A Phase 1/2 Study of Oral Selpercatinib (LOXO-292) in Patients With Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors With RET Activation (LIBRETTO-001)
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer, Medullary Thyroid Cancer, Colon Cancer, Any Solid Tumor
Sponsor: Eli Lilly and Company

Protocol J2G-OX-JZJA (12) 
 
A Phase 1/2 Study of Oral Selpercatinib (LOXO-292) in Patients With Advanced Solid 
Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other 
Tumors With RET Activation (LIBRETTO-001) 
 
NCT03157128 
 
Approval Date: 15-Aug-2023 
 

Eli Lilly and Company 
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Selpercatinib 
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CLINICAL PROTOCOL LOXO-RET-17001 
(J2G-OX-JZJA) 
A Phase 1/2 Study of Oral Selpercatinib (LOXO-292) in Patients 
with Advanced Solid Tumors, Including RET Fusion-Positive Solid 
Tumors, Medullary Thyroid Cancer, and Other Tumors with RET 
Activation (LIBRETTO-001) 
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) and investigational device generic name or device name if applicable, 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. 
Investigational Product: 
Selpercatinib (LY3527723) 
Protocol Number: 
LOXO-RET-17001 (J2G-OX-JZJA) 
Development Phase: 
1/2 
IND #: 
133193 
EudraCT #: 
2017-000800-59 
EU Trial #: 
2023-507702-13-00 
Sponsor: 
Loxo Oncology, Inc., a wholly owned 
subsidiary of Eli Lilly and Company 
Approval Date: Protocol Amendment 12.0 Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-117312 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Version 11.0 
20 October 2022 
Version 10.0 
19 October 2021 
Version 9.0 
03 June 2020 
Version 8.0 
10 June 2019 
Version 7.0 
18 October 2018 
Version 6.0 
11 September 2018 
Version 5.0 
30 May 2018 
Version 4.0 
20 November 2017 
Version 3.0 
20 July 2017 
Version 2.0 
27 March 2017 
Version 1.0 
01 March 2017 
Amendment [12.0]  
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the safety or the rights of the study participants. 
Overall Rationale for the Amendment: 
The purpose of this amendment is to consolidate the Germany and Denmark country-specific 
addenda into Appendix K, minor clarifications/corrections, update as per the latest Investigator 
Brochure, and to align with EU Clinical Trial Regulation (EU-CTR) requirements. 
Section # and Name Description of Change 
Brief Rationale 
Synopsis 
 Shortened 
 Added EU Trial 
Number 
 Added Eligibility 
Criteria 
 Added Ethical 
considerations of 
Benefit/Risk  
To align to EU-CTR format 
Phase 2 – corrected seven 
cohorts to six cohorts 
Correction 
List of Abbreviations 
and Definitions of 
Terms 
Updated abbreviations and 
definitions 
To align with EU-CTR format 
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Section # and Name Description of Change 
Brief Rationale 
3.6 Phase 2 
 Phase 2 – corrected 
seven cohorts to six 
cohorts 
 Cohort 7 removed 
from Figure 3-1 Study 
Schema 
For accuracy, as Cohort 7 was 
removed from the study as of 01 June 
2022 
4.1 Inclusion Criteria 
for Phase 1 
Inclusion Criterion [3]: 
removed reference to Section 
4 in notes 
Clarification 
4.2. Inclusion 
Criteria for Phase 2 
Inclusion Criterion [7] 
removed 
For accuracy, as Cohort 7 was 
removed from the study as of 01 June 
2022 
6.1 Investigational 
Product 
Removed 20 mg/mL oral 
suspension 
Oral suspension no longer provided 
Clarification to extenuating 
circumstances to include 
“where allowed by regional 
regulatory authorities” 
Clarification 
 Added statement 
about EU 
authorization.  
 Added “Packaging 
and Labeling” 
To align to EU-CTR format 
6.2.4. Dose 
Delays/Modifications  
Updated dose modification 
guidance for  
 Interstitial Lung 
Disease/Pneumonitis 
 Chylothorax and 
Chylous Ascites 
As per updated Investigator Brochure 
Table 7-1 Schedule 
of Assessments  
Corrected Footnote q: 
urinalysis is only required 
beyond cycle C1D15 if 
clinically indicated 
Correction 
7.3. Cycles 2 and 
Higher 
Urinalysis – removal of “Day 
1 of each cycle starting with 
C2” 
Correction 
7.8. Procedures for 
Special Tests 
Section 7.8.7 added for 
Thyroid function 
As per updated Investigator Brochure 
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Section # and Name Description of Change 
Brief Rationale 
8.2. Analysis 
Populations 
Added a paragraph on 
handling of missing, unused, 
and spurious data 
To align with EU-CTR format 
9. Adverse Events 
Events meeting AE definition 
added 
To align with EU-CTR format 
9.4.1. Serious 
Adverse Event 
Reporting – 
Procedures for 
Investigators: Initial 
Report 
Added SAE Regulatory 
Reporting 
To align with EU-CTR format 
10.1. Regulatory and 
Ethical 
Considerations 
Added statement about 
reporting of significant issues 
related to participant’s safety, 
rights, and data integrity 
To align with EU-CTR format 
10.2. Data 
Management 
Added a subsection on “Data 
Protection” 
To align with EU-CTR format 
10.4. Termination 
Added required language on 
“Reports” 
To align with EU-CTR format 
Appendix K 
Country-Specific 
Requirements 
Germany: Consolidation of 
Germany-specific protocol 
addendum into Appendix K 
For harmonization of the protocol 
and to avoid country and region-
specific protocol versions in the EU 
 
Denmark: Consolidation of 
Denmark-specific protocol 
addendum into Appendix K 
For harmonization of the protocol 
and to avoid country and region-
specific protocol versions in the EU 
 
Throughout the 
protocol 
Minor editorial revisions 
Clarification 
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SYNOPSIS  
TITLE:  
A Phase 1/2 Study of Oral Selpercatinib (LOXO-292) in Patients with Advanced Solid Tumors, Including RET 
Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors with RET Activation 
(LIBRETTO-001) 
PROTOCOL NUMBER:  
LOXO-RET-17001 (J2G-OX-JZJA) 
EudraCT #: 2017-000800-59 
EU Trial #: 2023-507702-13-00 
OBJECTIVES: 
Primary Objective (Phase 1): 
 To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of selpercatinib. 
Secondary Objectives (Phase 1):  
 To determine the safety profile and tolerability of selpercatinib. 
 To characterize the pharmacokinetic (PK) properties of selpercatinib. 
 To assess the anti-tumor activity of selpercatinib by determining objective response rate (ORR) using 
Response Evaluation in Solid Tumors Version 1.1 (RECIST 1.1) or Response Assessment in Neuro-
Oncology (RANO), as appropriate to tumor type. 
Primary Objective (Phase 2): 
 To assess, for each Phase 2 expansion cohort, the anti-tumor activity of selpercatinib by determining 
ORR using RECIST 1.1 or RANO, as appropriate for tumor type, as assessed by independent review 
committee (IRC). 
Secondary Objectives (Phase 2): 
 To assess, for each expansion cohort, the anti-tumor activity of selpercatinib by determining:  
o ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, as assessed by Investigator;  
o Best change in tumor size from baseline as assessed by IRC and Investigator;  
o Duration of response (DOR) as assessed by IRC and Investigator;  
o Central nervous system (CNS) ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, 
as assessed by IRC (for patients with brain metastases); 
o CNS DOR as assessed by IRC (for patients with brain metastases); 
o Time to any and best response based on RECIST 1.1 or RANO, as appropriate to tumor type, as 
assessed by IRC and Investigator; 
o Clinical Benefit Rate (CBR) based on the proportion of patients with best overall response of 
complete response (CR), partial response (PR), or stable disease (SD) lasting 16 or more weeks 
following initiation of selpercatinib as assessed by IRC and Investigator; 
o Progression-free survival (PFS) as assessed by IRC and Investigator;  
o Overall survival (OS) following initiation of selpercatinib. 
 To determine the safety profile and tolerability of selpercatinib. 
 To characterize the PK properties of selpercatinib. 
STUDY DESIGN: 
This is an open-label, multi-center Phase 1/2 study in patients with advanced solid tumors, including RET 
fusion-positive solid tumors (e.g., non-small cell lung cancer [NSCLC], thyroid, pancreas, colorectal), 
RET-mutant MTC, and other tumors with RET activation (e.g., mutations in other tumor types or other 
evidence of RET activation). This study includes two parts: Phase 1 (dose escalation) and Phase 2 (dose 
expansion). Patients with RET alterations in tumor and/or blood will be identified through molecular assays, 
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as performed in the routine course of clinical care. The RET alteration result should be generated from a 
laboratory with certification by Clinical Laboratory Improvement Amendments (CLIA), International 
Organization for Standardization/Independent Ethics Committee (ISO/IEC), College of American 
Pathologists (CAP), or other similar certification as per local guidelines including but not limited to In Vitro 
Diagnostic Regulation (IVDR) compliance as applicable. The Sponsor should be contacted to discuss test 
results to ensure trial eligibility. 
Phase 2: 
A dose of 160 mg BID has been selected by the SRC as the recommended Phase 2 dose (RP2D). 
Therefore, up to ~875 patients with advanced solid tumors harboring a RET gene alteration in tumor 
and/or blood (e.g., gene fusions and/or mutations, excluding synonymous, frameshift, or nonsense 
mutations) will be enrolled to one of six Phase 2 cohorts (refer to Study Schema). 
Eligibility Criteria: 
 
Patients with a locally advanced or metastatic solid tumor who: 
o 
have progressed on or are intolerant to standard therapy 
o 
no standard therapy exists  
o 
in the opinion of the Investigator, are not candidates for or would be unlikely to tolerate or 
derive significant clinical benefit from standard therapy, or  
o 
decline standard therapy.  
 
Have a RET gene alteration identified through molecular assays at a laboratory with CLIA, ISO/IEC, 
CAP or other similar, either from tumor or blood.  
 
Patients with additional validated oncogenic driver that could cause resistance to selpercatinib 
treatment are not eligible. 
 
Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to 
tumor type. 
 
At least 18 years of age, or at least 12 years of age for countries and sites where approved.  
 
Eastern Cooperative Oncology Group performance status score of 0, 1, or 2. 
 
Archived tumor tissue sample available. 
ETHICAL CONSIDERATIONS OF BENEFIT/RISK: 
Patients with RET-fusion positive cancers (NSCLC, papillary thyroid cancer, colon, others) and RET-mutant 
cancers (MTC) represent populations with high unmet need. Available therapies for these patients provide 
short-term palliation (i.e., chemotherapy), may be less effective in cancers driven by kinase fusions (i.e., 
immunotherapy) and/or are very toxic (i.e., multikinase inhibitors). Therefore, there is an urgent need to identify 
new targeted therapies that potently inhibit RET in tumors, while sparing other kinase and non-kinase off-
targets that contribute to significant toxicity. 
These considerations indicate the benefit/risk ratio for selpercatinib in this study is favorable. 
 
 
 
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PLANNED SAMPLE SIZE: 
Phase 1: ~15 patients for each dose cohort in order to define the MTD/recommended dose for further study of 
selpercatinib for a total of ~120 patients.  
Phase 2: up to ~875 patients. 
STATISTICAL METHODS: 
Safety Analyses: 
The Safety Analysis Set will consist of all enrolled patients who receive at least one dose of selpercatinib. 
A baseline measurement and at least one laboratory or other safety-related measurement obtained after 
treatment of study drug may be required for inclusion in the analysis of a specific safety parameter. 
An SRC will be established to oversee the safety aspects of the Phase 1 portion of the study. The SRC will 
perform ongoing review of SAEs and other safety-related data throughout the conduct of the study. For Phase 
1, the SRC will be convened for each dose escalation decision or as needed. For Phase 2, the SRC will 
convene at a minimum of every 6 months. 
Efficacy Analyses: 
The efficacy analysis will be conducted on the Safety Analysis Set - patients with at least 6 months of 
treatment from the first dose of selpercatinib. These analyses will be summarized per tumor indication, 
including patients from both the Phase 1 and Phase 2 portions A Statistical Analysis Plan (SAP) will provide 
specific details on the efficacy analysis set. 
 
ORR will be estimated for tumor indication based on the observed proportion of patients whose best overall 
response, based on RECIST 1.1 or RANO, is confirmed CR or PR as determined by IRC and by the treating 
Investigator. The estimates of the ORR will be accompanied by a 2-sided 95% confidence interval (CI). 
Waterfall plots will be used to depict graphically the maximum decrease from baseline in the sum of longest 
diameters of target lesions. The duration of objective response, PFS, and OS will be summarized descriptively 
for each cohort using the Kaplan-Meier method. 
  
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 2 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS .......................................................................................................... 8 
LIST OF TABLES .................................................................................................................. 12 
LIST OF FIGURES ................................................................................................................ 12 
LIST OF APPENDICES ......................................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 14 
1. 
INTRODUCTION ...................................................................................................... 19 
1.1 
Tumors with RET Abnormalities and Current Treatment Options ................ 19 
1.2 
Rationale ......................................................................................................... 21 
1.3 
Selpercatinib Pre-Clinical Data Summary ...................................................... 21 
1.4 
Rationale for Enrolling Patients Younger than Age 18 Years ........................ 23 
1.5 
Benefit/Risk .................................................................................................... 23 
1.6 
Determination of Recommended Starting Dose ............................................. 24 
1.7 
Clinical Experience ......................................................................................... 24 
1.7.1 Known and Anticipated Risks ............................................................ 24 
1.7.2 Potential Drug Interactions ................................................................. 25 
2. 
STUDY OBJECTIVES ............................................................................................... 26 
2.1 
Primary Objective (Phase 1) ........................................................................... 26 
2.2 
Secondary Objectives (Phase 1)...................................................................... 26 
2.3 
Primary Objective (Phase 2) ........................................................................... 26 
2.4 
Secondary Objectives (Phase 2)...................................................................... 26 
2.5 
Exploratory Objectives (Phase 1 and Phase 2) ............................................... 26 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 28 
3.1 
Study Design ................................................................................................... 28 
3.2 
Length of Study and End of Study .................................................................. 28 
3.2.1 Length of Study................................................................................... 28 
3.2.2 End of Study ....................................................................................... 29 
3.3 
General Treatment Procedures ........................................................................ 29 
3.4 
Phase 1 and Maximum Tolerated Dose Determination .................................. 29 
3.5 
Dose-Limiting Toxicity (DLT) Definition...................................................... 33 
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3.6 
Phase 2 ............................................................................................................ 34 
3.6.1 Rationale for the Starting Dose of 160 mg BID for Phase 2 .............. 37 
3.7 
Definition of RET Alterations ........................................................................ 37 
3.8 
Number of Patients ......................................................................................... 38 
3.9 
Investigational Sites ........................................................................................ 38 
4. 
SELECTION OF STUDY POPULATION ................................................................ 39 
4.1 
Inclusion Criteria for Phase 1 ......................................................................... 39 
4.2 
Inclusion Criteria for Phase 2 ......................................................................... 42 
4.3 
Exclusion Criteria for Phase 1 and Phase 2 .................................................... 43 
5. 
ENROLLMENT PROCEDURES .............................................................................. 46 
6. 
TREATMENT ............................................................................................................ 47 
6.1 
Investigational Product ................................................................................... 47 
6.2 
Selpercatinib Administration .......................................................................... 47 
6.2.1 General Dosing Instructions ............................................................... 47 
6.2.2 Cycle 1: Phase 1 and Phase 2 .............................................................. 48 
6.2.3 Cycles 2 and Higher: Phase 1 and Phase 2 ......................................... 48 
6.2.4 Dose Delays/Modifications ................................................................. 48 
6.3 
Prior and Concomitant Medications ............................................................... 53 
6.3.1 General ................................................................................................ 53 
6.3.2 Allowed Concomitant Medications .................................................... 53 
6.3.3 Restricted Concomitant Medications .................................................. 54 
6.3.4 Contraindications ................................................................................ 55 
6.3.5 Transporter Interactions ...................................................................... 55 
6.3.6 Effect of Selpercatinib on the PK of other Drugs ............................... 55 
6.4 
Removal of Patients from Therapy or Assessment ......................................... 55 
6.5 
Reasons for End of Study ............................................................................... 56 
7. 
TESTS AND EVALUATIONS .................................................................................. 57 
7.1 
Screening Period ............................................................................................. 65 
7.2 
Cycle 1 ............................................................................................................ 67 
7.3 
Cycles 2 and Higher ........................................................................................ 69 
7.4 
Intra-Patient Dose Escalation .......................................................................... 71 
7.5 
End of Treatment Visit (All Patients) ............................................................. 72 
7.6 
Safety Follow-Up Visit ................................................................................... 73 
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7.7 
Long-Term Follow-Up.................................................................................... 74 
7.8 
Procedures for Special Tests ........................................................................... 74 
7.8.1 Tumor Measurements ......................................................................... 74 
7.8.2 Central Collection of Radiographic Studies ....................................... 74 
7.8.3 Pharmacokinetics ................................................................................ 74 
7.8.4 Collection of EORTC QLQ-C30, PedsQL for Teens, PedsQL for Children, 
and Bowel Diary ................................................................................. 75 
7.8.5 Correlative Studies .............................................................................. 75 
7.8.6 Growth Plate Monitoring .................................................................... 77 
7.8.7 Thyroid Function ................................................................................ 78 
7.9 
Continued Access............................................................................................ 78 
8. 
PLANNED ANALYSES ............................................................................................ 79 
8.1 
Study Endpoints .............................................................................................. 79 
8.2 
Analysis Populations ....................................................................................... 80 
8.2.1 Safety Analysis Set ............................................................................. 80 
8.3 
Determination of Sample Size ........................................................................ 80 
8.4  
Futility Monitoring.......................................................................................... 82 
8.5 
Statistical Methods .......................................................................................... 83 
8.5.1 Demographics and Baseline Characteristics ....................................... 83 
8.5.2 Safety Analyses ................................................................................... 83 
8.5.3 Efficacy Analyses ............................................................................... 85 
8.5.4 Pharmacokinetic Analyses .................................................................. 86 
9. 
ADVERSE EVENTS .................................................................................................. 88 
9.1 
Safety Review Committee .............................................................................. 88 
9.2 
Grading and Intensity of Adverse Events ....................................................... 88 
9.3 
Relationship to Underlying Disease, Other Medical Condition or Concomitant 
Medications ..................................................................................................... 89 
9.4 
Serious Adverse Event Reporting ................................................................... 90 
9.4.1 Serious Adverse Event Reporting – Procedures for Investigators: Initial 
Report .................................................................................................. 90 
9.5 
Serious Adverse Event Follow-Up ................................................................. 91 
9.6 
Pregnancy Reporting ....................................................................................... 92 
10. 
STUDY ADMINISTRATION.................................................................................... 93 
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10.1 
Regulatory and Ethical Considerations ........................................................... 93 
10.1.1 Regulatory Authority Approval .......................................................... 93 
10.1.2 Ethics Approval .................................................................................. 93 
10.1.3 Patient Informed Consent ................................................................... 93 
10.1.4 Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ................................................ 94 
10.1.5 Sponsor Safety Reporting to Regulatory Authorities ......................... 94 
10.2 
Data Management ........................................................................................... 95 
10.2.1 Data Protection.................................................................................... 95 
10.3 
Study Monitoring ............................................................................................ 96 
10.4 
Termination ..................................................................................................... 96 
10.5 
Records Retention ........................................................................................... 97 
10.6 
Confidentiality of Information ........................................................................ 97 
11. 
APPENDICES ............................................................................................................ 98 
12. 
REFERENCES ......................................................................................................... 128 
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LIST OF TABLES  
Table 3-1 
Actual Dose Escalations for Selpercatinib ............................................................ 31 
Table 3-2 
Selpercatinib Participant Enrollment Schema for Dose-Limiting Toxicity (DLT) 
Evaluation ............................................................................................................. 33 
Table 3-3 
Definition of RET Alterations .............................................................................. 38 
Table 4-1 
Standard of Care Therapies for Cohorts 1-4 ......................................................... 42 
Table 6-1 
Suggested Toxicity Management .......................................................................... 52 
Table 7-1 
Schedule of Assessments ...................................................................................... 58 
Table 7-2  
Continued Access Schedule of Assessments ........................................................ 64 
Table 8-1 
Futility Assessment: Information Fractions and Futility Boundaries ................... 82 
Table 8-2 
Futility Assessment for a sample size of 250........................................................ 82 
Table 8-3 
Futility Assessment for a sample size of 200........................................................ 83 
Table 8-4 
Futility Assessment for a sample size of 50.......................................................... 83 
Table 11-1 
Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity.................. 99 
Table 11-2 
Examples of RET Activating Mutations ............................................................. 100 
Table 11-3 
Examples of Validated Oncogenic Drivers......................................................... 101 
Table 11-4 
Inhibitors of CYP3A4 ......................................................................................... 102 
Table 11-5 
Inducers of CYP3A4 ........................................................................................... 102 
Table 11-6 
Examples of Proton Pump Inhibitors (PPIs) ....................................................... 104 
Table 11-7 
Eastern Cooperative Oncology Group (ECOG) Performance Scale .................. 105 
Table 11-8 
Lansky Performance Status ( 16 years old) ...................................................... 105 
Table 11-9 
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Guidelines 
for Tumor Response ............................................................................................ 109 
Table 11-10 
Overall Response Criteria: Time Point Response ............................................... 110 
Table 11-11 
Response Assessment in Neuro-Oncology (RANO) Criteria ............................. 111 
Table 11-12 
Examples of Agents Known to Cause QTc Prolongation ................................... 114 
 
LIST OF FIGURES  
Figure 3-1 
Study Schema........................................................................................................ 36 
 
LIST OF APPENDICES  
Appendix A 
Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity.................. 99 
Appendix B 
Examples of RET Activating Mutations ............................................................. 100 
Appendix C 
Examples of Validated Oncogenic Drivers......................................................... 101 
Appendix D 
Inhibitors and Inducers of CYP3A4 ................................................................... 102 
Appendix E 
Proton Pump Inhibitors (PPIs) ............................................................................ 104 
Appendix F 
Performance Scales ............................................................................................. 105 
Appendix G 
Tumor Measurements and Assessment of Disease Response using RECIST, 
Version 1.1 .......................................................................................................... 106 
Appendix H 
Response Assessment in Neuro-Oncology (RANO) Criteria for Primary CNS 
Malignancies ....................................................................................................... 111 
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Appendix I 
European Organization for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire-Core 30 (QLQ-C30) and PedsQL-Core Module (PedsQL) 
and Bowel Diary ................................................................................................. 113 
Appendix J 
Examples of Agents Known to Cause QTc Prolongation ................................... 114 
Appendix K 
Country-Specific Requirements .......................................................................... 115 
Appendix L 
Provisions for Changes in Study Conduct During Exceptional Circumstances . 119 
Appendix M Protocol Amendment History ............................................................................. 122 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation  
or Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ACTH 
adrenocorticotropic hormone 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-PD-1 
anti-programmed cell death protein 1 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the concentration versus time curve 
AUC0–∞ 
area under the concentration versus time curve from time 0 extrapolated to infinity 
AUC0-t 
area under the concentration versus time curve from time 0 to t 
AUC0-24 
area under the concentration versus time curve from time 0 to 24 hours 
AUCtau 
area under the concentration versus time curve calculated during the dosing interval 
at steady state 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BUN 
blood urea nitrogen 
BSA 
body surface area 
C 
Cycle 
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CDMS 
Clinical Data Management System 
CEA 
carcinoembryonic antigen 
cfDNA 
circulating free tumor deoxyribonucleic acid 
CI 
confidence interval 
CL/F 
apparent oral clearance of drug 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum drug concentration 
Cmin 
minimum drug concentration 
CNS 
central nervous system 
CR 
complete response 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
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Abbreviation  
or Term 
Definition 
CYP 
Cytochrome P450 
CYP3A4 
Cytochrome P450 3A4 
D 
Day 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer  
EORTC QLQ-
C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 
EOT 
End of Treatment 
ER 
estrogen receptor 
FAS 
Full Analysis Set 
FISH 
Fluorescence In Situ Hybridization 
FLAIR/T2 
T2-weighted fluid-attenuated inversion recovery 
GCP 
Good Clinical Practices 
GDPR 
EU General Data Protection Regulation 
GLP 
Good Laboratory Practice 
GnRH 
gonadotropin-releasing hormone 
5-HT3 
serotonin type 3 
H2 
Histamine-2 
Hb 
Hemoglobin 
hERG 
Human ether-à-go-go related gene 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
IC90 
90% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICH GCP 
International Conference on Harmonisation-Good Clinical Practices 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
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Abbreviation  
or Term 
Definition 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
IRB 
Institutional Review Board 
IRC 
independent review committee 
ISO/IEC 
International Organization for Standardization/ Independent Ethics Committee 
IUD 
intrauterine device  
IUS 
intrauterine hormone-releasing system 
IV 
Intravenous 
IVDR 
In vitro diagnostic regulation 
KRAS 
Kirsten rat sarcoma virus oncogene 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LHRH 
luteinizing hormone-releasing hormone 
LOXO-292 
investigational product; selpercatinib 
LPS 
Lansky Performance Score 
LTFU 
Long-Term Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or 
more of the five “rights” of medication use: the right participant, the right drug, the 
right dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication 
errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with 
the medication's labeling (for example, Summary of Product Characteristics, IB, 
local label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
mg 
milligram 
MHC-I 
Major Histocompatibility Complex class I 
MKIs 
multikinase inhibitors 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
mRNA 
messenger ribonucleic acid 
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Abbreviation  
or Term 
Definition 
MRSD 
maximum recommended starting dose 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
NGS 
next-generation sequencing 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease  
PD-1 
programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PedsQL 
Pediatric Quality of Life Inventory-Core Module 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
PO 
per os (oral) 
PP 
Per-protocol Analysis Set 
PPI 
proton pump inhibitors 
PR 
partial response 
PRO 
patient-reported outcomes 
PTC 
papillary thyroid cancer 
Q12W 
every 12 weeks 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate (Fridericia's formula) 
QTcI 
individual animal heart rate corrected QT intervals 
RANO 
Response Assessment in Neuro-Oncology 
RBC 
red blood cell 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RTK  
receptor tyrosine kinase 
SAD 
short axis diameter 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SERDs 
selective estrogen receptor degraders  
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Abbreviation  
or Term 
Definition 
SERMs 
selective estrogen receptor modulators 
SFU 
Safety Follow-Up 
SOC 
system organ class 
SOD 
sum of the diameters 
SRC 
Safety Review Committee 
SRS 
stereotactic radiosurgery 
SUSARs 
suspected unexpected serious adverse reactions 
Refers to an adverse event that occurs in a clinical trial participant, which is 
assessed by the sponsor and or study investigator as being unexpected, serious and 
as having a reasonable possibility of a causal relationship with the study 
intervention 
t1/2  
terminal elimination half-life 
T3 
triiodothyronine 
T4 
Thyroxine 
TBD 
to be determined 
TEAE 
treatment-emergent adverse event 
TKIs 
tyrosine kinase inhibitors 
Tmax 
time to maximum plasma concentration 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WBRT 
whole brain radiation therapy 
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1. 
INTRODUCTION  
1.1 
Tumors with RET Abnormalities and Current Treatment Options  
RET is a receptor tyrosine kinase (RTK) with critical roles in normal organogenesis and in the 
maintenance of several adult tissue types, including neural, neuroendocrine, hematopoietic, and 
male germ cell (Mulligan 2014). Genetic alterations in the RET gene are implicated in the 
pathogenesis of several human cancers. RET can be oncogenically activated by two primary 
mechanisms: (1) chromosomal rearrangements, producing cytoplasmically localized oncogenic 
hybrid proteins that fuse the RET kinase domain with a partner protein dimerization domain 
(e.g., CCDC6/PTC1, KIF5B, NCOA4/PTC3), thus endowing the kinase with ligand-
independent, constitutive activity; and (2) point mutations that directly or indirectly activate the 
kinase. The oncogenic potential of RET was first identified as a result of its ability to transform 
NIH 3T3 cells through deoxyribonucleic acid (DNA) rearrangement (Takahashi, Ritz et al. 
1985). Since its oncogenic potential was first discovered, the identification of additional, 
activating RET gene alterations in several different tumor types clearly implicates RET in the 
pathogenesis of human cancers. RET gene fusions have been identified in ~6% of sporadic 
papillary thyroid cancers (PTCs) (Fusco, Grieco et al. 1987, Cancer Genome Atlas Research 
2014) and at even higher frequency in radiation-induced PTCs (Ito, Seyama et al. 1994, 
Fugazzola, Pilotti et al. 1995, Bounacer, Wicker et al. 1997, Nikiforov, Rowland et al. 1997). In 
patients with PTC, RET gene fusions are associated with adverse prognostic features (Prasad, 
Vyas et al. 2016, Su, He et al. 2016). In addition, activating RET gene mutations occur at high 
frequency in human medullary thyroid cancer (MTC) (> 90% hereditary, ~50–60% sporadic) 
(Donis-Keller, Dou et al. 1993, Mulligan, Kwok et al. 1993, Carlson, Dou et al. 1994, 
Eng, Smith et al. 1994, Hofstra, Landsvater et al. 1994, Agrawal, Jiao et al. 2013, Ji, Oh et al. 
2015). The application of next-generation sequencing (NGS) approaches to a large collection of 
human tumors has led to the identification of RET gene fusions in a small fraction (1–2%) of 
non-small cell lung cancers (NSCLC, adenocarcinomas) and in an even smaller fraction of other 
tumor types, including colorectal cancer, breast cancer, and chronic myeloproliferative 
neoplasms (Ballerini, Struski et al. 2012, Ju, Lee et al. 2012, Kohno, Ichikawa et al. 2012, 
Lipson, Capelletti et al. 2012, Takeuchi, Soda et al. 2012, Bossi, Carlomagno et al. 2014, 
Stransky, Cerami et al. 2014).  
In addition to direct, mutation-mediated activation of RET, increased RET expression in the 
absence of RET mutation may contribute to the growth and survival of some human cancers. For 
example, RET has been shown to be a direct transcriptional target of the estrogen receptor (ER) 
(Boulay, Breuleux et al. 2008, Wang, Mayer et al. 2012), a finding that is consistent with 1) 
possible ER-mediated increased RET expression in tumors from rare families with MTC (Smith, 
Read et al. 2016); 2) increased RET expression in some ER-positive breast cancers that have 
acquired resistance to anti-estrogens (Plaza-Menacho, Morandi et al. 2010, Spanheimer, Park et 
al. 2014); and 3) re-sensitization to anti-estrogen treatment through RET inhibition (Plaza-
Menacho, Morandi et al. 2010, Morandi, Martin et al. 2013, Spanheimer, Park et al. 2014). 
Finally, a recent study identified RET as a strong negative regulator of Major Histocompatibility 
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Complex class I (MHC-I) expression in several human cancer cell lines of diverse histologies 
(Brea, Oh et al. 2016). This finding suggests a possible role for RET inhibition in upregulating 
the anti-cancer immune response. 
The combination of low-frequency alterations in a highly prevalent cancer like NSCLC, 
high-frequency alterations in a less-prevalent cancer like MTC and potential additional roles for 
RET in other contexts indicates that a significant number of patients with advanced, RET fusion-
positive NSCLC, RET-mutant MTC, and other cancers with RET activation could benefit from 
potent and selective RET kinase inhibition.  
Highly selective tyrosine kinase inhibitors (TKIs) that inhibit RET are lacking, but several 
multikinase inhibitors (MKIs) with some degree of anti-RET activity are already in the clinic, 
and two MKIs, cabozantinib and vandetanib, have received regulatory approval for advanced 
MTC (irrespective of the presence or absence of a RET mutation), with tumor response rates of 
28% and 45% and progression-free survival (PFS) improvements (over placebo) of 7.2 and 
11.2 months, respectively (Wells, Robinson et al. 2012, Elisei, Schlumberger et al. 2013). 
The different degree of benefit observed in each study was most likely due to the eligibility 
requirement for recent tumor progression in the cabozantinib study but not the vandetanib study. 
In subset analyses of both studies, patients whose tumors harbored RET activating mutations 
derived greater benefit than RET mutation–negative patients (Wells, Robinson et al. 2012, 
Sherman, Clary et al. 2016) . Preliminary data suggests similar, moderate activity for MKIs with 
anti-RET activity in RET fusion-positive lung cancer, with response rates of 16-53% (depending 
on the specific MKI and patient population), but PFS of only 3.6–7.3 months, in several ongoing 
Phase 2 studies (Drilon, Rekhtman et al. 2016, Lee 2016, Velcheti 2016, Yoh, Seto et al. 2016). 
The efficacy of these MKIs is ultimately limited by incomplete inhibition of RET in tumors in 
patients, significant toxicity from stronger inhibition of other targets (e.g., KDR/VEGFR2, 
EGFR, MET), and poor pharmacokinetics (PK) (i.e., significant drug accumulation and long 
half-life contributing to toxicity but not efficacy) in patients. As a result, the majority of patients 
treated with these agents experience significant toxicities requiring dose interruptions, 
reductions, and/or treatment cessation.  
Patients with RET fusion-positive cancers (NSCLC, PTC, colon, others) and RET-mutant cancers 
(such as MTC) represent populations with high unmet need. Combination chemotherapy has 
short-term palliative potential in advanced NSCLC, while anti-programmed cell death protein 1 
(anti-PD-1) monoclonal antibodies (e.g., nivolumab, pembrolizumab), which have recently been 
approved for NSCLC patients, may be less effective in tumors marked by single-gene driver 
oncogenic kinase alterations (including kinase fusions) with otherwise low mutational burdens 
and low neo-antigen production (Borghaei, Paz-Ares et al. 2015, Rizvi, Hellmann et al. 2015, 
Gainor, Shaw et al. 2016, Herbst, Baas et al. 2016). Chemotherapy is ineffective for MTC and 
PTC. Therefore, there is an urgent need to identify new targeted therapies that potently inhibit 
RET in tumors, while sparing other kinase and non-kinase off-targets that contribute to 
significant toxicity.  
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1.2 
Rationale  
Selpercatinib is a highly potent and specific inhibitor of the RET RTK, with minimal inhibition 
of other kinase and non-kinase targets, and therefore may be of benefit to patients with tumors 
(such as NSCLC, MTC, PTC, and colon or breast carcinomas) that harbor RET alterations and/or 
depend on RET activation. This Phase 1/2 study of selpercatinib is required to understand the 
PK, safety, and maximum tolerated dose (MTD) for selpercatinib in patients and to permit the 
preliminary assessment of efficacy. 
1.3 
Selpercatinib Pre-Clinical Data Summary  
Selpercatinib is a small molecule designed to block the adenosine triphosphate (ATP) binding 
site of the RET RTK; there is no evidence of covalent or irreversible binding. Selpercatinib 
causes dose-dependent inhibition of tumor growth in multiple, biologically relevant RET-
dependent tumor models in vitro and in vivo, including NSCLC, MTC, and colorectal cancer 
cells and tumors harboring KIF5B-RET and non-KIF5B-RET fusions, with and without the RET 
V804M gatekeeper mutation and activating RET mutations found in MTC.  
Selpercatinib was selective for 98% of 329 non-RET kinases tested in a large in vitro screen. 
This high degree of selectivity was maintained in additional enzyme and cell-based assays. 
Selpercatinib at clinically and toxicologically relevant concentrations had no significant effects 
on a range of other targets and receptors. 
Selpercatinib was absorbed and bioavailable in five animal species tested.  
Selpercatinib produced a 50% inhibitory concentration (IC50) value of 1.1 µM in the Good 
Laboratory Practices (GLP) in vitro human ether-a-go-go (hERG) channel assay; no drug-related 
changes in any cardiovascular endpoint, including individual animal heart rate corrected QT 
intervals (QTcI) at doses up to 12 mg/kg in the cardiovascular study using conscious minipigs. In 
the 3-month repeated-dose study, an increase in QTc interval was noted in female minipigs 
administered 5 mg/kg/day of selpercatinib, but the degree of the increase was small 
(approximately 7 to 12%). These low magnitude QTc changes were potentially selpercatinib-
related, but were not considered adverse. 
The toxicity of selpercatinib was evaluated in rats and minipigs in 14- and 28-day repeat dose, 
nonclinical studies. Dose groups were comprised of a vehicle control and low, medium, and high 
doses of selpercatinib. Rats and minipigs were chosen as appropriate test species for all in vivo 
toxicology studies based on PK and metabolic considerations. Additional detail is provided in the 
selpercatinib Investigator’s Brochure (IB). 
In an additional study in juvenile rats, changes in bone observed at therapeutically relevant 
exposures included increased physeal thickness of multiple bones, characterized by hypertrophy, 
hyperplasia, and dysplasia which resolved during the recovery phase and decreases in femur 
length observed at recovery, indicative of impaired longitudinal bone growth.   
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Additional information on the nonclinical pharmacology, PKs, and toxicity of selpercatinib are 
provided in the selpercatinib IB. 
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1.4 
Rationale for Enrolling Patients Younger than Age 18 Years  
The rationale for inclusion of patients younger than 18 years (where allowed by the Institutional 
Review Board [IRB]/Research Ethics Board [REB]/Independent Ethics Committee [IEC]) is the 
crucial role of RET mutations and fusions in the pathogenesis of thyroid cancer in younger 
patients. Germline RET gene mutations account for the majority of patients with hereditary MTC 
syndromes, and patients may develop cancer as children or adolescents (Castinetti, Moley et al. 
2017). In addition, a recent report described a surprisingly high frequency of RET gene fusions 
(22%) in pediatric patients with PTC in the Northeast United States (US) (Prasad, Vyas et al. 
2016). In this study, all RET-fusion patients were between the ages of 13 to 18 years, and the 
presence of a RET fusion was associated with high-risk pathologic features, including larger size, 
diffuse thyroid involvement, lympho-vascular invasion, and metastasis. Limited available 
clinical data suggests moderate efficacy and significant toxicity for such patients when treated 
with MKIs (Robinson, Paz-Ares et al. 2010).  
In vitro data show that selpercatinib is metabolized primarily by cytochrome P450 3A4 
(CYP3A4). CYP3A4 is expressed at a very low level at birth; it increases to adult levels at 
approximately 2 years of age (Wildt, Johnson et al. 2003). Thus, well before age 12, CYP3A4 
has reached its adult level of expression, as have most drug clearance mechanisms. Furthermore, 
a recent review of 126 products with at least one pediatric trial completed under the Food and 
Drug Administration (FDA) in 2007 identified 92 products with adolescent indications 
concordant with adult indications. Of these 92 products, 87 (94.5%) have identical adolescent 
and adult dosing (Momper, Mulugeta et al. 2013). Thus, the dose level for patients age 12 to 17 
years in this study will be the same as their adult counterparts.  
The nonclinical bone-related findings suggest a potential risk for growth plate abnormalities in 
patients with open growth plates, the impact of which could include decreased longitudinal bone 
growth. No clinically significant findings have been identified in the small number of patients 
under age 18 enrolled in selpercatinib clinical trials to date. However, participants who have not 
yet obtained full adult height are recommended to undergo growth plate monitoring.  
As described in Section 9.1, a Safety Review Committee (SRC) will be established to oversee 
the safety aspects of the study. Additional meetings will be held after every fifth patient between 
the ages of 12 to 17 years (inclusive) is enrolled.  
1.5 
Benefit/Risk  
When viewed as a whole, the preclinical data indicate that selpercatinib is a highly potent and 
specific inhibitor of the RET RTK, with minimal inhibition of other kinase and non-kinase off 
targets. Since selpercatinib is an experimental medicine, it is possible that unforeseen, unknown, 
or unanticipated drug reactions and toxicities may occur. However, as detailed below, this 
clinical protocol is designed to mitigate risks to patients through a detailed plan for cautious dose 
escalation, careful safety monitoring, systematic review of adverse events (AEs), serious AEs 
(SAEs), and PK, and active pharmacovigilance review to assess for safety signals or trends.  
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Patients with RET-fusion positive cancers (NSCLC, PTC, colon, others) and RET-mutant cancers 
(MTC) represent populations with high unmet need. As discussed in Section 1.1, available 
therapies for these patients provide short-term palliation (i.e., chemotherapy), may be less 
effective in cancers driven by kinase fusions (i.e., immunotherapy) and/or are very toxic (i.e., 
MKIs). Therefore, there is an urgent need to identify new targeted therapies that potently inhibit 
RET in tumors, while sparing other kinase and non-kinase off-targets that contribute to 
significant toxicity. 
These considerations indicate the benefit/risk ratio for selpercatinib in this study is favorable. 
1.6 
Determination of Recommended Starting Dose  
The maximum recommended starting dose (MRSD) was established as 44 mg/day based on the 
FDA’s guidance “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers” (2015) (US-FDA 2005) and the actual starting dose 
was 20 mg/day, given once daily. Additional information is provided in the selpercatinib IB. 
1.7 
Clinical Experience  
As of May 8, 2022, a total of 821 of the 825 (99.5%) patients treated in this study (LOXO-RET-
17001 [J2G-OX-JZJA]) experienced at least 1 treatment-emergent adverse event (TEAE) 
(regardless of relationship to study drug) of any grade. The TEAEs were coded according to the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC). Across the 
9 dose levels ranging from 20 mg to 480 mg (240 mg twice daily [BID]) daily, most TEAEs 
were mild or moderate (Grade 1 or 2) in severity. The most frequently reported AEs of special 
interest are listed in Section 1.7.1. 
Refer to the selpercatinib IB for the most current summary of clinical experience including 
anticipated risks and dose modification plans for specific AEs.  
1.7.1 
Known and Anticipated Risks  
As of a clinical data cut-off (May 8, 2022) for this study (LOXO-RET-17001 [J2G-OX-JZJA]), 
the following AEs of special interest include: 
 Dry mouth (48.7% total, 38.4% related)   
 Hypertension (41.5% total; 28.7% related) 
 AST increased (37.8% total; 28.8% related) 
 ALT increased (36.2% total; 29.1% related) 
 Electrocardiogram QT prolonged (20.5% total, 16.1% related)  
Additional details on the safety profile of selpercatinib are provided in the selpercatinib IB. 
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1.7.2 
Potential Drug Interactions  
Selpercatinib has pH-dependent solubility and its PK can be affected by agents that modify 
gastric pH such as PPIs (e.g., omeprazole). Coadministration with multiple daily doses of 
omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax by 69% and 88%, respectively 
when selpercatinib was administered fasting. Coadministration with multiple daily doses of 
omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when selpercatinib 
was administered with food. Additional guidance is provided in the selpercatinib IB. 
Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a 
single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib 
constituted 86% of the radioactive drug components in plasma. In addition, coadministration of 
selpercatinib with sensitive CYP3A4 substrates or CYP2C8 substrates may increase their plasma 
concentrations, which may increase the incidence or severity of adverse reactions. 
Coadministration of selpercatinib with strong and moderate CYP3A inhibitors, strong and 
moderate CYP3A inducers, and CYP2C8 and CYP3A substrates should be avoided. Additional 
guidance is provided in the selpercatinib IB. 
Selpercatinib inhibits drug transporter substrates MATE1, P-gp, and BCRP, but does not inhibit 
OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically 
relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular 
secretion of creatinine via inhibition of MATE1. Consider alternative markers of renal function if 
persistent elevations in serum creatinine are observed. 
The potential for selpercatinib inhibition of P-gp or BCRP in the intestine cannot be ruled out. If 
coadministration of a sensitive P-gp or BCRP substrate cannot be avoided, patients should be 
monitored for increased adverse reactions of these drugs. 
Additional details are provided in the selpercatinib IB. 
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2. 
STUDY OBJECTIVES  
2.1 
Primary Objective (Phase 1)  
 To determine the MTD/recommended Phase 2 dose (RP2D) of selpercatinib. 
2.2 
Secondary Objectives (Phase 1)  
 To determine the safety profile and tolerability of selpercatinib. 
 To characterize the PK properties of selpercatinib. 
 To assess the anti-tumor activity of selpercatinib by determining objective response rate 
(ORR) using Response Evaluation in Solid Tumors Version 1.1 (RECIST 1.1) or 
Response Assessment in Neuro-Oncology (RANO), as appropriate to tumor type. 
2.3 
Primary Objective (Phase 2)  
 To assess, for each Phase 2 expansion cohort, the anti-tumor activity of selpercatinib by 
determining ORR using RECIST 1.1 or RANO, as appropriate to tumor type, as 
assessed by independent review committee (IRC). 
2.4 
Secondary Objectives (Phase 2)  
 To assess, for each expansion cohort, the anti-tumor activity of selpercatinib by 
determining: 
 
ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, as assessed by 
Investigator; 
 
Best change in tumor size from baseline as assessed by IRC and Investigator;  
 
Duration of response (DOR) as assessed by IRC and Investigator;  
 
Central nervous system (CNS) ORR based on RECIST 1.1 or RANO, as appropriate for 
tumor type, as assessed by IRC (for patients with brain metastases); 
 
CNS DOR as assessed by IRC (for patients with brain metastases); 
 
Time to any and best response based on RECIST 1.1 or RANO, as appropriate for tumor 
type, as assessed by IRC and Investigator; 
 
Clinical Benefit Rate (CBR) based on the proportion of patients with best overall 
response of complete response (CR), partial response (PR), or stable disease (SD) lasting 
16 or more weeks following initiation of selpercatinib, as assessed by IRC and 
Investigator; 
 
Progression-free survival (PFS) as assessed by IRC and Investigator; 
 
Overall survival (OS) following initiation of selpercatinib. 
 To determine the safety profile and tolerability of selpercatinib. 
 To characterize the PK properties of selpercatinib. 
2.5 
Exploratory Objectives (Phase 1 and Phase 2)  
To determine the relationship between PK and drug effects, including efficacy and safety. 
To evaluate the serum tumor markers, carcinoembryonic antigen (CEA) and calcitonin 
(for patients with MTC), thyroglobulin (for patients with non-MTC thyroid cancer, unless 
not measurable due to presence of anti-thyroglobulin antibodies), and adrenocorticotropic 
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hormone (ACTH)/cortisol (for patients with Cushing’s disease related to their cancer), 
before, during, and at the end of treatment with selpercatinib.  
To characterize RET gene fusions and mutations and concurrently activated oncogenic 
pathways by molecular assays, including NGS from tumor biopsies and circulating free 
tumor DNA (cfDNA). 
To collect patient-reported outcomes (PRO) data to explore disease-related symptoms 
and health-related quality of life (HRQoL). 
 
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3. 
INVESTIGATIONAL PLAN  
3.1 
Study Design  
This is an open-label, multi-center Phase 1/2 study in patients with advanced solid tumors, 
including RET fusion-positive solid tumors (e.g., NSCLC, thyroid, pancreas, colorectal), 
RET-mutant MTC, and other tumors with RET activation (e.g., mutations in other tumor types or 
other evidence of RET activation). This study includes two parts: Phase 1 (dose escalation) and 
Phase 2 (dose expansion).  
Patients with RET alterations in tumor and/or blood will be identified through molecular assays, 
as performed in the routine course of clinical care. The RET alteration result should be generated 
from a laboratory with certification by Clinical Laboratory Improvement Amendments (CLIA), 
International Organization for Standardization (ISO)/IEC, College of American Pathologists 
(CAP), or other similar certification as per local guidelines including but not limited to In Vitro 
Diagnostic Regulation (IVDR) compliance as applicable. The Sponsor should be contacted to 
discuss test results to ensure trial eligibility. 
Both Phase 1 and Phase 2 will consist of a screening period, a treatment period, an End of 
Treatment (EOT) visit, a Safety Follow-Up (SFU) visit, and Long-Term Follow-Up (LTFU). 
Ongoing safety and disease assessments (for patients without progressive disease [PD]), disease 
status, survival, and subsequent anticancer therapy(ies) will be assessed during LTFU. 
Selpercatinib will be administered in oral form, once daily (QD) or BID, depending upon cohort 
assignment. Dosing will be fixed as total milligram (mg; as opposed to weight-based or body 
surface area [BSA]–based). 
3.2 
Length of Study and End of Study  
3.2.1 
Length of Study  
It is anticipated that a patient on this study will receive treatment with open-label selpercatinib 
until the patient meets criteria requiring discontinuation of treatment (refer to Section 6.4 
Removal of Patients from Therapy or Assessment). The study may be terminated if selpercatinib 
does not obtain marketing approval or the development of selpercatinib is no longer being 
pursued by the Sponsor. The Sponsor also reserves the right to discontinue the study for clinical 
or administrative reasons at any time. 
 
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) once it has been determined by the Sponsor that the evaluation of efficacy and 
safety of the populations of interest are sufficient and complete.  Investigators will continue to 
follow the study schedule for all patients until notified that study completion for that 
patient/cohort has occurred.  Patients who are still on study intervention at the time of study 
completion may continue to receive study intervention (continued access) if they are 
experiencing clinical benefit and no undue risks (as determined by the investigator). The 
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continued access period begins after study completion and will continue until the end of study 
(refer to Section 7.9). 
3.2.2 
End of Study  
The end of study is defined as the date when the last remaining patient has: 
 Completed the last visit where the patient completed the SFU visit, or completes any 
applicable continued access follow-up, or 
 consent has been withdrawn, or 
 is lost to follow-up, or 
 has died, or 
 has transferred to a separate study to receive further medication or treatment continuation 
has been secured by other means.  
3.3 
General Treatment Procedures  
Patients will receive the assigned selpercatinib dose on Cycle (C) 1 Day (D) 1 in accordance with 
the cohort assignment. Cycles are measured in 28-day increments and the dose limiting toxicity 
(DLT) observation period during Phase 1 comprises the first 28 days of treatment during C1. 
During this time, blood samples for drug levels will be collected and patients will be monitored 
for safety. 
Individual patients will continue daily selpercatinib dosing until PD, unacceptable toxicity, 
or other reasons for treatment discontinuation, as outlined in Section 6.4. Twenty-eight days after 
the last dose of study drug (+7 days), all treated patients will undergo an SFU visit. Patients with 
documented PD may be allowed to continue selpercatinib if the patient is tolerating treatment 
and, in the opinion of the Investigator, the patient is deriving clinical benefit from continuing 
study treatment, and continuation of treatment is approved by the Sponsor. 
After treatment discontinuation, LTFU will occur approximately every 3 months (±1 month) 
until the patient has withdrawn consent for further participation, is lost to follow-up, has died, or 
the Sponsor makes a decision to close the study. Assessments may include: subsequent 
anticancer therapy(ies) and survival status. LTFU may be conducted by phone. For any patient 
who is lost to follow-up, the study site will attempt to ascertain survival information via public 
database search. If survival status still cannot be ascertained, patients will be considered lost to 
follow-up and will be censored appropriately.  
3.4 
Phase 1 and Maximum Tolerated Dose Determination  
During Phase 1, patients with advanced cancer are initially eligible if they have progressed on or 
are intolerant to available therapies, or no standard or available curative therapy exists, or in the 
opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical 
benefit from appropriate standard of care therapy, or they declined standard therapy. Treatment 
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with any number of prior therapies, including any number of prior MKIs with anti-RET activity, 
is allowed (see Appendix A for examples). However, prior treatment with a selective RET 
inhibitor is prohibited (including investigational selective RET inhibitors). 
Preclinical data indicate that a selpercatinib plasma level of 70 ng/mL is equivalent to the IC50 
for RET (corrected for human plasma protein binding). Therefore, once a dose level is achieved 
that: (1) is associated with a DLT rate of < 33%; (2) is deemed safe by the SRC; and (3) is 
associated with a minimum drug concentration (Cmin) of > 70 ng/mL at steady state in ≥ 70% of 
patients in the same dosing cohort (e.g., 3/3, 3/4, 4/5, 5/6 patients, etc.), enrollment to subsequent 
dose levels during dose escalation will be restricted to patients with: (1) RET fusion-positive 
solid tumors; (2) MTC; (3) an advanced solid tumor that harbors a RET gene alteration 
(excluding synonymous, frameshift, or nonsense mutations); or (4) with prior Sponsor approval, 
an advanced solid tumor with other evidence of RET activation (refer to Section 4). A positive 
germline DNA test for a RET mutation is acceptable for patients with MTC. RET gene alterations 
in tumor tissue and/or blood will be identified through molecular assays, as performed for 
clinical evaluation. The RET alteration result should be generated from a laboratory with CLIA, 
ISO/IEC, CAP, or other similar certification as per local guidelines including but not limited to 
IVDR compliance as applicable. The Sponsor should be contacted to discuss test results from 
labs where such certification is not clearly demonstrated to determine eligibility. 
The starting dose of selpercatinib in oral capsule form is 20 mg/day (e.g., 20 mg QD). Should the 
observed human exposure match that predicted by modeling based on in vitro and animal data, 
this starting dose is likely to provide some degree of RET target engagement in patients without 
compromising patient safety. 
Dose escalations will be in increments of 100% above the previous dose level for the first 3 dose 
escalations. After the third dose increase, a modified Fibonacci dose escalation (Penel and 
Kramar 2012) will be employed for any subsequent dose escalations, with increments of ~67%, 
~50%, and ~33%. Additional dose escalations, if needed, will be with increments of ~33%. Each 
dose level after the starting dose represents the maximum dose to which patients will be 
escalated, and no individual dose escalation will be more than twice the dose at the previous 
level. However, the actual dose escalated to may be modified by the SRC to be compatible with 
the capsule strengths available and to minimize capsule burden for patients, while maintaining 
the modified Fibonacci design. 
The dose escalation scheme will revert to a modified Fibonacci design (i.e., without further 
100% increments initially specified for the first three dose escalations) if either of the following 
are observed (whichever occurs first): (1) the occurrence of two or more treatment-related 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 toxicities within a dosing 
cohort; or (2) a dose level is achieved that is consistent with causing RET target engagement 
(refer to Section 4.1 for target exposure). The actual dose levels used in this ongoing study are 
indicated in Table 3-1. 
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Table 3-1 
Actual Dose Escalations for Selpercatinib  
Level 
Dose 
Frequency 
Total Daily Dose 
1 
20 mg 
QD 
20 mg 
2 
20 mg 
BID 
40 mg 
3 
40 mg 
80 mg 
4 
60 mg 
120 mg 
5 
80 mg 
160 mg 
6 
120 mg 
240 mg 
7  
160 mg 
320 mg 
8 
240 mg 
480 mg 
9 
200 mg 
400 mg 
Additional potential doses  
10 and higher 
Per SRC 
TBD 
TBD 
Abbreviations: BID-twice daily; mg-milligram; QD-once daily; SRC-Safety Review committee; TBD-to be 
determined. 
 
A meeting of the SRC will be convened for each cohort dose escalation decision (see 
Section 9.1). For each cohort dose escalation decision, the SRC will recommend the dose for 
escalation, determination of DLT(s) recommended dose for further study. Smaller dose 
escalation increments will be considered in the event of frequent, unexpected AEs or DLTs as 
noted below. 
A minimum of 3 patients in a given cohort must have completed 28 days of safety assessment in 
C1 without DLT, and a maximum of one DLT may be seen in 6 patients who have completed the 
DLT window before the next cohort initiates accrual.  
Dose escalation will follow the 3+3 design. A minimum of 3 and a maximum of 6 persons will 
be concurrently enrolled into a single dosing cohort, depending on the occurrence of DLTs. 
Each patient in a given cohort must have completed safety assessments through the first 28 days 
of treatment in C1, and received a minimum of 75% (e.g., 42/56 doses with BID dosing) of the 
planned total dose during that time (unless due to toxicity) to be eligible for the assessment of a 
DLT. Patients who receive less than 75% of planned doses due to reasons other than a DLT will 
be replaced for the determination of the MTD but will remain part of the safety population if 
they received at least one dose of study drug. 
If 3 patients in a dosing cohort are evaluable for toxicity (i.e., have completed 28 days of safety 
assessment in C1 and have received at least 75% of planned doses) and no DLT has been 
observed, the next three patients may be enrolled to the next higher dose level with approval of 
the SRC.  
If one patient within a three-person dosing cohort experiences a DLT, then a total of 6 patients 
will be enrolled to that cohort for the purposes of DLT evaluation. If none of the additional 
patients have a DLT (i.e., 1 of 6 patients), then enrollment to the next higher dose level may 
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begin with approval of the SRC. If ≥ 2 patients within a dose escalation cohort experience a 
DLT, then the DLT Dose Level has been reached, and dose escalation will be stopped.  
The MTD is defined as the highest dose level at which none of the first 3 treated patients, or not 
more than 1 of the first 6 treated patients, experiences a DLT. Therefore, if two or more patients 
(≥ 33%) at the same dose level experience a DLT, then further enrollment to that cohort will stop 
and the cohort data will be reviewed by the SRC. In order for the MTD to be accurately 
determined, the SRC will evaluate whether the dose level previous to the dose level at which 
≥ 33% of patients experience a DLT will be considered the MTD, whether an intermediate dose 
level or a different dosing frequency should be evaluated, and/or whether additional patients 
need to be evaluated at this dose level if the DLTs seen at this dose level are considered to be not 
serious or can be reasonably attributed to the patient’s underlying disease, other medical 
conditions, or concomitant medications, rather than to selpercatinib. 
During the dose escalation phase, selected cohorts previously declared safe by the SRC may be 
expanded to a total of approximately 15 patients to further investigate the tolerability, PK and 
biological activity of selpercatinib. These additional patients will have confirmed RET status, and 
priority will be given to patients with RET alterations as defined in Table 3-3. The SRC will 
continue to monitor the cumulative safety data from the cohorts previously declared safe and the 
current dose cohort under evaluation. Enrollment of patients to the current dose cohort under 
evaluation will take precedent.  
There may be situations indicated by safety, efficacy, or PK that warrant exploration of 
additional, lower dose levels not specified in (or by the dose levels after an earlier switch to a 
modified Fibonacci design as a result of meeting criteria 1 or 2 above). These include the 
occurrence of frequent, unexpected AEs; frequent DLTs (e.g., DLTs that occur in more than one 
dose level, though at a rate < 33% in the any one dose level); or PK considerations. The 
occurrence of any of these may warrant consideration of smaller dose escalation increments than 
specified above or a change in dose schedule. Therefore, each dose level specified in Table 3-1 
(or by an earlier institution of a modified Fibonacci design) is the maximum dose to which 
patients will be escalated to at that level. Prior to enrollment of the first patient at each level, the 
actual dose escalated to may be lowered or the dosing schedule may change upon review of 
safety and available PK data by the SRC, to minimize the risk of toxicity for patients, more 
closely characterize DLT(s), and/or more accurately identify the MTD. 
Escalation will proceed through all dose levels or until the SRC and the Sponsor determine that a 
suitable dose has been achieved based on available data (safety, PK exposure, clinical activity).  
After completion of the 28-day DLT period in C1, intra-patient dose escalation may be permitted 
by the Sponsor, provided that the patient is tolerating their current dose and the dose level to 
which the patient will be escalated has already been evaluated, has a DLT rate of < 33%, and has 
been declared safe by the SRC. Refer to Section 7.4 for required assessments for intra-patient 
dose escalation. 
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The participant enrollment schema is summarized in Table 3-2. 
Table 3-2 
Selpercatinib Participant Enrollment Schema for Dose-Limiting Toxicity 
(DLT) Evaluation  
Criteria 
3+3 
Minimum number of patients per cohort 
3 
Maximum number patients per cohort 
6* 
Criteria to increase from 3 to 6 patients 
1/3 DLTs 
Criteria to escalate dose 
0/3 DLTs 
OR 
1/6 DLTs 
Criteria to stop dose escalation 
≥ 2 DLTs 
Criteria to de-escalate dose cohort 
≥ 2 DLTs at current dose level and < 33% DLT rate in 
previous dose level 
Maximum tolerated dose 
≤ 1/6 DLTs 
*See above for situations warranting accrual of additional patients. 
 
3.5 
Dose-Limiting Toxicity (DLT) Definition  
A DLT is defined as any of the TEAEs (a TEAE is defined as an AE that starts on or after the 
first administration of study medication) listed below, as defined by the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events, version 4.03 (NCI CTCAE 
v4.03), occurring during the first 28 days of treatment, provided that the participant has received 
at least 75% of planned doses and the AE is not reasonably attributed to the patient’s underlying 
disease, other medical conditions, or concomitant medications. The DLT definitions are:  
Grade 3 hematologic or non-hematologic toxicity, excluding:  
 Grade 3 AST, ALT, and/or total bilirubin elevation for less than 7 days. 
 Grade 3 neutropenia (without fever and not requiring growth factor support) for less than 
7 days. 
 Grade 3 thrombocytopenia without clinically significant bleeding. 
 Grade 3 lymphopenia. 
 First occurrence of Grade 3 electrolyte abnormalities and/or creatinine clearance decrease 
resolving to less than Grade 2 (or baseline if baseline is Grade 2 or above) within 48 hours 
with supportive treatment. 
 Grade 3 fatigue, weakness, nausea, or other manageable constitutional symptom. 
 Grade 3 vomiting or diarrhea that lasts for less than 48 hours with antiemetic or 
antidiarrheal medications.  
Grade 4 hematologic or non-hematologic toxicity, excluding:  
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 First occurrence of Grade 4 electrolyte abnormalities resolving to less than Grade 2 
(or baseline if baseline is Grade 2 or above) within 24 hours with supportive treatment. 
 Grade 4 lymphopenia. 
 Grade 4 manageable constitutional symptom. 
 Grade 4 vomiting or diarrhea that lasts for less than 24 hours with antiemetic or 
antidiarrheal medications. 
Any toxicity, regardless of the NCI CTCAE grade, resulting in discontinuation, dose 
reduction, or treatment with less than 75% of planned doses will be reviewed by the SRC and 
will be considered a DLT if the SRC determines the toxicity cannot be attributed to the 
patient’s underlying disease, other medical condition, or concomitant medications. 
AEs in the above categories that manifest after the DLT window (e.g., the first 28 days of 
treatment in C1) or other cumulative toxicities will be considered in the final definition of the 
MTD and/or the ultimate dose selected for further investigation.  
For purposes of defining the MTD, patients will be evaluated according to the actual starting 
dose of selpercatinib on the first day of treatment. For most patients, this will be defined by the 
cohort to which they are assigned. Patients who receive at least 75% of the planned total dose in 
the first 28 days of treatment in C1 will be considered to have sufficient study drug exposure to 
be evaluated in support of dose escalation. Each patient who receives less than 75% of planned 
doses during C1 will be reviewed by the SRC. If the SRC determines that the reason(s) for 
treatment discontinuation is not related to the patient’s underlying disease, other medical 
condition, or concomitant medications, the treatment discontinuation will be considered a DLT. 
Otherwise, the patient will be considered to have inadequate drug exposure and will be replaced 
for the determination of the MTD but will remain part of the safety population if they received at 
least one or more doses of study drug.  
3.6 
Phase 2  
A dose of 160 mg BID has been selected by the SRC as the RP2D. Therefore, up to ~875 
patients with advanced solid tumors with evidence of a RET gene alteration in tumor and/or 
blood (e.g., gene fusions and/or mutations, excluding synonymous, frameshift, or nonsense 
mutations) will be enrolled to one of  six Phase 2 cohorts (Figure 3-1) as noted below to better 
characterize the safety and efficacy of selpercatinib in patients with specific abnormalities in 
RET. For all cohorts except Cohort 5, evidence of a RET gene alteration in tumor (i.e., not just 
blood) as defined in Table 3-3 is required (a positive germline test for a RET mutation is 
acceptable for patients with MTC). 
Enrollment will be based on tumor type, type of RET alteration, and prior treatment: 
 Cohort 1 (up to ~250 patients): RET fusion-positive solid tumor progressed on or intolerant 
to ≥ 1 prior standard first-line therapy (see Table 4-1 for standard first-line therapies)  
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 Cohort 2 (up to ~125 patients): RET fusion-positive solid tumor without prior standard first-
line therapy (for countries and sites where approved; Germany and South Korea is excluded.) 
 Cohort 3 (up to ~125 patients): RET-mutant MTC progressed on or intolerant to ≥ 1 prior 
standard first-line cabozantinib and/or vandetanib  
 Cohort 4 (up to ~125 patients): RET-mutant MTC without prior standard first-line 
cabozantinib or vandetanib or other kinase inhibitors(s) with anti-RET activity (see Appendix 
A for examples, for countries and sites where approved; Germany and South Korea is 
excluded). 
 Cohort 5 (up to ~200 patients): 
 
Cohorts 1-4 without measurable disease; 
 
MTC not meeting the requirements for Cohorts 3 or 4; 
 
MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with 
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers with 
other RET alteration/activation may be allowed with prior Sponsor approval;  
 
cfDNA positive for a RET gene alteration not known to be present in a tumor sample. 
 Cohort 6 (up to ~50 patients): Patients who are otherwise eligible for Cohorts 1-5 who 
discontinued another RET inhibitor may be eligible with prior Sponsor approval.  
 Cohort 7 (up to ~19 patients): Patients with a histologically confirmed stage IB-IIIA NSCLC 
and a RET fusion; determined to be medically operable and tumor deemed resectable by a 
thoracic surgical oncologist, without prior systemic treatment for NSCLC. This cohort was 
removed from study as of 01June2022. One patient from a site in the US was enrolled and 
has discontinued treatment.  
These patients will be treated at the MTD if one is identified or at a lower dose level (i.e., the 
recommended dose for further study) chosen by the SRC that has a DLT rate < 33%, is safe, and 
is likely to provide RET target engagement (i.e., the observed drug exposure in patients at that 
dose is associated with preliminary evidence of efficacy and is in agreement with the exposure-
efficacy relationship predicted from preclinical data). In addition, the dose chosen for Phase 2 
may be changed by the SRC based on emerging data (e.g., PK, safety, and/or efficacy), as long 
as the new dose is not greater than the highest dose that has a DLT < 33% and is determined to 
be safe by the SRC in Phase 1. If the RP2D is changed, patients enrolled to Phase 2 at a different 
dose may have the dose changed to the new dose.  
Selpercatinib will be administered in oral form at the dose determined during dose escalation 
(MTD or recommended dose for further study). Each cycle will consist of either 28 days or 84 
days, depending on the patient’s duration on treatment (see Section 7). Patients treated during 
Phase 1 at the dose chosen for further study and who also meet the criteria for one of the Phase 2 
cohorts may be considered as part of the evaluable patients for that cohort. 
The study drug schedule and treatment assessments for Phase 2 are described in Section 6.2.3 
and Table 7-1, respectively.  
A statistical justification for cohort size is discussed in Section 8.3. 
 
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Figure 3-1 
Study Schema  
 
 
Abbreviations: cfDNA = circulating free tumor DNA; MTC = medullary thyroid cancer; MTD = maximum tolerated dose. 
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3.6.1 
Rationale for the Starting Dose of 160 mg BID for Phase 2  
In this study (LOXO-RET-17001 [J2G-OX-JZJA]), patients were enrolled in a dose escalation 
design that proceeded through the proposed dose levels until the SRC and the Sponsor 
determined that a suitable dose was achieved based on the available data (safety, PK exposure, 
clinical activity).  
Following the completion of the DLT period for the 160 mg BID dose, 3 patients were 
DLT-evaluable and 1 patient was not DLT-evaluable (due to missed doses secondary to 
unrelated hypertension). There were no significant AEs, laboratory or other abnormalities 
reported for the 3 patients. Therefore, the SRC recommended to open the next dose escalation 
cohort at a dose of 240 mg BID while continuing to enroll patients at 160 mg BID (“backfill”). 
At a dose of 240 mg BID, 2 of 6 patients experienced DLTs: Grade 3 tumor lysis syndrome and 
Grade 3 thrombocytopenia (refer to IB Section 5.5.1.3). Based on the cumulative PK, safety and 
efficacy data for all patients enrolled to date at doses of 20 mg QD through 240 mg BID mg BID 
(n=89), which included a total of 24 patients treated at a dose of 160 mg BID (4 during dose 
escalation and 20 during backfill), the SRC selected 160 mg BID as the RP2D while 
recommending continued dose exploration at a dose of 200 mg BID. Three patients were treated 
at this dose without DLTs. 
In summary, a dose of 160 mg BID was selected as the RP2D after careful and slow dose escalation; 
and based on the cumulative PK, safety and efficacy data for a meaningful number of patients treated 
at multiple doses. Although the clinical experience with patients ages 12 to 17 years is limited to 
date, selpercatinib exposure is not expected to be significantly different for patients in this age group 
than from older patients. The Sponsor has implemented a careful and robust safety monitoring plan 
as part of the protocol that consists of regular clinic visits and evaluations and frequent monitoring of 
laboratory values and electrocardiograms (ECGs). 
3.7 
Definition of RET Alterations  
The specific RET gene alterations required for enrollment to Cohorts 1-4 during Phase 2 are 
defined in Table 3-3 and Appendix B (Table 11-2). RET mutations and fusions will be identified 
from a laboratory with CLIA, ISO/IEC, CAP, or similar certification as per local guidelines 
including but not limited to IVDR compliance as applicable, so long as a written Molecular 
Pathology Report is available and clearly asserts the presence of the referenced RET alteration.  
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Table 3-3 
Definition of RET Alterations  
RET mutation* 
Previously reported activating RET gene mutation excluding synonymous, frameshift, or nonsense 
mutations. See Appendix B (Table 11-2) for examples. 
 
For MTC, RET gene mutation not known to be activating, negative, or unknown may be enrolled during 
Phase 1, and with Sponsor approval, to Cohort 5 of Phase 2.  
RET fusion* 
By PCR or NGS (FISH as the only molecular result is acceptable for Phase 1 dose escalation and Cohort 5 
but not Cohorts 1 and 2 of Phase 2 [dose expansion]). 
Abbreviations: CAP = College of American Pathologists; CLIA = Clinical Laboratory Improvement Amendments; 
FISH = Fluorescence in Situ Hybridization; ISO/IEC = International Organization for 
Standardization/Independent Ethics Committee; MTC = medullary thyroid cancer; NGS = next generation 
sequencing; PCR = polymerase chain reaction. 
* According to laboratory with CLIA, ISO/IEC, CAP, or similar certification as per local guidelines including but 
not limited to IVDR compliance as applicable, so long as a written Molecular Pathology Report is available and 
clearly asserts the presence of the referenced RET alteration. 
3.8 
Number of Patients  
During Phase 1, it is anticipated that approximately 30 patients (up to 6 patients per dose cohort) 
will be required to be enrolled in order to define the MTD (or RP2D) of selpercatinib. The actual 
number of patients enrolled is dependent on the number of patients enrolled in each dose 
escalation cohort, the number of cohorts enrolled, and when DLTs occur (if they occur). The 
safety of the patients enrolled is ensured with careful monitoring and rules for escalation so that 
an excessive number of patients are not unnecessarily exposed to a dose level that exceeds the 
MTD. Allowing intra-patient dose escalation (provided that the patient is tolerating their current 
dose and the dose level to which the patient will be escalated has already been evaluated, has a 
DLT rate of < 33%, and has been declared safe by the SRC) can minimize the chances that 
patients are exposed to a sub-therapeutic dose. Selected dose levels previously declared safe by 
the SRC may be expanded during Phase 1 to include a total of approximately 15 patients to 
further investigate the tolerability, PK, and biological activity of selpercatinib. If approximately 
15 patients are enrolled in each planned dose level (levels 1-8), a total of approximately 
120 patients will be enrolled in Phase 1. 
During Phase 2, up to ~875 patients will be enrolled.  
Refer to Section 8.3 for the statistical justification of initial sample/cohort size. 
3.9 
Investigational Sites  
Approximately 50 to 100 institutions will be recruited to enroll patients. 
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4. 
SELECTION OF STUDY POPULATION  
Potential patients age 18 years and older must sign an informed consent form (ICF) before any 
study-specific screening tests may be conducted.  
Potential patients younger than age 18 years will require an assent according to local rules and 
regulations in addition to an informed consent signed by a parent or legal guardian. Screening 
tests are described in Section 7.1. 
4.1 
Inclusion Criteria for Phase 1  
1. Patients with a locally advanced or metastatic solid tumor who: 
 have progressed on or are intolerant to standard therapy, or  
 no standard therapy exists, or  
 in the opinion of the Investigator, are not candidates for or would be unlikely to 
tolerate or derive significant clinical benefit from standard therapy, or  
 decline standard therapy.  
2. Prior MKIs with anti-RET activity are allowed. Refer to Appendix A for examples of 
MKIs with anti-RET activity. The specific agent(s), duration of treatment, clinical 
benefit, and reason for discontinuation (e.g., PD, drug toxicity, or intolerance) should be 
documented for all kinase inhibitors the patient has been exposed to. 
3. A RET gene alteration is not required initially. Once adequate PK exposure is achieved 
(see below), evidence of RET gene alteration in tumor and/or blood is required (e.g., gene 
rearrangement and/or mutation, excluding synonymous, frameshift, or nonsense 
mutations) as identified through molecular assays, as performed for clinical evaluation. 
The RET alteration result should be generated from a laboratory with CLIA, ISO/IEC, 
CAP or other similar certification as per local guidelines including but not limited to 
IVDR compliance as applicable. The Sponsor should be contacted to discuss test results 
from labs where such certification is not clearly demonstrated to determine eligibility. 
Notes:  
 During Phase 1, a RET gene alteration is not required initially. The Sponsor’s 
preclinical data indicates that a selpercatinib plasma level of 70 ng/mL is equivalent 
to the IC50 for RET (corrected for human plasma protein binding). Therefore, once a 
dose level is achieved that: (1) is associated with a DLT rate of < 33%; (2) is deemed 
safe by the SRC; and (3) is associated with a Cmin of > 70 ng/mL at steady state in 
≥ 70% of patients in the same dosing cohort (e.g., 3/3, 3/4, 4/5, 5/6 patients, etc.), 
enrollment to subsequent dose levels during Phase 1 will be restricted to patients 
with: (1) RET fusion-positive solid tumors; (2) MTC; (3) an advanced solid tumor 
that harbors a RET gene alteration (excluding synonymous, frameshift, or nonsense 
mutations); or (4) with prior Sponsor approval, an advanced solid tumor with other 
evidence of RET activation.  
 A positive germline test for a RET mutation is acceptable for patients with MTC. 
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 Local testing in a CLIA, ISO/IEC, CAP, or other similar certified laboratory as per 
local guidelines including but not limited to IVDR compliance as applicable, is 
sufficient. 
 In all cases, an anonymized/redacted Molecular Pathology Report or other report(s) 
describing tumor RET (and other) alteration analysis should be submitted to the 
Sponsor or designee during/prior to eligibility. 
4. Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as 
appropriate to tumor type. 
5. At least 18 years of age.  
 For countries and sites where approved, patients as young as 12 years of age may be 
enrolled. (Canada, South Korea, and Germany are excluded from enrolling minors 
[patients under 18 years of age] into the study). 
6.  Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 
2 (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years) with no 
sudden deterioration 2 weeks prior to the first dose of study treatment. 
7.  Life expectancy of at least 3 months. 
8.  Archived tumor tissue sample available.  
Notes:  
 Patients who do not have adequate archival tumor tissue available (refer to specific 
archival tissue requirements in Section 7.8.5.1) should undergo a fresh tumor biopsy, 
if it is considered safe to perform, prior to treatment (requirement may be waived 
with Sponsor approval).  
 If archived tumor tissue was obtained prior to progression on the last MKI with 
anti-RET activity, the patient should undergo a fresh tumor biopsy, if it is considered 
safe to perform prior to treatment (optional).  
9.  Adequate hematologic status, defined as: 
 Absolute neutrophil count (ANC) ≥ 1.0  109/L not requiring growth factor support 
for at least 7 days prior to treatment, and 
 Platelet count ≥ 75  109/L not requiring transfusion support for at least 7 days prior 
to treatment, and 
 Hb ≥ 9 g/dL not requiring transfusion support or erythropoietin for at least 7 days 
prior to treatment. 
10. Adequate hepatic function, defined as: 
 
ALT and AST ≤ 2.5  the upper limit of normal (ULN) or ≤ 5  ULN with 
documented liver involvement (such as liver metastasis or a primary biliary tumor); 
and 
 
Total bilirubin ≤ 1.5  ULN or ≤ 3  ULN with documented liver involvement 
(patients with Gilbert’s Disease may be enrolled with prior Sponsor approval). 
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11. Adequate renal function, with estimated glomerular filtration rate ≥ 30 mL/minute (up to 
6 patients with an estimated glomerular filtration rate [eGFR]) ≥ 15 and < 30 mL/minute 
will be allowed to enroll with Sponsor approval). 
12. Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, 
and required clinic visits for the duration of study participation.  
13. Willingness of men and women of reproductive potential to observe conventional and 
effective birth control for the duration of treatment and for 1 month following the last 
dose of study treatment. 
Notes:  
 A postmenopausal woman will be defined as having no menses for 12 months 
without an alternative medical cause. Male sterility will be defined as only men 
sterilized surgically. For male patients with a pregnant partner, a condom should be 
used for contraception. For male patients with a non-pregnant female partner of child-
bearing potential and woman of child-bearing potential one of the following birth 
control methods with a failure rate of less than 1% per year when used consistently 
and correctly are recommended: 
a. Combined estrogen and progesterone containing hormonal contraception 
associated with inhibition of ovulation given orally, intravaginally, or 
transdermally 
b. Progesterone-only hormonal contraception associated with inhibition of 
ovulation given orally, by injection, or by implant 
c. Intrauterine device (IUD) 
d. Intrauterine hormone-releasing system (IUS) 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence 
▪ Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject. 
 Birth control methods unacceptable for this clinical trial are: 
a. Periodic abstinence (calendar, symptothermal, or post-ovulation methods) 
b. Withdrawal (coitus interruptus) 
c. Spermicide only 
d. Lactational amenorrhea method 
Male study participants should refrain from sperm donation during study treatment and 
up to 6 months following the last dose of selpercatinib. 
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Women of childbearing potential is a woman who is fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. 
4.2 
Inclusion Criteria for Phase 2  
Inclusion Criteria are the same as for Phase 1, with the following modifications: 
1. Cohorts 1 and 3: failed or intolerant to standard of care; Cohorts 2 and 4: without prior 
standard-first line therapy. See Table 4-1 for examples. 
Table 4-1 
Standard of Care Therapies for Cohorts 1-4  
COHORT 
THERAPY 
Cohort 1: RET Fusion-
Positive Solid Tumor  
NSCLC: platinum-based chemotherapy (or other chemotherapy if not eligible 
for platinum) or PD-1/PD-L1 immunotherapy or both 
Thyroid: sorafenib and/or lenvatinib, patients must also be radioactive iodine-
refractory as appropriate 
Colorectal: fluoropyrimidine-based chemotherapy, with or without anti-VEGF-
directed therapy or anti-EGFR-directed therapy as appropriate for the disease 
Pancreas: fluoropyrimidine-based, gemcitabine-based, or S-1 chemotherapy  
Breast: anthracycline, taxane, HER2-directed therapy and/or hormonal therapy 
or other standard therapy appropriate for the disease 
Other: prior standard therapy for the disease  
Cohort 2: RET Fusion-
Positive Solid Tumor 
Without prior standard-first line therapy, only if Inclusion Criteria 1 from 
Phase 1 is met: 
 
no standard therapy exists, or  
 
in the opinion of the Investigator is not a candidate for or would be unlikely 
to tolerate or derive significant clinical benefit from standard therapy, or  
 
decline standard therapy 
Cohort 3: RET-mutant MTC  
Cabozantinib or vandetanib or both agents  
Cohort 4: RET-mutant MTC 
Without prior standard-first line therapy, only if Inclusion Criteria 1 from 
Phase 1 is met: 
 
no standard therapy exists, or  
 
in the opinion of the Investigator is not a candidate for or would be unlikely 
to tolerate or derive significant clinical benefit from standard therapy, or  
 
decline standard therapy 
Abbreviations: EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; MTC 
= medullary thyroid cancer; NSCLC = non-small cell lung cancer; PD-1 = programmed cell death protein 1; PD-
L1 = program death-ligand 1; VEGF = vascular endothelial growth factor.  
Note: Standard of Care may vary by country 
 
2. Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene 
alteration in tumor (i.e., not just blood) as defined in Table 3-3. However, a positive 
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germline DNA test for a RET gene mutation as defined in Table 3-3 is acceptable in the 
absence of tumor tissue testing for patients with MTC. 
3. Cohorts 1-4: at least one measurable lesion as defined by RECIST 1.1 or RANO, as 
appropriate to tumor type and not previously irradiated (unless PD for the irradiated 
lesion[s] has been radiographically documented).  
4. Cohort 4: radiographic PD within the previous 14 months.  
Note: Patients otherwise eligible for Cohort 4 who do not demonstrate radiographic PD 
within the previous 14 months may be enrolled to Cohort 5 if a compelling rationale is 
provided by the investigator and approved by the Sponsor. 
5. Cohort 6: patients otherwise eligible for Cohorts 1-5 who discontinued another selective 
RET inhibitor(s) may be eligible with prior Sponsor approval. 
Note:  
Examples of RET inhibitors may include TPX0046, pralsetinib (BLU-667), or 
BOS172739. 
6. Cohort 5: Patients who otherwise are eligible for: 
 Cohorts 1-4 without measurable disease; 
 MTC not meeting the requirements for Cohorts 3 or 4; 
 MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with 
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers 
with other RET alteration/activation may be allowed with prior Sponsor approval; 
 cfDNA positive for a RET gene alteration not known to be present in a tumor 
sample. 
7. Criterion 7 is removed. 
4.3 
Exclusion Criteria for Phase 1 and Phase 2  
Patients meeting any of the following criteria are to be excluded from study participation: 
1. Phase 2 Cohorts 1-4: an additional validated oncogenic driver that could cause resistance 
to selpercatinib treatment. See Appendix C (Table 11-3) for examples.  
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2. Cohorts 1-5: prior treatment with a selective RET inhibitor(s) (including investigational 
selective RET inhibitor[s]). 
Notes:  
Patients otherwise eligible for Cohorts 1-5 who discontinued another selective RET 
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.  
3. Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, 
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 
half-lives or 2 weeks (whichever is shorter) prior to planned start of selpercatinib. In 
addition, no concurrent investigational anti-cancer therapy is permitted. Refer to Section 
6.3.2 for allowable concurrent therapies. 
Note: Potential exception for this exclusion criterion will require a valid scientific 
justification and approval from the Sponsor. 
4. Major surgery (excluding placement of vascular access) within 2 weeks prior to planned 
start of selpercatinib. 
5. Radiotherapy with a limited field of radiation for palliation within 1 week of the first 
dose of study treatment, with the exception of patients receiving radiation to more than 
30% of the bone marrow or with a wide field of radiation, which must be completed at 
least 4 weeks prior to the first dose of study treatment. 
6. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of 
starting study treatment with the exception of alopecia and Grade 2, prior platinum-
therapy related neuropathy. 
7. Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or 
untreated spinal cord compression. 
Exception: Patients are eligible if neurological symptoms and CNS imaging are stable 
and steroid dose is stable for 14 days prior to the first dose of selpercatinib and no CNS 
surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery 
(SRS). 
Note: During the Phase 2 portion of the study, all prior local treatments for CNS disease 
(e.g., surgery, whole brain radiation [WBRT], SRS), the start and stop dates for each 
prior local therapy, the specific lesions treated (if SRS and/or surgery), whether the 
patient developed intracranial progression after the last prior local treatment, and which 
lesions progressed since completion of the local therapy must be documented. 
8. Clinically significant active cardiovascular disease or history of myocardial infarction 
within 6 months prior to planned start of selpercatinib or prolongation of the QT interval 
corrected for heart rate using Fridericia’s formula (QTcF) interval > 470 msec during 
Screening. Correction of suspected drug-induced QTcF prolongation may be attempted at 
the Investigator’s discretion if clinically safe to do so. 
Notes: 
 Patients with implanted pacemakers may enter the study without meeting QTc 
criteria due to nonevaluable measurement if it is possible to monitor for QT 
changes. 
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 Patients with bundle branch block may be considered for study entry if QTc is 
appropriate by a formula other than Fridericia’s and if it is possible to monitor 
for QT changes. 
9. Active uncontrolled systemic bacterial, viral, or fungal infection, or serious ongoing 
intercurrent illness, such as hypertension or diabetes, despite optimal treatment. 
Screening for chronic conditions is not required. 
10. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal absorption of the study drug. 
11. Uncontrolled symptomatic hyperthyroidism or hypothyroidism. 
12. Uncontrolled symptomatic hypercalcemia or hypocalcemia. 
13. Pregnancy or lactation. 
14. Active second malignancy other than minor treatment of indolent cancers. 
15. History of hypersensitivity to any of the study drug capsule components, or any of the 
liquid suspension components (for patients that cannot swallow capsules). 
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5. 
ENROLLMENT PROCEDURES  
For all patients, a copy of the anonymized/redacted Molecular Pathology Report, or other 
report(s) describing tumor RET (and/or other) mutation analysis should be submitted to the 
Sponsor or designee during Screening for review prior to patient enrollment. As part of 
pre-screening, it is advised to provide this upon patient identification for the study. If a patient 
does not have a prior Molecular Pathology Report or other report and is being considered for 
enrollment during the initial part of Phase 1 when a RET gene alteration is not required, this 
requirement may be waived with prior Sponsor approval. 
A representative from the investigational site will contact the Sponsor or designee when a 
potential study candidate is identified and a patient number (which will consist of a 3-digit site 
number followed by a sequential accession number) will be assigned that will be used throughout 
both Screening and study participation. Once screening procedures have been completed for the 
patient, a completed enrollment form will be submitted to the Sponsor or designee in order to 
confirm eligibility.  
Patients who are determined to be screen failures can be re-screened. Re-screened patients will 
be provided a new patient number.  
The enrollment form will be returned to the site with the cohort assignment (if applicable) and 
must be received by the site before treatment may commence. Refer to the Study Manual for 
enrollment form, contact numbers, and other details of enrollment.  
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6. 
TREATMENT  
6.1 
Investigational Product  
Selpercatinib 30% simple blend is provided in 40-mg capsules that will be made available to the 
sites in bottles of 60 capsules/bottle, and 80-mg capsules that will be provided to the sites in 
bottles of 120 capsules/bottle. The site pharmacist will dispense capsules or bottles (as permitted 
by the site) to the patient in an amount necessary to allow for outpatient administration at the 
assigned dose level. Dosing is intended to be fixed (i.e., not weight-based or BSA-based).  
Capsules are to be stored at controlled room temperature (between 15° C and 30° C).  
Intervention Name a 
Selpercatinib 
Authorized as defined by EU 
Clinical Trial Regulation 
Authorized and not used according to EU 
authorization 
a 
Study intervention is defined as any medicinal product(s) or medical device(s) intended to be administered to or 
used by a study participant according to the study protocol. 
Additional details regarding the investigational product and instructions for dissolving capsules 
are provided in the selpercatinib Pharmacy Manual and the selpercatinib IB. 
Under extenuating circumstances (e.g., personal emergencies, natural disasters, civil unrest, etc.), 
and where allowed by regional regulatory authorities, IP shipment direct from site to patient is 
permitted on case-by-case basis and with sponsor approval.  
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 
6.2 
Selpercatinib Administration  
6.2.1 
General Dosing Instructions  
Dosing for an individual should be at a consistent time each day and BID dosing will be 
separated by approximately 12 hours (a minimum of 6 hours between consecutive doses). 
Selpercatinib may be given with or without food, but should be taken in a consistent fashion. 
The patient will keep a daily diary to record dosing compliance, which will also be assessed at 
each clinic visit by means of a capsule count in the returned bottle(s). Late doses (i.e., 4 or more 
hours after scheduled time) should be noted in the diary. Doses that are late by more than 6 hours 
should be skipped and recorded in the dosing diary as missed. Vomiting after dosing should be 
noted in the diary and a vomited dose should not be re-dosed or replaced.  
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6.2.2 
Cycle 1: Phase 1 and Phase 2  
Patients will begin dosing on C1D1 according to their assigned cohort. Serial blood samples for 
PK monitoring will be collected and the patient will be monitored for safety as outlined in 
Section 7.2. Cycle length is 28 days during both Phase 1 and Phase 2; the DLT 
treatment/observation period during Phase 1 will consist of Days 1-28 of C1. 
6.2.3 
Cycles 2 and Higher: Phase 1 and Phase 2  
In accordance with the assigned dose level (or for Phase 2, the RP2D), each patient will receive 
selpercatinib QD or BID in continuous 28-day cycles until PD, unacceptable toxicity, or other 
reasons for treatment discontinuation. Patients with documented PD may be allowed to continue 
selpercatinib if the patient is tolerating treatment and, in the opinion of the Investigator, the 
patient is deriving clinical benefit from continuing study treatment and continuation of treatment 
is approved by the Sponsor. 
6.2.4 
Dose Delays/Modifications  
Cycles are 28 days in duration regardless of dose interruption unless the dose interruption 
includes D1 of the next cycle in which case the next cycle will start with resumption of study 
drug. In this situation, disease assessments should continue to follow the original schedule. 
For Phase 1 and Phase 2, toxicities such as nausea, vomiting, or diarrhea or dizziness or 
dehydration related to these symptoms, may be managed with increased supportive care, 
including hydration, electrolyte repletion, and the use of anti-emetics such as serotonin type 3 
(5-HT3) antagonists and/or anti-diarrheals such as loperamide as appropriate. 
Dose Delays/Modifications for Specific Adverse Events  
Safety and dose modification guidance is provided below for hypersensitivity, LFT 
abnormalities, thrombocytopenia, hypertension, hemorrhage, and dry mouth. Additional safety 
guidance is provided in Section 6 of the selpercatinib IB. 
Hypersensitivity 
Drug hypersensitivity reactions to selpercatinib have been reported. Patients developed a 
constellation of symptoms and findings characterized by a maculopapular rash, often preceded 
by fever, with associated arthralgias or myalgias during the patient’s initial weeks of treatment, 
which were then followed by at least one of the following:  
 more commonly: platelet decrease and AST/ALT increase 
 less commonly: blood pressure decrease, tachycardia, and creatinine increase 
If selpercatinib drug hypersensitivity is suspected, study drug should be held and treatment with 
steroids at 1 mg/kg prednisone (or equivalent) may be initiated at investigator discretion. Upon 
resolution, selpercatinib may be resumed at a reduced dose of 40 mg BID while continuing 
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steroids at the same dose. Hypersensitivity has recurred in some patients, typically at 3-6 hours 
following drug administration. If recurrence is severe, selpercatinib should again be held; 
patients with mild recurrence (e.g., isolated instances of rash or myalgias or low-grade fever) 
have been able to cautiously continue treatment with supportive therapy (e.g., topical treatments, 
ibuprofen).  
After a minimum of 7 days, and in the absence of clinically significant recurrent drug 
hypersensitivity, the dose of selpercatinib may be escalated sequentially to 80 mg BID, 120 mg 
BID and 160 mg BID. Once the patient has tolerated treatment for a minimum of 7 days at the 
final dose, steroids may be tapered slowly. If the patient experiences a clinically significant 
recurrence of drug hypersensitivity at the initial re-exposure dose of 40 mg BID, selpercatinib 
should be discontinued. 
Liver Function Test Abnormalities 
LFT laboratory testing (AST, ALT, total and direct bilirubin, ALP) should be performed every 2 
weeks through C4D1 and then D1 of every subsequent treatment cycle. If a patient experiences 
≥ Grade 3 elevated LFT increases, study drug should be held and evaluation for potential 
alternative causes should be conducted (e.g., history of other hepatotoxic medications/ 
substances, viral serologies, liver imaging). LFTs should be monitored at least weekly until 
resolution to normal/baseline (depending on the clinical situation, resolution to Grade 1 if 
baseline is normal may be acceptable but awaiting normalization is preferable). If the LFT 
abnormalities do not begin to resolve (or worsen) within 5 days of the AE, a hepatology 
consultation should be considered to evaluate the need for a liver biopsy. Some but not all 
patients were previously treated with immune checkpoint inhibitors (ICIs), and increased 
hepatotoxicity has been previously associated with sequential ICI therapy and TKIs in NSCLC 
(Lin et al, 2018). Therefore, prior ICIs may be a potential contributing factor in these patients; 
for some, concomitant treatment with steroids correlated with improvement in persistent LFT 
abnormalities. Therefore, in patients in whom there is thought to be an immune component to 
the LFT abnormalities observed, i.e., prior ICI exposure or liver biopsy results demonstrating 
an immune infiltrate, treatment with steroids may be added to the dose interruption 
recommendations below.  
Upon resolution, for patients who received 160 mg BID, selpercatinib may be resumed at 
a reduced dose of 80 mg BID with weekly LFT monitoring. In the absence of recurrent LFT 
abnormalities, the dose of selpercatinib may be escalated sequentially to 120 mg BID after 
a minimum of 2 weeks at 80 mg BID, and again to 160 mg BID, and after a minimum of 4 weeks 
at 120 mg BID. Once the patient has been treated at a stable dose of selpercatinib for a minimum 
of 1 cycle without recurrent LFT abnormalities, the frequency of LFT monitoring may be 
decreased (e.g., additional midcycle evaluation for 2 cycles and then at the start of every cycle 
thereafter). For patients who experience ≥ Grade 3 elevated LFTs on a different dose than 
160 mg BID, the dose should be reduced by 2 dose levels with subsequent re-escalation and 
monitoring as noted above upon resolution. If the patient experiences ≥ Grade 3 elevated LFTs at 
a dose of 40 mg BID, selpercatinib should be discontinued. 
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Thrombocytopenia 
A complete blood count (CBC) should be performed during Screening, C1D1, C1D15 and Day 1 
of every subsequent cycle. If a patient is discovered to have thrombocytopenia ≥ Grade 3, study 
drug should be held and the patient should be evaluated for alternative causes 
(medications/substances, viral studies). A hematology consultation may be considered as 
necessary to understand the etiology and to consider a role for concomitant steroid therapy. 
The patient should undergo weekly CBC testing until the event has recovered to normal/baseline. 
Upon recovery, the patient should resume selpercatinib at a reduced dose (e.g., 120 mg BID or 
80 mg BID) with weekly CBC surveillance for 1 full cycle.  
Hypertension 
All Investigators should optimize patients’ blood pressure to an ideal reading of ≤ 140/90 mmHg 
(if necessary) prior to initiation of study drug. If hypertension, defined as a sustained increase in 
blood pressure from baseline on ≥ 2 readings on ≥ 2 separate occasions, or a clinically significant 
elevation requiring acute treatment, occurs, study drug may be interrupted at the discretion of the 
Investigator while considering initiation of a new anti-hypertensive medication regimen, or 
alteration of a preexisting regimen is optimized to improve BP control; ideally to a reproducible 
reading of ≤ 140/90 mmHg. If study drug is interrupted, it may be resumed at the same or a 
lower dose at the discretion of the Investigator (i.e., rechallenge is allowable with adequate 
management of hypertension). In all cases, the patient should continue to undergo regular blood 
pressure monitoring to ensure adequate blood pressure control. Dose re-escalation to the 
patient’s original dose can be considered once adequate BP control has been obtained; with 
clinically appropriate monitoring to ensure elevated BP does not recur. If the patient experiences 
uncontrolled ≥ Grade 3 hypertension despite anti-hypertensive regimen optimization and study 
drug dose reduction to 40 mg BID, selpercatinib should be discontinued. 
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Hemorrhage 
Rare patients have reported serious hemorrhagic AEs related to study drug. The majority of 
hemorrhagic events have been Grade 1-2 and non-serious in nature. Clinical signs and symptoms 
of bruising and bleeding should be monitored while patients are on selpercatinib. For patients 
who develop an AE ≥ Grade 3, selpercatinib should be held until the event resolves to ≤ Grade 1 
(or baseline) and patients with severe or life-threatening hemorrhagic events should discontinue 
selpercatinib therapy. 
Dry Mouth 
Dry mouth (xerostomia) occurs in about 42% of patients in this study, and 37% were deemed by 
Investigators as related to selpercatinib. Although these events have been Grades 1-2, prolonged 
and inadequately managed dry mouth can lead to severe xerostomia and tooth carries resulting in 
tooth extractions. Clinical signs and symptoms of dry mouth should be monitored while patients 
are on selpercatinib. Management can include oral rinses or other medication that 
stimulates saliva production, such as pilocarpine- or cevimeline-containing agents, and dose 
reductions. 
Interstitial Lung Disease/Pneumonitis 
For Grade 2, hold dosing until resolution. Resume at next lower dose level. Discontinue 
selpercatinib for recurrent interstitial lung disease/pneumonitis. For Grade 3 or 4, discontinue 
selpercatinib. 
Chylothorax and Chylous Ascites 
If a patient develops a pleural effusion or abdominal ascites or both while on selpercatinib, fluid 
sampling and testing should be considered as part of the management algorithm whenever 
possible. The etiology of this finding varies and distinguishing chylous fluid from malignant (as 
well as other causes such as infectious) may impact management significantly (for example, 
presumption of disease progression with premature discontinuation of therapy). Additionally, a 
diagnosis of chylous effusions or ascites or both may indicate a role for conservative measures 
such as fluid replacement, dietary alteration, or medical therapy or both (for example, 
somatostatin analogue) prior to consideration of more invasive measures.  
Selpercatinib interruption and dose modification should follow the general strategy based upon 
severity of the event. 
Phase 1, Cycle 1  
Dose reductions are permitted but will be considered a DLT if the dose was reduced for a 
toxicity(ies) that cannot be reasonably attributed to the patient’s underlying disease, other 
medical condition or concomitant medications. 
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A patient who experiences a DLT may have selpercatinib dosing held for up to 28 days to allow 
for recovery (to Grade 1 or less or baseline if baseline is Grade 2 or above).  
The patient may restart therapy if it is considered in his/her best interest to continue therapy. 
Upon restarting, the patient may have the dose reduced by one dose level (Table 6-1). If the 
patient requires a dose delay of > 28 days, the patient will have treatment permanently 
discontinued unless there is a compelling clinical rationale for additional dose reduction(s) 
articulated by the Investigator and approved by the Sponsor. For each patient, a maximum of 
2 dose reductions will be allowed, unless there is a compelling clinical rationale for additional 
dose reduction(s) articulated by the Investigator and approved by the Sponsor. 
All dose interruptions and dose modifications and the reasons for those changes will be recorded 
in the electronic Case Report Form (eCRF).  
Phase 1 Cycle 2 and Beyond, and Phase 2  
A patient who experiences a clinically significant AE (i.e., greater than Grade 2 or more than 
1 grade change from baseline if baseline is Grade 2 or above) may have selpercatinib dosing 
held for up to 28 days to evaluate the AE and to allow for recovery (to Grade 1 or baseline level).  
Upon recovery, the patient may restart therapy if it is considered in his/her best interest to 
continue therapy. Upon restarting, the patient may have the dose reduced by at least one dose 
level (Table 6-1). If the AE does not recover to Grade 1 or less within 28 days (or baseline), the 
patient will have treatment permanently discontinued, unless there is a compelling clinical 
rationale for additional dose reduction(s) articulated by the Investigator and approved by the 
Sponsor. For each patient, a maximum of 2 dose reductions will be allowed, unless there is a 
compelling clinical rationale for additional dose reduction(s) articulated by the Investigator and 
approved by the Sponsor (Table 6-1). 
Table 6-1 
Suggested Toxicity Management  
Dose Level 
Dose of selpercatinib 
Starting Dose 
160 mg BID 
First Dose Reduction 
120 mg BID* 
Second Dose Reduction 
80 mg BID* 
Third Dose Reduction and Beyond 
Only permitted if there is a compelling clinical rationale articulated by the 
Investigator and approved by the Sponsor 
Abbreviations: AE = adverse event; BID = twice daily; LFT = liver function test. 
*For some AEs (e.g., hypersensitivity reactions and LFT increases), an alternative re-escalation strategy should be 
followed, which includes a dose reduction to 40 mg BID and alternative dosing at 60 mg BID. Occurrence of 
these AEs as well as implementation of the mentioned dosing should be discussed with the Sponsor. Additional 
information is provided in Section 6 of the selpercatinib IB, Summary of Data and Guidance for the Investigator. 
Patients who have been dose reduced and who tolerate selpercatinib without toxicity for at least 
one cycle may be re-escalated to their previous dose level with the agreement of the Investigator 
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and the Sponsor. Some AEs (e.g., hypersensitivity reactions and LFT increases) have an 
alternative re-escalation strategy. For additional information, refer to Section 6 of the 
selpercatinib IB, Summary of Data and Guidance for the Investigator. 
All dose interruptions and dose modifications and the reasons for those changes will be recorded 
in the eCRF. 
6.3 
Prior and Concomitant Medications  
6.3.1 
General  
All medications that were used from the time that written informed consent has been obtained 
through the SFU visit (at least 28 days [+7 days] after the last dose of study drug) will be 
recorded in the eCRF. These are to include prescription and nonprescription medications, 
transfusions, vitamins, nutritional supplements, vaccinations, and other remedies. Additional 
prior excluded medications are indicated in the Exclusion Criteria (Section 4.3).  
6.3.2 
Allowed Concomitant Medications  
Standard supportive medications may be used in accordance with institutional guidelines and 
Investigator discretion. These may include hematopoietic growth factors to treat neutropenia, 
anemia, or thrombocytopenia in accordance with American Society for Clinical Oncology 
guidelines (but not for prophylaxis in C1); RBC and platelet transfusions; anti-emetic, analgesic, 
and antidiarrheal medications; electrolyte repletion (e.g., calcium and magnesium) to correct low 
electrolyte levels; systemic glucocorticoids (approximately 10 mg per day prednisone or 
equivalent, unless there is a compelling clinical rationale for a higher dose articulated by the 
Investigator and approved by the Sponsor; no dose restriction for administration routes other 
than IV or oral), including short courses to treat asthma, chronic obstructive pulmonary disease, 
etc.; thyroid replacement therapy for hypothyroidism; and bisphosphonates, denosumab. and 
other medications for the treatment of osteoporosis, prevention of skeletal-related events from 
bone metastases, and/or hypoparathyroidism. Continuation of standard of care medications, 
including hormonal therapy for patients with prostate cancer (e.g., gonadotropin-releasing 
hormone [GnRH] or luteinizing hormone-releasing hormone [LHRH] agonists) and breast cancer 
(e.g., GnRH/LHRH agonists, aromatase inhibitors, selective estrogen receptor modulators 
[SERMs] or degraders [SERDs]), that the patient has been on for the previous 28 days, are 
allowed, provided they are not on the list of prohibited concomitant medications (refer to 
Section 6.3.3 and Appendix D).  
Local treatment of tumor sites or target lesions while receiving selpercatinib (e.g., palliative 
radiation therapy or surgery for bone metastases) is permitted with Sponsor approval; however, 
the Sponsor recommends holding selpercatinib for approximately 5 half-lives (approximately 2-3 
days) before and after radiation therapy or surgery. Any concern for disease flare due to a 
prolonged period off of selpercatinib should be discussed with the Sponsor, who may permit 
holding selpercatinib for a shorter period of time. 
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6.3.3 
Restricted Concomitant Medications  
Avoid concomitant use of strong and moderate CYP3A inhibitors (refer to Appendix D) with 
selpercatinib which increase selpercatinib plasma concentrations, which may increase the risk of 
selpercatinib adverse reactions, including QTc interval prolongation. If concomitant use of 
strong and moderate CYP3A inhibitors cannot be avoided, reduce the selpercatinib dosage and 
monitor the QT interval with ECGs more frequently (refer to the selpercatinib IB). 
Avoid coadministration of strong or moderate CYP3A inducers (refer to Appendix D) with 
selpercatinib which decrease selpercatinib plasma concentrations. If during the study, patients 
require initiation of treatment with strong inhibitors or inducers of CYP3A4 for clinical reasons, 
then the Sponsor should be consulted to determine whether selpercatinib should be stopped, and 
therefore whether the patient should be removed from the study.  
Avoid concomitant use of a PPI, H2 receptor antagonists, or locally acting antacids with 
selpercatinib. If concomitant use cannot be avoided, the following guidance should be adhered 
to: 
 
Take selpercatinib with food when co-administered with a PPI. 
 
Take selpercatinib 2 hours before (± 30 minutes) or 10 hours after (± 30 minutes) 
administration of an H2 receptor antagonist. 
 
Take selpercatinib 2 hours before (± 30 minutes) or 2 hours after (± 30 minutes) 
administration of a locally-acting antacid. 
Examples of PPIs are omeprazole (Prilosec®), esomeprazole (Nexium®), lansoprazole 
(Prevacid®), pantoprazole (Protonix®), rabeprazole (Aciphex®), and dexlansoprazole (Dexilant®) 
(refer to Appendix E). Examples of H2 blocking agents are ranitidine (Zantac®), famotidine 
(Pepcid®), and cimetidine (Tagamet®). Examples of antacids are aluminum 
hydroxide/magnesium hydroxide/simethicone (Maalox®), and calcium carbonate (TUMS®). 
Patients taking these agents are encouraged to record the time of each dose in relationship to 
each dose of selpercatinib in the dosing diary (inaccurate recording will not be considered a 
protocol violation). 
Coadministration of medications known to prolong QTc should be avoided if possible (refer to 
Appendix J for examples). 
In addition, except as indicated in Section 6.3.2, patients are not allowed to receive concomitant 
systemic anti-cancer agents, hematopoietic growth factors for prophylaxis in C1, therapeutic 
monoclonal antibodies, drugs with immunosuppressant properties, medications, or any other 
investigational agents besides selpercatinib. No new, alternative systemic anticancer therapy is 
allowed prior to documentation of PD in accordance with protocol-specified disease response 
criteria.  
Any exceptions to the above must be approved by the Sponsor. 
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6.3.4 
Contraindications  
Selpercatinib is contraindicated in patients with known hypersensitivity to any of its capsule 
components. 
6.3.5 
Transporter Interactions  
Selpercatinib is a substrate for the drug transporters P-gp and BCRP and in principle inhibitors of 
these transporters would lead to increased oral absorption of selpercatinib. However, inhibitors 
of these transporters are not prohibited because interim results of a clinical study of selpercatinib 
show that absolute bioavailability of selpercatinib is approximately 74%, thus there is little 
potential for increased absorption because bioavailability cannot go over 100%. In vitro, 
selpercatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), 
but is not a substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or 
MATE2-K. In a clinical study, the PK of selpercatinib was not affected significantly by a 
P-gp inhibitor. 
6.3.6 
Effect of Selpercatinib on the PK of other Drugs  
Avoid coadministration of selpercatinib with CYP2C8 and CYP3A substrates which may 
increase their plasma concentrations, which may increase the risk of adverse reactions related to 
these substrates and lead to increased adverse reactions. If coadministration cannot be avoided, 
follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product 
labeling, and monitor patients for increased adverse reactions of these drugs. 
Additional information regarding coadministration of selpercatinib with sensitive CYP2C8 
substrates, sensitive CYP3A4 substrates, and other CYP450 Substrates is provided in the 
selpercatinib IB. 
6.4 
Removal of Patients from Therapy or Assessment  
Patients will be advised that they are free to discontinue study treatment at any time and that they 
will be followed for survival after discontinuing treatment (see Section 7.7). Over the course of 
the study, the Investigator and/or the Sponsor should remove a patient from treatment for any of 
the reasons listed below: 
 PD 
Exception: Patients with documented PD who are tolerating treatment and, in the opinion 
of the Investigator, are deriving clinical benefit from continuing study treatment, may 
continue treatment with prior Sponsor approval. Sponsor approval is not required for 
continuing selpercatinib treatment upon a subsequent progression, provided that 
continued benefit to the patient is documented.  
 Unacceptable toxicity 
 Intercurrent illness compromising ability to fulfill protocol requirements 
 Pregnancy 
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 Requirement for alternative treatment in the opinion of the Investigator, unless such 
treatment is temporary (e.g., local radiation or surgery for disease that does not meet the 
definition of PD) 
 Significant noncompliance with protocol 
 Withdrawal of consent by the patient 
 Loss to follow-up 
 Death 
 Study terminated by Sponsor 
At the time a patient discontinues treatment, all safety data normally required at the EOT visit 
will be obtained if possible, as outlined in Section 7.5. Patients will enter LTFU where they may 
be required to undergo disease assessments (see Section 7.7). 
6.5 
Reasons for End of Study  
Reasons for end of study could be: 
 
Withdrawal of consent by the patient 
 
Loss to follow-up 
 
Death  
 
Study terminated by Sponsor 
A clinical trial is to be discontinued or terminated in case of an unacceptable risk, any relevant 
toxicity, or a negative change in the risk/benefit assessment. This might include the occurrence 
of AEs which character, severity or frequency is new in comparison to the existing risk profile. 
In addition, any data deriving from other clinical trials or toxicological studies which negatively 
influence the risk/benefit assessment might cause discontinuation or termination of the study. 
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7. 
TESTS AND EVALUATIONS  
All required observations and their schedules are summarized in Table 7-1 and are described in 
more detail in the following subsections.  
Routine laboratories, for example serum chemistries, hematology, and urinalysis, may be 
performed locally. Special assessments, such as PK and correlative studies, may be performed 
centrally or as individually indicated. For each thyroid cancer patient, tests for calcitonin and 
CEA (MTC patients) and thyroglobulin (non-MTC thyroid cancer patients) should be performed 
in the same laboratory to minimize intra-patient, lab-to-lab variability in their measurement. 
Additional information regarding handling and processing of these special samples is provided in 
the separate Laboratory Manual.  
Patients who are tolerating selpercatinib may have a reduced in-clinic visit assessment schedule 
after 6 months on treatment as described in Table 7-1. From Cycle 7 and onward, patients will be 
required to return to the clinic for in-person visits only during cycles where radiographic disease 
assessments are required, and for EOT and SFU visits. During non-disease assessment cycles, 
patients may continue to return for in person visits or may opt to have routine laboratory tests 
(e.g., serum chemistries, hematology, and liver function tests) completed at local healthcare 
facilities in conjunction with a telemedicine visit (telephone or equivalent). During the remote 
assessment, the site will perform an ECOG assessment, an AE assessment including whether the 
patient is experiencing any new, or changes to existing, AEs/SAEs and concomitant medications, 
and will confirm study drug compliance and record missed doses. Patient responses during 
telemedicine visits will be recorded in source documents and results from any local assessments 
must be provided to the site for data entry into EDC. Patients who are on selpercatinib treatment 
for at least 2 years will be required to return to the clinic for in-person visits only during cycles 
where radiographic disease assessments are required, and for EOT and SFU visits. Routine 
laboratory tests and telemedicine visits are not required but should be performed as clinically 
indicated during non-disease assessment cycles. 
Should telemedicine visits result in patient complaint or concern from the study Investigator, the 
patient should return to the study site or be seen by a local provider for further assessment(s).  
Beyond Cycle 7, physical examination, and vital signs are not required during local, non-disease 
assessment cycles, but should be collected when the patient returns to the clinic for disease 
assessment cycles. 
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Table 7-1 
Schedule of Assessments  
Visit Window 
Screenin
g 
Cycle 1 
Cycle 2-6 
 
Cycle 7-higher b 
Intra-
patient 
Dose 
Escalation EOT c SFU d LTFU e 
Day -28 to 
Day -1 
D1 
±2 
Days 
D8 
±2 
Days 
D15 
±2 
Days 
D22 a  
±2 
Days 
±3 Days 
 
±7 Days 
D1 
±3 
Days 
D8 
±3 
Days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, 
malignancy history 
X 
 
 
 
 
 
 
 
 
 
 
 
Molecular Pathology 
Report(s) describing 
RET and other 
alterations f 
X 
 
 
 
 
 
 
 
 
 
 
 
Archived tumor tissue 
or fresh biopsy g  
X 
 
 
 
 
 
 
 
 
X 
 
 
Physical examination 
and ECOG or LPS h 
X 
X 
X 
X 
 
D1 of C2-C6 
±7 days of each 
radiologic disease 
assessment 
X 
X 
X 
X 
 
Vital signs i 
X 
X 
X 
X 
 
D1 of C2-C6 
±7 days of each 
radiologic disease 
assessment 
X 
X 
X 
X 
 
12-lead ECGj  
X 
X 
X 
 
 
D1 of C2-C6 
D1 of odd cycles 
(C7, C9, C11, C13) 
and then every 12 
weeks until C26.  
After C26, obtain as 
clinically indicated. 
X 
X 
X 
X k 
 
Urine or serum 
pregnancy test l  
X 
X 
 
 
 
D1 of C2-C6 
D1 of C7, 8, 9, etc.* 
 
 
X 
X 
 
Hematology m 
X 
X 
 
X 
 
D1 of C2-C6 
D1 of C7, 8, 9, etc.* 
X 
 
X 
X 
 
Serum chemistries n  
X 
X 
 
X 
 
D1 of C2-C6 
D1 of C7, 8, 9, etc.* 
X 
 
X 
X 
 
Liver function tests o 
X 
X 
 
X 
 
D1 of C2-C6 and 
C2D15 and C3D15 
D1 of C7, 8, 9, etc.* 
 
X 
X 
X 
 
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Visit Window 
Screenin
g 
Cycle 1 
Cycle 2-6 
 
Cycle 7-higher b 
Intra-
patient 
Dose 
Escalation EOT c SFU d LTFU e 
Day -28 to 
Day -1 
D1 
±2 
Days 
D8 
±2 
Days 
D15 
±2 
Days 
D22 a  
±2 
Days 
±3 Days 
 
±7 Days 
D1 
±3 
Days 
D8 
±3 
Days 
Thyroid panel p 
X 
 
 
X 
 
C3D1 and then ±7 
days of each 
radiologic disease 
assessment 
±7 days of each 
radiologic disease 
assessment 
 
 
 
 
 
Urinalysis q 
X 
 
 
X 
 
As clinically 
indicated 
As clinically 
indicated.* 
 
 
X 
X 
 
Calcitonin, CEA (MTC 
only) r  
X 
X 
 
X 
 
C2D1 and then ±7 
days of each radiologic 
disease assessment 
±7 days of each 
radiologic disease 
assessment 
 
 
X 
 
 
Thyroglobulin (non-
MTC thyroid cancers 
only) s 
X 
X 
 
X 
 
C2D1 and then ±7 days 
of each radiologic 
disease assessment 
±7 days of each 
radiologic disease 
assessment 
 
 
X 
 
 
Serum cortisol, serum 
ACTH, 24-hour urine 
for free cortisol t 
X 
X 
 
X 
 
C2D1 and then ±7 days 
of each radiologic 
disease assessment 
±7 days of each 
radiologic disease 
assessment 
 
 
X 
 
 
Radiograph of kneegg  
X 
 
 
 
 
Every 6 months 
Every 6 months 
 
 
 
 
 
Whole blood for 
cfDNA analysis u 
 
X 
 
X 
 
C2D1  
 
 
 
X 
 
 
Whole blood for 
genomic DNA  
X 
 
 
 
 
 
 
 
 
 
 
 
Disease assessment v 
X 
 
 
 
 
Every 8 weeks (±7 
days) starting with 
C3D1 through C13D1. 
Every 12 weeks (±7 
days) thereafter. 
Every 8 weeks (±7 
days) through 
C13D1. Every 12 
weeks (±7 days) 
thereafter. 
 
 
X w 
 
X 
Confirmatory disease 
assessment y  
 
 
 
 
 
At least 4 weeks post 1st 
PR 
At least 4 weeks post 
1st PR 
 
 
 
 
 
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Visit Window 
Screenin
g 
Cycle 1 
Cycle 2-6 
 
Cycle 7-higher b 
Intra-
patient 
Dose 
Escalation EOT c SFU d LTFU e 
Day -28 to 
Day -1 
D1 
±2 
Days 
D8 
±2 
Days 
D15 
±2 
Days 
D22 a  
±2 
Days 
±3 Days 
 
±7 Days 
D1 
±3 
Days 
D8 
±3 
Days 
Telemedicine Visit z 
 
 
 
 
 
 
In parallel with local 
visits on non-disease 
assessment 
timepoints*  
 
 
 
 
 
Blood sample for PK aa  
 
 
X 
 
 
 
 
 
X 
 
 
 
EORTC QLQ-C30 or 
PedsQL bb 
 
X 
 
 
 
±7 days of each 
radiologic disease 
assessment 
±7 days of each 
radiologic disease 
assessment 
 
 
X 
 
 
Selpercatinib 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
Patient dosing diary 
 
 
 
 
 
 
 
 
 
 
 
 
Patient bowel diary 
(MTC only) cc 
 
X 
X 
X 
X 
D1 of C2-C6 
D1 of C7, 8, 9, etc.* 
 
 
X 
 
 
Adverse events dd 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications ee  
 
 
 
 
 
 
 
 
 
 
 
 
Survival ff 
 
 
 
 
 
 
 
 
 
 
 
X 
_______________________________ 
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Abbreviations (for Table 7-1 and Footnotes): ACTH = adrenocorticotropic hormone; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; C = cycle; C1D1 = Cycle 1 Day 1; CEA = carcinoembryonic antigen; cfDNA = circulating free tumor 
deoxyribonucleic acid; CR = complete response; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EDC = electronic data capture; EORTC-QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Core 30; EOT = End of Treatment; IB = Investigator’s Brochure; IV = intravenous; LDH = lactate dehydrogenase; LFT = liver function test; LPS = Lansky 
Performance Score; LTFU = Long-Term Follow-Up; MTC = medullary thyroid cancer; MRI = magnetic resonance imaging; PD = progressive disease; 
PedsQL = Pediatric Quality of Life Inventory-Core Module; PK = pharmacokinetics; PR = partial response; Q12W = every 12 weeks; QTcF = QT interval 
corrected for heart rate (Fridericia's formula); RANO = Response Assessment in Neuro-Oncology; RBC = red blood cell; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event; SFU = Safety Follow-Up; TSH = thyroid-stimulating hormone; T3 = free triiodothyronine; T4 = free 
thyroxine; ULN = upper limit of normal; WBC = white blood cell.  
 
* For Cycle 7 and beyond, patients may have laboratories (e.g., serum chemistries, hematology, liver function tests, and urinalysis) completed at the study site or 
at local healthcare facilities during non-disease assessment cycles. As a result of this reduced in-clinic visit assessment schedule, the Sponsor understands that 
certain assessments (e.g., physical examination, vital signs) may not be obtainable during visits at local healthcare facilities. Beyond Cycle 7, these 
assessments are optional during local, non-disease assessment cycles, but should be collected when the patient returns to the clinic for disease assessment 
cycles. Patients who are on selpercatinib treatment for at least 2 years will be required to return to the clinic for in-person visits only during cycles where 
radiographic disease assessments are required, and for EOT and SFU visits. As a result, visit frequency is increased from 4 weeks to 12 weeks, in line with 
imaging assessment schedule. Cycle length will be increased from 28 days to 84 days (see Section 7.3 for additional details). Routine laboratory tests and 
telemedicine visits are not required but should be performed as clinically indicated during non-disease assessment cycles.  
a. 
Telephone contact for safety. 
b. For Cycle 7 and beyond, patients may attend clinic visits only during cycles where radiographic disease assessments are required (Cycle 7, 9, 11, 13, 
and then Q12W thereafter) if telemedicine visit can be completed along with locally obtained lab assessments. 
c. 
End of Treatment (EOT): +7 days of the last dose or the decision to terminate treatment. 
d. Safety Follow-Up (SFU): 28 days (+7 days) after final dose of study drug. 
e. 
Long-Term Follow-Up (LTFU): approximately every 3 months (±1 month) after the last dose of study drug. 
f. 
For all patients, anonymized/redacted report(s) to be submitted to Sponsor or designee during Screening /prior to enrollment. 
g. Adequate availability of archived tumor tissue should be confirmed, either tumor block (preferred) or ~25 × 5 um unstained slides. Patients who do not 
have sufficient archival tumor tissue available should undergo an optional fresh tumor biopsy, if it is considered safe to perform, prior to treatment. If 
sufficient archived tumor tissue is not available and a fresh biopsy cannot be safely performed, the patient may still be eligible with prior Sponsor 
approval. A tissue biopsy to show PD may be collected at the time of progression if it can be safely performed. If oligometastatic disease constituting 
progression is identified, but the patient is otherwise stable and will continue selpercatinib beyond progression, the patient may undergo an optional 
fresh tumor biopsy to evaluate tumor changes that may have resulted from treatment.  
h. Physical examination of and review of relevant systems at Screening, body weight, and height. Symptom-directed physical examinations, including 
measurement of weight may be performed at other time points. Beyond Cycle 7, physical examination is only required when the patient returns to the 
clinic for disease assessment cycles. 
i. 
Systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature. Beyond Cycle 7, vital sign collection is only required when the 
patient returns to the clinic for disease assessment cycles.  
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j. 
Obtain a single pre-dose ECG during Screening and again on C1D1. If the C1D1 pre-dose QTcF > 470 msec (QTcF = QT (msec)/RR1/3), where RR 
(msec) = 60*1000/BPM), the Sponsor should be notified prior to dosing to determine whether the patient remains eligible. On C1D8 and thereafter, 
perform a single ECG at 2 hours (± 10 minutes) post-selpercatinib dosing. On days of PK collection, the ECG should be timed prior to the PK sample 
being drawn. Dose patients in the clinic to ensure accuracy of timing. If any ECG demonstrates QTcF 481500 msec, perform an additional- ECG at 4 
hours (± 10 minutes) post dosing. If any ECG demonstrates QTcF > 500 msec, repeat the ECG twice (triplicate in total) and manually review to confirm 
accuracy. If QTcF > 500 msec is confirmed on 2/3 ECGs, hold selpercatinib and assess for alternative causes (concomitant medications, electrolyte 
abnormalities). Potassium should be ≥ 4 mEq/L and < ULN and magnesium and calcium should be within normal limits. selpercatinib may be resumed 
at one reduced dose level when QTcF has returned to baseline value, and with continued ECG monitoring as noted in the assessment schedule. Please 
refer to protocol Section 6.2.4. and/or the selpercatinib IB for comprehensive dose modification information. For intra-patient dose escalation, ECGs 
should be performed pre-dose (up to 4 hours predose-) on Day 1 of the patient’s new dose, and 2 hours post-selpercatinib-dosing (±10 minutes) on Days 
1 and 8 of the patient’s new dose. For patients on treatment post cycle 26, ECG to be obtained as clinically indicated.  
k. Repeat only if EOT reading showed treatment-emergent abnormalities. 
l. 
For women of childbearing potential: Serum pregnancy test at Screening, serum or urine pregnancy test at Day 1 of every cycle, and at EOT and SFU 
(surgically sterilized females or those who have not experienced menses for at least 2 years are not required to be tested).  
m. Hematology including hemoglobin, hematocrit, RBC count, WBC count with differential (neutrophils [count and percent] and lymphocytes, monocytes, 
eosinophils, basophils [percent]), and platelet count). For intra-patient dose escalation, if Day 1 of the new dose falls on the same day (±3 days) of a 
previous hematology assessment (e.g., Day 1 of C2 and beyond), it is not necessary to repeat. Patients found to have treatment-emergent hematologic 
toxicity of Grades 3 or 4 will be monitored at least weekly until resolution.  
n. Serum chemistries (non-fasting), including BUN (urea where BUN not tested), total cholesterol, creatinine, glucose, LDH, , sodium, potassium, 
calcium, chloride, bicarbonate, magnesium, phosphorus, albumin, and total protein. For intra-patient dose escalation, if Day 1 of the new dose falls on 
the same day (±3 days) of a previous serum chemistry assessment (e.g., Day 1 of C2 and beyond), it is not necessary to repeat. Patients found to have 
treatment-emergent laboratory toxicity of Grades 3 or 4 will be monitored at least weekly until resolution.  
o. LFTs, including ALT, AST, alkaline phosphatase, and total and direct bilirubin. For intra-patient dose escalation, if Day 1 of the new dose falls on the 
same day (±3 days) of a previous liver function assessment (e.g., Day 1 of C2 and beyond), it is not necessary to repeat. Patients found to have 
treatment-emergent laboratory toxicity of Grades 3 or 4 will be monitored at least weekly until resolution. Increased LFT monitoring should be 
conducted following dose resumption and any dose re-escalation after toxicity (refer to Section 6 of the selpercatinib IB, Summary of Data and 
Guidance for the Investigator).  
p. Thyroid-stimulating hormone (TSH), free triiodothyronine (T3), and free thyroxine (T4). 
q. Complete urinalysis, including color, appearance, specific gravity, pH, glucose, ketones, occult blood, protein, leukocytes, nitrites. Beyond Cycle 
C1D15, urinalysis is only required if clinically indicated. 
r. 
Calcitonin and CEA only for patients with a diagnosis of MTC. These should be performed in the same laboratory to minimize intra-patient, lab-to-lab 
variability in their measurement. 
s. 
Thyroglobulin only for patients with non-MTC thyroid cancers (unless not measurable due to the presence of anti-thyroglobulin antibodies). These 
should be performed in the same laboratory to minimize intra-patient, lab-to-lab variability in their measurement. 
t. 
Optional for patients with Cushing’s disease related to their cancer. If performed, urine collection should begin pre-dose. 
u. Whole blood for cfDNA analysis should be obtained at C1D1 (pre-dose),  C1D15 and C2D1. Whole blood for cfDNA analysis should be obtained at the 
EOT visit, even if radiologic disease assessment is not performed. If oligometastatic disease constituting progression is identified, but the patient is 
otherwise stable and will continue selpercatinib beyond progression, patients should have blood collected for cfDNA analysis.  
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v. Baseline disease assessment with radiographic tumor measurements using CT or MRI of chest, abdomen, and pelvis or any other areas with suspected 
disease involvement within 28 days of C1D1. During Phase 2, brain imaging is required at baseline for all RET fusion-positive patients, patients with a 
history of CNS metastases, or other patients if clinically indicated and subsequent serial scans if brain metastases are present at baseline (MRI preferred, 
CT with contrast is acceptable if MRI contraindicated). For each modality, IV and oral contrast should be utilized (chest CT does not require IV 
contrast) unless there is a clear contraindication (e.g., decreased renal function or allergy that cannot be addressed with standard prophylactic 
treatments). In the absence of known or suspected disease involvement, head and neck CT/MRI scans are not required for malignancies other than those 
originating in the head and neck region. Other areas of scanning may also differ depending on disease type. Post-baseline scans should be performed 
every 8 weeks (±7 days) for one year and every 12 weeks (±7 days) thereafter, including imaging of the chest, abdomen, and pelvis, using the same 
modality(ies) as used for baseline imaging assessment until PD, withdrawal of consent, or initiation of a new anticancer therapy(ies). Additionally, any 
studies performed at baseline that are positive for sites of disease should be repeated at all post-baseline assessments. Additional studies can also be 
performed as clinically indicated. In addition, Investigators may conduct an initial tumor evaluation on C2D1 (±7 days) and a confirmatory tumor 
evaluation a minimum of 4 weeks (i.e., 28 days) after the first tumor evaluation that shows a CR or PR by RECIST 1.1 (or RANO, as appropriate to 
tumor type), if consistent with local regulatory authority requirements. In addition, an initial post baseline assessment on C2D1 (±7 days) is encouraged 
if consistent with regulatory guidelines. If a scan is performed on C2D1, the next scan should continue according to the schedule above (beginning at 
C3D1). All scans will be collected and stored at a central facility to permit central reviewer assessment if desired. Please see the Site Imaging Manual 
for guidelines on how the various imaging studies should be performed. 
w. If not performed within the last 8 weeks. 
x. Patients who discontinue study drug for reasons other than PD (e.g., AE, noncompliance, etc.) may (but for practical reasons and to minimize patient 
inconvenience, are not required to) undergo additional disease assessment by imaging (as specified above until PD, withdrawal of consent or initiation 
of a new anticancer therapy[ies]). 
y. Confirmatory scans: Minimum of 4 weeks (e.g., 28 days) after the first tumor evaluation showing a CR or PR by RECIST 1.1 or RANO, as appropriate 
to tumor type, if permitted by regulatory authorities. The next scan should continue according to the schedule above. 
z. 
Study sites will conduct a telemedicine visit when no in-clinic visit occurs to confirm whether the patient is experiencing any new, or changes to 
existing, AEs/SAEs and concomitant medications, and to confirm study drug compliance and missed doses. 
aa. Up to 1-hour pre-dose, and post-dose 1, 2, and 4 hours (±15 minutes) and 8 hours (±30 minutes). For intra-patient dose escalation, PK samples should be 
collected pre-dose (up to 1 hour prior to dosing) and post-dose at 1, 2, and 4 hours (±15 minutes) and 8 hours (±30 minutes) on Day 8 (±3 days) of the 
patient’s new dose. 
bb. EORTC QLQ-C30 (patients 18 years and older) and PedsQL (patients age 12-17 years). The questionnaires should be answered by the subject to the 
best of his/her ability, prior to receiving drug on C1D1 and preferably prior to learning the results of the radiologic disease assessment for subsequent 
cycles. 
cc. Only for patients with a diagnosis of MTC and diarrhea at baseline. For Cycle 7 and beyond, the patient should personally maintain bowel diary and 
discuss the diary with the site during telemedicine visits. The bowel diaries should be returned at the next in-clinic visit or provided to study site 
electronically.  
dd. AEs and SAEs should be recorded from the time that written informed consent has been obtained through the SFU Visit. 
ee. Concomitant, ongoing medication(s) plus those administered within 14 days prior to the planned start of treatment. 
ff. Patients will be followed for survival status, date of progression, and subsequent anticancer therapy(ies) by telephone or other method. 
gg. This is required for adolescents who have not reached adult height (see Section 7.8.6). 
 
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7.1 
Screening Period  
The following must be obtained within 28 days of C1D1 unless otherwise noted. Patients who 
cannot complete the procedures within the screening window may be rescreened, and certain 
screening procedures may not need to be repeated, including certain procedures that were 
obtained as part of the patient’s standard care prior to providing informed consent for this study 
(provided the patient provides informed consent), with the approval of the Sponsor. Screening 
tests that are completed in the 48 hours prior to start of study drug administration and that 
duplicate C1D1 tests according to the Schedule of Assessments (Table 7-1) will be accepted as 
fulfilling the C1D1 assessments; repeat testing on C1D1 is not necessary for this scenario, and 
results should be recorded in the Screening set of eCRFs. 
 Informed Consent. 
 Medical, surgical, and malignancy history, including histologic confirmation of solid 
tumor, primary and metastatic diagnosis dates, prior treatments for the malignancy, etc.  
 Submission of anonymized/redacted Molecular Pathology Report(s) describing RET and 
other alterations to Sponsor or designee. 
 Confirmation of availability of archived tumor tissue to be submitted, either tumor block 
(preferred) or ~25 × 5 um unstained slides. If archived tumor tissue is not available or is 
of insufficient quantity or quality, a fresh tumor biopsy should be obtained prior to 
selpercatinib. If in the opinion of the Investigator, a fresh biopsy cannot be safely 
performed, the patient may still be eligible with prior Sponsor approval. 
 Physical examination, including relevant review of systems, body weight and height, and 
ECOG performance status or Lansky Performance Score (refer to Appendix F). 
 Vital signs, including systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature. 
 Resting 12-lead ECG. 
 Serum pregnancy test for women of childbearing potential (surgically sterilized females 
or those who have not experienced menses for at least 2 years are not required to be 
tested). 
 Hematology, including hemoglobin, hematocrit, RBC count, WBC count with differential 
(neutrophils [count and percent] and lymphocytes, monocytes, eosinophils, basophils 
[percent]), and platelet count. 
 Serum chemistries (non-fasting), blood urea nitrogen (BUN; urea is acceptable for 
countries where BUN is not tested), total cholesterol, creatinine, glucose, lactate 
dehydrogenase (LDH), sodium, potassium, calcium, chloride, bicarbonate, magnesium, 
phosphorus, albumin, and total protein.  
 LFTs, including ALT, AST, alkaline phosphatase, and total and direct bilirubin. 
 Thyroid panel, including thyroid-stimulating hormone (TSH), free triiodothyronine (T3), 
and free thyroxine (T4). 
 Urinalysis, including color, appearance, specific gravity, pH, glucose, bilirubin, ketones, 
occult blood, protein, leukocytes, nitrites, and urobilinogen. 
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 Calcitonin, CEA: for patients with MTC only. For each patient, all tests for calcitonin and 
CEA should be performed in the same laboratory to minimize intra-patient, lab-to-lab 
variability in their measurement. 
 Thyroglobulin: for patients with non-MTC thyroid cancers only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, 
lab-to-lab variability in their measurement. 
 Serum cortisol, Serum ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer.  
 Participants under age 18 who have not yet obtained full adult height should undergo 
radiograph of one knee at baseline for growth plate assessment. 
 Whole blood for genomic DNA: obtained any time within 28 days prior to treatment on 
C1D1. 
 Baseline disease assessment with radiographic tumor measurements using: 
o All patients: computerized tomography (CT) or magnetic resonance imaging 
(MRI) of chest, abdomen, and pelvis, and any other areas with suspected disease 
involvement, within 28 days of C1D1.  
o All fusion-positive solid tumor patients, patients with a history of CNS 
metastases, or other patients if clinically indicated: brain imaging, MRI with and 
without contrast is preferred, CT with and without contrast is acceptable if MRI is 
medically contraindicated, within 28 days of C1D1. 
o For each modality, intravenous (IV) and oral contrast should be utilized (chest CT 
does not require IV contrast) where applicable unless medically contraindicated.  
o If CT/positron emission tomography (PET) is utilized, the CT component of 
CT/PET must be of the same quality as a dedicated diagnostic CT scan, i.e., with 
IV and oral contrast and 5 mm or less slice thickness. 
Notes: 
 In patients with thyroid and other head and neck cancers, imaging of the relevant 
areas (e.g., neck, skull base) is required at baseline; other areas of scanning may differ 
depending on disease type. See the separate Imaging Manual that will be distributed 
to the sites for details. 
 Additional scans can be performed as needed to evaluate potential sites of disease. 
 Disease assessments will utilize RECIST 1.1 or RANO as appropriate to tumor type 
(refer to Section 7.8.1). 
 Guidelines on the technical parameters of how scans should be performed will be 
provided in the Imaging Manual  
 Concomitant, ongoing medications plus those administered within 14 days prior to the 
planned start of treatment. 
 
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7.2 
Cycle 1  
The procedures listed below will be performed at the indicated intervals. Observations, routine 
laboratory tests, and HRQoL assessments will be performed prior to selpercatinib dosing on that 
day unless otherwise indicated. Routine clinic visits and C1D1 evaluations performed within 
±2 days of the nominal visit day will not be considered protocol deviations, with the exception of 
ECGs and PK, which must be performed relative to the dose of selpercatinib on that day as 
indicated below.  
Laboratory values on C1D1 pre-dose must meet the inclusion/exclusion criteria for treatment to 
proceed. 
Day 1  
 Symptom-directed physical examination, weight, and ECOG or Lansky score. 
 Vital signs. 
 Resting 12-lead ECG: pre-dose (up to 4 hours pre-dose). 
 Serum or urine pregnancy test for women of childbearing potential (surgically sterilized 
females or those who have not experienced menses for at least 2 years are not required to 
be tested). 
 Hematology (as described in Section 7.1). 
 Serum chemistries (as described in Section 7.1). 
 Liver function tests (as described in Section 7.1). 
 Calcitonin, CEA: for patients with MTC only. For each patient, all tests for calcitonin and 
CEA should be performed in the same laboratory to minimize intra-patient, lab-to-lab 
variability in their measurement. 
 Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, 
lab-to-lab variability in their measurement. 
 Serum cortisol, serum ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer. If done, urine collection should begin pre-dose. 
 Whole blood for cfDNA analysis: obtained prior to treatment on C1D1. 
 Selpercatinib administration. 
 Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids. 
 AEs. 
 Concomitant medications. 
 Patient-reported outcomes to be completed pre-dose: 
o For MTC patients with diarrhea present at baseline: bowel diary. 
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o For patients 18 years or older: European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). 
o For patients age 13 to 17 years: Pediatric Quality of Life Inventory-Core Module 
(PedsQL) for teens. 
o For patients age 12 years: PedsQL for children. 
Day 8 
 Symptom-directed physical examination, weight, and ECOG or Lansky score. 
 Vital signs. 
 Resting 12-lead ECG: 2 hours post-dose (±10 minutes) and prior to PK blood draw at 
this time point. Further ECGs may be required based upon results of the 2 hours post-
dose ECG (refer to Table 7-1, footnote “j” for specific instruction based upon QTcF 
value observed).  
 Blood sample for PK (2 mL whole blood): pre-dose (within 1 hour prior to dosing), and 
post-dose at 1, 2 and 4 hours (±15 minutes) and 8 hours (±30 minutes).  
 Selpercatinib administration. 
 Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids. 
 AEs. 
 Concomitant medications. 
 For MTC patients with diarrhea present at baseline: bowel diary. 
Day 15 
 Symptom-directed physical examination, weight, and ECOG or Lansky score. 
 Vital signs. 
 Hematology (as described in Section 7.1). 
 Serum chemistries (as described in Section 7.1). 
 LFTs (as described in Section 7.1). 
 Thyroid panel, including TSH, free T3, and free T4. 
 Urinalysis. 
 Calcitonin, CEA: for patients with MTC only. For each patient, all tests for calcitonin and 
CEA should be performed in the same laboratory to minimize intra-patient, lab-to-lab 
variability in their measurement. 
 Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, 
lab-to-lab variability in their measurement. 
 Serum cortisol, serum ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer. If done, urine collection should begin pre-dose. 
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 Whole blood for cfDNA analysis. 
 Selpercatinib administration. 
 Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids. 
 AEs. 
 Concomitant medications. 
 For MTC patients with diarrhea present at baseline: bowel diary. 
Day 22 
Telephone contact for safety: The site will contact the patient by telephone to assess for 
selpercatinib tolerability, continuation of study drug, and whether the patient needs to return to 
the clinic earlier than planned. If not tolerating the drug well, the patient should be seen at least 
every 14 days to assess AEs, and the patient should be contacted regularly to assess AE status. 
The patients should be reminded to complete the bowel diary for the previous week and bring the 
diary to the C2D1 visit. 
7.3 
Cycles 2 and Higher  
The following procedures will be performed prior to dosing as noted. Routine clinic visits 
performed within ±3 days of the nominal visit day will not be considered protocol deviations. 
 Symptom-directed physical examination, weight, and ECOG or Lansky score: Day 1 of 
each cycle starting with C2. Beyond Cycle 7, physical examination is only required when 
the patient returns to the clinic for disease assessment cycles (C7, C9, C11, and C13, then 
every 12 weeks [Q12W] thereafter). 
 Vital signs: Day of 1 each cycle starting with C2. Beyond Cycle 7, vital signs are only 
required when the patient returns to the clinic for disease assessment cycles (C7, C9, 
C11, and C13, then Q12W thereafter). 
 Resting 12-lead ECG (2 hours post-dose on C2D1, C3D1, C4D1, C5D1 and C6D1 
[±10 minutes]) and subsequently in alignment with required disease assessment 
timepoints (C7, C9, C11, and C13, then Q12W thereafter through Cycle 26). Further 
ECGs may be required based upon results of the 2 hours post-dose ECG (refer to 
Table 7-1, footnote “j” for specific instruction based upon QTcF value observed). 
Additional ECGs may be performed if clinically indicated. 
 Serum or urine pregnancy test for women of childbearing potential (surgically sterilized 
females or those who have not experienced menses for at least 2 years are not required to 
be tested): Day 1 of each cycle starting with C2. For Cycle 7 and beyond, patients may 
have serum or urine pregnancy test completed at local healthcare facilities during non-
disease assessment cycles.  
 Hematology (as described in Section 7.1): Day 1 of each cycle starting with C2. For 
Cycle 7 and beyond, patients may have hematology completed at local healthcare 
facilities during non-disease assessment cycles.  
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Note: Patients found to have treatment-emergent hematologic toxicity of Grades 3 or 
4 will be monitored at least weekly until resolution. 
 Serum chemistries (as described in Section 7.1): Day 1 of each cycle starting with C2. 
For Cycle 7 and beyond, patients may have serum chemistries completed at local 
healthcare facilities during non-disease assessment cycles.  
Note: Patients found to have treatment-emergent laboratory toxicity of Grades 3 or 4 
will be monitored at least weekly until resolution. 
 LFTs (as described in Section 7.1): C2D1, C2D15, C3D1, C3D15, and D1 of each cycle 
starting with C4. For Cycle 7 and beyond, patients may have LFTs completed at local 
healthcare facilities during non-disease assessment cycles. 
Note: Patients found to have treatment-emergent laboratory toxicity of Grades 3 or 4 
will be monitored at least weekly until resolution. 
 Thyroid panel: C3D1 and then ±7 days of each radiologic disease assessment.  
 Urinalysis: Beyond C1D15, urinalysis is only required when clinically indicated. 
 Calcitonin, CEA: for patients with MTC only; should be measured C2D1 and then 
±7 days of each radiologic disease assessment. For each patient, all tests for calcitonin 
and CEA should be performed in the same laboratory to minimize intra-patient, lab-to-lab 
variability in their measurement. 
 Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies); should be measured C2D1 and then 
±7 days of each radiologic disease assessment. For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, 
lab-to-lab variability in their measurement. 
 Serum cortisol, serum ACTH, 24-hour urine for free cortisol: for patients with Cushing’s 
disease related to their cancer; should be measured C2D1 and then ±7 days of each 
radiologic disease assessment. If done, urine collection should begin pre-dose. 
 Participants under age 18 who have not yet obtained full adult height should undergo 
radiograph of one knee every 6 months for growth plate assessment. Image the same knee 
that was imaged at baseline. 
 Whole blood for cfDNA analysis: C2D1 only 
 Radiographic disease assessment: every 8 weeks (±7 days) beginning with C3D1 through 
C13D1 and every 12 weeks (±7 days) thereafter until PD, withdrawal of consent, or 
initiation of a new anticancer therapy(ies), including imaging of the chest, abdomen, and 
pelvis, utilizing the same modality(ies) as used for the baseline imaging assessment. 
Additionally, any studies performed at baseline that are positive for sites of disease 
should be repeated at all post baseline assessments. Additional studies can also be 
performed as clinically indicated. Please see the Imaging Manual for guidelines on how 
the various imaging studies should be performed.  
Notes:  
- 
Patients who discontinue study drug for reasons other than PD (e.g., AE, 
noncompliance, etc.) may (but, for practical reasons and to minimize patient 
inconvenience, are not required to) have scans performed and collected as defined 
above.  
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- 
Post-baseline imaging of the brain using the same modality as at baseline should 
be performed for patients with evidence of CNS disease at baseline and if 
clinically indicated. 
- 
If consistent with local regulatory guidelines, an initial post-baseline assessment 
after 4 weeks of treatment (±7 days) is encouraged. If this scan is performed, the 
next scan should continue according to the schedule above (beginning at C3D1). 
- 
If consistent with local regulatory guidelines, confirmatory imaging a minimum 
of 4 weeks (e.g., 28 days) after the first imaging studies that demonstrate a tumor 
CR or PR by RECIST 1.1 or RANO is encouraged. If this scan is performed, the 
next scan should continue according to the schedule above. 
 Outpatient diaries for recording daily selpercatinib dosing, PPIs, H2 blockers, and 
antacids (refer also to Restricted Concomitant Medications, Section 6.3.3). 
 AEs. 
 Concomitant medications. 
 Patient-reported outcomes:  
o For MTC patients with diarrhea present at baseline: bowel diary, Day 1 of each 
cycle starting with C2. 
o 
For patients 18 years or older: EORTC QLQ-C30 completed at the same cycle 
visits as disease assessments until EOT. 
o 
For patients age 13 to 17 years: PedsQL for teens completed at the same cycle 
visits as disease assessments until EOT. 
o 
For patients age 12 years: PedsQL for children completed at the same cycle visits 
as disease assessments until EOT. 
7.4 
Intra-Patient Dose Escalation  
As discussed in Section 3.4, intra-patient dose escalation may be permitted by the Sponsor 
following completion of the 28-day DLT period in Cycle 1. Please note that this guidance applies 
to Phase 1 intra-patient dose escalation, and does not apply to patients who dose reduce and are 
re-escalated to the starting dose.  
The following procedures will be performed (refer to Table 7-1): 
 Day 1 of new dose (±3 days): 
o Symptom-directed physical examination, weight, and ECOG or Lansky score. 
o Vital signs. 
o Resting 12-lead ECGs: pre-dose, up to 4 hours pre-dose),2 hours postdose- (±10 
minutes). Further ECGs may be required based upon results of the 2 hours post-dose 
ECG (refer to Table 7-1, footnote “j” for specific instruction based upon QTcF value 
observed). 
o Hematology (as described in Section 7.1). 
o Serum chemistries (as described in Section 7.1). 
 Day 8 of new dose (±3 days):  
o Symptom-directed physical examination, weight, and ECOG or Lansky score. 
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o Vital signs. 
o Resting 12-lead ECG: 2 hours post-dose (±10 minutes) prior to blood draw for PK 
sample if performed at this time point. Further ECGs may be required based upon 
results of the 2 hours post-dose ECG (refer to Table 7-1, footnote “j” for specific 
instruction based upon QTcF value observed).  
o LFTs (as described in Section 7.1). 
o Blood sample for PK (2 mL whole blood): pre-dose (within 1 hour prior to dosing) 
and post-dose at 1, 2 and 4 hours (±15 minutes) and 8 hours (±30 minutes). 
If Day 1 of the new dose falls on the same day (±3 days) of a previous hematology and serum 
chemistry assessment, and LFTs, it is not necessary to perform a repeat assessment (exam, vital 
signs, and ECGs must still be performed as indicated). Patients found to have treatment-
emergent laboratory toxicity of Grades 3 or 4 will be monitored at least weekly until resolution.  
Requests for intra-patient dose escalation must be made to the Sponsor prior to treating a patient 
with a new dose. Treatment with a new dose should start on Day 1 (±3 days) of a cycle unless 
discussed with the Sponsor.  
Exceptions to these assessments will not be considered protocol violations if approved by the 
Sponsor.  
7.5 
End of Treatment Visit (All Patients)  
Within 7 days of last dose of study drug or at the time of premature discontinuation of treatment, 
the following procedures will be performed: 
 Scheduling of tumor tissue biopsy from patients who experience PD (optional and if it 
can be safely performed in the judgement of the Investigator). 
 Symptom-directed physical examination, weight, and ECOG or Lansky score. 
 Vital signs. 
 Resting 12-lead ECG: only if prior ECG reading showed treatment-emergent 
abnormalities. 
 Hematology (as described in Section 7.1). 
 Serum chemistries (as described in Section 7.1). 
 Pregnancy test for women of childbearing potential (surgically sterilized females or those 
who have not experienced menses for at least 2 years are not required to be tested).  
 LFTs (as described in Section 7.1). 
 Urinalysis.  
 Calcitonin, CEA: for patients with MTC only. For each patient, these should be 
performed in the same laboratory as prior testing to minimize intra-patient variability in 
measurement.  
 Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
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thyroglobulin should be performed in the same laboratory to minimize intra-patient, 
lab-to-lab variability in their measurement. 
 Serum cortisol, serum ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer. 
 Whole blood for cfDNA analysis: obtained at the EOT visit even if radiologic disease 
assessment is not performed. 
 Radiographic disease assessment (if not performed within the last 2 cycles). Patients who 
have an ongoing CR or PR and discontinue study drug for reasons other than PD 
(e.g., AE, noncompliance, etc.), may (but, for practical reasons and to minimize patient 
inconvenience, are not required to) have scans collected ~ every 8–12 weeks as outlined 
above until documented PD.  
 Return unused selpercatinib. 
 Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids. 
 AEs. 
 Concomitant medication(s). 
 Patient-reported outcomes:  
o For MTC patients with diarrhea present at baseline: Bowel diary. 
o For patients 18 years or older: EORTC QLQ-C30. 
o For patients age 13 to 17 years: PedsQL for teens. 
o For patients age 12 years: PedsQL for children. 
7.6 
Safety Follow-Up Visit  
Twenty-eight (28) days (+7 days) after the final dose of study drug (may be performed as part of 
the EOT visit if the latter was performed at least 28 days after final dose of the last cycle), the 
following will be performed: 
 Symptom-directed physical examination, weight, and ECOG or Lansky score. 
 Vital signs. 
 Resting 12-lead ECG.  
 Hematology (as described in Section 7.1). 
 Serum chemistries (as described in Section 7.1). 
 Pregnancy test for women of childbearing potential (surgically sterilized females or those 
who have not experienced menses for at least 2 years are not required to be tested).  
 LFTs (as described in Section 7.1). 
 Urinalysis. 
 AEs. 
 Status of unresolved SAEs (if unresolved SAEs exist at the time of this visit, subsequent 
assessment for resolution may be conducted by phone if the patient is not able to return to 
the clinic). 
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 Concomitant medication(s). 
7.7 
Long-Term Follow-Up  
After treatment discontinuation, LTFU will occur approximately every 3 months (±1 month) 
until the patient has withdrawn consent for further participation, is lost to follow-up, has died, or 
the Sponsor makes a decision to close the study. Assessments may include: subsequent 
anticancer therapy(ies) and survival status. LTFU may be conducted by phone. For any patient 
who is lost to follow-up, the study site will attempt to ascertain survival information via public 
database search. If survival status still cannot be ascertained, patients will be considered lost to 
follow-up and will be censored appropriately. 
7.8 
Procedures for Special Tests  
7.8.1 
Tumor Measurements  
Tumors will be assessed by the Investigator according to the guidelines provided in Section 7 
and the Imaging Manual. Investigators should use the same method consistently for an individual 
patient throughout the study. Assessments of both measurable and non-measurable disease will 
be made by the Investigator using RECIST 1.1 (refer to Appendix G) or RANO criteria 
(Appendix H) as appropriate to tumor type; or a comparable assessment method depending on 
location of tumor. 
7.8.2 
Central Collection of Radiographic Studies  
Baseline screening radiographic studies and all subsequent radiographic studies and their 
associated reports will be collected and stored for future independent radiological review. 
7.8.3 
Pharmacokinetics  
Plasma samples will be obtained for patients as outlined in Section 7. Additional PK assessments 
may be conducted in patients when considered necessary by the Investigator to understand 
exposure in relationship to possible safety or efficacy findings or if there is a change to the 
formulation of selpercatinib administered. Samples will be collected and handled as outlined in 
the Laboratory Manual, and concentrations of selpercatinib will be determined with a validated 
bioanalytical method. These data will be used to determine parameters such as AUC0-t and 
plasma terminal elimination half-life (t1/2). The 0-8-hour duration of sample collection will be 
sufficient to cover a significant fraction of the area under the plasma concentration versus time 
curve. 
Plasma samples will be obtained on C1D8 and D8 of a patient’s new dose (if the patient is intra-
patient dose escalated). PK parameters calculated from the drug concentrations in these samples 
will be used to compare the area under the concentration versus time curve from time 0 to 
infinity (AUC0-∞) on D1 with the area under the concentration versus time curve calculated 
during the dosing interval at steady state (AUCtau) and detect any auto-inhibition or auto-
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induction of the PKs of selpercatinib (none is expected). Exploratory analyses to determine the 
presence and structures of metabolites of selpercatinib may also be conducted and the results of 
these analyses, if conducted, will be reported separately by the Sponsor. 
7.8.4 
Collection of EORTC QLQ-C30, PedsQL for Teens, PedsQL for Children, and 
Bowel Diary  
Paper HRQoL instruments will be administered pre-dose on C1D1.  
The EORTC QLQ-C30, PedsQL for teens, or PedsQL for children questionnaires and a bowel 
diary (for MTC patients only) will be used as appropriate for the patient (refer to Appendix I) 
and should be implemented for newly enrolled patients. Only patients who have completed 
questionnaires at baseline should complete subsequent questionnaires at the specified follow-up 
periods. 
For EORTC QLQ-C30, PedsQL for teens, or PedsQL for children, subsequent assessments will 
occur at the same cycle visits as disease assessments until EOT. Each assessment should be 
performed before the subject learns the results of his or her restaging.  
For MTC patients, the bowel diary assessments will be collected weekly on Cycle 1, and on Day 
1 of every cycle thereafter through EOT. Inaccurate recording will not be considered a protocol 
violation. 
7.8.5 
Correlative Studies  
7.8.5.1  
Archived Tumor Samples  
Archived tumor samples prior to treatment with selpercatinib are required if available for 
participation in the trial. Tissue blocks are preferred, otherwise ~25 × 5 um unstained slides, with 
verification of at least 20% tumor content, should be provided. If sufficient quantity or quality of 
tissue cannot be provided, patients should undergo a fresh tumor biopsy, if it is considered safe 
to perform, prior to treatment (refer to Section 7.8.5.2). The samples will be used for 
identification or confirmation of molecular abnormalities in RET and other genes.  
The sample collection must be captured on the appropriate eCRF and requisition page(s). Refer 
to the Laboratory Manual for detailed sample collection, storage, and shipment information. 
7.8.5.2  
Fresh Tumor Biopsies  
Fresh tumor samples will be used to identify putative mutations arising in the RET gene (or other 
genes) that may confer acquired resistance to selpercatinib (or prior MKIs with anti-RET 
activity) and for other investigations into potential causes of acquired resistance. Fresh tumor 
biopsies are strongly encouraged when the Investigator feels it is appropriate and safe to do so.  
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Prior to selpercatinib treatment 
Required: A fresh tumor biopsy be obtained prior to selpercatinib for all patients who do not 
have archival tumor tissue available (or who have insufficient tissue quantity or quality—refer to 
Section 7.8.5.1) and for whom, in the opinion of the Investigator, a fresh tumor biopsy can be 
safely performed. If archived tumor tissue is not available and a fresh biopsy cannot be safely 
performed, the patient may still be eligible with prior Sponsor approval.  
Optional: If archived tumor tissue was obtained prior to progression on the last MKI with 
anti-RET activity, a fresh biopsy of a lesion may be obtained if the patient provides informed 
consent and it can be safely performed. The purpose of the fresh tumor biopsy is to identify 
genetic alterations related to progression after the previous MKI(s).  
At progression after treatment with selpercatinib 
Optional: A fresh biopsy of a lesion should be obtained if oligometastatic disease constituting 
progression on selpercatinib is identified, the patient provides informed consent, and it can be 
safely performed. The purpose of the fresh tumor biopsy is to evaluate tumor changes that may 
have resulted from treatment.  
Optional: A fresh biopsy of a lesion should be obtained if overt progression on selpercatinib is 
reported, the patient provides informed consent, and it can be safely performed. The purpose of 
the fresh tumor biopsy is to evaluate tumor changes that may have resulted from treatment.  
The biopsy (Table 7-3 ) must be captured on the appropriate eCRF and requisition page(s). Refer 
to the Laboratory Manual for detailed sample collection, storage, and shipment information. 
Table 7-3 Tissue/Whole Blood Sampling upon Progression  
For patients who progress during therapy, biopsy upon progression should be done if clinically safe to 
perform and if the patient consents. The clinician should consider if study therapy will continue beyond 
progression or be discontinued due to progression. 
Scenario 
Sampling 
At time of progression where study therapy will 
be discontinued 
 
Tumor tissue sample from patients who experienced PD 
and consent to biopsy, if it does not jeopardize the 
patient’s health 
 
Whole blood for cfDNA analysis 
At any progression, including if the patient will 
continue study therapy as treatment beyond 
progression 
 
Whole blood for cfDNA analysis 
 
Optional tumor biopsy 
Abbreviations: cfDNA = circulating free tumor DNA; PD = progressive disease. 
 
7.8.5.3  
Blood Biomarkers  
Whole blood will be collected for evaluating cfDNA pre-dose C1D1, C1D15 and C2D1; and at 
the time of progression and/or EOT. If oligometastatic disease constituting progression is 
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identified but the patient is otherwise stable and will continue selpercatinib beyond progression, 
patients should continue to have blood collected for cfDNA analysis (refer to Laboratory 
Manual) at the time of each progression, to evaluate tumor changes that may have resulted from 
treatment.  
If overt progression is reported and study drug therapy will be discontinued (i.e., EOT), patients 
should have blood collected for cfDNA analysis (refer to Table 7-3  to evaluate tumor changes 
that may have resulted from treatment. 
The primary purposes of collection of blood for cfDNA analysis are to identify early indicators 
of selpercatinib treatment efficacy (e.g., by measuring a decrease in cfDNA) and to identify 
potential mechanisms of resistance through the identification of new genetic alterations that arise 
in the RET or other genes at progression after treatment with selpercatinib. 
In addition, a whole blood sample collected at Screening may be used for DNA sequencing to 
determine the somatic or germline origin of mutations identified from analysis of archival or 
fresh tumor samples. Biomarker analyses will not produce interpretable results on germline DNA 
and therefore no incidental findings will be reported.  
The sample collection must be captured on the appropriate eCRF and requisition page(s). Refer 
to the Laboratory Manual for detailed sample collection, storage, and shipment information.  
7.8.5.4 
Biomarker Samples  
Archived tumor, fresh biopsy, and blood samples may be assessed by various methods including 
gene panel sequencing and DNA candidate gene studies. Regardless of the technology utilized, 
data generated will be used only for the specific genomic research scope described in the study 
objectives or to develop research methods and validate new diagnostic tools or assays. 
7.8.6 
Growth Plate Monitoring  
Participants who have not yet obtained full adult height will undergo radiograph of one knee at 
baseline and every 6 months while the growth plate remains patent. Whichever knee is imaged at 
baseline should be imaged at all time points. 
Adolescents who have had a documented growth rate of <1 cm/year over the prior 2 years and/or 
have reached a midparental height of over 152 cm in girls and 167 cm in boys are likely to have 
obtained full adult height. If it is unclear that a patient has obtained full adult height, 
pretreatment tibial radiographs (AP and lateral views) of the right knee should be obtained to 
determine if the growth plate remains patent. If the growth plate remains patent, the patient will 
have radiographs performed every 6 months until the growth plate is no longer patent. Follow-up 
MRI is recommended for any unexpected abnormalities identified on radiographs. 
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7.8.7 
Thyroid Function  
Hypothyroidism was reported in patients receiving selpercatinib in clinical trials. Monitor 
patients for hypothyroidism and treat as medically appropriate. Baseline laboratory measurement 
of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism 
should be treated as per standard medical practice prior to the start of selpercatinib treatment. All 
patients should be observed closely for signs and symptoms of thyroid dysfunction during 
selpercatinib treatment. Thyroid function should be monitored periodically throughout treatment 
with selpercatinib. Patients who develop thyroid dysfunction should be treated as per standard 
medical practice, however patients could have an insufficient response to substitution with 
levothyroxine (T4) as selpercatinib may inhibit the conversion of levothyroxine to liothyronine 
(T3) and supplementation with liothyronine may be needed.  
7.9 
Continued Access  
Participants who are still on study intervention at the time of study completion may continue to 
receive study intervention in the continued access period if they are experiencing clinical benefit 
and no undue risks. The continued access period will apply to this study only if at least 1 
participant is still on study treatment when study completion occurs. The Sponsor will notify 
investigators when the continued access period for each participant begins based on cohort 
assignment or other relevant parameters. 
 
Participants are not required to sign a new ICF before treatment is provided during the continued 
access period; as of Protocol Amendment 11, the ICF includes information on continued access. 
 
The participant’s continued access to study treatment will end when a criterion for 
discontinuation is met (Section 6.4). Continued access follow-up will begin when the participant 
and the investigator agree to discontinue study treatment and lasts approximately 30 days (±7).  
 
Follow-up procedures will be performed as shown in the Continued Access SoA (see Table 7-2).  
 
Participants who are in short-term follow-up when the continued access period begins will 
continue in short-term follow-up until the 30-day short-term follow-up visit is completed. 
Participants who are in long-term follow-up when the continued access period begins will be 
discontinued from study.  
 
During Continued Access, long-term follow-up does not apply. Survival and progression 
information will be collected only for MTC patients (see Table 7-2). 
 
In all cases, no follow-up procedures will be performed for a participant who withdraws 
informed consent unless he or she has explicitly provided permission and consent. 
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8. 
PLANNED ANALYSES  
A full Statistical Analysis Plan (SAP) will provide specific details on the analytical methods and 
data displays. 
8.1 
Study Endpoints  
Primary Endpoint (Phase 1) 
 MTD/RP2D 
Secondary Endpoints (Phase 1) 
 Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and 
blood chemistry values, assessments of physical examinations, vital signs, and ECGs 
 Plasma concentrations of selpercatinib and PK parameters, including but not limited to 
area under the concentration versus time curve from time 0 to 24 hours (AUC0-24), Cmax, 
time to maximum plasma concentration (Tmax), and degree of accumulation 
 ORR based on RECIST 1.1 or RANO, as appropriate to tumor type 
Primary Endpoint (Phase 2) 
 ORR based on RECIST 1.1 or RANO, as appropriate to tumor type, assessed by IRC 
Secondary Endpoints (Phase 2) 
 Parameters of anti-tumor activity/clinical benefit, including: ORR (by Investigator), best 
change in tumor size from baseline (by IRC and Investigator), DOR (by IRC and 
Investigator), CNS ORR (by IRC), CNS DOR (by IRC), time to any and best response 
(by IRC and Investigator), CBR (by IRC and Investigator), PFS (by IRC and 
Investigator), and OS  
 Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and 
blood chemistry values, and assessments of physical examinations, vital signs, and ECGs 
 Plasma concentrations of selpercatinib and PK parameters, including but not limited to 
AUC0-24, Cmax, and Tmax 
Exploratory Endpoints  
 Differences in efficacy and safety based on selpercatinib PK parameters 
 Changes in CEA and calcitonin (patients with MTC), thyroglobulin (non-MTC thyroid 
cancer patients), and ACTH and cortisol (patients with Cushing’s disease related to their 
cancer) with selpercatinib treatment 
 Identity of RET gene fusions, mutations, and concurrently activated oncogenic pathways 
in tumor biopsies and cfDNA 
 Changes from baseline in disease-related symptoms and HRQoL, as measured by 
EORTC QLQ-C30 (adults), PedsQL for teens (ages 13-17 years), PedsQL for children 
(age 12 years), and patient bowel diaries (MTC patients only) 
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8.2 
Analysis Populations  
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
8.2.1 
Safety Analysis Set  
The Safety Analysis Set will be used for the analysis of safety data and will consist of all 
enrolled patients who receive at least one dose of selpercatinib. A baseline measurement of at 
least one laboratory or other safety-related measurement obtained after treatment of study drug 
may be required for inclusion in the analysis of a specific safety parameter. 
The analysis populations for other trial objectives (e.g., PK, tumor markers) will be defined in 
the Statistical Analysis Plan. 
8.3 
Determination of Sample Size  
Phase 1 
Three to 6 patients will be enrolled in each dose cohort based on a 3+3 design. Each patient will 
participate in only a single dose cohort for the purpose of DLT evaluation (though, as discussed 
in Section 3.4, after completion of the DLT evaluation period, intra-patient dose escalation may 
be permitted, provided that the patient is tolerating their current dose, and the dose level to which 
the patient will be escalated has already been evaluated, has a DLT rate of < 33%, and has been 
declared safe by the SRC).  
A starting sample size of at least 3 patients per dose cohort, expanding to 6 patients in the event 
of a marginal DLT rate (30%) was deemed to be a safe and conventional approach in the dose 
escalation of a novel oncologic agent. Assuming a true DLT rate of 5% or less, there would be a 
3% chance that dose escalation would be halted in a given cohort (i.e., observing 2 or more 
patients with DLT). If a true DLT rate of 50% is assumed, then there would be an 89% chance 
that dose escalation would be halted in a given cohort. 
During Phase 1, selected dose cohorts previously declared safe by the SRC may be expanded to a 
total of approximately 15 patients to further investigate the tolerability, PK, and biological 
activity of selpercatinib. 
The total number of patients to be enrolled in Phase 1 is dependent upon the observed safety 
profile, which will determine the number of patients per dose cohort, as well as the number of 
dose escalations required to achieve the MTD/RP2D for further study. If approximately 
15 patients are enrolled in each planned dose cohort (Cohorts 1–8), a total of approximately 
120 patients will be enrolled in Phase 1.  
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Phase 2 
For Cohort 1 (patients with RET fusion-positive solid tumors who have progressed on or are 
intolerant to standard first-line therapy for their cancers), a true ORR of ≥ 50% is hypothesized 
when selpercatinib is administered to patients with such malignancies. A sample size of 
55 patients is estimated to provide 85% power to achieve a lower boundary of a two-sided 95% 
exact binomial confidence interval (CI) about the estimated ORR that exceeds 30%. Ruling out 
a lower limit of 30% is considered clinically meaningful and consistent with the estimated 
response rates seen with approved targeted therapies in molecularly-defined patient populations 
who have failed prior therapies (e.g., osimertinib [Tagrisso®], crizotinib [Xalkori®], alectinib 
[Alecensa®], and others).  
For Cohort 2 (patients with RET fusion-positive solid tumors without prior standard first-line 
therapy), a true ORR of ≥ 55% is hypothesized when selpercatinib is administered to such 
patients. A sample size of 59 patients is estimated to provide 85% power to achieve a lower 
boundary of a two-sided 95% exact binomial CI about the estimated ORR that exceeds 35%. For 
Cohort 3 (patients with RET-mutant MTC who have progressed on or are intolerant to 
vandetanib and/or cabozantinib), a true ORR of ≥ 35% is hypothesized when selpercatinib is 
administered to such patients. A sample size of 83 patients is estimated to provide 85% power to 
achieve a lower boundary of a two-sided 95% exact binomial CI about the estimated ORR that 
exceeds 20%. Ruling out a lower limit of 20% is considered clinically meaningful in patients 
who have failed prior MKI therapy (e.g., cabozantinib) and currently have limited treatment 
options for their advancing disease. 
For Cohort 4 (patients with RET-mutant MTC who are MKI-naïve), a true ORR of ≥ 50% is 
hypothesized when selpercatinib is administered to such patients. A sample size of 55 patients is 
estimated to provide 85% power to achieve a lower boundary of a two-sided 95% exact binomial 
CI about the estimated ORR that exceeds 30%. 
Notwithstanding the statistical considerations above, if approved by the SRC, enrollment beyond 
the above sample sizes in each of Cohorts 1-5, will be allowed, in order to accommodate 
enrollment demand and allow for the characterization of AEs that may occur with low frequency. 
With a sample size of 150 patients, the probability of observing one or more instances of a 
specific AE within a cohort with a true incidence rate of 1% and 2% is 77.9% and 95.2%, 
respectively. The sample size for Cohort 1 was increased to ~250 to accommodate enrollment 
demand. Additional enrollment will also allow for the characterization of AEs that may occur 
with low frequency which would enhance knowledge of the safety profile of selpercatinib. 
Further, this cohort allows for the enrollment of patients with RET fusion-positive solid tumors 
other than NSCLC. While the enrollment demand for patients with RET fusion-positive NSCLC 
has been adequate for statistical analysis, additional solid tumor types remain underrepresented 
and enrollment expansion allows for data capture in this population. 
Up to ~50 patients will be enrolled into Cohort 6 based on clinical consideration. Exploring 
efficacy in patients with a history of prior exposure to RET specific inhibitors may enhance 
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understanding of the risk:benefit of additional RET specific therapy in these patients and aid in 
the consideration of resistance mechanisms in response to this type of therapy.  
8.4  
Futility Monitoring  
A futility analysis of the response rate (including confirmed or unconfirmed PR or CR) will be 
performed after every 25 subjects are enrolled for each cohort of Cohorts 1-5. The purpose of the 
futility assessment is to safeguard future patients from exposure to unequivocally inferior 
treatment. A response rate of less than 10% (null hypothesis) is deemed as futile. The stopping 
boundaries are specified as following with Lan-DeMets (O'Brien-Fleming) spending function. If 
at least 1, 2, 7, 13 and 18 responders are observed from the first 25, 50, 75, 100 and 125 subjects 
enrolled, then enrollment will proceed without interruption. Otherwise, enrollment will be halted 
pending the results of each futility assessment. If the true ORR is at least 20%, the probability of 
stopping at each futility analysis is less than 3%. If the true ORR is significantly higher than that 
hypothesized (i.e., 50%) the probability is close to zero. 
The information fractions and futility boundaries based on a sample size of 150 patients are 
outlined in Table 8-1. 
Table 8-1 
Futility Assessment: Information Fractions and Futility Boundaries  
Look 
# 
Information 
Fraction 
Sample 
Size 
Futility Boundary 
Incremental Boundary Crossing 
Probabilities 
Response 
Rate 
Responder 
(n) 
Under H0: 
π = 0.1 
Under H1: 
π = 0.2 
1 
0.167 
25 
0 
1 
0 
0 
2 
0.333 
50 
0.035 
2 
0.064 
0.002 
3 
0.500 
75 
0.093 
7 
0.357 
0.009 
4 
0.667 
100 
0.121 
13 
0.340 
0.017 
5 
0.833 
125 
0.137 
18 
0.160 
0.021 
Note: The information fractions and futility boundaries are based on a sample size of 150 patients. 
The information boundaries based on sample sizes of 250, 200 and 50 patients are outlined in 
Table 8-2, Table 8-3, and Table 8-4, respectively. For each look, if the number of responders 
specified under the futility boundary is observed, enrollment will proceed without interruption. 
Table 8-2 
Futility Assessment for a sample size of 250  
Look  
# 
Information 
Fraction 
Sample 
Size 
Futility Boundary 
Incremental Boundary Crossing Probabilities  
Response 
Rate 
Responder 
(n) 
Under H0: 
π = 0.1 
Under H1: 
π = 0.2 
1 
0.1 
25 
0.000 
1 
0.000 
0.000 
2 
0.2 
50 
0.000 
1 
0.000 
0.000 
3 
0.3 
75 
0.000 
1 
0.000 
0.000 
4 
0.4 
100 
0.040 
5 
0.021 
0.000 
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Look  
# 
Information 
Fraction 
Sample 
Size 
Futility Boundary 
Incremental Boundary Crossing Probabilities  
Response 
Rate 
Responder 
(n) 
Under H0: 
π = 0.1 
Under H1: 
π = 0.2 
5 
0.5 
125 
0.072 
10 
0.131 
0.000 
6 
0.6 
150 
0.094 
15 
0.256 
0.000 
7 
0.7 
175 
0.110 
20 
0.259 
0.001 
8 
0.8 
200 
0.121 
25 
0.176 
0.002 
9 
0.9 
225 
0.130 
30 
0.092 
0.002 
Table 8-3 
Futility Assessment for a sample size of 200  
Look  
# 
Information 
Fraction 
Sample 
Size 
Futility Boundary 
Incremental Boundary 
Crossing Probabilities  
Response 
Rate 
Responder 
(n) 
Under H0: 
π = 0.1 
Under H1: 
π = 0.2 
1 
0.125 
25 
0.000 
1 
0.000 
0.000 
2 
0.25 
50 
0.000 
1 
0.000 
0.000 
3 
0.375 
75 
0.039 
3 
0.039 
0.000 
4 
0.5 
100 
0.081 
9 
0.222 
0.001 
5 
0.625 
125 
0.105 
14 
0.320 
0.003 
6 
0.75 
150 
0.122 
19 
0.232 
0.005 
7 
0.875 
175 
0.133 
24 
0.116 
0.007 
Table 8-4 
Futility Assessment for a sample size of 50  
Look  
# 
Information 
Fraction 
Sample 
Size 
Futility Boundary 
Incremental Boundary Crossing 
Probabilities  
Response 
Rate 
Responder 
(n) 
Under H0: 
π = 0.1 
Under H1: 
π = 0.2 
1 
0.5 
25 
0.156 
4 
0.827 
0.293 
8.5 
Statistical Methods  
8.5.1 
Demographics and Baseline Characteristics  
Descriptive summaries of demographic and baseline characteristics for all enrolled patients will 
be tabulated. Patients will be tabulated by tumor indication.  
8.5.2 
Safety Analyses  
Safety will be assessed by clinical review of all relevant parameters including AEs, SAEs, 
laboratory values, vital signs, ECG results, concomitant medications, and thyroid function. 
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Unless specified otherwise, the safety analyses will be conducted for the safety population 
defined in Section 8.2.1. The results of these analyses will be presented by tumor indication. 
Summary tables and listings will be provided for all reported TEAEs, defined as AEs that start 
on or after the first administration of study drug. The reported AE term will be assigned 
standardized coding using MedDRA; the MedDRA version shall be specified in study 
documents, including but not limited to the coding plan and data management plan.  
TEAEs will be summarized based on the number and percentage of patients experiencing the 
event by MedDRA System Organ Class and preferred term. The causal relationship between the 
occurrence of an AE and study drug will be judged by the Investigator based on the conventions 
described in Section 9.3. In the event a patient experiences repeat episodes of the same AE, then 
the event with the highest severity grade and strongest causal relationship to study drug will be 
used for purposes of incidence tabulations. 
Tabular summaries will be provided for: 
 All TEAEs. 
 TEAEs by relationship (yes, no) to underlying disease, other medical conditions, or 
concomitant medications, and maximum severity grade. 
 TEAEs with action of study drug delayed/interrupted or treatment reduced. 
 TEAEs with action of study drug discontinued. 
 All SAEs. 
 SAEs by relationship (yes, no) to underlying disease, other medical conditions or 
concomitant medications. 
 SAEs with action of study drug delayed/interrupted or treatment reduced. 
The observed DLT rate in each dose cohort will be calculated by the crude proportion of patients 
who experience DLT. Multiple concurrent AEs leading to DLT will be considered a single DLT. 
The estimate of the DLT rate will be accompanied by a 2-sided 95% exact binomial CI.  
All deaths, including on-study deaths, that occur within 28 days of treatment discontinuation will 
be reported in a patient listing, which will include the primary cause of death and the number of 
days between the date of the last dose of study drug and death. For patients undergoing LTFU, 
the duration of survival following the initiation of study drug will be summarized in a descriptive 
manner using the Kaplan-Meier method. A summary of the anticancer therapies received after 
discontinuation of study drug will be provided. 
Hematology and serum chemistries will be summarized in a descriptive manner by calculating 
the mean, standard deviation, median, and range, as follows: 
 Baseline value 
 Minimum post-baseline value 
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 Maximum post-baseline value 
 Average post-baseline value 
 Last post-baseline value. 
Laboratory values will be assigned toxicity grades when available using the NCI CTCAE, 
version 4.03. Directional shifts in laboratory toxicity grades (comparing baseline grade with 
worst post-baseline grade) will be analyzed using standard shift tables, presenting number and 
proportion of patients and their maximum grade shift. For analytes without a toxicity grading 
scale, the shift table will present directional shifts from baseline to above or below the laboratory 
standard normal range using the maximum increase and/or decrease observed throughout the 
course of treatment/observation.  
All patients will have pre-treatment baseline vital signs and pre-dose measurements on D1 of 
each cycle. The results for each vital sign will be summarized in a descriptive manner by 
calculating the mean, standard deviation, median, and range by time point in the same manner 
described for laboratory values. For these analyses, the minimum, maximum, average, and last 
post-baseline value will be determined relative to the baseline vital sign measurements only. In 
addition, serial vital signs measurements will be obtained pre- and post-dose on the first day of 
each patient’s selpercatinib treatment in conjunction with serial PK sampling. For each patient, 
the vital signs change from the pre-dose value will be summarized in a descriptive manner. The 
Wilcoxon signed rank test may be used to assist in the identification of any systematic changes. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
(WHO Drug) Dictionary; the WHO Drug version shall be specified in study documents, 
including but not limited to the study coding plan and data management plan.  
8.5.3 
Efficacy Analyses  
The efficacy analyses will be conducted on the Safety Analysis Set of patients with at least 6 
months of treatment from the first dose of selpercatinib. These analyses will be summarized per 
tumor indication, including patients from both the Phase 1 and Phase 2 portions. A Statistical 
Analysis Plan (SAP) will provide specific details on the efficacy analysis set. 
ORR will be assessed using RECIST 1.1 (Table 11-9) or RANO (Table 11-11, for patients with 
primary CNS tumors), as appropriate to tumor type. The estimate of the ORR will be calculated 
based on the maximum likelihood estimator (i.e., crude proportion of patients with best overall 
response of CR or PR that are confirmed based on RECIST 1.1 or RANO). The estimate of the 
ORR will be accompanied by 2-sided CIs with various coverage probabilities (e.g., 80%, 95%). 
The analysis of ORR will be conducted both by the responses determined by each Investigator 
and responses as determined by IRC. 
Waterfall plots will be used to depict graphically the maximum decrease from baseline in the 
sum of longest diameters of target lesions.  
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DOR will be calculated for patients who achieve CR or PR. For such patients, DOR is defined as 
the number of months from the start date of CR or PR (whichever response status is observed 
first) and subsequently confirmed, to the first date that PD is objectively documented. If a patient 
dies, irrespective of cause, without documentation of PD beforehand, then the patient’s date of 
death will be used to denote the response end date. 
PFS will be derived for each patient as the number of months from the date of the first dose of 
study drug to the earlier of documented PD or death due to any cause. Patients who are alive and 
without documented PD as of a data analysis cutoff date will be right-censored according to the 
censoring methods described later in this section. Whenever appropriate, the same censoring 
methods will be used for DOR.  
OS will be derived for each patient as the number of months from the date of the first dose of 
study drug to the date of death, irrespective of cause. Patients who are alive or lost to follow-up 
as of a data analysis cutoff date will be right-censored. The censoring date will be determined 
from the last date the patient was known to be alive or data analysis cutoff date, whichever 
occurs first. 
DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method with 95% 
CIs. Median follow-up for each endpoint will be estimated according to the Kaplan-Meier 
estimate of potential follow-up (Schemper and Smith 1996).  
For patients who meet one or more of the following conditions, DOR and PFS will be right-
censored as appropriate: 
 Patients with no baseline or post-baseline disease assessments unless death occurred prior 
to the first planned post-baseline assessment (in which case the death will be considered a 
PFS event) 
 Patients who initiate subsequent anticancer therapy in the absence of documented PD 
 Patients who die or have PD after missing 2 or more consecutively scheduled disease 
assessment visits 
 Patients who are last known to be alive and without documented PD on or before the data 
cut-off date 
For such patients, the progression or censoring date will be determined based on described 
conventions (U.S.-Food-and-Drug-Administration 2007). 
Analyses of secondary and exploratory endpoints will be provided in the full SAP. 
8.5.4 
Pharmacokinetic Analyses  
Plasma concentrations of selpercatinib will be determined with a validated bioanalytical assay. 
The following PK parameters will be calculated from plasma concentrations determined on 
C1D8 if feasible: Cmax, Tmax, area under the concentration versus time curve from time 0 to t 
(AUC0–t), AUC0–∞, apparent oral clearance (CL/F), apparent volume of distribution (Vz/F), and 
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t1/2. If appropriate, those PK parameters may also be calculated from plasma concentrations on 
C1D1, C3D1, and C5D1. 
Summary statistics will be generated by dose cohort and across cohorts as appropriate. 
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9. 
ADVERSE EVENTS  
An AE is any unfavorable medical occurrence in a patient administered an investigational 
product, which does not necessarily have a causal relationship with the treatment. Events 
meeting the AE definition include medication error, misuse, or abuse of IMP, including signs, 
symptoms, or clinical sequelae.  
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of the investigational product, whether or not considered related to the 
investigational product. All AEs that occur prior to the first dose are considered medical history 
unless the AE develops or worsens due to study related procedures. All SAEs, regardless of 
causality, that occurred from time of informed consent to SFU are to be recorded on the 
appropriate eCRF. Documentation must be supported by an entry in the patient’s source medical 
records. Laboratory test abnormalities considered by the Investigator to be clinically relevant 
should be reported in the eCRF as an AE. Each AE is to be evaluated for duration, severity, and 
causal relationship with the investigational product or other factors. Serious AEs, including 
death, caused by disease progression should not be reported unless the investigator deems them 
to be possibly related to study treatment. 
9.1 
Safety Review Committee  
An SRC will be established to oversee the safety aspects of the Phase 1 portion of the study, and 
to render dose escalation decisions. Specifically, the SRC will perform ongoing review and 
adjudication of SAEs and other safety trends throughout the conduct of the study. The SRC 
membership will consist of the Sponsor’s Medical Monitor, a Clinical Operations representative, 
and the Principal Investigator (or clinically qualified designee) from each active clinical site 
contributing patients to that cohort. The SRC will be convened for each cohort dose escalation 
decision or as needed. The SRC will only be required to convene prior to a cohort dose 
escalation if there is a DLT reported in a cohort. Decisions will be documented in written 
minutes. 
The SRC established to oversee the safety aspects of the Phase 2 portion of the study will 
consist, at a minimum, of the Sponsor’s Medical Monitor, a Clinical Operations representative, 
and the Global Principal Investigator. The Phase 2 safety committee will convene at a minimum 
of every 6 months for the first 5 years of the study, then annually (or more frequently depending 
on enrollment or observed safety profile) and perform ongoing review of SAEs and other safety-
related data throughout the conduct of the study.  
9.2 
Grading and Intensity of Adverse Events  
The Investigator will grade the severity of each AE using, when applicable, the NCI CTCAE, 
version 4.03. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as mild, moderate, severe, life-threatening, or fatal, as defined below.  
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 Mild (Grade 1) – An event that is usually transient in nature and generally not interfering 
with normal activities. 
 Moderate (Grade 2) – An event that is sufficiently discomforting to interfere with normal 
activities. 
 Severe (Grade 3) – An event that is incapacitating with inability to work or do usual 
activity or inability to work or perform normal daily activity. 
 Life-threatening (Grade 4) – An event that puts the patient at immediate or potential risk 
of death. 
 Fatal (Grade 5). 
9.3 
Relationship to Underlying Disease, Other Medical Condition or 
Concomitant Medications  
The Investigator will categorize each AE as to its potential relationship to underlying disease, 
other medical conditions or concomitant medications using the categories of Yes (causally 
related) and No (unrelated) as defined below. The assessment of the relationship of an AE to the 
underlying disease, other medical conditions, or concomitant medications is a clinical decision 
based on all available information at the time. In the absence of prior human data for this first-in-
human study of selpercatinib, if the AE cannot be attributed to the patient’s underlying disease, 
other medical conditions, or concomitant medication, and the temporal relationship of the 
occurrence of the AE with administration of the study drug suggests, then the AE will be 
assumed to be due to selpercatinib. 
No: 
The time course between the occurrence or worsening of the AE and underlying disease, other 
medical conditions, or concomitant medications rules out a causal relationship and another cause 
is suspected. 
Yes: 
The time course between the occurrence or worsening of the AE and the underlying disease, 
other medical conditions, or concomitant medications is consistent with a causal relationship. 
The following factors should also be considered: 
 Temporal sequence from treatment with the study drug. 
 Preclinical and prior clinical data regarding whether a particular AE could be an effect of 
the study drug (or class of drug). 
 Pharmacology and PK of the investigational product. 
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An unexpected AE is an experience not previously reported or an AE that occurs with 
specificity, severity, or frequency that is not consistent with the current selpercatinib IB. 
9.4 
Serious Adverse Event Reporting  
An SAE is any untoward medical occurrence that, at any dose: 
 Results in death. 
 Is life-threatening. 
 Requires hospitalization or prolongation of existing hospitalization. 
 Results in disability/incapacity. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event. 
Medical or scientific judgment should be exercised in deciding whether 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 patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious. 
Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded as an 
SAE under this criterion, nor will hospitalization for a procedure scheduled or planned before 
signing of the informed consent. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 
seriousness. Admission to the hospital for social or situational reasons (i.e., no place to stay, live 
too far away to come for hospital visits) will not be considered inpatient hospitalizations. 
In the event of an accidental or intentional overdose by a patient, the site staff must immediately 
inform Medpace Clinical Safety. The eCRF must be updated to reflect this information. In the 
event that the overdose is associated with an SAE, the two events should be linked. In the event 
of an AE associated with an overdose, an SAE report form must be completed detailing the AE 
and the overdose details. 
Disease progression (PD) is an efficacy finding and will not be reported as an AE or an SAE. 
9.4.1 
Serious Adverse Event Reporting – Procedures for Investigators: Initial Report  
All SAEs occurring from the time informed consent is signed through 28 days after the last dose 
must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence 
(this refers to any AE that meets any of the aforementioned serious criteria). All SAEs that the 
Investigator considers related to study drug occurring after the 28-day follow-up period must be 
reported to the Sponsor.  
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To report the SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, Medpace Safety personnel will be notified electronically and will retrieve 
the form. If the event meets serious criteria and it is not possible to access the internet, send an 
email to Medpace Safety at medpace-safetynotification@medpace.com or call the Medpace SAE 
hotline (phone number listed below), and fax the completed paper SAE form to Medpace (fax 
number listed below) within 24 hours of awareness. When the EDC system becomes available, 
the SAE information must be entered within 24 hours of the system becoming available. 
Safety Contact Information: 
 
Medpace Clinical Safety 
 
Medpace SAE hotline – USA/Asia-Pacific: 
 
Telephone: +1-800-730-5779, dial “3” or +1-513-579-9911, dial “3” 
 
Fax: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
Medpace SAE hotline – Europe: 
 
Telephone: +49 89 89 55 718 44 
 
Fax: +49 89 89 55 718 104 
e-mail: medpace-safetynotification@medpace.com 
The Investigator will be requested to supply detailed information regarding the event. SAEs must 
also be reported to the IRB/IEC and a copy of that report must be retained at the investigative 
site and filed in the Investigator Site File in accordance with the requirements of that institution.  
Although not considered an AE per se, the Sponsor must be notified of any patient or patient’s 
partner who becomes pregnant during a clinical study. 
SAE Regulatory Reporting: 
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 evaluate the reported SAEs, including confirmation of relatedness and assessment 
of expectedness. The sponsor has processes for safety reports for identification, recording, and 
expedited reporting of SUSARs according to local regulatory requirements. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
9.5 
Serious Adverse Event Follow-Up  
For all SAEs occurring during the study, the Investigator must submit follow-up reports to the 
Sponsor regarding the status of the SAE and the patient’s subsequent course until the SAE has 
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resolved, or until the condition stabilizes or is deemed chronic (in the case of persistent 
impairment), or the patient dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
9.6 
Pregnancy Reporting  
If the patient or partner of a patient participating in the study becomes pregnant during the study 
or within 28 days of discontinuing study drug, the Investigator should report the pregnancy to 
Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero form to the Investigator for completion. 
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The patient or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an 
SAE. 
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10. 
STUDY ADMINISTRATION  
10.1 
Regulatory and Ethical Considerations  
The investigator will be responsible for reporting to the sponsor or designee significant issues 
related to participant safety, participant rights, or data integrity. 
10.1.1 
Regulatory Authority Approval  
This study will be conducted in accordance with the standard of International Conference on 
Harmonisation-Good Clinical Practices (ICH-GCP), an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting studies that involve human patients. 
All applicable country and local regulations will also be observed. Compliance with these 
standards provides assurance that the rights, safety, and well-being of study patients are 
protected, consistent with the principles in the Declaration of Helsinki, and that the clinical study 
data are credible.  
10.1.2 
Ethics Approval  
It is the responsibility of the Investigator to ensure that the appropriate IRB/IEC has reviewed 
and approved this protocol prior to initiating the study. The Investigator must provide the 
Sponsor or Sponsor’s representative with current and revised IRB/IEC membership rosters that 
include the members’ occupations and qualifications. Sites within the US may provide a copy of 
the US Department of Health and Human Services Assurance Number. 
The IRB/IEC must also review and approve the clinical site’s ICF, other written information 
provided to the patient, and all advertisements that may be used for patient recruitment. The 
Investigator will provide the study monitor with copies of these documents and of dated IRB/IEC 
approval(s) prior to the start of the study. 
If the protocol or the ICF is amended during the study, the Investigator is responsible for 
ensuring that the IRB/IEC has reviewed and approved these amended documents. Approval of 
the amended documents must be obtained from the IRB/IEC before implementation and before 
new patients are consented to participate in the study using the amended version of the ICF. The 
Investigator must provide the Sponsor with the dated IRB/IEC approval of the amended 
documents as soon as available. 
10.1.3 
Patient Informed Consent  
Prior to study entry, the Investigator or designee will explain the nature, purpose, benefits, and 
risks of participation in the study to each patient, patient’s legally acceptable representative, or 
impartial witness. Written informed consent must be obtained prior to the patient entering the 
study (before initiation of any study-related screening procedure). Sufficient time will be allowed 
to discuss any questions raised by the patient. The ICF, which will contain all US federally-
required elements, all International Conference on Harmonisation (ICH)-required elements, and 
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Health Insurance Portability and Accountability Act authorization information in a language that 
is understandable to the patient, must be signed by all patients. The process of obtaining consent 
will be in compliance with all applicable local and country regulations and ICH requirements. 
If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to IRB/IEC approval of the amended form. The clinical site must use the 
amended ICF for all new patients and must re-consent any ongoing patients with the amended 
ICF, if instructed to do so by the IRB/IEC.  
The sample ICF prepared by the Sponsor may be found in the Study Manual. The consent and 
re-consenting process should be properly documented in the source documentation. 
10.1.4 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee  
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC 
according to their institutional policy by the Investigator or Sponsor (or Sponsor designee) 
according to country requirements. Copies of each report and documentation of IRB/IEC 
notification and acknowledgement of receipt will be kept in the Investigator’s study file.  
10.1.5 
Sponsor Safety Reporting to Regulatory Authorities  
The Sponsor or its representative is required to report certain study events in an expedited 
manner to the Food and Drug Administration, the European Medicines Agency’s EudraVigilance 
electronic system according to Directive 2001/20/EC, and to all country Regulatory Authorities 
where the study is being conducted, according to local applicable regulations.  
The following describes the safety reporting timeline requirements for SUSARs and other 
reportable events:  
Immediately and within 7 calendar days: 
 Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and fatal or life-threatening. Follow-up information must be reported in the 
following 8 days.  
Immediately and within 15 calendar days:  
 Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and serious, but not fatal or life-threatening, and there is evidence to suggest 
a causal relationship between the study drug and the reaction.  
 Any finding from tests in laboratory animals that suggest a significant risk for human 
patients, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
 Any event in connection with the conduct of the study or the development of the study 
drug that may affect the safety of the study patients. In addition, periodic safety reporting 
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to regulatory authorities will be performed by the Sponsor or its representative according 
to national and local regulations. 
10.2 
Data Management  
Source documents will be maintained by sites and used to enter data and complete the eCRFs in 
the clinical database (EDC or Clinical Data Management System [CDMS]). The Sponsor’s 
monitors will routinely review the source documentation and verify the corresponding data 
entered on eCRFs in the clinical database. All entered, changed, and final data shall be available 
with a validated audit trail report or data extract report. The eCRFs shall be considered complete 
when all expected data has been entered and all discrepancies have been resolved or 
documented.  
The Investigator must sign all eCRFs according to the EDC (CDMS) requirements. 
10.2.1 
Data Protection  
Participants will be assigned a unique identifier by the sponsor to protect the participant’s 
personal data. Any participant information, such as 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. This is done by the site personnel through the informed 
consent process. 
The participant must be informed through the informed consent by the site personnel 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 information security, data integrity, and data 
protection. These processes address management of data transfer, and prevention and 
management of unauthorized access, disclosure, dissemination, alteration or loss of information 
or personal data. These processes include appropriate contingency plan(s) for appropriate and 
timely response in the event of a data security breach. 
The transfer of personal data is subject to appropriate safeguards through contractual agreements 
and processes. The sponsor’s processes are compliant with local privacy laws and relevant 
legislations including the General Data Protection Regulation (GDPR). 
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10.3 
Study Monitoring  
Prior to the start of the study, the Sponsor’s monitor will contact the clinical site to discuss the 
protocol and data collection procedures and conduct applicable training of site personnel. The 
Sponsor and its designees will also periodically contact the clinical site during the conduct of the 
study (which will include on-site visits) in accordance with applicable regulations and Good 
Clinical Practices (GCP). During these contacts, the monitoring activities will include: 
 Checking and assessing the progress of the study. 
 Reviewing study data collected to date for completeness and accuracy. 
 Conducting source document verifications by reviewing each patient’s eCRF against 
source documents. 
 Identifying any issues and addressing resolutions. 
 Recording and reporting protocol deviations not previously reported to the Sponsor. 
 Confirming that SAEs have been properly reported to the Sponsor and submitted to the 
IRB/IEC if appropriate. 
These activities will be done in order to verify that the data are authentic, accurate, and complete; 
that the safety and rights of the patient are being protected; and that the study is conducted in 
accordance with the currently approved protocol, ICH GCP, and all applicable regulatory 
requirements. Additionally, to ensure compliance with ICH GCP and all applicable regulatory 
requirements, the Sponsor or designee may conduct a quality assurance audit.  
10.4 
Termination  
Upon completion of the study, the following activities, when applicable, must be conducted by 
the site monitor and the Investigator: 
 Submission of all study data to the Sponsor. 
 Completion of all data clarifications and/or resolutions. 
 Reconciliation and final disposition of investigational product. 
 Review of site study files for completeness. 
 In addition, the Sponsor reserves the right to temporarily suspend or prematurely 
terminate this study for any reason. 
If the study is suspended or terminated for safety reasons, the Sponsor will promptly inform the 
Investigator and will also inform the IRB/IEC with the reasons for the action. In the event of 
prematurely termination, all study data must be submitted to the Sponsor. In addition, the clinical 
site must document final disposition of all unused investigational product in accordance with the 
Sponsor’s procedures. 
 
 
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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 dataset 
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. 
10.5 
Records Retention  
Patient records, source documents, monitoring visit logs, investigational product inventory, 
regulatory documents, and other correspondence pertaining to the study must be maintained in 
the appropriate site study files according to ICH GCP and applicable regulatory requirement(s). 
These records will be retained for the period required by the institution or site policy. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing. 
10.6 
Confidentiality of Information  
Patient names will remain confidential and will not be supplied to the Sponsor or its designee. 
The Investigator will maintain a personal patient identification list (patient and treatment 
numbers with the corresponding patient names) to enable records to be identified. 
 
 
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11. 
APPENDICES  
 
 
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Appendix A 
Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity  
Table 11-1 
Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity  
Multikinase Inhibitors 
cabozantinib 
vandetanib 
lenvatinib 
alectinib 
ponatinib 
regorafenib 
sunitinib 
sorafenib 
motesanib 
RXDX-105 
sitravatinib (MGCD516) 
 
 
 
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Appendix B 
Examples of RET Activating Mutations  
Table 11-2 
Examples of RET Activating Mutations  
Exon 
RET mutation 
5 
V292M, G321R 
8 
A510V, E511K, C515S, C531R, G533C 
10 
V591I, R600Q, K603E/Q, Y606C, C609F/G/R/S/W/Y, C611F/G/R/S/W/Y, 
C618F/G/R/S/W/Y, C620F/G/R/S/W/Y 
11 
C630R/Y, D631Y, E632K, C634F/G/R/S/W/Y, S649L, K666E/M 
13 
E768D, R770Q, N777S, V778I, Q781R, L790F 
14 
V804L, V804M, Y806C, E819K, R833C, R844Q, R866W, M848T 
15 
L881V, A883F/S/T/V, R886W, S891A, S904C/F 
16 
G911D, R912P, M918T, E921K, S922P, T930M 
Complex 
D631del, E632-L633del, D898-E901del, E632-A639> HR 
Other 
Because the list of published activating RET mutations is constantly being updated, 
other mutations (e.g., other complex mutations, overlapping deletions, substitutions 
with different amino acids at the same site) may be eligible if a compelling rationale is 
provided by the Investigator and approved by the Sponsor. 
References: (Dvorakova, Vaclavikova et al. 2008, Agrawal, Jiao et al. 2013, Krampitz and Norton 2014, Ji 2015, 
Oh et al. 2015, Wells, Asa et al. 2015, Heilmann, Subbiah et al. 2016, Romei, Casella et al. 2016, Kato 2017, 
Subbiah et al. 2017). 
 
For all other non-MTC cancers with RET mutation, the Sponsor should have final 
determination regarding eligibility based upon review of all genomic findings. 
 
 
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Appendix C 
Examples of Validated Oncogenic Drivers  
The following are example oncogenic drivers that may cause resistance to selpercatinib. 
Table 11-3 
Examples of Validated Oncogenic Drivers  
Tumor Type 
Oncogenic Driver(s) 
NSCLC 
Targetable mutation in EGFR or MET, targetable rearrangement involving ALK or 
ROS1, or activating mutation in KRAS 
Thyroid 
(non-MTC) 
Targetable mutation in BRAF, NTRK fusion, or activating mutation in RAS genes 
MTC 
Targetable rearrangement involving ALK, NTRK fusion, or activating mutation in 
RAS genes 
Pancreatic 
Activating mutation in KRAS 
Colorectal 
Targetable mutation in BRAF or PIK3CA or activating mutation in RAS genes 
Breast 
Targetable mutation in PIK3CA or alteration in HER2 
Other 
Targetable mutation/rearrangement known to occur in the specific disease type 
 
 
 
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Appendix D 
Inhibitors and Inducers of CYP3A4  
Note: Non-systemic (e.g., topical creams, eye drops, mouthwashes, etc.) applications of the 
following are permissible. 
Table 11-4 
Inhibitors of CYP3A4  
Strong inhibitors a 
Moderate inhibitors b 
boceprevir 
amprenavir 
clarithromycin 
aprepitant 
conivaptan 
atazanavir 
grapefruit juice 
ciprofloxacin 
indinavir 
darunavir 
itraconazole 
diltiazem 
ketoconazole 
erythromycin 
lopinavir 
fluconazole 
mibefradil 
fosamprenavir 
nefazodone 
imatinib 
nelfinavir 
verapamil 
posaconazole 
 
ritonavir 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4. 
a Increases the AUC of the substrate by ≥5-fold. 
b Increases the AUC of the substrate by 2- to 5-fold. 
 
Table 11-5 
Inducers of CYP3A4  
Strong inducers a 
Moderate inducers b 
avasimibe 
bosentan 
carbamazepine 
efavirenz 
enzalutamide 
etravirine 
phenytoin 
modafinil 
rifampin 
nafcillin 
St John’s wort 
 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4. 
a Decreases the AUC of the substrate by ≥80%. 
b Decreases the AUC of the substrate by 50–80%. 
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Note: The above lists are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm. 
 
 
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Appendix E 
Proton Pump Inhibitors (PPIs)  
Since selpercatinib is more soluble in an acidic environment than a neutral one, absorption may 
be impacted by stomach acidity. Therefore, the concomitant use of proton pump inhibitors (PPIs) 
is restricted. If PPIs cannot be avoided, selpercatinib should be taken with food.  
Table 11-6 
Examples of Proton Pump Inhibitors (PPIs)  
Omeprazole (Prilosec®) 
Esomeprazole (Nexium®) 
Lansoprazole (Prevacid®) 
Pantoprazole (Protonix®) 
Rabeprazole (Aciphex®) 
Dexlansoprazole (Dexilant®) 
 
 
 
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Appendix F 
Performance Scales  
Table 11-7 
Eastern Cooperative Oncology Group (ECOG) Performance Scale  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
Table 11-8 
Lansky Performance Status ( 16 years old)  
 
Score 
Lansky Description 
100% 
Fully active, normal 
90% 
Minor restrictions in strenuous physical activity 
80% 
Active, but tired more quickly 
70% 
Greater restriction of play and less time spent in play activity 
60% 
Up and around, but active play minimal; keeps busy by being involved in quieter 
activities 
50% 
Lying around much of the day, but gets dressed; no active playing, participates in all 
quiet play and activities 
40% 
Mainly in bed; participates in quiet activities 
30% 
Bed bound; needing assistance even for quiet play 
20% 
Sleeping often; play entirely limited to very passive activities 
10% 
Doesn't play; doesn't get out of bed 
0% 
Unresponsive 
Source: (Lansky, S. B., List M. A. et al. 1987).  
 
 
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Appendix G 
Tumor Measurements and Assessment of Disease Response using 
RECIST, Version 1.1  
Tumor measurements are to be performed for all patients during Screening as follows 
(as summarized in Section 7.1):  
 Baseline disease assessment: radiographic tumor measurements using CT) or magnetic 
resonance imaging (MRI) of chest, abdomen, and pelvis, and any other areas with 
suspected disease involvement, and CT or MRI of brain within 28 days of C1D1. For 
brain imaging, MRI without and with contrast is preferred, CT without and with contrast 
is acceptable if MRI is medically contraindicated. For each modality, IV and oral contrast 
should be utilized (chest CT does not require IV contrast) where applicable unless 
medically contraindicated. If CT/PET is utilized, the CT component of CT/PET must be 
of the same quality as a dedicated diagnostic CT scan, i.e., with IV and oral contrast, and 
5 mm or less slice thickness. 
Notes: 
 In patients with thyroid and other head and neck cancers, imaging of the relevant areas 
(e.g., neck, skull base) is required at baseline; other areas of scanning may differ 
depending on disease type. See Imaging Manual for details. 
 Additional scans can be performed as needed to evaluate potential sites of disease. 
 Disease assessments will utilize RECIST 1.1 or RANO, as appropriate to tumor type 
(refer to Section 7.8.1). 
 Guidelines on the technical parameters of how scans should be performed will be 
provided in a separate Imaging Manual that will be distributed to the sites. 
Thereafter, tumor measurements and disease response assessments are to be performed as 
follows (as summarized in Section 7.3): 
 Radiographic disease assessment: every 8 weeks (±7 days) beginning with C3D1 through 
C13D1 and every 12 weeks (±7 days) thereafter until PD, withdrawal of consent, or 
initiation of a new anticancer therapy(ies), including imaging, of the chest, abdomen, and 
pelvis, utilizing the same modality(ies) as used for the baseline imaging assessment. 
Additionally, any studies performed at baseline that are positive for sites of disease 
should be repeated at all post baseline assessments. Additional studies can also be 
performed as clinically indicated. Please see the Site Imaging Manual for guidelines on 
how the various imaging studies should be performed.  
Notes:  
 
Patients who have an ongoing CR or PR and discontinue study drug for reasons 
other than PD (e.g., AE, noncompliance, etc.) may (but, for practical reasons and 
to minimize patient inconvenience, are not required to) have scans collected as 
defined above.  
 
Post-baseline imaging of the brain using the same modality as at baseline should 
be performed for patients with evidence of CNS disease at baseline, and if 
clinically indicated. 
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If consistent with local regulatory guidelines, an initial post-baseline assessment 
after 4 weeks of treatment (±7 days) is encouraged. If this scan is performed, the 
next scan should continue according to the schedule above (beginning at C3D1). 
 If consistent with local regulatory guidelines, confirmatory imaging a minimum 
of 4 weeks (e.g., 28 days) after the first imaging studies that demonstrate a tumor 
CR or PR by RECIST 1.1 or RANO, as appropriate to tumor type, is encouraged. 
If this scan is performed, the next scan should continue according to the schedule 
above. 
Such assessments also are to be performed at the EOT visit if they had not been performed 
within the previous 2 cycles.  
Anatomical measurements (summed across target lesions) will be documented during Screening 
and each subsequent evaluation. When possible, the same qualified physician will interpret 
results to reduce variability. Radiographic images will be maintained at the study site and sent to 
a central image collection warehouse. Central reading of some or all of the scans may be 
performed by a third-party vendor who has expertise in evaluating image data. Test results and 
Investigator’s findings will be filed in the patient’s source documents. 
During Screening, tumor lesions are to be categorized as measurable versus non-measurable and 
target versus non-target, as follows.  
Measurable versus non-measurable 
 Measurable: Lesions that could accurately be measured in at least one dimension, the 
longest diameter in the plane of measurement to be recorded as: 
o Tumor lesions: 10 mm by CT scan  
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, the node must be ≥ 15 mm in short axis when assessed by CT scan. 
At baseline and in follow up, only the short axis will be measured and followed. 
Nodes that have a short axis < 10 mm are considered non-pathological and should 
not be recorded or followed.  
 Non-measurable: All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), and truly non-measurable 
lesions.  
Target versus non-target 
 Target: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and 
measured and recorded at Screening. Target lesions are to be selected on the basis of their 
size (i.e., those with the longest diameter) and suitability for accurate repeated 
measurement. Lymph nodes may be selected as target lesions; they must be defined as 
measurable, and only the short axis of the node will contribute to the baseline sum. All 
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other pathologic nodes with short axis ≥ 10 mm but < 15 mm should be considered non-
target lesions.  
 Non-target: All other lesions not classified as target lesions (or sites of disease) are to be 
identified as non-target lesions and are to be recorded in the eCRF. Measurement of non-
target lesions is not required. 
The sum of the diameters (longest for non-nodal lesions and short axis for nodal lesions) for all 
target lesions is to be calculated and recorded in the eCRF as the baseline sum diameters.  
Disease response in target and non-target lesions will be assessed by the Investigator using 
RECIST 1.1, according to the categories and criteria described in Table 11-9. The best overall 
response for each patient will be reported as the best response documented over the sequence of 
objective statuses recorded using the categories and criteria in Table 11-10. 
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Table 11-9 
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) 
Guidelines for Tumor Response  
Disease Response Criteria for Target and Non-Target Lesions 
Evaluation of Target lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathologic nodes (whether 
target or non-target lesions) must have a reduction in short axis diameter 
(SAD) to less than 10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters (SOD) (LD for non-
nodal lesions and SAD for nodal lesions) of target lesions, taking as 
reference the baseline sum LD. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest sum on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5.0 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. 
Abbreviations: LD = longest diameter. 
Source: (Eisenhauer, Therasse et al. 2009). Available at: 
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf. 
 
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Table 11-10 Overall Response Criteria: Time Point Response  
Patients with Target and Non-Target Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR / Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / 
Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; SD = 
stable disease. 
Source: (Eisenhauer, Therasse et al. 2009). Available at: 
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
 
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Appendix H 
Response Assessment in Neuro-Oncology (RANO) Criteria for Primary 
CNS Malignancies  
The RANO criteria (Ellingson, Wen et al. 2017) were developed to evaluate efficacy of 
investigational agents in glioblastoma clinical trials, and have been more broadly utilized for 
lower grade primary CNS malignancies. These criteria were developed in part to address issues 
faced when assessing some lesions based on MacDonald criteria, particularly lesions with central 
necrosis and with a T2 component. 
Table 11-11 Response Assessment in Neuro-Oncology (RANO) Criteria  
RESPONSE CATEGORY 
CRITERIA 
Complete Response 
Disappearance of all measurable and non-measurable enhancing disease 
Stable or improved non-enhancing FLAIR/T2 lesions 
No new lesions 
Clinically stable or improved with no reliance on corticosteroids 
(except for physiological replacement) 
Partial Response 
≥ 50% decrease from baseline of all measurable enhancing lesions 
No progression of non-measurable disease 
Stable or improved non-enhancing FLAIR/T2 lesions 
No new lesions 
Clinically stable or improved, with stable or reduced corticosteroids 
compared to baseline 
Progressive Disease 
≥ 25% increase from baseline in enhancing lesions despite stable or 
increasing steroid dose 
Significant increase in non-enhancing FLAIR/T2 lesions not 
attributable to other non-tumor causes 
Any new lesions 
Clinical deterioration not attributable to other non-tumor causes and not 
due to steroid decrease 
Stable Disease 
Does not meet other criteria for response or progression 
Stable non-enhancing FLAIR/T2 lesions 
Clinically stable with stable or reduced corticosteroids compared to 
baseline 
Abbreviations: FLAIR/T2 = T2-weighted fluid-attenuated inversion recovery; RANO = Response Assessment in 
Neuro-Oncology. 
 
A measurable lesion is evaluated by contrast-enhancing MRI and: 
 Has clearly defined margins 
 Is visible on two or more axial slices, preferably < 5 mm thick 
 At least 10 mm in size if slice thickness is < 5 mm (or 2 × slice thickness if > 5 mm) 
 Does not measure a cystic cavity 
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Non-measurable lesions are those that do not fit the criteria above, and specifically lesions that 
are cystic, necrotic, or include a surgical cavity should not be considered measurable. 
Measurements are calculated by summing the products of perpendicular diameters of all 
measurable enhancing lesions. 
If there are multiple contrast-enhancing lesions, a minimum of the two largest lesions should be 
measured. However, emphasis should be placed on selecting lesions that allow reproducible 
repeated measurements. For patients who have multiple lesions for which only one or two are 
increasing in size, the enlarging lesions should be considered the target lesions for evaluation of 
response. 
 
 
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Appendix I 
European Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire-Core 30 (QLQ-C30) and PedsQL-Core 
Module (PedsQL) and Bowel Diary  
EORTC QLQ-C30 
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients. It is a copyrighted instrument, which has been translated and validated in over 
100 languages and is used in more than 3,000 studies worldwide. This study is utilizing version 
3.0, and the study manual should be consulted for instructions on implementing and scoring. 
References: 
EORTC website: http://groups.eortc.be/qol/eortc-qlq-c30 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376 (Aaronson, Ahmedzai et al. 1993).  
PedsQL 4.0 Core Module 
The Pediatric Quality of Life inventory is a modular tool to measure health-related QOL in 
children and adolescents and validated for patients age 2 to 18 years. The instrument uses child 
self-reporting as a generic core measure integrated into disease specific modules to provide one 
assessment. 
References: 
PedsQL website: www.pedsql.org 
Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P. The PedsQL in pediatric cancer: 
reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, 
Multidimensional Fatigue Scale, and Cancer Module. Cancer. 2002;94(7):2090-2106 (Varni, 
Burwinkle et al. 2002).  
Bowel Diary 
References: 
Bowel Diary adapted and modified from patient-reported questionnaire (STIDAT) by Michelle 
Lui et al., Development and validation of a patient-reported questionnaire assessing systemic 
therapy induced diarrhea in oncology patients, HEALTH AND QUALITY OF LIFE 
OUTCOMES 15:249 (2017). Copyright © 2017 Michelle Lui, Daniela Gallo-Hershberg and 
Carlo DeAngelis (Lui, Gallo-Hershberg et al. 2017). STIDAT distributed as-is and as-available, 
with no warranties, under the Creative Commons Attribution 4.0 International License 
(https://creativecommons.org/licenses/by/4.0/legalcode).  
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Appendix K 
Country-Specific Requirements  
Germany  
This section describes protocol changes applicable for participants in study sites in Germany. 
 
This table describes the changes and provides a rationale for the changes. 
 
Protocol Section Number and Name 
Description of the Change 
Brief Rationale 
Synopsis, Section 3.6 Phase 2, 
Section 4.2. Inclusion Criteria for 
Phase 2, Section 4.3. Exclusion 
Criteria for Phase 1 and Phase 2 
Removed language 
regarding Cohort 7 and 
modified schema 
Per regulatory feedback 
Synopsis, Section 3.6. Phase 2 
Phase 2: corrected 
number of cohorts to 
“six” 
Correction 
Section 4.1. Inclusion Criteria for 
Phase 1 
Added inclusion criterion 
14 for Germany 
 
Section 6.4 Removal of Patients 
from Therapy or Assessment 
Added note sites in 
Germany 
 
Section 7 Tests and Evaluations, 
Section 7.3 Cycles 2 and Higher 
Updates were made to 
remove language 
regarding reduced visit 
frequency and the use of 
local healthcare facilities  
Per regulatory request 
Table 7-1 Schedule of Assessments 
Footnote for Cycle 7 and 
beyond was modified; 
Note was added for 
footnote z to exclude 
Germany; footnote cc 
was revised to remove 
telemedicine. 
Per regulatory request 
Section 8.3. Determination of 
Sample Size 
Added language to justify 
the increase of sample 
size  
Per regulatory request 
Appendix L Provisions for Changes 
in Study Conduct During 
Exceptional Circumstances 
Appendix L does not 
apply to Germany 
Per regulatory request 
 
The revised text in the following sections show the changes applicable for adult participants at 
study sites in Germany. Deletions are identified by strikethrough format. 
Synopsis 
 Cohort 6: Patients otherwise eligible for Cohorts 1-5 who discontinued another selective 
RET inhibitor(s) may be eligible with prior Sponsor approval (up to ~50 patients). 
 Cohort 7: (up to ~19 patients): Patients with a histologically confirmed stage IB IIIA 
NSCLC and a RET fusion; determined to be medically operable and tumor deemed 
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resectable by a thoracic surgical oncologist, without prior systemic treatment for NSCLC. 
Cohort 7 is described in a separate addendum to this protocol. 
3.6. Phase 2 
Cohort 7 (up to ~19 patients): Patients with a histologically confirmed stage IB-IIIA NSCLC and 
a RET fusion; determined to be medically operable and tumor deemed resectable by a thoracic 
surgical oncologist, without prior systemic treatment for NSCLC. 
4.1. Inclusion Criteria for Phase 1 
For patients in Germany: Only adult patients capable of understanding the nature, significance 
and consequences of the clinical trial and providing informed consent are eligible for 
participation in the planned clinical trial. 
4.2. Inclusion Criteria for Phase 2 
Cohort 7: Patients with a histologically confirmed stage IB IIIA NSCLC and a RET fusion; 
determined to be medically operable and tumor deemed resectable by a thoracic surgical 
oncologist, without prior systemic treatment for NSCLC. Cohort 7 is described in a separate 
addendum to this protocol. 
4.3. Exclusion Criteria for Phase 1 and Phase 2 
16. Phase 2 Cohort 7 (neoadjuvant treatment): Patient must not have received prior systemic 
therapy for NSCLC. 
6.4. Removal of Patients from Therapy or Assessment 
 Unacceptable toxicity 
Note: In Germany, this must be due to > Grade 3 or intolerable Grade 2 adverse event by 
CTCAE 4.3 considered related to study drug and despite protocol-allowed dose reduction 
 
7. TESTS AND EVALUATIONS 
Patients who are tolerating selpercatinib may have a reduced in clinic visit assessment schedule 
after 6 months on treatment as described in Table 7 1. From Cycle 7 and onward, patients will be 
required to return to the clinic for in person visits only during cycles where radiographic disease 
assessments are required, and for EOT and SFU visits. During non disease assessment cycles, 
patients may continue to return for in person visits or may opt to have routine laboratory tests 
(e.g., serum chemistries, hematology, and liver function tests) completed at local healthcare 
facilities in conjunction with a telemedicine visit (telephone or equivalent). During the remote 
assessment, the site will perform an ECOG assessment, an AE assessment including whether the 
patient is experiencing any new, or changes to existing, AEs/SAEs and concomitant medications, 
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and will confirm study drug compliance and record missed doses. Patient responses during 
telemedicine visits will be recorded in source documents and results from any local assessments 
must be provided to the site for data entry into EDC. Patients who are on selpercatinib treatment 
for at least 2 years will be required to return to the clinic for in-person visits only during cycles 
where radiographic disease assessments are required, and for EOT and SFU visits. Routine 
laboratory tests and telemedicine visits are not required but should be performed as clinically 
indicated during non-disease assessment cycles. 
Should telemedicine visits result in patient complaint or concern from the study Investigator, the 
patient should return to the study site or be seen by a local provider for further assessment(s).  
Table 7-1: Schedule of Assessments 
* For Cycle 7 and beyond, patients may have laboratories (e.g., serum chemistries, hematology, liver function tests, 
and urinalysis) completed at the study site or at local healthcare facilities during non disease assessment cycles. 
As a result of this reduced in clinic visit assessment schedule, the Sponsor understands that certain assessments 
(e.g., physical examination, vital signs) may not be obtainable during visits at local healthcare facilities. Beyond 
Cycle 7, these assessments are optional during local, non disease assessment cycles, but should be collected 
when the patient returns to the clinic for disease assessment cycles. Patients who are on selpercatinib treatment 
for at least 2 years will be required to return to the clinic for in-person visits only during cycles where 
radiographic disease assessments are required, and for EOT and SFU visits. Routine laboratory tests and 
telemedicine visits are not required but should be performed as clinically indicated during non-disease 
assessment cycles.  
b. For Cycle 7 and beyond, patients may attend clinic visits only during cycles where radiographic disease 
assessments are required (Cycle 7, 9, 11, 13, and then Q12W thereafter) if telemedicine visit can be 
completed along with locally obtained lab assessments. Not applicable for Germany. 
z. 
Study sites will conduct a telemedicine visit when no in-clinic visit occurs to confirm whether the patient is 
experiencing any new, or changes to existing, AEs/SAEs and concomitant medications, and to confirm 
study drug compliance and missed doses. Not applicable for Germany. 
cc. Only for patients with a diagnosis of MTC and diarrhea at baseline. For Cycle 7 and beyond, the patient 
should personally maintain bowel diary and discuss the diary with the site during telemedicine visits. The 
bowel diaries should be returned at the next in-clinic visit or provided to study site electronically.  
 
8.3 Determination of Sample Size 
Notwithstanding the statistical considerations above, if approved by the SRC, enrollment beyond 
the above sample sizes in each of Cohorts 1-5, will be allowed, in order to accommodate 
enrollment demand and allow for the characterization of AEs that may occur with low frequency. 
With a sample size of 150 patients, the probability of observing one or more instances of a 
specific AE within a cohort with a true incidence rate of 1% and 2% is 77.9% and 95.2%, 
respectively. With a sample size of 250 patients, the probability of observing one or more 
instances of a specific AE within a cohort with a true incidence rate of 1% and 2% is increased to 
91.9% and 99.4%, respectively. The sample size for Cohort 1 was increased to ~250 to 
accommodate enrollment demand. Additional enrollment will also allow for the characterization 
of AEs that may occur with low frequency which would enhance knowledge of the safety profile 
of selpercatinib. Further, this cohort allows for the enrollment of patients with RET fusion-
positive solid tumors other than NSCLC. While the enrollment demand for patients with RET 
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fusion-positive NSCLC has been adequate for statistical analysis, additional solid tumor types 
remain underrepresented and enrollment expansion allows for data capture in this population. 
Appendix L Provisions for Changes in Study Conduct During Exceptional Circumstances 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. Please note that Appendix L does not apply to Germany and should any of the 
events described herein requiring mitigation of study procedures be required, these will only be 
implemented in Germany after approval of a substantial amendment. 
Denmark  
This section describes protocol changes applicable for participants in study sites in Denmark. 
 
In Denmark, continued access to the investigational medicinal product is not possible as part of 
the clinical trial. If patients are experiencing clinical benefit with no undue risks at the time of 
study completion, as determined by the investigator, access to the investigational medicinal 
product will be provided through permitted alternate approaches if needed. 
 
 
 
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Appendix L 
Provisions for Changes in Study Conduct During Exceptional 
Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits,” 
 a change in the method of study intervention administration,   
 dispensation of additional study intervention during an extended treatment period,  
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
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Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
 
The following changes in study conduct will not be considered protocol deviations. 
 
Remote visits 
 
Types of remote visits 
In source documents and the electronic Case Report Form (eCRF), the study site should capture 
the visit location and the method (e.g., telemedicine, mobile healthcare, etc.), with a specific 
explanation that includes the term ‘COVID-19 related’ (when applicable) for any data missing 
because of missed in-person site visits.  
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, 
but are not limited to, concomitant medications, review of systems, Eastern Cooperative 
Oncology Group (ECOG) performance status (PS), dosing information, patient reported 
outcome measures, and information regarding local healthcare utilization/hospitalization.  
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider 
at locations other than the study site when patients cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the Sponsor. Procedures 
performed at such visits include, but are not limited to, review of systems, physical 
examinations, and laboratory studies (e.g., hematology, chemistry, etc.).  
Other alternative locations: Other procedures that may be done at an alternative 
location in exceptional circumstances include, but are not limited to, review of systems, 
physical examination, electrocardiogram (ECG) tracings, laboratory studies (e.g., 
hematology, chemistry), and radiologic imaging.  
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of adverse events (AEs), serious adverse events (SAEs), and product complaints 
remain unchanged. Furthermore, every effort should be made to enable patients to return to on-
site visits as soon as reasonably possible, while ensuring the safety of both the patients and the 
site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
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Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies (including study drug) 
during normal on-site visits, the site should work with the sponsor to determine appropriate 
actions.  These actions may include:   
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit,  
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 
arranging delivery of study supplies. 
 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Documentation 
 
Changes to study conduct will be documented 
 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
 
Source documents at alternate locations 
 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
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Appendix M 
Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [11.0]  
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a 
significant impact on the 
 safety or the rights of the study participants, and 
 reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
The purpose of this amendment is provided in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Updated to match 
changes in the main 
protocol 
Alignment with main protocol updates 
Section 1.7 Clinical 
Experience; Section 
1.7.1. Known and 
Anticipated Risks 
Updated data and 
simplified list of AEs of 
special interest 
Update 
Section 3.1 Study 
Design 
Sentence added in regard 
to In Vitro Diagnostic 
Regulation 
Update 
Section 3.2.1. Length 
of Study 
Added language 
regarding end of study 
and continued access 
Update to study design 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3.2.1 Length 
of Study and Section 
3.4 Phase 1 and 
Maximum Tolerated 
Dose Determination; 
Section 3.7 
Definition of RET 
Alterations; Table 3-
3 Definition of RET 
Alterations; Section 
4.1. Inclusion 
Criteria for Phase 1 
Added statement 
regarding RET alteration 
result should be generated 
as per local guidelines 
including but not limited 
to IVDR compliance as 
applicable 
To comply with the IVDR and ensure 
that RET testing meets EU clinical 
laboratory requirements 
Section 3.2.2. End of 
Study 
Added language 
regarding continued 
access follow-up 
Update to study design 
Section 3.6 Phase 2; 
Section 4.2 Inclusion 
Criteria for Phase 2; 
Section 4.3. 
Exclusion Criteria 
for Phase 2 
 Removed Cohort 7 
wording  
 Deleted exclusion 
criterion 16 
 Align with leadership decision to end 
enrolment to most populations and 
remove cohort 7 
 
Section 3.6. Phase 2; 
Figure 3-1 Study 
Schema 
 Updated total number 
of patients and cohort 
patient distribution 
 Excluded Germany 
from Cohort 2 and 4 
 Deleted language 
regarding Cohort 8 
wording 
 Updated language 
regarding cycle length 
 Updated study 
schema  
 Align with leadership decision to end 
enrolment to most populations and 
remove cohort 7 
 Clarification 
 Correction 
 Update 
Section 3.8. Number 
of Patients 
 Updated total number 
of patients from 950 
to 875 
Align with leadership decision to end 
enrolment to most populations and 
remove cohort 7 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1. 
Inclusion Criteria for 
Phase 1 
 Updated inclusion 
criterion 13: birth 
control duration 
changed from 3 
months to 1 month 
 Moved inclusion 
criterion 14 to 
Appendix K: 
Country-specific 
Requirement 
 To align with label 
 For harmonization of the protocol 
and to avoid country and region-
specific protocol versions in the EU 
Section 6.1. 
Investigational 
Product 
 Simplified language 
regarding 
selpercatinib 
provision 
Clarification  
Section 6.3.2. 
Allowed 
Concomitant 
Medications  
 Clarified language 
regarding dose 
restriction for 
administration routes 
for systemic 
glucocorticoids 
 
Section 6.4. 
Removal of Patients 
from Therapy or 
Assessment 
 Remove requirement 
for additional 
consultation/approval 
of post progression 
continuation (2nd or 
further PD) 
 Moved note for 
Germany into 
Appendix K: 
Country-specific 
Requirements  
 Per new requirements 
 
 
 
 
 For harmonization of the protocol 
and to avoid country and region-
specific protocol versions in the EU 
Table 7-1 Schedule 
of Assessments; 
Section 7.3. Cycles 2 
and Higher 
 12-lead ECG: added 
language in Cycle 7 
column regarding 
ECG assessments 
until cycle 26 and 
beyond as clinically 
indicated; updated 
footnote “j”. 
Clarification  
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Section # and Name 
Description of Change 
Brief Rationale 
Table 7-1 Schedule 
of Assessments; 
Section 7.3 Cycles 2 
and Higher 
 Clarified that 
Urinalysis will be 
conducted "as 
clinically indicated” 
beyond C1D15; 
updated footnote “q” 
Clarification  
Table 7-1 Schedule 
of Assessments; 
Section 7.3. Cycles 2 
and Higher; Section 
7.8.5.3. Blood 
Biomarkers 
 Whole blood for 
cfDNA analysis: 
updated number of 
collections; updated 
footnote “u” 
To reduce the burden on patients. 
Table 7-1 Schedule 
of Assessments; 
Section 7.3. Cycles 2 
and Higher 
 Updated language in 
Cycle 7-higher 
column 
To align with local standard-of-care 
Section 7.8.5.3. 
Blood Biomarkers 
 Added language on 
use of samples 
Addition  
Section 7.8.5.4 
Biomarker Samples 
 Added section 
Clarification on use of biomarker 
samples 
Section 7.9. 
Continued Access 
 Added section 
Update to study design 
Section 8.2.1. Safety 
Analysis Set 
 Deleted statement 
regarding efficacy 
analysis 
Clarification 
Section 8.3. 
Determination of 
Sample Size 
 Deleted language 
regarding exploring 
efficacy in patients 
with oncogenic 
drivers 
Correction 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5.1. 
Demographics and 
Baseline 
Characteristics; 
Section 8.5.2. Safety 
Analyses 
 Clarified that patients 
will be tabulated, and 
safety analyses will be 
presented by tumor 
indication 
Clarification  
Section 8.5.3. 
Efficacy Analyses  
 Updated language; 
added reference to 
SAP 
Update 
Section 8.5.4. 
Pharmacokinetic 
Analyses 
 Updated language to 
match with Synopsis 
Correction 
Section 9.1. Safety 
Review Committee 
 Clarified that Phase 2 
safety committee will 
convene every 6 
months for the first 5 
years, and then 
annually 
 Removed language 
regarding additional 
SRC meetings after 
every fifth patient 
between ages 12 and 
17  
Aligned with Safety Steering Committee 
Appendix K: 
Country-specific 
Requirements 
 Added new section to 
capture protocol 
changes applicable for 
participants in study 
sites in Germany 
Addition 
Appendix L: 
Provisions for 
Changes in Study 
Conduct During 
Exceptional 
Circumstances 
 Added new section to 
capture provisions for 
changes in study 
conduct during 
exceptional 
circumstances 
Addition 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix M: 
Protocol Amendment 
History 
 Added new section to 
capture amendment 
history 
Addition 
Throughout 
Minor editorial and 
document formatting 
revisions. 
These are minor changes; therefore, they 
have not been summarized 
 
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12. 
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