A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians Choice of Cabozantinib or Vandetanib in Patients With Progressive, Advanced, Kinase Inhibitor Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531)
Phase: PHASE3
Conditions: Medullary Thyroid Cancer
Sponsor: Loxo Oncology, Inc.

Protocol J2G-MC-JZJB(i) 
 
A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians 
Choice of Cabozantinib or Vandetanib in Patients with Progressive, Advanced, Kinase Inhibitor 
Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531) 
 
NCT04211337 
 
Approval Date: 11-Aug-2023 

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Protocol J2G-MC-JZJB(i) 
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Title Page  
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investigation of selpercatinib (LY3527723), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
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otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib 
to Physicians Choice of Cabozantinib or Vandetanib in Patients with Progressive, Advanced, 
Kinase Inhibitor Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531) 
Protocol Number: J2G-MC-JZJB 
Amendment Number: i 
Compound Number: LY3527723 
Study Phase: Phase 3  
Short Title: A Phase 3 Trial Comparing Selpercatinib to Cabozantinib or Vandetanib in Patients 
with RET-Mutant Medullary Thyroid Cancer 
Acronym: JZJB 
Sponsor Name: Eli Lilly and Company  
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 144696 
EudraCT: 2019-001978-28 
EU trial number: 2023-506782-56-00 
Approval Date: Protocol Amendment (i) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-109469 
 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Amendment (h) 
10-May-2023 
Amendment (g) 
28-Oct-2022 
Amendment (f) 
06-Apr-2022 
Amendment (e)  
04-Nov-2021 
Amendment (d) 
15-Feb-2021 
Amendment (c) 
10-Jun-2020 
Amendment (b) 
18-Nov-2019 
Amendment (a) 
12-Nov-2019 
Original Protocol  
30-Jun-2019 
Amendment (i)  
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 primary purpose of this amendment is to update as per the latest Investigator Brochure (IB) 
and to align with EU Clinical Trial Regulation (EU-CTR) requirements. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Added 
 
Regulatory Agency Identifier 
Number(s) 
 
Study Population 
 
Ethical Considerations of 
Benefit/Risk 
For EU-CTR compliance 
6. Study Intervention 
Updated the definition of study 
intervention 
For EU-CTR compliance 
6.1.1. Adult Dosing 
Added last row for “Authorized as 
defined by EU Clinical Trial Regulation” 
For EU-CTR compliance 
6.1.2. Adolescent Dosing 
Added last row for “Authorized as 
defined by EU Clinical Trial Regulation” 
For EU-CTR compliance 
6.1.4. Packaging and 
labeling 
Added new section 
For EU-CTR compliance 
6.6.1. Dose Modifications 
for Selpercatinib 
Hypersensitivity 
Updated the language in second 
paragraph 
Updated as per Selpercatinib IB 
(Aug 2023) 
6.6.5 Dose Modification for 
Selpercatinib Interstitial 
Lung Disease or 
Pneumonitis 
Added new section for updated dose 
modification guidance for Interstitial 
Lung Disease/Pneumonitis 
Updated as per Selpercatinib IB 
(Aug 2023) 
8.2.2.2. Chylothorax and 
Chylous Ascites Monitoring 
Added new section 
Updated as per Selpercatinib IB 
(Aug 2023) 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.2.3. Renal Safety 
Monitoring 
Added new section 
Updated as per Selpercatinib IB 
(Aug 2023) 
8.2.2.4. Thyroid Function 
Monitoring 
Added new section for hypothyroidism 
to provide additional guidance 
Updated as per Selpercatinib IB 
(Aug 2023) 
8.3 Adverse Events and 
Serious Adverse Events 
Added definition and details for adverse 
events 
For EU-CTR compliance 
8.3.3. Regulatory Reporting 
Requirements for SAEs 
Updated the language 
For EU-CTR compliance 
9.4.1. General Statistical 
Considerations 
Added a paragraph on handling of 
missing, unused, and spurious data 
For EU-CTR compliance 
10.1.1. Regulatory and 
Ethical Considerations 
Added a bullet point regarding reporting 
of significant issues related to 
participant’s safety, rights, and data 
integrity 
For EU-CTR compliance 
10.1.3. Data Protection 
Updated the required language 
For EU-CTR compliance 
10.1.5. Dissemination of 
Clinical Study Data 
Added paragraph on “Reports” 
For EU-CTR compliance 
Throughout the protocol 
Minor formatting and editorial changes  
Minor, therefore, not detailed 
  
 
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Table of Contents  
Protocol Amendment Summary of Changes Table ....................................................................2 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................13 
1.3.1. 
Pre-screening Schedule of Activities ..............................................................................14 
1.3.2. 
Screening, On-Study, and Post-Study Treatment Follow-Up 
Schedule of Activities for Patients on Arm A and Arm B ..............................................15 
1.3.3. 
Exceptional Control Arm Switch Treatment (for participants 
switching from vandetanib to cabozantinib) ...................................................................29 
1.3.4. 
Optional Crossover Treatment (for patients crossing over from 
Arm B to Arm A) ............................................................................................................33 
1.3.5. 
Continued Access Schedule of Activities for all patients ...............................................40 
2. 
Introduction ...................................................................................................................41 
2.1. 
Study Rationale ...............................................................................................................41 
2.2. 
Background .....................................................................................................................41 
2.2.1. 
Selpercatinib ...................................................................................................................43 
2.3. 
Benefit/Risk Assessment ................................................................................................45 
3. 
Objectives and Endpoints ............................................................................................46 
4. 
Study Design ..................................................................................................................48 
4.1. 
Overall Design ................................................................................................................48 
4.2. 
Scientific Rationale for Study Design ............................................................................49 
4.3. 
Justification for Dose ......................................................................................................50 
4.3.1. 
Selpercatinib ...................................................................................................................50 
4.3.2. 
Cabozantinib ...................................................................................................................51 
4.3.3. 
Vandetanib ......................................................................................................................51 
4.4. 
End of Study Definition ..................................................................................................51 
5. 
Study Population ...........................................................................................................52 
5.1. 
Inclusion Criteria ............................................................................................................52 
5.2. 
Exclusion Criteria ...........................................................................................................54 
5.2.1. 
Eligibility Criteria for Crossover Treatment ...................................................................56 
5.3. 
Lifestyle Considerations .................................................................................................56 
5.4. 
Screen Failures ................................................................................................................56 
6. 
Study Intervention ........................................................................................................58 
6.1. 
Study Intervention(s) Administered................................................................................58 
6.1.1. 
Adult Dosing ...................................................................................................................58 
6.1.2. 
Adolescent Dosing ..........................................................................................................59 
6.1.3. 
Exceptional Switch from Vandetanib to Cabozantinib ...................................................60 
6.1.4. 
Packaging and Labeling ..................................................................................................61 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................61 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................62 
6.4. 
Study Intervention Compliance ......................................................................................62 
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6.5. 
Concomitant Therapy .....................................................................................................63 
6.5.1. 
CYP3A4 Inducers or Inhibitors ......................................................................................63 
6.5.2. 
Agents That Alter Gastric Acidity (PPIs and H2 blockers) ............................................64 
6.5.3. 
P-gp Substrates or MRP2 Inhibitors ...............................................................................64 
6.5.4. 
Palliative Medicine and Supportive Care .......................................................................64 
6.6. 
Dose Modification ..........................................................................................................65 
6.6.1. 
Dose Modifications for Selpercatinib Hypersensitivity ..................................................69 
6.6.2. 
Dose Modifications for Selpercatinib Related Liver Test 
Abnormalities ..................................................................................................................69 
6.6.3. 
Dose Modifications for Thrombocytopenia ....................................................................70 
6.6.4. 
Dose Modifications for Hypertension .............................................................................70 
6.6.5. 
Dose Modification for Selpercatinib Interstitial Lung 
Disease/Pneumonitis .......................................................................................................70 
6.7. 
Intervention after the End of the Study ...........................................................................71 
6.7.1. 
Treatment after Study Completion..................................................................................71 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................72 
7.1. 
Discontinuation of Study Intervention ............................................................................72 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................73 
7.2.1. 
Discontinuation of Inadvertently Enrolled Patients ........................................................73 
7.3. 
Lost to Follow up ............................................................................................................73 
8. 
Study Assessments and Procedures.............................................................................75 
8.1. 
Efficacy Assessments .....................................................................................................75 
8.1.1. 
Imaging ...........................................................................................................................75 
8.1.2. 
BICR Assessment ...........................................................................................................76 
8.2. 
Safety Assessments .........................................................................................................77 
8.2.1. 
Electrocardiograms .........................................................................................................78 
8.2.2. 
Clinical Safety Laboratory Assessments ........................................................................79 
8.3. 
Adverse Events and Serious Adverse Events .................................................................81 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................84 
8.3.2. 
Follow-up of AEs and SAEs ...........................................................................................84 
8.3.3. 
Regulatory Reporting Requirements for SAEs ...............................................................84 
8.3.4. 
Pregnancy ........................................................................................................................85 
8.3.5. 
Cardiovascular and Death Events ...................................................................................85 
8.3.6. 
Complaint Handling ........................................................................................................85 
8.4. 
Treatment of Overdose ...................................................................................................85 
8.5. 
Pharmacokinetics ............................................................................................................85 
8.6. 
Pharmacodynamics .........................................................................................................86 
8.7. 
Genetics ..........................................................................................................................86 
8.7.1. 
Blood Samples for Pharmacogenetic Research ..............................................................86 
8.8. 
Biomarkers ......................................................................................................................87 
8.8.1. 
Samples Required for Eligibility ....................................................................................87 
8.8.2. 
Biomarkers ......................................................................................................................87 
8.9. 
Medical Resource Utilization and Health Economics ....................................................88 
8.9.1. 
Patient-reported Outcomes ..............................................................................................88 
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8.9.2. 
Bristol Stool Form Scale and Bowel Movement Frequency ..........................................89 
8.9.3. 
Worst Pain Numeric Rating Scale (NRS) .......................................................................89 
8.9.4. 
PRO-CTCAE ..................................................................................................................89 
8.9.5. 
FACT-GP5 ......................................................................................................................89 
8.9.6. 
HRQoL (EORTC QLQ-C30) ..........................................................................................89 
8.9.7. 
Health Status (EQ-5D-5L) ..............................................................................................90 
8.9.8. 
Healthcare Resource Utilization .....................................................................................90 
9. 
Statistical Considerations .............................................................................................91 
9.1. 
Statistical Hypotheses .....................................................................................................91 
9.2. 
Sample Size Determination ............................................................................................91 
9.3. 
Populations for Analyses ................................................................................................92 
9.4. 
Statistical Analyses .........................................................................................................92 
9.4.1. 
General Statistical Considerations ..................................................................................92 
9.4.2. 
Treatment Group Comparability .....................................................................................93 
9.4.3. 
Efficacy Analyses ...........................................................................................................94 
9.4.4. 
Safety Analyses ...............................................................................................................97 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................97 
9.4.6. 
Biomarker Analysis ........................................................................................................98 
9.4.7. 
Other Analyses ................................................................................................................98 
9.5. 
Interim Analyses .............................................................................................................98 
10. 
Supporting Documentation and Operational Considerations ................................101 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ..............................................................................................................101 
10.1.1. Regulatory and Ethical Considerations .........................................................................101 
10.1.2. Informed Consent Process ............................................................................................101 
10.1.3. Data Protection..............................................................................................................102 
10.1.4. Committees Structure....................................................................................................103 
10.1.5. Dissemination of Clinical Study Data...........................................................................103 
10.1.6. Data Quality Assurance ................................................................................................103 
10.1.7. Source Documents ........................................................................................................104 
10.1.8. Study and Site Closure ..................................................................................................104 
10.1.9. Provisions for Changes in Study Conduct During Emergencies ..................................105 
10.2. 
Appendix 2: Clinical Laboratory Tests .........................................................................106 
10.3. 
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information .................................................................................................108 
10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments ..................................................................................................................111 
10.5. 
Appendix 5: Country-specific Requirements ...............................................................112 
10.5.1. Discontinuation of Inadvertently Enrolled Patients in the UK and 
Germany ........................................................................................................................112 
10.6. 
Appendix 6: RET activating mutations in MTC ...........................................................113 
10.7. 
Appendix 7: Restricted and Prohibited Concomitant Medications ..............................114 
10.8. 
Appendix 8: Country-Specific Requirements ...............................................................117 
10.8.1. Addendum 3.1 (Country-Specific Content for Germany) ............................................117 
10.8.2. Addendum 8 (Country-Specific Content for the Netherlands) .....................................118 
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10.8.3. Addendum 10 (Country-Specific Content for the Czech 
Republic) .......................................................................................................................119 
10.8.4. Addendum 11 (Country-Specific Content for Belgium) ..............................................122 
10.8.5. Addendum 12.2 (Country-Specific Content for Czech Republic, 
Germany, Italy, Netherlands, Poland, Spain, Brazil, United 
States, United Kingdom, Australia, and Canada) .........................................................125 
10.8.6. Addendum 13.1 (Country-Specific Content for All Study 
Countries) ......................................................................................................................138 
10.9. 
Appendix 9: Abbreviations and Definitions .................................................................142 
10.10. 
Appendix 10: Protocol Amendment History ................................................................148 
11. 
References ....................................................................................................................168 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title:  
A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians 
Choice of Cabozantinib or Vandetanib in Patients with Progressive, Advanced, Kinase Inhibitor 
Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531) 
Short Title:  
A Phase 3 Trial Comparing Selpercatinib to Cabozantinib or Vandetanib in Patients with 
Medullary Thyroid Cancer 
Regulatory Agency Identifier Number(s) 
IND: 144696 
EudraCT: 2019-001978-28 
EU trial number: 2023-506782-56-00 
Rationale:  
Medullary thyroid cancer (MTC) accounts for 1% to 2% of thyroid cancers in the United States 
(SEER 2018). The majority of MTCs are sporadic, with approximately 20% to 25% hereditary 
due to a germline activating mutation in the RET gene. Most sporadic MTCs harbor activating 
RET mutations as well. The clinical course of MTC is highly heterogeneous, varying from 
indolent tumors that remain unchanged for many years to aggressive cancers associated with 
high mortality. Although surgery can be curative for the approximately 85% of patients who 
present with localized disease, approximately 50% develop recurrent disease. Metastatic MTC is 
incurable. Treatment with the multikinase inhibitors (MKIs) cabozantinib or vandetanib is the 
standard treatment for patients with symptomatic and/or progressive metastatic MTC. However, 
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 and poor pharmacokinetics 
(PK). As a result, most patients treated with these agents experience significant toxicities 
requiring dose interruptions, reductions (35% to 79%), and/or treatment cessation (12% to 16%) 
(Wells et al. 2012, Elisei et al. 2013).  
Selpercatinib is a highly potent and specific small molecule inhibitor of the RET kinase, with 
minimal inhibition of other kinase and non-kinase targets. A Phase 1/2 study (LIBRETTO-001) 
was designed to assess the safety, PK and anti-tumor activity of selpercatinib in patients with 
RET-altered solid tumors. The Phase 1 portion of the study has been completed and the Phase 2 
portion is ongoing. Initial data from Phase 1 was recently presented (Drilon et al. 2018; Oxnard 
et al. 2018; Wirth et al. 2018). As of 02 April 2018, 82 patients were treated at 8 dose levels 
(20 mg QD to 240 mg BID). Treatment-emergent adverse events (TEAEs) were monitorable and 
reversible. A dose of 160 mg BID has been selected for Phase 2.  
The investigator-assessed overall response rate (ORR) and confirmed ORR (cORR) by Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with RET mutant MTC were 59% 
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(n = 17/29) and 56% (n = 15/27, respectively, with 94% (n = 16/17) of responses ongoing with a 
median follow up of 7.6 months (8.4 months for responders).  
Given its manageable toxicity profile and evidence of durable antitumor activity in patients with 
advanced RET mutant MTC, selpercatinib may be of benefit in delaying treatment failure and 
disease progression and improving survival in patients with progressive, advanced MTC who 
have not previously received cabozantinib or vandetanib. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
 
To compare PFS of patients with progressive, 
advanced, kinase inhibitor naïve, RET-mutant 
MTC treated with selpercatinib versus 
cabozantinib or vandetanib. 
 
PFS by BICR 
Secondary 
 
 
To compare other efficacy outcomes, based on 
RECIST 1.1 criteria, observed in patients with 
progressive, advanced, kinase inhibitor naïve, 
RET-mutant MTC treated with selpercatinib versus 
cabozantinib or vandetanib. 
 
TFFS by BICR 
 
TFFS by investigator 
 
PFS by investigator 
 
ORR by investigator and BICR 
 
DoR by investigator and BICR 
 
OS 
 
PFS2 by investigator 
 
To evaluate the safety and tolerability of 
selpercatinib compared to cabozantinib or 
vandetanib. 
 
Safety per CTCAE v5.0 (including but not limited 
to): incidence and severity of TEAEs, SAEs, 
deaths, and clinical laboratory abnormalities. 
 
To compare the tolerability of selpercatinib versus 
cabozantinib or vandetanib. 
 
Proportion of time with high-side-effect bother 
based on FACT-GP5  
 
To assess/evaluate performance of local RET 
laboratory tests compared to a single, central test. 
 
RET mutation status 
 
To assess the PK of selpercatinib in patients 
receiving selpercatinib. 
 
Predose plasma concentrations at Day 8 of 
Cycle 1, and at Day 1 of Cycles 2 through 6. 
Abbreviations: BICR = blinded independent central review; CTCAE = Common Terminology Criteria for Adverse 
Events; DoR = duration of response; FACT-GP5 = Functional Assessment of Cancer Therapy-Side Effects; 
MTC = medullary thyroid cancer; ORR = overall response rate; OS = overall survival; PFS = progression free 
survival; PFS2 = progression-free survival 2; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in 
Solid Tumors; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TFFS = treatment 
failure-free survival. 
 
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Overall Design: 
This is a global, multicenter, randomized (2:1), open-label, Phase 3 study comparing 
selpercatinib (treatment Arm A) to physician’s choice of cabozantinib or vandetanib (treatment 
Arm B) in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant MTC. 
Patients will be stratified based on: 
 RET mutation: M918T vs. other  
 Intended treatment if randomized to control arm: cabozantinib vs. vandetanib. 
Patients with histologically confirmed, unresectable, locally advanced, or metastatic MTC who 
have not received previous treatment with a kinase inhibitor are eligible. Patients are required to 
have radiologic progressive disease per RECIST 1.1 at screening compared with an image 
obtained within the prior 14 months and to have a documented RET mutation in tumor or 
germline DNA. Both radiographic progression and RET mutation must be confirmed by the 
sponsor prior to patient randomization. 
Patients will be randomized in a 2:1 ratio to receive selpercatinib (treatment Arm A) or 
physician’s choice of cabozantinib (treatment Arm B1) or vandetanib (treatment Arm B2). 
Patients assigned to the control arm cannot switch from cabozantinib to vandetanib or from 
vandetanib to cabozantinib during the study (under exceptional circumstances, switch from 
vandetanib to cabozantinib may be allowed as outlined in Section 6.1.3). Treatment will continue 
until disease progression, unacceptable toxicity, or death.  
Patients randomized to Arm B who discontinue treatment and who have radiographic disease 
progression that is confirmed by blinded independent central review (BICR) may be eligible for 
crossover to selpercatinib if they meet the eligibility criteria for crossover (see Section 5.2.1). 
Disclosure Statement:  
This is a randomized, active-treatment study with 2 arms where the participant and investigator 
will not be blinded, however, to preserve the integrity of the trial, the sponsor will not have 
unblinded access to aggregate data from the clinical database.  
Study Population 
 Participants of an acceptable age to provide informed consent according to local 
regulations and are at least 18 years of age (patients as young as 12 years of age will be 
allowed if permitted by local regulatory authorities and institutional review boards). 
 Histologically or cytologically confirmed, unresectable, locally advanced and/or 
metastatic MTC and no prior history of treatment with kinase inhibitors for 
advanced/metastatic disease.  
 Radiographic progressive disease per RECIST 1.1 at screening compared with a previous 
image taken within the prior 14 months as assessed by the BICR. Patients with 
measurable or non-measurable but evaluable disease are eligible; however, patients with 
non-measurable disease may not have disease limited to bone sites only.  
 A RET gene alteration identified in a tumor, germline DNA or blood sample (for 
example, circulating free DNA [cfDNA]). 
 Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2. 
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Number of Participants: 
Approximately 250-400 patients will be enrolled to the study.  
Intervention Groups and Duration: 
 
Arm A 
Arm B1 
Arm B2 
Intervention 
Selpercatinib 
Cabozantinib 
Vandetanib 
Adult Dose 
160 mg BID 
140 mg QD 
300 mg QDb 
Adolescent Dosea 
Approximate Adult 
Equivalent dose 
92 mg/m2 BID 
160 mg BID 
40 mg/m2 QD 
72 mg QD 
See dosing guide 
Cycle length is 28 days for all treatment arms. 
Abbreviations: BID = twice daily; QD = once daily 
a refer to respective nomograms in Section 6.1 for the exact dosing in adolescent patients. A reduced starting dose of 
vandetanib should be used in adolescent patients with moderate renal impairment as per the dose reduction table in 
Section 6.6. 
b starting dose of vandetanib should be 200 mg in adult patients with moderate renal impairment (creatinine 
clearance results between 30 and 50 mL/min). In case vandetanib 100-mg tablets are not available, see 
Section 6.6. 
Ethical Considerations of Benefit/Risk: 
Based on the manageable toxicity profile and evidence of durable antitumor activity in patients 
with advanced RET-mutant MTC, selpercatinib may be of benefit in delaying treatment failure 
and disease progression and in improving survival in patients with progressive, advanced MTC 
who have not previously received cabozantinib or vandetanib. Therefore, the sponsor considers 
that the benefit/risk balance is positive and supports the proposed Phase 3 Study JZJB, exploring 
administration of selpercatinib in comparison to cabozantinib or vandetanib in adult and 
adolescent patients.  
Data Monitoring Committee: Yes 
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1.2. 
Schema  
 
Abbreviations: BICR = blinded independent central review; BID = twice a day; DNA = deoxyribonucleic acid; 
MTC = medullary thyroid cancer; NGS = next-generation sequencing; PCR = polymerase chain reaction; 
QD = once daily; RECIST 1.1= Response Evaluation Criteria in Solid Tumors, version 1.1. 
a See RET activating mutations in MTC (Appendix 6). 
b To selpercatinib allowed ONLY at radiographic disease progression confirmed by BICR. 
c Adolescent dose is as follows:  
 
Selpercatinib: 92 mg/m2 BID 
 
Cabozantinib: 40 mg/m2 QD 
 
Vandetanib: See dosing guide in Section 6.1. 
(Refer to respective nomograms in Section 6.1 for the exact dosing in adolescent patients). 
 
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1.3. 
Schedule of Activities (SoA)  
This section includes the following SoAs:  
 Pre-screening SoA 
 Screening, On-Study, and Post-Study Treatment Follow-Up SoA for Patients on Arm A 
and Arm B 
 Exceptional Control Arm Switch Treatment (for participants switching from vandetanib 
to cabozantinib) 
 Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
 Continued Access SoA for All Patients 
 
 
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1.3.1. 
Pre-screening Schedule of Activities  
Abbreviations: AE = adverse event; BICR = blinded independent central review; eCRF = electronic case report form; FNA = fine needle aspirate; 
ICF = informed consent form. 
 
 
Visit 
Prescreening  
Instructions 
Prescreening ICF for RET 
testing 
X 
OPTIONAL: In geographies or sites where RET testing is not standard of care and/or an acceptable 
local test (as defined by Sponsor) is not available, a pre-screening consent will be used to provide 
information to the patient regarding testing to determine tumor RET status. 
If it is considered safe to perform, patients who do not have sufficient available tumor tissue may 
undergo a fresh tumor biopsy/FNA to determine initial eligibility. 
 
If it is unclear that a patient’s RET result will be considered eligible for enrollment, the RET result 
may be submitted to the Sponsor for review prior to main study consent. 
Prescreening ICF for radiologic 
imaging submission for BICR 
review 
X 
OPTIONAL: If the imaging was performed as a part of standard of care, the imaging can be 
submitted to confirm progression by BICR. 
Demographic Information 
X 
 
AE collection 
X 
See Section 8.3. During Pre-Screening, only AEs reasonably possibly related to study procedures 
should be recorded in the eCRF. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
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15 
 
1.3.2. 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B  
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Molecular 
Pathology 
Report(s) 
describing RET 
alterations 
(germline or 
tumor) 
X 
  
  
  
  
  
  
  
  
  
For all patients, redacted report(s) must be 
submitted for review. The test may have 
been performed prior to consent, but 
sponsor must confirm acceptability of 
results, preferably prior to other screening 
procedures. 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
ICF must be signed before any protocol-
specific procedures are performed. Any 
procedures performed as standard of care 
before consent that fall within the screening 
window may be used. See Appendix 1. 
Demographic 
Information 
X 
 
 
 
 
 
 
 
 
 
If this information is collected at the Pre-
screening visit, do not collect again at the 
Screening visit. 
Inclusion/ 
exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
See Section 5. Must be confirmed before 
any on treatment procedures are performed. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
16 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
Including assessment of pre-existing 
conditions, historical illnesses, prior 
anticancer therapy, and habits. 
Concomitant 
medication 
X 
  
X 
X 
X 
  
• At baseline, record prior and concurrent 
medications. 
• Record all premedication, supportive care, 
and concomitant medication continuously 
at every visit and throughout the study. 
Physical 
examination 
(≥18 years of 
age) 
X 
  
X 
X 
  
See 
Instructions 
X 
  
X 
  
Physical examination and review of 
relevant systems at Screening. Symptom-
directed physical examinations may be 
performed at other time points. 
Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Physical 
examination  
(<18 years of 
age) 
X 
  
X 
X 
  
X 
X 
  
X 
  
Physical examination and review of 
relevant systems at Screening. Symptom-
directed physical examinations may be 
performed at other time points. Physical 
exam will be performed on adolescent 
patients every 4 weeks starting on Day 1 of 
Cycle 2-n and throughout. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
17 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Vital signs 
(≥18 years of 
age) 
X 
  
X 
X 
  
See 
Instructions 
X 
  
X 
  
Measure vital signs: height at baseline only. 
Perform on Day 1 of Cycles 2-16: weight, 
systolic and diastolic blood pressure, pulse 
rate, and body temperature.  
After completion of 1 year of treatment, 
obtain every 12 weeks in adult patients 
(Cycles 16, 19, 22 etc.). 
Vital signs 
(<18 years of 
age) 
X 
  
X 
X 
  
X 
X 
  
X 
  
Vital signs will be performed on adolescent 
patients every 4 weeks starting on Day 1 of 
Cycle 2-n and throughout. Height should be 
measured every 6 months until they reach 
the age of 18. 
Tanner staging 
X 
  
  
  
  
See 
instructions 
X 
  
X 
  
For patients under age 18. Perform every 
6 months (±2 weeks); may discontinue 
when sexual maturity is reached. 
AE collection 
X 
  
X 
X 
X 
 Collect continuously at every visit and 
throughout the study 
 CTCAE Version 5.0 
 During the short term follow-up visits, 
collect all AEs/SAEs. Thereafter, collect 
only SAEs related to study treatment or 
protocol procedures 
 Ongoing drug related AEs at the end of 
short-term follow-up the patient should be 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
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18 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
followed every 30 days until the event is 
resolved, the event is no longer considered 
to be drug related, the event becomes stable 
or returns to baseline, a new treatment is 
initiated for the patient, or the patient dies 
or is lost to follow-up. 
ECOG PS 
(≥18 years of 
age) 
X 
  
X 
  
  
See 
Instructions 
X 
  
X 
  
During study treatment, perform 3 days 
prior to treatment, perform on Day 1 of 
Cycles 2-16, then obtain every 12 weeks in 
adult patients (Cycles 16, 19, 22, etc.). 
ECOG PS 
(<18 years of 
age) 
X 
  
X 
  
  
X 
X 
  
X 
  
During study treatment, perform 3 days 
prior to treatment. ECOG PS will be 
performed on adolescent patients every 4 
weeks starting on Day 1 of Cycle 2-n and 
throughout. 
ECG 
X 
  
X 
X 
  
See 
instructions 
  
  
  
  
Obtain triplicate local ECGs at Screening, 
C1D1, C1D8, and on Day 1 of C2-6. It is 
preferable to obtain ECGs approximately 
2 hours after dosing. Patients receiving 
vandetanib (Arm B2) continue to have 
ECGs performed every 3 months post 
Cycle 6 (consider additional ECG at C16D1 
so subsequent ECGs align with onsite 
clinical visit schedule). See Section 8.2.1. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
19 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Hematology  
(≥18 years of 
age) 
 X 
 
X 
  
X 
See 
Instructions 
X 
  
X 
  
If screening testing is performed ≤7 days 
prior to C1D1, repeat testing does not need 
to occur on C1D1. See Appendix 2. 
Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Hematology 
(<18 years of 
age) 
 X 
 
X 
  
X 
X 
X 
  
X 
  
If screening testing is performed ≤7 days 
prior to C1D1, repeat testing does not need 
to occur on C1D1. See Appendix 2. 
Hematology will be performed on 
adolescent patients every 4 weeks starting 
on Day 1 of Cycle 2-n and throughout. 
Coagulation 
X 
  
  
  
  
  
  
  
X  
  
See Appendix 2. Perform at baseline and as 
clinically indicated. 
Chemistry panel 
(≥18 years of 
age) 
 X 
 
X 
  
  
See 
Instructions 
X 
  
X 
  
If screening testing is performed ≤7 days 
prior to C1D1, repeat testing does not need 
to occur on C1D1. See Appendix 2. 
Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.).  
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
20 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Chemistry panel 
(<18 years of 
age) 
X 
 
X 
 
 
X 
X 
 
X 
 
If screening testing is performed ≤7 days 
prior to C1D1, repeat testing does not need 
to occur on C1D1. See Appendix 2.  
Chemistry panel will be performed on 
adolescent participants every 4 weeks 
starting on Day 1 of Cycle 2-n and 
throughout. 
Hepatic 
monitoring 
  
  
  
  
X 
See 
instructions 
  
  
  
  
See Appendix 2. Should be performed on 
C1D15, C2D15, and C3D15, then as 
clinically indicated. 
Thyroid panel 
X 
  
  
  
  
See 
instructions 
  
  
  
  
See Appendix 2. Collect at baseline and as 
clinically indicated. 
Pregnancy test 
  
X 
X 
See Instructions 
See 
Instructions 
X 
  
• Applies only to women of childbearing 
potential. 
• Note: during study treatment, perform at 
screening, C1D1 (within 24 hours prior to 
first dose of study drug), and thereafter as 
required per local regulations and/or 
institutional guidelines. 
• See Appendix 2 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
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21 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Urine Protein 
(≥18 years of 
age) 
 
 
 
X 
 
See 
Instructions 
X 
 
X 
 
Only for patients receiving cabozantinib. 
Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Urine Protein 
(<18 years of 
age) 
 
 
 
X 
 
X 
X 
 
X 
 
Only for patients receiving cabozantinib. 
Urine protein will be performed on 
adolescent patients every 4 weeks starting 
on Day 1 of Cycle 2-n and throughout 
Calcitonin, CEA 
(≥18 years of 
age) 
  
X 
  
  
X 
See 
Instructions 
X 
  
X 
  
Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Calcitonin, CEA 
(<18 years of 
age) 
  
X 
  
  
X 
X 
X 
  
X 
  
Calcitonin, CEA will be performed on 
adolescent patients every 4 weeks starting 
on Day 1 of Cycle 2-n and throughout. 
Serum Cortisol, 
ACTH 
  
X 
  
  
X 
See 
instructions 
  
  
X 
  
Only in patients with Cushing’s disease 
related to their cancer. Baseline, C1D15, 
then q 8 weeks (±7 days) for the first 24 
weeks after C1D1 and q 12 weeks (±7 
days) thereafter (i.e., at the same time as 
imaging assessments). 
Phone visit 
(collection of 
  
  
  
  
  
See 
Instructions 
  
  
  
  
Applicable only for adult patients. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
22 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
concomitant 
medications, 
AEs, labs, and 
patient dosing 
diary) 
Onsite clinical visit will occur every 28 
days from C2 to C16. After C16 the onsite 
visit will occur every 12 weeks (i.e., C19, 
C22, C25, etc.). 
A phone follow-up visit will occur at every 
non-clinical visit after C16 (i.e., C17, C18, 
C20, C21, C23, C24, etc.) where details 
related to concomitant medications, AEs, 
chemistries, pregnancy test (if required), 
and patient dosing diary will be captured. 
Growth plate 
imaging 
X 
  
See instructions 
  
  
  
  
Only for patients <18 years of age who 
have not reached full adult height. Knee 
MRI at baseline and every 6 months ±2 
weeks). See Section 8.2. 
Radiologic 
imaging (neck, 
chest, abdomen, 
pelvis and other 
known sites of 
disease)  
X 
(28 
days)   
See instructions 
See 
instructions 
X 
  
• Perform according to RECIST 1.1 criteria, 
by the same method used at baseline, q 8 
weeks (±7 days) for the first 24 weeks after 
C1D1 and q 12 weeks (±7 days) thereafter 
until radiographic disease progression or 
death, whichever occurs first. 
• If the imaging submitted to confirm 
progression by BICR was performed more 
than 28 days prior to dosing, new imaging 
should be completed as the pre-dosing 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
23 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
baseline (but does not need reconfirmed by 
BICR). 
• See Section 8.1 for details, including 
information on suggested modalities. 
Submit scans 
X 
  
See instructions 
X 
X 
  
All scans taken for tumor assessment 
should be submitted to Lilly’s designee 
preferably within 5 business days of 
collection for central review by the BICR. 
Repeated submission of scans greater than 
10 business days after date of collection 
will be considered a protocol deviation 
(unless previously approved by sponsor). 
Survival and 
PFS2 assessment 
  
  
  
  
  
  
  
  
X 
See instructions 
Perform q 3 months (±7 days) for the first 
year off treatment, q 4 months (±14 days) 
for the second year off treatment, then 
approximately every 6 months thereafter. 
Will last until the final analysis for OS.  
If an in-person visit is not possible, confirm 
survival by contacting the patient directly 
via phone. See Section 8.1.1 regarding 
PFS2 assessment.  
Collection of 
poststudy-
treatment 
  
  
  
  
  
  
  
  
X 
X 
  
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
24 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
anticancer 
therapy 
information 
Review patient 
dosing diary 
  
  
X 
X 
  
See 
Instructions 
  
  
  
  
Provide patient diary Day 1. Completed 
daily by patient. Review at each study visit 
and on phone visits for adult patients from 
Cycle 16 onward. 
Bristol Stool 
Form Scale and 
bowel movement 
frequency 
  
  
X 
X 
  
X 
  
Completed electronically daily by the 
patient, not site administered except on 
C1D1 when this should be collected while 
patient is on site prior to first treatment 
dose. To be completed through 1 year of 
treatment then discontinued. 
Worst Pain NRS 
  
  
X 
X 
  
X 
  
Completed electronically daily by the 
patient, not site-administered except on 
C1D1 when this should be collected while 
patient is on site prior to first treatment 
dose. To be completed through 1 year of 
treatment then discontinued. 
Patient-reported 
AEs (PRO-
CTCAE) 
  
  
X 
X 
  
X 
  
Completed electronically by the patient 
each week, not site-administered except on 
C1D1 when this should be collected while 
patient is on site prior to first treatment 
dose 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
25 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Patient-reported 
side-effect 
burden (FACT-
GP5) 
  
  
X 
X 
  
X 
  
Completed electronically by the patient 
each week, not site-administered except on 
C1D1 when this should be collected while 
patient is on site prior to first treatment 
dose. 
Physical function 
(EORTC IL19) 
  
  
X 
X 
  
X 
  
Completed electronically by the patient 
each week, not site-administered except on 
C1D1 when this should be collected while 
patient is on site prior to first treatment 
dose. 
HRQoL 
(EORTC QLQ-
C30) 
  
  
X 
  
  
X 
X 
  
X 
X 
Site-administered at D1 of each cycle using 
the device provided prior to study 
intervention, and during follow up at 
scheduled clinic visits until disease 
progression. If the patient completed their 
30 day assessments (V201) and 
discontinued prior to crossing over, they 
will not need to complete the Visit 801 
assessments. Starting with C16, obtain 
every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
26 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Health Status 
(EQ-5D-5L) 
  
  
X 
  
  
X 
X 
  
X 
X 
Site-administered at D1 of each cycle prior 
to study intervention using the device 
provided and during follow up at scheduled 
clinic visits until disease progression. If the 
patient completed their 30-day assessments 
(V201) and discontinued prior to crossing 
over, they will not need to complete the 
Visit 801 assessments. Starting with C16, 
obtain every 12 weeks in adult patients 
(Cycles 16, 19, 22, etc.). 
Blood sample for 
pharmacokinetics   
  
  
X 
  
 See 
Instructions 
  
  
  
  
Arm A only: Samples to be drawn pre-dose 
(-2 to 0 hour) in Cycles 1-6. See Section 
8.5. 
Whole Blood for 
genomic DNA 
(PGx) 
  
  
X 
  
  
  
  
  
  
  
Sample can be collected at any time if not 
collected on C1D1. 
Archived tumor 
tissue or fresh 
biopsy 
  
See 
Instructions   
  
  
  
  
  
  
This sample must be submitted, preferably 
within 30 days of C1D1. A single sample 
collected outside of the specific time 
window will not be considered a protocol 
deviation. Please submit sample from the 
most recent biopsy with adequate tissue. 
See Section 8.8. 
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Protocol J2G-MC-JZJB(i) 
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Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety 
assessments 
prior to 
crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for 
patients on 
  
Arm B) 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Optional post-
progression 
tumor biopsy 
  
  
  
  
  
  
  
See 
instructions 
  
Can be obtained any time prior to the start 
of next therapy. 
Plasma for 
cfDNA  
  
  
X (Pre-
dose) 
  
X 
See 
Instructions 
X 
  
X 
  
Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of treatment, obtain 
every 12 weeks (Cycles 16, 19, 22, etc.). 
Obtain plasma for cfDNA as soon as its 
possible after progression or treatment 
discontinuation. 
Administer 
selpercatinib 
(Arm A) 
  
  
See instructions 
  
  
  
  
See Section 6.1. 
Administer 
cabozantinib 
(Arm B1) 
  
  
See instructions 
  
  
  
  
See Section 6.1. 
Administer 
vandetanib 
(Arm B2) 
  
  
See instructions 
  
  
  
  
See Section 6.1. 
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Abbreviations: ACTH = adrenocorticotropic hormone; AE = adverse event; BICR = blinded independent review committee; CEA = carcinoembryonic antigen; 
cfDNA = circulating free deoxyribonucleic acid; CTCAE = Common Terminology Criteria for Adverse Events; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EORTC QLQ-C30 = European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0; EORTC IL19 = European Organisation for Research and Treatment of Cancer Quality 
of Life questionnaire, item library 19; EQ-5D-5L = 5-level-EuroQol; FACT-GP5 = Functional Assessment of Cancer Therapy-Side Effects; HRQoL = health-
related quality of life; ICF = informed consent form; IV = intravenous; MRI = magnetic resonance imaging; NRS = numeric rating scale; PFS = progression-free 
survival; PRO-CTCAE = patient-reported outcome Common Terminology Criteria for Adverse Events; Q = every; RECIST 1.1 = Response Criteria in Solid 
Tumors Version 1.1; SAE = serious adverse event. 
a Short-term follow-up begins when the patient and investigator agree that the patient will no longer continue study treatment and lasts approximately 30 days 
(±7 days). Please note this is done only for patients not crossing over to selpercatinib after control arm treatment is completed. 
All patients in Arm A should complete V801 and will not complete V201.  
All patients in Arm B (who are considering crossing over to selpercatinib) will enter Visit 201.  
Patients in Arm B that cross over to selpercatinib >37 days (30 days ±7 days) after the last dose of study treatment should complete V201 assessments. If a 
patient in V201 that has completed the V201 assessments does not enter crossover (V300) they do not need to complete the V801 assessments, but will 
need to complete V802 assessments.  
Patients in Arm B that cross over to selpercatinib in less than 37 days should discontinue from V201 when the decision to be screened for crossover is 
made. They will not complete the V201 assessments, but rather enter visit 300 and complete the screening assessments for crossover. 
Patients in Arm B that will not crossover to selpercatinib should not enter V201. They will not complete the V201 assessment, but rather subsequently 
enter V801 and complete the V801 assessments 
b Long-term follow-up begins when the patient completes the 30-day (±7 days) follow-up visit and ends with the patient’s death, upon loss to follow-up, or 
upon overall study completion, whichever is earlier. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or 
she has explicitly provided permission and consent. 
Note: Baseline/screening assessments and laboratory values drawn within the indicated window of C1D1 may be used for both screening/baseline and C1D1 
assessments. There is not a defined interval required from randomization to C1D1.  
 
 
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Protocol J2G-MC-JZJB(i) 
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1.3.3. 
Exceptional Control Arm Switch Treatment (for participants switching from vandetanib to cabozantinib)  
This SoA table reflects the additional or revised procedures for control arm switch. Refer to the SoA table, Section 1.3.2 for complete 
schedule. 
Exceptionala Control Arm Switch Treatment (for participants switching from vandetanib to cabozantinib) 
 
  
Switch Screening 
 
On-Treatment 
 
Cycle = 28 days 
Days relative to 
start of switch 
treatment 
 
Cycle X+1  
Cycle X+2 – 3 
Instructions 
 
(±3 days) 
(±3 days) 
  
≤42 
D1 
D8 
D15 
D1 
  
Procedure 
  
  
  
  
  
  
Eligibility criteria for control 
arm switch 
X 
  
  
  
  
See Section 6.1.3.1. Must be confirmed before 
any switch phase procedures are performed. 
Informed consent form 
X 
  
  
  
  
ICF must be signed before any switch phase 
procedures are performed.  
Vital signs 
(≥18 years of age)  
X 
X 
X 
  
See Instructions 
Measure vital signs: Perform on Day 1 of Cycles 
X+2 - X+3: weight, systolic and diastolic blood 
pressure, pulse rate, and body temperature. After 
the first 3 cycles of switch treatment, go back to 
previous frequency, i.e., completion of 1 year of 
study treatment, obtain every 12 weeks in adult 
participants only. 
Vital signs 
(<18 years of age) 
X 
X 
X 
  
See instructions 
Vital signs will be performed on adolescent 
participants every 4 weeks starting on Day 1 of 
Cycle X+2-n and throughout. Height should be 
measured every 6 months. 
ECG 
X 
X 
X 
  
See Instructions 
Obtain triplicate local ECGs at screening, on D1 
and D8 of Cycle X+1, on Day 1 of 
Cycles X+2 - X+3. After 3 cycles of switch 
treatment, go back to previous frequency. It is 
preferable to obtain ECGs approximately 2 hours 
after dosing. See Section 8.2.1. 
Approved on 11 Aug 2023 GMT

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Protocol J2G-MC-JZJB(i) 
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Exceptionala Control Arm Switch Treatment (for participants switching from vandetanib to cabozantinib) 
 
  
Switch Screening 
 
On-Treatment 
 
Cycle = 28 days 
Days relative to 
start of switch 
treatment 
 
Cycle X+1  
Cycle X+2 – 3 
Instructions 
 
(±3 days) 
(±3 days) 
  
≤42 
D1 
D8 
D15 
D1 
  
Procedure 
  
  
  
  
  
  
Hematology 
(≥18 years of age) 
X 
X 
  
X 
See Instructions 
If testing is performed ≤7 days prior to D1 of 
Cycle X+1, repeat testing does not need to occur 
on D1 of Cycle X+1. See Appendix 2. Perform 
on Day 1 of Cycles X+2 - X+3. After completion 
of 1 year of study treatment, obtain every 12 
weeks in adult participants (e.g., Cycles X+16, 
X+19, X+22, etc.).  
Hematology 
(<18 years of age) 
X 
X 
  
X 
X 
If testing at switch screening is performed 
≤7 days prior to D1 of Cycle X+1, repeat testing 
does not need to occur on D1 of Cycle X+1. See 
Appendix 2.  
Hematology will be performed on adolescent 
participants every 4 weeks starting on Day 1 of 
Cycle X+2 - X+3, and after, go back to previous 
frequency. 
Coagulation 
X 
  
  
  
  
See Appendix 2. Perform at switch screening, 
and as clinically indicated. 
Chemistry panel  
(≥18 years of age) 
X 
X 
  
  
See Instructions 
If testing at switch screening is performed 
≤7 days prior to D1 of Cycle X+1, repeat testing 
does not need to occur on D1 of Cycle X+1. See 
Appendix 2. Perform on Day 1 of Cycles 
X+2 - X+3. After completion of 1 year of study 
treatment, obtain every 12 weeks in adult 
participants. 
Chemistry panel  
(<18 years of age) 
X 
X 
 
 
X 
If testing at switch screening is performed 
≤7 days prior to D1 of Cycle X+1, repeat testing 
does not need to occur on D1 of Cycle X+1. See 
Appendix 2. 
Chemistry panel will be performed on adolescent 
participants every 4 weeks starting on Day 1 of 
Approved on 11 Aug 2023 GMT

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Protocol J2G-MC-JZJB(i) 
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Exceptionala Control Arm Switch Treatment (for participants switching from vandetanib to cabozantinib) 
 
  
Switch Screening 
 
On-Treatment 
 
Cycle = 28 days 
Days relative to 
start of switch 
treatment 
 
Cycle X+1  
Cycle X+2 – 3 
Instructions 
 
(±3 days) 
(±3 days) 
  
≤42 
D1 
D8 
D15 
D1 
  
Procedure 
  
  
  
  
  
  
Cycle X+2 - 3 and after 3 first switch cycles, go 
back to previous frequency. 
Hepatic monitoring 
 
 
 
X 
See Instructions 
See Appendix 2. Should be performed at switch 
screening, on D15 of Cycles X+1, X+2, and X+3, 
then as clinically indicated. 
Thyroid panel 
X 
  
  
  
See Instructions 
 See Appendix 2. Collect at switch screening and 
as clinically indicated. 
Pregnancy test 
X 
X 
See instructions 
• Applies only to women of childbearing 
potential. 
• Note: during switch treatment, perform at 
switch screening, on D1 of Cycle X+1 (within 
24 hours prior to dose) and thereafter as required 
per local regulations and/or institutional 
guidelines.  
• See Appendix 2. 
Urine protein 
(≥18 years of age) 
 
 
X 
 
See Instructions 
Perform on Day 1 of Cycles X+2 - X+n. After 
completion of 1 year of study treatment, obtain 
every 12 weeks in adult participants 
(Cycles X+16, X+19, X+22, etc.). 
Urine protein 
(<18 years of age) 
 
 
X 
 
X 
Urine protein will be performed on adolescent 
participants every 4 weeks starting on Day 1 of 
Cycle X+2 - n and throughout. 
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Protocol J2G-MC-JZJB(i) 
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Exceptionala Control Arm Switch Treatment (for participants switching from vandetanib to cabozantinib) 
 
  
Switch Screening 
 
On-Treatment 
 
Cycle = 28 days 
Days relative to 
start of switch 
treatment 
 
Cycle X+1  
Cycle X+2 – 3 
Instructions 
 
(±3 days) 
(±3 days) 
  
≤42 
D1 
D8 
D15 
D1 
  
Procedure 
  
  
  
  
  
  
Radiologic imaging (neck, 
chest, abdomen, pelvis, and 
other known sites of disease) 
X 
See instructions  
• Perform according to RECIST 1.1 criteria, by 
the same method used at baseline, q 8 weeks 
(±7 days) for the first 24 weeks after C1D1 and q 
12 weeks (±7 days) thereafter until radiographic 
disease progression or death, whichever occurs 
first. 
• Perform as scheduled, even if study treatment is 
omitted. 
• Perform scans at switch screening if last scan 
on vandetanib is more than 8 weeks prior to D1 
of Cycle X+1. 
• Brain or bone imaging required only for 
participants with known or suspected disease at 
those sites. 
See Section 8.1. 
Submit scans 
X 
See instructions 
All scans taken for tumor assessment should be 
submitted to Lilly’s designee in a timely manner. 
Administer cabozantinib 
  
 See instructions 
See Section 6.1. 
Abbreviations: ECG = electrocardiogram; ICF = informed consent form; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1. 
a Cycle X refers to the last cycle of control arm treatment before the switch. 
 
 
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Protocol J2G-MC-JZJB(i) 
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1.3.4. 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A)  
Only applicable for patients initially randomized Arm B (cabozantinib or vandetanib) who have progression that is confirmed by the 
BICR and who are eligible for crossover treatment.  
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Inclusion/exclusion 
criteria for crossover 
phase 
X 
  
  
  
  
  
  
See Section 5.2.1. Must be confirmed before any 
crossover phase procedures are performed 
Informed consent form 
X 
  
  
  
  
  
  
ICF must be signed before any crossover phase 
procedures are performed. Any procedures performed 
as standard of care before consent that fall within the 
screening window may be used. 
Concomitant medication 
X 
X  
X 
  
• At baseline, record prior and concurrent 
medications. 
• Record all premedication, supportive care, and 
concomitant medication continuously at every visit 
and throughout the study. 
Physical examination 
(≥18 years of age) 
X 
X 
X 
  
See 
Instructions 
X 
  
Physical examination and review of relevant systems 
at Screening. Symptom-directed physical 
examinations may be performed at other time points. 
Perform on Day 1 of Cycles 2-16. After completion of 
1 year on crossover treatment, obtain every 12 weeks 
in adult patients (Cycles 16, 19, 22, etc.). 
Physical examination 
(<18 years of age) 
X 
X 
X 
  
X 
X 
  
Physical examination will be performed on adolescent 
patients every 4 weeks starting on Day 1 of Cycle 2-n 
and throughout. 
Approved on 11 Aug 2023 GMT

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Protocol J2G-MC-JZJB(i) 
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Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Vital signs 
(≥18 years of age)  
X 
X 
X 
  
See 
Instructions 
X 
  
Measure vital signs: height (at baseline only). Perform 
on Day 1 of Cycles 2-16: weight, systolic and 
diastolic blood pressure, pulse rate, and body 
temperature. After completion of 1 year of crossover 
treatment, obtain every 12 weeks in adult patients 
(Cycles 16, 19, 22, etc.) only.  
Vital signs 
(<18 years of age) 
X 
X 
X 
  
X 
X 
  
Vital signs will be performed on adolescent patients 
every 4 weeks starting on Day 1 of Cycle 2-n and 
throughout. Height should be obtained every 6 
months until the age of 18. 
Tanner Staging 
X 
  
  
  
See 
Instructions 
X 
  
For patients under age 18. Perform every 6 months 
(±2 weeks); may discontinue when sexual maturity is 
reached. 
AE collection 
X 
X 
X 
X 
 
Collect continuously at every visit and throughout 
the study 
 
CTCAE Version 5.0 
 
During the short term follow-up visits, collect all 
AEs/SAEs. Thereafter, collect only SAEs related 
to study treatment or protocol procedures 
ECOG PS 
(≥18 years of age) 
X 
X 
  
  
See 
Instructions 
X 
  
During study treatment, perform 3 days prior to 
treatment. Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of crossover treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 19, 22, 
etc.). 
ECOG PS 
(<18 years of age) 
X 
X 
  
  
X 
X 
  
ECOG PS will be performed on adolescent patients 
every 4 weeks starting on Day 1 of Cycle 2-n and 
throughout. 
ECG 
X 
X 
X 
  
See 
Instructions 
  
  
Obtain triplicate local ECGs at screening, C1D1, 
C1D8, on Day 1 of C2-6. It is preferable to obtain 
ECGs approximately 2 hours after dosing. See 
Section 8.2.1. 
Approved on 11 Aug 2023 GMT

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Protocol J2G-MC-JZJB(i) 
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Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Hematology 
(≥18 years of age) 
X 
X 
  
X 
See 
Instructions 
X 
  
If testing is performed ≤7 days prior to C1D1, repeat 
testing does not need to occur on C1D1. See 
Appendix 2. Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of crossover treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 19, 22, 
etc.). 
Hematology 
(<18 years of age) 
X 
X 
  
X 
X 
X 
  
If testing is performed ≤7 days prior to C1D1, repeat 
testing does not need to occur on C1D1. See 
Appendix 2. Hematology will be performed on 
adolescent patients every 4 weeks starting Cycle 2-n 
and throughout. 
Coagulation 
X 
  
  
  
  
X 
  
See Appendix 2. Perform at crossover screening, 
V801, and as clinically indicated. 
Chemistry panel  
(≥18 years of age) 
X 
X 
  
  
See 
Instructions 
X 
  
If testing is performed ≤7 days prior to C1D1, repeat 
testing does not need to occur on C1D1. See 
Appendix 2. Perform on Day 1 of Cycles 2-16. After 
completion of 1 year of crossover treatment, obtain 
every 12 weeks in adult patients (Cycles 16, 19, 22, 
etc.). 
Chemistry panel  
(<18 years of age) 
X 
X 
 
 
X 
X 
 
If testing is performed ≤7 days prior to C1D1, repeat 
testing does not need to occur on C1D1. See 
Appendix 2. Chemistry panel will be performed on 
adolescent patients every 4 weeks starting Cycle 2-n 
and throughout. 
Hepatic monitoring 
  
  
  
X 
See 
Instructions 
  
  
See Appendix 2. Should be performed on C1D15, 
C2D15, and C3D15, then as clinically indicated. 
Thyroid panel 
X 
  
  
  
See 
Instructions 
  
  
 See Appendix 2. Collect at crossover baseline and as 
clinically indicated. 
Approved on 11 Aug 2023 GMT

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Protocol J2G-MC-JZJB(i) 
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Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Pregnancy test 
X 
X 
See instructions 
X 
  
• Applies only to women of childbearing potential. 
• Note: during study treatment, perform C1D1 (within 
24 hours prior to dose) and thereafter as required per 
local regulations and/or institutional guidelines.  
• See Appendix 2. 
Calcitonin, CEA 
(≥18 years of age) 
X 
  
  
X 
See 
Instructions 
X 
  
Perform on Day 1 of Cycles 2-16. After completion of 
1 year of crossover treatment, obtain every 12 weeks 
in adult patients (Cycles 16, 19, 22, etc.). 
Calcitonin, CEA 
(<18 years of age) 
X 
 
 
X 
X 
X 
 
Calcitonin, CEA will be performed on adolescent 
patients every 4 weeks starting on Day 1 of Cycle 2-n 
and throughout. 
Serum Cortisol and 
ACTH 
X 
  
  
X 
See 
Instructions 
X 
  
Only for patients with Cushing’s disease related to 
their cancer. Collect at crossover screening, C1D15, 
then q 8 weeks (±7 days) for the first 24 weeks after 
C1D1 and q 12 weeks (±7 days) thereafter (i.e., at the 
same time as imaging assessments). 
Phone visit (collection 
of concomitant 
medications, AEs, labs, 
and patient dosing 
diary) 
  
  
  
  
See 
Instructions 
  
  
Applicable only for adult patients. 
Onsite clinical visit will occur every 28 days from C2 
to C16. After C16 the onsite visit will occur every 12 
weeks (i.e., C19, C22, C25, etc.). 
A phone follow-up visit will occur at every non-
clinical visit after C16 (i.e.: C17, C18, C20, C21, 
C23, C24, etc.) where details related to concomitant 
medications, AEs, chemistries, pregnancy test (if 
required), and patient dosing diary will be captured. 
Growth plate imaging 
  
See instructions 
  
  
Only for patients <18 years of age who have not 
reached full adult height. Knee MRI at baseline and 
every 6 months (±2 weeks). See Section 8.2. 
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Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Radiologic imaging 
(neck, chest, abdomen, 
pelvis and other known 
sites of disease)  
X 
See instructions  
X 
  
• Perform according to RECIST 1.1 criteria, by the 
same method used at baseline, q 8 weeks (±7 days) 
for the first 24 weeks after C1D1 (V301) and q 
12 weeks (±7 days) thereafter until radiographic 
disease progression or death, whichever occurs first. 
• Perform as scheduled, even if study treatment is 
omitted. 
• Brain/bone imaging required only for patients with 
known/ suspected disease at those sites. 
See Section 8.1. 
Submit scans 
X 
See instructions 
X 
  
All scans taken for tumor assessment should be 
submitted to Lilly’s designee in a timely manner. 
Survival assessment 
  
  
  
  
  
X 
See 
instructions 
Perform q 3 months (±7 days) for the first year off 
treatment, q 4 months (±14 days) for the second year 
off treatment, then approximately every 6 months 
thereafter. If an in-person visit is not possible, 
confirm survival by contacting the patient directly via 
phone. 
Collection of poststudy-
treatment anticancer 
therapy information 
  
  
  
  
  
X 
X 
  
Review patient dosing 
diary 
  
X 
X 
  
X 
  
  
Provide patient diary Day 1. Completed daily by 
patient. Review at each study visit and on phone visits 
for adult patients from Cycle 16 onward. 
Bristol Stool Form Scale 
and bowel movement 
frequency 
  
X 
 X 
  
Completed electronically daily by the patient, not site 
administered, except on C1D1 when this should be 
collected while patient is on site prior to first 
treatment dose. To be completed through 1 year of 
study treatment then discontinued. 
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Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Worst Pain NRS 
  
X 
X 
  
Completed electronically daily by the patient, not site-
administered, except on C1D1 when this should be 
collected while patient is on site prior to first 
treatment dose. To be completed through 1 year of 
study treatment then discontinued. 
Patient-reported AEs 
(PRO-CTCAE) 
  
X 
X 
X 
X 
X 
  
Completed electronically weekly by the patient, not 
site-administered, except on C1D1 when this should 
be collected while patient is on site prior to first 
treatment dose. 
Patient-reported side-
effect burden (FACT-
GP5) 
  
X 
X 
X 
X 
X 
  
Completed electronically weekly by the patient, not 
site-administered, except on C1D1 when this should 
be collected while patient is on site prior to first 
treatment dose. 
Physical function 
(EORTC IL19) 
  
X 
X 
X 
X 
X 
  
Completed electronically weekly by the patient, not 
site-administered, except on C1D1 when this should 
be collected while patient is on site prior to first 
treatment dose. 
HRQoL (EORTC QLQ-
C30) 
  
X 
  
  
See 
Instructions 
X 
X 
Site-administered at D1 of each cycle using the device 
provided, and during follow up at scheduled clinic 
visits until disease progression. Please collect at C1-n, 
D1 prior to study intervention. Starting with C16, 
obtain every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Health Status (EQ-5D-
5L) 
  
X 
  
  
See 
Instructions 
X 
X 
Site-administered at D1 of each cycle using the device 
provided and during follow up at scheduled clinic 
visits until disease progression. Please collect at C1-n, 
D1 prior to study intervention. Starting with C16, 
obtain every 12 weeks in adult patients (Cycles 16, 
19, 22, etc.). 
Blood sample for 
pharmacokinetics 
  
  
X  
  
X 
  
  
Samples to be drawn pre-dose (-2 to 0 hour) in Cycles 
1-6. See Section 8.5. 
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Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-term 
follow-upa 
Long term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Optional post-
progression tumor 
biopsy 
 
  
  
  
  
See 
Instructions 
  
Can be obtained any time prior to the start of next 
therapy 
Plasma for cfDNA  
  
X  
Pre-dose 
  
 X 
See 
Instructions 
X 
  
Perform on Day 1 of Cycles 2-16. After completion of 
1 year of treatment, obtain every 12 weeks (Cycles 
16, 19, 22, etc.). 
Obtain plasma for cfDNA as soon as its possible after 
progression or treatment discontinuation. 
Administer selpercatinib 
  
 See instructions 
  
  
See Section 6.1. 
Abbreviations: ACTH = adrenocorticotropic hormone; AE = adverse event; CEA = carcinoembryonic antigen; cfDNA = circulating free deoxyribonucleic acid; 
CTCAE = Common Terminology Criteria for Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group performance status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
Version 3.0; EORTC IL19 = European Organisation for Research and Treatment of Cancer Quality of Life questionnaire, item library 19; EQ-5D-5L = 5-level-
EuroQol; FACT-GP5 = Functional Assessment of Cancer Therapy-Side Effects; HRQoL = health-related quality of life; ICF = informed consent form; MRI = 
magnetic resonance imaging; NRS = numeric rating scale; PFS = progression-free survival; PRO-CTCAE = patient-reported outcome Common Terminology 
Criteria for Adverse Events; Q = every; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1; SAE = serious adverse event. 
a Short-term follow-up begins when the patient and investigator agree that the patient will discontinue study treatment.  
b Long-term follow-up begins when the patient completes the 30-day (±7 days) follow-up visit and ends with the patient’s death, upon loss to follow-up, or 
upon overall study completion, whichever is earlier. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or 
she has explicitly provided permission and consent. 
Note: Crossover baseline/screening assessments and laboratory values drawn within the indicated window of C301D1 may be used for both crossover 
screening/baseline and C301D1 assessments.  
 
 
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1.3.5. 
Continued Access Schedule of Activities for all patients  
 
Continued Access Schedule of Activities for all patients 
 
Study 
Treatment 
30-day 
Follow-Upa 
 
Visit 
501-5XX 
901 
 
Procedureb 
 
 
Instructions 
AE collection 
X 
X 
As part of AE collection, monitor vital signs and perform standard 
laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
testing) at a minimum frequency of every 12 weeks. All laboratory 
tests during the continued access period will be performed in local 
laboratories only. 
Administer selpercatinib (Arm A) 
X 
 
See Section 6.1. 
Administer cabozantinib (Arm B1) 
X 
 
See Section 6.1. 
Administer vandetanib (Arm B2) 
X 
 
See Section 6.1. 
Abbreviations: AE = adverse event. 
a Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent to allow for follow-up. If it is deemed to be in the best interest of the patient to start a new anticancer treatment 
prior to the scheduled end of the follow-up visits, the visit duration may be shortened. In this case, the follow-up assessments should be completed prior to the 
initiation of the new therapy. 
b Efficacy assessments will be done at the investigator’s discretion based on the standard of care.  
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2. 
Introduction  
2.1. 
Study 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 MTC that 
harbor RET alterations and/or depend on RET activation. This Phase 3 study is intended to 
confirm the benefit from selpercatinib seen in patients with advanced/metastatic MTC in the 
LIBRETTO-001 trial and to better understand this benefit in the context of other available 
treatments for advanced/metastatic MTC. 
2.2. 
Background  
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 2 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 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 approximately 6% of sporadic papillary 
thyroid cancers (PTCs) (Fusco et al. 1987, Cancer Genome Atlas Research 2014) and at even 
higher frequency in radiation-induced PTCs (Ito et al. 1994, Fugazzola et al. 1995, Bounacer et 
al. 1997, Nikiforov et al. 1997). In patients with PTC, RET gene fusions are associated with 
adverse prognostic features (Prasad et al. 2016, Su et al. 2016). In addition, activating RET gene 
mutations occur at high frequency in human MTC (>90% hereditary, approximately 50% to 60% 
sporadic) (Donis Keller et al. 1993, Mulligan et al. 1993, Carlson et al. 1994, Eng et al. 1994, 
Hofstra et al. 1994, Agrawal et al. 2013, Ji et al. 2015). 
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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 et al. 2008, Wang et al. 2012), a finding that is consistent with: 
1. possible ER-mediated increased RET expression in tumors from rare families with MTC 
(Smith et al. 2016);  
2. increased RET expression in some ER-positive breast cancers that have acquired 
resistance to anti estrogens (Plaza-Menacho et al. 2010, Spanheimer et al. 2014); and  
3. re-sensitization to anti-estrogen treatment through RET inhibition (Plaza-Menacho et al. 
2010, Morandi et al. 2013, Spanheimer et al. 2014).  
Finally, a recent study identified RET as a strong negative regulator of Major Histocompatibility 
Complex class I (MHC-I) expression in several human cancer cell lines of diverse histologies 
(Brea et al. 2016). This finding suggests a possible role for RET inhibition in upregulating the 
anti-cancer immune response. 
Medullary thyroid cancer accounts for 1% to 2% of thyroid cancers in the United States, with 
approximately 1000 new cases per year (SEER 2018). The majority of MTCs are sporadic, with 
approximately 20% to 25% hereditary due to a germline activating mutation in the RET gene. 
Most sporadic MTCs harbor activating RET mutations as well. National Comprehensive Cancer 
Network (NCCN) guidelines thus recommend germline RET testing for all patients diagnosed 
with MTC. The clinical course of MTC is highly heterogeneous, varying from indolent tumors 
that remain unchanged for many years to aggressive cancers associated with high mortality. 
Although surgery can be curative for the approximately 85% of patients who present with 
localized disease, approximately 50% develop recurrent disease, indicated by a rising level of 
serum tumor markers calcitonin (Ct) and/or carcinoembryonic antigen (CEA), which can predate 
the development of radiographically measurable metastases. Locally recurrent disease is treated 
with reoperation and/or external beam radiation therapy; however, these treatments are 
associated with significant morbidity and are often not curative. Metastatic MTC is incurable. 
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 et al. 2012, Elisei et al. 2013). However, 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 PK (i.e., 
significant drug accumulation and long half-life contributing to toxicity but not efficacy). As a 
result, most patients treated with these agents experience significant toxicities requiring dose 
interruptions, reductions (35% with vandetanib, 79% with cabozantinib), and/or treatment 
cessation (12% with vandetanib, 16% with cabozantinib). There are no approved systemic 
therapies with proven efficacy after failure of 1 prior MKI. 
Adolescent medullary thyroid cancer is rare, making up about 5% of adolescent thyroid cancer 
(Gerber et al 2015, Hogan et al 2009). Hereditary MTC syndromes are present in almost all 
children and young adults diagnosed with MTC and are known to be caused by missense 
mutation in the RET proto-oncogene. Treatment options are limited and identical to those of 
adults. Although the data are limited in adolescent patients with RET alterations, vandetanib and 
cabozantinib have emerged as the standard of care for adolescent patients with RET alterations. 
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In Phase 1 evaluations objective responses with an acceptable safety profile have been reported 
for both agents (Chuk et al, 2018 and Fox et al 2013).  
The combination of high frequency alterations in a less-prevalent cancer like MTC indicates that 
a significant number of patients with advanced, RET mutant MTC could benefit from potent and 
selective RET kinase inhibition. 
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 et al. 2012, Sherman 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% to 53% (depending on the specific 
MKI and patient population), but PFS of only 3.6 to 7.3 months, in several ongoing Phase 2 
studies (Drilon et al. 2016, Lee et al. 2016, Velcheti et al. 2016, Yoh et al. 2016). 
Patients with RET mutant MTC comprise a population with high unmet need. Chemotherapy is 
ineffective for MTC; 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. 
2.2.1. 
Selpercatinib  
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 non-small cell lung cancer (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 5 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. 
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.  
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Selpercatinib is currently being studied in an ongoing global Phase 1/2 first-in-human Study 
LOXO-RET-17001 in patients with advanced solid tumors including RET fusion-positive 
NSCLC, RET-mutant MTC, and other tumors with increased RET activity. As of a 
30 March 2019 data cut-off date, safety data was available from 422 patients with 240 mg BID 
as the highest dose administered. 
During dose escalation, 2 dose-limiting toxicities (DLTs) were reported, both at the 240 mg BID 
dose level: 1 DLT of Grade 3 tumor lysis syndrome and 1 DLT of Grade 3 thrombocytopenia. 
The remaining 4 patients treated at this dose level cleared the 28-day DLT window and 
continued on study. The dosage of 160 mg BID was selected as the recommended Phase 2 dose 
(RP2D) based on safety data (N = 82) and preliminary efficacy data in 64 evaluable patients 
treated at doses from 20 mg QD through 240 mg BID (Drilon et al. 2018). 
Across 9 dose levels ranging from 20 mg QD to 240 mg BID in these 422 patients, TEAEs 
occurring in ≥15% patients were: dry mouth (30.8% total; 25.1% related), diarrhea (27.7% total; 
12.8% related), hypertension (27.3% total; 16.8% related), fatigue (22.3% total; 14.5% related), 
constipation (21.8% total; 10.0% related), aspartate aminotransferase (AST) increased (21.6% 
total; 15.6% related), alanine aminotransferase (ALT) increased (20.4% total; 15.4% related), 
headache (18.7% total; 6.9% related), nausea (18.0% total; 6.6% related), edema peripheral 
(17.3% total; 9.5% related), and blood creatinine increased (14.9% total; 7.3% related). 
A total of 205 (48.6%) patients across all dose levels experienced ≥Grade 3 TEAEs. Treatment-
emergent adverse events of ≥Grade 3 that were considered to be related to study drug were 
reported in 95 (22.5%) patients across all dose levels. The most common Grade ≥3 TEAEs 
included hypertension (12.3%; 7.1% related), ALT increased (6.2%; 4.7% related), AST 
increased (4.7%; 3.1% related), hyponatremia (4.3%; 0.2% related), electrocardiogram (ECG) 
QT prolonged (2.8%; 2.1% related), dyspnea and lymphopenia (each 2.6%; 0% and 0.9% 
related, respectively), diarrhea and thrombocytopenia (each 2.1%; 0.7% and 1.7% related, 
respectively). All other Grade ≥3 TEAEs occurred in less than 2% of patients overall. Guidance 
on the management of hypersensitivity, liver test abnormalities, thrombocytopenia, and 
hypertension are provided in Section 6.6 and the IB. 
As presented at World Conference on Lung Cancer (WCLC) 2018 and American Thyroid 
Association (ATA) 2018, with a data cutoff of July 19, 2018, the overall response rate (ORR) 
was 68% (95% confidence interval [CI] 51% to 83%, n = 26/38) in NSCLC, 78% (95% CI 40% 
to 97%, n = 7/9) in papillary thyroid cancer, 50% (n = 1/2) in pancreatic adenocarcinoma, 59% 
(95% CI 39% to 77%, n = 17/29) in MTC and 0% (n = 0/4) in patients without a known 
activating RET alteration in their cancers among the first 82 patients enrolled in Study LOXO-
RET-17001. Updated interim results from the study are publicly available (Drilon et al. 2020; 
Wirth et al. 2020). 
Additional information on the nonclinical pharmacology, PKs, and toxicity of selpercatinib are 
provided in the selpercatinib Investigator’s Brochure (IB). 
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2.3. 
Benefit/Risk Assessment  
Adult and adolescent patients with RET-mutant MTC comprise a population with high unmet 
need. Chemotherapy is ineffective for MTC. Therefore, there is an urgent need to identify new 
targeted therapies that potently inhibit RET-mutant MTC, while sparing other kinase and 
nonkinase off-targets that contribute to significant toxicity. Study JZJB is being conducted to 
confirm the benefit from selpercatinib seen in patients with advanced/metastatic MTC in the 
LIBRETTO-001 trial and to better understand this benefit in the context of other available 
treatments for advanced/metastatic MTC. As selpercatinib is a highly potent and specific 
inhibitor of the RET RTK with minimal inhibition of other kinase and nonkinase targets, there 
may be a potential benefit to adult and adolescent patients with MTC that harbor RET alterations 
and/or depend on RET activation. 
The safety profile of selpercatinib is well-tolerated, clinically manageable, and distinct from 
available therapies, with the low rates of study drug discontinuation due to adverse events, 
particularly when compared to other TKIs such as cabozantinib or vandetanib. As outlined in the 
IB, the most common toxicities associated with selpercatinib are manageable and the majority of 
events were Grade 1 or 2. 
Although the study procedures in Study JZJB are generally consistent with standard of care, 
increased monitoring of vital signs (including blood pressure), hematology, hepatic panels, and 
ECGs occur in the initial cycles to monitor for potential toxicities of interest. Additionally, an 
Independent Data Monitoring Committee (IDMC) will assess unblinded safety data during the 
trial on a regular basis. The IDMC will evaluate all safety-related data provided for each meeting 
to determine whether a change in the conduct of the trial is warranted for the safety of adult and 
adolescent patients.  
Given its manageable toxicity profile and evidence of durable antitumor activity in patients with 
advanced RET-mutant MTC, selpercatinib may be of benefit in delaying treatment failure and 
disease progression and in improving survival in patients with progressive, advanced MTC who 
have not previously received cabozantinib or vandetanib. Therefore, the sponsor considers that 
the benefit/risk balance is positive and supports the proposed Phase 3 study, Study JZJB, 
exploring administration of selpercatinib in comparison to cabozantinib or vandetanib in adult 
and adolescent patients. 
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of selpercatinib (LY3527723) may be found in 
the IB. 
More detailed information about the known and expected benefits and risks of cabozantinib or 
vandetanib may be found in the following: Patient Information Leaflet, Package Insert, or 
Summary of Product Characteristics. 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
 
To compare PFS of patients with progressive, 
advanced, kinase inhibitor naïve, RET-mutant 
MTC treated with selpercatinib versus 
cabozantinib or vandetanib. 
 
PFS by BICR 
Secondary 
 
 
To compare other efficacy outcomes, based on 
RECIST 1.1 criteria, observed in patients with 
progressive, advanced, kinase inhibitor naïve, 
RET-mutant MTC treated with selpercatinib versus 
cabozantinib or vandetanib. 
 
TFFS by BICR 
 
TFFS by investigator 
 
PFS by investigator 
 
ORR by investigator and BICR 
 
DoR by investigator and BICR 
 
OS 
 
PFS2 by investigator 
 
To evaluate the safety and tolerability of 
selpercatinib compared to cabozantinib or 
vandetanib. 
 
Safety per CTCAE v5.0 (including but not limited 
to): incidence and severity of TEAEs, SAEs, 
deaths, and clinical laboratory abnormalities. 
 
To compare the tolerability of selpercatinib versus 
cabozantinib or vandetanib 
 
Proportion of time with high-side-effect bother 
based on FACT-GP5 
 
To assess/evaluate performance of local RET 
laboratory tests compared to a single, central test. 
 
RET mutation status 
 
To assess the PK of selpercatinib in patients 
receiving selpercatinib. 
 
Predose plasma concentrations at Day 8 of 
Cycle 1, and at Day 1 of Cycles 2 through 6. 
Exploratory 
 
 
To compare the calcitonin and CEA response rate 
of patients with progressive, advanced, kinase 
inhibitor naïve, RET-mutant MTC treated with 
selpercatinib versus cabozantinib or vandetanib. 
 
Calcitonin response rate 
 
CEA response rate 
 
 
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Objectives 
Endpoints 
Exploratory 
 
 
To compare the PROs of disease-related 
symptoms, symptomatic adverse events and 
overall side effect burden, physical function, and 
HRQoL of patients with progressive, advanced, 
kinase inhibitor naïve, RET-mutant MTC treated 
with selpercatinib versus cabozantinib or 
vandetanib.  
 
Bristol Stool Form Scale and bowel movement 
frequency 
 
Physical Function (EORTC IL19)  
 
HRQoL (EORTC QLQ-C30) 
 
Health Utilities (EQ-5D-5L)  
 
Worst Pain NRS 
 
Patient-reported AEs (PRO-CTCAE) 
 
To assess the efficacy and safety of selpercatinib in 
patients assigned to Arm B who crossover to 
selpercatinib after progression 
 
PFS after crossover 
 
Safety per CTCAE v5.0 after crossover (including 
but not limited to) 
o 
incidence and severity of TEAEs 
o 
SAEs 
o 
deaths, and  
o 
clinical laboratory abnormalities. 
 
To compare the TTNT of patients with 
progressive, advanced, kinase inhibitor naïve, 
RET-mutant MTC treated with selpercatinib versus 
cabozantinib or vandetanib. 
 
TTNT 
 
To compare RET mutation status in tumor and 
circulating free tumor DNA (cfDNA) samples. 
 
Biomarker analyses 
 
To assess the relationship between biomarkers and 
clinical outcomes 
 
Biomarkers assessed from blood or tissue samples, 
unless precluded by local regulations 
 
Clinical outcomes data 
Abbreviations: BICR = blinded independent review committee; CEA = carcinoembryonic antigen; CTCAE = 
Common Terminology Criteria for Adverse Events; DNA = deoxyribonucleic acid; DoR = duration of response; 
FACT-GP5 = Functional Assessment of Cancer Therapy-Side Effects; EORTC-QLQ30 = European Organisation 
for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0; EORTC IL19 = European 
Organisation for Research and Treatment of Cancer, item library 19; EQ-5D-5L = 5-level-EuroQol; HRQoL = 
health-related quality of life; MTC = medullary thyroid cancer; NRS = numeric rating scale; ORR = overall 
response rate; OS = overall survival; PFS = progression free survival; PFS2= progression-free survival 2; PK = 
pharmacokinetics; PRO = patient reported outcomes; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; TEAE = treatment-emergent adverse event; TFFS = treatment failure-free survival; 
TTNT = time to initiation of new anticancer therapy. 
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4. 
Study Design  
4.1. 
Overall Design  
This is a global, multicenter, randomized (2:1), open-label, Phase 3 study comparing 
selpercatinib (treatment Arm A) to physician’s choice of cabozantinib or vandetanib (treatment 
Arm B) in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant MTC. 
Patients will be randomized in a 2:1 ratio to selpercatinib or physician’s choice of cabozantinib 
or vandetanib. 
Patients will be stratified based on: 
 RET mutation: M918T vs. other 
 Intended treatment if randomized to control arm: cabozantinib vs. vandetanib. 
Approximately 250 patients will be initially enrolled to the study. A sample size re-estimation 
based on comparative data will be conducted at the interim efficacy analysis. The total number of 
patients could be increased from the initially planned 250 up to a maximum of approximately 
400 depending on the results of the interim efficacy analysis.  
Patients with histologically confirmed, unresectable, locally advanced or metastatic MTC who 
have not received previous treatment with a kinase inhibitor are eligible for enrollment in this 
study. Patients are required to have radiologic progressive disease per RECIST 1.1 at screening 
compared with an image obtained within the prior 14 months. Patients are also required to have a 
documented RET mutation (Appendix 6) in tumor or germline DNA identified through molecular 
assays. The RET 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. In regions or at sites where RET is not standard of care 
and/or an acceptable local test (as defined by Lilly) is not available, a pre-screening consent will 
be used to provide the patient with a sponsor-supported testing option to determine tumor RET 
status. In addition, the sponsor or it’s designee will review all imaging to confirm progressive 
disease per RECIST 1.1 in the prior 14 months and all molecular pathology reports to confirm 
the presence of a valid RET alteration prior to enrollment.  
After confirmation of eligibility, patients will be randomized in a 2:1 ratio to receive 
selpercatinib at a starting dose of 160 mg BID (treatment Arm A), cabozantinib at a starting dose 
of 140 mg QD (treatment Arm B1), or vandetanib at a starting dose of 300 mg QD (treatment 
Arm B2). Adolescent participants will have weight-based dosing as outlined in Section 6.1. The 
selection of cabozantinib or vandetanib for each eligible patient is required by the investigator 
prior to randomization and will be documented in the Interactive Web Response System (Study 
Schema Section 1.2). This selection is a stratification factor. Up to 2 dose reductions for 
treatment-related toxicity (see Section 6.6) will be allowed. Dosing will be in oral capsule/tablet 
form.  
Treatment will continue until disease progression, unacceptable toxicity, or death. The treatment 
decision will be made by investigator assessment (see Section 7). Patients with disease 
progression per investigator assessment may continue treatment while awaiting BICR 
confirmation of progression. 
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Patients discontinuing treatment for any reason other than death, lost to follow-up, or withdrawal 
of consent will enter the survival follow-up period and be followed every 3 months for the 
development of radiographic disease progression (if not already occurred) and initiation of 
subsequent anti-cancer therapies (as allowed by their next treatment regimen [see Section 8.1.1 
for additional details]) until death, lost to follow-up, or withdrawal of consent (whichever comes 
first). 
Patients who discontinue treatment and who have radiographic disease progression that is 
confirmed by BICR and were randomized to cabozantinib or vandetanib may be eligible for 
crossover to selpercatinib if they meet the eligibility criteria for crossover (see Section 5.2.1). 
The primary endpoint, progression free survival (PFS) by BICR, will act as a gatekeeper for the 
key secondary endpoints of treatment failure-free survival (TFFS) by BICR and comparative 
tolerability, i.e., these key secondary endpoints will be tested conditionally on achieving a 
statistical significance for the primary endpoint. TFFS will act as a gatekeeper for another key 
secondary endpoint of comparative tolerability. 
4.2. 
Scientific Rationale for Study Design  
Selpercatinib is a highly potent and specific small molecule inhibitor of the RET kinase, with 
minimal inhibition of other kinase and non-kinase targets.  
Given its manageable toxicity profile and evidence of durable antitumor activity in patients with 
advanced RET mutant MTC, selpercatinib may be of benefit in delaying treatment failure and 
disease progression and improving survival in patients with progressive, advanced MTC who 
have not previously received cabozantinib or vandetanib. PFS was selected as the primary 
endpoint. A key secondary endpoint of TFFS was selected as this endpoint takes into account 
potential improvement in both efficacy and toxicity profile relative to comparator agents. The 
key secondary endpoint of TFFS will be type I error-controlled. 
Another key secondary type I error-controlled endpoint is the comparative tolerability defined as 
a comparison of the proportion of time on treatment with a high side effect burden as assessed by 
the single item Functional Assessment of Cancer Therapy - Side Effects (FACT-GP5) 
instrument. This endpoint allows evaluation of the patient’s perception of tolerability, in 
particular the burden of side effects while on treatment, to understand if the improvement in 
tolerability further supports the clinical benefit of selpercatinib.  
With PFS as the primary endpoint, TFFS and comparative tolerability as key secondary 
endpoints, and additional steps taken to maximize the robustness of these endpoints, the sponsor 
believes the study design has the potential to generate a timely and clinically important result 
that elucidates both safety and efficacy differences of selpercatinib and cabozantinib or 
vandetanib. 
The choice of control arm agent, either cabozantinib or vandetanib, is allowed due to regional 
differences in the standard of care in this global trial. Options in the treatment for the control arm 
also minimizes the number of patients that have to be excluded due to medical conditions (which 
is critical in this trial in an extremely rare disease state) as the medical exclusions for 
cabozantinib and vandetanib do not overlap greatly.  
An open-label study design was selected since the AE profile of the comparator agents, 
cabozantinib and vandetanib, differ greatly and thus it would be impractical to blind the patients 
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or investigators to treatment arm. Additionally, as the dosing schedule and number of pills vary 
for each of the 3 treatment regimens, patients could conceivably be confused by the regimens 
and over or underdose their active agent. 
There is significant uncertainty as to the performance of both treatment arms: Arm A and Arm B. 
Specifically: 
 Monitoring of MKI-naïve patients participating in LIBRETTO-001 provides some insight 
into the potential outcomes of patients treated with selpercatinib on Arm A. Reliable 
prediction of median PFS for Arm A based on the LIBRETTO-001 data is challenging 
due to the immature data with a high censoring rate at the time of protocol amendment. 
 Arm B uses two drugs with very large differences in reported median PFS time. It is 
unclear if the differences are due to differences in the treated population, inherent 
differences in drug effects, or both. However, these factors all contribute to the 
uncertainty of estimating median PFS for Arm B. 
o In the EXAM study, the median PFS was 11 months for cabozantinib-treated 
patients with documented progression within 14 months of treatment enrollment 
(irrespective of the presence of a RET mutation) (Elisei et al. 2013, Schlumberger 
et al. 2017), and was longer (13.9 months) for the subset of patients with cancers 
harboring RET M918T mutations (the most common RET mutation) (Sherman et 
al. 2016).  
o In the ZETA study, the median PFS was 30.5 months for vandetanib-treated 
patients with newly diagnosed advanced MTC and patients with progression 
(Wells et al. 2012). A post hoc analysis provided median PFS results for two 
subgroups of patients that are similar to those enrolling in Study JZJB based on 
the presence of progressive disease within 12 months of enrollment. For those 
with both disease progression and symptoms in the prior 12 months, median PFS 
was 21.4 months and for those with disease progression only in the prior 12 
months, median PFS was not reached at a median follow-up of 95 months 
(Kreissel et al. 2020).  
An adaptive design with sample size re-estimation based on comparative data at the interim 
efficacy analysis is selected to mitigate the uncertainties of the true treatment effect by allowing 
the study to adjust to information that is currently not available.  
Patients randomized to the control arm will be allowed to crossover to receive the investigational 
product at the time of BICR confirmed radiographic progression. This will allow patients access 
to a highly specific RET-inhibitor after progression on an MKI. It will also add to the amount of 
safety and efficacy data for selpercatinib in the second line setting in this difficult to enroll 
population (due to rarity of disease). 
4.3. 
Justification for Dose  
4.3.1. 
Selpercatinib  
Based on preclinical pharmacology experiments with human cancer cells in vitro and in murine 
xenograft models, meaningful inhibition of RET in tumors is expected to be achievable with oral 
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dose regimens at total daily doses ≥40 mg/day. The dosage of 160 mg BID was selected as the 
RP2D based on safety data (N=82) and preliminary efficacy data in 64 evaluable patients treated 
at doses from 20 mg QD through 240 mg BID (Drillson et al 2018, NCT03157128). Additional 
information is provided in Section 2.2.1 and in the selpercatinib IB. 
4.3.2. 
Cabozantinib  
The cabozantinib starting dose of 140 mg daily is the globally approved dose for adult patients 
with MTC, based on the results of the Phase 3 EXAM trial in patients with progressive MTC 
(Elisei et al 2013). Despite the toxicity observed at this dose, there is no evidence that a lower 
dose is safer or equally effective. An ongoing study of 2 different doses of cabozantinib (60 mg 
daily and 140 mg daily) is examining whether a lower dose is has equivalent PFS and fewer AEs 
in MTC patients (NCT01896479). Available data for a lower dose in patients with renal cell 
carcinoma (RCC) from the CABOSUN trial and hepatocellular carcinoma in the CELESTIAL 
trial indicates that the percentage of patients experiencing AEs (any grade or Grade ≥3) and dose 
reductions or discontinuations for AEs are similar between RCC patients who received 60 mg 
daily and MTC patients who received 140 mg daily (Choueiri et al 2018; Abou-Alfa et al 2018). 
Existing guidelines for MTC patients indicate that whether a lower starting dose is more 
reasonable remains an unresolved question (Wells et al 2015). For these reasons, the starting 
dose of cabozantinib in the current study is 140 mg daily. Cabozantinib was assessed in a Phase 
1 study in a Children’s Oncology Group study in pediatric/adolescent participants with recurrent 
or refractory solid tumors, including CNS tumors. The dose recommended for further evaluation 
(40 mg/m2/d) will be used in Study JZJB (Chuk et al 2018). 
4.3.3. 
Vandetanib  
The vandetanib starting dose of 300 mg daily is the globally approved dose for patients with 
MTC, based on the results of the Phase 3 ZETA trial in patients with unresectable locally 
advanced or metastatic disease (Wells et al. 2012). Despite the toxicity observed at this dose, 
there is currently no evidence that a lower dose is safer or equally effective. Existing guidelines 
for MTC patients indicate that whether a lower starting dose is more reasonable remains an 
unresolved question (Wells et al 2015). In a Phase I/II study in pediatric/adolescent participants 
the vandetanib Css in children receiving 100 mg/m2/d was similar to the Css in adults receiving 
the recommended adult dose of 300 mg (Fox et al. 2013). As a result, 100 mg/m2/d was 
recommended as the dose for further study in adolescent patients with locally advanced or 
metastatic MTC. In Study JZJB doses will be administered as outlined in Section 6.1. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoAs for the last participant in the trial globally. 
The total study duration will be capped at 6 years from the first patient visit. A duration of 6 
years is considered to be a relevant timeframe considering that the treatment landscape may 
change substantially and continuation on study follow-up may present an undue burden on 
participants. 
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5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Are of an acceptable age to provide informed consent according to local regulations and 
are at least 18 years of age (patients as young as 12 years of age will be allowed if 
permitted by local regulatory authorities and institutional review boards). 
a. All patients of 12 years of age and older, after giving assent / legally designated 
representative/ participant written consent. 
Type of Participant and Disease Characteristics 
2. Histologically or cytologically confirmed, unresectable, locally advanced and/or 
metastatic MTC and no prior history of treatment with kinase inhibitors for 
advanced/metastatic disease.  
a. Prior systemic (agents other than kinase inhibitors) or radiation therapy occurring 
>14 months before enrollment is allowed. Prior systemic therapy or radiation 
therapy within the 14 months before enrollment may be allowed with discussion 
and approval by the Lilly medical team.  
b. Patients with prior kinase inhibitor therapy of less than 7 days and discontinued 
for reasons other than intolerance or progression may be allowed with approval by 
the Lilly medical team. 
c. Patients with mixed histology (e.g., incidental papillary thyroid cancer identified 
at the time of resection) are eligible if MTC is the dominant histology. 
3. Radiographic progressive disease per RECIST 1.1 (Eisenhauer et al. 2009) at screening 
compared with a previous image taken within the prior 14 months as assessed by the 
BICR. Patients with measurable or non-measurable but evaluable disease are eligible; 
however, patients with non-measurable disease may not have disease limited to bone sites 
only.  
4. A RET gene alteration identified in a tumor, germline DNA or blood sample ( for 
example, circulating free DNA [cfDNA]), as defined in Appendix 6. The RET alteration 
result should be generated from a laboratory with CLIA, ISO/IEC, CAP, or other similar 
certification. Lilly should be contacted to discuss test results from labs where such 
certification is not clearly demonstrated to determine eligibility; if certification is not 
required in the patient’s country, the Sponsor may allow enrollment using a result from a 
non-certified lab if sufficient evidence can be provided as to the accuracy of the result. A 
positive germline test for a RET mutation is acceptable given the test was determined by 
internal institutional quality standards and performed for clinical evaluation. In all cases, 
a redacted Molecular Pathology Report or other report(s) describing RET (and any co-
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occurring findings, if applicable) alteration analysis should be submitted to Lilly or 
designee during/prior to eligibility.  
a. Mandatory provision of an unstained, archived tumor tissue sample in a quantity 
sufficient to allow for retrospective central analysis of RET mutation status (for 
confirmation). Please refer to Section 8.8.1 for details. 
 
5. Eastern Cooperative Oncology Group (ECOG) performance status score (Oken et al. 
1982) of 0 to 2. 
6. Ability to swallow capsules and comply with treatment, laboratory monitoring, and 
required clinic visits for the duration of study participation. 
7. Patients must have discontinued from previous treatments as shown below and fully 
recovered. Consult with the Lilly medical team for the appropriate length of time prior to 
the first dose of study treatment on additional therapies not mentioned. 
Previous Treatment 
Length of Time Prior to First Treatment Dose  
Radiotherapy (full field or if ≥25% bone marrow 
irradiated 
within ≥28 days 
Limited field radiotherapy (i.e., <25% bone marrow 
affected) 
14 days 
Major surgery, excluding biopsy and placement of 
vascular access 
28 days if patient is intended to receive 
cabozantinib vs selpercatinib 
≥14 days if patient is intended to receive vandetanib 
vs selpercatinib 
 
8. Have adequate organ function, as defined below:  
System 
Laboratory Value 
Hematologic 
ANCa 
1.5×109/L 
Platelets 
100×109/L 
Hemoglobin 
9 g/dL 
Note: transfusions to increase a patient’s hemoglobin level or initiation of erythropoietin or G-CSF therapy to 
meet enrollment criteria are not allowed in the 7 days preceding the first dose of study drug. If a patient receives 
transfusions, erythropoietin, or G-CSF therapy ≥7 days prior to the first dose, the hematologic criteria listed 
above must be met following the 7 day window prior to the first dose of study therapy. 
Hepatic 
Total bilirubin 
≤1.5× ULN OR 
<3.0 x ULN for patients who have Gilbert’s syndrome 
ALT and AST 
≤2.5 × the upper limit of normal (ULN) OR 
≤5× ULN if the liver has tumor involvement 
Renal 
Creatinine clearance 
≥30 mL/min 
a Patients with a demonstrated history of benign ethnic neutropenia (Hsieh 2010) may be enrolled with lower ANC 
with approval from the Lilly medical team. 
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9. Patients must have serum potassium, calcium, and magnesium levels above the lower 
limit of normal (may be receiving supplements) and not clinically significantly above the 
upper limit of normal. 
Sex 
10. Men with partners of childbearing potential or women of childbearing potential must 
agree to use a highly effective contraceptive method (for example, intrauterine device 
[IUD], birth control pill, or barrier method) during treatment with study drug and for 
4 months following the last dose of study drug. See Appendix 3. 
Note: Unless not allowed by local regulations, women of childbearing potential who are 
abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must agree to either 
remain abstinent or stay in a same-sex relationship without sexual relationships with 
males unless they agree to use contraceptive method known to be highly effective. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
11. Women of childbearing potential must  
 have a negative pregnancy test (serum or urine, consistent with local regulations) 
documented within 24 hours prior to treatment with study drug. 
 not be breast-feeding during treatment and for at least 4 months after the last dose 
of study drug.  
Informed Consent 
12. Capable of giving signed informed assent/consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in this protocol 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
13. An additional validated oncogenic driver in MTC if known that could cause resistance to 
selpercatinib treatment. Examples include, but are not limited to RAS or BRAF gene 
mutations and NTRK gene fusions. 
14. Symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated spinal cord 
compression. Patients are eligible if neurologically stable and without increase in steroid 
dose for 14 days prior to the first dose of study treatment and no CNS surgery or 
radiation has been performed for 28 days, 14 days if stereotactic radiosurgery (SRS). 
15. Clinically significant active cardiovascular disease or history of myocardial infarction 
within 6 months prior to planned start of study treatment, history of Torsades de pointes, 
or prolongation of the QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) >470 msec on more than one ECG during Screening. Correction of suspected 
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drug-induced QTcF prolongation may be attempted at the investigator’s discretion if 
clinically safe to do so. Patients who are intended to receive vandetanib if randomized to 
the control arm are ineligible if QTcF is >450 msec.  
a. Note: Patients with implanted pacemakers may enter study without 
meeting QTc criteria due to nonevaluable measurement if QT changes are 
considered monitorable 
b. Note: Patients with bundle branch block may be considered for study 
entry if QTc is appropriate by a formula other than Fridericia’s and if QT 
changes are considered monitorable. 
16. Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing 
intercurrent illness, such as hypertension or diabetes, despite optimal treatment, a clinical 
diagnosis or symptoms of interstitial lung disease (ILD), or other serious medical 
conditions which in the medical judgment of the investigator would prevent the patient 
from safely participating (screening for chronic conditions is not required). 
17. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal absorption of the study drug. 
18. Uncontrolled symptomatic hyperthyroidism or hypothyroidism 
19. Uncontrolled symptomatic hypercalcemia or hypocalcemia 
20. Active hemorrhage or at significant risk for hemorrhage. 
21. Other malignancy unless nonmelanoma skin cancer, carcinoma in situ or malignancy 
diagnosed ≥2 years previously and not currently active. Patients receiving adjuvant 
hormone therapy for breast or prostate cancer with no evidence of disease are eligible. 
Participants with MEN2-associated pheochromocytoma are eligible if the 
pheochromocytoma is, in the opinion of the investigator, documented to be stable or has 
been resected (and patient has fully recovered from surgery).  
Prior/Concomitant Therapy 
22. Prior systemic treatment with kinase inhibitor(s) (Refer to Section 5.1, Inclusion 
Criterion 2b). 
23. Are taking a concomitant medication that is known to cause QTc prolongation (for 
examples, see Appendix 7). 
Prior/Concurrent Clinical Study Experience 
24. Have participated, within the last 30 days (4 months for studies conducted in Japan; 3 
months for studies conducted in the UK), in a clinical study involving an investigational 
product. If the previous investigational product has a long half-life, 5 half-lives or 30 
days (4 months for studies conducted in Japan; 3 months for studies conducted in the 
UK) (whichever is longer) should have passed. Exceptions will be considered on a case 
by case basis by the Lilly medical team. 
Other Exclusions 
25. Life expectancy ≤3 months 
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26. Have a known hypersensitivity to any of the excipients of selpercatinib, cabozantinib, or 
vandetanib. 
5.2.1. 
Eligibility Criteria for Crossover Treatment  
A crossover to selpercatinib will be allowed only at radiographic disease progression confirmed 
by BICR. In order for participants to crossover to selpercatinib, they must meet the following 
criteria.  
Eligibility criteria for crossover to selpercatinib: 
a) Radiographic PD by RECIST 1.1 as assessed by BICR 
b) Willing and able to provide written informed consent to crossover 
c) Adequate hematologic, hepatic, and renal function as defined above for initial eligibility 
d) All toxicities attributed to cabozantinib or vandetanib have resolved or decreased to 
Grade 1 
e) Remains ECOG 0-2 
f) Has discontinued cabozantinib or vandetanib and has not received any other systemic 
therapy since 
Patients are eligible to be considered for crossover if:  
 they meet the criteria above and  
 can initiate treatment with selpercatinib after a minimum of 15 days and within 42 days 
the time of BICR confirmed progression. 
No exceptions will be made for eligibility criterion a. However, other exceptions may be made 
on a case-by-case basis following approval from the sponsor.  
Patients that may crossover should not: 
 
complete V801 at the end of their initial treatment, but should enter V201 and/or V300 
prior to starting selpercatinib (Section 1.3, SoA). Visit 201 will allow for the collection of 
Arm B post-treatment safety information for patients that do not cross over to 
selpercatinib within 30 (+/-7 days) of the last dose of study treatment. 
 
initiate selpercatinib any earlier than 21 days after their last dose of study treatment. 
5.3. 
Lifestyle Considerations  
There are no specific lifestyle restrictions for Study JZJB, other than as noted in Inclusion 
Criteria 10. 
5.4. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number. The interval 
between rescreening should be ≥2 weeks. Each time rescreening is performed, the individual 
must sign a new ICF and will be assigned a new identification number. Repeating of laboratory 
tests during the screening period or repeating screening tests to comply with the protocol 
designated screening period does not constitute rescreening. 
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6. 
Study Intervention  
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. 
6.1. 
Study Intervention(s) Administered  
A cycle is defined as 28 days in length with treatment on days 1 through 28 of each cycle, 
regardless of treatment arm assignment. A delay of the start of a cycle due to holiday, weekend, 
bad weather, or other unforeseen circumstances will be permitted for a maximum of 7 days or 
situations noted in Section 10.1.9 and not counted as a protocol deviation. Cycles should not be 
delayed for AEs. If needed for AEs, doses should be omitted within a cycle. Treatment should be 
initiated within 7 days of randomization.  
Regardless of treatment arm, drug will initially be dispensed as a 28-day supply. For adult 
patients remaining on treatment after Cycle 15, drug will be dispensed as an 84-day supply, 
starting at Cycle 16. 
Selpercatinib doses will be administered at approximately the same times on each day and BID 
dosing will be separated by approximately 12 hours (a minimum of 6 hours between consecutive 
doses). Selpercatinib can be taken with or without food. Cabozantinib or vandetanib will be 
administered at approximately the same time on each day. Cabozantinib should be taken without 
food; patients should not eat for at least 2 hours before and at least 1 hour after each dose. 
Vandetanib can be taken with or without food. 
All patients 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 for selpercatinib) should be noted in the diary. Doses of selpercatinib 
that are late by more than 6 hours and doses of cabozantinib or vandetanib that are late by more 
than 12 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. 
6.1.1. Adult Dosing  
 
Arm A 
Arm B1 
Arm B2 
Intervention 
Selpercatinib 
Cabozantinib 
Vandetanib 
Adult Dose 
160 mg BID 
140 mg QD 
300 mg QDa 
Authorized as defined by EU Clinical 
Trial Regulation 
Authorized and used 
according to EU 
authorization 
 
Authorized and not 
used according to EU 
authorization 
 
Authorized and used 
according to EU 
authorization 
 
Abbreviations: BID = twice daily; QD = once daily. 
a Starting dose of vandetanib should be 200 mg in patients with moderate renal impairment (creatinine clearance 
results between 30 and 50 mL/min). In case vandetanib 100-mg tablets are not available, see Section 6.6. 
 
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6.1.2. Adolescent Dosing  
 
Arm A 
Arm B1 
Arm B2 
Intervention 
Selpercatinib 
Cabozantinib 
Vandetanib 
Adolescent Dosea 
92 mg/m2 BID (not to 
exceed 160 mg BID) 
40 mg/m2 
See dosing guide 
Approximate adult equivalent dose 
160 mg BID 
72 mg QD 
Authorized as defined by EU Clinical 
Trial Regulation 
Authorized and used 
according to EU 
authorization 
 
Authorized and not 
used according to EU 
authorization 
Authorized and used 
according to EU 
authorization 
 
Abbreviations: BID = twice daily; QD = once daily. 
a Please refer to nomograms below for the exact dosing.  
Adolescent patients will have BSA-adjusted dosing as outlined in the tables below. BSA should 
be determined according to the Mosteller Formula (Mosteller 1987). 
Selpercatinib 
Selpercatinib dosing will be rounded according to guidelines in the table below. The maximum 
starting dose will be no higher than 160 mg BID.  
Selpercatinib Capsule Dose Rounding (all doses BID) 
BSA (m2) 
Rounded Dose (mg) 
<0.76 
40 mg 
0.76 – <1.2 
80 mg 
1.2 – <1.6 
120 mg 
≥1.6 
160 mg 
 Abbreviations: BSA = body surface area. 
Vandetanib 
Vandetanib Dosing Nomogram for Adolescent Participants 
BSA (m2) 
Start dose (mg)a 
0.7 - <0.9 
100 QOD 
0.9 - <1.2 
100 QD 
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BSA (m2) 
Start dose (mg)a 
1.2 - <1.6 
7 day schedule: 
100-200-100-200-100-200-100 
≥1.6 
200 QD 
Abbreviations: BSA = body surface area; QD = once daily; QOD = once every other day. 
a A reduced starting dose of vandetanib should be used in adolescent patients with moderate renal impairment as per 
the dose reduction table in Section 6.6. 
Cabozantinib 
Cabozantinib Dosing Nomogram for Adolescent Participants 
BSA (m2) 
Weekly Dose/ Schedule for Initial Dosing 
0.35 – 0.39 
100 mg = 20 mg M, W, Th, Sat, Sun 
0.40 – 0.45 
120 mg =20 mg M, T, W, F, Sat, Sun 
0.46 – 0.55 
140 mg =20 mg QD 
0.56 – 0.64 
160 mg = 40 mg M, W, F, Sun 
0.65 – 0.78 
200 mg = 40 mg M, W, Th, Sat, Sun 
0.79 – 0.90 
240 mg = 40 mg M, T, W, F, Sat, Sun 
0.91 – 1.09 
280 mg = 40 mg QD 
1.10 – 1.17 
300 mg = 60 mg M, W, Th, Sat, Sun 
1.18 – 1.36 
360 mg = 60 mg M, T, W, F, Sat, Sun 
1.37 – 1.65 
420 mg = 60 mg QD 
1.66 – 1.85 
480 mg = 80 mg M, T, W, F, Sat, Sun 
1.86 – 2.07 
560 mg = 80 mg QD 
≥ 2.08 
600 mg = 100 mg M, T, W, F, Sat, Sun 
Abbreviations: BSA = body surface area; QD = once daily. 
 
6.1.3. Exceptional Switch from Vandetanib to Cabozantinib  
Participants assigned to the control arm should not switch between control arm treatments. In 
exceptional situations where vandetanib is not available:  
 participants originally assigned to vandetanib may be allowed to switch to cabozantinib 
during the study.  
 physician’s choice in the control arm may be limited to cabozantinib only.  
If vandetanib is not available and participant fulfills the eligibility criteria listed in Section 
6.1.3.1, the participant may be allowed to switch to cabozantinib.  
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If participant is on reduced dose level of vandetanib due to toxicities, then the corresponding 
dose level should be considered for starting dose of cabozantinib at switch.  
6.1.3.1. 
Eligibility Criteria for Switching from Vandetanib to Cabozantinib  
A switch from vandetanib to cabozantinib will be allowed if study intervention supply is 
unavailable and after approval by study sponsor.  
Conduct safety assessments more frequently during the first 3 cycles of switch treatment. See 
SoA table, Section 1.3.3. 
Eligibility criteria for switching from vandetanib to cabozantinib:  
a) Willing and able to provide written informed consent to switch. 
b) No ongoing AEs impacting hematologic, hepatic, and renal function > G2. 
c) Participant has not previously discontinued due to vandetanib-related AE. 
d) All toxicities attributed to vandetanib have resolved or decreased to Grade 1.  
e) Has discontinued vandetanib for a minimum of 15 days and up to 42 days before 
treatment with cabozantinib is initiated.  
f) Participant has no disease progression by investigator assessment.  
Exceptions to criteria b may be made on a case-by-case basis, following approval from the 
sponsor. 
6.1.4. 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. 
Preparation/Handling/Storage/Accountability  
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, as appropriate, and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized staff may administer study intervention and/or supply study intervention to 
participant. All study intervention. must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
5. Investigators should consult the study drug information provided in the Pharmacy 
Manual or label for the specific administration information (including warnings, 
precautions, contraindications, adverse reactions, and dose modifications). 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is an open-label study. However, to preserve the integrity of the trial, Lilly will not have 
unblinded access to aggregate data from the clinical database. An Independent Data Monitoring 
Committee (IDMC) will evaluate aggregate interim efficacy results to provide recommendations 
of adaptation at the interim analysis and monitor aggregate safety data during the course of the 
trial on a regular basis. An external Statistical Analysis Center will conduct interim efficacy and 
safety analyses and report the results to the IDMC. This practice will ensure that Lilly personnel 
involved in the day-to-day management and conduct of the trial do not have access to unblinded 
comparative results, even inadvertently. Additional details are specified in Section 9.5 and 
separate IDMC and Adaptive Design Charters. 
To maintain the trial integrity after the sample size re-estimation, other measures will be taken to 
avoid disclosure of the interim comparative results: 
 Any members of the study team that have access to the adaptation decision will be 
prespecified and documented. Other Lilly study team members will be shielded as much 
as possible from the knowledge of adaptive changes. 
 The adaptation algorithm and details on the sample size re-estimation will be preserved in 
an Adaptive Design Charter and stored confidentially in a restricted access area. Only the 
IDMC, SAC and the Lilly statisticians involved in the adaptive design will have access to 
the Adaptive Design Charter. No other study team members will have access. 
 Investigators and trial participants will not be provided with any details regarding an 
adaptive decision. For example, if the study will continue (sample size may or may not 
increase) after the interim efficacy analysis, they will be informed that the targeted 
patient/event number hasn’t been reached rather than being notified of the specific 
targeted final sample size/number of events. Lilly personnel who have direct interaction 
with study sites will be appropriately trained on this expectation. 
More detailed actions to maintain the trial integrity will be described in the Statistical Analysis 
Plan. 
To minimize investigator bias on the efficacy assessment, the primary endpoint of PFS will be 
determined based on the assessment of a BICR (see Section 8.1.2). Patients on Arm B will be 
allowed to cross over to selpercatinib only after progression has been confirmed by the BICR. 
Details of the BICR will be described in a separate BICR Charter.  
6.4. 
Study Intervention Compliance  
Participant compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by direct questioning, counting returned tablets/capsules, and reviewing patient diaries. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.  
A participant will be considered noncompliant if he or she takes <75% of the planned doses for 
assigned study drug in a cycle. A participant will also be considered noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken ≥125% of the planned doses 
of study drug in a cycle.  
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6.5. 
Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 Reason for use 
 Dates of administration including start and end dates. 
Patients receiving selpercatinib should avoid concomitant use of CYP2C8-sensitive substrates. If 
co-administration of a CYP2C8-sensitive substrate cannot be avoided, monitor patients for 
increased adverse reactions of these drugs. 
Caution should be used when co-administration of a P-gp substrate (for example, fexofenadine, 
loperamide, and digoxin), MATE1 substrate (for example, metformin), or BCRP substrate (for 
example, sulfasalazine) cannot be avoided in patients receiving selpercatinib. Consider increased 
monitoring as appropriate. The concurrent use of drugs known to prolong QTc is prohibited 
(Appendix 7). Drugs with a possible or conditional risk should be avoided if possible. Patients 
eligible to receive vandetanib should refrain from sun exposure during and up to 4 months after 
discontinuation of treatment due to possible photosensitivity. 
The Lilly medical team should be contacted if there are any questions regarding concomitant or 
prior therapy. Except as indicated in Section 6.1, patients are not allowed to receive concomitant 
systemic anti-cancer agents (including immunotherapy agents), hematopoietic growth factors for 
prophylaxis in C1, drugs with immunosuppressant properties (other than as listed in Section 
6.5.4), or any other investigational agents. No new, alternative systemic anticancer therapy is 
allowed prior to documentation of PD in accordance with protocol specified disease response 
criteria. No surgical resection of tumor or radiation therapy is permitted except as described in 
Section 6.5.4.  
6.5.1. 
CYP3A4 Inducers or Inhibitors  
For patients receiving selpercatinib: The concomitant use of the strong CYP3A4 inhibitors or 
inducers should be avoided. See Appendix 7. 
If, during the study, patients require initiation of treatment with strong inhibitors or inducers of 
CYP3A4 for clinical reasons, investigators should consider increased monitoring for the 
development of new AEs. 
Co-administration of selpercatinib with sensitive CYP3A4 substrates may increase their plasma 
concentrations, which may increase the incidence or severity of adverse reactions for sensitive 
substrates with narrow therapeutic windows.  
For patients receiving cabozantinib: The concomitant use of strong inhibitors or inducers of 
CYP3A4 should be avoided. If strong CYP3A4 inhibitors cannot be avoided, the cabozantinib 
dose should be reduced by 20 mg daily; if the CYP3A4 inhibitor is to be discontinued, the 
regular dose cabozantinib should be resumed 2 to 3 days after discontinuation of the strong 
inhibitor. If strong CYP3A4 inducers cannot be avoided, the cabozantinib dose should be 
increased by 20 mg daily; if the CYP3A4 inducer is to be discontinued, resume the regular dose 
of cabozantinib 2-3 days after discontinuation of the strong inducer. See Appendix 7. 
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For patients receiving vandetanib: The concomitant use of strong inducers of CYP3A4 should 
be avoided. See Appendix 7. 
6.5.2. 
Agents That Alter Gastric Acidity (PPIs and H2 blockers)  
Since selpercatinib absorption from the gastrointestinal tract may be impacted by stomach 
acidity, concomitant use of pH-altering agents require additional instructions for patients 
randomly assigned to treatment arm A.  
Avoid concomitant use of a PPI, H2 receptor antagonist, or a locally-acting antacid 
with selpercatinib. If concomitant use cannot be avoided, 
 
Take selpercatinib with food (at least 400 calories) when co-administered with a PPI. 
 
Take selpercatinib 2 hours before or 10 hours after administration of an H2 receptor 
antagonist. 
 
Take selpercatinib 2 hours before or 2 hours after administration of a locally-acting 
antacid. 
There are no restrictions on PPI or H2 blocker use for patients randomized to the control arm and 
who are receiving cabozantinib or vandetanib. 
6.5.3. 
P-gp Substrates or MRP2 Inhibitors  
Cabozantinib and Vandetanib may have the potential to increase plasma concentrations of co‐
administered substrates of P‐gp (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, 
digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, 
tolvaptan). Therefore, appropriate clinical (e.g., ECG) and/or laboratory monitoring is 
recommended for patients receiving concomitant digoxin and such patients may require a lower 
dose of digoxin. Appropriate clinical monitoring is recommended for patients receiving other P-
gp substrates such as dabigatran when given in combination with vandetanib or cabozantinib.  
Similarly, the administration of MRP2 inhibitors (e.g., cyclosporine, efavirenz, emtricitabine) 
may result in increases in cabozantinib plasma concentrations. The use of MRP2 inhibitors 
should be approached with caution. 
6.5.4. 
Palliative Medicine and Supportive Care  
Standard supportive medications may be used in accordance with institutional guidelines and 
Investigator discretion. The use of granulocyte-colony stimulating factor (G-CSF) is permitted at 
the discretion of the investigator based on American Society of Clinical Oncology (ASCO) 
(Smith et al. 2015) and European Society for Medical Oncology (Crawford et al. 2009) 
guidelines, though may not be used prophylactically in Cycle 1. 
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008). Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013). 
Continuation of standard of care medications, including anti-emetic, analgesic, and antidiarrheal 
medications; electrolyte repletion (e.g., calcium and magnesium) to correct low electrolyte 
levels; thyroid replacement therapy for hypothyroidism; corticosteroid replacement for 
adrenalectomy; bisphosphonates, denosumab, and other medications for the treatment of 
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osteoporosis, prevention of skeletal-related events from bone metastases, and/or 
hypoparathyroidism; or adjuvant hormonal therapy for patients with a history of 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 Appendix 7).  
Local treatment while receiving study treatment (e.g., palliative radiation therapy or surgery for 
bone metastases) may be permitted with sponsor approval (which may include confirmation of 
no PD by BICR); discussion with the Lilly medical team and documentation of approval is 
required. The disease site under consideration for palliative radiation or surgery must not be a 
target lesion for response assessment and must not be considered to be clinically or 
radiographically progressing. Lilly recommends holding selpercatinib for approximately 5 half-
lives (approximately 7 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 Lilly, who 
may permit holding selpercatinib for a shorter period of time. 
Any herbal drugs, dietary supplements, etc. known to have anti-tumor activity are not permitted. 
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate discontinuation from the study.  
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications throughout the patient’s participation in the trial must be captured on the case report 
form (CRF). 
6.6. 
Dose Modification  
Intolerable AEs that lead to treatment discontinuation (except alopecia) will meet criteria to be 
included in the TFFS endpoint. Intolerable AEs are defined as any study drug-related AE that 
meets protocol guidance for treatment discontinuation. 
 Permanently discontinue treatment for any of:  
o Cabozantinib: development of visceral perforation or fistula formation, severe 
hemorrhage, serious arterial thromboembolic event (e.g., myocardial infarction, 
cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, 
persistent uncontrolled hypertension despite optimal medical management, 
osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome 
o Vandetanib: development of prolonged QT interval not improved with electrolyte 
correction and/or dose reduction, severe skin reactions, ILD, ischemic 
cerebrovascular events, hemorrhage, heart failure, persistent uncontrolled 
hypertension despite optimal medical management, or reversible posterior 
leukoencephalopathy syndrome 
o Selpercatinib: malignant hypertension, hypertensive crisis, persistent uncontrolled 
hypertension despite optimal medical management, or severe/life-threatening 
hemorrhage. Patients with clinical benefit who experience recurrent hypersensitivity 
reaction or recurrent AST or ALT increase despite dose reductions should be 
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discussed with the Lilly medical team and may be allowed to continue treatment with 
more than 2 dose reductions if continuation is considered to be safe and in their best 
interest 
Dose reductions should be made according to the following parameters using the dose reduction 
table below. Interrupt dosing for CTCAE v5.0 Grade 3 or greater AEs or Grade 2 AEs not 
resolved within 48 hours with appropriate supportive care (e.g., nausea not improved with 
antiemetics) and considered intolerable by the patient or the investigator. 
 For selpercatinib related hypersensitivity, liver function test abnormalities, 
thrombocytopenia, and hypertension, see dose adjustments below in Sections 6.6.1, 6.6.2, 
6.6.3, and 6.6.4, respectively. 
 Regardless of treatment arm, study treatment may continue for hypertension that is 
considered Grade 3 on the basis of requiring ≥2 anti-hypertensives or more intensive anti-
hypertensive therapy than baseline once blood pressure is stabilized. 
 Dose modifications for ECG changes are described in Section 8.2.1. If a patient receiving 
selpercatinib or cabozantinib experiences QTCF >500 msec despite 2 dose reductions and 
if the investigator deems it in the best interest of the patient, the patient may continue 
treatment with study drug with Lilly medical approval. In addition, Lilly will request a 
copy of the ECGs for adjudication. 
 Upon resolution (or return to patient’s baseline) of AEs at least possibly related to 
treatment, reduce the dose as follows: 
o If previously receiving dose level 1, resume treatment at dose level -1 
o If previous receiving dose level -1, resume treatment at dose level -2  
o If previously receiving dose level -2, resume treatment at the same dose level. If a 
second AE requiring dose modification occurs at dose level -2, discontinue study 
treatment. 
o For AEs clearly unrelated to study treatment that resolve or return to patient’s 
baseline in ≤14 days, dose reduction is not required. 
o Re-escalation to a prior dose level after a dose reduction is permitted once the AE 
requiring dose reduction is resolved. See Sections 6.6.1 through 6.6.4 and the IB for 
specific dose adjustments required for patients receiving selpercatinib.  
o Above are guidelines and may be superseded by local practice guidelines or advice 
per the local cabozantinib/vandetanib labels when appropriate.  
Except as noted, a maximum of 2 dose level reductions will be allowed. Any patient requiring 
>42 days omission of treatment for drug-related toxicities will meet the criteria for study 
treatment discontinuation. Treatment omissions of >42 days in extenuating circumstances that 
are not drug-related (e.g. recovery from motor vehicle accident) may be approved by the Lilly 
medical team. 
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General Dose Reductions for Treatment Related Toxicitiesa 
Dose Level 
Time 
Selpercatinib Dose 
(mg) 
Cabozantinib Dose 
(mg)b 
Vandetanib Dose (mg) 
Dose Level 1 
AM 
160 
140 
300 
PM 
160 
- 
- 
Dose Level -1 
AM 
120 
100 
200 
PM 
120 
- 
- 
Dose Level -2 
AM 
80 
60 
100 
PM 
80 
- 
- 
a Unless other specific dose reductions, as per Sections 6.6.1, 6.6.2, 6.6.3, and 6.6.4. 
 
In the instance that vandetanib 100-mg tablets are unavailable, but vandetanib 300-mg tablets are 
available, the below table is to be followed in adult patients. 
Vandetanib Dose Modification using 300-mg Tablets for Adult Patients 
Dose Level of Vandetanib 
Vandetanib 300-mg tabletsa 
Dose Level 1 
1 tablet QD every day 
Dose Level -1b 
1 tablet QD for 2 days, every 3 days 
Dose Level -2b 
1 tablet QD for 1 day, every 3 days 
Abbreviations: QD = once daily. 
a A starting dose of vandetanib should be 200 mg in adult patients with moderate renal impairment (creatinine 
clearance results between 30 and 50 mL/min).  
b These dose regimens are expected to give similar reduced exposure corresponding to dose levels -1 and -2 in the 
standard dose modification table (General Dose Reductions for Treatment Related Toxicities). 
 
Selpercatinib General Dose Reductions for Treatment Related Toxicities for Adolescent 
Patients 
The dose (regardless of BSA calculation) should be no higher than the corresponding adult level 
for dose adjustments (e.g. Dose Level -1, 120 mg and Dose Level -2, 80 mg). Please see the table 
in Section 6.1.2 for selpercatinib dose rounding.  
 
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Dose Level 
Time 
Selpercatinib Dose (mg/m2) 
Dose Level 1 
AM 
92 
PM 
92 
Dose Level -1 
AM 
70 
PM 
70 
Dose Level -2 
AM 
46 
PM 
46 
Vandetanib General Dose Reductions for Treatment Related Toxicities and Starting Dose 
for Moderate Renal Impairment for Adolescent Participants 
BSA (m2) 
Dose Reduction (mg)a 
or 
Starting Dose with Moderate Renal Impairment 
0.7 - <0.9 
- 
0.9 - <1.2 
100 QOD 
1.2 - <1.6 
100 QD 
≥1.6 
7 day schedule: 
100-200-100-200-100-200-100 
Abbreviations: BSA = body surface area; QD = once daily; QOD = once every other day. 
a Participants with an adverse reaction requiring a dose reduction should stop taking vandetanib for at least a week. 
Dosing can be resumed at a reduced dose thereafter upon resolution or return to patient’s baseline.  
See Section 8.2.1 for additional information on dose reduction related to prolonged QTc. 
Cabozantinib General Dose Reductions for Treatment Related Toxicities for Adolescent 
Participants 
BSA (m2) 
Weekly Dose/Schedule 
for 1st Dose Reduction 
due to Toxicity 
Weekly Dose/Schedule for 2nd Dose Reduction 
due to Toxicity 
0.35 – 0.39 
60 mg = 20 mg M, W, F 
Off therapy 
0.40 – 0.45 
80 mg = 20 mg M, W, F, Sun 
60 mg = 20 mg M, W, F 
0.46 – 0.55 
100 mg = 20 mg M, W, Th, Sat, Sun 
60 mg = 20 mg M, W, F 
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BSA (m2) 
Weekly Dose/Schedule 
for 1st Dose Reduction 
due to Toxicity 
Weekly Dose/Schedule for 2nd Dose Reduction 
due to Toxicity 
0.56 – 0.64 
120 mg = 20 mg M, T, W, F, Sat, Sun 
80 mg = 20 mg M, W, F, Sun 
0.65 – 0.78 
140 mg = 20 mg QD 
100 mg = 20 mg M, W, Th, Sat, Sun 
0.79 – 0.90 
160 mg = 40 mg M, W, F, Sun 
120 mg = 20 mg M, T, W, F, Sat, Sun 
0.91 – 1.09 
200 mg = 40 mg M, W, Th, Sat, Sun 
140 mg = 20 mg QD 
1.10 – 1.17 
200 mg = 40 mg M, W, Th, Sat, Sun 
140 mg = 20 mg QD 
1.18 – 1.36 
240 mg = 40 mg M, T, W, F, Sat, Sun 
160 mg = 40 mg M, W, F, Sun 
1.37 – 1.65 
300 mg = 60 mg M, W, Th, Sat, Sun 
200 mg = 40 mg M, W, Th, Sat, Sun 
1.66 – 1.85 
360 mg = 60 mg M, T, W, F, Sat, Sun 
240 mg = 40 mg M, T, W, F, Sat, Sun 
1.86 – 2.07 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, Sat, Sun 
≥ 2.08 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, Sat, Sun 
Abbreviations: BSA = body surface area; QD = once daily. 
6.6.1. 
Dose Modifications for Selpercatinib Hypersensitivity  
If selpercatinib drug hypersensitivity is suspected, study drug should be held and treatment with 
steroids at 1 mg/kg prednisone (or equivalent) should be initiated. Upon resolution, selpercatinib 
may be resumed at a reduced dose of 40 mg BID (or adolescent equivalent dose) while 
continuing steroids at the same dose. Note that this dose reduction does not require sponsor 
approval. Hypersensitivity has recurred in some patients, typically at 3 to 6 hours following drug 
administration.  
Discontinue selpercatinib for recurrent clinically significant hypersensitivity. 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 (or adolescent equivalent doses) for a 
minimum of 7 days at each dose. Once the patient has tolerated treatment for a minimum of 7 
days at the final dose, steroids may be tapered slowly.  
6.6.2. 
Dose Modifications for Selpercatinib Related Liver Test Abnormalities  
If a patient experiences Grade ≥3 elevated hepatic lab increases (ALT, AST, or direct bilirubin), 
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). The 
grading is according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
with slight modification as described in Section 8.3. A repeat value 3 to 5 days after the initial 
finding of elevation of labs should be obtained to confirm the abnormality and to confirm if it is 
increasing or decreasing. Thereafter, hepatic labs 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 
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. Due to the question of a 
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possible immune component to the lab abnormalities observed, some patients with persistent 
increases have initiated treatment with steroids, with subsequent improvement. 
Upon resolution, selpercatinib may be resumed at a reduced dose of 2 dose levels lower than at 
which the abnormalities occurred with weekly lab monitoring. In the absence of recurrent 
abnormalities, the dose of selpercatinib may be escalated sequentially to the next higher dose 
level after a minimum of 2 weeks at the lowest dose level, and again to the dose level at which 
the abnormalities occurred after a minimum of 4 weeks at the dose level below which the 
abnormalities occurred. Once the patient has been treated at a stable dose of selpercatinib for a 
minimum of 4 weeks without recurrent lab abnormalities, the frequency of monitoring may be 
decreased (e.g., every 2 weeks for 2 months and then monthly thereafter). For patients who 
experience Grade ≥3 elevated hepatic labs on a dose of 80 mg BID (or adolescent equivalent 
dose), the Lilly medical team should be contacted for additional guidance to determine if 
continuation with dose modification is acceptable. If the patient experiences ≥Grade 3 elevated 
ALT, AST, or direct bilirubin at a dose of 40 mg BID, selpercatinib should be discontinued. 
Please refer to Section 8.2.2. for additional monitoring that may need to be initiated. 
6.6.3. 
Dose Modifications for Thrombocytopenia  
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 to Grade 1 or better, the patient 
should resume selpercatinib at a reduced dose of one dose level reduction (if thrombocytopenia 
is determined to be related to selpercatinib) with weekly CBC surveillance for 1 full cycle.  
6.6.4. 
Dose Modifications for Hypertension  
For the purpose of the study, hypertension is defined as  
 a sustained increase in blood pressure from baseline, as evidenced by ≥2 readings on 
≥2 separate occasions, or  
 a clinically significant elevation requiring acute treatment. 
If hypertension occurs, study drug may be interrupted at the discretion of the investigator while  
 a new anti-hypertensive medication regimen is initiated, or  
 a pre-existing regimen is optimized 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. In all cases, the patient should continue to undergo regular blood pressure 
monitoring to ensure adequate blood pressure control. 
6.6.5. 
Dose Modification for Selpercatinib Interstitial Lung Disease/Pneumonitis  
For Grade 2, withhold selpercatinib until resolution. Resume at next lower dose. Discontinue 
selpercatinib for recurrent ILD/pneumonitis. 
For Grade 3 or 4, discontinue selpercatinib. 
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6.7. 
Intervention after the End of the Study  
The end of study definition is defined in Section 4.4. Investigators will follow the schedule of 
activities provided in Section 1.3 until notified by Lilly that end of study has occurred. 
6.7.1. 
Treatment after Study Completion  
Study completion occurs after the clinical trial database is locked and final analysis of primary 
and secondary endpoints has been performed. Investigators will continue to follow SoAs 
(Section 1.3) for all patients until notified by Lilly that study completion has occurred. 
6.7.1.1. 
 Continued Access  
Participants who are still on study intervention at the time of study completion may continue to 
receive study intervention 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. Lilly will notify investigators when the continued 
access period begins. 
Participants are not required to sign a new ICF before treatment is provided during the continued 
access period; the initial ICF for this study includes continued access under this protocol. 
The participant’s continued access to study intervention will end when a criterion for 
discontinuation is met (Section 7). Continued access follow-up will begin when the participant 
and the investigator agree to discontinue study intervention and lasts approximately 30 days. 
Follow-up procedures will be performed as shown in the Continued Access Schedule of 
Activities. 
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. Long-
term follow-up does not apply. 
Participants who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Intervention  
Possible reasons leading to permanent discontinuation of investigational product: 
 Subject Decision 
o the participant or the participant’s designee, for example, parents or legal guardian 
requests to discontinue investigational product. 
If a clinically significant finding is identified after enrollment, the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed.  
In addition, participants will be discontinued from the investigational product in the following 
circumstances: 
 the patient becomes pregnant during the study. See Section 8.3 regarding regulatory 
reporting requirements on fetal outcome. 
 the patient is significantly noncompliant with study procedures and/or treatment 
 disease progression (radiographic or clinical progression). Patients with disease 
progression per investigator assessment may continue treatment while awaiting BICR 
confirmation of progression. Exceptions for continuing study treatment beyond suspected 
radiographic progression may be made on a case-by-case basis for patients who are 
believed to be clinically benefiting from study treatment, and the investigator and Lilly 
medical team agree that continuing study treatment is in the patient’s best interest. 
Expectations for required study procedures and data collection for each patient will be 
made at the time of approval. 
 the patient experiences unacceptable toxicity from study treatment 
 the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication. Discontinuation 
from study treatment will occur prior to introduction of the new agent 
 the investigator decides that the patient should be discontinued from study treatment.  
Participants discontinuing from the investigational product for any reason should complete AE 
and other follow-up procedures, including imaging assessments, per Section 1.3 (Schedule of 
Activities), Section 8.3 (Adverse Events and Serious Adverse Events), and Section 8.2 (Safety 
Assessments) of the protocol. 
Participants assigned to treatment Arm B who experience progression may cross-over to 
selpercatinib after meeting criteria in Section 5.2.1 and comply with procedures noted in 
Section 1.3.  
 
 
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7.2. 
Participant Discontinuation/Withdrawal from the Study  
Participants will be discontinued in the following circumstances:  
 enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
 participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and Good Clinical 
Practices (GCP) 
 subject decision 
o the participant or the patient’s designee, for example, parents or legal guardian] 
requests to be withdrawn from the study. 
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and 
Serious Adverse Events), and Section 8.2 (Safety Assessments) of this protocol. 
Participants discontinuing from study procedures may continue to be followed for survival, as 
long as they have not withdrawn consent for follow-up. If an in-person visit is not possible, 
survival status may be obtained by the site by contacting the patient directly via phone. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Patients  
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment. If the investigator and the sponsor agree it is medically appropriate to continue, 
the investigator must obtain documented approval from the sponsor to allow the inadvertently 
enrolled participant to continue in the study with or without treatment with investigational 
product. Safety follow up is as outlined in Section 1.3 (Schedule of Activities), Section 8.3 
(Adverse Events and Serious Adverse Events), and Section 8.2 (Safety Assessments) of the 
protocol. 
For sites located in the United Kingdom (UK) and Germany, refer to Appendix 5 for country-
specific discontinuation guidelines. 
7.3. 
Lost to Follow up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
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Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get investigational product. Public sources may be searched for vital status 
information, subject to local regulations. If vital status is determined, this will be documented 
and the participant will not be considered lost to follow-up. 
Lilly personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
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8. 
Study Assessments and Procedures  
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results. Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
 Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All screening evaluations must be completed and reviewed by the investigator to confirm 
that potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
 Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
 Additional safety assessments (for example, ECG and labs) may be performed at 
investigator’s discretion. 
8.1. 
Efficacy Assessments  
8.1.1. 
Imaging  
Efficacy assessments include tumor evaluation every 8 weeks after treatment initiation through 
week 24, and then every 12 weeks thereafter as noted in the SoA. Images are to be submitted for 
BICR evaluation within 5 days of completion. Patients who discontinue treatment without 
radiographic progression by BICR should continue to be assessed per the above schedule until 
radiographic disease progression is confirmed by BICR or death.  
All patients are required to undergo neck, chest, abdomen, and pelvis imaging at baseline and 
subsequent serial imaging at disease assessment time points. All images will be collected at a 
central facility for central reviewer assessment during the study. Response will be assessed per 
RECIST 1.1 requirements (Eisenhauer et al., 2009).  
Finally, all patients will enter Long-Term Follow-Up (LTFU) for confirming disease progression 
(if not occurring on treatment), subsequent anticancer therapy(ies), and survival. 
Baseline disease assessment with radiographic tumor measurements using computed tomography 
(CT) or magnetic resonance imaging (MRI) of neck, chest, abdomen, and pelvis or any other 
areas with suspected disease involvement must be completed within 28 days of C1D1. MRI with 
contrast is the preferred imaging modality for imaging the abdomen and pelvis of subjects with 
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MTC given the inherent challenges in RECIST 1.1 assessment of MTC liver metastases. If MRI 
is not obtainable, triple phase CT of the abdomen (nonenhanced, arterial phase, and portal 
venous phase imaging) with pelvis is recommended. Routine single-phase CT of the abdomen 
and pelvis in the portal venous phase if the recommendations listed above are not obtainable. 
Brain imaging is required at baseline only for patients with a history of CNS metastases, or if 
clinically indicated and subsequent serial scans are required if brain metastases are present at 
baseline (MRI preferred, CT with contrast is acceptable if MRI contraindicated). Bone imaging 
is required at baseline only for patients with known bone metastases or if clinically indicated, 
and subsequent serial scans are required if bone metastases are present at baseline (MRI or CT 
with bone windows preferred). 
For each modality, IV and oral contrast should be utilized (chest CT does not require contrast) 
unless there is a clear contraindication (e.g., decreased renal function or allergy that cannot be 
addressed with standard prophylactic treatments). Post-baseline imaging should be performed 
every 8 weeks (±7 days) for 24 weeks and every 12 weeks (±7 days) thereafter, including 
imaging of the neck, chest, abdomen, and pelvis, and any other known sites of disease, using the 
same modality(ies) as used for baseline imaging obtained during the screening period until PD, 
withdrawal of consent, or death. For the purpose of determining progression for eligibility, a 
change in modality may be acceptable if clear progression can be confirmed by central review, 
especially when a less sensitive modality was used for the second scan (e.g., liver metastases 
present on CT abdomen occurring after a previously normal MRI abdomen). Additional studies 
can also be performed at any time as clinically indicated. Please see the Site Imaging Manual for 
guidelines on how the various imaging studies should be performed and transmitted for central 
review. 
For patients who progress on study treatment and begin a different anti-cancer therapy (including 
patients who are initially assigned to the control arm and crossover to receive selpercatinib), 
PFS2 will be collected. It is recommended to maintain the study imaging schedule in patients 
who have discontinued treatment; that is, to continue imaging every 8 weeks for the first 
24 weeks of the next therapy, then every 12 weeks, as much as allowed according to the patient’s 
new treatment standard of care. These images will be collected centrally and the overall tumor 
assessment should be entered into the CRF. 
8.1.2. 
BICR Assessment  
Response assessments, including verification of PR or CR and disease progression will be 
assessed by BICR. These data will constitute the primary assessment for PFS and best overall 
response (BOR) analyses. The BICR will conduct assessment of tumor response by RECIST 1.1. 
Following each scan, the investigator will assess for progression using RECIST 1.1 and submit 
the scan for BICR review as outlined in Section 1.3. The table below outlines the potential 
actions following BICR review of imaging. 
 
 
 
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Investigator assessment 
BICR assessment 
Actions 
Progressive Diseasea 
Progression verified  
 Discontinue study treatment OR 
 Continue study treatment with sponsor 
approval if the patient is believed to be 
clinically benefitting OR 
 Crossover to selpercatinib (only patients 
progressing on Arm B are eligible for 
crossover) 
Progression not verified 
 Continue on study treatment if the patient is 
believed to be clinically benefitting until a 
criterion for discontinuation is met OR 
 Discontinue study treatment; imaging and 
submission for central review should continue 
until  
1. radiographic disease is verified 
by the BICR, 
2. death,  
3. withdrawal of consent, or  
4. study completion.  
Patients on Arm B would be eligible to cross over 
upon BICR documentation of progression.  
Non-progression 
In the case of investigator-
assessed non-progression, 
results are not reported back 
to investigator as BICR 
assessment is only used for 
endpoint assessment. 
 Continue on study treatment until progressive 
disease or another criterion for discontinuation 
is met 
 
a For patients where the investigator assessment is PD, it is at the discretion of the investigator if study treatment is 
continued until the BICR assessment is received. 
 
In the crossover period scans will be collected and stored for future review, if needed. 
8.2. 
Safety Assessments  
For each patient, AEs, ECGs, vital signs, laboratory tests, and other tests should be collected as 
shown in the SoA (Section 1.3).  
Results from any clinical laboratory test analyzed by a central laboratory (refer to Section 10.2) 
will be provided to investigative sites by Lilly or its designee.  
Refer to Section 8.3 for details on the recording of AEs. 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. 
Planned time points for all safety assessments are provided in the SoA. 
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Tanner staging (Marshall and Tanner 1969, Marshall and Tanner 1970) is required for any 
patient under age 18 (until sexual maturity is reached) in order to monitor the development of 
adolescent patients treated with selpercatinib. 
Participants who have not yet obtained full adult height will undergo MRI of one knee at 
baseline and every 6 months while the growth plate remains patent. Right knee is preferred, but 
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 and 
MRI performed only if the growth plate remains patent. If the growth plate remains patent, the 
patient will have a MRI performed every 6 months until the growth plate is no longer patent. 
In addition, a Safety Follow-up (SFU) visit 28 days (±7 days) after the last dose of selpercatinib, 
cabozantinib, or vandetanib will occur to determine the status of unresolved AEs.  
8.2.1. 
Electrocardiograms  
 ECG monitoring should be performed as outlined in the SoA (Section 1.3). QTcF values 
should be recorded on the CRF. In addition, Lilly may request a copy of the ECGs for 
adjudication.  
The actions below should be taken if the QTcF is greater than 500 msec on at least 2 of 3 ECGs 
(i.e., Grade 3 prolongation per CTCAE) and the triplicate average QTcF is greater than 500 msec 
OR is >60 msec longer than baseline QTcF:  
 Manually review to confirm accuracy. ECGs will be interpreted by a qualified physician 
(the investigator or qualified designee) at the site for immediate patient management. 
 Assess for alternative causes (concomitant medications, electrolyte abnormalities, 
presence of pacemaker). Clinical chemistry should be assessed and if electrolytes are 
abnormal, they should be repleted as indicated. Potassium should be ≥4 meq/L and less 
than the upper limit of normal (ULN) and magnesium and calcium should be within 
normal limits. Dose adjustment is not required if an alternative cause is found and if, in 
the medical judgment of the investigator, the patient is able to safely continue study 
treatment at his/her current dose while the cause of QTc change is being addressed. 
 Institutional guidelines or standard of care measures for management of QTcF interval 
>500 msec and/or associated arrhythmias should be initiated.  
 If the patient is on Arm A, selpercatinib should be reduced at least 1 dose level.  
 If the patient is on Arm B1 (cabozantinib), dose adjustments should occur per 
label/institutional guidelines. 
 If the patient is on Arm B2 (vandetanib), treatment should be held until QTcF returns to 
<450 msec, then reduce vandetanib by 1 dose level. If a further event of CTCAE Grade 3 
or higher toxicity or prolongation of the ECG QTc interval occurs, dosing with 
vandetanib should be permanently stopped. The patient must be monitored appropriately. 
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Fridericia’s QT Correction Formula 
Formula 
Fridericia  
QTcF = QT / (RR) 1/3 
Abbreviations: QT = ECG interval measured from the onset of the QRS complex to the offset of the T wave; 
QTcF = QT interval corrected for heart rate using Fridericia’s formula; RR = time between corresponding points on 
2 consecutive R waves on ECG.  
8.2.2. 
Clinical Safety Laboratory Assessments  
 
Investigator sites should use local laboratories to determine patient eligibility and 
treatment decisions.  
o See Appendix 2 for the list of clinical laboratory tests to be performed and 
Section 1.3 (SoA) for the timing and frequency. 
 
All laboratory tests, with the exception of tumor markers, with values considered 
clinically significantly abnormal during participation in the study or until completion of 
V801 should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or Lilly medical team. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA. 
8.2.2.1. 
Hepatic Safety Monitoring  
In study participants with baseline ALT/AST <1.5X ULN 
If a study participant enrolled with baseline ALT/AST <1.5X ULN experiences elevated 
ALT/AST ≥3X ULN and elevated TBL ≥2X ULN, or ALT/AST ≥5X ULN liver testing 
(Appendix 4) including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase, and 
creatine kinase should be repeated within 3 to 5 days to confirm the abnormality and to 
determine if it is increasing or decreasing. If the abnormality persists or worsens, clinical and 
laboratory monitoring and evaluation for possible causes of abnormal liver tests, should be 
initiated by the investigator in consultation with the study CRP/CRS. Monitoring of ALT, AST, 
and TBL should continue until levels normalize or return to approximate baseline levels.  
In study participants with baseline ALT/AST ≥1.5X ULN 
If a study participant enrolled with baseline ALT/AST ≥1.5X ULN experiences elevated 
ALT/AST ≥3X baseline or ALT/AST ≥2X baseline and TBL ≥2X ULN, liver testing (Appendix 
4) including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase 
should be repeated within 3 to 5 days to confirm the abnormality and to determine if it is 
increasing or decreasing. If the abnormality persists or worsens, clinical and laboratory 
monitoring and evaluation for possible causes of abnormal liver tests, should be initiated by the 
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investigator in consultation with the study CRP/CRS. Monitoring of ALT, AST, and TBL should 
continue until levels normalize or return to approximate baseline levels. 
Hepatic data (Appendix 4) should be collected in the event that 1 (or more) of the following 
conditions is met for the patient during the course of the study:  
 In patients enrolled with baseline ALT/AST <1.5X ULN:  
a. Elevated ALT/AST ≥3X ULN and elevated total bilirubin ≥2X ULN  
b. ALT/AST ≥5X ULN on 2 consecutive tests. 
 In patients enrolled with baseline ALT/AST ≥1.5X ULN (regardless of whether or not 
they have hepatic metastasis):  
a. Elevated ALT/AST ≥2X baseline and elevated TBL ≥2X ULN 
b. Elevated ALT/AST ≥3X baseline on 2 consecutive tests. 
 All patients 
a. Discontinuation from study treatment due to a hepatic event or abnormality of 
liver tests 
b. Occurrence of a hepatic event considered to be a SAE. 
8.2.2.2. 
Chylothorax and Chylous Ascites Monitoring  
If a participant 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 as outlined in Section 6.6 
(Dose Modification), based upon severity of the event. 
8.2.2.3. 
Renal Safety Monitoring  
In vitro, selpercatinib is an inhibitor of the drug transporter MATE1 and may reduce the 
clearance of MATE1 substrates (for example, creatinine). Selpercatinib may increase serum 
creatinine due to inhibition of the renal tubular secretion transporter MATE1, without affecting 
glomerular function. Complementary markers such as blood urea nitrogen (BUN), cystatin C, or 
calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered 
to determine whether renal function is impaired. 
8.2.2.4. 
Thyroid Function Monitoring   
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 preexisting hypothyroidism 
should be treated as per standard medical practice prior to the start of selpercatinib treatment. All 
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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. 
8.3. 
Adverse Events and Serious Adverse Events  
The investigator should provide AE verbatim terms and then the terms will be mapped by Lilly 
or its designee to corresponding terminology within the Medical Dictionary for Regulatory 
Activities (MedDRA) Lower Level term (LLT) dictionary. The investigator will use Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 to assign AE severity grades. 
Lilly recommends a slight modification when implementing the CTCAE V5.0. Post baseline 
grading for all laboratory values should be done per normal limit references, where specified, 
regardless of whether the assessment is normal or abnormal at baseline. 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study. The participant should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is otherwise explained. The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each participant’s pre-existing conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study. In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure, investigational product, via CRF.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE. 
The investigator answers yes/no when making this assessment.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AEs. 
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Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
If a participant’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF, clarifying if possible, the circumstances leading 
to any dosage modifications, or discontinuations of treatment. Dose modifications and treatment 
discontinuation due to an AE should follow criteria defined in Section 6.6 (Dose Modifications). 
An independent review committee will review blinded data to determine which treatment 
discontinuations due to an AE meet the treatment failure event criteria for the primary analysis. 
Only AEs reasonably possibly related to study procedures should be recorded in the eCRF, after 
signing the prescreening ICF. If an SAE occurs after signing the pre-screen ICF, the SAE should 
be reported to the sponsor as per SAE reporting requirements and timelines if it is considered 
reasonably possibly related to study procedures.  
All AEs occurring after signing the main study ICF are recorded in the eCRF and assessed for 
serious criteria. The SAE reporting to the sponsor begins after the patient has signed the main 
study ICF and has received investigational product. However, if an SAE occurs after signing the 
main Study ICF, but prior to receiving investigational product, the SAE should be reported to the 
sponsor as per SAE reporting requirements and timelines if it is considered possibly related to 
study procedures. 
Adverse events 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, or investigational 
combination product, whether or not related to the medicinal (investigational) product or 
investigational combination product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational device. 
Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments, for example, ECG, radiological scans, and vital signs 
measurements, including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator, that is, not related to 
progression of underlying disease. 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
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 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae.  
 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT meeting the AE definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease or disorder being studied or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure, for example, endoscopy, appendectomy. The condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Serious Adverse Events 
An SAE is any AE from this study that results in one of the following outcomes: 
 death 
 initial or prolonged inpatient hospitalization 
 a life-threatening experience (that is, immediate risk of dying) 
 persistent or significant disability/incapacity 
 congenital anomaly/birth defect 
 important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria. 
The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received investigational product. However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 8.3.1) only if it is considered reasonably 
possibly related to study procedure. 
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Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment. Study site personnel 
must alert Lilly or its designee of any SAE within 24 hours of investigator awareness of the 
event via a sponsor-approved method. If alerts are issued via telephone, they are to be 
immediately followed with official notification on study-specific SAE forms. This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information. 
Participants with a serious hepatic adverse event should have additional data collected using the 
CRF. 
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE. However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the participant disposition CRF has been completed). 
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure. 
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the 
identification, recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours. The investigator will submit any updated SAE data to 
the sponsor within 24 hours of it being available.  
8.3.2. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).  
8.3.3. 
Regulatory Reporting Requirements for SAEs  
 Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will evaluate the reported SAEs, including confirmation of 
relatedness and assessment of expectedness. The sponsor has processes for safety reports 
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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, Institutional Review 
Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
 An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.4. 
Pregnancy  
 Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the completion 
of V801. 
 If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 3. 
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 3. 
 The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
8.3.5. 
Cardiovascular and Death Events  
Not applicable. 
8.3.6. 
Complaint Handling  
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements. 
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
8.4. 
Treatment of Overdose  
Refer to the IB and/or product label for selpercatinib, cabozantinib, or vandetanib for available 
information on the signs, symptoms, and treatment of overdose. 
8.5. 
Pharmacokinetics  
At the visits and times specified in the SoA (Section 1.3), blood samples will be collected to 
determine the plasma concentrations of selpercatinib.  
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A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor. Instructions for the 
collection and handling of blood samples will be provided by the sponsor. The actual date and 
time [24-hour clock time] of each sampling and prior dose will be recorded. 
Blood for PK assessment will be collected on C1D8, and at first day of each consecutive cycle 
up to Cycle 6 and should be collected regardless even if study drug will be held for the next 
cycle. Samples are to be drawn within  hours prior to dose, and exact time of sample collection 
should be recorded. In addition, time of previous dose should be recorded. Additional PK may 
also be assessed in patients when considered necessary by the Investigator to understand 
exposure in relationship to possible safety. Additional samples should be considered for patients 
experiencing selpercatinib-related drug hypersensitivity at onset of event, and at resolution of 
event. 
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding will be retained for a maximum of 2 years following last 
participant visit for the study. During this time, samples remaining after the bioanalyses may be 
used for exploratory analyses, such as metabolism, transport and/or protein binding work.  
8.6. 
Pharmacodynamics  
Not applicable. 
8.7. Genetics  
8.7.1. 
Blood Samples for Pharmacogenetic Research  
A blood sample will be collected for pharmacogenetic analysis as specified in the SoA (Section 
1.3) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to selpercatinib and to 
investigate genetic variants thought to play a role in MTC and to determine whether genetic 
alterations identified in tumor samples are somatic or germline variants. Assessment of variable 
response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number. These samples and any data generated can be 
linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after the last 
participant visit for the study, or for a shorter period if local regulations and/or ethical review 
boards (ERBs)/ IRBs impose shorter time limits. This retention period enables use of new 
technologies, response to regulatory questions, and investigation of variable response that may 
not be observed until later in the development of selpercatinib or after selpercatinib becomes 
commercially available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies. Regardless of 
technology utilized genotyping data generated will be used only for the specific research scope 
described in this section. 
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8.8. 
Biomarkers  
8.8.1. 
Samples Required for Eligibility  
Eligibility is dependent on having adequate tumor tissue for confirmatory central RET testing. 
Mandatory provision of an unstained, archived tumor tissue sample in a sufficient quantity to 
allow for retrospective central analysis of RET mutation status. 
a) Tumor samples must be formalin fixed and paraffin embedded (FFPE). Blocks should be 
provided wherever possible, but unstained slides are also permitted. Acceptable sample 
collection methods include surgical resection (preferred) core biopsy, or FFPE fine 
needle aspiration. Biopsy samples taken from bone metastasis and cytology samples are 
unsuitable for testing and should not be provided. Sample may be collected from primary 
or metastatic tumor sites.  
b) The investigator will be asked to provide 
a. FFPE tumor tissue blocks, or 
b. A minimum of 16 unstained slides from FFPE tissue block presented on slides. 
Preferably, each section should be approximately 5 µm thick. In certain 
circumstances, fewer slides may be acceptable, only with sponsor approval (i.e., 
where it can be demonstrated by the site that fewer slides will provide a sample in 
sufficient quantity for retrospective central analysis of RET alteration). Note that 
these slides are required in addition to any slides required prospectively to determine 
RET status for study eligibility. 
c. If it is considered safe to perform, patients who do not have sufficient available tumor 
tissue may undergo a fresh tumor biopsy to meet eligibility requirements. 
d. For patients who had eligibility determined by germline testing, the investigator 
should contact the sponsor to determine if a smaller amount of tissue is required.  
Patients must agree to have any leftover tissue (tissue that remains after confirmatory RET 
testing) retained for the use of secondary studies outlined below and in Section 5.1, inclusion 
criterion 4a. 
8.8.2. 
Biomarkers  
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, resistance mechanisms, variability of 
participant response (including safety), and clinical outcome. Sample collection is incorporated 
into clinical studies to enable examination of these questions through measurement of 
biomolecules including DNA, cfDNA, ribonucleic acid (RNA), proteins, lipids, and other 
cellular elements. 
Archived tumor tissue will be obtained for patients, if available. Archived tumor tissue should be 
submitted, either via tumor block (preferred) or unstained slides. Lilly has a right to retain a 
portion of the submitted tissue. Archival blocks will be sectioned and returned to the study site. 
Slides and tissue samples collected on-study will not be returned. Patients who do not have 
sufficient archival tumor tissue available must undergo a fresh tumor biopsy, if it is considered 
safe to perform, prior to treatment. A tissue biopsy may be collected at the time of progression if 
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it can be safely performed. For biopsies performed in the setting of disease progression, please 
contact the sponsor to inform them of the planned biopsy. Samples collected will be utilized for 
retrospective concordance of one or more companion diagnostic tests.  
Blood and tissue samples for biomarker research will be collected at the times specified in the 
SoA (Section 1.3), where local regulations allow. Whole blood will be collected to characterize 
RET mutations and concurrently activated oncogenic pathways in cfDNA and to compare RET 
mutation status in tumor and cfDNA samples. It is possible that biomarker data for patients in the 
study has already been generated from samples that were collected and analyzed prior to 
enrolling in this study. This may include pathology reports and data generated from genetic 
analyses. If available, these data may be requested from medical records for use in the research 
described in Sections 8.7 and 8.8. Patients must have a RET alteration as outlined in Section 5.1. 
For all patients, a redacted Molecular Pathology Report or other report(s) describing tumor or 
germline RET mutations should be submitted to the sponsor, designee, or central laboratory. In 
regions or at sites where RET is not standard of care and/or an acceptable local test (as defined 
by Lilly) is not available, a pre-screening consent will be used to provide information to the 
patient regarding testing to determine tumor RET status. The results of the initial or retrospective 
concordance testing will include other genes in addition to RET. 
Samples will be used for research on the drug target, disease process, variable response to 
selpercatinib, pathways associated with MTC and the mechanism of action of selpercatinib. 
These samples may also be used to develop research methods or in validating diagnostic tools or 
assays.  
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly for a maximum 15 years after the last 
participant visit for the study, or for a shorter period if local regulations and ERBs/IRBs impose 
shorter time limits. This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of selpercatinib or after selpercatinib become commercially available. Technologies 
are expected to improve during the 15-year storage period and, therefore, cannot be specifically 
named. Existing approaches, including mutation profiling, copy number variability analysis, 
gene expression assays, multiplex assays, and/or immunohistochemistry may be performed on 
these tissue samples to assess potential associations between these biomarkers and clinical 
outcomes. 
8.9. Medical Resource Utilization and Health Economics  
8.9.1. 
Patient-reported Outcomes  
Self-reported questionnaires will be administered according to the SoA (Section 1.3) in countries 
where the questionnaires have been translated into the native language of the region. Only 
patients age 18 or older who are literate in an available translation will complete the 
questionnaires. Since no paper version of the questionnaires is provided, patients with religious 
objection to using electronic devices are not required to complete these activities. Instruments 
that are completed daily will be collected for the first year of patient treatment then will be 
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discontinued; instruments that are collected weekly or less frequently will be continued for the 
full duration of patient treatment as described in the Schedule of Activities (Section 1.3).  
8.9.2. 
Bristol Stool Form Scale and Bowel Movement Frequency  
The Bristol Stool Form Scale is a single item that asks about worst stool form (Lewis and Heaton 
1997). The bowel movement frequency is a single item that asks the participant to quantify the 
number of bowel movements in the past 24 hours. Patients will complete these items daily on the 
device provided; sites will not administer this instrument.  
8.9.3. 
Worst Pain Numeric Rating Scale (NRS)  
The Worst Pain Numeric Rating Scale (NRS) is a single item, subject-administered, 11-point 
horizontal scale anchored at 0 and 10, with 0 representing “no pain” and 10 representing “pain as 
bad as you can imagine.”  
The recall period is the last 24 hours, and will be completed daily by the patient on the device 
provided; sites will not administer this instrument. 
8.9.4. 
PRO-CTCAE  
The PRO-CTCAE is a patient-reported outcome measurement system developed by the National 
Cancer Institute to collect symptomatic AEs from cancer patients enrolled in clinical trials 
(Basch et al. 2014; Dueck et al. 2015). These items have been developed to assess symptomatic 
AEs from the patient perspective associated with cancer therapy, to complement the CTCAE 
data collected at the site level (Basch et al. 2014, Atkinson et al. 2016). The information from the 
PRO-CTCAE will not be available to the patient or onsite clinicians for clinical patient 
management. Specific items were selected from the library that occurred in at least 24% of the 
study population receiving selpercatinib, cabozantinib or vandetanib; additionally, a minimum of 
the 5 most common side effects of each agent were also included (Schlumberger et al. 2017; 
Elisei et al. 2013; Wells et al. 2012; cabozantinib USPI 2016; cabozantinib SmPC 2016; 
vandetanib USPI 2014; vandetanib SmPC 2014). The PRO-CTCAE will be completed weekly 
by the patient via the device provided; sites will not administer this instrument. 
8.9.5. 
FACT-GP5  
This is a single item from the Functional Assessment of Cancer Therapy (FACT) general scale to 
assess overall side-effect burden (FACT-GP5). This item will be completed weekly by the 
patient via the device provided; sites will not administer this instrument. 
8.9.6. 
HRQoL (EORTC QLQ-C30)  
Health-related quality of life will be assessed with the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30 
[Aaronson et al. 1993]). 
The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 items covered by 
1 of 3 dimensions: 
 global health status/quality of life (2 items) 
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 functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
social functioning) 
 symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact). 
Electronic versions of the questionnaires will be used and will be available to the patient on the 
provided device. The full scale will be completed electronically on day 1 of each cycle at the 
site, whereas the physical function items of this scale, item library 19 (EORTC IL19) will be 
completed weekly by the patient; sites will not administer this instrument. 
8.9.7. 
Health Status (EQ-5D-5L)  
Health status will be assessed using the EQ-5D-5L (Janssen et al. 2008). This utility measure is 
an important input for economic evaluations concerning the value of treatment interventions. 
Patients will complete the 5-dimension (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), 5-level (no problem, slight, moderate, severe, or extreme problem) 
assessment according to the SoA (Section 1.3). A unique EQ-5D health state is defined by 
combining 1 level from each of the 5 dimensions. Additionally, patients will indicate their 
current health status by marking on a visual analogue scale (VAS) ranging from 100 (best 
imaginable health state) to 0 (worst imaginable health state). The recall period is “today.” The 
EQ-5D-5L is designed for self-completion by respondents and is cognitively simple, taking only 
a few minutes to complete, and will be administered electronically at the study site on Day 1 of 
each cycle of therapy. EQ-5D-5L responses may be incorporated into cost utility analyses, but 
will not be included in the clinical study report.  
8.9.8. 
Healthcare Resource Utilization  
Health care resource utilization will be collected in the CRF by the investigator and study-site 
personnel for all participants throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. 
The data collected will include: 
 Hospitalization (Yes or no) and duration of hospitalization (admit and discharge dates) 
 Emergency room visits (Yes or no) and dates 
 Supportive care medications (G-CSF use, analgesics, transfusions) 
Pain medication will be classified into medication categories, using the World Health 
Organization analgesic ladder. A medication category will be assigned based on the maximum 
analgesic therapy administered for that cycle on a routine basis. 
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9. 
Statistical Considerations  
9.1. 
Statistical Hypotheses  
Treatment of patients with progressive, advanced, kinase inhibitor-naïve, RET-mutant MTC with 
selpercatinib in the first line setting will provide a clinically meaningful increase in PFS over 
treatment with cabozantinib/vandetanib. 
9.2. 
Sample Size Determination  
An initial assumption of 74 PFS events at the final analysis provides approximately 80% power 
to detect a HR of 0.5 using the log-rank test and a 1-sided type I error of 2.5%. Given the 
historical data outlined in Section 4.2, a median PFS of 25 months is assumed for Arm B. HR of 
0.5 corresponds to an improvement in median PFS from 25 months for Arm B to 50 months for 
Arm A. Approximately 250 patients will be enrolled based on these initial assumptions.  
The sample size re-estimation will be based on the actual number of observed PFS events at the 
time of the pre-specified interim efficacy analysis, so the sample size adjustment has the purpose 
of modifying the number of events. The number of patients will be adjusted accordingly so that 
the required total number of events could be achieved in a desired timeframe. 
Re-estimation of the number of PFS events will be conducted only once, during the pre-specified 
interim efficacy analysis, based on the unblinded comparative results observed at this analysis. 
Based on prespecified criteria described in the Adaptive Design Charter the following scenarios 
are possible: 
 the study will be declared positive due to overwhelming efficacy 
 the study will continue without change to the final analysis (i.e., the re-estimated total 
number of events will be equal to the initial planned total number of events) 
 the re-estimated total number of events required for the final analysis will be determined 
and the study will continue to the final analysis. 
The re-estimated total number of events could be increased from the initial assumption of 74 to a 
maximum of approximately 284 events to maintain the conditional power (conditional 
probability of a statistically significant treatment effect at the end of the trial) at a prespecified 
level. A maximum of 284 PFS events was selected based on the original protocol under a fixed 
study design to provide approximately 80% power to detect a HR of 0.7. The total number of 
patients could be increased from approximately 250 up to approximately 400. The total study 
duration will be capped at 6 years from the first patient visit regardless of actual number of 
events observed. A duration of 6 years is considered to be a relevant timeframe considering that 
the treatment landscape may change substantially and continuation on study follow-up may 
present an undue burden on participants. Details of adaptation decision rules are described in the 
Section 9.5 and the Adaptive Design Charter. 
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9.3. 
Populations for Analyses  
For purposes of analysis, the following populations are defined: 
Population 
Description 
Entered 
All participants who sign informed consent for treatment 
ITT/Enrolled 
All randomized patients, even if a patient does not take the assigned treatment, 
does not receive the correct treatment, or otherwise does not follow the protocol. 
Patients will be analyzed according to the treatment group they were assigned to 
regardless of what actual treatment they receive. 
Evaluable 
Defined in specific subsections below, where applicable 
Crossover 
A subpopulation of patients included in the ITT population who were randomly 
assigned to Arm B, crossed over and took at least 1 dose of selpercatinib 
Safety 
All randomized participants who take at least 1 dose (including a partial dose) of 
study treatment. Analysis will be based on the actual treatment a participant 
received on the first study treatment administration, regardless of which treatment 
they were assigned to receive (“as treated”). 
Tolerability Evaluable 
All patients who were randomized prior to the interim efficacy analysis and 
received the first dose of study treatment at least 6 months prior to the data cutoff 
date. Analysis of tolerability will be based on the actual treatment a patient 
received on the first study treatment administration regardless of which treatment 
they were randomized to receive (“as treated”) 
Abbreviations: ITT = Intent to treat.  
9.4. 
Statistical Analyses  
9.4.1. 
General Statistical Considerations  
All efficacy analyses will be performed using the intention-to-treat (ITT) population, unless 
otherwise specified. 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Efficacy analyses will be conducted on the ITT data set, as defined in Section 9.3. This set 
includes all randomized patients, according to the treatment arm to which they were assigned. 
Safety analyses will be conducted on the safety data set, as defined in Section 9.3. This set 
includes all data from all participants who received at least 1 dose of the study drug according to 
the treatment the participants actually received. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05 (or equivalently 
1-sided alpha level of 2.5%), as appropriate, unless otherwise stated. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR). Additional exploratory analyses of the data will be conducted 
as deemed appropriate. 
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Handling of missing, unused, and/or spurious data is addressed prospectively in the overall 
statistical methods described in the protocol, and/or in the SAP, where appropriate. Adjustments 
to the planned analyses are described in the final CSR. 
9.4.2. 
Treatment Group Comparability  
9.4.2.1. 
Participant Disposition  
A detailed description of patient disposition will be provided according to CONSORT publishing 
requirements, including a summary of the number and percentage of patients entered into the 
study, enrolled in the study, and treated, as well as number and percentage of patients completing 
the study (patients who receive ≥1 dose of study drug and have ≥1 postbaseline tumor 
assessment), or discontinuing (overall and by reason for discontinuation). A summary of all 
important protocol deviations will be provided.  
9.4.2.2. 
Participant Characteristics  
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population. 
A summary of baseline patient and disease characteristics, historical diagnoses, pre-existing 
conditions, and prior therapies will be reported by arm and stage using descriptive statistics. 
Other patient baseline characteristics will be summarized as deemed appropriate. 
9.4.2.3. 
Concomitant Therapy  
A summary of concomitant medications and transfusions by arm and stage will be reported. 
9.4.2.4. 
Treatment Compliance  
Oral drug compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments. Study 
treatment taken will be derived from the difference between the total number of capsules/tablets 
dispensed and returned over the course of the patient’s treatment. A patient will be considered 
noncompliant if he or she takes <75% or ≥125% of the planned doses. 
9.4.2.5. 
Extent of Exposure  
The duration on therapy, dose omissions, dose reductions, and dose intensity for each drug will 
be summarized for all treated patients by parts and arms. 
9.4.2.6. 
Post-Study-Treatment Therapy  
The numbers and percentages of patients receiving post-study-treatment anticancer therapies will 
be provided by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug class 
and/or name, overall, and by line of therapy. 
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9.4.3. 
Efficacy Analyses  
9.4.3.1. 
Primary Analyses  
Progression-free survival confirmed (PFS) by BICR is defined as the time from randomization 
until the occurrence of documented disease progression by the BICR, per RECIST 1.1 criteria 
(Eisenhauer et al. 2009), or death from any cause in the absence of BICR-documented PD. 
Patients known to be alive and without disease progression will be censored at the time of the 
last adequate tumor assessment. 
The BICR PFS will be compared between treatment arms using the Cui, Hung and Wang (CHW) 
testing procedure (Cui et al. 1999) to control the type I error at an overall 1-sided 2.5% 
significance level: 
 At the interim efficacy analysis, the BICR PFS will be compared using a conventional 
stratified logrank test, stratified by the 2 randomization strata based on IWRS data: RET 
mutation (M918T vs. other) and intended control treatment (cabozantinib vs. vandetanib).  
 At the final analysis, the BICR PFS will be compared using a CHW test based on re-
weighted stratified logrank test statistics. If the re-estimated total number of events is 
equal to the initial planned total number of events, the CHW test will be reduced to the 
conventional stratified logrank test. Details of the CHW method will be described in the 
SAP. 
The corresponding HR between treatment arms will be estimated using a stratified Cox 
regression model (Cox 1972), stratified by randomization strata. Progression free survival 
curves, medians, and PFS rates at various time points with 95% CI for each treatment arm will 
be estimated using the Kaplan-Meier method (Kaplan and Meier 1958).  
PFS censoring scheme and sensitivity analyses will be described in the SAP. 
9.4.3.2. 
Key Secondary Analyses  
9.4.3.2.1. Treatment Failure Free Survival  
Treatment Failure Free Survival (TFFS) per BICR is defined as the time from randomization to 
the first occurrence of: 
 documented radiographic disease progression per RECIST 1.1 as assessed by BICR; or 
 unacceptable toxicity leading to treatment discontinuation as assessed by the investigator. 
To qualify as an event, the toxicity must be from an intolerable AE (defined as any study 
drug-related AE that meets protocol guidance for treatment discontinuation, with the 
exception of alopecia); or 
 death (due to any cause). 
An independent review committee will review blinded data to determine whether an AE leading 
to treatment discontinuation meets protocol guidance and thus should be considered as a TFFS 
event. Independent review will occur retrospectively and will not impact patient care decisions or 
study conduct. 
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Since TFFS events include PFS events with additional events of treatment failure due to toxicity, 
TFFS is sufficiently powered as result of sample size determination based on PFS events. TFFS 
will be analyzed at the time of the final analysis which is triggered by the PFS events. 
Conditional on achieving a statistical significance for the primary endpoint of PFS, TFFS will be 
tested in a manner that will preserve the 1-sided overall type I error rate at 2.5%: 
 If the study remains at the initial planned total number of PFS events and sample size, the 
TFFS will be compared between treatment arms using a stratified logrank test, stratified 
by the 2 randomization strata based on IWRS data: RET mutation (M918T vs. other) and 
intended control treatment (cabozantinib vs. vandetanib).  
 If the total number of PFS events required for the final analysis increases after sample 
size re-estimation, the TFFS will be compared between treatment arms using the CHW 
test in a similar manner of the primary efficacy analysis. Details will be described in the 
SAP. 
The corresponding HR between treatment arms will be estimated using a stratified Cox 
regression model (Cox 1972), stratified by randomization strata. Treatment failure free survival 
curves, medians, and TFFS rates at various time points with 95% CI for each treatment arm will 
be estimated using the Kaplan-Meier method (Kaplan and Meier 1958).  
TFFS censoring scheme and sensitivity analyses will be described in the SAP. 
9.4.3.2.2. Comparative Tolerability  
Comparative tolerability, as assessed by the FACT-GP5, is also a key secondary endpoint and 
will be tested conditionally on achieving a statistical significance for PFS and TFFS by BICR. 
Comparative tolerability will be defined as a comparison of the proportion of time on treatment 
with a high symptom burden as assessed by FACT-GP5 between Arm A and Arm B. A detailed 
analytical approach will be provided in the SAP.  
Comparative tolerability will be assessed in the Tolerability Evaluable Population, i.e., patients 
enrolled by the time of the interim analysis (approximately 250 patients projected to be enrolled) 
regardless of the sample size re-estimation result. Since the sample size is fixed for the 
comparative tolerability endpoint, no adjustment of test statistic will be applied, and the type I 
error will not be inflated by a potential sample size increase.  
9.4.3.2.3. Overall Survival  
The study is not powered for OS but will continue to approximately 125 OS events or until a 
maximum of 6 years from the first patient visit, whichever comes first. If the true OS HR is 0.7, 
125 OS events will provide approximately 98% probability that the observed OS HR would be 
less than 1.0, indicating no OS detriment associated with the selpercatinib treatment. A HR of 
0.7 translates into a 42.9% relative and 30 months absolute increase in median OS (if assuming a 
median OS of 70 months for cabozantinib/vandetanib and 100 months for selpercatinib). 
Overall survival (OS) is defined as the time from randomization until death from any cause. If 
the patient is alive or lost to follow-up at the time of data analysis, OS data will be censored on 
the last date the patient is known to be alive. Overall survival will be compared between 
treatment arms using a stratified log-rank test, stratified by the randomization strata for RET 
mutation (M918T vs. other) and intended treatment (cabozantinib vs. vandetanib). The 
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corresponding HR between treatment arms will be estimated using a stratified Cox regression 
model (Cox 1972), stratified by the randomization strata. Overall survival curves, the median and 
survival rates at various time points with 95% CI, for each treatment arm will be estimated using 
the Kaplan-Meier method (Kaplan and Meier 1958). Sensitivity analyses for OS will be 
described in the SAP. 
9.4.3.3. 
Other Secondary Analyses  
Overall response rate will be assessed for Arm A versus Arm B using a Cochran-Mantel-
Haenszel test stratified by the randomization strata. 
 ORR per RECIST 1.1 as assessed by BICR  
 ORR per RECIST 1.1 per investigator assessment 
The following secondary outcomes will be assessed for Arm A vs. Arm B using a logrank test 
stratified by the randomization strata. The corresponding HR between treatment arms will be 
estimated using a stratified Cox regression model (Cox 1972), stratified by the randomization 
strata. Point estimates with 95% CI, for each treatment arm will be estimated using the Kaplan-
Meier method (Kaplan and Meier 1958).: 
 TFFS as assessed by investigator 
 PFS as assessed by investigator 
 DoR as assessed by investigator 
 DoR as assessed by BICR 
 PFS2 as assessed by investigator 
Progression-free survival per investigator assessment is defined in the same manner as BICR 
PFS. 
TFFS per investigator assessment is defined as the time from randomization to the first 
occurrence of documented radiographic disease progression per RECIST 1.1 as assessed by 
the investigator or unacceptable toxicity leading to treatment discontinuation as assessed by the 
investigator (regardless of a study drug-related AE meets protocol guidance for treatment 
discontinuation or not); or death (due to any cause). 
Progression-free survival 2 (PFS2) is defined as the time from randomization to disease 
progression (radiographic or symptomatic progression as determined by the investigator) on the 
next line of treatment or death from any cause in the absence of observed disease progression. If 
the patient is alive at the cutoff for analysis, and disease progression has not been observed, 
PFS2 data will be censored on the latest date of last progression-free assessment or start of the 
next line of treatment.  
Duration of response (DOR) is defined as the time from the date that measurement criteria for 
complete response (CR) or partial response (PR) (whichever is first recorded) are first met by the 
BICR or investigator assessment, as applicable, until the first date that disease is recurrent 
or documented disease progression is observed, per RECIST 1.1 criteria, or the date of death 
from any cause in the absence of documented disease progression or recurrence.  
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Overall response rate (ORR) is defined as the number of patients who achieve a best overall 
response (BOR) of CR or PR divided by the total number of patients randomized to each 
treatment arm. The ORR, with 95% CI, will be summarized for each treatment arm. 
Best overall response is determined from a sequence of responses assessed. Two objective status 
determinations of CR before progression are required for a best response of CR. Two 
determinations of PR before progression, but not qualifying for a CR, are required for a best 
response of PR. The second objective response is required to be ≥28 days after the initial 
response. 
9.4.3.4. 
RET-Testing Concordance Analysis  
The concordance between RET testing results based on local laboratory tests and centrally 
assessed results will be evaluated. Details regarding analyses involving centrally assessed 
RET-testing results will be described in a separate Diagnostics SAP. 
9.4.3.5. 
Tertiary/Exploratory Analyses  
The following endpoints with be assessed as tertiary/exploratory analyses, with detailed methods 
provided in the SAP: 
Time to initiation of new anticancer therapy, defined as the time from randomization to 
documentation in the CRF of a new local (e.g., surgery, radiation) or systemic anticancer 
treatment administered to the patient. 
PFS after crossover, defined as the time from start of selpercatinib treatment until the 
occurrence of disease progression or death from any cause for crossover population. 
Calcitonin and CEA response rate, defined as percentage of patients who had a decline from 
baseline in the calcitonin or CEA level of at least 50% maintained for at least 4 weeks. 
9.4.4. 
Safety Analyses  
Detailed tabulations of safety data (AEs and clinical laboratory tests) will be provided for all 
subjects receiving the study drug. The number and percent of subjects with TEAEs will be 
summarized. Summary of other safety parameters by treatment group will be provided where 
appropriate. 
Safety data after crossover will be summarized for crossover population. TEAEs and clinical 
laboratory abnormalities will be defined according to the crossover baseline with details 
provided in the SAP. 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses  
Selpercatinib plasma concentrations will be summarized by descriptive statistics and graphics. 
Additionally, the data will be evaluated through population PK methodology.  
The relationship between selpercatinib plasma exposure and pharmacodynamic markers, such as 
tumor size, efficacy, as well as selected safety outcomes, will be explored. 
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9.4.6. 
Biomarker Analysis  
Biomarker results will be summarized and may be analyzed for correlations with clinical 
outcomes. 
9.4.7. 
Other Analyses  
9.4.7.1. 
Health Economics  
9.4.7.1.1. Patient Reporting Outcomes (PROs)  
For each instrument, percentage compliance will be calculated as the number of completed 
assessments divided by the number of expected assessments. Data will be separately summarized 
using descriptive statistics.  
Further details will be provided in the SAP for each PRO instrument, respectively.  
9.4.7.1.2. Healthcare Resource Utilization  
Frequency counts of hospitalizations, duration of stay, emergency room visits, GCSF use, 
transfusions and analgesic use will be reported descriptively for each treatment arm by cycle. 
9.4.7.2. 
Subgroup Analyses  
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, TFFS and ORR (with a nominal 95% CI) will be 
estimated and plotted within each category of the following subgroups (defined based on eCRF 
data): 
 Age category (≤65 vs. >65 years) 
 ECOG Performance Scale (0-1 vs. 2) 
 Sex (female vs. male) 
 Race (Asian vs. non-Asian) 
 Tissue vs. blood RET mutation detection 
 RET mutation: M918T vs. other 
 Investigator’s choice of treatment with cabozantinib vs. vandetanib 
If a level of a factor includes fewer than 5% of the ITT population, analysis within that level will 
be omitted. Additional subgroup analyses may be performed as deemed appropriate. 
9.5. 
Interim Analyses  
An interim analysis will be triggered after approximately 56 PFS events by BICR have occurred 
(at 75% information fraction). Based on the observed HR of PFS by BICR and pre-specified 
criteria, the study results at interim analysis will be categorized into 4 determination zones: 
efficacious, favorable, promising, and unfavorable.  
 If the study results fall into the efficacious zone, a positive study will be declared due to 
overwhelming efficacy, enrollment will be stopped, and regulatory interactions will be 
initiated.  
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 If the study results fall into the favorable zone, the study will continue to the final 
analysis with the initially planned total number of events at 74 (i.e., no re-estimation will 
be conducted).  
 If the study falls into the promising zone, the total number of events will be increased. 
The events re-estimation will be based on the observed PFS HR according to the method 
provided in Cui et al. (1999). The total number of patients will be increased and 
determined accordingly so that the required number of events could be achieved in a 
desired timeframe. 
 If the study results fall into the unfavorable zone, enrollment will be halted, and the 
study will continue to the final analysis.  
The criteria for each zone will be prespecified in the Adaptive Design Charter. 
The figure below provides an overview of the proposed adaptive design. At the pre-specified 
interim efficacy analysis, the sample size/total number of events for the final analysis will be 
determined. If the study is not declared positive, final analysis will be conducted according to a 
determination zone (favorable, promising, or unfavorable), based on where the interim results 
fall. At final analysis, the study will be declared positive if the critical boundary is met. To 
preserve the type I error, the Rho family alpha spending function (Kim and DeMets 1987) will 
be used to account of multiple analyses, and a weighted test statistic proposed in the CHW 
method will be used as the primary test at final analysis. All significance levels and weights in 
CHW method will be based on the actual number of events observed at the time of analyses. 
 
Abbreviations: IF=Information Fraction; HR=Hazards Ratio 
An independent Data Monitoring Committee (IDMC) will be established to conduct interim 
efficacy and safety analyses and will follow an approved IDMC charter. The IDMC may initiate 
a consultation with an appropriate expert (such as cardiac) if additional expertise is needed 
regarding evaluation of any safety signals. The IDMC will communicate back to a Lilly Senior 
Management Designee (SMD) about their assessment. 
An early safety analysis will be performed after approximately 50 subjects have been 
randomized and had the opportunity to be treated for 2 cycles. This analysis will focus on deaths, 
treatment discontinuations, SAEs, and Grade 3/4 AEs. The IDMC will meet and review data 
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approximately every 6 months thereafter. Detailed information on the role of the IDMC and 
frequency of meetings will be provided in the IDMC charter separate from this protocol. 
For interim efficacy analysis and the sample size re-estimation, the IDMC will be provided with 
pre-specified decision rules as described in the Adaptive Design Charter. The SAC will be 
responsible for preparing and reporting interim efficacy analysis results to the IDMC. This 
practice will ensure that Lilly personnel involved in the day-to-day management and conduct of 
the trial do not have access to unblinded comparative results, even inadvertently. The IDMC will 
review unblinded results and make a recommendation on declaring the study positive for 
overwhelming efficacy or continuing the study with a certain total number of events according to 
the plan. IDMC recommendations will exclude any details of the interim efficacy analysis 
results. 
Following the determination of the required number of events for the final analysis by the IDMC, 
Lilly study team will confirm the total number of patients in order to ensure achievement of the 
required number of events for the final analysis. This determination will be made in a blinded 
manner using the pooled PFS data.  
 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
o Reporting to the sponsor or designee significant issues related to participant safety, 
participant rights, or data integrity 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.  
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study. 
10.1.2. 
Informed Consent Process  
 The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study. 
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 Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.3. 
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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10.1.4. 
Committees Structure  
The primary endpoint TFFS will be assessed by BICR. The BICR will be composed of 
independent radiologists to perform response assessments and determination of disease 
progression per RECIST 1.1 and if needed, independent clinicians to review the case report 
forms (CRF) and determine whether discontinuation for unacceptable toxicity meets the criteria 
for a TFFS event as defined above 
10.1.5. 
Dissemination of Clinical Study Data  
Dissemination of study data will be performed according to all applicable Lilly and international 
policies. 
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. 
10.1.6. 
Data Quality Assurance  
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following: 
 provide instructional material to the study sites, as appropriate 
 provide sponsor start-up training to instruct the investigators and study 
coordinators. This training will give instruction on the protocol, the completion of 
the CRFs, and study procedures. 
 make periodic visits to the study site 
 be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
 review and verify data reported to detect potential errors  
In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site. The study may be audited by the 
sponsor or its representatives and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs. 
The investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
 
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Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, electronic Clinical Outcome Assessment (eCOA) data questionnaires and scales 
will be directly recorded by the patient, into an instrument (e.g., an electronic device). The eCOA 
data will serve as the source documentation and the investigator does not maintain a separate, 
written or electronic record of these data. 
Data collected via the sponsor-provided data capture system will be stored at third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.  
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and the results will be provided to the investigator for 
review and retention. Data will subsequently be transferred from the central vendor to the Lilly 
data warehouse.  
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
10.1.7. 
Source Documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
10.1.8. 
Study and Site Closure  
10.1.8.1. Discontinuation of the Study  
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 
10.1.8.2. Discontinuation of Study Sites  
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP. 
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10.1.9. 
Provisions for Changes in Study Conduct During Emergencies  
There may be times due to exceptional circumstances where it may not be feasible for patients to 
come to investigator sites for study-required visits. To mitigate the risk of patients missing visits, 
to allow patients to safely continue to receive care, and maintain the data integrity of the study, 
the following may be allowed on a case-by-case basis following approval from the sponsor and if 
permitted by local regulations. 
 
Remote/virtual visits and/or extended visit windows may be used. Medically qualified 
site personnel may collect study required information (e.g., AEs, concomitant 
medications, ECOG status, and study treatment compliance) via videoconference 
(preferred) or phone. Visit or cycle windows as defined in the schedule of activities may 
be extended to facilitate the ability to perform study-specific assessments at the site, 
which is preferred to remote/virtual visits. Every effort should be made to return to in-
clinic visits as soon as reasonably possible and safe for the patient and investigator/site 
staff.  
 
Labs, ECGs and/or tumor imaging may be obtained at a local (non-study) site. 
Laboratory results (including reference ranges), ECGs and/or scans obtained at a local 
lab must be filed and reviewed by the study investigator or qualified designee in a timely 
manner.  
 
For patients that meet the protocol criteria to continue or restart dosing, local processes 
may be leveraged to deliver drug directly to patients.  
 
A remote informed consent process may be implemented. 
Site personnel are responsible for documenting in the source records all changes in study 
conduct, relevant communications (patient and sponsor), and dispensing/shipment records of IP 
and indicating the actions taken as a result of exceptional circumstances mitigation. If 
mitigations are approved by the sponsor, additional instructions on the process and 
documentation will be provided to the site. Additional mitigations may be approved by the 
sponsor and will be tracked as protocol deviations as required. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed below will be performed by the indicated laboratory. 
 Local laboratory results are required only in the event that the central laboratory results 
are not available in time for inclusion/exclusion determination, study intervention 
administration, and/or response evaluation or for assessments that are performed 
remotely/virtually. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time (e.g., hepatic safety labs). Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, this should be reported into the CRF as an AE. If there is an abnormal 
laboratory value or abnormal value for any other diagnostic or screening test (e.g., blood 
pressure increased, neutrophils decreased, etc.) and it is known to be related to a 
diagnosis (e.g., hypertension, neutropenia, etc.) this should be reported into the CRF as 
an AE. Do not enter the test abnormality, enter the disease diagnosis or categorical term. 
 Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations, and clinically significant findings 
should be reported in the CRF as an AE. 
 Enrollment and treatment decisions may be based upon local laboratory results. 
Discrepancies between local and central laboratory results will not be considered a 
protocol deviation. 
 
Hematology – local laboratory 
 
Leukocytes (WBC) 
 
Neutrophilsa 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
Erythrocytes (RBC) 
 
Hemoglobin (HGB) 
 
Hematocrit (HCT) 
 
Platelets (PLT) 
Coagulation – local laboratory 
 
Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) 
 
International normalized ratio (INR) or prothrombin time (PT) 
Chemistry –central laboratoryb,c 
Serum concentrations of: 
 
 
Alanine aminotransferase (ALT) 
 
Albumin 
 
Alkaline phosphatase 
 
Aspartate aminotransferase (AST) 
 
Bicarbonate 
 
Bilirubin, total 
 
BUN or blood urea 
 
Calcium 
 
Chloride 
 
Creatinine 
 
Glucose, random 
 
Magnesium 
 
Phosphorus 
 
Potassium 
 
Sodium 
 
Total protein 
Hepatic monitoring –central laboratoryb,c 
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Alkaline phosphatase 
 
Bilirubin, direct 
 
Bilirubin, total 
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Thyroid panel – local laboratory 
 
Triiodothyronine (T3) (free or total, per local standard of care) 
 
Thyroxine (T4) (free or total, per local standard of care) 
 
Thyroid stimulating hormone (TSH) 
Calcitonin, CEA – central laboratory 
Cortisol, ACTH– local laboratory 
Pregnancy test (for female patients of childbearing potential) – local laboratory 
 
Urine or serum, per institutional standard 
 
Urine pregnancy test, if used, must have a minimum sensitivity of 25 IU/L or equivalent units of β-hCG. If 
urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required 
Urine protein – local laboratory d 
Abbreviations: BUN = blood urea nitrogen; DNA = deoxyribonucleic acid; RBC = red blood cells; 
RNA = ribonucleic acid; T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cells. 
Note: Study eligibility and decisions about treatment will be based on local laboratory results. 
a Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands. 
b Treatment and enrollment decisions should be based on local laboratory results. Investigators may use central 
laboratory results to guide treatment and enrollment decisions if local laboratories are not available. Local 
laboratory results are not required to be recorded on a CRF if a sample is sent to the central laboratory at the 
same time.  
c Central laboratory may be used for Lilly investigational analysis. 
d   If urine dipstick shows a positive result then sample should be sent for urinalysis.  
 
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10.3. 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information  
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
 A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required.  
 Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS)c 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days.) 
Highly Effective Methodsb That Are User Dependent  
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
injectable 
 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
oral 
o 
injectable 
 
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 intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction). 
 
 
 
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Collection of Pregnancy Information 
Male participants with partners who become pregnant 
 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female Participants who become pregnant 
 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant's pregnancy.  
 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor as described in Section 8.3.2. While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 
 
 
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10.4. 
Appendix 4: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly medical team. In general, the 
labs below should be sent at first occurrence of Grade ≥3 elevated hepatic lab increases (ALT, 
AST, or direct bilirubin). For subsequent occurrences, these labs may be repeated at the 
discretion of the investigator. 
Hepatic Safety Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin (HGB) 
 
Hematocrit (HCT) 
Hepatic Coagulationa 
Erythrocytes (RBC) 
Prothrombin time (PT) 
Leukocytes (WBC) 
Prothrombin time, INR 
Neutrophilsb 
 
Lymphocytes 
Hepatic Serologiesa,c 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Platelets (PLT) 
Hepatitis B surface antigen 
Hepatitis B virus DNAc 
 
Hepatitis B surface antibody 
Hepatic Chemistrya 
Hepatitis B Core antibody 
Total bilirubin 
Direct bilirubin 
Hepatitis C antibody 
Hepatitis C virus RNA PCRc 
Alkaline phosphatase 
Hepatitis E antibody, IgG 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Hepatitis E antibody, IgM 
Hepatitis E virus RNA PCRc 
Gamma-glutamyl transferase (GGT) 
 
Creatine phosphokinase (CPK)  
Recommended Autoimmune Serology 
 
Anti-nuclear antibodya 
 
Anti-smooth muscle antibodya 
 
Anti-actin antibodya 
Abbreviations: CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells. 
a Assayed by central laboratory. 
b Neutrophils reported by automated differential hematology instruments include both segmented and band forms. 
Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands. 
c Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
 
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10.5. 
Appendix 5: Country-specific Requirements  
10.5.1. 
Discontinuation of Inadvertently Enrolled Patients in the UK and Germany  
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment and 
safety follow up should be performed as outlined in Section 1.3 (Schedule of Activities), 
Section 8.3 (Adverse Events and Serious Adverse Events), and Section 8.2 (Safety Assessments) 
of the protocol. 
 
 
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10.6. 
Appendix 6: RET activating mutations in MTC  
 
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, S904F 
16 
S904C/F, 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. 
No other known validated MTC driver alteration(s). These include RAS or BRAF gene mutations and NTRK 
gene fusions. 
Mutation identified in a tumor, germline DNA or blood sample according to laboratory with CLIA, ISO/IEC, 
CAP, or similar certification, as long as a written Molecular Pathology Report is available and clearly asserts 
the presence of the referenced RET alteration (Dvorakova et al. 2008, Agrawal et al. 2013, Krampitz et al. 2014, 
Ji et al. 2015, Wells et al. 2015, Heilmann et al. 2016, Romei et al. 2016, Kato et al. 2017). 
Abbreviations: CAP-College of American Pathologists; CLIA-Clinical Laboratory Improvement Amendments; 
ISO/IEC-International Organization for Standardization/Independent Ethics Committee; MTC-medullary thyroid 
cancer. 
 
 
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10.7. 
Appendix 7: Restricted and Prohibited Concomitant Medications  
The table(s) below describes the drug class and associated medications that will be restricted or 
prohibited during the study treatment period.  
This is not an all-inclusive list; in general, all strong and moderate CYP3A4 inhibitors, strong 
and moderate inducers of CYP3A4, sensitive CYP2C8 substrates, and protein pump inhibitors 
(PPI’s) are restricted during the study treatment period. Agents known to cause QTc 
prolongation are prohibited in patients receiving selpercatinib or vandetanib during the study 
treatment period. 
Note: Non-systemic (e.g., topical creams, eye drops, mouthwashes, etc.) applications of the 
following are permissible. 
Inhibitors of CYP3A4 
Strong Inhibitorsa 
Moderate Inhibitorsb 
boceprevir 
Amprenavir 
clarithromycin 
Atazanavir 
conivaptan 
Ciprofloxacin 
grapefruit juicec 
Darunavir 
Indinavir 
Diltiazem 
Itraconazole 
Erythromycin 
Ketoconazole 
Fluconazole 
Lopinavir 
Fosamprenavir 
Mibefradil 
Imatinib 
Nefazodone 
Verapamil 
Nelfinavir 
 
Posaconazole 
 
Ritonavir 
 
Saquinavir 
 
Telaprevir 
 
Telithromycin 
 
Voriconazole 
 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4. 
a Increases the AUC of sensitive index substrates of a given metabolic pathway by ≥5-fold. 
b Increases the AUC of sensitive index substrates of a given metabolic pathway by 2- to 5-fold. 
c When excessive amounts are consumed. 
 
 
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Inducers of CYP3A4 
Strong Inducersa 
Moderate Inducersb 
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 sensitive index substrates of a given metabolic pathway by ≥ 80%. 
b Decreases the AUC of the sensitive index substrates of a given metabolic pathway by 50–80%. 
 
Sensitive CYP2C8 substrates 
Repaglinide 
Dasabuvir 
Selexipag 
 
Examples of Proton Pump Inhibitors (PPIs) 
omeprazole  
pantoprazole  
esomeprazole  
rabeprazole  
lansoprazole  
dexlansoprazole  
Note: The above lists are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm. 
 
 
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Examples of Agents Known to Cause QTc Prolongation 
Amiodarone 
ibogaine  
Anagrelide 
Ibutilide 
Azithromycin 
levofloxacin 
Chloroquine 
levomepromazine (methotrimeprazine)  
Chlorpromazine 
levosulpiride  
Cilostazol 
Methadone 
Ciprofloxacin 
moxifloxacin 
Citalopram 
Ondansetron 
Clarithromycin 
papaverine HCl (intracoronary) 
Cocaine 
Pentamidine 
Disopyramide 
Pimozide 
Dofetilide 
procainamide 
domperidone  
Propofol 
Donepezil 
Quinidine 
Dronedarone 
roxithromycin  
Droperidol 
Sevoflurane 
Erythromycin 
Sotalol 
Escitalopram 
sulpiride  
Flecainide 
sultopride  
Fluconazole 
terlipressin  
halofantrine  
terodiline  
Haloperidol 
Thioridazine 
hydroquinidine, dihydroquinidine  
 
Note: The above list is not exhaustive. Please refer to https://www.crediblemeds.org/for a current 
list of agents known to cause QTc prolongation as well as agents with a possible or conditional 
risk.  
Examples of H2 blocking agents 
Famotidine 
cimetidine 
Ranitidine 
nizatidine 
Note: The above lists are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm 
 
 
 
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10.8. 
Appendix 8: Country-Specific Requirements  
The country-specific addenda presented in this appendix must be performed in each of the 
respective countries, in addition to all procedures required by current version of Protocol J2G-
MC-JZJB (JZJB) where applicable. The consolidation of these country-specific addenda into this 
appendix is to facilitate transition of this trial to the CTIS system under the new clinical trial 
regulation in Europe. 
10.8.1. 
Addendum 3.1 (Country-Specific Content for Germany)  
This addendum addresses the additional requirements for Study JZJB sites in Germany. 
The following table describes the changes being made to Protocol JZJB for participants in 
Germany. 
Main Protocol Section # and Name 
Description of Change 
5.1. Inclusion Criteria 
Modified criterion 1 to remove text related to 
allowing participants as young as 12 years of age. 
 
Protocol Revisions 
For JZJB Protocol Addendum, additions have been identified by use of underscore and deletions 
have been identified by strikethrough. 
Section 5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Are of an acceptable age to provide informed consent according to local regulations and 
are at least 18 years of age (patients as young as 12 years of age will be allowed if 
permitted by local regulatory authorities and institutional review boards). 
 
 
 
 
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10.8.2. 
Addendum 8 (Country-Specific Content for the Netherlands)  
This addendum addresses feedback from the METC of the Netherlands Cancer Institute (Central 
Ethics Review Board). 
The following table describes the changes being made to Protocol JZJB for participants in the 
Netherlands. 
Main Protocol Section # and Name 
Description of Change 
5.1. Inclusion Criteria 
Modified criterion 1 to allow participants at least 
16 years of age. 
Protocol Additions 
Section 5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Are of an acceptable age to provide informed consent according to local regulations and 
are at least 16 years of age. 
 
 
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10.8.3. 
Addendum 10 (Country-Specific Content for the Czech Republic)  
This addendum addresses feedback from The Czech Competent Authority (Státní ústav pro 
kontrolu léčiv (SUKL). 
The following table describes the changes being made to Protocol JZJB for participants in the 
Czech Republic. 
Main Protocol Section # and Name 
Description of Change 
1.3.2. Screening, On-Study, and Post-Study 
Treatment Follow-Up Schedule of Activities for 
Patients on Arm A and Arm B 
After screening period pregnancy test 24 hours 
prior to first dose, a monthly pregnancy test must 
be performed on women of child-bearing potential 
during study drug treatment 
1.3.4. Optional Crossover Treatment (for patients 
crossing over from Arm B to Arm A) 
After screening period pregnancy test 24 hours 
prior to first dose, a monthly pregnancy test must 
be performed on women of child-bearing potential 
during study drug treatment 
Protocol Additions
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Section 1.3.2. Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and 
Arm B 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
 
Screening 
On-Treatment 
Cycle = 28 days 
Safety assessments 
prior to crossover  
(only for patients on  
Arm B) 
Post-Study Treatment 
 
(Day Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-term 
Follow-upa 
Long term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 1-30 
(±7 days) 
1-x 
days 
(30 ± 7 days) 
(90 ± 14 
days) 
28
7
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
N/A 
N/A 
V801 
V802-8XX 
 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Test 
 
X 
X 
See Instructions 
See Instructions 
X 
 
 
Applies only to women of 
childbearing potential. 
• Note: during study 
treatment, perform at 
screening, C1D1 (within 24 
hours prior to first dose of 
study drug), and monthly 
(+/-7 days) thereafter as 
required per local 
regulations and/or 
institutional guidelines.  
• See Appendix 2 
 
 
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 Section 1.3.4. Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
 
Crossover 
Screening 
On-Treatment 
Cycle = 28 days 
Post-Study Treatment 
 
Visit 300 (Day 
relative to start of 
treatment) 
Visit 301 
Cycle 1 
Visit 302-n 
Cycle 2-n 
Short-term 
Follow-upa 
Long 
term 
Follow-
upb 
Instructions 
(±3 days) 
(±3 days) 
(30 ± 7 days) 
(90 ± 14d
ays) 
≤42 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D 
22 
V801 
V802-
8XX 
  
Procedure 
 
  
  
  
  
  
 
  
 
  
  
  
Pregnancy Test 
X 
X 
  
  
 See Instructions 
  
  
 X 
  
• Applies only to women of 
childbearing potential. 
• Note: during study treatment, 
perform C1D1 (within 24 hours 
prior to dose) and monthly (+/-7 
days) thereafter as required per local 
regulations and/or institutional 
guidelines.  
• See Appendix 2. 
 
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10.8.4. 
Addendum 11 (Country-Specific Content for Belgium)  
This addendum addresses protocol items to comply with local laws and regulatory requirements 
in Belgium. 
The following table describes the changes being made to Protocol JZJB for participants in 
Belgium. 
Main Protocol Section # and Name 
Description of Change 
5.1. Inclusion Criteria 
Modified criterion 10 to add duration of 4 months 
regarding the use of a highly effective 
contraceptive method following the last dose of 
study drug. Removed text related to condom use. 
 
Modified criterion 11 to add text regarding use of 
highly effective contraceptive method for at least 
4 months after the last dose of study drug. 
5.2. Exclusion Criteria 
Modified criterion 26 to add having known 
hypersensitivity to any of the excipients of 
“selpercatinib”. 
6.5. Concomitant Therapy 
Added sentence indicating that caution should be 
used when co-administration of P-gp, MATE1, or 
BCRP substrates cannot be avoided in patients 
receiving selpercatinib. 
6.5.1. CYP3A4 Inducers or Inhibitors 
Added text regarding the co-administration of 
selpercatinib with sensitive CYP3A4 substrates. 
1.3.2. Screening, On-Study, and Post-Study 
Treatment Follow-Up Schedule of Activities for 
Patients on Arm A and Arm B 
Modified text in Instructions column for 
pregnancy test timing to meet local regulations. 
 
Protocol Additions 
The revised text in the following sections show the changes applicable to patients in Belgium. 
All additions have been identified by the use of underscore; and deletions have been identified 
by strikethrough. 
Sections 5.1. and 5.2. Inclusion and Exclusion Criteria  
10.      Men with partners of childbearing potential or women of childbearing potential must 
agree to use a highly effective contraceptive method (for example, intrauterine device 
[IUD], birth control pill, or barrier method) during treatment with study drug and for 4 
months following the last dose of study drug (for men and women).  If a condom is used 
as a barrier contraceptive, a spermicidal agent should be added as double-barrier 
protection.  See Appendix 3. 
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Note:  Unless not allowed by local regulations, women of childbearing potential who are 
abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must agree to either 
remain abstinent or stay in a same-sex relationship without sexual relationships with 
males unless they agree to use contraceptive method known to be highly effective. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception. 
 
11. 
Women of childbearing potential must  
 have a negative pregnancy test (serum or urine, consistent with local regulations) 
documented within 24 hours prior to treatment with study drug. 
 not be breast-feeding during treatment and for at least 4 months after the last dose of 
study drug.  
 agree to use a highly effective contraceptive method for at least 4 months after the last 
dose of study drug. 
 
26. 
Have a known hypersensitivity to any of the excipients of either cabozantinib, or 
vandetanib, or selpercatinib. 
 
Section 6.5. Concomitant Therapy 
Patients receiving selpercatinib should avoid concomitant use of CYP2C8-sensitive substrates.  
If co-administration of a CYP2C8-sensitive substrate cannot be avoided, monitor patients for 
increased adverse reactions of these drugs. 
Caution should be used when co-administration of a P-gp substrate (e.g., fexofenadine, 
loperamide, digoxin), MATE1 substrate (e.g., metformin) or BCRP substrate (e.g., sulfasalazine) 
cannot be avoided in patients receiving selpercatinib.  Consider increased monitoring as 
appropriate. 
 
Section 6.5.1. CYP3A4 Inducers or Inhibitors 
For patients receiving selpercatinib:  The concomitant use of the strong CYP3A4 inhibitors or 
inducers should be avoided.  See Appendix 7. 
If, during the study, patients require initiation of treatment with strong inhibitors or inducers of 
CYP3A4 for clinical reasons, investigators should consider increased monitoring for the 
development of new AEs. 
Co-administration of selpercatinib with sensitive CYP3A4 substrates may increase their plasma 
concentrations, which may increase the incidence or severity of adverse reactions for sensitive 
substrates with narrow therapeutic windows.
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Section 1.3.2. Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and 
Arm B  
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
 
Screening 
On-Treatment 
Cycle = 28 days 
Safety 
assessments 
prior to 
crossover  
(only for 
patients on  
Arm B) 
Post-Study 
Treatment 
 
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-n 
V201a 
Short-
term 
Follow
-upa 
Long 
term 
Follo
w-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 
1-30 
(±7 
days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 
14 
days) 
2
8
7
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
N/A 
N/A 
V801 
V802-
8XX 
 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
X 
See Instructions 
X 
See Instructions 
See 
Instructions 
X 
 
• Applies only to women of childbearing 
potential. 
• Note:  during study treatment, perform at 
screening, C1D1(within 24 hours prior to first 
dose of study drug), and on day 1 of each 28 
day treatment cycle thereafter as required per 
local regulations and/or institutional 
guidelines.  
• See Appendix 2 
 
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10.8.5. 
Addendum 12.2 (Country-Specific Content for Czech Republic, Germany, Italy, 
Netherlands, Poland, Spain, Brazil, United States, United Kingdom, Australia, 
and Canada)  
This addendum addresses protocol items to comply with local laws and regulatory requirements 
in the Czech Republic, Germany, Italy, Netherlands, Poland, Spain, Brazil, United States, United 
Kingdom, Australia, and Canada. 
The following table describes the changes being made to Protocol JZJB. 
Main Protocol Section # and Name 
Description of Change 
Addition of addendum  
Details how a study participant’s perspective on 
the secondary endpoint of comparative tolerability 
will be obtained and evaluated 
 
1. Rationale for Addendum 
This addendum is part of a comprehensive research plan related to the secondary endpoint of the 
trial evaluating comparative tolerability. This addendum details how a study participant’s 
perspective on the secondary endpoint of comparative tolerability will be obtained and evaluated. 
J2G-MC-JZJB (JZJB) includes a comparative tolerability endpoint as a key secondary outcome 
based on the comparison of high-side-effect bother of study treatment arms as assessed by the 
FACT-GP5. In addition to the quantitative data collection and analyses described in the protocol, 
complementary qualitative data via semi-structured participant interviews will be obtained at the 
sites in participating countries. To understand if the FACT-GP5 captures the participant 
experience and to explore factors related to the endpoint definition and responder threshold, the 
sponsor seeks to solicit direct feedback from participants about these concepts. An appendix 
titled “Participant Interview Guide” has been added as supporting documentation to this 
addendum describing the interview procedure. 
 
2. Qualitative Interviewing Research Plan 
2.1. Objectives 
The overall objectives of these qualitative interviews are to understand 
1) The concept of tolerability from the participant’s perspective 
a. Experience of symptomatic (participant-felt) adverse events (AEs) since initiating 
study treatment in the clinical trial 
i. Description of symptomatic AEs 
ii. Onset or trajectory of symptomatic AEs 
iii. Bother or burden of these AEs, including most bothersome or least bothersome 
AE(s), and 
iv. Impact of AEs on their lives. 
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2) Interpretation or meaning of the concepts associated with the endpoint, and 
a. Side-effect bother 
b. Side-effect burden, and 
c. Tolerability. 
3) How participants interpret the FACT-GP5 item and response choices, including their 
perception of which response option constitutes “high-side-effect bother” and at what point they 
would speak to their doctor about changing the treatment or stopping/discontinuing the treatment 
(“impacts their ability or desire to adhere to the dose or intensity of therapy”). 
2.2. Methodology 
2.2.1. Overview 
An independent vendor (Modus Outcomes®) paid by the sponsor will interview a subset of 
participants who are enrolled in Study JZJB. Enrollment will continue until conceptual saturation 
has been reached (described below). These interviews will comprise 2 parts, (a) concept 
elicitation to collect information about the participant’s experience of side effects and their 
interpretation or meaning of the concepts associated with the endpoint, and (b) cognitive 
debriefing of the FACT-GP5 item (a patient-reported outcome [PRO] question that assesses the 
overall burden of side effects) to assess participants’ interpretation of the item and response 
choices. These interviews will be recorded, transcribed, and analyzed using inductive thematic 
coding. Modus Outcomes will follow the sponsor’s data management and pharmacovigilance 
policies.  
2.2.2. Study Steps 
2.2.2.1. Site Initiation Meetings 
Modus Outcomes will schedule a virtual meeting with site coordinators to describe the nature of 
the qualitative interviews and explain the screening process, the procedure to obtain informed 
consent, and the process by which to securely send contact information to Modus Outcomes. 
This meeting will be a 30-minute telephone call and provides a base knowledge for site 
coordinators and study personnel about the qualitative study. 
Modus Outcomes will send a confirmation email to sites after the site initiation meeting has 
taken place to serve as a record of completion. This communication will also provide sites with 
Modus Outcomes’ contact information should any screening or consent questions arise during 
the course of the study that need immediate attention. 
2.2.2.2. Scheduling Participants 
Once a participant consents to being contacted, the site will send Modus Outcomes a copy of this 
completed form using a secure cloud-based upload (Citrix ShareFile). The original consent form 
will be stored at the site. A Modus Outcomes researcher will follow up with the participant for 
further screening and to schedule an interview. 
2.2.2.3. Recording and Transcription 
Interviews will be recorded and transcribed using an independent transcription agency. All 
information that could identify a participant, for example, if they state full name or address 
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during recorded interview, will be redacted from the transcript, so an anonymized version will be 
used for all analyses. These transcribed interviews will serve as units for analysis and qualitative 
coding. 
2.2.3. Population and Sample Size 
Adult participants on active study treatment in Study JZJB will be eligible to enroll in this 
addendum. Enrollment can occur at any time after baseline (Cycle 1). Additional informed 
consent will be required prior to completing a qualitative interview. Enrollment will be continued 
until conceptual saturation (as described in Section 2.3.2) has been reached; up to 40 interviews 
will be conducted if conceptual saturation is not reached with fewer interviews.  
2.2.4. Conduct of Interviews 
2.2.4.1. Schedule for Interview 
Participants will be eligible for inclusion in the qualitative interview after they start study 
treatment and completed the FACT-GP5 on Day 1 of the first Cycle and have been consented by 
the site. Participants in JZJB who are exempt from completing PRO instruments will not be 
eligible for the qualitative interview. Participants who consent to participate in this study will be 
contacted by Modus Outcomes to schedule and conduct the interview. The ideal window for the 
interview is 10 to 14 weeks from start of treatment based on the FDA’s recommendation for 
when peak toxicity can be accurately evaluated (session 2 of the 2020 FDA ASCO workshop; 
https://www.fda.gov/media/140370/download). However, the interview may occur at any time 
and will be conducted in the preferred language of the participant. 
2.2.4.2. Interview Components 
The semi-structured interviews will contain the following components: 
• The concept elicitation section of the interviews will begin with open-ended questions. 
Participants will be encouraged to describe their experience in their own words. Targeted 
probes will be used to obtain specific information on concepts of interest after the 
participant has been given the opportunity to respond to the open-ended questions 
spontaneously. 
• Cognitive debriefing will be conducted with the single-item FACT-GP5 instrument. 
Participants will be asked about the item’s clarity and relevance, and their understanding 
and interpretation of the recall period and response options. 
• Interpretation of high- versus low-side-effect bother will consist of participants describing 
the difference between each level of the response scale and which response level is tied to 
their perception of tolerability. 
2.2.4.3. Pharmacovigilance 
All interviewers will complete the sponsor’s pharmacovigilance training prior to conducting 
participant interviews. Interviewers will determine whether AEs should be reported to sites or 
directly to the sponsor according to the sponsor’s standards and procedures. Internal standard 
operating procedures at Modus Outcomes include senior review of AE forms and sign-off prior 
to reporting for quality assurance. The sponsor will supply an AE form to submit the documented 
patient report of a given event. 
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2.3. Analysis 
2.3.1. Qualitative Analysis 
For interviews conducted in a language other than English, transcripts will be translated into 
English. The transcripts will be analyzed thematically with inductive coding methods (Braun 
and Clarke 2006) using detailed line-by-line open and inductive coding (Bryman and Burgess 
2002; Thomas 2006; Bowling 2009) with ATLAS.ti software using a general inductive 
approach (Thomas 2006). This means that, based on the content of the transcripts, relevant 
participant quotes will be assigned short codes, which will be used to organize the data. 
Coding will be tailored to the research objectives of the study: understanding the participant 
experience of AEs, and their understanding of the concepts of tolerability, bother, and burden. 
Independent parallel coding will be used to initiate the coding and ensure consistency using 
the first 2 transcripts. The lists of codes and associated quotes obtained by the independent 
coders will be compared for overlaps and inconsistencies. The coding will be revised as 
needed to reach coder agreement following the identification of new concepts in the remaining 
transcripts. A data dictionary will be developed and modified as necessary throughout the 
process and codes will be cleaned by a senior researcher. Codes will be inductively 
categorized based on coherent patterns into higher order conceptual domains forming a 
conceptual model using standard analytical techniques (Bryman and Burgess 2002; Bowling 
2009; Klassen et al. 2009). 
A codebook will be developed after the first 2 interviews are coded and will be modified as more 
codes are added. After each set of 5 interviews, the sponsor will conduct saturation analysis and 
will complete and discuss with the sponsor a table summarizing the way participants define 
bother, burden, and tolerability. 
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Table 1. Tracking Matrix: Concepts of Interest  
Concepts of 
Interest 
Code 
Illustrative 
Patient Quotes 
Underlying 
Symptomatic AEs 
or Impacts, as 
Described by 
Patient 
Importance in Tolerability 
Perception 
(Ability or Desire to 
Adhere) 
Bother 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
Burden 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
Tolerability 
 
 
 
 
 
Once coding is complete, findings from the interviews will be used to develop a conceptual 
framework of the participant experience of tolerability of treatment for thyroid cancer. The 
sponsor will ensure that the themes represented in the conceptual framework reflect the meaning 
of the data to provide an accurate representation of the participant experience of tolerability. 
2.3.2. Saturation Analysis 
A saturation analysis will be conducted to determine how much new information on the 
participant experience is obtained in each group of 5 interviews. The transcripts will be ordered 
chronologically, based on the interview completion dates, and then divided into groups of 5 
transcripts. If important new concepts providing significant information regarding the 
components of side-effect burden/bother/tolerability arise in the last group, additional interviews 
will be considered to ensure all relevant concepts are elicited (principle of saturation). An 
example of a saturation table is provided below. 
 
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Table 2. Sample Saturation Table  
Interviews 
1-5 
6-10 
11-15 
16-20 
21-25 
25-30 
 
New Concepts New Concepts New Concepts New Concepts New Concepts New Concepts 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
 
… 
 
New Concepts per 
Group 
10 
5 
4 
2 
1 
0 
 
2.3.3. Cognitive Debriefing 
For interviews conducted in a language other than English, transcripts will be translated into 
English. The transcripts will be analyzed for participant feedback on the FACT-GP5. Structured 
codes will be used to compile data on understanding of instructions (specifically impact of 7-day 
recall period on item completed daily), appropriateness, comprehensiveness and understanding 
of item content, interpretation of item response options, relevance of the response options, and 
participant’s perspectives on the interpretation and relevance or meaningfulness of the thresholds 
between answer choices (most specifically between somewhat and quite a bit), and the 
participant opinion on where the threshold is for high-side-effect bother. 
Table 3. Sample Cognitive Debriefing Summary Table  
Relevance 
Clarity, Comprehension, 
and Interpretation 
Retrieval of 
Information 
Response 
Option 
Feedback 
Meaning of 
Response Options 
Is the FACT-GP5 relevant to 
their experience of 
bother/burden/tolerability? 
Does it summarize the 
patient experience 
appropriately? 
How do patients 
understand the item? 
Do they interpret as 
intended? (to be discussed 
since we need to clearly 
define what was intended) 
What do patients 
consider when 
arriving at a 
response? 
(symptoms, 
impacts, timeframe, 
etc.) 
Are response 
options 
appropriate for 
respondents? 
 
Description of 
meaning and 
differences between 
all options. 
 
Table 4. Participant Opinion on Threshold for High-Side-Effect Bother  
Response Option at Which: 
A Little Bit 
Somewhat 
Quite a Bit 
Very Much 
“high-side-effect bother” starts 
n 
n 
n 
n 
They no longer consider current 
treatment “tolerable”a 
n 
n 
n 
n 
Abbreviation: n = number 
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a Defined as “affects the ability or desire of the participant to adhere to the dose or intensity of therapy.” 
2.4. Reporting 
A summary of the study findings will be compiled in a final report developed by Modus 
Outcomes. This report will include recommendations for how best to measure this concept and 
aid interpretation of the participant experience of tolerability with selpercatinib, cabozantinib, 
and vandetanib in MTC. Additionally, the anonymized transcripts will be provided to the 
sponsor. Provided that the recording does not contain any identifiable information, these 
recordings will be provided to the sponsor; however, any recordings that include information that 
required anonymization at the transcript level will not be shared with the sponsor. 
2.5. 
General Information 
2.5.1. Data Transfer, Management, and Storage 
All personal data collected during this study will be de-identified according to Modus Outcomes’ 
internal Quality Management System. If needed, de-identified data will be shared with the 
regulatory agency should they request such information. 
Modus Outcomes uses an encrypted Citrix ShareFile server for data transfer from external 
parties and for storing all electronic project data. A specific folder will be created to upload or 
download the data that will be accessible only with a login and password, in compliance with 
regulatory guidance, for example, FDA, 21 CFR Part 11. Duplicate copies of electronic data are 
destroyed at the conclusion of the study. Master copies of all electronic data generated during the 
research study will be retained for 7 years after the conclusion of the study. After 7 years, these 
electronic data are destroyed using secure delete methods. 
All analyses will be performed by trained and experienced Modus Outcomes personnel. Modus 
Outcomes’ quality control process will be applied to ensure data integrity and accuracy of the 
results. 
2.5.2. Ethical and Regulatory Considerations 
2.5.2.1. Participant Data Protection 
All participants will be assigned a separate, unique identifier, and computer-processed data will 
be identified by this unique identifier only, thereby ensuring that participants’ identities remain 
unknown to the sponsor and cannot be linked to the primary clinical trial ID. As outlined in 
Section 2.1.4, no data that could identify a participant’s identity will be provided to the sponsor. 
2.5.2.2. Ethical Conduct of Study 
The investigator and research personnel will conduct this study in accordance with ethical 
principles outlined in the Declaration of Helsinki. Research practices will be guided by Good 
Clinical Practice and regulatory requirements as applicable. 
2.5.2.3. Risks and Benefits to Participants 
This is a non-interventional plan. Participants will be informed that there is no specific health 
benefit to participation in these interviews; there is minimal risk posed to participants by 
participating in interviews. During or following concept elicitation and cognitive debriefing, 
participants may become more cognizant of aspects of their condition, including the symptoms 
and impacts of symptom severity they experience. This method of interviewing may cause 
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feelings of discomfort. Despite the efforts to protect participant privacy and to anonymize all 
data collection documents, there remains a potential risk of loss of participant confidentiality. 
Otherwise, there are no other risks of participation in these interviews. If participants have 
questions or concerns related to their condition or medical treatment, they will be encouraged to 
speak with their health care provider. 
3. References 
Bowling A. Research methods in health: investigating health and health services. 3rd ed. Open 
University Press; 2009. 
Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77-90. 
http://doi.org/10.1191/1478088706qp063oa 
Bryman A, Burgess B. Analyzing qualitative data. Routledge; 2002. 
Klassen AF, Pusic AL, Scott A, et al. Satisfaction and quality of life in women who undergo 
breast surgery: a qualitative study. BMC Womens Health. 2009;9:11. 
http://doi.org/10.1186/1472-6874-9-11 
Thomas DR. A general inductive approach for analyzing qualitative evaluation data. Am J Eval. 
2006;27(2):237-246. 
4. Supporting Documentation 
4.1 Appendix [10]: Participant Interview Guide 
Introduction  
Introduce yourself and the purpose of the study 
Hello, my name is [Interviewer name] and I work for Modus Outcomes. Modus Outcomes is a 
company that talks to people about various health conditions. Currently, we are working with a 
pharmaceutical company to find out more about your experience in the LIBRETTO-531/JZJB 
trial. 
Interview procedures 
Today, you will have the opportunity to tell me about your experience in the trial, specifically 
about how you felt during the trial, including any side-effects you might have experienced and 
how they have affected you and your life. This discussion will last approximately 60 minutes. If 
you need to take a break or want to end the interview for any reason, you can do so at any time.  
Before we start the discussion, I’d like to take a moment to describe how we will use the 
information you tell me today. As a participant in this trial, you’ve been asked to answer 
questions about how you feel and function on a “digital device” that looks like a cell phone or 
tablet. When we analyze and report the answers that all of the patients in this trial have sent us 
(you included), it’s important that we do it in a way that’s accurate. In other words, we want to 
get it right and report everyone’s answers in a way that’s true to your experiences. We’re not 
going to ask you to think back and remember your answers you’ve sent, but we will take a look 
at one of the questions you’ve been asked so you can help us understand how patients like you 
answer and what you think about it.  
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I will start by asking you open-ended questions about your experience taking the cancer 
treatment you are receiving in the study, and may ask more specific questions later to make sure 
I understand what you mean. Then I will ask questions about some other topics, including how 
you think about side-effect burden or bother, and will ask for your feedback on one of the 
questions you have been asked in the trial.  
There aren’t any “right” or “wrong” answers to the questions I will ask you today. We are really 
interested in knowing about YOUR experience, so we appreciate anything you can tell us.  
Audio recording 
This interview will be audio recorded to make sure we capture all the information you share with 
us. Please try to speak clearly. If you need to take any breaks, please let me know. I can pause 
the recording at any time. 
Anonymity and data handling 
Recordings will be transcribed by an independent transcription agency. All information that 
could identify you will be left out of the transcriptions. These de-identified transcripts will be 
shared with the study sponsor and used in our analysis. Results of this interview will be 
anonymized, so no answers are attributable to any specific individual. 
Adverse event reporting 
During the interview, we will discuss your experience while taking the trial drug, including any 
side effects. We are required to report this to the company even if it has already been reported by 
you directly or by your physician to the company or the regulatory authorities. You will remain 
anonymous and only be identified by your participant ID number. 
Closing 
Do you have any questions for me before we begin? 
Answer any questions that the participant may have. Ensure that they agree to have the 
interview recorded for the designated amount of time. Start the recording. State your name and 
the participant ID of the person you are interviewing along with the current date and time of 
the interview. 
This is [Interviewer name] with participant [participant ID]. It is [date] at [time]. Do you agree to 
have this interview recorded?  
Concept elicitation 
Side effects from trial drug and impact on life 
1. Can you begin by telling me how long have you been participating in the clinical trial? 
2. Have you experienced any symptoms or side effects since you started the cancer treatment as 
part of this clinical trial? Can you tell me the different side-effects you’ve experienced? 
a. PROBE: [for each side effect] Can you describe what [side effect] was like? 
b. PROBE: [for each side effect] When did you first experience [side effect]? 
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c. PROBE: [for each side effect] How long did [side effect] last? 
d. PROBE: [for each side effect] Did [side effect] tend to get better or worse day-to-day? 
How does it/did it get better or worse?  
e. PROBE: [for each side effect] Did that side-effect bother you?  
i. As needed: How much did it bother you?  
ii. Why did it bother you? 
f. PROBE: What was the impact of [each side effect] on your daily life? 
3. Of the side-effects you’ve experienced since taking the treatment for this study, which bothered 
you the most? Which bothered you the least? 
4. How have these side effects affected your daily life?  
5. Can you tell me, in your own words, what “bothered by side-effects of treatment” means to 
you? 
a. When talking about side-effects, is there a difference between the word “bother” and 
the word “burden”, or do they mean the same thing?  
[Note: if patient is unfamiliar with the term “burden,” the following probes may be 
skipped.] 
i. Probe: How do you describe the difference between bother and burden?  
ii. Probe: If we were to ask you how all of the side-effects you’re currently 
experiencing impact you, would you prefer me to use the word bother or 
burden? 
6. If I were to ask you “do you think the study treatment you’re taking is tolerable” what do you 
think of when answering?  
a. PROBE: What does the word tolerable mean to you? 
b. PROBE: Do you think “side-effect bother”, as we discussed earlier, is related to 
tolerability? 
c. PROBE: Do you think “side-effect burden”, as we discussed earlier is related to 
tolerability? 
i. What makes a cancer treatment tolerable? 
ii. What makes a cancer treatment not tolerable? 
d. At what point would you speak to your doctor about changing your treatment? 
i. PROBE: Does this vary according to the number of side-effects? 
(type/duration/severity?) 
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e. At what point would you speak to your doctor about stopping/discontinuing treatment? 
i. PROBE: Does this vary according to the number of side-effects? 
(type/duration/severity?) 
[NOTE: if patient indicated a strong preference for bother or burden above, or does not 
know what one of the words means, only ask the applicable question here] 
7. What is it like to have side effects over a long period of time that are bothersome/burdensome? 
a. How long is a “long time”?  
b. Are some side effects more or less bothersome/burdensome over time?  
8. How do you tell the difference between symptoms of your cancer and side effects of treatment? 
9. Did you discontinue study treatment earlier than planned? 
a. PROBE (if yes): Why? 
 
 
 
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Cognitive debriefing of the FACT-GP5 
Initial debriefing of item 
Direct the patient’s attention to the FACT-GP5 and explain that we would like their feedback about this 
question - “Here is an image of a question you have been asked during the trial”. 
Instruct patient to read the question aloud and let them know that the interviewer will ask follow-up questions 
afterwards. Ask them to verbalize their thinking process and point out anything that seems vague, difficult to 
understand or to respond to, or not relevant to them. 
Reassure the patient that we are looking for honest feedback on the item, and we hope to learn from them. 
There are no right or wrong things to say.  
Inform the patient that follow-up questions will be asked to understand their perspective on the following: 
 
Clarity of instructions 
 
Format of question 
 
Item understanding, relevance, and interpretation  
 
Response option understanding, coverage, and consistency 
1. What does this question mean to you in your own words? 
a. Is there anything unclear about this question? If yes, how would you ask the 
question to make it easier to understand? 
2. When you have been asked this question during the study, what did you think about while 
answering? 
3. What was it like for you to think back over the past 7 days while answering?  
Response options and thresholds 
In the question above, there are different answer choices. We call those “response options”. I am 
going to ask you about each of those response options now. 
1. Can you describe for each of the following response options: 
a. What it means in your own words? 
b. What it would mean if you chose that answer during the trial?  
c. How you would experience the side effect at each answer level? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
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2. Can you describe the difference between each category in your own words? Specifically, 
what would be different for you if you moved from one category to the next?  
a. Not at all to a little bit 
b. A little bit to somewhat 
c. Somewhat to quite a bit 
d. Quite a bit to very much 
3. If you had to draw the line between two response options and on one side it meant “high 
side-effect bother” and on the other side it meant “not high side-effect bother” – where 
would that line be? 
4. Thinking about cancer treatment in general, what side effect frequency/response option 
would be associated with you stopping treatment? 
5. [if time remains] If you were asked this question about how much you were bothered by 
side-effects at the beginning of the trial, before you took the study treatment for the first 
time, how would you answer?  
 
Closing 
Opportunity for participant to share additional information 
Those are all the questions I have for you today. Is there anything else you want to tell me about 
your experience in the clinical trial and side effects that would be important for researchers to 
know?  
[Follow up as appropriate.] 
Closing the interview 
Thank you very much for helping us with this research. We appreciate your time and effort!  
Conclude recording and close the interview.  
 
 
 
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10.8.6. 
Addendum 13.1 (Country-Specific Content for All Study Countries)  
This addendum addresses protocol items to comply with local laws and regulatory requirements 
in all participating countries. 
The following table describes the changes being made to Protocol JZJB. 
Main Protocol Section # and Name 
Description of Change 
1.3.2. Screening, On-Study, and Post-Study 
Treatment Follow-Up Schedule of Activities for 
Patients on Arm A and Arm B 
To provide clarification regarding the modality of 
imaging used for monitoring for premature 
growth plate closure 
1.3.4. Optional Crossover Treatment (for patients 
crossing over from Arm B to Arm A) 
To provide clarification regarding the modality of 
imaging used for monitoring for premature 
growth plate closure 
8.2 Safety Assessments 
Correction 
 
Rationale for Addendum 
The purpose of this addendum is to provide clarification regarding the modality of imaging used 
for monitoring for premature growth plate closure. For sites where the standard of care for this 
monitoring is bone age assessment, a radiograph of the hand will be used rather than MRI of the 
knee. 
Protocol Additions 
All deletions have been identified by strikethroughs and all additions have been identified by the 
use of underscores. 
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Section 1.3.2. Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and 
Arm B 
Screening, On-Study, and Post-Study Treatment Follow-Up Schedule of Activities for Patients on Arm A and Arm B 
  
Screening 
On-Treatment 
Safety assessments 
prior to crossover 
Post-Study Treatment 
  
Cycle = 28 days 
(only for patients 
on Arm B) 
  
(Day 
Relative 
to C1D1) 
Cycle 1 
Cycle 2-
n 
V201a 
Short-term 
Follow-upa 
Long-term 
Follow-upb 
Instructions 
(±3 days) 
(±3 days) 
Day 1-30 
(±7 days) 
1-x 
days 
(30 ± 7 
days) 
(90 ± 14 
days) 
42
7
D1 
D8 
D15 
D1 
N/A 
N/A 
V801 
V802-8XX 
  
Procedure 
  
  
  
  
  
  
  
  
  
  
  
Growth plate 
imaging 
X 
  
See instructions 
  
 
 
 
Only for patients <18 years of age who have not 
reached full adult height. Knee MRI Hand 
radiograph at baseline and every 6 months ±2 
weeks). See Section 8.2. 
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Section 1.3.4. Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
Only applicable for patients initially randomized to Arm B (cabozantinib or vandetanib) who have progression that is confirmed by 
the BICR and who are eligible for crossover treatment. 
Optional Crossover Treatment (for patients crossing over from Arm B to Arm A) 
  
Crossover 
Screening 
On-Treatment 
Post-Study 
Treatment 
  
Cycle = 28 days 
Visit 300 
(Day 
relative to 
start of 
treatment) 
Visit 301 
Visit 302-n 
Short-
term 
Follow-
upa 
Long-term 
Follow-upb 
Instructions 
Cycle 1 
Cycle 2-n 
(±3 days) 
(±3 days) 
(30 ± 7 
days) 
(90 ± 14 
days) 
  
≤42 
D1 
D8 
D15 
D1 
V801 
V802-
8XX 
  
Procedure 
  
  
  
  
  
  
  
  
Growth plate 
imaging 
  
See instructions 
  
  
Only for patients <18 years of age who have not 
reached full adult height. Knee MRI Hand 
radiograph at baseline and every 6 months (±2 
weeks). See Section 8.2. 
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Section 8.2. Safety Assessments 
Participants who have not yet obtained full adult height will undergo MRI of one knee 
radiograph of one hand at baseline and every 6 months while the growth plates remain patent. 
Right knee is preferred, but Whichever knee hand 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 hand should be obtained 
and MRI further monitoring performed only if the growth plates remain patent. If the growth 
plates remain patent, the patient will have a MRI radiograph performed every 6 months until the 
growth plates are no longer patent. 
 
 
 
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10.9. 
Appendix 9: Abbreviations and Definitions 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATA 
American Thyroid Association 
ATP 
adenosine triphosphate 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, 
which is used as an investigational medicinal product 
blinding 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
BICR 
blinded independent central review 
BID 
twice daily 
BOR 
best overall response 
BUN 
Blood Urea Nitrogen 
CAP 
College of American Pathologists 
CEA 
carcinoembryonic antigen 
cfDNA 
circulating free DNA 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
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CLIA 
Clinical Laboratory Improvement Amendments 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CONSORT 
Consolidated Standards of Reporting Trials 
cORR 
confirmed ORR 
CRF 
case report form 
CRP/CRS 
clinical research physician/scientist: Individual responsible for the medical conduct of 
the study. Responsibilities of the CRP may be performed by a physician, clinical 
research scientist, global safety physician or other medical officer. 
CSR 
Clinical study report 
Ct 
calcitonin 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLTs 
Dose limiting toxicities 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
Duration of response 
eCOA 
electronic Clinical Outcome Assessment 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
EDC 
electronic data capture system 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
EORTC-IL 19 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 Version 3.0, item library 19 
EQ-5D-5L 
5-level-EuroQol 
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ER 
Estrogen receptor 
ERB 
ethical review board 
FACT-GP5 
Functional Assessment of Cancer Therapy-Side Effects 
FOIA 
Freedom of Information Act 
GCP 
good clinical practice 
GDPR 
EU General Data Protection Regulation 
GFR 
Glomerular Filtration Rate 
GLP 
Good Laboratory Practices 
GnRH 
gonadotropin-releasing hormone 
hERG 
human ether-a-go-go 
HIPPA 
Health Insurance Portability and Accountability Act of 1996 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
Informed consent 
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
IRB 
Institutional Review Boards 
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investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
ISO/IEC 
International Organization for Standardization/Independent Ethics Committee 
ITT 
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
IUD 
intrauterine device 
LHRH 
luteinizing hormone-releasing hormone 
LLT 
Lower Level term 
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 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the core 5 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. 
MHC-I 
Major Histocompatibility Complex class I 
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 
MKIs 
multikinase inhibitors 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
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NCCN 
National Comprehensive Cancer Network 
NRS 
numeric rating scale 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
PFS2 
Progression free survival 2 
PK 
pharmacokinetics 
PPIs 
Protein pump inhibitors 
PR 
partial response 
PRO 
patient-reported outcomes 
PTCs 
papillary thyroid cancers 
ORR 
Overall response rate 
OS 
Overall survival 
QD 
once daily 
QT 
ECG interval measured from the onset of the QRS complex to the offset of the T wave 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTcI 
Corrected QT interval 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RR 
time between corresponding points on 2 consecutive R waves on ECG 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
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SAP 
statistical analysis plan 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SERD 
selective estrogen receptor degraders 
SERM 
selective estrogen receptor modulators 
SMD 
Senior Management Designee 
SoA 
schedule of activities 
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. 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
TTF 
time-to-treatment failure 
TFFS 
treatment failure-free survival 
TTNT 
time to initiation of new anticancer therapy 
UK 
United Kingdom 
ULN 
upper limit of normal 
WCLC 
World Conference on Lung Cancer 
WOCBP 
woman of childbearing potential 
 
 
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10.10. 
Appendix 10: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment (h)  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to consolidate country-specific requirements into 
protocol appendix to meet EU CTR requirements. The changes are summarized in this table. 
Section # and Name 
Description of Change 
Brief Rationale 
10.8. Appendix 8: 
Country-Specific 
Requirements 
Added an appendix to include EU-specific 
requirements for the following countries: 
 
To consolidate country-specific 
requirements into protocol 
appendix to meet EU CTR 
requirements 
 
10.8.1. Addendum 3.1 (Germany) 
 
 
10.8.2. Addendum 8 (Netherlands) 
 
 
10.8.3. Addendum 10 (Czech Republic) 
 
 
10.8.4. Addendum 11 (Belgium) 
 
 
10.8.5. Addendum 12.2 (Czech Republic, Germany, 
Italy, Netherlands, Poland, Spain, Brazil, United States, 
United Kingdom, Australia, and Canada) 
 
 
10.8.6. Addendum 13.1 (All Study Countries) 
 
Throughout 
Minor editorial and formatting changes 
Minor; therefore, not detailed 
Amendment (g) (28 October 2022) 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
In this amendment, the following changes are incorporated to provide a mechanism for dose 
modifications using 300-mg tablets for instances when vandetanib 100-mg tablets are not 
available. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
In the Intervention Groups and Duration table: 
Updated cross-reference text to footnote b. 
For clarity. 
6.1.1. Adult Dosing 
In the Adult Dosing table: Updated cross-
reference text to footnote a. 
For clarity. 
6.6. Dose Modification 
Added text and table outlining dose modification 
using 300-mg tablets. 
Change made to provide a 
mechanism for dose modifications 
using 300-mg tablets for instances 
when vandetanib 100-mg tablets are 
not available. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout  
Minor editorial and formatting changes. 
Minor, therefore, not detailed. 
Amendment [f]: (06 April 2022)  
The amendment is considered to be substantial because it is likely to have a significant impact on 
the  
 reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
In this amendment, the following changes are incorporated in response to fluctuating vandetanib 
availability: 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Added language regarding the switch from 
vandetanib to cabozantinib 
Change incorporated in response to 
fluctuating vandetanib availability. 
1.3. Schedule of 
Activities 
Included a Control Arm Switch Table with title 
“Exceptional Control Arm Switch Treatment (for 
participants switching from vandetanib to 
cabozantinib)” 
Change incorporated in response to 
fluctuating vandetanib availability, 
to ensure participants on control arm 
remain on active treatment. 
1.3. Schedule of 
Activities 
Assigned Level 3 section numbers (1.3.1, 1.3.2, 
1.3.3, 1.3.4, and 1.3.5) to each SoA table 
For clarification. 
1.3. Schedule of 
Activities 
In SoA table 1.3.2., in row “Vital signs (<18 
years of age)”, added that “Height should be 
measured every 6 months until they reach the age 
of 18.” 
For clarification. 
1.3. Schedule of 
Activities 
In SoA table 1.3.2., in row “Chemistry panel 
(<18 years of age)”, added that ‘Chemistry panel 
will be performed on adolescent participants 
every 4 weeks starting on Day 1 of Cycle 2-n and 
throughout.” 
Frequency of chemistry panel 
clarified for adolescents for 
consistency.  
1.3. Schedule of 
Activities 
In SoA table 1.3.4., in row “Vital signs (<18 
years of age)”, added that “Height should be 
obtained every 6 months until the age of 18.” 
For clarification. 
1.3. Schedule of 
Activities 
In SoA table 1.3.4., in row “Hematology (<18 
years of age)”, added that ‘If testing is performed 
≤7 days prior to C1D1, repeat testing does not 
need to occur on C1D1. See Appendix 2.” 
Frequency of hematology tests for 
adolescents clarified for consistency. 
1.3. Schedule of 
Activities 
In SoA table 1.3.4., in row “Chemistry panel 
(<18 years of age)”, added that ‘Chemistry panel 
will be performed on adolescent patients every 4 
weeks starting Cycle 2-n and throughout.” 
Frequency of chemistry clarified for 
adolescents for consistency. 
5.2.1. Eligibility Criteria 
for Crossover Treatment 
Section title changed from “Enrollment Criteria 
for Crossover Treatment” to “Eligibility Criteria 
for Crossover Treatment” 
For clarification, as participants who 
are crossing over are already 
enrolled to the study. 
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Section # and Name 
Description of Change 
Brief Rationale 
Updated the language of eligibility criteria for 
crossover 
A minimum time window was added 
for the crossover, to allow for 
washout of control arm before the 
crossover to selpercatinib treatment. 
6.1.3. Exceptional 
Switch from Vandetanib 
to Cabozantinib 
Included this new section to add the language for 
switching 
Change incorporated in response to 
fluctuating vandetanib availability to 
ensure participants on control arm 
remain on active treatment. 
6.1.3.1. Eligibility 
Criteria for Switching 
from Vandetanib to 
Cabozantinib 
Included this new section to add eligibility 
criteria for switch from vandetanib to 
cabozantinib 
Change incorporated in response to 
fluctuating vandetanib availability to 
ensure participants on control arm 
remain on active treatment. 
8. Study Assessments 
and Procedures 
Added language regarding safety assessments 
Based on feedback from 
investigators and that if clinically 
indicated, more frequent assessments 
may be required in certain cases. 
10.2. Appendix 2: 
Clinical Laboratory 
Tests 
Added method for screening for protein in urine 
of participants 
Based on feedback from sites and 
investigators, specifically if urine 
dipstick is used and result is 
positive, then a urine sample should 
be sent for urinalysis. 
Throughout  
Minor editorial and formatting changes  
Minor, therefore, not detailed. 
Amendment (e)  
The amendment is considered to be substantial because it is likely to have a significant impact on 
the  
 scientific value of the trial 
 conduct or management of the trial 
Overall Rationale for the Amendment: 
In this amendment, the following changes are incorporated in response to,  
 Regulatory feedback 
o Added progression free survival (PFS), as a primary endpoint and removed it as a 
secondary endpoint  
o Removed treatment failure free survival (TFFS), as a primary endpoint and added 
it as a secondary endpoint 
 New external data disclosure: The study has been updated to an adaptive design to allow 
sample size re-estimation based on results at an interim analysis 
 Site feedback: Updated the cycles to align the visits with the schedule 
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The remainder of changes include correction of errors from amendment (d) and to incorporate 
feedback from Ethics Committee/Institutional Review Boards and investigators to improve the 
conduct of the study. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 3. 
Objectives and 
Endpoints, 4.1. Overall 
Design 
Removed treatment failure free survival (TFFS), 
as a primary endpoint and added it as a secondary 
endpoint  
Added progression free survival (PFS), as a 
primary endpoint and removed it as a secondary 
endpoint 
Based on regulatory agency 
feedback 
1.1 Synopsis, 4.1. 
Overall Design 
Number of Participants 
Number of participants revised to 250-400 
Change to adaptive study design and 
sample size re-estimation 
1.1 Synopsis 
Intervention Groups 
and Duration 
Revised footnote a to include reduced starting 
dose of vandetanib in adolescent patients with 
moderate renal impairment 
Revised footnote b to add the term ‘adult’ 
Based on local clinical feedback 
1.2 Schema 
Number of participants revised to 250-400 
Removed measurable disease by RECIST 1.1  
Removed treatment failure  
Removed separate number of participants from 
Arm A and Arm B 
Change to adaptive study design 
1.3 Schedule of 
Activities (SoA) 
Addition of AE collection to the Pre-screening 
SoA 
To maintain internal document 
consistency 
1.3 Schedule of 
Activities (SoA) 
In the instructions throughout, Cycles 2-14 is 
updated to Cycles 2-16 and Cycles 14, 17, 20 are 
updated to 16, 19, 22, etc. 
To align the visits with the schedule 
1.3 Schedule of 
Activities (SoA) 
Updated instructions for ECG procedure to 
include additional ECG at C16D1 
To align subsequent ECGs with 
onsite clinical visit schedule 
1.3 Schedule of 
Activities (SoA) 
Updated instructions for Phone visit procedure 
with online clinical visit timepoints  
Updated the cycles after which a phone follow-up 
visit will occur at every non-clinical visit 
To align the visits with the schedule 
and for clarification 
1.3 Schedule of 
Activities (SoA) 
Added hematology procedure for participants 
≥18 years of age and <18 years of age at 
Screening at ≤42 day and removed from 7 day 
Clarification for sites 
1.3 Schedule of 
Activities (SoA) 
Added chemistry panel procedure for participants 
≥18 years of age and <18 years of age at 
Screening at ≤42 day and removed from 7 day 
Clarification for sites 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SoA) 
Added 28 days for radiologic imaging procedure 
at Screening (≤42 day) 
Removed initiation of other anti-cancer therapy 
in instructions for radiologic imaging  
Clarification for sites and based on 
regulatory agency feedback 
1.3 Schedule of 
Activities (SoA) 
Updated instructions for HRQoL and Health Status 
(EQ-5D-5L) procedures from “After completion of 
1 year of treatment” to “Starting with C16” 
To align the visits with the schedule 
1.3 Schedule of 
Activities (SoA) 
Updated instructions for Plasma for cfDNA 
collection  
Clarification for sites 
2.3 Benefit/Risk 
Assessment 
Revised safety profile of selpercatinib 
Correction and clarification 
3 Objectives and 
Endpoints 
Added safety assessment per (CTCAE) v5.0 of 
selpercatinib in patients assigned to Arm B who 
crossover to selpercatinib after progression in 
exploratory objectives and endpoints 
Based on local clinical feedback 
4.1 Overall Design 
Revised the patient enrollment data and updated 
the section with change in primary endpoint and 
key secondary endpoint.  
Change to adaptive study design 
4.2 Scientific Rationale 
for Study Design 
Updated the section with change in primary 
endpoint and key secondary endpoint.  
Rationale for another key secondary endpoint, 
comparative tolerability has been added 
Added rationale for adaptive design  
Based on regulatory agency 
feedback 
4.4 End of Study 
Definition 
Added total study duration 
Based on regulatory agency 
feedback 
5.1 Inclusion Criteria 
Revised Inclusion Criterion 2  
Clarification for sites 
Clarified Inclusion Criterion 9 
Requirement for treatment with 
Vandetanib  
5.2 Exclusion Criteria  
Added Inclusion Criterion 2b as a reference to 
Exclusion Criterion 22 
Clarification for sites 
5.2.1 Enrollment 
Criteria for Crossover 
Treatment 
Clarified exceptions to be made or not for 
participants to crossover to selpercatinib based on 
eligibility criteria  
Based on local clinical feedback 
6.1 Study 
Intervention(s) 
Administered 
Clarified that cycles should not be delayed for 
AEs. 
Cycle 13 was updated to Cycle 15 
Clarification for sites 
6.1.1 Adult dosing  
Added footnote a to adult dose of Arm B2 and 
removed it from intervention Arm B2 
Added footnote a in the table for Vandetanib 
dosing nomogram for adolescent participants  
Clarification for sites 
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Section # and Name 
Description of Change 
Brief Rationale 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Updated to include evaluation of aggregate 
interim efficacy results and safety data. 
Added measures to maintain trial integrity after 
the sample size re-estimation to avoid disclosure 
of the interim results 
Based on regulatory agency 
feedback  
6.6 Dose Modification 
Updated the table title for Vandetanib general 
dose reductions for treatment related toxicities to 
include starting dose for moderate renal 
impairment for adolescent participants 
Clarification for sites 
6.6.2 Dose 
Modifications for 
Selpercatinib Related 
Liver Test 
Abnormalities 
Added CTCAE version 5.0 with slight 
modification as a reference for grading liver test 
abnormalities 
Based on local clinical feedback 
6.6.3 Dose 
Modifications for 
Thrombocytopenia 
Added “if thrombocytopenia is determined to be 
related to selpercatinib” for patient upon recovery 
to Grade 1 or better, the patient should resume 
selpercatinib at a reduced dose of one dose level 
reduction  
Based on local clinical feedback 
7.1 Discontinuation of 
Study Intervention  
Updated the disease progression circumstance 
with expectations for procedures for each 
participant  
Clarification for sites 
8.1.1 Imaging 
Removed initiation of new anticancer therapy as 
part of radiographic disease progression 
assessment for patients who discontinue 
treatment without radiographic progression by 
BICR 
Based on regulatory agency 
feedback 
8.1.2 BICR Assessment 
8.3 Adverse Events and 
Serious Adverse Events 
Added CTCAE version 5.0 with slight 
modification as a reference for post baseline 
grading for all laboratory values 
Added SAE reporting guidance after signing the 
prescreening ICF and the main study ICF 
Clarification for sites 
8.5 Pharmacokinetics 
Updated collection of blood for PK assessment  
Clarification for sites 
8.9.4 PRO-CTCAE 
Updated information that the PRO-CTCAE will 
not be available to the patient or onsite clinicians 
for clinical patient management 
Clarification for sites 
9.1 Statistical 
Hypothesis 
Removed TFFS and added PFS evaluation for 
treatment of patients 
Based on regulatory agency 
feedback 
9.2 Sample Size 
Determination 
Revised the section to include adaptive study 
design and sample size re-estimation based on 
PFS. 
Change to adaptive study design 
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Section # and Name 
Description of Change 
Brief Rationale 
9.3 Populations for 
Analyses 
Added crossover and tolerability evaluable 
populations and their respective descriptions 
Based on regulatory agency 
feedback and to maintain 
consistency 
9.4.3.1 Primary 
Analyses 
Added PFS as primary analysis. Removed TFFS 
as primary analysis  
Based on regulatory agency 
feedback 
9.4.3.2.1 Treatment 
Failure Free Survival 
Added TFFS as a key secondary analysis 
Based on regulatory agency 
feedback 
9.4.3.2.2 Comparative 
Tolerability 
Added comparative tolerability as another key 
secondary analysis  
Based on regulatory agency 
feedback 
9.4.3.2.3 Overall 
Survival  
Updated OS analysis 
Change according to adaptive study 
design 
9.4.3.3 Other 
Secondary Analyses 
Updated language for secondary outcomes 
assessment based on changes made to the 
primary and key secondary analyses 
Based on regulatory agency 
feedback and to maintain 
consistency 
9.4.3.5 
Tertiary/Exploratory  
Added PFS after crossover as an endpoint 
Based on regulatory agency 
feedback 
9.4.4 Safety Analyses 
Added details for safety data after crossover 
Based on local clinical feedback 
9.5 Interim Analyses 
Added the trigger for interim analyses and 
guidance for the study results categorization at 
interim analysis 
Removed TFFS interim analysis 
Based on regulatory agency 
feedback and to maintain 
consistency. Change to adaptive 
study design 
10.2. Appendix 2: 
Clinical Laboratory 
Tests 
Removed the exception for adult patients not 
requiring a visit concurrently with labs from local 
laboratory results 
Correction and clarification 
10.2. Appendix 2: 
Clinical Laboratory 
Tests 
Added assessments performed remotely/virtually 
for requirement of local laboratory results. 
Standard of care language updated for 
Triiodothyronine (T3) and Thyroxine (T4)  
Clarification for sites 
10.4. Appendix 4: Liver 
Safety: Suggested 
Actions and Follow-up 
Assessments 
Added language for tests to be done at 
occurrence of Grade ≥3 elevated hepatic lab 
increases (ALT, AST, or direct bilirubin) 
Clarification for sites 
10.6. Appendix 6: RET 
activating mutations in 
MTC 
Removed Y791F/N  
Based on latest scientific evidence 
10.7. Appendix 7: 
Restricted and 
Prohibited Concomitant 
Medications 
Revised the reference for a current list of agents 
known to cause QTc prolongation 
Editorial consistency 
11. References 
Added cited guidance documents 
Editorial consistency. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout  
Minor editorial and formatting changes 
Minor, therefore, not detailed 
Amendment (d) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment was to update information around the comparative 
tolerability key secondary objective based on regulatory agency feedback. Changes from 
additional regulatory and investigator feedback and minor corrections are also incorporated. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1. Synopsis, 
Section 3. Objectives 
and Endpoints 
Added language related to secondary 
endpoint of comparative tolerability 
Clarification based on regulatory agency 
feedback 
Section 4.1 Overall 
Design 
Added language about the secondary 
endpoint of comparative tolerability 
Clarification based on regulatory agency 
feedback 
Section 1.1. Synopsis 
Removed footnote b below the 
Intervention Groups and Duration table 
Correction 
Section 1.2. Schema 
Updated schema with minor changes 
Corrections 
Section 1.3. Schedule of 
Activities (SoA) 
Added language to the prescreening ICF 
for RET testing row in the prescreening 
SoA 
To provide flexibility to patients in 
prescreening 
Section 1.3. Schedule of 
Activities (SoA) 
Added a row for prescreening ICF for 
radiologic imaging submission for BICR 
review 
To provide flexibility to patients in 
prescreening 
Section 1.3 Schedule of 
Activities (SoA) 
Added a row for demographic information 
in the prescreening SoA and the screening, 
on-study, and post-study treatment follow-
up SoA for patients on Arm A and Arm B 
Clarification 
Section 1.3 Schedule of 
Activities (SoA) 
Removed C1 D22, C2-n D8, C2-n D15 
and C2-n D22 from the screening, on-
study, and post-study treatment follow-up 
SoA for patients on Arm A and Arm B 
and the optional crossover treatment SoA  
No sample collection at these visits 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3. Schedule of 
Activities (SoA) 
Increased screening duration from 28 to 
42 days 
To account for additional time needed to 
arrange imaging, imaging review, RET 
review, etc. 
Section 1.3. Schedule of 
Activities (SoA) 
Added coagulation sample to be collected 
at short-term follow-up visit 
Correction 
Section 1.3. Schedule of 
Activities (SoA) 
Clarified instructions on when to collect 
certain measurements and perform 
specific tests 
Following standard of care for changes 
to collection of chemistry panel; 
Clarification for remainder of changes 
Section 1.3. Schedule of 
Activities (SoA) 
Added a row for chemistry panel (<18 
years of age) 
Clarification 
Section 1.3. Schedule of 
Activities (SoA) 
Added a sentence about information on 
suggested modalities being found in 
Section 8.1 
Clarification 
Section 1.3. Schedule of 
Activities (SoA) 
Changed language stating that repeated 
submission of scans greater than 10 
business days after date of collection will 
be considered a protocol deviation 
Correction 
Section 1.3. Schedule of 
Activities (SoA); 
Section 8.9.1. Patient-
Reported Outcomes 
Added a statement restricting collection of 
Bristol Stool Form Scale, bowel 
movement frequency, and worst pain NRS 
to 1 year in both the main and crossover 
SoAs 
Based on regulatory agency feedback 
Section 1.3. Schedule of 
Activities (SoA) 
Corrected sample collection for HRQoL 
(EORTC-QLQ-C30) and Health status 
(EQ-5D-5L)  
Correction 
Section 1.3. Schedule of 
Activities (SoA) 
Removed language related to sample 
usage in the archived tumor tissue or fresh 
biopsy row 
Correction 
Section 1.3. Schedule of 
Activities (SoA) 
Removed ‘analysis and exploratory 
biomarkers’ from Plasma for cfDNA row 
Clarification 
Section 1.3. Schedule of 
Activities (SoA) 
Added collection times for Plasma for 
cfDNA 
Clarification 
Section 2.2.1. 
Selpercatinib 
Added a sentence to reflect interim 
analysis data 
Updated to reflect new data 
Section 5.1. Inclusion 
Criteria 
Amended Inclusion Criterion 2 to address 
inclusion of patients with mixed histology 
Updated to align with clinical standard 
practice 
Section 5.1. Inclusion 
Criteria 
Amended Inclusion Criterion 3 to specify 
eligibility based on evaluable disease 
Updated to align with clinical standard 
practice 
Section 5.1. Inclusion 
Criteria 
Amended Inclusion Criterion 4 
requirements for germline assays  
Clarification 
Section 5.1. Inclusion 
Criteria 
Amended Inclusion Criterion 7 to specify 
and/or amend length of time prior to first 
treatment dose 
Updated for consistency with drug labels 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1. Inclusion 
Criteria 
Amended Inclusion Criterion 10 to reduce 
use of the highly effective contraceptive 
method from 6 to 4 months following the 
last dose of study drug 
Updated for consistency with 
comparator drug labels 
Section 5.1. Inclusion 
Criteria 
Removed sentence regarding condom 
usage from Inclusion Criterion 10 
Based on regulatory agency feedback 
Section 5.2. Exclusion 
Criteria 
Amended Exclusion Criterion 15 language 
for QT changes, and added language for 
patients with bundle branch block 
Clarification 
Section 5.2. Exclusion 
Criteria 
Amended Exclusion Criterion 21 to 
remove references to cervical carcinoma 
in situ 
Updated to align with clinical standard 
practice 
Section 5.2. Exclusion 
Criteria 
Amended Exclusion Criterion 26 to 
specify drug name 
Based on regulatory agency feedback 
Section 5.4. Screen 
Failures 
Removed restriction for number of times a 
participant may be rescreened 
Clarification/no medical justification for 
prior restriction 
Section 6.5. 
Concomitant Therapy 
Added language related to exercising 
caution when a P-gp substrate, MATE1 
substrate, or BCRP substrate is co-
administered with selpercatinib 
Based on regulatory agency feedback 
Section 6.5.1. CYP3A4 
Inducers or Inhibitors 
Added guidance about co-administration 
of selpercatinib with sensitive CYP3A4 
substrates 
Based on regulatory agency feedback 
Section 6.6. Dose 
Modification 
Moved up language related to permanent 
discontinuation from later in the section 
Based on regulatory agency feedback 
Section 6.6. Dose 
Modification 
Added language addressing study 
treatment continuation in the case of 
hypertension 
Updated to align with clinical standard 
practice 
Section 6.6. Dose 
Modification 
Changed timing related to omission of 
treatment for drug-related toxicities from 
>28 days to >42 days 
To provide additional time to patients 
for recovery from toxicities 
Section 6.6. Dose 
Modification;  
Section 8.2.1. 
Electrocardiograms 
Moved toxicity language related to 
prolongation of the ECG QTc interval as a 
result of vandetanib dosing to Section 
8.2.1 
Redundant; moved from Section 6.6. to 
Section 8.2.1. to have all ECG dose 
adjustment information in one place 
Section 6.6.2. Dose 
Modifications for 
Selpercatinib Related 
Liver Test 
Abnormalities 
Specified pertinent hepatic labs described 
(ALT, AST, or direct bilirubin) 
Clarification 
Section 6.6.3. Dose 
Modifications for 
Thrombocytopenia 
Modified language to address resumption 
of selpercatinib after a thrombocytopenia 
event 
Updated to align with clinical standard 
practice 
Section 8.1.1. Imaging 
Amended language to clarify all imaging 
is required 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1. Imaging 
Added language for imaging guidance 
Updated to align with clinical standard 
practice 
Section 8.1.1. Imaging 
Added information on suggested imaging 
modalities 
Clarification 
Section 8.2.1. 
Electrocardiograms 
Specified QTcF greater than 500 msec is a 
Grade 3 prolongation per CTCAE 
Clarification 
Section 8.2.1. 
Electrocardiograms 
Added language related to dose 
adjustment requirements for an alternative 
cause 
Clarification 
Section 8.5. 
Pharmacokinetics 
Added a sentence related to additional 
sample collection in patients experiencing 
selpercatinib-related drug hypersensitivity 
Clarification 
Section 8.8.1. Samples 
Required for Eligibility 
Amended timing of sponsor approval prior 
when fewer slides are collected than 
requested 
Clarification 
Section 9.3. Populations 
for Analyses 
Removed language related to safety data  
Clarification 
Section 9.4.3.1. Primary 
Analyses 
Added sentence and censoring details 
related to independent review.  
Amended censoring rules for TFFS 
Clarification based on Ethical Review 
Board feedback 
Section 9.4.3.2. 
Secondary Analyses 
Changed hierarchy of secondary endpoints 
Clarification 
Section 9.4.3.2. 
Secondary Analyses 
Added definition of progression-free 
survival assessed by BICR 
Clarification  
Section 9.4.3.2. 
Secondary Analyses 
Added definition of TFFS per investigator 
assessment 
Clarification  
Section 9.4.3.2. 
Secondary Analyses 
Deleted reference to cfDNA 
Correction 
Section 9.4.3.2. 
Secondary Analyses 
Added definition of comparative 
tolerability 
Clarification based on regulatory agency 
feedback 
Section 9.4.7.1.1. 
Patient Reporting 
Outcomes (PROs) 
Removed description related to time to 
event analyses 
Clarification based on regulatory agency 
feedback 
Section 9.5. Interim 
Analyses 
Moved and amended language related to 
early stopping for PFS and TFFS 
Clarification based on regulatory agency 
feedback 
Section 9.5. Interim 
Analyses 
Added details about comparative 
tolerability testing 
Clarification based on regulatory agency 
feedback 
Appendix 2: Clinical 
Laboratory Tests 
Removed unnecessary testing components 
Correction 
Appendix 4: Liver 
Safety: Suggested 
Actions and Follow-up 
Assessments 
Changed local to central laboratory in 
footnote a 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 7: Restricted 
and Prohibited 
Concomitant 
Medications 
Removed Aprepitant from the list of 
moderate inhibitors 
Correction 
Throughout the protocol 
Minor formatting and editorial changes  
Minor, therefore not detailed 
Amendment (c) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
There are two major changes within amendment (c):  
 Changing of the criteria of events counted toward the primary endpoint of treatment 
failure free survival (TFFS), and  
 Aligning the required visit schedule and procedures to better align with standard of care 
treatment with prolonged use of oral kinase inhibitors.  
The previous criteria for including intolerable events to be considered in TFFS was considered to 
be too narrow, and the new wording better incorporates treatment-emergent adverse events 
(TEAEs) that may require immediate discontinuation of study treatment. The timing between 
study visits and most study procedures is lengthened to 12 weeks (from 4 weeks) for adult 
patients who remain on treatment for greater than 1 year.  
The remainder of changes include new information from the latest version of the Investigator’s 
Brochure (IB), correct errors from amendment (b), and incorporate feedback from Ethics 
Committee/Institutional Review Boards and investigators to improve the conduct of the study. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1. Synopsis 
(Rationale) 
Section 2.2. Background 
Changed prevalence of RET gene mutations 
accounting for MTC 
Correction 
Section 1.1. Synopsis 
(Objectives and Endpoints) 
Section 3. Objectives and 
Endpoints 
Removed PRO-CTCAE as a secondary 
endpoint, added it as an exploratory 
endpoint 
Change in study design; 
Clarification 
Section 1.1. Synopsis 
(Objectives and Endpoints) 
Section 3. Objectives and 
Endpoints 
Changed secondary objective related to PK 
Clarification 
Schedule 1.3. Schedule of 
Activities 
Separated pre-screening SoA from 
screening, on-study and post-treatment 
follow-up SoA for Patients on Arm A and 
B 
Clarification 
Schedule 1.3. Schedule of 
Activities 
Updated short-term and long-term follow-
up visit ranges in both the Screening, On-
Study, and Post-Study Treatment Follow-
Up SoA as well as the optional crossover 
treatment SoA 
Clarification 
Schedule 1.3. Schedule of 
Activities 
Clarified collection schedules for physical 
examination, vital signs, ECOG PS, 
hematology, urine protein, calcitonin, CEA, 
patient diary, HRQoL (EORTC QLQ-C30), 
Health Status (EQ-5D-5L) and plasma for 
cfDNA analysis and exploratory 
biomarkers in both the Screening, On-
Study, and Post-Study Treatment Follow-
Up SoA as well as the optional crossover 
treatment SoA 
Align with changes in visit 
frequency 
Section 1.3. Schedule of 
Activities 
Added a phone visit for the collection of 
concomitant medications, AEs, labs, and 
patient dosing diary in both the Screening, 
On-Study, and Post-Study Treatment 
Follow-Up SoA as well as the optional 
crossover treatment SoA 
Support changes in visit 
frequency 
Section 1.3. Schedule of 
Activities 
Added a range to collection window for 
Tanner staging and growth plant 
monitoring in both the Screening, On-
Study, and Post-Study Treatment Follow-
Up SoA as well as the optional crossover 
treatment SoA 
Clarification 
Section 1.3. Schedule of 
Activities 
Updated serum cortisol and ACTH 
language; removed 24-hour urine for free 
cortisol collection and language in both the 
Screening, On-Study, and Post-Study 
Treatment Follow-Up SoA as well as the 
optional crossover treatment SoA 
Removed unnecessary procedure 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3. Schedule of 
Activities 
Added rows and instructions for specific 
adolescent patient procedures in both the 
Screening, On-Study, and Post-Study 
Treatment Follow-Up SoA as well as the 
optional crossover treatment SoA 
Clarification associated with 
change in visit frequency for 
adult patients 
Schedule 1.3. Schedule of 
Activities 
Changed collection window for ECG 
measurement in both the Screening, On-
Study, and Post-Study Treatment Follow-
Up SoA as well as the optional crossover 
treatment SoA 
Change in guidance in IB 
Schedule 1.3. Schedule of 
Activities 
Clarified testing expectations for pregnancy 
testing in both the Screening, On-Study, 
and Post-Study Treatment Follow-Up SoA 
as well as the optional crossover treatment 
SoA 
Clarification 
Schedule 1.3. Schedule of 
Activities 
Updated specifications related to 
performance and submission of results of 
radiologic scans in both the Screening, On-
Study, and Post-Study Treatment Follow-
Up SoA as well as the optional crossover 
treatment SoA 
Clarification 
Schedule 1.3. Schedule of 
Activities 
Updated language related to collection of 
Bristol Stool Form scale and bowel 
movement frequency, worst pain NRS, pro-
CTCAE, FACT-GP5, EORTC IL 19 in 
both the Screening, On-Study, and Post-
Study Treatment Follow-Up SoA as well as 
the optional crossover treatment SoA  
Clarification 
Schedule 1.3. Schedule of 
Activities 
Increased pre-dose blood draw window for 
blood samples for pharmacokinetics in both 
the Screening, On-Study, and Post-Study 
Treatment Follow-Up SoA as well as the 
optional crossover treatment SoA 
Facilitate single lab collection for 
relevant visits 
Schedule 1.3. Schedule of 
Activities 
Updated archived tumor or fresh biopsy 
and optional post-progression tumor biopsy 
collection instructions in the Screening, 
On-Study, and Post-Study Treatment 
Follow-Up SoA 
Clarification 
Section 3. Objectives and 
Endpoints 
Amended type of DNA sample in 
exploratory objective related to RET 
mutation status 
Clarification 
Section 5.1. Inclusion Criteria 
Clarified language for histological 
diagnosis in Inclusion Criterion 2 
Clarification 
Section 5.1. Inclusion Criteria 
Updated RET alteration analysis description 
in Inclusion Criterion 4 
Clarification 
Section 5.1. Inclusion Criteria 
Removed sentence related to archived 
tumor tissue requirements in Inclusion 
Criterion 4 
Removed duplicate language 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2. Exclusion 
Criteria Medical Conditions 
Updated gene mutations and fusions in 
Exclusion Criterion 13 
Updated for clinical relevance in 
MTC 
Section 6.1. Study 
Intervention(s) Administered 
Updated cycle instructions for AEs 
Clarification 
Section 6.1. Study 
Intervention(s) Administered 
Added clarification related to drug 
dispensation 
Clarification 
Section 6.1.2. Adolescent 
Dosing 
Updated language around BSA-adjusted 
dosing of selpercatinib 
Clarification 
Section 6.1.2. Adolescent 
Dosing 
Removed dose increase guidance column 
related to vandetanib dosing and updated 
BSA dose column for selpercatinib 
Correction of erroneously 
included information 
Section 6.5. Concomitant 
Therapy 
Updated prior concomitant therapy 
language and added surgery or RT 
permissions 
 Detail added for needed clarity 
Section 6.5.2. Agents that 
alter gastric acidity (PPIs and 
H2 blockers) 
Amended language related to concomitant 
use of PPIs  
New data resulted in updated 
guidance 
Section 6.6. Dose 
Modification 
Updated definition for Intolerable AEs 
Added guidance related to additional dose 
adjustments for AEs that are resolved 
following a dose reduction 
Clarification/Modification 
Section 6.6. Dose 
Modification 
Addition of severe/life-threatening 
hemorrhage as a criterion for permanent 
discontinuation in patients receiving 
selpercatinib 
For consistency with updated IB 
Section 6.6. Dose 
Modification 
Added definition for intolerable AEs 
Amended guidance related to general dose 
level reductions 
For consistency with updated IB 
Section 6.6.1. Dose 
Modifications for 
Selpercatinib Hypersensitivity 
Removed recommended lab testing for 
selpercatinib drug hypersensitivity 
For consistency with updated IB 
Section 6.6.2. Dose 
Modifications for 
Selpercatinib Related Liver 
Test Abnormalities 
Updated dose modification guidelines for 
selpercatinib related liver test abnormalities 
For consistency with updated IB 
Section 6.6.3. Dose 
Modifications for 
Thrombocytopenia 
Updated dose modification guidelines; 
Removed sponsor notification instructions 
For consistency with updated IB 
Section 8.1.1. Imaging 
Clarified assessment instructions for 
patients who discontinue treatment without 
radiographic progression by BICR 
Clarified scan interval schedule 
Clarification 
Section 8.1.2. BICR 
Assessment 
Added clarification that the required 
actions are regarding imaging which needs 
collection and submission, but not 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
regarding post discontinuation imaging 
without requirement of submission. 
Section 8.5. Pharmacokinetics 
Updated PK sample draw language (in 
relation to dosing) 
Clarification  
Section 8.8.2. Biomarkers 
Added language related to whole blood 
collection 
Added language to account for gene testing 
other than RET 
Clarification 
Section 8.9.1. Patient-reported 
Outcomes 
Modified language regarding use of 
electronic questionnaires 
Clarification and correction 
Section 9.2. Sample Size 
Determination 
Corrected OS percentages 
Correction of error 
Section 9.4.3.1 Primary 
Analyses 
Clarified study drug related AE 
qualifications 
Clarification 
Section 9.4.3.1 Primary 
Analyses 
Added a sentence describing TFFS 
determination by an independent review 
committee 
Clarification 
Section 9.4.3.2 Secondary 
Analyses 
Added clarification of censoring rules for 
PFS2  
Clarification 
Section 10.1.9. Provisions for 
Changes in Study Conduct 
During Emergencies 
Added details related to emergency 
mitigation 
Risk mitigation for patients 
during an emergency. 
Section 10.2. Appendix 2 
Clinical and Laboratory Tests 
Added clarification related to exception for 
local testing 
Updated cortisol and urine pregnancy test 
language 
Clarification 
Section 10.6. Appendix 6: 
RET activating mutations in 
MTC 
Amended list of genes that are known 
driver alterations in MTC 
Specify appropriate eligible 
population 
Section 10.7. Appendix 7 
Restricted and Prohibited 
Concomitant Medications 
Updated language around CYP inhibitors 
Not updated in Amendment b 
Section 10.7. Appendix 7 
Restricted and Prohibited 
Concomitant Medications 
Removed guidance related to timeframe of 
PPI usage and PPI instructions 
Not updated in Amendment b 
Throughout the protocol 
Minor formatting and editorial changes  
Minor, therefore not detailed 
Amendment [b]: (18 November 2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
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Overall Rationale for the Amendment: 
In the original protocol version, the starting dose of the control arm treatment vandetanib for 
patients with mild to moderate renal impairment was not included. In this amendment, the 
starting dose for these patients is incorporated, in order to maximize patient safety. Other 
clarifications and corrections are included as outlined below. 
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Added text for unstained, 
archived tumor tissue in 
Inclusion Criterion 4. 
Based on regulatory agency 
feedback. 
1.1 Synopsis; 3 Objectives and Endpoints 
A secondary objective was 
added.  
To assess/evaluate performance 
of local RET laboratory tests 
compared to a single, central 
test. 
1.1 Synopsis; 3 Objectives and Endpoints 
A secondary objective was 
added. 
To assess the PK of selpercatinib 
in the patient population. 
6.1 Study Intervention(s) Administered 
Replaced text for the starting 
dose of vandetanib for patients 
with moderate renal 
impairment. 
Per vandetanib label, patients 
with moderate renal impairment 
should begin treatment at a dose 
of 200 mg. 
1.1 Synopsis 
Added text for starting dose of 
vandetanib for patients with 
moderate renal impairment. 
Per vandetanib label, patients 
with moderate renal impairment 
should begin treatment at a dose 
of 200 mg. 
9.4.5 Pharmacokinetic/Pharmacodynamic 
Analyses 
Updated text to include a plan 
for conducting population PK 
and exposure-response analyses. 
Selpercatinib plasma 
concentrations will be 
summarized by descriptive 
statistics and graphics. 
Additionally, the data will be 
evaluated through population PK 
methodology. 
4.1 Overall Design 
Further clarified physician’s 
choice language. 
Clarification for sites. 
1.1 Synopsis; 4.1 Overall Design 
Removed geographic region 
stratification factor. 
No expected difference in 
outcomes based on geographic 
region. 
1.3 Schedule of Activities 
Removed tobacco and alcohol 
use. 
The medical history does not 
include tobacco and alcohol use.  
1.3 Schedule of Activities 
Updated text about sample 
collection. 
Based on regulatory agency 
feedback. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
Removed Pregnancy Test LTFU 
Instructions. 
Pregnancy Test not needed in 
LTFU. 
1.3 Schedule of Activities 
Added ECGs every 3 months 
after Cycle 8 for participants 
receiving selpercatinib. 
Clarification 
1.3 Schedule of Activities 
Clarified language for survival 
and PFS2 assessment. 
Clarification 
1.3 Schedule of Activities 
Updated collection for Plasma 
for cfDNA analysis and 
exploratory biomarkers. 
Clarification 
1.3 Schedule of Activities 
Added cortisol, ACTH, 24-hour 
urine for free cortisol for short 
term follow up. 
Inadvertently deleted. 
5.2 Exclusion Criteria 
Clarified exclusion in Exclusion 
Criterion 16. 
Based on regulatory feedback. 
5.2 Exclusion Criteria; 6.5 Concomitant 
Therapy; 6.5.1 CYP3A4 Inducers or 
Inhibitors; 6.5.2 Agents That Alter Gastric 
Acidity (PPIs and H2 blockers); Appendix 
7 Restricted Concomitant Medications 
Removed prohibition on 
CYP3A4 and PPI concomitant 
medications in Exclusion 
Criterion 23 and 24 and 
throughout. 
Based on updated information.  
5.2 Exclusion Criteria 
Added exception for 
participants with MEN2-
associated pheochromocytoma 
in Exclusion Criterion 21. 
Based on feedback. 
Throughout  
Updated the name for EORTC-
QLQ30-C30-PF. 
Clarification. 
Throughout  
Updated the name for LOXO-
292 to selpercatinib. 
Clarification. 
Section 9.2 Sample Size Determination 
Removed sentence for 
increasing sample size 
consideration. 
Based on regulatory agency 
feedback. 
9.4.3.2 Secondary Analyses 
Removed CNS ORR. 
Inadvertently included in 
original protocol.  
8.2.1 Electrocardiograms 
Added text about ECG. 
Added for patient safety. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.8 Biomarkers 
Updated text about sample 
collection and split section into 
two subsections.  
Based on regulatory agency 
feedback. 
9.4.3.2.1 RET-Testing Concordance 
Analysis 
Added subsection regarding 
concordance analysis. 
Based on regulatory agency 
response on RET testing, 
concordance between 
RET-testing results based on 
local laboratory tests and 
centrally assessed results will be 
evaluated. 
Appendix 7 Restricted Concomitant 
Medications 
Added examples of H2 blocking 
agents. 
Clarification for sites. 
Amendment [a]: (12 November 2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 1.2 Schema, 4.1 Overall 
Design, 6.1 Study Intervention(s) 
Administered; 6.6 Dose Modification 
Adolescent dose was added for 
each intervention.  
Adolescent participants will be 
dosed different than adult 
participants.  
1.3 Schedule of Activities 
AE collection was further 
clarified for ongoing drug 
related AEs. 
Clarified per regulatory 
feedback.  
1.3 Schedule of Activities, Appendix 2: 
Clinical Laboratory Tests 
Urine protein was added for 
patients receiving cabozantinib 
Monitoring added per regulatory 
feedback. 
1.3 Schedule of Activities; 8.2 Safety 
Assessments 
Growth plate imaging was 
added for patients <18 years of 
age who have not reached full 
adult height. 
Monitoring added per regulatory 
feedback. 
2.2 Background 
Additional information was 
added for adolescent 
participants.  
Added per regulatory feedback.  
2.2.1 LOXO-292 
Clarification was added on the 
management of hypersensitivity, 
liver test abnormalities, 
thrombocytopenia, and 
hypertension.  
Clarified per regulatory 
feedback. 
2.3 Benefit/Risk Assessment 
Additional information on the 
benefit/risk for Study JZJB was 
added.  
Added per regulatory feedback. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.3.2 Cabozantinib, 4.3.3 Vandetanib 
Additional justification for 
adolescent dose was added.  
Adolescent participants will be 
dosed different than adult 
participants.  
5.1 Inclusion Criteria 
Inclusion criteria 1 was 
modified to clarify patients will 
be permitted after giving 
assent/written consent. 
Modified per regulatory 
feedback. 
5.1 Inclusion Criteria 
Inclusion criteria 11 was 
modified to clarify women of 
childbearing potential will be 
included if they are no breast 
feeding during treatment and at 
least 4 months after last study 
dose.  
Modified per regulatory 
feedback. 
5.2 Exclusion Criteria 
Exclusion criteria 15 was 
updated to exclude patients with 
a history of Torsades de pointes. 
Updated per regulatory feedback. 
5.2 Exclusion Criteria 
Exclusion criteria 28 was added 
excluding patients with a known 
hypersensitivity to any of the 
excipients of either cabozantinib 
or vandetanib. 
Added per regulatory feedback. 
6.5.3 P-gp Substrates or MRP2 Inhibitors 
Section 6.5.3 was added with 
special instructions for patients 
co-administered P-gp substrates 
or MRP2 inhibitors.  
Added per regulatory feedback. 
6.6.1 Dose Modifications for LOXO-292 
Hypersensitivity 
Special instructions were added 
if hypersensitivity occurs.  
Added per regulatory feedback. 
 
 
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11. 
References  
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NF, Filiberti A, Flechtner 
H, Fleishman SB, de Haes JC, 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. 
Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, 
Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu 
MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in 
Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 
2018;379(1):54-63. 
Agrawal N, Jiao Y, Sausen M, Leary R, Bettegowda C, Roberts NJ, Bhan S, Ho AS, Khan Z, 
Bishop J, Westra WH, Wood LD, Hruban RH, Tufano RP, Robinson B, Dralle H, Toledo SP, 
Toleda RA, Morris LG, Ghossein RA, Fagin JA, Chan TA, Velculescu VE, Vogelstein B, 
Kinzler KW, Papadopoulos N, Nelkin BD, Ball DW. Exomic sequencing of medullary thyroid 
cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin 
Endocrinol Metab. 2013;98(2):E364-369. 
Atkinson TM, Ryan SJ, Bennett AV, Stover AM, Saracino RM, Rogak LJ, Jewell ST, Matsoukas 
K, Li Y, Basch E. The association between clinician-based common terminology criteria for 
adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review. Support 
Care Cancer. 2016;24(8):3669-3676. 
Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, Mendoza TR, Hay J, 
Atkinson TM, Abernethy AP, Bruner DW, Cleeland CS, Sloan JA, Chilukuri R, Baumgartner 
P, Denicoff A, St Germain D, O'Mara AM, Chen A, Kelaghan J, Bennett AV, Sit L, Rogak L, 
Barz A, Paul DB, Schrag D. Development of the National Cancer Institute's patient-reported 
outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). 
J Natl Cancer Inst. 2014;106(9):dju244. 
Blumenthal GM, Gong Y, Kehl K, Mishra-Kalyani P, Goldberg KB, Khozin S, Kluetz PG, 
Oxnard GR, Pazdur R. Analysis of time-to-treatment discontinuation of targeted therapy, 
immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung 
cancer. Ann Oncol. 2019;30(5):830-838. 
Boulay A, Breuleux M, Stephan C, Fux C, Brisken C, Fiche M, Wartmann M, Stumm M, Lane 
HA, Hynes NE. The Ret receptor tyrosine kinase pathway functionally interacts with the 
ERalpha pathway in breast cancer. Cancer Res. 2008;68(10):3743-3751. 
Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, Suarez HG. High 
prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients 
who had received external radiation. Oncogene. 1997;15(11):1263-1273. 
Brea EJ, Oh CY, Manchado E, Budhu S, Gejman RS, Mo G, Mondello P, Han JE, Jarvis CA, 
Ulmert D, Xiang Q, Chang AY, Garippa RJ, Merghoub T, Wolchok JD, Rosen N, Lowe SW, 
Scheinberg DA. Kinase Regulation of Human MHC Class I Molecule Expression on Cancer 
Cells. Cancer Immunol Res. 2016;4(11):936-947. 
Cabozantinib [package insert]. South San Francisco, CA; Exelixis, Inc.; 2016. 
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169 
Cabozantinib [Summary of Product Characteristics]. Boulogne-Billancourt, France; Ipsen 
Pharma; 2016. 
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary 
thyroid carcinoma. Cell. 2014;159(3):676-690. 
Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA Jr, Goodfellow PJ, 
Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET 
protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U 
S A. 1994;91(4):1579-1583. 
Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, 
Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. 
Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of 
intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free 
survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125. 
Chuk MK, Widemann BC, Minard CG, Liu X, Kim A, Bernhardt MB, Kudgus RA, Reid JM6, 
Voss SD, Blaney S, Fox E, Weigel BJ. A phase 1 study of cabozantinib in children and 
adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial 
ADVL1211, a report from the Children's Oncology Group. Pediatr Blood Cancer. 2018 
Aug;65(8):e27077. 
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;34(2):187-220. 
Crawford J, Armitage J, Balducci L, Bennett C, Blayney DW, Cataland SR, Dale DC, Demetri 
GD, Erba HP, Foran J, Freifeld AG, Goemann M, Heaney ML, Htoy S, Hudock S, Kloth DD, 
Kuter DJ, Lyman GH, Michaud LB, Miyata SC, Tallman MS, Vadhan-Raj S, Westervelt P, 
Wong MK; National Comprehensive Cancer Network. Myeloid growth factors. J Natl Compr 
Cancer Netw. 2009;7(1):64-83. 
Cui L, Hung HMJ, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-857. https://doi.org/10.1111/j.0006-341X.1999.00853.x 
Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, 
Goodfellow P, Wells SA Jr. Mutations in the RET proto-oncogene are associated with MEN 
2A and FMTC. Hum Mol Genet. 1993;2(7):851-856. 
Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, Van Voorthuysen M, Somwar R, 
Smith RS, Montecalvo J, Plodkowski A, Ginsberg MS, Riely GJ, Rudin CM, Ladanyi M, Kris 
MG. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an 
open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17(12):1653-1660. 
Drilon AE, Subbiah V, Oxnard GR, Bauer TM, Velcheti V, Lakhani NJ, Besse B, Park K, Patel 
JD, Cabanillas ME, Johnson ML, Reckamp KL, Boni V, Loong HHF, Schlumberger M, 
Solomon B, Cruickshank S, Rothenberg SM, Shah MH, Wirth LJ. A phase 1 study of LOXO-
292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin 
Oncol. 2018;36(suppl; abstr 102). 
Drilon AE, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi 
O, Besse B, Chao BC, Peled N, Weiss J, Kim Y, Ohe Y, Nishio M, Park K, Patel J, Seto T, 
Sakamoto T, Rosen E, Shah MH, Barlesi F, Cassier PA, Bazhenova L, De Braud F, Garralda 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
170 
E, Velcheti V, Satouchi M, Ohashi K, Pennell NA, Reckamp KL, Dy GK, Wolf J, Solomon B, 
Falchook G, Ebata K, Nyugen M, Nair B, Zhu EY, Yang L, Huang X, Olek E, Rothenberg M, 
Goto K, Subbiah V. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung 
Cancer. NEJM. 2020;383:813-824. 
Dueck AC, Mendoza TR, Mitchell SA, Reeve BB, Castro KM, Rogak LJ, Atkinson TM, Bennett 
AV, Denicoff AM, O'Mara AM, Li Y, Clauser SB, Bryant DM, Bearden JD 3rd, Gillis TA, 
Harness JK, Siegel RD, Paul DB, Cleeland CS, Schrag D, Sloan JA, Abernethy AP, Bruner 
DW, Minasian LM, Basch E; National Cancer Institute PRO-CTCAE Study Group. Validity 
and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of 
the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. 
2015;1(8):1051-1059. 
Dvorakova S, Vaclavikova E, Sykorova V, Vcelak J, Novak Z, Duskova J, Ryska A, Laco J, Cap 
J, Kodetova D, Kodet R, Krsdova L, Vleck P, Astl J, Vesely D, Bendlova B. Somatic 
mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas. Mol Cell 
Endocrinol. 2008;284(1-2):21-27. 
Eisenhauer EA, Therasse P, Boqaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247. 
Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, 
Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, 
Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 
2013;31(29):3639-3646. 
Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann 
GF, Jackson CE, Tunnacliffe A, et al. Point mutation within the tyrosine kinase domain of the 
RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. 
Hum Mol Genet. 1994;3(2):237-241. 
Flowers CR, Seidnefled J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston 
AA, Marr KA, Rolston KV, Ramsey SD. Antimicrobial prophylaxis and outpatient 
management of fever and neutropenia in adults treated for malignancy: American Society of 
Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2013;31(6):794-810. 
Fox E, Widemann BC, Chuk MK, et al. Vandetanib in children and adolescents with multiple 
endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res. 
2013;19(15):4239-4248.  
Fugazzola L, Pilotti S, Pinchera A, Vorontsova TV, Mondellini P, Bongarzone I, Greco A, 
Astakhova L, Butti MG, Demidchik EP, et al. Oncogenic rearrangements of the RET proto-
oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear 
accident. Cancer Res. 1995;55(23):5617-5620. 
Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio 
G. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. 
Nature. 1987;328(6126):170-172. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
171 
Gerber ME. Pediatric Thyroid Cancer. Medscape Reference. [Online] 13 August 2021 [Cited 01 
October 2021] Available from: https://emedicine.medscape.com/article/853737-
overview#a0199. 
Heilmann AM, Subbiah V, Wang K, Sun JX, Elvin JA, Chmielecki J, Sherman SI, Murthy R, 
Busaidy NL, Subbiah I, Yelensky R, Nangia C, Vergilio JA, Khan SA, Erlich RL, Lipson D, 
Ross JS, Miller VA, Shah MH, Ali SM, Stephens PJ. Comprehensive Genomic Profiling of 
Clinically Advanced Medullary Thyroid Carcinoma. Oncology. 2016;90(6):339-346. 
Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener 
JW, van Amstel HK, Romeo G, et al. A mutation in the RET proto-oncogene associated with 
multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 
1994;367(6461):375-376. 
Hogan AR, Zhuge Y, Perez EA et al. Pediatric thyroid carcinoma: incidence and outcomes in 
1753 patients. J Surg Res. 2009; 156(1):167-72. https://doi.org/10.1016/j.jss.2009.03.098. 
Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF. Neutrophil count in 
African Americans: Lowering the target cutoff to initiate or resume chemotherapy? J Clin 
Oncol. 2010;28(10):1633-1637. 
Ito T, Seyama T, Iwamoto KS, Mizuno T, Tronko ND, Komissarenko IV, Cherstovoy ED, Satow 
Y, Takeichi N, Dohi K, et al. Activated RET oncogene in thyroid cancers of children from 
areas contaminated by Chernobyl accident. Lancet. 1994;344(8917):259. 
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value Health. 2008;11(2):274-284. 
Ji JH, Oh YL, Hong M, Yun JW, Lee HW, Kim D, Ji Y, Kim DH, Park WY, Shin HT, Kim KM, 
Ahn MJ, Park K, Sun JM. Identification of Driving ALK Fusion Genes and Genomic 
Landscape of Medullary Thyroid Cancer. PLoS Genet. 2015;11(8):e1005467. 
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481. 
Kato S, Subbiah V, Marchlik E, Elkin SK, Carater JL, Kurzrock R. RET Aberrations in Diverse 
Cancers: Next-Generation Sequencing of 4,871 Patients. Clin Cancer Res. 2017;23(8):1988-
1997. 
Krampitz, G.W. and J.A. Norton, RET gene mutations (genotype and phenotype) of multiple 
endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer. 
2014;120(13):1920-1931. 
Kreissl MC, Bastholt L, Elisei R, et al. Efficacy and safety of vandetanib in progressive and 
symptomatic medullary thyroid cancer: post hoc analysis from the ZETA trial. J Clin Oncol. 
2020;38(24):2773-2781. https://doi.org/10.1200/JCO.19.02790. 
Lee SH LJ, Ahn MJ, et al. A phase II study of vandetanib in patients with non-small cell lung 
cancer harboring RET rearrangement. J Clin Oncol. 2016;34(suppl):abstr 9013. 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997;32(9):920-924. 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
172 
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 
1970;45 (239): 13–23. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis 
Child. 1969;44 (235):291–303. 
Morandi A, Martin LA, Gao Q, Pancholi S, Mackay A, Robertson D, Zvelebil M, Dowsett M, 
Plaza-Menacho I, Isacke CM. GDNF-RET signaling in ER-positive breast cancers is a key 
determinant of response and resistance to aromatase inhibitors. Cancer Res. 
2013;73(12):3783-3795. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317(17):1098. 
Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore 
JK, Papi L, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine 
neoplasia type 2A. Nature. 1993;363(6428): 458-460. 
Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 
2014;14(3):173-186.  
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 5.0, DCTD, NCI, NIH, DHHS. 2009. Publish date: 
27 November 2017.Available at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed: 27 
June 2019. 
Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret 
oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid 
papillary carcinomas in children. Cancer Res. 1997;57(9): 1690-1694. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:(6):649-655. 
Oxnard, GRS, Subbiah V, Park K, Bauer TM, Wirth LJ, Velcheti V, et al. Clinical Activity of 
LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell 
Lung Cancer An Update from ASCO 2018. IASLC 19th World Conference on Lung Cancer, 
2018. OA12.07 ID 13922. 
Plaza-Menacho I, Morandi A, Robertson D, Pancholi S, Drury S, Dowsett M, Martin LA, Isacke 
CM. Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen 
treatment and reveals a role for RET in endocrine resistance. Oncogene. 2010;29(33):4648-
4657. 
Prasad M L, Vyas M, Horne MJ, Virk RK, Morotti R, Liu Z, Tallini G, Nikiforova MN, 
Christison-Lagay ER, Udelsman R, Dinauer CA, Nikiforov YE. NTRK fusion oncogenes in 
pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122(7):1097-
1107. 
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
173 
Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149. 
Erratum in: J Clin Oncol. 2008;26(7):1192. 
Romei C, Casella F, Tacito A, Bottici V, Valerio L, Viola D, Cappagli V, Matrone A, Ciampi R, 
Piaggi P, Ugolini C, Torregrossa L, Basolo F, Materazzi G, Vitti P, Elisei R. New insights in 
the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of 
cases with double RET mutations. J Med Genet. 2016;53(11):729-734. 
Schlumberger M, Elisei R, Müller S, Schöffski P, Brose M, Shah M, Licitra L, Krajewska J, 
Kreissl MC, Niederle B, Cohen EEW, Wirth L, Ali H, Clary DO, Yaron Y, Mangeshkar M, 
Ball D, Nelkin B, Sherman S. Overall survival analysis of EXAM, a phase III trial of 
cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann 
Oncol. 2017;28(11):2813-2819. 
Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, 
Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, 
Dutcus CE, de las Heras B, Zhu J, Sherman SI. Lenvatinib versus placebo in radioiodine-
refractory thyroid cancer. N Engl J Med. 2015:372(7): 621-630. 
SEER-Database. SEER Cancer Stat Facts: Thyroid Cancer. National Cancer Institute. 2018. 
Available from: https://seer.cancer.gov/statfacts/html/thyro.html. Accessed: 26 June 2019.  
Sherman SI, Clary DO, Elisei R, Schlumberger MJ, Cohen EE, Schoffski P, Wirth LJ, 
Mangeshkar M, Aftab DT, Brose MS. Correlative analyses of RET and RAS mutations in a 
phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. 
Cancer. 2016;122(24):3856-3864. 
Sridhara R, Zhou J, Theoret MR, Mishra-Kalyani PS. Time to treatment failure (TTF) as a 
potential clinical endpoint in real-world evidence (RWE) studies of melanoma. J Clin Oncol. 
2018:36(15_suppl): 9578-9578. 
Smith TJ, Bohlke K, Lyman GH, Carson KR, Carwford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO; 
American Society of Clinical Oncology. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin 
Oncol. 2015;33(28):3199-3122.  
Smith J, Read ML, Hoffman J, Brown R, Bradshaw B, Campbell C, Cole T, Navas JD, Eatock F, 
Gundara JS, Lian E, McMullan D, Morgan NV, Mulligan L, Morrison PJ, Robledo M, 
Simpson MA, Smith VE, Stewart S, Trembath RC, Sidhu S, Togneri FS, Wake NC, Wallis Y, 
Watkinson JC, Maher ER, McCabe CJ, Woodward ER. Germline ESR2 mutation predisposes 
to medullary thyroid carcinoma and causes up-regulation of RET expression. Hum Mol Genet. 
2016;25(9): 1836-1845. 
Spanheimer PM, Park JM, Askeland RW, Kulak MV, Woodfield GW, De Andrade JP, Cyr AR, 
Sugg SL, Thomas A, Weigel RJ. Inhibition of RET increases the efficacy of antiestrogen and 
is a novel treatment strategy for luminal breast cancer. Clin Cancer Res. 2014;20(8):2115-
2125. 
Su S, He C, Ma J, Tang T, Zhang X, Ye Z, Long Y, Shao Q, Shao J, Yang A. RET/PTC 
Rearrangements Are Associated with Elevated Postoperative TSH Levels and Multifocal 
Approved on 11 Aug 2023 GMT

CONFIDENTIAL 
Protocol J2G-MC-JZJB(i) 
LY3527723 
174 
Lesions in Papillary Thyroid Cancer without Concomitant Thyroid Benign Disease. PLoS One. 
2016;11(11):e0165596. 
Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA 
rearrangement. Cell. 1985;42(2):581-588. 
Vandetanib [package insert]. Cambridge, MA; Sanofi Genzyme; 2014. 
Vandetanib [summary of product characteristics]. Amsterdam, The Netherlands; Genzyme 
Europe BV; 2014. 
Velcheti V, Hida T, Reckamp KL, Yang JC, Nokihara H, Sachdev P, Feit K, Kubota T, Nakada 
T, Dutcus CE, Ren M, Tamura T. Phase 2 study of lenvatinib (LN) in patients (Pts) with RET 
fusion-positive adenocarcinoma of the lung. Annals of Oncology. 2016;27(suppl 6):1204. 
Wang C, Mayer JA, Mazumdar A, Brown PH. The rearranged during transfection/papillary 
thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of 
estrogen receptor positive breast cancer cells. Breast Cancer Res Treat. 2012;133(2): 487-500. 
Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, 
Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients 
with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind 
phase III trial. J Clin Oncol. 2012;30(2):134-141. 
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, 
Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, 
Shah M, Waguespack SG; American Thyroid Association Guidelines Task Force on 
Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the 
management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. 
Wirth LJ, Cabanillas ME, Sherman EJ, Solomon B, LeBoulleux S, et al. Clinical Activity of 
LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET-Altered Thyroid Cancers: 
An Update from ASCO 2018. 88th Annual Meeting of the American Thyroid Association, 
Oct 3-7, 2018. 
Wirth LJ, Sherman EJ, Robinson B, Solomon B, Kang H, Lorch J, Worden F, Brose M, Patel J, 
Leboulleux S, Godbert Y, Barlesi F, Morris JC, Owonikoko TK, Tan DSW, Gautschi O, Weiss 
J, de la Fouchardière C, Burkard ME, Laskin J, Taylor MH, Kroiss M, Medioni J, Goldman 
JW, Bauer TM, Levy B, Zhu VW, Lakhani N, Moreno V, Ebata K, Nguyen M, Heirich D, Zhu 
EY, Huang X, Yang L, Kherani K, Rothenberg M, Drilon A, Subbiah V, Shah MH, Cabanillas 
ME. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. NEJM. 2020;383:825-835. 
Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, Nogami N, Matsumoto S, 
Kohno T, Tsuta K, Tsuchihara K, Ishii G, Nomura S, Sato A, Ohtsu A, Ohe Y, Goto K. 
Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung 
cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med. 2016;5(1):42-
50. 
Approved on 11 Aug 2023 GMT

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