Data 
All subjects who received a dose of LOXO-292 and have at least 1 postdose safety assessment 
will be included in the safety analyses. All safety assessments, including AEs and SAEs, vital 
signs measurements, clinical laboratory (including CK) results, PE results, concomitant 
medications, and ECG interpretations, will be tabulated and summarized where possible, using 
descriptive methodology by hepatic function group and, as needed, by timepoint. Unless 
otherwise specified, baseline value is defined as the last nonmissing measurement before 
administration of the study drug. No formal statistical analyses are planned for the safety data. 
The incidence of AEs for each hepatic function will be presented by severity (matched control 
healthy subjects, mild, moderate, and severe) and by relationship to study drug as determined by 
the Investigator (see Appendix 1 for AE reporting). All treatment-emergent AEs will be 
summarized by system organ class and preferred term, with a breakdown by hepatic function, 
using Medical Dictionary for Regulatory Activities. 
8.7. 
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 clinical site 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. 
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Data will be validated during data entry by the clinical site and verified by the Study Monitor. 
Data will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be reviewed 
by the Covance scientific team. The eCRF and ancillary data will be converted into final SAS® 
datasets following Study Data Tabulation Model or client-provided specifications. The final 
datasets structure will be verified using Web Submission Data Manager®, while the dataset 
content will be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will be 
peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by the 
Covance scientific team during the dry run and data review meetings. 
The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.8. 
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. 
Administrative aspects including regulatory, ethical, and study oversight considerations are 
described in Appendix 4. 
 
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9. REFERENCES 
1. Loxo Oncology, Inc. LOXO-292 – Investigator’s Brochure (Version 3.0). 05 April 2018. 
2. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The Liver and 
Portal Hypertension. Philadelphia, PA: Saunders; 1964:50-64. 
3. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-649. 
4. Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function: Study 
Design, Data Analysis, and Impact on Dosing and Labeling. U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER), May 2003. 
5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York, NY: Marcel Dekker Inc.; 
1982. 
 
 
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10. APPENDICES 
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Appendix 1: Adverse Event Reporting 
1.1 Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy subject, whether or not considered drug related by the 
Investigator (or designee). A treatment-emergent AE is an AE that is reported after a dose of 
study drug. 
The following are all AEs: 
• Unfavorable changes in general condition; 
• Subjective or objective signs/symptoms; 
• Concomitant diseases or accidents; 
• Clinically relevant adverse changes in laboratory parameters observed in a subject during 
a clinical study. 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant by 
the Investigator or designee), and accidents observed in the context of a clinical trial, irrespective 
of a possible causal relationship with the administration of the trial substance. Events occurring 
in the framework of a clinical trial during drug-free and post-treatment periods, under placebo, or 
in a reference group receiving drug or nondrug therapy are also to be designated as AEs. 
1.2 Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2 Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*  
• Grade 3 Severe or medically significant but not immediately life threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**  
• Grade 4 Life-threatening consequences: Urgent intervention indicated 
• Grade 5 Death related to AE 
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 
5 options for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option.  
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
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**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
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. 
 
1.3 Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed during the study and for up to 90 days after study drug administration should 
be reported by the Investigator (or designee) via eFax to the Sponsor’s clinical safety 
representative within 24 hours of being notified. The Sponsor’s safety representative will then 
forward the Pregnancy Form to the Investigator for completion. 
eFax: +1 (203) 643-2013 
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. The subject or partner should be 
followed by the Investigator until completion of the pregnancy. If the pregnancy ends for any 
reason before the anticipated date, the Investigator should notify the Sponsor’s clinical safety 
representative. At the completion of the pregnancy, the Investigator will document the outcome 
of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as a serious AE (SAE; ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an 
SAE. 
Male subjects will be instructed to notify the Investigator immediately if they discover their 
sexual partner is pregnant. In this instance, the partner must provide written consent before 
pregnancy information can be collected. When a site becomes aware that the female partner of a 
male subject is pregnant, they are to contact the Covance Medical Monitor immediately (within 
24 hours of the site staff becoming aware of the event) in addition to notifying the Sponsor’s 
safety representative via eFax. 
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All pregnancies should be recorded on the AE electronic Case Report Form, 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. 
1.4 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.  
1.5 Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed in 
the Reference Safety Information section of the IB or if it is not listed at the specificity or 
severity that has been observed for an unapproved investigational medicinal product. 
1.6 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 clinical site to the Sponsor, the Covance 
Medical Monitor, and the responsible Institutional Review Board (IRB). Final determination of 
whether an event represents a SUSAR will be the responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or reported, 
and within 24 hours of any SAE (regardless of whether the event is assessed as related or 
unrelated to study drug) being first recognized or reported, the Sponsor’s clinical safety 
representative will be notified by the Investigator or designee in writing (eg, facsimile) using the 
following eFax number or email: 
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eFax: +1 (203) 643-2013 
email: safety@loxooncology.com 
To report the SAE, the completed report form should be sent by eFax to the Sponsor’s clinical 
safety representative within 24 hours of awareness. Incoming reports are reviewed during normal 
business hours. Additional reporting instructions and the SAE Report Form are provided in the 
Study Manual.  
The IRB will be notified of any FDA-reportable AE within the timeframe required by the IRB. 
The IRB Serious and Unexpected Adverse Experience Submission Form will be completed and 
submitted with the copy of the written confirmation or summary of the AE. 
 
 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel (Fasted): 
Complete Blood Count: 
Other Tests: 
Alanine aminotransferase 
Hematocrit 
Hemoglobin A1c (for hepatic 
impairment subjects only) 
Thyroid-stimulating hormone 
 
Albumin 
Hemoglobin 
Alkaline phosphatase 
Mean corpuscular hemoglobin 
Amylase 
Aspartate aminotransferase 
Mean corpuscular hemoglobin 
concentration 
Bilirubin (direct and total) 
Mean corpuscular volume 
Blood urea nitrogen  
Platelet count 
Coagulation Parameters: 
Calcium 
Red blood cell (RBC) count 
Activated partial thrombin time 
Chloride 
RBC distribution width 
Partial thromboplastin time 
Cholesterol 
Creatine kinase 
Creatinine (Renal function will be 
calculated using the MDRD formula) 
Glucose 
Lipase 
Potassium  
Sodium 
Total protein  
Triglycerides  
Uric acid 
White blood cell (WBC) count  
WBC differential (percent and 
absolute):  
Prothrombin time 
International normalized ratio 
 
Basophils 
Eosinophils  
Lymphocytes  
Monocytes 
Neutrophils 
Serology: 
Human immunodeficiency virus 
antibody  
Hepatitis B surface antigen 
Hepatitis C virus antibody  
 
 
 
Drug Screen: 
 
Urinalysis: 
 
For Female Subjects only: 
Including but not limited to the 
following:  
Alcohol (ethanol)  
Amphetamines 
Barbiturates 
Benzodiazepines 
Bilirubin  
Color and appearance  
Glucose  
Ketones  
Leukocyte esterase  
Nitrite 
Pregnancy test (serum qualitative) 
Follicle-stimulating hormone 
(postmenopausal females only) 
Cannabinoids  
Cocaine (metabolite)  
Methadone  
Opiates  
Phencyclidine  
Cotinine (healthy subjects only) 
Occult blood  
pH and specific gravity  
Protein  
Urobilinogen  
Microscopic exam including 
bacteria, casts, crystals, epithelial 
cells, RBCs, and WBCs (if protein, 
leukocyte esterase, nitrite, or blood is 
positive) 
 
 
 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Purpose 
Approximate Blood 
Volume per Sample (mL) 
Maximum Number 
of Blood Samples 
Approximate Total 
Volume (mL) 
Serology 
4 
1 
4 
Hemoglobin A1c (hepatic 
impairment subjects only) 
4 
1 
4 
Primary Pharmacokinetic (PK) 
Sampling 
4 
21 
84 
Unbound Drug PK Sampling 
4 
1 
4 
Clinical Laboratory Tests: 
Complete Blood Count 
Clinical Chemistry 
Coagulation Parameters 
 
4 
4 
3 
 
6 
6 
6 
 
24 
24 
18 
Serum Pregnancy Test 
(females only) 
2 
3 
6 
Serum Follicle-stimulating 
Hormone Test 
(postmenopausal females only) 
2 
1 
2 
Thyroid-stimulating hormone 
2 
1 
2 
Total: 
172 mL 
Note: Although the total maximum volume to be analyzed is anticipated to be approximately 
172 mL, due to the variability in sampling requirements at different laboratories, the total volume 
of blood collected from each subject may vary. 
  
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Appendix 4: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an Institutional Review 
Board (IRB) by the Investigator and reviewed and approved by the IRB before the study is 
initiated.  
Any amendments to the protocol will require IRB and regulatory authority (as locally required) 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB. 
• Notifying the IRB of serious AEs or other significant safety findings as required by IRB 
procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects will 
be instructed that they are free to obtain further information from the Investigator (or designee) 
and that their participation is voluntary and they are free to withdraw from the study at any time. 
Subjects will be given an opportunity to ask questions about the study prior to providing consent 
for participation. 
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Following discussion of the study with clinical site personnel, subjects will sign 2 copies of the 
ICF in the presence of a suitably trained member of staff to indicate that they are freely giving 
their informed consent. One copy will be given to the subject, and the other will be maintained in 
the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in eCRFs, 
study-related forms, study reports, or any related publications. Subject and Investigator personal 
data will be treated in compliance with all applicable laws and regulations. In the event the study 
protocol, study report, or study data are included in a public registry, all identifiable information 
from individual subjects or Investigators will be redacted according to applicable laws and 
regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data may 
be examined by Sponsor or Contract Research Organization (CRO [ie, Covance]) auditors or 
other authorized personnel appointed by the Sponsor, by appropriate IRB members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of 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. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality checking 
of the data. Predefined agreed risks, monitoring thresholds, quality tolerance thresholds, 
controls, and mitigation plans will be documented in a risk management register. 
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Additional details of quality checking to be performed on the data may be included in a 
Data Management Plan.  
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and transmitted 
to Covance electronically, will be integrated with the subject’s eCRF data in accordance with the 
Data Management Plan.  
An eCRF must be completed for each enrolled subject who undergoes any screening procedures, 
according to the eCRF completion instructions. The Sponsor, or CRO, will review the supporting 
source documentation against the data entered into the eCRFs to verify the accuracy of the 
electronic data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data on 
the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical study 
agreement (CSA). Unless otherwise specified in the CSA, the following process will occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and or other presentation 
materials to the Sponsor for review before submission for publication or presentation. The 
Sponsor will have 60 days to respond with any requested revisions, including without limitation, 
the deletion of confidential information. The Investigator will act in good faith upon requested 
revisions, except the Investigator will delete any confidential information from such proposed 
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publications. The Investigator will delay submission of such publication or presentation materials 
for up to an additional 90 days in order to have a patent application(s) filed. 
 
 
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Appendix 5: Schedule of Assessments 
Study Procedures 
Screening 
(Days -29 to -2) 
Check-in  
(Day -1) 
 
Day 1 
 
Days 2 to 
10 
Discharge or ET
Day 11 
Follow-up Phone Call 
~7 days post Discharge 
Confined to the Study Site 
 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Child-Pugh Class Scorea 
X 
X 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
Height/Weight/BMI 
X 
Xc
 
 
 
 
Physical Examinationd 
X 
X 
X 
 
X 
 
12-Lead ECGe 
X 
X 
 
 
X 
 
Vital Signsf 
X 
X 
X 
X 
X 
 
HDYF? Inquiryg 
X 
X 
X 
X 
X 
X 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
LOXO-292 Dosei 
 
 
X 
 
 
 
Primary PK Blood Samplesj 
 
 
X 
X 
X 
 
Unbound Drug PK Blood Samplek 
 
 
X 
 
 
 
Clinical Laboratory Evaluationsl 
X 
X 
 
X
X 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
Hemoglobin A1c Testm 
X
 
 
 
 
 
Drug Screenn 
X 
X 
 
 
 
 
Prior and Concomitant Medicationso 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testp 
X 
X 
 
 
X 
 
Follicle-Stimulating Hormone Testq 
X 
 
 
 
 
 
Thyroid-Stimulating Hormone Test 
X 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; ET = early termination; HDYF? = How Do You Feel?; HIV = human immunodeficiency 
virus; PK = pharmacokinetic; SAE = serious adverse event. 
a Subjects with hepatic impairment only. Child-Pugh (CP) scores will be calculated at Screening and Check-in (Day -1); hepatically impaired subjects will be assigned to groups 
according to CP scores at Check-in (Day -1) to ensure stability of hepatic impairment and subject safety, as determined by the Investigator (or designee). 
b Interim medical history only. 
c Weight and BMI (based on Screening height) only. 
d A complete physical examination (PE) will be performed at Screening and Discharge (or ET). An abbreviated PE will be performed at Check-in (Day -1) and 1 hour postdose on 
Day 1.  
Page 143 of 163
I 
I 


Protocol 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
Protocol Final, 15 October 2018  
Page 55 of 55 
e Electrocardiograms will be collected after the subject has rested in the supine position for at least 10 minutes, and will be obtained prior to and as close as possible to the 
scheduled blood draws. 
f Vital signs measurements (oral temperature, respiratory rate, and supine blood pressure and heart rate [HR]) will be obtained at Screening and Check-in (Day -1), predose, at 
2 hours (± 10 minutes) and 4 hours (± 10 minutes) postdose, and at each Study Day through Clinic Discharge (or ET). Vital signs measurements should be carried out prior to and 
as close as possible to having blood drawn. Blood pressure and HR will be measured using the same arm for each reading after the subject has been supine for at least 5 minutes. 
g An HDYF? inquiry performed at Screening (after the Informed Consent Form 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 recorded beginning at informed consent. 
i Dose administration is to be given during the morning of Day 1. 
j Primary PK blood samples will be collected prior to dosing (within 30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours 
postdose (Day 11). The allowed sampling window for PK blood samples will be the following: within 15 minutes prior to dosing for the predose sample timepoint; ± 5 minutes 
for sampling timepoints within the first 12 hours; ± 30 minutes for sampling timepoints > 12 hours < 36 hours; and ± 60 minutes for the sampling timepoints ranging from 48 to 
240 hours. 
k For assessment of unbound plasma concentrations of LOXO-292, a blood sample will be collected predose (ie, within 15 minutes prior to dosing). 
l Clinical chemistry panel (fasted at least 8 hours), coagulation parameters, complete blood count, and urinalysis will be performed at Screening, Check-in (Day -1), 24 hours 
postdose (Day 2), Day 5, Day 8, and at Clinic Discharge (Day 11) or ET. 
m Hemoglobin A1c test performed at Screening for subjects with hepatic impairment only.  
n Alcohol breath test and drugs of abuse urine test. Results from the alcohol and drug tests will be used to determine subject eligibility per the inclusion/exclusion criteria. 
o Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 
30 days prior to study drug administration for prescription medications, and 14 days prior to study drug administration for nonprescription medications, will be recorded on the 
subject’s electronic Case Report Form. 
p Female subjects only. 
q Postmenopausal female subjects only. 
Page 144 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
Letter of Administrative Change (LOAC) No. 5 
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, 
and Pharmacokinetic Study of LOX0-292 Administered to Fasted Hepatically 
Impaired Male and Female Subjects and Fasted Matched-control Healthy 
Subjects 
O1iginal Protocol Date: 15 October 2018 
Letter of Administrative Change (LOAC) No. 1 Effective Date: 01 November 2018 
Study Contact 
Protocol Amendment 1 Date: 19 December 2018 
LOAC No. 2 Effective Date: 17 April 2019 
LOAC No. 3 Effective Date: 10 May 2019 
LOAC No. 4 Effective Date: 10 July 2019 
LOAC No. 5 Effective Date: 02 August 2019 
Sponsor Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Number: 133193 
Pl 
MD, PhD 
Principal Investigator 
Multiple Investigators 
Pl 
to Loxo Oncology, Inc. 
"='"'~--
701 Gateway Boulevard 
South San Francisco, California 94080 
Tel:PI 
Desniption of Changes: 
The pmpose of this LOAC is to claiify that all subjects will have serology screening for 
hepatitis C vim s pe1f o1m ed as pa.it of Screening procedmes, and that the results of this screen 
must be negative for subjects to be eligible. 
Section 4.1, Screening Procedures, #8, of the Protocol will be revised as follows: 
Screens for hepatitis C vims (HCV) antibody (fer health3/ st4jects oaly), hepatitis B smface 
antigen (HBsAg), and human immunodeficiency vims (HIV) antibody (Appendix 2); 
Section 4.4, Exclusion Criteria, Subsection All Subjects, No. 4, co1Tectly states that all subjects 
will have serology testing perfmmed: 
Final, 02 Aug 2019 
Page I of 4 
Page 145 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 02 Aug 2019 
Page 2 of 4 
 
4. 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 will not be eligible;  
 
Section 4.4, Exclusion Criteria, Subsection Additional exclusion criteria for matched-control 
healthy subjects, #30, of the protocol will be revised as follows: 
30. Positive serologic test for HCV antibody at Screening. 
Exclusion criteria No. 31 through No. 41 will be renumbered to No. 30 through No. 40, 
respectively, as a result of this update. 
 
Reason for Changes: 
Hepatitis C virus screening is to be performed for healthy subjects as well as hepatically 
impaired subjects. Instances in the text implying that hepatitis C virus screening would only be 
performed for healthy subjects were removed. 
Page 146 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 02 Aug 2019 
Page 3 of 4 
 
INVESTIGATOR AGREEMENT 
 
 
 
 
 
 
 
 
 
Name, Qualifications  
Date 
Principal Investigator 
Page 147 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
SPONSOR AGREEMENT 
rr~ocuSigned by: 
02- Aug-19 I 16:02 : 37 PDT 
Sionet,;Na111e.p 1 
J 
~
,op~rove this document 
, _ 
s,g~·,ng Time: 8/212019 7:02:35 PM EDT 
Loxo~6~45B48DE60B79BAD69CBA 
Date 
Final, 02 Aug 2019 
Page4 of 4 
Page 148 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
Letter of Administrative Change (LOAC) No. 4 
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, 
and Pharmacokinetic Study of LOX0-292 Administered to Fasted Hepatically 
Impaired Male and Female Subjects and Fasted Matched-control Healthy 
Subjects 
Protocol Date: 15 October 2018 
Letter of Administrative Change (LOAC) No. 1 Effective Date: 01 November 2018 
Protocol Amendment 1 Date: 19 December 2018 
LOAC No. 2 Effective Date: 17 April 2019 
LOAC No. 3 Effective Date: 10 May 2019 
LOAC No. 4 Effective Date: 10 July 2019 
Sponsor Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Number: 133193 
Study Contact 
Pl -
-
MD, PhD 
Principal Investigator 
Multiple Investigators 
Pl 
to Loxo Oncology, Inc. 
701 Gateway Boulevard 
South San Francisco, California 94080 
Tel:PI 
Desuiption of Changes: 
The pmpose of this LOAC is to amend the text in Section 4.3, Inclusion Criteria, Sub-Section, 
All Subjects of the Protocol (Version 2, dated 19 December 2018) to include bilateral tubal 
libgation as an acceptable fonn of ste1ilization for female study paiticipants. 
Section 4.3, Inclusion Criteria, Sub-Section, All Subjects of the Protocol will be revised as 
follows: 
Females ofnonchildbeaiing potential, defined as being pennanently ste1ile (ie, due to 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal ligation or 
confnm ed tubal occlusion more than 6 months prior to study drng administration) or 
postmenopausal (defined as at least 12 months postcessation of menses without an alternative 
medical cause). Postmenopausal status will be confumed with a screening senun follicle-
stimulating hon none level within the site laborato1y 's range for postmenopausal status. All 
Final, 10 Jul 2019 
Page I of 4 
Page 149 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 10 Jul 2019 
Page 2 of 4 
 
females must have a negative qualitative serum pregnancy test (serum human chorionic 
gonadotropin) at Screening and Check-in (Day -1). 
 
Reason for Changes: 
Bilateral tubal libgation was erroneously not listed as an acceptable form of sterilization for 
female study participants in Section 4.3, Inclusion Criteria, Sub-Section, All Subjects, in the 
Protocol (Version 2, dated 19 December 2018).
Page 150 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 10 Jul 2019 
Page 3 of 4 
 
INVESTIGATOR AGREEMENT 
 
 
 
 
 
 
 
 
 
Name, Qualifications  
Date 
Principal Investigator 
Page 151 of 163


Clinical Protocol 
Covance Study 8393612 
n
~ocuSigned by: 
Final, 10 Jul 2019 
SPONSOR AGREEMENT 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
10- Jul - 19 I 20:06:57 PDT 
Date 
Page 4 of 4 
Page 152 of 163 


Clinical Protocol 
Covance Study 8393612 
Letter of Administrative Change No. 3 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
OPEN-LABEL, NONRANDOMIZED, SINGLE-DOSE, PARALLEL-GROUP, SAFETY, 
TOLERANCE, AND PHARMACOKINETIC STUDY OF LOX0-292 ADMINISTERED 
TO FASTED HEPATICALLY IMP AIRED MALE AND FEMALE SUBJECTS AND 
FASTED MATCHED-CONTROL HEALTHY SUBJECTS 
Protocol Date: 15 October 2018 
Letter of Administrative Change (LOAC) No. 1 Effective Date: 01 November 2018 
Protocol Amendment 1 Date: 19 December 2018 
LOAC No. 2 Effective Date: 17 Aptil 2019 
LOAC No. 3 Effective Date: 10 May 2019 
Sponsor Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Number: 133193 
Study Contact 
Pl 
MD. PhD 
to Loxo Oncology, Inc. 
---------
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
Tel: I 
Description of Changes: 
Ptinciple Investigator 
Multiple Investigators 
The purpose of this LOAC is to allow re-screening of subjects who have failed an initial screen, 
and to allow the Sponsor to provide approval of enrolled subjects by email. 
Section 4.2 cunently reads as follows: 
"The Covance Medical Monitor will review the medical histo1y and all screening evaluations for 
potential subjects p1ior to enrollment. Ptior to dosing, the Sponsor will provide written approval 
of subjects selected for enrollment by the Investigator. 
Subjects who meet all the inclusion c1iteria 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), Covance Medical Monitor, or Sponsor." 
Final, 10 May 2019 
Page I of 4 
Page 153 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 10 May 2019 
Page 2 of 4 
 
This LOAC revises Section 4.2 to read as follows:  
“The Covance Medical Monitor will review the medical history and all screening evaluations for 
potential subjects prior to enrollment. Prior to dosing, the Sponsor will provide written approval 
of subjects selected for enrollment by the Investigator. 
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), Covance Medical Monitor, or Sponsor. 
Subjects who are determined to be screen failures are permitted to be re-screened if the PI (or 
designee), with agreement from the Covance Medical Monitor and the Sponsor, feels that the 
subject may meet eligibility criteria upon re-screen. Re-screened patients will be provided a new 
subject number.” 
Reason for Changes: 
These changes are being made to allow re-screening of subjects that have failed their initial 
screen but are believed to be eligible for enrollment if a second screen is completed, and to allow 
approval of enrolled subjects by email.  
 
Page 154 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 10 May 2019 
Page 3 of 4 
 
INVESTIGATOR AGREEMENT 
 
 
 
 
 
 
 
 
 
Name, Qualifications  
Date 
Principal Investigator 
Page 155 of 163


Clinical Protocol 
Covance Study 8393612 
(1~ocuSigned by: 
Lox 
Final, 10 May 2019 
SPONSOR AGREEMENT 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
13- May- 19 I 22:24: 14 PDT 
Date 
Page 4 of 4 
Page 156 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
Letter of Administrative Change No. 2 
OPEN-LABEL, NONRANDOMIZED, SINGLE-DOSE, PARALLEL-GROUP, SAFETY, 
TOLERANCE, AND PHARMACOKINETIC STUDY OF LOX0-292 ADMINISTERED 
TO FASTED HEPATICALLY IMP AIRED MALE AND FEMALE SUBJECTS AND 
FASTED MATCHED-CONTROL HEALTHY SUBJECTS 
Protocol Date: 15 October 2018 
Letter of Administrative Change (LOAC) No. 1 Effective Date: 01 November 2018 
Protocol Amendment 1 Date: 19 December 2018 
LOAC No. 2 Effective Date: 17 Aptil 2019 
Sponsor Reference Nwnber: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Nwnber: 133193 
Study Contact 
Pl 
MD, PhD 
Pl 
to Loxo Oncology, Inc. 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
Tel:?I 
Descl'iption of Changes: 
Principal Investigator 
Multiple Investigators 
This purpose of this LOAC is to increase the upper age limit of the 01iginal protocol. 
Inclusion Crite1ion #1 in Section 4.3 cutTently reads as follows: 
1. Males, and females of nonchildbeaiing potential, between 18 and 65 years of age, 
inclusive, at Screening; 
This LOAC revises Inclusion Crite1ion #1 to read as follows: 
1. Males, and females of nonchildbeai·ing potential, between 18 and 69 years of age, 
inclusive, at Screening; 
The Synopsis will also be revised to reflect this change. 
Final, 17 April 2019 
Page I of 4 
Page 157 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 17 April 2019 
Page 2 of 4 
 
Reason for Changes: 
This change is being made to allow Screening and inclusion of additional potential participants. 
Review of interim safety and tolerability data shows that doses of LOXO-292 were well-
tolerated in subjects with hepatic impairment and healthy volunteers (age range 38 to 64 years 
old) with no Grade ≥ 3 toxicities reported.
Page 158 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 17 April 2019 
Page 3 of 4 
 
INVESTIGATOR AGREEMENT 
 
 
 
 
 
 
 
 
 
Name, Qualifications  
Date 
Principal Investigator 
Page 159 of 163


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
SPONSOR AGREEMENT 
(c 
DocuSigned by: 
IF' 
L 
111::.:.s,noAr &1,./T!e'. Pl 
l---------
'a~ n: I approve this document 
emta~me: 
4/fill19 7:40:06 PM EDT 
01A6C83~l5145848DE60879BAD69CBA 
Final, 17 April 2019 
17- Apr-19 I 16 : 40:14 PDT 
Date 
Page 4 of 4 
Page 160 of 163 


Clinical Protocol 
Covance Study 8393612 
Letter of Administrative Change No. 1 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
OPEN-LABEL, NONRANDOMIZED, SINGLE-DOSE, PARALLEL-GROUP, SAFETY, 
TOLERANCE, AND PHARMACOKINETIC STUDY OF LOXO-292 ADMINISTERED 
TO FASTED HEPATICALLYIMPAIRED MALE At~D FEMALE SUBJECTS At~D 
FASTED MATCHED-CONTROL HEALTHY SUBJECTS 
Protocol Date: 15 October 2018 
Letter of Administrative Change (LOAC) Effective Date: 01 November 2018 
Sponsor Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
IND Number: 133193 
Stud Contact 
Pl 
MD, PhD 
to Loxo Oncology, Inc . 
.__.,_.._-.,_.....,....-
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
Tel: Pl 
Description of Changes: 
Principal Investigator 
Multiple Investigators 
This purpose of this LOAC is to clarify which se1ious adverse events (SAEs) should be rep01ted. 
The last 2 sentences of the third paragraph of Section 7 .2.1 on page 36 of the Protocol ClllTently 
reads as follows: 
All SAEs that develop from the time ofICF signing until Study Completion are to be rep01ted. 
Following Clinic Discharge, only AEs or SAEs assessed as related to sn1dy diug should be 
repo1ted 
This LOAC revises SAE rep01ting to read as follows: 
All SAEs that develop from the time ofICF signing until Study Completion are to be repo1ted. 
Following Clinic Discharge through Study Completion, all SAEs must be repo1ted and only AEs 
assessed as related to study diug should be rep01ted. 
Reason for Changes: 
The change in SAE rep01ting is being made to eliminate contradict01y infonnation in the 
Protocol and to clarify that all SAEs should be rep01ted. 
Final, 01 November 2018 
Page I of3 
Page 161 of 163 


Clinical Protocol 
Covance Study 8393612 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
 
 
Final, 01 November 2018 
Page 2 of 3 
 
INVESTIGATOR AGREEMENT 
 
 
 
 
 
 
 
 
 
Name, Qualifications  
Date 
Principal Investigator 
Page 162 of 163


Clinical Protocol 
Covance Study 8393612 
Final, 01 November 2018 
SPONSOR AGREEMENT 
CONFIDENTIAL 
Protocol LOXO-RET-18022 
01- Nov- 18 I 17:20:58 EDT 
Date 
Page 3 of3 
Page 163 of 163 

SAP_001.pdf: 
Statistical Analysis Plan J2G-OX-JZJD
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Pharmacokinetic 
Study of LOXO-292 Administered to Fasted Hepatically Impaired Male and Female Subjects and 
Fasted Matched-control Healthy Subjects
NCT05436912
Approval date: 28-Feb-2019


Clinical Study Report 
CONFIDENTIAL 
Covance Study: 8393612 
Protocol Reference: LOXO-RET-18022 
  
16.1.9. 
Documentation of Statistical Methods 
20 May 2020
Page 1 of 22


Final 1: 28 February 2019 
Page 1 of 21 
STATISTICAL ANALYSIS PLAN 
Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, 
and Pharmacokinetic Study of LOXO-292 Administered to Fasted Hepatically 
Impaired Male and Female Subjects and Fasted Matched-control Healthy 
Subjects 
Statistical Analysis Plan Status: Final 1 
Statistical Analysis Plan Date: 28 February 2019 
Study Drug:  LOXO-292 
Sponsor Reference Number: LOXO-RET-18022 
Covance Study Number: 8393612 
Clinical Phase 1 
Sponsor: 
 
Loxo Oncology, Inc. 
701 Gateway Boulevard, 
Suite 420 
South San Francisco,  
California  
94080 
Study Site: 
Multiple sites 
Sponsor Signatory: 
 of Biostatistics 
Principal Investigator: 
Multiple Investigators 
Page 2 of 22
PI
PI--


Statistical A nal ysis Pla n  
C O N FI D E N TI A L 
C o va nce St u d y:  8 3 9 3 6 1 2 
S p o ns or Refere n ce: L O X O- R E T- 1 8 0 2 2 
Fi nal 1: 2 8 Fe br uar y 2 0 1 9 
P ag e 2  o f 2 1
1  S T A TI S TI C A L A N A L Y SI S P L A N A P P R O V A L SI G N A T U R E S 
B y si g ni n g t his pa ge w he n t he Statistical A nal ysis Pla n ( S A P) i s c o nsi dere d fi nal, t he si g nat ories 
a gree t o t he statistical a n d p har mac o ki netic ( P K) a nal ys es t o b e perf or me d f or t his st u d y, a n d t o 
t he  basic  f or mat  of  t he  ta bles,  fi g ures,  a n d  listi n gs  ( T F Ls).  Once  t he  S A P  has  bee n  si g ne d, 
pr o gra m mi n g of t he T F Ls base d u p o n t his d oc u m e nt ca n pr ocee d. A n y m o dificati o ns t o t he S A P 
a n d T F Ls ma d e aft er si g ni n g ma y res ult i n a w or k-sc o pe c h a n ge.  
C o v a nce a p pr o v al: 
St atistici a n 
D
P h ar m a c o ki neticist  
D at
S p o ns or a p pr o v al: 
, P h
of Bi ost atistics 
D ate 
, P h
o f Bios t atistics
Pa ge 3 of 2 2
PI
PI
PI
PI
PI
PI
PI
PI
St atisti ci a n 
P h a r m a c o ki n eti cist 
R e a s o n : I a ppr o v e t his d oc u m e nt 
....,. _""'S"""J_a- n"'"i _.g · Ti m e: 3/ 1 2/ 2 0 1 9 1 2: 3 6 :4 4 P M E D T 
.. _ _ _ _, 9 C 4 2 5 7 7 0 4 0 7 9 AF 5 8 1 F 0 2 2 F 7 F F 5 18 
D at e 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8393612 
 
Sponsor Reference: LOXO-RET-18022  
 
Final 1: 28 February 2019  
 
Page 3 of 21 
 
2  TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................... 2 
2 
TABLE OF CONTENTS ................................................................................................... 3 
3 
ABBREVIATIONS ............................................................................................................ 5 
4 
INTRODUCTION .............................................................................................................. 8 
5 
STUDY OBJECTIVE ......................................................................................................... 8 
6 
STUDY DESIGN ............................................................................................................... 8 
7 
TREATMENTS ................................................................................................................ 10 
8 
SAMPLE SIZE JUSTIFICATION ................................................................................... 11 
9 
DEFINITION OF ANALYSIS POPULATIONS ............................................................ 11 
10 STATISTICAL METHODOLOGY ................................................................................. 11 
10.1 General ....................................................................................................................... 11 
10.1.1 Definition of Baseline and change from baseline ............................................ 12 
10.1.2 Repeat and Unscheduled Readings .................................................................. 12 
10.2 Demographics and Subject Disposition ..................................................................... 12 
10.3 Pharmacokinetic Assessment ..................................................................................... 13 
10.3.1 Pharmacokinetic Parameters ............................................................................ 13 
10.3.2 Criteria for Handling Plasma Concentrations Below the Limit (CBLL) of 
Quantification ................................................................................................... 14 
10.3.3 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life .. 14 
10.3.4 Calculation of AUC .......................................................................................... 15 
10.3.5 Anomalous Values ........................................................................................... 15 
10.3.6 Handling Rules for Missing or BLQ Values .................................................... 15 
10.4 Statistical Methods for Pharmacokinetic Data .......................................................... 16 
10.4.1 Descriptive Statistics ........................................................................................ 16 
10.4.2 Primary Analysis .............................................................................................. 16 
10.4.3 Analysis of Covariance .................................................................................... 17 
10.5 Safety and Tolerability Assessments ......................................................................... 18 
10.5.1 Adverse Events ................................................................................................. 18 
10.5.2 Clinical Laboratory Parameters ........................................................................ 18 
10.5.3 Vital Signs ........................................................................................................ 19 
10.5.4 Electrocardiogram ............................................................................................ 19 
10.5.5 Other Assessments ........................................................................................... 20 
10.5.6 Safety and Tolerability Statistical Methodology .............................................. 20 
Page 4 of 22


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8393612 
 
Sponsor Reference: LOXO-RET-18022  
 
Final 1: 28 February 2019  
 
Page 4 of 21 
 
11 INTERIM ANALYSES .................................................................................................... 20 
12 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 20 
13 DATA PRESENTATION ................................................................................................ 21 
13.1 Insufficient Data for Presentation ............................................................................... 21 
14 REFERENCES ................................................................................................................. 21 
Page 5 of 22


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8393612 
 
Sponsor Reference: LOXO-RET-18022  
 
Final 1: 28 February 2019  
 
Page 5 of 21 
 
 
3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADaM 
analysis data model 
AE 
adverse event 
ANCOVA 
analysis of covariance  
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC0-∞,u 
unbound area under the concentration-time curve extrapolated to infinity   
AUC0-t 
area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUC0-t,u 
unbound area under the concentration-time curve from time 0 to the last measurable 
concentration 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CBC 
Complete Blood Count 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval 
CL/F 
apparent systemic clearance 
CL/F,u 
unbound apparent systemic clearance 
Page 6 of 22


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8393612 
 
Sponsor Reference: LOXO-RET-18022  
 
Final 1: 28 February 2019  
 
Page 6 of 21 
 
Cmax 
maximum observed plasma concentration 
Cmax,u 
unbound maximum observed concentration 
CP 
Child-Pugh 
CSR 
Clinical Study Report 
CV% 
coefficient of variation 
EC 
Early Clinical 
ECG 
Electrocardiogram 
fu 
fraction unbound in plasma 
ICF 
Informed consent  
ICH 
International Conference on Harmonisation 
LLOQ 
lower limit of quantification 
 
apparent terminal elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTlast 
Mean residence time 
NC 
Not calculated 
NR 
No result 
PE 
Physical examination 
PK 
Pharmacokinetic 
PT 
preferred term 
Page 7 of 22


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8393612 
 
Sponsor Reference: LOXO-RET-18022  
 
Final 1: 28 February 2019  
 
Page 7 of 21 
 
QTc 
QT correction; QT interval corrected for heart rate 
QTcF 
QTc calculated using the Fridericia correction  
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
t½ 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed concentration 
Vd/F 
apparent volume of distribution during the terminal phase 
Vd/F,u 
unbound apparent volume of distribution during the terminal phase 
 
 
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Statistical Analysis Plan  
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Page 8 of 21 
4  INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 dated 
15 October 2018). 
This SAP describes the planned analysis of the safety, tolerability and PK 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 shell document. 
The intent of this document is to provide guidance for the statistical analyses of PK data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Loxo Oncology, Inc. and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning 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 agreed upon and finalized, they will 
serve as the template for this study’s CSR. 
This SAP supersedes the 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 in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Loxo Oncology, Inc. and Covance EC Biometrics and identified in the CSR. 
The SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5  STUDY OBJECTIVE 
The objectives of this study are: 
•
To evaluate the PK profile of LOXO-292 in subjects with impaired hepatic function compared
to matched-control healthy subjects; 
•
To evaluate safety and tolerability of LOXO-292 in subjects with impaired hepatic function
and matched-control healthy subjects. 
6  STUDY DESIGN 
This study will be an open-label, nonrandomized, multi-center, single-dose, parallel-group, 
safety, tolerability, and PK study of LOXO-292 administered orally at a dose of 160 mg in fasted 
matched control healthy males and females with normal hepatic function compared to fasted, 
hepatically impaired subjects. 
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Subjects will be recruited in this study so that up to 24 subjects with hepatic impairment (up to 8 
subjects within each of the mild, moderate, and severe impairment groups, per Child-Pugh [CP] 
classification – assessed at Screening and Check-in [Day -1]), and approximately 8 to 16 subjects 
with normal hepatic function are enrolled. Subjects will be enrolled within the following groups 
based on their CP score at Screening and assuming no change in underlying hepatic status at 
Check-in (Day -1) as judged by the Investigator (or designee), the Covance Medical Monitor, 
and the Sponsor: 
• Group 1: Matched-control healthy subjects with normal hepatic function; 
• Group 2: Subjects with mild hepatic impairment (CP Class A, score of 5 or 6); 
• Group 3: Subjects with moderate hepatic impairment (CP Class B, score of 7 to 9); 
• Group 4: Subjects with severe hepatic impairment (CP Class C, score of 10 to 15). 
A parallel design strategy will be adopted for the hepatic impairment groups, with interim 
reviews of safety data after the first 4 subjects from Group 2 (mild hepatic impairment subjects), 
the first 4 subjects from Group 3 (moderate hepatic impairment subjects), and the first 2 subjects 
from Group 4 (severe hepatic impairment subjects) are enrolled and have completed all study-
related assessments including the Follow-up phone call. Enrollment and dosing for remaining 
subjects in any group may occur after the interim data for that group are reviewed and the 
Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is safe to proceed 
with dosing. If available, PK data and matched-control healthy subject data may also be used 
during the interim review. 
Each matched-control healthy subject (Group 1) will be demographically matched (1:1) by age 
(± 10 years), body mass index (BMI; ± 20%), and sex to the enrolled hepatic impairment 
subject(s). Should another hepatic impairment subject be identified with whom an already 
enrolled healthy subject is demographically matched, the healthy subject may also be matched 
with that impaired subject as long as the impaired subject is in a different hepatic impairment 
group. Each subject with normal hepatic function may be matched with up to 1 subject within 
each hepatic impairment group. 
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 site on Day -1 (Check-in). Replacement subjects 
may be enrolled only if deemed necessary by the Sponsor.  
Subjects will be confined at the clinical site from the time of Check-in (Day  1) until Clinic 
Discharge on Day 11 upon completion of all PK and safety assessments. A Follow-up phone call 
will occur approximately 7 days after Clinic Discharge. 
On the morning of Day 1, after at least a 2-hour fast, an oral dose of 160 mg LOXO 292 
administered as two 80-mg capsules will be given with 240 mL water. No food will be allowed 
for up to 1 hour postdose. Glucose tablets may be administered as needed for treatment of 
hypoglycemia. 
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Figure 1 Study design schematic 
 
ICF = Informed Consent Form; PK = pharmacokinetic. 
Note: Single oral dose of LOXO-292 at 160 mg administered orally after at least a 2-hour fast. 
 
In this study design, physical examinations (PEs), 12-lead electrocardiograms (ECGs), vital 
signs, How Do You Feel? inquiries, clinical chemistry panel, coagulation parameters, complete 
blood count, and urinalysis will be performed at Screening and at specified times during the 
study. All adverse events (AEs) will be recorded throughout the study (ie, from signing of the 
ICF until Study Completion), either as subject medical history (if the event is reported as 
occurring prior to signing of the ICF) or as AEs (if the event occurs after administration of 
LOXO-292). Between the time of ICF signing to administration of LOXO-292 only AEs 
assessed as related to study procedures should be reported. All serious AEs (SAEs) that develop 
from the time of ICF signing until Study Completion are to be reported. 
Study Completion is defined as the time of the last subject’s Follow-up phone call. 
7  TREATMENTS 
The following is a list of the study treatment abbreviations and ordering that will be used in the 
TFLs 
Hepatic 
Function 
Designation 
Child-Pugh 
Classification 
Study Treatment Name 
Abbreviation 
Order 
on 
TFLs 
Normal Hepatic 
Function 
< 5 points 
Single dose of 160 mg 
LOXO-292 
160 mg 
LOXO-292 
1 
Mild Hepatic 
Impairment 
5 or 6 points 
(Class A) 
Single dose of 160 mg 
LOXO-292 
160 mg 
LOXO-292 
2 
Moderate Hepatic 
Impairment 
7 to 9 points 
(Class B) 
Single dose of 160 mg 
LOXO-292 
160 mg 
LOXO-292 
3 
Severe Hepatic 
Impairment 
10 to 15 points 
(Class C) 
Single dose of 160 mg 
LOXO-292 
160 mg 
LOXO-292 
4 
 
Page 11 of 22
Screening 
Study Treatment ( Days -1 to 11) 
Days -29 to -2 
Check-in: 
Day -1 
Dosing: Day 1 
Discharge: 
Day 11 
PK sampling: Days 1 to 11 (0-240 hours postdose) 
Safety assessments: From signing of the ICF to Follow-up phone call 
Follow-up 
7 (± 2) days 
after Discharge 


Statistical Analysis Plan  
 
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8  SAMPLE SIZE JUSTIFICATION 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations to detect statistically significant 
differences among groups. Six subjects each per hepatic function group are planned to complete 
the study. This is considered a sufficient sample size to evaluate the PK of LOXO-292 under 
various degrees of hepatic function. 
9  DEFINITION OF ANALYSIS POPULATIONS 
The Safety Population will consist of all subjects who received at least 1 dose of study drug 
(LOXO-292) and have at least 1 post dose safety assessment. 
The PK population will comprise all subjects who comply sufficiently with the protocol and 
display an evaluable PK profile (e.g., exposure to treatment, availability of measurements and 
absence of major protocol violations). Samples from all subjects will be assayed even if the 
subjects do not complete the study. PK population will comprise all subjects who comply 
sufficiently with the protocol and display an evaluable PK profile (e.g., exposure to treatment, 
availability of measurements and absence of major protocol violations). A subject who 
experiences emesis at or before 2 times median Tmax for the given treatment during the PK 
sampling period time course may be excluded from the PK summary statistics and statistical 
analysis   
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
The All Subjects Populations will consist of any subjects who enrolled on to the study (signed 
informed consent, met all inclusion and exclusion criteria, and had study assessments recorded 
on the database as per the protocol). 
10  
STATISTICAL METHODOLOGY 
10.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation (SD), median, minimum, maximum, and number. For log-normal data (eg, the PK 
parameters: areas under the concentration-time curve [AUCs] and maximum observed 
concentration [Cmax]), the geometric mean and geometric coefficient of variation (CV%) will 
also be presented. For categorical data, frequency counts and percentages will be presented. Data 
listings will be provided for all subjects up to the point of withdrawal, with any subjects 
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excluded from the relevant population highlighted. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.4. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilized to ensure 
compliance with CDISC standards.         
10.1.1 Definition of Baseline and change from baseline  
 Baseline for each parameter is defined as the last non-missing value measured prior to dosing, 
including repeat (vital signs andECGs and unscheduled (clinical laboratory parameters) readings 
(see Section 10.1.2 for definitions of repeat and unscheduled readings).  
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate. 
10.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires a recheck. Repeat 
readings are labelled as ‘Repeat’ in the listings. Prior to dosing, all readings taken in addition to 
the original reading are defined as predose repeats. Unscheduled post-dose repeat readings will 
not be used in the summarization and calculations.” 
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Unscheduled readings are labelled as ‘Unscheduled’ in the listings. Because unscheduled 
readings are not associated with any scheduled timepoint, they are excluded from all summaries 
(with the exception that they may be used as baseline, as stated in Section 10.1.1). 
10.2 Demographics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and BMI will be 
summarized and listed by hepatic function group. The CP score will be listed. Subject disposition 
will be summarized and listed by hepatic function group.  
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10.3 Pharmacokinetic Assessment 
10.3.1 Pharmacokinetic Parameters 
The following PK parameters will be determined where possible from the plasma concentrations 
of  LOXO-292 using non-compartmental methods performed using Phoenix WinNonlin (Certara 
USA, Inc.) version 6.4 or higher:) 
Parameter 
Definition 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
AUC0-t 
area under the concentration-time curve (AUC) from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for 
increasing and decreasing concentrations 
AUC0- 
AUC extrapolated to infinity, calculated using the formula: 
AUC0- = AUC0-t + 
z
t
λ
C
 
where Ct is the last measurable concentration and Z is the apparent terminal 
elimination rate constant 
%AUCextrap 
percentage extrapolation for AUC 
Z 
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 
t1/2 
apparent terminal elimination half-life (whenever possible),  
where t1/2 = natural log (ln)(2)/Z 
CL/F 
apparent systemic clearance 
Vd/F 
apparent volume of distribution during the terminal phase 
MRTlast 
mean residence time  
 
Based on data from in vitro equilibrium dialysis study of a sample of pre-dose plasma from each 
subject, spiked with LOXO-292, the unbound fraction (fu) in plasma, expressed as a decimal, 
will be calculated from protein binding concentration data as the unbound drug concentration 
(concentration in buffer chamber) divided by the total drug concentration in plasma 
(concentration in the plasma chamber). The fu value determined for each subject will be used to 
calculate the following unbound LOXO 292 PK parameters for each individual subject: 
Cmax,u  
Unbound Cmax, calculated as Cmax*fu 
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AUC0-t,u 
Unbound AUC0-t, calculated as AUC0-t*fu 
AUC0-,u 
Unbound AUC0-, calculated as AUC0-*fu 
CL/F,u  
Unbound CL/F, calculated as Dose/AUC0-,u 
Vd/F,u  
Unbound Vd/F, calculated as CL/F,u/Z 
Additional PK parameters may be determined where appropriate. The number of points used to 
estimate Z, the lower and upper limits of the points used in estimation, and the adjusted 
coefficient for determination of exponential fit (R2 adjusted) will be presented in a listing. 
PK analysis will, where possible, be carried out using actual 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.  
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. 
10.3.2 Criteria for Handling Plasma Concentrations Below the Limit (CBLL) of 
Quantification 
Concentration values that are below the level 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 predose concentration is missing, these values are set to zero in PK analysis by default within 
Phoenix WinNonlin. 
10.3.3 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
Number of Data points 
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At least three data points will be included in the regression analysis and preferably should not 
include Cmax. 
Goodness of fit 
When assessing terminal elimination phases, the 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 (AUC0-, λZ, t1/2, CL/F, and Vd/F) will only be calculated if the R2 
adjusted value of the regression line is greater than or equal to 0.7 
Period of Estimation  
Time period used for the estimation of apparent terminal elimination half-lives, where possible, 
will be over at least two half-lives.  
Where an elimination half-life is estimated over a time period of less than two 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 study report. 
10.3.4 Calculation of AUC 
 The minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with at 
least one of these concentrations following Cmax.  
 AUC0- values where the percentage extrapolation is less than 20% will be reported. 
AUC0- values where the percentage extrapolation is between 20 to 30% will be flagged 
and included in the descriptive statistics, whilst AUC0- values where the percentage 
extrapolation is greater than 30% will be reported but excluded from descriptive statistics.   
10.3.5 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 study report. 
Embedded BLQ values may be considered anomalous depending on the route of administration 
and the characteristics of the drug. 
 Positive predose value(s) greater than 5% of Cmax may be excluded from the summary 
statistics of PK tables and statistical analysis at the discretion of the Pharmacokineticist. 
10.3.6 Handling Rules for Missing or BLQ Values   
For Pharmacokinetic Plasma Drug Concentration Data 
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The following rules will be applied if there are values that are BLQ or if there are missing values 
(eg, no result [NR]) in a 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 fewer than three values in the data series, only the min, max 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 SD, median, min and max 
will be presented as zero, and the geometric mean and geometric CV% will be denoted as 
NC. 
 If the value of the arithmetic mean or median is below the lower limit of quantification, 
these values will be presented as zero and the geometric mean and geometric CV% will be 
denoted as NC. 
For 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 three 
concentrations, and/or three concentrations if the last is Cmax. 
10.4 Statistical Methods for Pharmacokinetic Data 
10.4.1 Descriptive Statistics  
Arithmetic means, %CV, SD, median, Min, Max, and n will be calculated for PK parameters 
separately in healthy subjects and subjects with hepatic impairment. Geometric mean and 
geometric %CV will be provided for all PK parameters except tmax. Median, min, max, and n will 
be calculated for tmax. In addition, summary statistics for protein binding will be tabulated by 
hepatic function group. 
10.4.2 Primary Analysis 
To evaluate the effect of hepatic function group on the PK of a single dose of LOXO-292, paired 
t-test will be performed for each hepatic impairment group versus the normal group with respect 
to 1 to 1 matching. The 1 to 1 matching comparisons of interests include: 
• Subjects with severe hepatic impairment versus healthy matched control subjects. 
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• Subjects with moderate hepatic impairment versus healthy matched control subjects. 
• Subjects with mild hepatic impairment versus healthy matched control subjects. 
Since the comparison groups of subjects are independent in terms of degrees of hepatic 
impairment and dependent based on the matching criteria, paired Proc ttest in SAS will be used 
for this comparison on the natural log transformed PK parameters (AUC0-t, AUC0-∞, and 
Cmax). The 90% confidence interval for the ratio between each level of impaired hepatic 
function versus the matched-control healthy subject group will be presented. The normality 
assumption will be explored to ensure no major deviation to the assumption exists. The 
corresponding results along with any outliers will be evaluated and can be included in the CSR 
appendix as needed. Any major outliers will be investigated case by case and determine the 
appropriate action on how to handle them. 
Example SAS code: 
proc ttest data= logpk alpha=0.1; 
by paramcd; 
paired normal*impairment; 
run; 
 
where; 
paramcd = categorical variable to indicate different PK parameters 
impairment= natural log-transformed PK parameters for the subjects with hepatic impairment 
normal= natural log-transformed PK parameters for the healthy matched controlled subjects 
 
10.4.3 Analysis of Covariance  
To evaluate the effect of hepatic function group on the PK of a single dose of LOXO-292In 
addition, an analysis of covariance (ANCOVA) will be performed on the natural log transformed 
AUC0-t, AUC0-∞, and Cmax. The ANCOVA model will contain a categorical factor of population 
for subjects with various degrees of hepatic impairment (mild, moderate, and severe) and healthy 
matched control subjects, a categorical covariate (sex), and continuous covariates (age and BMI). 
The ratios of least square means (LSM) and 90% CI for the ratio of the PK parameter for each 
hepatic function group versus the matched normal group will be constructed using the 
exponentiation of the difference and the CIs from the ANCOVA analyses. These ratios will be 
expressed as a percentage relative to the healthy matched control cohort.  
The 1 to 1 matching comparisons of interests include: 
 Subjects with severe hepatic impairment versus healthy matched control subjects. 
 Subjects with moderate hepatic impairment versus healthy matched control subjects. 
 Subjects with mild hepatic impairment versus healthy matched control subjects. 
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Example SAS code: 
proc mixed data = dataset; 
class group sex; 
model lPK = group sex age BMI / alpha=0.1 cl solution outpred=resids; 
lsmeans group / pdiff alpha=0.1; 
ods output lsmeans=lsmeans; 
ods output diffs=diffs; 
run;  
quit; 
 
Residual plots will be produced to assess the adequacy of the model. 
10.5 Safety and Tolerability Assessments 
10.5.1 Adverse Events 
All safety data will be listed by subject. All AEs occurring during this clinical trial will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA®), Version 21.0. A baseline 
sign and symptom is defined as an AE that starts after the subject has provided written informed 
consent and that resolves prior to the receipt of first dose of study drug, or an AE that starts prior 
to the first dosing occasion and does not increase in severity after dosing. A treatment-emergent 
AE (TEAE) is defined as an AE that occurs postdose or that is present predose and becomes 
more severe postdose. The severity of AEs will be categorized based on the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The 
Investigator (or designee) will make a determination of the relationship of the AE to the study 
drug using a 2-category system (i.e. Not Related or Related). Onset times postdose are calculated 
from the last dose administered. The AE severity and relationship are determined by the 
investigator at the site. 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, part, severity grade, relationship to study treatment, outcome, and action. 
TEAEs, drug-related TEAEs, and TEAEs by severity will be summarized by each hepatic 
function group. The frequency of TEAEs (the number of TEAEs, the number of subjects 
experiencing a TEAE, and the percentage of subjects experiencing a TEAE) will be summarized 
by each hepatic function group, and Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class (SOC) and Preferred Term (PT). The summary and frequency TEAE tables 
will be presented for all causalities and for those TEAEs considered related to the study drug 
(those that have a relationship of ’RELATED’). Any severe TEAEs, serious TEAEs (SAEs), or 
TEAEs leading to discontinuations will be tabulated. For any AEs that change severity ratings 
the AE will be included only once under the maximum severity rating in the summaries.    
10.5.2 Clinical Laboratory Parameters 
Clinical chemistry, hematology and coagulation data will be summarized by hepatic function 
group and timepoint. Changes from baseline will be calculated. In addition, all Clinical 
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Chemistry, CBC, hematology, coagulation and urinalysis data outside the clinical reference 
ranges will be listed by parameter and hepatic function group.  
Values for any clinical chemistry, hematology, coagulation and urinalysis values outside the 
clinical reference ranges will be flagged on the individual subject data listings. Reference ranges 
will be presented in the listing and used to determine either the low or high values in comparison 
to the reference ranges. Hemoglobin A1c Test Data will be listed by Subject. 
All out of range laboratory evaluation data (including clinical chemistry, hematology, and 
urinalysis) deemed clinically relevant by the PI (or designee) will be listed by parameter. 
10.5.3 Vital Signs 
The vital signs data (including oral temperature, supine blood pressure, heart rate, and respiratory 
rate) will be summarized by hepatic function group and time point, together with changes from 
baseline.  Figures of mean vital signs and mean change from baseline profiles will be presented 
by hepatic function group.  
Vital signs values outside the clinical reference ranges will be flagged in the individual subject 
data listings. 
Repeat and unscheduled readings will be handled as defined in Section 10.1.2  
10.5.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the Fridericia correction (QTcF), the PR and QT intervals, the QRS 
duration, and heart rate.  
The ECG data along with change from baseline will be listed and summarized by timepoint.  
Values for ECG parameters outside the clinical reference ranges will be flagged on the individual 
subject data listings. 
An outlier analysis will be performed including all maximum individual postdose measurements 
(not the mean data), including all repeat and unscheduled readings. All incidences of QTc and 
QTcF (>450 and ≤ 480, >480 and ≤ 500, and >500 ms) will be flagged in the listings. Change of 
> 30msec in QTcF will be flagged. 
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10.5.5 Other Assessments 
PE and concomitant medications(coded using WHODrug Version 01 September 2018 Global 
Dictionary DDE+HD Version B3 format ) will be listed by hepatic function group and time point 
using descriptive statistics. 
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
Medical history data will be presented. 
10.5.6 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11  
INTERIM ANALYSES 
Interim reviews of safety data will be conducted for each group when the first 4 subjects from 
Group 2 (mild hepatic impairment subjects) are enrolled and have completed the study, when the 
first 4 subjects from Group 3 (moderate hepatic impairment subjects) are enrolled and have 
completed the study, and when the first 2 subjects from Group 4 (severe hepatic impairment 
subjects), are enrolled and have completed the study. Subjects will be considered to have 
completed the study if they have undergone all study-related assessments as described in the 
Schedule of Assessments, including the Follow-up phone call. These safety data will include 
AEs and serious AEs, vital signs, PEs, ECGs, and clinical laboratory tests. If available, PK data 
and matched-control healthy subject data may also be used during the review. Enrollment and 
dosing for remaining subjects in any group may occur after the interim data for that group are 
reviewed and the Covance Medical Monitor, Investigator (or designee), and Sponsor agree it is 
safe to proceed with dosing. 
Each interim review will be a teleconference between the Covance Medical Monitor, 
Investigator (or designee), and/or Sponsor to discuss safety data.  
Following the interim review of safety data for a group, the dose level may be decreased for the 
remaining subjects in any group pending discussion and agreement between the Covance 
Medical Monitor, Investigator (or designee), and/or Sponsor. If dosing is decreased, it will also 
be decreased for the impaired subjects’ respective matched-control healthy subjects. 
12  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
The statistical methods for analysing the PK data outlined in the synopsis and main body of the 
protocol (version 1.0) and  have been clarified in further detail in Sections 10.4.2 and 10.4.3, 
including an additional analysis suitable for the hepatic design of the trial. 
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Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8393612 
 
Sponsor Reference: LOXO-RET-18022  
 
Final 1: 28 February 2019  
 
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13  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
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