Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single Dose Selpercatinib on the Pharmacokinetics of Rosuvastatin in Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol Addendum J2G-MC-JZPB (a) 
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single Dose 
Selpercatinib on the Pharmacokinetics of Rosuvastatin in Healthy Participants
NCT05906836 
Approval Date: 19-May-2023

CONFIDENTIAL 
Protocol Number J2G-MC-JZPB(a) 
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Title Page  
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of selpercatinib (LY3527723) unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
 
Protocol Title:  
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single Dose 
Selpercatinib on the Pharmacokinetics of Rosuvastatin in Healthy Participants 
Protocol Number: J2G-MC-JZPB 
Amendment Number: a  
Compound: LY3527723 (selpercatinib) 
Brief Title:  
A drug interaction study to investigate the effect of selpercatinib on the pharmacokinetics of 
rosuvastatin. 
Study Phase: Phase 1 
Acronym: JZPB 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Eli Lilly and Company, Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number: 
IND: 133193 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-116682 
 
 
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Protocol Number J2G-MC-JZPB(a) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
03-Apr-2023 
Amendment [a]  
Overall Rationale for the Amendment: 
The protocol is being amended to remove language specific to case report form entry. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8  
Study Assessments 
and Procedures 
Removed bullet 5. 
To remove language regarding sample 
collection actual time case report form 
(CRF) entry for consistency with the 
study electronic case report form (eCRF) 
build. 
 
 
 
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Table of Contents  
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
2. 
Introduction ...................................................................................................................12 
2.1. 
Study Rationale ...............................................................................................................12 
2.2. 
Background .....................................................................................................................12 
2.3. 
Benefit/Risk Assessment ................................................................................................13 
3. 
Objectives and Endpoints ............................................................................................14 
4. 
Study Design ..................................................................................................................15 
4.1. 
Overall Design ................................................................................................................15 
4.2. 
Scientific Rationale for Study Design ............................................................................15 
4.3. 
Justification for Dose ......................................................................................................16 
4.4. 
End of Study Definition ..................................................................................................16 
5. 
Study Population ...........................................................................................................17 
5.1. 
Inclusion Criteria ............................................................................................................17 
5.2. 
Exclusion Criteria ...........................................................................................................18 
5.2.1. 
Rationale for Exclusion of Certain Study Participants ...................................................20 
5.3. 
Lifestyle Considerations .................................................................................................21 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................21 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................21 
5.3.3. 
Activity ...........................................................................................................................21 
5.4. 
Screen Failures ................................................................................................................21 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................21 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................22 
6.1. 
Study Interventions Administered ..................................................................................22 
6.1.1. 
Administration Details ....................................................................................................22 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................23 
6.3. 
Assignment to Study Intervention ..................................................................................23 
6.4. 
Blinding ..........................................................................................................................23 
6.5. 
Study Intervention Compliance ......................................................................................23 
6.6. 
Dose Modification ..........................................................................................................23 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................23 
6.8. 
Treatment of Overdose ...................................................................................................24 
6.9. 
Prior and Concomitant Therapy ......................................................................................24 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................25 
7.1. 
Discontinuation of Study Intervention ............................................................................25 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................26 
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7.1.2. 
QTc Stopping Criteria .....................................................................................................26 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................27 
7.3. 
Lost to Follow up ............................................................................................................27 
8. 
Study Assessments and Procedures.............................................................................28 
8.1. 
Efficacy Assessments .....................................................................................................28 
8.2. 
Safety Assessments .........................................................................................................28 
8.2.1. 
Physical Examinations ....................................................................................................28 
8.2.2. 
Vital Signs .......................................................................................................................28 
8.2.3. 
Electrocardiograms .........................................................................................................29 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................29 
8.2.5. 
Pregnancy Testing ...........................................................................................................30 
8.2.6. 
Safety Monitoring ...........................................................................................................30 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................34 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................35 
8.3.2. 
Pregnancy ........................................................................................................................36 
8.4. 
Pharmacokinetics ............................................................................................................37 
8.4.1. 
Bioanalysis ......................................................................................................................38 
8.5. 
Pharmacodynamics .........................................................................................................38 
8.6. 
Genetics ..........................................................................................................................38 
8.7. 
Biomarkers ......................................................................................................................38 
8.8. 
Immunogenicity Assessments.........................................................................................38 
8.9. 
Health Economics ...........................................................................................................38 
9. 
Statistical Considerations .............................................................................................39 
9.1. 
Statistical Hypotheses .....................................................................................................39 
9.2. 
Analyses Sets ..................................................................................................................39 
9.2.1. 
Study Participant Disposition .........................................................................................39 
9.2.2. 
Study Participant Characteristics ....................................................................................39 
9.3. 
Statistical Analyses .........................................................................................................39 
9.3.1. 
General Considerations ...................................................................................................40 
9.3.2. 
Primary Endpoint Analysis: Pharmacokinetic Analyses ................................................40 
9.3.3. 
Secondary Endpoint Analysis: Safety Analyses .............................................................40 
9.3.4. 
Exploratory Endpoint Analysis .......................................................................................41 
9.4. 
Interim Analysis ..............................................................................................................41 
9.5. 
Sample Size Determination ............................................................................................42 
10. 
Supporting Documentation and Operational Considerations ..................................43 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................43 
10.1.1. Regulatory and Ethical Considerations ...........................................................................43 
10.1.2. Financial Disclosure........................................................................................................44 
10.1.3. Informed Consent Process ..............................................................................................44 
10.1.4. Data Protection................................................................................................................44 
10.1.5. Dissemination of Clinical Study Data.............................................................................45 
10.1.6. Data Quality Assurance ..................................................................................................45 
10.1.7. Source Documents ..........................................................................................................47 
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10.1.8. Study and Site Start and Closure ....................................................................................47 
10.1.9. Publication Policy ...........................................................................................................48 
10.1.10. Investigator Information .................................................................................................48 
10.1.11. Sample Retention ............................................................................................................48 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................49 
10.2.1. Blood Sampling Summary ..............................................................................................51 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................52 
10.3.1. Definition of SAE ...........................................................................................................53 
10.3.2. Definition of Product Complaints ...................................................................................54 
10.3.3. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................54 
10.3.4. Reporting of SAEs ..........................................................................................................56 
10.3.5. Regulatory Reporting Requirements ...............................................................................57 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................58 
10.4.1. Definitions.......................................................................................................................58 
10.4.2. Contraception Guidance..................................................................................................58 
10.4.3. Contraception Methods ...................................................................................................60 
10.5. 
Appendix 5: Genetics......................................................................................................61 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................62 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................63 
10.8. 
Appendix 8: Abbreviations and Definitions ...................................................................64 
11. 
References ......................................................................................................................67 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title:  
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single Dose 
Selpercatinib on the Pharmacokinetics of Rosuvastatin in Healthy Participants 
Brief Title:  
A drug interaction study to investigate the effect of selpercatinib on the pharmacokinetics of 
rosuvastatin. 
Regulatory Agency Identifier Number:  
IND: 133193 
Rationale: 
Rosuvastatin is a commonly used index substrate for breast cancer resistance protein (BCRP) 
(FDA, 2021). Selpercatinib may potentially inhibit BCRP in the intestine according to in vitro 
evaluation. Therefore, this study aims to investigate a potential drug-drug interaction (DDI) by 
evaluating the pharmacokinetics (PK), safety, and tolerability of rosuvastatin in the presence of 
selpercatinib.   
Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
 
 To evaluate the effect of a single dose 
of selpercatinib on BCRP activity in 
healthy participants 
 Cmax and AUC(0-∞) of rosuvastatin 
Secondary 
 
 To describe the safety and tolerability 
of rosuvastatin in combination with 
selpercatinib in healthy participants 
 Incidence of TEAEs and SAEs 
Abbreviations: AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; BCRP = breast 
cancer resistance protein; Cmax = maximum observed drug concentration; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event. 
 
Overall Design: 
Study J2G-MC-JZPB is a Phase 1, open-label, fixed-sequence, drug interaction study to 
investigate the effect of a single dose of selpercatinib on the PK of rosuvastatin in healthy 
participants. 
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Brief Summary: 
The purpose of this study is to investigate a potential DDI by measuring PK of rosuvastatin with 
selpercatinib in healthy participants.   
Study details include: 
● The study duration will be approximately 8 weeks. 
● The study intervention will be administered on Days 1 and 5. 
● The visit frequency will be 9 continuous days in the clinical research unit (CRU). 
Study Population: 
Healthy participants will be enrolled in this study.   
Number of Participants: 
Approximately 28 participants will be enrolled to ensure that a least 20 evaluable participants 
complete the study. 
Intervention Groups and Duration: 
All participants will be screened for inclusion within 42 days prior to enrollment. Eligible 
participants will be admitted to the CRU on Day -1 and remain resident in the CRU until 
discharge on Day 8. A follow-up visit will be performed 7 to 10 days (Days 12 to 15) after the 
final dose of study intervention. 
Participants will receive the following study intervention while resident in the CRU: 
 Day 1: 20 mg rosuvastatin alone 
 Day 5: 20 mg rosuvastatin coadministered simultaneously with 160 mg selpercatinib 
Ethical Considerations of Benefit/Risk: 
The following are the risks and discomforts associated with selpercatinib: dry mouth, diarrhea, 
hypertension, fatigue, constipation, alanine aminotransferase (ALT)/aspartate aminotransferase 
(AST) elevation, headache, nausea, edema peripheral, abdominal pain, rash, electrocardiogram 
QT prolonged, cough, vomiting, dyspnea, and increased blood creatinine. 
Adverse events of special interest include hypersensitivity, liver injury, QT prolongation, and 
hypertension. Therefore, these reactions will be monitored during the course of the study. 
The following are the risks and discomforts associated with rosuvastatin: headache, myalgia, 
abdominal pain, asthenia, nausea, ALT/AST elevation, myopathy, and rhabdomyolysis. 
Data Monitoring Committee: No 
 
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1.2. 
Schema  
 
 
 
 
 
Day
-1
Follow-Up Visit
(7 to 10 days after last dose)
1
2
3
4
5
6
7
Rosuvastatin 20 mg
Rosuvastatin 20 mg
+
Selpercatinib 160 mg
12
Resident in CRU
-42
Screening
Abbreviation: CRU = clinical research unit
-2
15
8
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1.3. 
Schedule of Activities (SoA)  
Study Procedure 
Screening 
Treatment  
FU/ED 
Comments 
Study Day 
-42 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
12 to 15 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
X 
 
 
Outpatient visit 
X 
 
 
 
 
 
 
 
 
 
X 
 
Participant eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Height and weight  
X 
X 
 
 
 
 
 
 
 
 
X 
Height: 
screening only. 
Physical examination 
 
X 
 
 
 
 
 
 
 
X 
 
Day -1: Full 
examination. 
Day 8: 
Symptom-driven 
examination. 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
X 
Serum 
pregnancy test: 
screening.  
Urine pregnancy 
test: all other 
time points.  
FSH 
X 
 
 
 
 
 
 
 
 
 
 
See 
Section 10.4.1. 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests 
X 
X 
 
 
X 
 
P 
 
X 
 
X 
 
12-lead ECG (hr) 
X 
 
P 
 
 
 
P, 2, 4 
24 
48 
72 
X 
 
Vital signs and body 
temperature (supine) 
(hr) 
X 
X 
P 
24 
X 
X 
P, 1, 2 
24 
X 
X 
X 
Temperature:  
screening and 
Day -1. 
Ethanol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
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Study Procedure 
Screening 
Treatment  
FU/ED 
Comments 
Study Day 
-42 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
12 to 15 
 
Genetic blood sample 
for screening 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic 
blood sample for 
storage 
 
 
P 
 
 
 
 
 
 
 
 
 
Rosuvastatin 
administration 
 
 
X 
 
 
 
X 
 
 
 
 
 
Selpercatinib 
administration 
 
 
 
 
 
 
X 
 
 
 
 
 
Rosuvastatin PK 
samples (hr) 
Selpercatinib PK 
samples (hr) 
Plasma 
coproporphyrin I 
samples (hr) 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FSH = follicle stimulating hormone; FU = follow-up; 
hr = hour; P = predose; PK = pharmacokinetics.
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2. 
Introduction  
2.1. 
Study Rationale  
The breast cancer resistance protein (BCRP) is a membrane-bound transporter located in the 
gastrointestinal tract, liver, kidney, brain endothelium, mammary tissue, testis, and placenta, 
responsible for exporting a wide range of substrates across biological membranes. Certain 
substrates of BCRP have been shown to have clinically significant drug interactions when 
administered with inhibitors of BCRP (International Transporter Consortium et al. 2010). 
Rosuvastatin is a commonly used index substrate for BCRP (FDA, 2021). Selpercatinib may 
potentially inhibit BCRP in the intestine according to in vitro evaluation. Therefore, this study 
aims to investigate a potential drug-drug interaction (DDI) by evaluating the pharmacokinetics 
(PK), safety, and tolerability of rosuvastatin in the presence of selpercatinib. 
2.2. 
Background  
Selpercatinib (LY3527723, Retevmo®) is a an orally available, highly selective, adenosine 
triphosphate (ATP)-competitive small molecule inhibitor of the REarranged during Transfection 
(RET) gene receptor tyrosine kinase (RTK) approved by the FDA for the treatment of  
 adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a 
RET gene fusion, as detected by an FDA-approved test 
 adult and pediatric patients 12 years of age and older with advanced or metastatic medullary 
thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who 
require systemic therapy 
 adult and pediatric patients 12 years of age and older with advanced or metastatic thyroid 
cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic 
therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)  
 adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that 
have progressed on or following prior systemic treatment or who have no satisfactory 
alternative treatment options 
Across clinical studies, single oral doses of selpercatinib were administered over a range of 20 to 
720 mg. In studies (LOXO-RET-18017 and LOXO-RET-18026), multiple oral doses of 
160 mg/day selpercatinib were administered orally twice daily for 10 days in healthy 
participants.  
In healthy participants, the median (range) time to maximum drug concentration (tmax) of 
selpercatinib is 2 (1.5 to 6.0) hours and selpercatinib is eliminated with a mean (range) terminal 
elimination half-life (t1/2) of 13.6 (9.82 to 19.6) hours. 
More detailed information about the PK and absorption, distribution, metabolism, and excretion 
properties of selpercatinib may be found in the Investigator’s Brochure (IB). 
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2.3. 
Benefit/Risk Assessment  
There is no anticipated therapeutic benefit for the participants in this study. However, 
participants may benefit from the screening procedures (through detection of unknown health 
issues) even if they receive no therapeutic benefit from the study. 
The single dose of selpercatinib to be given in this study is 160 mg (2 × 80-mg capsules), as it is 
the highest approved dose by the FDA. The safety profile of selpercatinib shows that 
selpercatinib is very well tolerated in healthy participants and is clinically manageable, with low 
rates of study drug discontinuation due to adverse events (AEs). As outlined in the IB, the most 
common toxicities associated with selpercatinib are monitorable and reversible, and include dry 
mouth, diarrhea, hypertension, fatigue, constipation, aspartate aminotransferase (AST)/ alanine 
aminotransferase (ALT) elevation, headache, nausea, edema peripheral, abdominal pain, rash, 
electrocardiogram (ECG) QT prolonged, cough, vomiting, dyspnea, and increased blood 
creatinine. Adverse events of special interest include hypersensitivity, liver injury, QT 
prolongation, and hypertension. In a recently completed DDI study with dabigatran in healthy 
participants (Study J2G-MC-JZJV), only 1 treatment-emergent adverse event (TEAE) considered 
to be related to selpercatinib was reported (dyspepsia). In a single 160-mg dose, crossover 
bioequivalent study in 224 healthy participants (Study J2G-MC-JZJZ), the most frequently 
reported TEAEs following dosing was headache (20 events in 16 participants) followed by 
COVID-19 (13 events in 13 participants). Four AEs of ALT increased and 2 AEs of AST 
increased were reported, all were mild in severity and resolved by the end of the study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of selpercatinib may be found in the IB. 
Rosuvastatin is a commonly used drug in DDI studies and the dosing regimen in the current 
study (20 mg) is consistent with the prescribing recommendations. The most frequent (≥2%) 
adverse reactions following rosuvastatin dosing are headache, myalgia, abdominal pain, asthenia, 
and nausea. Cases of myopathy and rhabdomyolysis have been reported with rosuvastatin. These 
risks can occur at any dose level, but are increased at the highest dose of 40 mg. The incidence of 
rhabdomyolysis is 0.3 to 13.5 cases per 1,000,000 (Mendes et al. 2014). During the current 
study, participants should promptly report any unexplained muscle pain, tenderness, or 
weakness. Elevations in liver enzymes (ALT and AST) have been reported following 
rosuvastatin dosing. In most cases, the elevations were transient and resolved or improved on 
continued dosing or after brief interruption of dosing. In the current study, blood samples to 
determine liver enzymes (as part of clinical laboratory tests) will be collected prior to each 
dosing occasion of rosuvastatin.  
More detailed information about the known and expected benefits and risk and reasonably 
expected AEs of rosuvastatin may be found in the prescribing information (Crestor® Prescribing 
Information, 2020). 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
 To evaluate the effect of a single dose 
of selpercatinib on BCRP activity in 
healthy participants 
 Cmax and AUC(0-∞) of rosuvastatin 
Secondary 
 
 To describe the safety and tolerability 
of rosuvastatin in combination with 
selpercatinib in healthy participants 
 Incidence of TEAEs and SAEs 
Exploratory 
 
 To assess the exploratory 
measurement of plasma 
coproporphyrin I as biomarker of 
transporter OATP1B1 and OATP1B3 
inhibition in healthy participants to 
further inform degree of transporter 
inhibition risk  
 Plasma concentrations of biomarker 
coproporphyrin I: Cmax and 
AUC(0-24)  
Abbreviations: AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; 
AUC(0-24) =area under the concentration versus time curve from time zero to 24 hours; BCRP = breast cancer 
resistance protein; Cmax = maximum observed drug concentration; OATP = organic anion transporting 
polypeptide; SAE = serious adverse event; TEAE = treatment-emergent adverse event. 
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4. 
Study Design  
4.1. 
Overall Design  
Study J2G-MC-JZPB is a Phase 1, open-label, fixed-sequence, drug interaction study to 
investigate the effect of a single dose of selpercatinib on the PK of rosuvastatin in healthy 
participants. 
The schema in Section 1.2 illustrates the study design. 
Approximately 28 participants will be enrolled to ensure that at least 20 evaluable participants 
complete the study. 
Screening 
All participants will be screened for study inclusion within 42 days prior to enrollment (Day 1). 
Screening should not occur less than 14 days prior to enrollment (Day 1) in order to allow 
sufficient time to receive genotyping results. 
Treatment and Assessment Period 
Participants will check in to the clinical research unit (CRU) on Day -1 and remain resident until 
discharge on Day 8. 
While resident at the CRU, all participants will receive study intervention as follows: 
 Day 1: 20 mg rosuvastatin alone 
 Day 5: 20 mg rosuvastatin coadministered simultaneously with 160 mg selpercatinib 
Pharmacokinetic blood sampling and safety assessments, including vital signs measurements, 
physical examinations, clinical laboratory tests, ECGs, and AE recording, will be performed 
according to the Schedule of Activities (SoA; Section 1.3) 
Participants will be discharged from the CRU on Day 8 following completion of study 
procedures, provided they are deemed medically fit by the investigator or designee. 
Follow-up 
Participants will attend an outpatient follow-up visit 7 to 10 days (Days 12 to 15) after the final 
dose of rosuvastatin coadministered with a single dose of selpercatinib. If participants are not 
able to attend the CRU for this visit, the CRU should contact the participant via phone call to 
conduct AE and concomitant medication review. 
4.2. 
Scientific Rationale for Study Design  
To allow each participant to act as their own control for safety and PK comparisons, a fixed 
sequence design has been selected. This study will be open label as the study primary endpoint 
PK measures are objective rather than subjective. 
Based on the t1/2 of rosuvastatin from label (19 hours; Crestor Prescribing Information, 2020) or 
observed from Study J2N-MC-JZNW (geometric mean of 8.21 hours with range of 3.02 to 
39.8 hours), a period of 4 days between rosuvastatin doses is considered sufficient time for the 
study intervention to washout. 
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The PK of rosuvastatin will be evaluated after a single dose on Day 1 and again on Day 5, 
coadministered simultaneously with selpercatinib, to assess the effect of selpercatinib on 
intestinal BCRP. 
Conducting the study in healthy participants mitigates the potential confounding effects of any 
disease state, other medical conditions, and concomitant medications in patients.  
4.3. 
Justification for Dose  
The single dose of 160 mg is the highest approved dose for selpercatinib. 
The dose of rosuvastatin (20 mg) has been chosen as this is the clinically relevant dose 
considered safe to administer and has been used concomitantly in previous clinical DDI studies.  
4.4. 
End of Study Definition  
The end of the study is defined as the last scheduled procedure shown in the SoA (Section 1.3) 
for the last participant in the study. 
A participant is considered to have completed the study if the participant has completed the 
treatment period of the study and the follow-up procedures as shown in the SoA (Section 1.3). 
 
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5. 
Study Population  
Eligibility of participants for enrollment in the study will be based on the results of the human 
BCRP transporter (also known as ABCG2) and the human organic anion transporting 
polypeptide 1B1 (OATP1B1) transporter (also known as SLCO1B1) genotyping, screening 
medical history, physical examination, vital signs, clinical laboratory tests, and ECG. The nature 
of any conditions present at the time of the physical examination and any preexisting conditions 
will be documented.  
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only unless otherwise specified, and not continuously throughout the trial. Clinical laboratory 
tests and vital signs may be repeated from screening through Day -1 at the discretion of the 
investigator in order to confirm eligibility. 
Screening may occur up to 42 days prior to enrollment (Day 1). Participants who are not enrolled 
within 42 days of screening may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. In such instances, repeat the following screening tests 
and procedures: body weight, vital signs, clinical laboratory tests, ECG, and pregnancy test 
(females only). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply:  
Age 
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent. 
Race 
2. Participant must be Caucasian. 
Type of Participant and Disease Characteristics 
3. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, vital signs, and ECGs. 
4. Participants who have clinical laboratory test results within the normal reference range for 
the population or investigative site, or results with acceptable deviations that are judged to 
be not clinically significant by the investigator. 
5. Participants who have venous access sufficient to allow for blood sampling as per the 
protocol. 
Weight 
6. Body mass index within the range 19.0 to 32.0 kg/m2 (inclusive). 
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Sex and Contraceptive/Barrier Requirements 
7.  Male and/or female 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Appendix 4, Section 10.4. 
Informed Consent 
8. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
Other Inclusion Criteria 
9. Are reliable and willing to make themselves available for the duration of the study and are 
willing to follow study procedures. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply:   
Medical Conditions 
10. Have known allergies to selpercatinib-related compounds or any components of the 
formulation of selpercatinib, or history of significant atopy.  
11. Have a known allergy, intolerance, or hypersensitivity to any component of rosuvastatin 
that would pose an unacceptable risk to the participant. 
12. Have a significant history of allergic reactions to medications or food products.  
13. Have a clinically significant abnormal blood pressure and/or pulse rate as determined by 
the investigator.  
14. Have a 12-lead ECG abnormality that, in the opinion of the investigator, 
 increases the risks associated with participating in the study 
 a QT interval corrected using Fridericia’s formula (QTcF) 
o  >450 msec for males or 
o  >470 msec for females 
If an ECG parameter is out of range in the screening ECG, the site may perform 
2 repeat ECGs and average the 3 results to assess eligibility. 
15. Have clinically significant active cardiovascular disease or history of myocardial 
infarction within 6 months prior to the planned start of dosing.  
16. Have a significant previous or current history or presence of cardiovascular, respiratory, 
renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; of constituting a 
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risk when taking the investigational product; or of interfering with the interpretation of 
data. NOTE: history of uncomplicated appendectomy is considered acceptable. 
17. Show a history of central nervous system conditions such as strokes, transient ischemic 
attacks, significant head trauma, seizures, central nervous system infections, migraine, 
brain surgery, or any other neurological conditions that, in the opinion of the investigator, 
increase the risk of participating in the study. 
18. Have a history or presence of neuropsychiatric disease (e.g., bipolar disorder, 
schizophrenia, depression) considered as clinically significant by the investigator.  
19. Have had lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
20. Have any medical conditions, medical history, or are taking any medications which are 
contraindicated in the selpercatinib or rosuvastatin label. 
21. Are lactating. 
Prior/Concomitant Therapy 
22. Vaccination with live vaccines within 28 days prior to screening or plans to receive such 
vaccines during the study. NOTE: use of non-live (inactivated) vaccinations will be 
allowed. 
23. Have used or are intending to use over-the-counter or prescription medication, including 
dietary supplements and herbal medications, within 14 days prior to dosing and until study 
discharge (apart from occasional acetaminophen (≤3 g/24 hours), hormonal contraception, 
or hormone replacement therapy). 
Prior/Concurrent Clinical Study Experience 
24. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
25. Have participated, within the last 30 days of admission, in a clinical study involving an 
investigational product. If the previous investigational product has a long half-life, 
5 half-lives or 30 days (whichever is longer) should have passed.  
26. Have previously completed or withdrawn from this study or any other study investigating 
selpercatinib.  
Diagnostic Assessments 
27. Show evidence of human immunodeficiency virus infection and/or positive human 
immunodeficiency virus antibodies. 
28. Have a positive HCV Ab test.  
 Participants who have spontaneously cleared HCV infection (positive HCV Ab in 
conjunction with a negative HCV RNA test at screening, in addition to no history of 
HCV antibody (anti-HCV) treatment) may be included in the study. 
29. Have a current infection with hepatitis B virus (HBV), that is, positive for hepatitis B 
surface antigen, polymerase chain reaction positive for HBV DNA or both.  
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Other Exclusion Criteria 
30. Have c.34AA, c.421AA, or c.34GA/421CA genotypes of ABCG2 as determined through 
genotyping.  
31. Have c.521TC and c/521CC genotypes of SLCO1B1 as determined by genotyping. 
32. Have a positive pregnancy test at screening or Day -1, where applicable.  
33. Are pregnant or intend to become pregnant or to breastfeed during the study. 
34. Regularly use known drugs of abuse or show positive findings on drug screening.  
35. Currently use or show evidence of substance abuse (including alcohol abuse) or 
dependence within the past 6 months based on medical history at screening visit. 
36. Have donated blood of more than 500 mL within the previous 2 months of study 
screening.  
37. Have an average weekly alcohol intake that exceeds 21 units per week (males ≤65 years 
old) and 14 units per week (females). 
38. Are unwilling to stop alcohol consumption 48 hours prior to admission to the CRU, and 
while resident at the CRU. At all other times, participants must agree to consume no more 
than 2 units per day. 
39. Smoke more than 10 cigarettes or e-cigarettes, or 3 cigars or 3 pipes, per day or are unable 
to abide by investigative site smoking restrictions. 
40. Unwilling to limit caffeine consumption to 2 servings per day during each dosing session. 
41. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
42. Are Lilly employees or are an employee of any third-party involved in the study who 
require exclusion of their employees. 
43. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
5.2.1. 
Rationale for Exclusion of Certain Study Participants  
Human BCRP, which is encoded by the gene ABCG2, is polymorphic. Participants with the 
c.34AA, c.421AA, and c.34GA/421CA genotypes will be excluded because these genetic 
polymorphisms are associated with impaired BCRP activity (Furukawa et al. 2009, Wan et al. 
2015, Keskitalo et al. 2009). Because the activity of BCRP is impaired with these participants, it 
would be anticipated that even complete inhibition of BCRP would not result in a substantial 
change in rosuvastatin exposure. Accordingly, excluding participants with these polymorphisms 
will ensure that the “worst-case” interaction between selpercatinib and rosuvastatin will be 
evaluated in this study. 
To reduce the number of participants who need to be screened for the study, participation is 
limited to Caucasians because c.421C>A and c.34G>A polymorphisms occur at lower 
frequencies in Caucasians (Kim et al, 2010). 
Human OATP1B1 transporter, which is encoded by the gene SLCO1B1, is also polymorphic. To 
minimize variability in rosuvastatin PK, participants with the c.521TC and c/521CC genotypes 
will be excluded from this study because this genetic polymorphism is associated with decreased 
transporting activity of OATP1B1 (Niemi et al. 2011) and higher plasma rosuvastatin 
concentrations (Crestor Prescribing Information, 2020). 
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5.3. 
Lifestyle Considerations  
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. 
5.3.1. 
Meals and Dietary Restrictions  
 Standard meals will be provided at all times while participants are resident at the CRU, 
as per the CRU’s policy. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco  
 During each dose administration, participants will be allowed to ingest 2 servings per 
day of caffeine or xanthine containing products.   
 Participants will abstain from alcohol for 48 hours prior to admission until discharge 
from the CRU. 
 Participants who use tobacco products (including, but not limited to, cigarettes, pipes, 
cigars, chewing tobacco, nicotine patches, nicotine lozenges, nicotine gum, or vaping 
products) will be instructed that use of nicotine-containing products (including nicotine 
patches) will not be permitted while they are in the clinical unit. 
5.3.3. 
Activity  
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may take part in light recreational activities during the study 
(for example, watching television, reading). 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled in the study.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention of 
a Participant  
Not applicable. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s) or marketed product(s) 
intended to be administered to/used by a study participant according to the study protocol.  
6.1. 
Study Interventions Administered  
This study involves the comparison of rosuvastatin administered alone and rosuvastatin 
coadministered with selpercatinib.  
This table lists the interventions used in this clinical study.   
Intervention Name 
Selpercatinib 
Rosuvastatin (Crestor) 
Dose Formulation 
Capsule 
Tablet 
Dosage Level(s) 
2 × 80-mg capsules 
(160-mg dose) 
1 × 20-mg tablet 
(20-mg dose) 
Route of Administration Oral 
Oral 
Dosing instructions 
2 capsules taken on Day 5 
1 tablet taken on Day 1 and 
Day 5 
 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
 
6.1.1. 
Administration Details  
Rosuvastatin will be administered orally with approximately 240 mL of room temperature water 
in the morning of Day 1 (see Section 1.3) in a sitting position. When rosuvastatin and 
selpercatinib are administered simultaneously on Day 5, approximately 240 mL of room 
temperature water will be used. Selpercatinib should be administered at the same time as 
rosuvastatin. If required to complete dosing, additional water may be given in 50 mL aliquots 
and will be recorded in the source but will not be considered as a protocol deviation. 
Participants will not be allowed to lie supine for 2 hours after dosing, unless clinically indicated 
or for study procedures. 
On Day 1, rosuvastatin will be administered alone after an overnight fast of at least 8 hours and 
participants will remain fasting for approximately 4 hours postdose. On Day 5, rosuvastatin and 
selpercatinib will be coadministered simultaneously after an overnight fast of at least 8 hours and 
participants will remain fasting for approximately 4 hours postdose. Water is permitted ad 
libitum during the fasting period, except for 1 hour before and after dose administration. 
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6.2. 
Preparation, Handling, Storage, and Accountability  
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention. Only 
authorized study personnel may supply, prepare, or administer study intervention.  
 All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized study personnel. 
 The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, 
and final disposition records). 
 Note: In some cases, sites may destroy the material if, during the investigative site 
selection, the evaluator has verified and documented that the site has appropriate 
facilities and written procedures to dispose of clinical materials.  
 Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual. 
6.3. 
Assignment to Study Intervention  
This is a nonrandomized, open-label study.   
6.4. 
Blinding  
Not applicable as this is an open-label study.  
6.5. 
Study Intervention Compliance  
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and will be provided to the sponsor as requested.   
Study site personnel will examine each participant’s mouth to ensure that the study intervention 
was ingested. 
6.6. 
Dose Modification  
Dose modification is not permitted in this study. 
6.7. 
Continued Access to Study Intervention after the End of the Study  
Not applicable. 
 
 
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6.8. 
Treatment of Overdose  
For this study, any dose of selpercatinib greater than 160 mg or rosuvastatin greater than 20 mg 
within a 24-hour time period will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
● Contact the medical monitor immediately. 
● Closely monitor the participant for any AE/serious adverse event (SAE) and 
laboratory abnormalities as medically appropriate. 
● Obtain a plasma sample for PK analysis if requested by the medical monitor 
(determined on a case-by-case basis). 
● Document the quantity of the excess dose as well as the duration of the overdose 
in the case report form (CRF). 
6.9. 
Prior and Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
● Reason for use 
● Dates of administration including start and end dates 
● Dosage information including dose and frequency for concomitant therapy of 
special interest 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 14 days prior to dosing and until discharge from the 
study, unless, in the opinion of the investigator and sponsor, the medication will not interfere 
with the study. 
If concomitant use of strong and moderate CYP3A inhibitors or drugs known to prolong the QT 
interval cannot be avoided, monitor the QT interval with ECGs for approximately 4 hours 
following the dose of selpercatinib. 
Acetaminophen, at doses of 3 g/24 hours, is permitted for use at the discretion of the 
investigator for the treatment of headache, etc. Other concomitant medication may be considered 
on a case-by-case basis by the investigator in consultation with the medical monitor if required. 
Contraceptive medication is permitted as per the contraception requirements (Appendix 4 
[Section 10.4]), and hormone replacement therapy is also allowed.  
Other medication may be considered on a case-by-case basis by the investigator in consultation 
with the Lilly clinical pharmacologist (CP)/clinical research physician (CRP), or designee. 
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 1.3 of this protocol.
Discontinuation of the study as a whole are handled as part of Appendix 1 (Section
).
7.1.
Discontinuation of Study Intervention
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will discontinue the study intervention (treatment), thereby discontinuing the 
treatment period, and will remain in the study to complete procedures for an early 
discontinuation visit and post-treatment follow-up, if applicable, as shown in the SoA. 
A participant should be permanently discontinued from the study if
●
the participant becomes pregnant during the study,
●
in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons
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7.1.1. 
Liver Chemistry Stopping Criteria  
Study drug will be discontinued for a participant if liver chemistry stopping criteria are met. 
Phase 1 Liver Chemistry Stopping Algorithm 
The study drug should be discontinued if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >5× ULN 
 
ALT or AST >3× ULN and either TBL >2× ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN. 
ALT or AST >3× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3× ULN, when the source of increased ALP is the liver 
 
ALP >2.5× ULN and TBL > 2×ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2× ULN. 
ALP >2.5× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
and other consensus guidelines, with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
FDA = Food and Drug Administration; INR = international normalized ratio; TBL = total bilirubin; ULN = upper 
limit of normal. 
 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly designated 
medical monitor and only if the liver test results return to baseline and if a self-limited non-drug 
etiology is identified. Otherwise, the study drug should be discontinued. 
 
7.1.2. 
QTc Stopping Criteria  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
QTcF) after enrollment, the investigator or qualified designee will determine if the participant 
can continue on the study intervention and if any change in participant management is needed. 
This review of the ECG printed at the time of collection must be documented. Any new 
clinically relevant finding should be reported as an AE. 
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7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
● at any time at the participant’s own request for any reason or without providing 
any reason 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
● if the participant, for any reason, requires treatment with a therapeutic agent that 
is prohibited by the protocol.  
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit, as shown in the SoA. If the participant has not already 
discontinued the study intervention, the participant will be permanently discontinued from the 
study intervention. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.  
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8. 
Study Assessments and Procedures  
● Study procedures and their timing are summarized in the SoA (Section 1.3).  
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
● Appendix 2 (Section 10.2) lists the laboratory tests that will be performed for this 
study. 
● Appendix 2 (Section 10.2.1) provides a summary of the maximum number and 
volume of invasive samples, for all sampling, during the study. 
● Unless otherwise stated in subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test 
results. Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards. 
8.1. 
Efficacy Assessments  
Efficacy is not evaluated in this study.  
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
● A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological, and neurological 
systems. Height and weight will also be measured and recorded. 
● A symptom-directed physical examination will be performed at other visits, as 
deemed necessary by the investigator.  
● Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
Vital Signs  
● For each participant, vital signs measurements should be conducted according to 
the SoA (Section 1.3). 
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● Blood pressure and pulse rate should be measured after at least 5 minutes in the 
supine position. When possible, measurements of blood pressure and pulse rate 
should be performed at approximately the same time of day at each scheduled 
time point. 
● If orthostatic measurements are required, participants should be supine for at least 
5 minutes and stand for at least 3 minutes. Unscheduled orthostatic vital signs 
should be assessed, if possible, during any AE of dizziness or posture-induced 
symptoms.  
● Additional vital signs may be measured during each study period if warranted. 
● If the participant feels unable to stand, supine vital signs only will be recorded. 
8.2.3. 
Electrocardiograms  
● For each participant, a single 12-lead digital ECG will be collected according to 
the SoA (see Section 1.3). Electrocardiograms must be recorded before collecting 
any blood samples. Participants must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection. 
Electrocardiograms may be obtained at additional times, when deemed clinically 
necessary. All ECGs recorded should be stored at the investigational site.  
● Any clinically significant findings from ECGs that result in a diagnosis and that 
occur after the participant receives the first dose of the investigational product, 
should be reported to Lilly, or its designee, as an AE via eCRF. 
● Electrocardiograms will be interpreted by a qualified physician (the investigator 
or qualified designee) as soon after the time of ECG collection as possible, and 
ideally while the participant is still present, to determine whether the participant 
meets entry criteria at the relevant visit(s) and for immediate participant 
management, should any clinically relevant findings be identified. 
● If a clinically significant finding is identified (including, but not limited to, 
changes in QT/QTc interval from baseline) after enrollment, the investigator will 
determine if the participant can continue in the study. The investigator, or 
qualified designee, is responsible for determining if any change in participant 
management is needed and must document his/her review of the ECG printed at 
the time of collection. Any new clinically relevant finding should be reported as 
an AE. 
8.2.4. 
Clinical Safety Laboratory Tests  
● See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be 
performed and the SoA for the timing and frequency. 
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● The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant's condition. 
● All laboratory tests with values considered clinically significantly abnormal 
during participation in the study after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
○ If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the SoA, standard collection requirements, 
and laboratory manual. 
● If laboratory values from non-protocol specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the investigator 
(for example, SAE or AE), then report the information as an AE. 
● If a central vendor is used for the study, Lilly or its designee will provide the 
investigator with the results of laboratory tests analyzed by a central vendor. 
8.2.5. 
Pregnancy Testing  
Where applicable, pregnancy tests will be performed as outlined in the SoA (see Section 1.3). 
8.2.6. 
Safety Monitoring  
The Lilly CP or CRP, or designee will monitor safety data throughout the course of the study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP will periodically review: 
 trends in safety data, 
 laboratory analytes, and 
 AEs.  
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist. 
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8.2.6.1. 
Hepatic Safety  
Close hepatic monitoring 
Laboratory tests, including ALT, AST, alkaline phosphatase (ALP), total bilirubin (TBL), direct 
bilirubin, gamma-glutamyl transferase, and creatine kinase, should be repeated within 
48 to 72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if 
1 or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN 
ALP <1.5× ULN 
ALP ≥2× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥1.5× baseline (except for participants with 
Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal.  
 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
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Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN with hepatic signs/symptomsa, 
or ALT or AST ≥5× ULN 
ALP <1.5× ULN 
ALP ≥3× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline with hepatic 
signs/symptomsa, or ALT or AST ≥3× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥2× baseline (except for participants with Gilbert’s 
syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal.  
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
or eosinophilia >5%. 
 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalization ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or computed tomography scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for: 
 hepatitis D virus, 
 cytomegalovirus, 
 Epstein-Barr virus, 
 acetaminophen levels, 
 acetaminophen protein adducts, 
 urine toxicology screen, 
 Wilson’s disease, 
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 blood alcohol levels, 
 urinary ethyl glucuronide, and  
 blood phosphatidylethanol.  
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a: 
 hepatologist or gastroenterologist consultation, 
 magnetic resonance cholangiopancreatography,  
 endoscopic retrograde cholangiopancreatography, 
 cardiac echocardiogram, or  
 a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to greater than or equal to 5× ULN on 2 or more consecutive 
blood tests (if baseline ALT is less than 1.5× ULN) 
o In participants with baseline ALT greater than or equal to 1.5× ULN, the 
threshold is ALT greater than or equal to 3× baseline on 2 or more consecutive 
tests 
2. Elevated TBL to greater than or equal to 2× ULN (if baseline TBL is less than 
1.5× ULN) (except for cases of known Gilbert’s syndrome) 
o In participants with baseline TBL equal to or greater than 1.5× ULN, the 
threshold should be TBL greater than or equal to 2× baseline 
3. Elevation of serum ALP to greater than or equal to 2× ULN on 2 or more consecutive 
blood tests (if baseline ALP is less than 1.5× ULN) 
o In participants with baseline ALP greater than or equal to 1.5× ULN, the 
threshold is ALP greater than or equal to 2× baseline on 2 or more consecutive 
blood tests 
4. Hepatic event considered to be a SAE 
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.6.2. 
Hypersensitivity Reactions 
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
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Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs 
 Product complaints (PCs) 
These events will be reported by the participant. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For PCs, 
the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Appendix 3, Section 10.3. 
Investigators and any qualified designees are responsible for monitoring the safety of participants 
who have entered this study and for alerting Lilly or its designee to any event that seems unusual, 
even if this event may be considered an unanticipated benefit to the participant.  
The investigator is responsible for the appropriate medical care of participants during the study. 
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8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Start of 
intervention  
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE updates 
– prior to start of study 
intervention and 
deemed reasonably 
possibly related to 
study procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE# and SAE 
updates – after start of 
study intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE* – after 
participant’s study 
participation has 
ended and the 
investigator becomes 
aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in female 
participants and 
female partners of 
male participants 
After the 
start of 
study 
intervention 
Discharge 
from the 
CRU 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy 
paper form 
Pregnancy 
paper form 
Product Complaints 
PC associated with an 
SAE or might have led 
to an SAE 
Start of 
study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not associated with 
an SAE 
Start of 
study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed 
Product 
Complaint form 
with all changes 
signed and 
dated by the 
investigator 
N/A 
PC (if investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product 
Complaint form 
 
Abbreviations: AE = adverse event; ICF = informed consent form; N/A = not applicable; PC = product 
complaints; SAE = serious adverse event. 
* Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator will 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
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Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 
24 hours of learning of a participant's pregnancy.  
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of gestational age, fetal 
status (presence or absence of anomalies) or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
● Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will be withdrawn from the study. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation. 
8.4. 
Pharmacokinetics  
● Venous blood samples of approximately 
 each will be collected for 
measurement of plasma concentrations of selpercatinib, rosuvastatin, and 
coproporphyrin I as specified in the SoA (Section 1.3).  
● A maximum of  samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the course of the study based on newly 
available data (for example, to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.  
● Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded. 
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8.4.1. 
Bioanalysis  
 Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  
 Concentrations of selpercatinib and rosuvastatin will be assayed using a validated liquid 
chromatography with tandem mass spectrometry method. 
 Concentrations of coproporphyrin I will be assayed using a validated liquid 
chromatography with tandem mass spectrometry method. 
 Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following the last participant visit for the study. During 
this time, samples remaining after the bioanalyses may be used for exploratory analyses 
such as metabolism work, protein binding, or bioanalytical method cross-validation 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics  
A blood sample for DNA isolation will be collected from participants at screening to determine 
genetic polymorphisms for participants to meet eligibility criteria prior to enrollment 
(Section 5.2 and Section 5.2.1).  
A separate blood sample will be collected for storage for potential pharmacogenetic analysis as 
specified in the SoA (Section 1.3). 
See Appendix 5 (Section 10.5) for information regarding genetic research and Appendix 5 
(Section 10.1.11) for details about sample retention and custody.  
8.7. 
Biomarkers  
Clinical study data indicate that the endogenous coproporphyrin I can be used to detect in vivo 
inhibition of hepatic OATPs; therefore, coproporphyrin I will be explored in this study as 
potential mechanistic biomarkers of OATP function. This may aid in mechanistic understanding 
of selpercatinib effect on OATPs versus BCRP.  
At the visits and times specified in the SoA, venous blood samples will be collected to determine 
the plasma concentrations of coproporphyrin I. The actual date and 24-hour clock time of each 
sampling will be recorded. Refer to the SoA (Section 1.3) for coproporphyrin I sampling 
time points.  
8.8. 
Immunogenicity Assessments  
Immunogenicity is not evaluated in this study.  
8.9. 
Health Economics  
This section is not applicable for this study.  
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9. 
Statistical Considerations  
9.1. 
Statistical Hypotheses  
The primary objective will be to evaluate the effect of a single dose of selpercatinib on BCRP 
activity in healthy participants assessed by considering the true DDI ratio of the inhibitory effect 
of selpercatinib on the BCRP substrate rosuvastatin 
([rosuvastatin + selpercatinib] / rosuvastatin).  
Approximately 28 participants will be enrolled to ensure that at least 20 evaluable participants 
complete the study. A total of 20 evaluable participants will provide at least 90% coverage 
probability to ensure the half-width of the 90% confidence interval (CI) for the AUC ratio of 
rosuvastatin falls within 25% of the true ratio ([rosuvastatin + selpercatinib] / rosuvastatin).  
9.2. 
Analyses Sets  
The following populations are defined: 
Population 
Description 
Entered 
All participants who sign the ICF. 
Enrolled/Safety 
All participants who receive at least 1 dose of rosuvastatin.  
Pharmacokinetic 
(Evaluable) 
All participants who receive at least 1 dose of rosuvastatin and 
have evaluable PK data. 
9.2.1. 
Study Participant Disposition  
A detailed description of participant disposition will be provided at the end of the study. 
9.2.2. 
Study Participant Characteristics  
The participant’s age, sex, weight, height, and other demographic characteristics will be 
recorded. 
9.3. 
Statistical Analyses  
Statistical analysis of this study will be the responsibility of the sponsor or its designee.  
Pharmacokinetic analyses will be conducted on data from all participants who receive at least 
1 dose of rosuvastatin and have evaluable PK. 
Safety analyses will be conducted for all enrolled participants who received study intervention, 
whether or not they completed all protocol requirements.  
Additional exploratory analyses of the data will be conducted as deemed appropriate. Study 
results may be pooled with the results of other studies for safety and population PK analysis 
purposes to avoid issues with post-hoc analyses and incomplete disclosures of analyses. 
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9.3.1. General Considerations  
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and/or in the statistical analysis plan, where 
appropriate. Adjustments to the planned analyses are described in the final clinical study report. 
9.3.2. 
Primary Endpoint Analysis: Pharmacokinetic Analyses  
All PK analyses will be made using the PK Population. 
9.3.2.1. 
Pharmacokinetic Parameter Estimation  
Pharmacokinetic parameter estimates for rosuvastatin will be calculated by standard 
noncompartmental methods of analysis.  
The primary parameters for analysis will be maximum observed drug concentration (Cmax) and 
area under the concentration versus time curve from time zero to infinity (AUC0-∞) of 
rosuvastatin. Other noncompartmental parameters, such as t1/2, tmax, apparent clearance, 
apparent volume of distribution, and area under the concentration versus time curve from time 
zero to time t, where t is the last time point with a measurable concentration (AUC[0-tlast]), will 
be reported. 
Blood samples collected for the PK of selpercatinib alone will be used to determine Cmax only to 
ensure sufficient selpercatinib exposure in systemic circulation. 
9.3.2.2. 
Pharmacokinetic Statistical Inference  
Pharmacokinetic parameters for rosuvastatin alone dosed on Day 1 will be compared to PK 
parameters for rosuvastatin with single dose of selpercatinib dosed on Day 5.  
If a participant has an AE of vomiting that occurs at or before 2 times median tmax of either 
rosuvastatin or selpercatinib, the impacted period of this participant will be excluded from the 
PK summary statistics and statistical analysis. 
Log-transformed Cmax and AUC(0-∞) of rosuvastatin will be evaluated in a linear mixed-effects 
model with fixed effects for treatment and a random effect for participant. The treatment 
differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% CIs. The test treatment is rosuvastatin in the presence of selpercatinib, and 
reference treatment is rosuvastatin alone. 
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the median difference 
based on the observed medians, 90% CIs and p-values from the Wilcoxon test will be calculated. 
9.3.3. 
Secondary Endpoint Analysis: Safety Analyses  
All safety analyses will be made using the Safety Population. 
The incidence of TEAEs and SAEs will be reported separately with respect to the dose date for 
selpercatinib (i.e., separate events and percentages will be reported for AEs pre-selpercatinib and 
post-selpercatinib).   
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9.3.3.1. 
Clinical Evaluation of Safety  
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.  
The incidence of AEs for each treatment will be presented by severity and by association with 
investigational product as perceived by the investigator. Each AE will be classified by the most 
suitable term from the medical regulatory dictionary. 
The number of SAEs will be reported. 
9.3.3.2. 
Statistical Evaluation of Safety  
Safety parameters that will be assessed include clinical laboratory parameters and vital signs. 
The parameters will be listed and summarized using standard descriptive statistics. Additional 
analysis will be performed if warranted upon review of the data. 
Additional details can be found in the statistical analysis plan. 
9.3.4. 
Exploratory Endpoint Analysis  
9.3.4.1. 
Analyses for Coproporphyrin I  
The effect of a single dose of selpercatinib (Day 5) on plasma coproporphyrin I, a biomarker of 
OATP inhibition in healthy participants, will be explored.  
Plasma concentrations of coproporphyrin I will be characterized by standard noncompartmental 
methods of analysis. Descriptive parameters, such as Cmax, tmax, and area under the 
concentration versus time curve from time zero to 24 hours (AUC0-24), will be summarized, if 
feasible. 
Pharmacokinetic parameters for coproporphyrin I at the presence of rosuvastatin dosed on Day 1 
will be compared to parameters for coproporphyrin I with single dose of selpercatinib dosed on 
Day 5.  
If a participant has an AE of vomiting that occurs at or before 2 times median tmax of 
selpercatinib, the impacted period of this participant will be excluded from the summary 
statistics and statistical analysis. 
9.3.4.2. 
Statistical Evaluation  
Log-transformed Cmax and AUC0-24 of coproporphyrin I will be evaluated in a linear 
mixed-effects model with fixed effects for treatment and a random effect for participant. The 
treatment differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% CIs. The test treatment is coproporphyrin I in the presence of selpercatinib, 
and reference treatment is coproporphyrin I alone. 
9.4. 
Interim Analysis  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.  
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9.5. 
Sample Size Determination  
Approximately 28 participants will be enrolled to ensure that at least 20 evaluable participants 
complete the study. 
A total of 20 evaluable participants will provide at least 90% coverage probability to ensure the 
half-width of the 90% CI for the AUC ratio of rosuvastatin falls within 25% of the true ratio 
([rosuvastatin + selpercatinib] / rosuvastatin). Participants are evaluable if adequate PK data are 
obtained sufficient for inclusion of the participant in this analysis of AUC ratio. This sample size 
of at least 20 evaluable participants (out of 28 treated) assumes unknown selpercatinib effect on 
rosuvastatin PK and intra-participant coefficient of variation of 33% for the PK parameter of 
interest for each treatment (precision method) based on internal data.  
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
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 International Ethical Guidelines 
○ Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
○ Reporting to the sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
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10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the potential participant and answer all 
questions regarding the study. 
● Potential participants must be informed that their participation is voluntary. 
Participants will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy, and 
data protection requirements, where applicable, and the IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant and is kept on file. 
10.1.4. 
Data Protection  
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s 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 participant who will be required 
to give consent for their data to be used as described in the informed consent. 
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
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10.1.5. 
Dissemination of Clinical Study Data  
Communication of Suspended or Terminated Dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible. It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
10.1.6. 
Data Quality Assurance  
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. This might include laboratory tests, 
medical records, and clinical notes. 
● The investigator must review and confirm that data entries are accurate and 
complete throughout the duration of the study, by physically or electronically 
signing the CRF, as instructed by the sponsor. All completed CRFs must be 
signed prior to archival. 
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source documents. 
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● Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations). 
● The sponsor or designee will perform monitoring to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants 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 for the time period outlined in the 
Clinical Trial Agreement (CTA) 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. 
● In addition, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by Sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture system will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive or access an 
archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the Sponsor data warehouse. 
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Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.7. 
Source Documents  
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on or entered in the CRF and are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
● Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.8. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or Site Termination 
The sponsor or sponsor’s designee reserves the right to terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study site will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
● Discontinuation of further study intervention development 
For site termination: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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10.1.9. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
10.1.10. 
Investigator Information  
Not applicable. 
10.1.11. 
Sample Retention  
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of selpercatinib or after selpercatinib become(s) commercially available. 
Sample Type 
Custodian 
Retention Period After Last 
Patient Visit* 
Long-term storage samples 
Sponsor or Designee 
15 years 
Pharmacokinetic 
Sponsor or Designee 
1 year  
Genetics 
Sponsor or Designee 
15 years 
 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
● The tests detailed in the table below will be performed by the local laboratory. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
● Investigators must document their review of the laboratory safety results.  
 
 
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Clinical Laboratory Tests 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Calcium  
Mean cell volume  
Phosphorus  
Mean cell hemoglobin  
Glucose (random) 
Mean cell hemoglobin concentration  
Creatine kinase 
Leukocytes (WBC) 
Blood urea nitrogen (BUN) 
Platelets 
Uric acid  
Differential WBC (absolute counts) of: 
Total protein 
Neutrophils 
Albumin 
Lymphocytes 
Total bilirubin 
Monocytes 
Alkaline phosphatase (ALP) 
Eosinophils 
Aspartate aminotransferase (AST) 
Basophils 
Alanine aminotransferase (ALT) 
 
Creatinine 
Urinalysis 
 
Specific gravity 
Pregnancy test  
pH 
FSH (if applicable)b 
Protein 
Ethanol testingc 
Glucose 
Urine drug screenc 
Ketones 
 
Bilirubin 
Serology 
Urobilinogen 
Hepatitis B surface antigenb 
Leukocytes 
Hepatitis C antibodyb,d 
Blood 
HIVb 
Nitrite 
 
Microscopic examination of sedimenta 
 
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus.  
a Test only if dipstick result is abnormal. 
b Performed at screening only. 
c Urine drug screen and ethanol (urine or breath) level performed at screening and may be repeated prior to 
admission to the clinical research unit. 
d Participants with a positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test. 
 
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10.2.1. 
Blood Sampling Summary  
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. 
Protocol J2G-MC-JZPB Sampling Summary 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
Clinical laboratory testsa 
Rosuvastatin pharmacokineticsb 
Selpercatinib pharmacokineticsb 
Coproporphyrin I pharmacokineticsb 
Pharmacogenetics 
Total 
Total for clinical purposes [rounded up to nearest 10 mL]  
a Additional samples may be drawn if needed for safety purposes. 
b Includes additional 3 samples, if required. 
 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae.  
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or SAE.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
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 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.1. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
 Results in death 
 Is life-threatening 
o The term life-threatening in the definition of serious refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
o In general, hospitalization signifies that the participant has been admitted to 
hospital or emergency ward (usually involving at least an overnight stay) for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
o Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent disability/incapacity 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (for example, sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
 Is a congenital anomaly/birth defect 
o Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Other situations: 
o Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
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o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
10.3.2. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a study intervention. When the ability to use the study intervention safely 
is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator to 
review all documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and product 
complaint information is reported on the Product Complaint Form. 
 Note: An event may meet the definition of both a product complaint and an AE/SAE. In 
such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested by 
Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
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 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. An 
AE that is assessed as severe should not be confused with a SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to Sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
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 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor or designee with a copy of any postmortem 
findings including histopathology. 
10.3.4. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see next 
section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a SAE paper form (see next section) 
or to the sponsor or designee by telephone. 
 Contacts for SAE reporting can be found in SAE Report.  
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in in SAE Report.  
 
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10.3.5. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
 An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (for example, summary or listing of SAEs) from the sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of childbearing potential 
(WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Females less than 18 years of age are considered WOCBP if they have 
 
had at least 1 cycle of menses, or 
 
Tanner stage 4 breast development. 
Any amount of spotting should be considered menarche. 
Women not of childbearing 
potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 
have a congenital anomaly such as Müllerian agenesis 
 
are infertile due to surgical sterilization, or 
 
are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral 
salpingo-oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman: 
 
at any age at least 6 weeks post-surgical bilateral 
oophorectomy with or without hysterectomy, confirmed by 
operative note; or 
 
aged at least 40 years and up to 55 years with an intact uterus, 
not on hormone therapya, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, 
AND with a follicle-stimulating hormone >40 mIU/mL; or 
 
55 years or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea, or 
 
aged at least 55 years with a diagnosis of menopause prior 
to starting hormone replacement therapy. 
a 
Women should not be taking medications during amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor modulators (SERMs), or 
chemotherapy that could induce transient amenorrhea. 
10.4.2. 
Contraception Guidance  
Male participants:  
 Are not required to adhere to contraceptive requirements. 
Female participants:  
 WNOCBP are not required to adhere to contraceptive requirements. This includes 
females who are: 
o Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy, bilateral tubal occlusion, or bilateral tubal ligation), 
or congenital anomaly (for example, Müllerian agenesis)  
o Postmenopausal 
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WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
 
Must… 
Must not… 
agree to either remain 
abstinent or stay in a same-
sex relationship without 
sexual relationships with 
males 
 
use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation 
 
declare abstinence just for the duration of a trial, or 
 
use the withdrawal method 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or NOT in a 
same-sex relationship as their preferred and usual lifestyle, must do the following: 
 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative urine result 
within 24 hours prior to treatment exposure. See the protocol Schedule of 
Activities for subsequent pregnancy testing requirements. 
Contraception 
Agree to use 2 forms of effective contraception, where at least 1 form must be 
highly effective. 
These forms of contraception must be used during the study and after the study for 
at least 30 days after the last dose of the study intervention. 
 
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10.4.3. 
Contraception Methods  
The table illustrates examples of highly effective, effective, and unacceptable methods of 
contraception. 
Methods 
Examples 
Highly effective 
contraception (less than 1% 
failure rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception 
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical sponges 
 
barrier method with use of a spermicide 
o 
condom with spermicide 
o 
diaphragm with spermicide, or 
o 
female condom with spermicide 
Ineffective forms of 
contraception whether used 
alone or in any 
combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical 
mucus, or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
 
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10.5. 
Appendix 5: Genetics  
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to selpercatinib or cancer and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to selpercatinib and/or interventions of this drug class and 
cancer. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome (as appropriate). 
● Additional analyses may be conducted if it is hypothesized that this may help 
further understand the clinical data. 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to selpercatinib or study interventions of this 
class to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the clinical study report (CSR) 
or in a separate study summary. 
● The sponsor will store the blood and/or DNA samples in a secure storage space 
with adequate measures to protect confidentiality. 
● The samples will be retained while research on selpercatinib or study 
interventions of this class or indication continues but no longer than 15 years or 
other period as per local requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
See Section 8.2.6.1 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing. The 
central laboratory will report results if a validated test or calculation is available. 
 
Hepatic Hematology Panel 
Hepatic Clinical Chemistry Panel 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
Lymphocytes 
Creatine kinase (CK) 
Monocytes 
Other Chemistry 
Basophils 
Acetaminophen 
Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Hepatic Coagulation Panel 
Copper 
Prothrombin time, INR (PT-INR) 
Ethyl alcohol (EtOH) 
Hepatitis A virus (HAV) testing: 
Haptoglobin 
HAV total antibody 
Immunoglobulin IgA (quantitative) 
HAV IgM antibody 
Immunoglobulin IgG (quantitative) 
Hepatitis B virus (HBV) testing: 
Immunoglobulin IgM (quantitative) 
Hepatitis B surface antigen (HBsAg) 
Phosphatidylethanol (PEth) 
Hepatitis B surface antibody (anti-HBs) 
Urine Chemistry 
Hepatitis B core total antibody (anti-HBc) 
Drug screen 
Hepatitis B core IgM antibody 
Ethyl glucuronide (EtG) 
HBV DNA b 
Other Serology 
Hepatitis C virus (HCV) testing: 
Anti-nuclear antibody (ANA) 
HCV antibody 
Anti-smooth muscle antibody (ASMA) a 
HCV RNA b 
Anti-actin antibody c 
Hepatitis D virus (HDV) testing: 
Epstein-Barr virus (EBV) testing: 
HDV antibody 
EBV antibody 
Hepatitis E virus (HEV) testing: 
EBV DNA b 
HEV IgG antibody 
Cytomegalovirus (CMV) testing: 
HEV IgM antibody 
CMV antibody 
HEV RNA b 
CMV DNA b 
Microbiology 
Herpes simplex virus (HSV) testing: 
Culture: 
HSV (Type 1 and 2) antibody 
Blood 
HSV (Type 1 and 2) DNA b 
Urine 
Liver kidney microsomal type 1 (LKM-1) antibody 
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio; PT-INR = prothrombin 
time-international normalized ratio. 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
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10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Not applicable. 
 
 
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10.8. 
Appendix 8: Abbreviations and Definitions  
Term 
Definition 
ab 
antibody 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC(0-∞) 
area under the concentration versus time curve from time zero to infinity 
AUC(0-24) 
area under the concentration versus time curve from time zero to 24 hours 
AUC(0-tlast) 
area under the concentration versus time curve from time zero to time t, where t is the 
last time point with a measurable concentration 
BCRP 
breast cancer resistance protein 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed drug concentration 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
COVID-19 
coronavirus disease 2019 
CP 
clinical pharmacologist 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CRU 
clinical research unit 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
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enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. See also “IMP.” 
OATP1B1 
organic anion transporting polypeptide 1B1 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK 
pharmacokinetics 
QTc 
corrected QT interval 
QTcB 
QT corrected using Bazett’s formula 
QTcF 
QT corrected using Fridericia’s formula 
SAE 
serious adverse event 
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Protocol Number J2G-MC-JZPB(a) 
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screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SoA 
Schedule of Activities 
t1/2 
terminal elimination half-life 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
tmax 
time to maximum drug concentration 
ULN 
upper limit of normal 
 
 
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Protocol Number J2G-MC-JZPB(a) 
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11. 
References  
Crestor® (rosuvastatin calcium) Tablets [Prescribing Information]. Wilmington, DE: 
AstraZeneca Pharmaceuticals LP; 2003. Revised May 2020. Accessed at 
https://www.azpicentral.com/crestor/crestor.pdf#page=1 on 19 December 2022. 
Food and Drug Administration (FDA). Drug Development and Drug Interactions. Table of 
Substrates, Inhibitors and Inducers. Accessed at https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers on 
02 December 2022. 
Furukawa T, Wakabayashi K, Tamura A, et al. Major SNP (Q141K) variant of human ABC 
transporter ABCG2 undergoes lysosomal and proteasomal degradations. Pharm Res. 
2009;26(2):469-479. https:// doi: 10.1007/s11095-008-9752-7.  
International Transporter Consortium; Giacomini KM, Huang SM, Tweedie J, et al. Membrane 
transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236. 
Keskitalo JE, Zolk O, Fromm MF, et al. ABCG2 polymorphism markedly affects the 
pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86(2):197-203. 
https:// doi: 10.1038/clpt.2009.79. 
Kim KA, Joo HJ, Park JY. ABCG2 polymorphisms, 34G>A and 421C>A in a Korean 
population: analysis and a comprehensive comparison with other populations. J Clin Pharm Ther. 
2010;35(6):705-712. https:// doi: 10.1111/j.1365-2710.2009.01127.x. 
Mendes P, Robles PG, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of 
case reports. Physiother Can. 2014;66(2):124-132. https:// doi: 10.3138/ptc.2012-65. 
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically 
polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 
2011;63(1):157-181. https:// doi: 10.1124/pr.110.002857. 
Wan Z, Wang G, Li T, et al. Marked alteration of rosuvastatin pharmacokinetics in healthy 
Chinese with ABCG2 34G>A and 421C>A homozygote or compound heterozygote. J 
Pharmacol Exp Ther. 2015;354(3):310-315. https:// doi: 10.1124/jpet.115.225045. 
Approved on 19 May 2023 GMT

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