A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients With Advanced RET-Altered Solid or Primary Central Nervous System Tumors
Phase: PHASE1
Conditions: Medullary Thyroid Cancer, Infantile Myofibromatosis, Infantile Fibrosarcoma, Papillary Thyroid Cancer, Soft Tissue Sarcoma
Sponsor: Eli Lilly and Company

Protocol: J2G-OX-JZJJ 
 
 
A Phase 1/2 Study of the Oral RET Inhibitor LOXO-292 in Pediatric Patients with Advanced 
RET-Altered Solid or Primary Central Nervous System Tumors 
 
 
NCT03899792 
 
Approval Date: 21-Feb-2025 
 
 
 

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CLINICAL PROTOCOL LOXO-RET-18036 (J2G-OX-JZJJ)  
A Phase 1/2 Study of the Oral RET Inhibitor LOXO-292 in 
Pediatric Patients with Advanced RET-Altered Solid or 
Primary Central Nervous System Tumors 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of selpercatinib (LY3527723), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Investigational Product: 
Selpercatinib (LY3527723) 
Protocol Number: 
LOXO-RET-18036 (J2G-OX-JZJJ) 
IND #: 
142299 
EudraCT #: 
2019-000212-28 
EU trial #: 
2023-507703-63-00 
Development Phase: 
1/2 
Sponsor: 
Loxo Oncology, Inc., a wholly owned subsidiary of 
Eli Lilly and Company 
Approval Date: Protocol Amendment 11 Electronically Signed and Approved by Lilly on date provided 
below. 
Document ID: VV-CLIN-076219 
 
 
Approved on 21 Feb 2025 GMT

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Clinical Protocol LOXO-RET-18036 (J2G-OX-JZJJ) 
Selpercatinib 
 
 
 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Version 10.0 
09 October 2024 
Version 9.0 
15 August 2023 
Version 8.0 
30 June 2023 
Version 7.0 
21 December 2022 
Version 6.0 
19 May 2021 
Version 5.0 
05 October 2020 
Version 4.0 
19 December 2019 
Version 3.0 
02 August 2019 
Version 2.0 
11 January 2019 
Version 1.0 
09 November 2018 
Amendment [11] 
 
This amendment is considered to be substantial because it is likely to have a significant impact 
on the safety or rights of the study participants. 
Overall Rationale for the Amendment: 
The purpose of this amendment is to update Appendix M to adjust the frequency of clinic visits 
and include remote visits in Spain and France. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix K Continued 
Access 
 
Included footnote b 
 
Added footnote for remote 
visits. 
 
Minor editorial update. 
 
Correction 
 
Alignment with 
Appendix M.  
Appendix M Country-
specific Requirements 
Updated the frequency of clinic visits 
and added remote visits in Spain and 
France. 
To reduce the burden on 
patients/align with the standard of 
care.  
 
 
 
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PROTOCOL SYNOPSIS  
TITLE: 
A Phase 1/2 Study of the Oral RET Inhibitor LOXO-292 in Pediatric Patients with Advanced RET-Altered Solid 
or Primary Central Nervous System Tumors. 
PROTOCOL NUMBER:  
LOXO-RET-18036 (J2G-OX-JZJJ) 
EudraCT #: 2019-000212-28 
EU trial #: 2023-507703-63-00 
STUDY SITES:  
Approximately 25 institutions will be recruited for participation in this study. 
PHASE:  
1/2  
OBJECTIVES: 
Study objectives are outlined below for Phase 1 and for Phase 2. 
PHASE 1 Objectives  
The objectives for the Phase 1 patient population (pediatric patients with advanced cancer harboring an activating 
RET alteration) are as follows: 
Primary 
The primary objective is to determine the safety, including dose-limiting toxicities (DLTs), of the oral RET 
inhibitor selpercatinib. 
Secondary 
 To characterize the pharmacokinetic (PK) properties of selpercatinib  
 To identify the maximum tolerated dose (MTD) and/or the appropriate dose of selpercatinib for further 
clinical investigation  
 ORR and CBR based on RECIST 1.1 or RANO as appropriate to tumor type as determined by an IRC and 
treating investigator 
 
 
 
 
 
 
 
 
  
 
 
  
 
PHASE 2 Objectives  
The objectives for the Phase 2 patient population (pediatric patients with advanced cancer harboring an activating 
RET alteration) are as follows: 
Primary 
To determine the objective response rate (ORR) as determined by an Independent Review Committee (IRC) 
and measured by the proportion of patients with best overall confirmed response of complete response (CR) or 
partial response (PR) by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), or 
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Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate, following treatment with 
selpercatinib. 
Secondary 
 
To determine the following: 
o ORR ba>0/:9?30?=0,?4929A0>?42,?:=N>=0>;:9>0,>>0>>809?@>492%&'v1.1 or RANO criteria, 
as appropriate to tumor type  
o Duration of response (DOR) in patients with best overall response of CR or PR as determined by 1) an 
IRC and 2) the treating Investigator 
o Duration of progression-free survival (PFS) following initiation of selpercatinib by 1) an IRC and 
2) the treating Investigator 
o Overall survival (OS) following initiation of selpercatinib 
o The clinical benefit rate (CBR) based on the proportion of patients with best overall response of CR, 
PR, or stable disease (SD) lasting 16 or more weeks following initiation of selpercatinib as determined 
by 1) an IRC and 2) the treating Investigator 
 To assess the safety profile and tolerability of selpercatinib 
 To characterize the PK properties of selpercatinib in pediatric patients 
 To evaluate the concordance of prior molecular profiling that detected an activating RET alteration within 
?30;,?409?N>?@8:=B4?3/4,29:>?4.?0>?(s) being evaluated by the Sponsor 
 To characterize post-operative staging and surgical margin status in patients who have definitive surgery 
following treatment with selpercatinib 
 To evaluate change from baseline in patient-reported pain at BOR visit as assessed by the Wong-Baker 
Faces Scale 
 To assess the acceptability and palatability of selpercatinib 
 in patients 
under age 18. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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STUDY DESIGN: 
Phase 1 Dose Escalation 
This is a multicenter, open-label, Phase 1/2 study in pediatric patients with an advanced solid or primary CNS 
tumor harboring an activating RET alteration. Selpercatinib will be administered orally twice daily (BID), with 
the dose adjusted by body surface area (BSA).  
The starting dose level is intended to deliver equivalent exposure to the recommended Phase 2 dose (RP2D) in 
. Planned dose levels are listed in Table 3-1. Body surface area (BSA) will be determined 
by the Mosteller I30423?PB0423?
Mosteller 1987). Doses for each cohort will be increased 
incrementally until an MTD or RP2D is reached. The maximum dose (regardless of BSA calculation) will be no 
higher than the recommended adult dose associated with the BSA-based dosing, i.e., patients in Dose Cohort 1 
will receive a dose no higher than 160 mg BID. 
This trial will use a 
 Dose Escalation 
 
 patients will be enrolled in each dose cohort, also referred to as dose levels. Each patient will 
participate in only 1 dose cohort. The total number of patients to be enrolled in the dose escalation phase is 
dependent upon the observed safety profile, which will determine the number of patients per dose cohort, as well 
as the number of dose escalations required to achieve the MTD. Each dose level in the dose escalation portion 
will enroll no more than 15 patients. 
A starting sample size of at least 3 patients per dose cohort, expanding to 6 patients in the event of a marginal 
DLT rate (30%), was deemed to be a safe and conventional approach in the dose escalation of a novel oncologic 
agent. 
Each patient in a given cohort must have completed safety assessments through Cycle 1, Day 28, and received a 
minimum of 75% of the planned total dose in Cycle 1 (unless due to toxicity) to be eligible for the assessment of 
DLT. 
 
 If no DLT then accrual in the next highest cohort will begin immediately. If the first 
3 patients have not cleared the DLT window, additional patients may be enrolled on the current dose level up to a 
maximum of . A minimum of  patients in a given cohort must have completed 28 days of safety assessment in 
Cycle 1 without DLT and a maximum of 
 in  patients who have completed the DLT window before the 
next cohort initiates accrual. Escalation will proceed through the  dose levels until the MTD or RP2D is reached. 
Based on the interim evaluation of the safety and tolerability data of the previous cohort, it may be decided to 
enroll additional patients in a previously studied cohort or at an intermediate dose level. 
1
 patients within a cohort experience a DLT, then the dose escalation will stop. In order for the 
MTD/RP2D, the Safety Review Committee (SRC) will evaluate whether the previous lower dose level will be 
considered the MTD (Table 3-1 shows example doses), whether an intermediate dose level should be evaluated, 
and/or whether additional patients need to be evaluated if the DLTs seen at this dose level are considered to be 
not serious or equivocal with regard to causal relationship to selpercatinib.  
Patients are eligible for intra-patient dose escalation to the highest dose cohort that has been determined safe. 
However, intra-patient dose escalation is not required; it is only appropriate if the treating Investigator and 
Sponsor believe it is in the best interest of the patient.  
Escalation will proceed through the planned dose levels, or until the MTD is reached, or until the Sponsor 
determines that a suitable dose has been achieved based on PK exposure and toxicity.  
Dose-Limiting Toxicity Definition 
A DLT is defined as any of the following treatment-emergent adverse events (TEAEs; a TEAE is defined as an 
adverse event [AE] that starts on or after the first administration of study drug) occurring in the first 28 days (i.e., 
in Cycle 1,9/9:?=0,>:9,-7D,??=4-@?0/?:;,?409?N>@9/0=7D492/4>0,>0:=:?30=80/4.,7.:9/4?4:9,9/deemed 
by the Investigator to be related to selpercatinib as assessed via CTCAE v5.0: 
 Any Grade 3 or higher nonhematologic toxicity, with the exception of Grade 3 fatigue, nausea, tendon 
reflex decrease, or weight gain attributable to normal growth and development 
 Grade 3 vomiting or diarrhea will be considered DLT only if it persists for > 48 hours despite standard of 
care treatment. Admission to the hospital of patients < 1 year of age with Grade 3 vomiting or diarrhea is 
recommended until these events resolve to Grade 1. 
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 Grade 4 vomiting or diarrhea will be considered DLT regardless of duration. Admission to the hospital of 
patients < 1 year of age with Grade 4 vomiting or diarrhea is recommended until these events resolve to 
Grade 1. 
 Any toxicity, regardless of the Common Terminology Criteria for Adverse Events (CTCAE) grade, 
resulting in discontinuation or dose reduction of treatment (with the exception of symptoms related to 
disease progression [PD]) 
 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with Grade 1 or higher bleeding 
 Grade 4 anemia lasting > 8 days, despite supportive therapy, not explained by underlying condition 
(transfusions are allowed during Cycle 1), and persists beyond the initial transfusion 
 Grade 4 neutropenia, lasting > 8 days, despite supportive therapy (Cycle 1 growth factor support not 
allowed for prophylaxis) 
 Grade 3 uncomplicated febrile neutropenia will not be considered a DLT 
Phase 2 Expansion Cohorts 
Additional patients may be enrolled to better characterize the safety and efficacy of the selpercatinib dose 
recommended for further study. Patients may enroll into each of the 4 cohorts below, depending on disease 
characteristics (refer to Synopsis Table 1).  
Synopsis Table 1: Disease Criteria for Enrollment for Cohorts 1 to 4 
Cohort 
Disease Criteria 
Cohort 1 
RET fusion-positive solid tumor (excluding CNS primary) with measurable disease 
Cohort 2 
RET-mutant MTC with measurable disease 
Cohort 3 
RET fusion-positive primary CNS tumor with measurable disease 
Cohort 4 
Any patient with RET mutation/alteration not fitting Cohort 1 to 3 criteria (i.e., 
RET alterations via plasma cfDNA or non-CLIA certified test, non-measurable 
(i.e., only evaluable) disease 
Abbreviations: cfDNA = circulating free DNA; CNS = central nervous system; MTC = medullary thyroid cancer. 
ELIGIBILITY CRITERIA: 
Inclusion Criteria 
1. Pediatric patients  6 months of age and  21 years of age at Cycle 1 Day 1 (C1D1) with a locally advanced 
or metastatic solid or primary CNS tumor that has relapsed, progressed or was nonresponsive to available 
therapies and/or for which no standard or available systemic curative therapy exists.  
a) Patients with locally advanced disease who would require, in the opinion of the Investigator, 
disfiguring surgery, or limb amputation to achieve a complete surgical resection are also eligible.  
b) In geographies where a selective RET-inhibitor is approved, patients may enroll without prior 
systemic treatment. 
2. Evidence of an activating RET gene alteration in tumor and/or blood (e.g., gene rearrangement and/or 
mutation, excluding synonymous, frameshift, or nonsense mutations) as identified through molecular assays, 
as performed for clinical evaluation.  
a) The RET alteration result should be generated from a laboratory with CLIA, ISO/IEC, CAP, or 
other similar certification as per local guidelines including but not limited to in vitro diagnostic 
regulation (IVDR) compliance as applicable. In cases where such certification is not clearly 
demonstrated to determine eligibility, the Sponsor should be contacted to discuss laboratory test 
results.  
b) A positive germline test for a RET mutation is acceptable for patients with MTC.  
c) In addition to RET fusion-positive solid tumors and RET-mutant MTC, MTC syndrome spectrum 
cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, or 
poorly differentiated thyroid cancers with other RET alteration/activation may be allowed with 
prior Sponsor approval.  
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3. Patients with primary CNS tumors or cerebral metastasis: 
a) Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment 
b) Must have not required increasing doses of steroids within the 7 days prior to enrollment to 
manage CNS symptoms  
4. Imaging study must be performed within 28 days of C1D1 while on stable dose steroid medication 
(if needed) for at least 7 days immediately before the imaging study. 
5. Histologic verification of malignancy at original diagnosis or relapse, except in patients with intrinsic brain 
stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebral spinal fluid 
(CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG). 
6. Must have measurable or non-measurable but evaluable disease. 
7. Karnofsky (patients 16 years and older) or Lansky (patients younger than 16 years) performance score of at 
least 50. 
8. Must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy to CTCAE 
(v5.0) Grade ≤ 2. 
a) Myelosuppressive chemotherapy: Start of selpercatinib must be at least 21 days after the last dose 
of myelosuppressive chemotherapy (42 days if prior nitrosourea). 
b) Investigational agent or anticancer therapy other than chemotherapy: Not within 2 weeks prior to 
planned start of selpercatinib or 5 half-lives, whichever is shorter. Full recovery of clinically 
significant toxicities from that therapy must be evident. Prior MKIs with anti-RET activity are 
allowed. Refer to Appendix I for examples of MKIs with anti-RET activity. Patients who have 
previously received selpercatinib are not eligible. 
c) Radiation therapy (XRT): Start of selpercatinib must be at least 14 days after local palliative 
radiation (small port); at least 42 days must have elapsed before start of selpercatinib if other 
substantial bone marrow radiation, including prior radio-iodized metaiodobenzylguanidine 
(131I-MIBG) therapy. 
d) Stem cell infusion (ASCT, Allogenic or CAR-T) without total body irradiation (TBI): No 
evidence of active graft versus host disease and at least 56 days must have elapsed before start of 
selpercatinib after transplant or stem cell infusion. 
e) Hematopoietic growth factors: Start of selpercatinib must be at least 14 days after the last dose of 
a long-acting growth factor (e.g., pegfilgrastim); or 7 days for short-acting growth factor.  
9. An archival (FFPE or fresh frozen) or fresh tumor tissue sample must be available (refer to Section 7.5). If 
archival tumor tissue sample is not available, a fresh biopsy (at a primary or metastatic site) should be 
performed. If an archival or fresh sample cannot be obtained safely, the patient may still be eligible with 
documented Sponsor approval.  
10. Adequate hematologic status, defined as: 
a) Absolute neutrophil count (ANC) ≥ 1.0  109/L not requiring growth factor support for at least 
7 days prior to treatment. 
b) Platelet count ≥ 75  109/L not requiring transfusion support for at least 7 days prior to treatment.  
c) Hb ≥ 8 mg/dL not requiring transfusion support or erythropoietin for at least 7 days prior to 
treatment.  
11. Adequate hepatic / pancreatic function, defined as: 
a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5  the upper limit of 
normal (ULN) or ≤ 5  ULN with documented liver involvement (such as liver metastasis or a 
primary biliary tumor), and 
b) Total bilirubin ≤ 1.5  ULN or ≤ 3  ULN with documented liver involvement or Gilbert’s 
Disease (patients with Gilbert’s Disease may be enrolled with prior Sponsor approval). 
12. Adequate renal function, defined as:  
a) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 based on local institutional practice for 
determination, or a maximum serum creatinine by age and gender as presented in Synopsis Table 2. 
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Synopsis Table 2: Serum Creatinine by Age and Gender 
 
Maximum Serum 
Creatinine (mg/dL) 
Maximum Serum 
Creatinine (µmol/L) 
Age 
Male 
Female 
Male 
Female 
6 months to < 1 year 
0.5 
0.5 
44 
44 
1 to < 2 years 
0.6 
0.6 
53 
53 
2 to < 6 years 
0.8 
0.8 
71 
71 
6 to < 10 years 
1 
1 
88 
88 
10 to < 13 years 
1.2 
1.2 
106 
106 
13 to < 16 years 
1.5 
1.4 
132 
124 
≥ 16 years 
1.7 
1.4 
150 
124 
13. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the 
duration of study participation. 
14. Willingness of male and female patients with reproductive potential to utilize double effective birth control 
methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and 
for 1 month following study completion. 
For male patients with a non-pregnant female partner of child-bearing potential, and women of child-bearing 
potential, one of the following highly effective birth control methods (with a failure rate of less than 1% per 
year when used consistently and correctly) are recommended:  
a) Combined estrogen and progestogen containing hormonal contraception associated with inhibition 
of ovulation given orally, intravaginally, or transdermally 
b) Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by 
injection, or by implant 
c) Intrauterine device (IUD) 
d) Intrauterine hormone-releasing system (IUS) 
e) Bilateral tubal occlusion 
f) 
Vasectomized partner 
g) Sexual abstinence: considered a highly effective method only if defined as refraining from 
heterosexual intercourse during an entire period of risk associated with the study treatment. The 
reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the 
usual lifestyle of the patient. 
15. Ability to swallow capsules, liquid suspension, or gastric access via a naso- or gastric tube. 
The patient and, when applicable, the parent/guardian of child or adolescent patient has the ability to 
understand, agree to, and sign the study Informed Consent Form (ICF) and applicable Pediatric Assent Form 
before initiation of any protocol-related procedures; patient has the ability to give assent, as applicable, at the 
time of parental/guardian consent 
16. [removed]. 
Exclusion Criteria 
Patients meeting any of the following criteria are to be excluded from study participation: 
1. Major surgery within 2 weeks prior to C1D1. 
2. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months 
prior to C1D1; ongoing cardiomyopathy; or current prolonged QT interval corrected for heart rate (QTc) 
interval > 440 milliseconds for patients ≤ 15 years old and > 470 milliseconds for patients > 15 years 
old. For patients ≤ 15 years old, Bazett’s Formula will be utilized to determine QTc. For patients > 15 
years old, either method, Fridericia or Bazett’s Formula may be applied.  
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3. Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator 
makes the risk: benefit ratio for the patient to participate in the trial unfavorable. Screening for chronic 
conditions is not required. 
4. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal 
absorption of the study drug. 
5. Pregnancy or lactation. 
6. Uncontrolled hypotension or hypertension H=,/0
'A5.0). 
7. Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e., the patient required a modification 
to current thyroid medication in the 7 days before start of selpercatinib). 
8. Uncontrolled symptomatic hypercalcemia or hypocalcemia. 
9. [Removed] 
10. Known hypersensitivity to any of the components of the investigational agent, selpercatinib or 
Ora-Sweet® SF and OraPlus®, for patients who will receive selpercatinib suspension. 
11. [Removed] 
12. [Removed] 
ETHICAL CONSIDERATIONS OF BENEFIT/RISK: 
Pediatric patients with RET-fusion cancers (papillary thyroid, soft tissue sarcoma, others) and RET mutated 
cancer represent populations with high unmet need. The available therapies for these patients provide short-term 
palliation (i.e., chemotherapy), may be less effective in cancers driven by kinase fusions (i.e., immunotherapy) 
and/or are very toxic (i.e., MKIs). Therefore, there is an urgent need to identify new targeted therapies that 
potently inhibit RET in tumors, while sparing other kinase and non-kinase off-targets that contribute to significant 
toxicity. 
These considerations indicate the benefit/risk ratio for selpercatinib in this study to be favorable. 
PLANNED SAMPLE SIZE: 
In the Phase 1 portion of the study, a minimum of  patients will be enrolled into a dose escalation cohort. Over-
enrollment (maximum of 
 patients per dose escalation cohort) may occur in the dose escalation cohorts as 
previously described above in Phase 1 Dose Escalation. 
In the Phase 2 portion of the study, additional patients may be enrolled to better characterize the safety and 
efficacy of the selpercatinib RP2D. The Phase 2 portion will enroll approximately 
 patients into Cohorts 1 
and 2. The total sample size for Phase 2 will not exceed 
. 
INVESTIGATIONAL DRUG: 
Selpercatinib will be provided as a liquid suspension, a capsule containing drug substance with a simple blend of 
excipients 
. The capsules 
 will be provided to the sites for distribution to the patient for 
outpatient administration. Liquid suspension is provided to the pharmacy as powder and subsequently 
compounded
TREATMENT PROCEDURES: 
Patients will begin BID dosing on C1D1 according to the assigned cohort. Each cycle will consist of 28 days of 
continuous dosing; for patients who reach 2 years of study treatment, cycles may be extended to 84 days in 
length. Individual patients will continue dosing until PD, unacceptable toxicity, or other reason for treatment 
discontinuation. Patients with documented PD may be allowed to continue selpercatinib if the patient is tolerating 
treatment and, in the opinion of the Investigator and Sponsor, is deriving clinical benefit from continuing study 
medication. Four weeks after the last dose, all treated patients will undergo a safety follow-up visit. 
STUDY ASSESSMENTS: 
Safety assessments will be performed, including physical examination, body weight, Karnofsky (patients 16 years 
and older) or Lansky (patients younger than 16 years) performance score, clinical AEs, laboratory variables 
(hematology, serum chemistries, and urinalysis), electrocardiogram (ECG), vital signs, and thyroid function.  
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Efficacy assessments include tumor evaluation at regularly scheduled intervals. Investigators may elect to 
conduct an initial tumor evaluation on Cycle 2 Day 1 or a confirmatory tumor evaluation at an otherwise 
unscheduled visit, as permitted by local regulatory authority and IRB requirements. All scans will be collected 
and stored at a central facility to permit central reviewer assessment if desired. An End of Treatment (EOT) visit 
is required within 7 days of the last dose of selpercatinib or the decision to terminate study drug. In addition, a 
Safety Follow-up (SFU) visit 28 days (+7 days) after the last dose of study drug is required.  
Finally, all patients will enter Long-Term Follow-Up (LTFU) (~every 3 months for up to 2 years) period of 
observation, for the purpose of confirming the resolution of any AEs, PD if not occurring on study, subsequent 
anticancer therapy(ies), and survival. LTFU may be conducted by phone. Patients who discontinue study drug for 
reasons other than disease progression, lost to follow-up, withdrawal of consent or initiation of a new anticancer 
therapy(ies), will continue undergoing disease assessment by imaging (as specified above; utilizing the same 
modality[ies] used for the baseline imaging assessment) until PD, withdrawal of consent, or initiation of a new 
anticancer therapy(ies). 
Blood for PK assessment will be collected in accordance with Appendix B (and Table 11-2). If patients have an 
Ommaya Reservoir or undergo lumbar puncture (LP) during the time of study drug administration, CNS fluid 
will also be 
  
Pain and Quality of Life (QoL) Assessments will be collected every Cycle. Pain will be assessed by the 
Wong-Baker Faces Scale (http://wongbakerfaces.org) at every office visit. QoL will be assessed using the 
PedsQL-Cancer Module for both the patient and their parent/caregiver: 
(http://www.proqolid.org/instruments/pediatric_quality_of_life_inventory_cancer_module_pedsql_cancer_modul
e) at every office visit.  
ENDPOINTS: 
Study endpoints are outlined below for Phase 1 and for Phase 2. 
PHASE 1 Endpoints 
Primary 
Frequency, severity and relatedness of TEAEs and SAEs, including DLTs in pediatric patients receiving 
selpercatinib 
Secondary 
 
Plasma concentrations of selpercatinib and PK parameters, including, but not limited to area under the 
concentration versus time curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), 
time to maximum plasma concentration (Tmax), degree of accumulation, and other characterizations 
 
The MTD and/or the RP2D of selpercatinib in pediatric patients  
 
ORR and CBR based on RECIST 1.1 or RANO as appropriate to tumor type as determined by an IRC and 
treating investigator 
 
 
 
 
 
 
 
 
 
 
 
PHASE 2 Endpoints 
Primary 
ORR based on RECIST v1.1 or RANO as appropriate to tumor type as determined by an IRC 
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Secondary 
 
ORR based on RECIST v:=%!",>,;;=:;=4,?0?:?@8:=?D;0;0=?30?=0,?4929A0>?42,?:=N>=0>;:9>0
assessment  
 
DOR (IRC and treating investigator) 
 
PFS (IRC and treating investigator) 
 
OS  
 
CBR (IRC and treating investigator) 
 
Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry 
values, and assessments of physical examinations, vital signs, and ECGs 
 
Plasma concentrations of selpercatinib and PK parameters, including, but not limited to AUC 0-24, Cmax, 
Tmax, degree of accumulation, and other characterizations 
 
The percent positive agreement between prior molecular profiling that detected a RET alteration within the 
;,?409?N>?@8:=and diagnostic test(s) being evaluated by the Sponsor 
 
Post-operative staging and surgical margin status in patients who have definitive surgery following treatment 
with selpercatinib 
 
Change from baseline in patient-reported pain at BOR visit as assessed by the Wong-Baker Faces Scale.  
 
Acceptability and palatability of selpercatinib 
 in patients under age 18. 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
STATISTICAL METHODS: 
Safety Analyses 
An SRC will be established to oversee the safety aspects of the study and to render dose escalation and RP2D or 
MTD decisions in the dose escalation portion of the study. Specifically, the Committee will perform ongoing 
review of serious adverse events (SAEs) and other safety trends throughout the conduct of the study. The 
:884??00808-0=>34;B477.:9>4>?:1?30&;:9>:=N>=0;=0>09?,?4A0>,9/clinically qualified individuals from 
each active clinical site. The Committee will be convened as needed and decisions will be documented in written 
minutes. 
Safety analyses will be conducted using the Safety Analysis Set (SAS), which consists of all patients treated with 
at least 1 dose of study drug.  
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TEAEs reported during the study will be tabulated and listed by Sponsor Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and Preferred Term (PT). Tables will display number and percentage of 
patients experiencing the event for the following categories: All AEs, AEs considered related to study drug, AEs 
by severity, DLTs, AEs occasioning treatment delay or discontinuation, and SAEs. For the dose escalation phase, 
the observed DLT rate in each dose cohort will be calculated by the proportion of patients who experienced DLT 
with a 2-sided 95% exact binomial confidence interval (CI). 
Efficacy Analyses 
The efficacy analyses will be conducted on Safety Analysis Set unless otherwise specified. The efficacy 
outcomes will be summarized by cohort or by tumor type as deemed appropriate. 
ORR will be estimated using disease-specific response criteria (e.g., RECIST v1.1 for patients with solid tumor). 
The estimate of the ORR will be calculated based on the maximum likelihood estimator (i.e., crude proportion of 
patients with best overall response of CR or PR. All responses will be confirmed by a second scan  28 days after 
the initial response. The estimate of the ORR will be accompanied by 2-sided 95% CIs. The primary analysis of 
ORR will be based on the responses determined by an IRC. A secondary analysis will be based on the treating 
Investigator’s assessment of response. 
Time-to-event endpoints (DOR, PFS and OS) will be summarized descriptively using the Kaplan-Meier method. 
The Kaplan-Meier estimate with 95% CI calculated using Brookmeyer and Crowley method will be provided for 
the median. The event-free rate with the 95% CI calculated using Greenwood’s formula will be provided for 
selected time points. Median follow-up for each endpoint will be estimated according to the Kaplan Meier 
estimate of potential follow-up.  
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TABLE OF CONTENTS 
CLINICAL PROTOCOL LOXO-RET-18036 (J2G-OX-JZJJ) ................................................. 1 
Protocol Amendment Summary of Changes Table ............................................................ 2 
PROTOCOL SYNOPSIS ......................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 13 
LIST OF TABLES .................................................................................................................. 18 
LIST OF FIGURES ................................................................................................................ 19 
LIST OF APPENDICES ......................................................................................................... 19 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 20 
1 
INTRODUCTION ................................................................................................ 26 
1.1 RET Gene and Receptor/Normal RET .................................................................... 26 
1.2 Tumors with RET Abnormalities and Current Treatment Options ......................... 26 
1.3 Role of RET in Pediatric Cancers ............................................................................ 27 
1.4 Rationale .................................................................................................................. 28 
1.5 SELPERCATINIB ................................................................................................... 28 
1.5.1 Pharmacokinetics ............................................................................................ 31 
1.5.2 Safety Pharmacology ...................................................................................... 33 
1.5.3 Toxicology ...................................................................................................... 33 
1.5.4 Benefit/Risk .................................................................................................... 34 
1.5.5 Clinical Experience ......................................................................................... 34 
1.5.6 Known and Anticipated Risks ........................................................................ 35 
1.5.7 Rationale for Selection of the Starting Dose................................................... 35 
2 
STUDY OBJECTIVES ......................................................................................... 40 
2.1 Phase 1 Study Objectives ......................................................................................... 40 
2.2 Phase 2 Study Objectives ......................................................................................... 40 
3 
INVESTIGATIONAL PLAN ............................................................................... 43 
3.1 Phase 1 ..................................................................................................................... 43 
3.1.1 Study Design ................................................................................................... 43 
3.1.1.1 General Treatment Procedures ................................................................ 43 
3.1.1.2 Dose Escalation Scheme and Assessment of Dose-Limiting 
Toxicity .................................................................................................... 44 
3.1.1.3 Dose-Limiting Toxicity Definition .......................................................... 45 
3.1.1.4 Number of Patients .................................................................................. 46 
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3.2 Phase 2 Dose Expansion Cohort .............................................................................. 46 
3.3 General Treatment Procedures ................................................................................. 47 
3.4 Investigational Sites ................................................................................................. 48 
4 
SELECTION OF STUDY POPULATION .......................................................... 49 
4.1 Inclusion Criteria ..................................................................................................... 49 
4.2 Exclusion Criteria .................................................................................................... 52 
4.3 Enrollment Procedures ............................................................................................. 52 
5 
TREATMENT ...................................................................................................... 54 
5.1 Investigational Product ............................................................................................ 54 
5.2 Selpercatinib Administration ................................................................................... 54 
5.2.1 General Dosing Instructions ........................................................................... 54 
5.2.2 Cycle 1 ............................................................................................................ 56 
5.2.3 Cycles 2 and Higher ........................................................................................ 56 
5.2.4 Dose Modifications ......................................................................................... 56 
5.2.5 Drug Treatment Holiday ................................................................................. 58 
5.3 Prior and Concomitant Medications ........................................................................ 58 
5.3.1 General ............................................................................................................ 58 
5.3.2 Allowed Concomitant Medications ................................................................ 58 
5.3.3 Prohibited Concomitant Medications ............................................................. 59 
5.3.3.1 Chemotherapeutic Agents or Hematopoietic Growth Factors ................. 59 
5.3.4 Concurrent Medications, Therapy, or Surgery ............................................... 60 
5.3.4.1 H2 Blockers ............................................................................................. 60 
5.3.4.2 PPIs .......................................................................................................... 60 
5.3.4.3 Antacids ................................................................................................... 60 
5.3.4.4 Palliative Radiotherapy ............................................................................ 60 
5.3.4.5 Elective Surgery or Surgical Resection ................................................... 60 
5.3.4.6 Inhibitors or Inducers of CYP3A4 ........................................................... 61 
5.4 Duration of Treatment.............................................................................................. 61 
6 
DISCONTINUATION / WITHDRAWAL CRITERIA ....................................... 63 
6.1 Removal of Patients from Therapy or Assessment .................................................. 63 
6.2 Reasons for End of Study ........................................................................................ 63 
7 
STUDY PROCEDURES AND ASSESSMENTS ................................................ 65 
7.1 Informed Consent / Pediatric Assent ....................................................................... 65 
7.2 Screening.................................................................................................................. 65 
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7.3 Enrollment................................................................................................................ 65 
7.4 Medical History and Malignancy History................................................................ 65 
7.5 Tissue Biopsy ........................................................................................................... 66 
7.6 Physical Examination............................................................................................... 66 
7.6.1 Karnofsky or Lansky Performance Status Scales ........................................... 66 
7.6.2 Vital Signs ....................................................................................................... 66 
7.7 Electrocardiograms .................................................................................................. 66 
7.8 Growth Plate Evaluation .......................................................................................... 67 
7.9 Dental Evaluation..................................................................................................... 67 
7.10 Pubertal Maturation Evaluation ............................................................................... 67 
7.11 Laboratory Tests ...................................................................................................... 67 
7.11.1 Pregnancy Test ................................................................................................ 68 
7.11.2 Hematology ..................................................................................................... 68 
7.11.3 Serum Chemistries .......................................................................................... 68 
7.11.4 Urinalysis ........................................................................................................ 68 
7.11.5 Calcitonin, Thyroglobulin and Carcinoembryonic Antigen ........................... 68 
7.11.6 Cortisol and Adrenocorticotropic Hormone ................................................... 68 
7.11.7 Thyroid Function ............................................................................................ 69 
7.12 Pharmacokinetic Samples: Blood (and Cerebrospinal Fluid, if Appropriate) ......... 69 
7.13 Disease Assessment ................................................................................................. 69 
7.13.1 Tumor Measurements ..................................................................................... 69 
7.13.1.1 Collection of Radiographic Studies for Independent Review ................. 70 
7.13.2 Correlative studies:
 
 
7.13.3 Pain and Health-Related Quality of Life: Wong-Baker Faces Scale 
and PedsQL-Core ............................................................................................ 71 
7.13.4 Telephone Follow-up ...................................................................................... 71 
7.13.5 Survival Status ................................................................................................ 71 
7.14 Study Drug Administration and Dosing Diary ........................................................ 71 
7.14.1 Formulation Acceptability and Palatability Assessments ............................... 72 
7.15 Concomitant Medication .......................................................................................... 72 
7.16 Adverse Events/Serious Adverse Events ................................................................. 72 
7.17 End of Treatment Visit............................................................................................. 72 
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7.18 Safety Follow-up Visit ............................................................................................. 73 
7.19 Long-Term Follow-up ............................................................................................. 73 
7.20 Continued Access..................................................................................................... 73 
8 
ADVERSE EVENTS ............................................................................................ 74 
8.1 Grading and Intensity of Adverse Events ................................................................ 74 
8.2 Relationship to Study Drug ...................................................................................... 75 
8.3 Serious Adverse Event Reporting ............................................................................ 75 
8.4 Serious Adverse Event Follow-up ........................................................................... 77 
8.5 Pregnancy Reporting ................................................................................................ 77 
9 
PLANNED ANALYSES ...................................................................................... 79 
9.1 Study Endpoints ....................................................................................................... 79 
9.1.1 Phase 1 Study Endpoints ................................................................................. 79 
9.1.1.1 Primary .................................................................................................... 79 
9.1.1.2 Secondary ................................................................................................ 79 
 
9.1.2 Phase 2 Study Endpoints ................................................................................. 80 
9.1.2.1 Primary .................................................................................................... 80 
9.1.2.2 Secondary ................................................................................................ 80 
 
9.2 Analysis Populations ................................................................................................ 81 
9.3 Determination of Sample Size ................................................................................. 81 
9.3.1 Phase 1 ............................................................................................................ 81 
9.3.2 Phase 2 ............................................................................................................ 81 
9.4 Demographics and Baseline Characteristics ............................................................ 82 
9.5 Safety Analyses ........................................................................................................ 82 
9.5.1 Assessment Committee ................................................................................... 82 
9.5.2 Safety Review Committee .............................................................................. 82 
9.5.3 Treatment Emergent Adverse Events ............................................................. 83 
9.5.4 Dose-Limiting Toxicity .................................................................................. 83 
9.5.5 Deaths ............................................................................................................. 83 
9.5.6 Laboratory Values ........................................................................................... 83 
9.5.7 Vital Signs ....................................................................................................... 84 
9.5.8 Concomitant Medications ............................................................................... 84 
9.6 Efficacy Analyses .................................................................................................... 84 
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9.7 Pharmacokinetic Analyses ....................................................................................... 85 
9.8 Pain and Health Related Quality of Life .................................................................. 86 
 
10 
STUDY ADMINISTRATION.............................................................................. 87 
10.1 Regulatory and Ethical Considerations .................................................................... 87 
10.1.1 Regulatory Authority Approval ...................................................................... 87 
10.1.2 Ethics Approval .............................................................................................. 87 
10.1.3 Patient Informed Consent and Pediatric Assent.............................................. 87 
10.1.4 Investigator Reporting Requirements ............................................................. 88 
10.2 Data Management .................................................................................................... 88 
10.2.1 Data Protection................................................................................................ 89 
10.3 Study Monitoring ..................................................................................................... 89 
10.4 Termination .............................................................................................................. 90 
10.5 Records Retention .................................................................................................... 91 
10.6 Confidentiality of Information ................................................................................. 91 
11 
REFERENCES ..................................................................................................... 92 
 
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LIST OF TABLES  
 
 
 
 
 
 
Table 3-1 
Planned Selpercatinib Dose Escalation Cohorts ................................................... 43 
Table 3-2 
Disease Criteria for Enrollment: Cohorts 1 to 4 ................................................... 47 
Table 4-1 
Serum Creatinine by Age and Gender .................................................................. 51 
Table 5-1 
Toxicities Requiring Dose Modification .............................................................. 57 
Table 5-2 
Dose Level Reductions for Selpercatinib ............................................................. 58 
Table 8-1 
NCI-CTCAE Definitions of Severity for Adverse Reactions ............................... 74 
Table 11-1 
Schedule of Assessments ...................................................................................... 98 
Table 11-2 
Schedule of Pharmacokinetic Sampling ............................................................. 104 
Capsule or Liquid Suspension Formulation ................................................................................ 104 
 
Table 11-3 
,=9:1>6D#0=1:=8,9.0&.:=0H 16 years old) .................................................. 105 
Table 11-4 
Lansky Performance Score (< 16 years old) ....................................................... 105 
Table 11-5 
Inhibitors of CYP3A4 ......................................................................................... 106 
Table 11-6 
Inducers of CYP3A ............................................................................................. 106 
Table 11-7 
Response Evaluation Criteria in Solid Tumors (RECIST) 
Guidelines for Tumor Response ......................................................................... 107 
Table 11-8 
Overall Response Criteria ................................................................................... 108 
Table 11-9 
RANO Response Criteria Incorporating MRI and Clinical Factor ..................... 109 
Table 11-10 
Examples of Proton Pump Inhibitors (PPIs) ....................................................... 111 
Table 11-11 
Selpercatinib Oral Suspension Dose Rounding: ................................................. 112 
Table 11-12 
Examples of Multikinase Inhibitors (MKIs) with Anti-RET 
Activity ............................................................................................................... 114 
Table 11-13 
Examples of RET-Activating Mutations ............................................................. 115 
Table 11-14 
Schedule of Continued Access Procedures ......................................................... 116 
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LIST OF FIGURES  
Figure 1-1 
Effect of Selpercatinib on RET Fusions and Mutations In Cells .......................... 29 
Figure 1-2 
Effect of Selpercatinib on RET Fusions and Mutations In Vivo .......................... 30 
Figure 1-3 
Inhibition of Tumor Growth in a RET Fusion-Dependent Patient 
Derived Xenograft (PDX) Tumor Model Implanted into the Brain ..................... 31 
 
 
 
 
 
 
LIST OF APPENDICES  
Appendix A 
Study Assessments ................................................................................................ 98 
 
 
Appendix C 
Karnofsky and Lansky Performance Status Scales ............................................. 105 
Appendix D 
Inhibitors and Inducers of CYP3A4 ................................................................... 106 
Appendix E 
Tumor Measurements and Assessment of Disease Response: 
RECIST, Version 1.1 .......................................................................................... 107 
Appendix F 
Response Assessment in Neuro-Oncology (RANO) Criteria for 
Primary CNS Malignancies ................................................................................ 109 
Appendix G 
Proton Pump Inhibitors (PPIs) ............................................................................ 111 
 
 
Appendix I 
Examples of Multikinase Inhibitors with Anti-RET Activity............................. 114 
Appendix J 
Examples of RET-Activating Mutations ............................................................. 115 
Appendix K 
Continued Access................................................................................................ 116 
Appendix L 
Provisions for Changes in Study Conduct during Exceptional 
Circumstances ..................................................................................................... 117 
Appendix M Country-specific Requirements .......................................................................... 121 
Appendix N 
Protocol Amendment History ............................................................................. 155 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation  
or term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
AIEOP-STSC 
Associazione Italiana Ematologia Oncologia Pediatrica–Soft Tissue Sarcoma Committee  
AKT 
protein kinase B 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society for Clinical Oncology 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the concentration versus time curve 
AUC0-12 
area under the curve time 0 to 12 hours 
AUC0-24 
area under the curve time 0 to 24 hours 
AUC0-t 
area under the concentration versus time curve from time 0 to t 
BDNF 
brain-derived neurotrophic factor 
BCRP 
breast cancer resistance protein  
BID 
twice daily 
BUN 
blood urea nitrogen 
BSA 
body surface area 
C 
Cycle 
C1D1 
Cycle 1 Day 1 
CBR 
clinical benefit rate 
CDMS 
Clinical Database Management System 
CEA 
carcinoembryonic antigen 
cfDNA 
circulating free DNA 
CI 
confidence interval 
CIPA 
congenital insensitivity to pain with anhidrosis 
CL/F 
apparent oral clearance of drug 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum drug concentration 
Cmin 
trough drug concentration 
CMN 
congenital mesoblastic nephroma tumors 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease  
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Abbreviation  
or term 
Definition 
CR 
complete response 
CRF 
Case Report Form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
CYP3A4 
cytochrome P450 3A4 
D 
Day 
DD 
dimerization domain 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EIAEDs 
enzyme-inducing anti-epileptic drugs 
ENS 
enteric nervous system 
EOT 
end of treatment 
ERK 
extracellular signal-related kinases 
ETV6 
ETS variant gene 6 
FACES 
Wong-Baker Faces Scale  
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor  
FISH 
fluorescence in situ hybridization 
FLAIR/T2 
T2-weighted fluid-attenuated inversion recovery 
FOB 
functional observational behavioral 
GAB1 
GRB2-associated-binding protein 1 
GALT 
gut-associated lymphoid tissue 
GCP 
Good Clinical Practices 
GDNF 
glial cell line-derived neurotrophic factor 
GDPR 
EU General Data Protection Regulation 
GFLs 
glial cell line-derived neurotrophic factor family ligands 
GI 
gastrointestinal 
GIT 
gastrointestinal tract 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GPI 
glycosylphosphatidylinositol 
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Abbreviation  
or term 
Definition 
GRB2  
growth factor receptor-bound protein 2 
H 
hour 
Hb 
hemoglobin 
HCG 
human chorionic gonadotropin 
HED 
human equivalent dose 
hERG 
human ether-à-go-go related gene 
HP--CD 
hydroxypropyl-beta-cyclodextrin 
HREC 
Human Research Ethics Board 
HRQoL 
Health Related Quality of Life 
HSA 
human serum albumin 
131I-MIBG 
radio iodized metaiodobenzylguanidine 
IB 
Investigator’s Brochure 
IC50 
concentration at which 50% inhibition is achieved 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFS 
infantile fibrosarcoma 
IHC 
immunohistochemistry 
IM 
infantile myofibromatosis  
IMP 
Investigational Medicinal Product 
A medicinal product which is being tested or used as a reference, including as a placebo, 
in a clinical trial. 
IMT 
infantile myofibroblastic tumors  
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRS 
insulin receptor substrate OR Intergroup Rhabdomyosarcoma Staging 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IVRS 
interactive voice response system 
KD  
kinase domain 
LDH 
lactate dehydrogenase 
LMA 
locomotor activity assessments 
LP 
lumbar puncture 
LTFU 
Long-term Follow-up 
MAP 
mitogen-activated protein 
MAPK 
mitogen-activated protein kinase 
MASC 
mammary analogue secretory carcinoma 
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Abbreviation  
or term 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, regardless 
of whether or not the medication is administered to the participant or the error leads to an 
AE. Medication error generally involve a failure to uphold one or more of the five 
“rights” of medication use: the right participant, the right drug, the right dose, right 
route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
MEK 
mitogen-activated protein kinase 
MIBG 
meta-iodobenzylguanidine scans 
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 
MKI 
multikinase inhibitor 
MRI 
magnetic resonance imaging 
MRSD 
maximum recommended starting dose 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
MYCN 
myelocytomatosis viral-related oncogene 
NA 
not applicable 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer  
NGF 
nerve growth factor 
NGS 
next generation sequencing 
NOAEL 
no-observable-adverse-effect-level 
NT-3, -4, -5 
neurotrophin-3, -4, -5 
NTRK genes 
neurotrophic tyrosine kinase receptor genes 
NTRK1, -2, -3 
human neurotrophic tyrosine kinase receptor gene or mRNA, types 1, 2, and 3, coding 
for TRKA, TRKB, and TRKC, respectively 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease or disease progression 
PDX 
patient-derived xenografts 
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Abbreviation  
or term 
Definition 
PedsQL-Core  
Pediatrics Quality of Life - Core Module 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein  
Ph+ 
Philadelphia chromosome positive 
PI3K 
Phosphoinositide 3-phosphate 
PK 
pharmacokinetic  
PNS 
peripheral nervous system 
PO 
per os, orally 
PPI 
proton pump inhibitor 
PR 
partial response 
PT 
prothrombin time or preferred term 
PTC 
papillary thyroid cancers 
PTT 
partial thromboplastin time 
QD 
once daily 
QoL 
quality of life 
QTc 
QT interval corrected for heart rate 
RAF  
raf kinase 
RANO 
Response Assessment in Neuro-Oncology (RANO) Criteria 
RAS 
ras protein 
RBC 
red blood cell(s) 
REB 
Research Ethics Board 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
RT-PCR 
reverse transcription polymerase chain reaction  
SAE 
serious adverse event 
SAS 
Safety Analysis Set 
SBC 
secretory breast cancer 
SD 
stable disease or standard deviation 
SEER 
Survey of Epidemiology and End Results 
SFU 
Safety Follow-up 
SGPT 
serum glutamic-pyruvic transaminase 
SHC 
Src Homology 2 Domain Containing Transforming Protein 
SIOP-MMT 
International Society of Pediatric Oncology–Malignant Mesenchymal Tumor Committee 
SOC 
system organ class 
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Abbreviation  
or term 
Definition 
SOS 
son of Sevenless protein 
SRC 
Safety Review Committee 
STD10 
severely toxic dose in 10% of animals 
STSs 
soft tissue sarcomas 
SUSAR 
suspected unexpected serious adverse reaction 
Refers to an adverse event that occurs in a clinical trial participant, which is assessed by 
the sponsor and or study investigator as being unexpected, serious and as having a 
reasonable possibility of a causal relationship with the study intervention. 
T1/2  
half-life 
TBI 
total body irradiation  
TEAE 
treatment-emergent adverse event (a TEAE is defined as an AE that starts on or after the 
first administration of study medication) 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum plasma concentration 
TRK 
tropomyosin-related kinase 
TTE 
time-to-event  
Tyr 
phosphorylated tyrosine 
ULN 
upper limit of normal 
US 
United States 
VA 
vincristine plus actinomycin-D 
V/F 
volume of distribution 
Vz/F 
apparent oral volume of distribution 
UICC 
Union for International Cancer Control 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
XRT 
X-ray therapy 
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1 
INTRODUCTION  
1.1 
RET Gene and Receptor/Normal RET  
RET is a receptor tyrosine kinase (RTK) with critical roles in normal organogenesis and in the 
maintenance of several tissue types, including neural, neuroendocrine, hematopoietic and male 
germ cell (Mulligan 2014).  
During embryogenesis, RET is expressed in the excretory and parasympathetic nervous systems. 
In the nervous system, RET is expressed in the progenitors of the enteric nervous system (ENS), 
in the enteric, autonomic, and sensory neurons of the peripheral nervous system (PNS), and in 
the motor and catecholaminergic neurons of the central nervous system (CNS). RET- 
homozygous mice have severe hypodysplasia or anaplasia of the kidneys. C-RET is also required 
for the development of the ENS. C-RET-homozygous mice lack all enteric ganglia posterior to 
the stomach. In humans, mutations of RET results in Hirschsprung’s disease.  
RET is the signaling component of multi-subunit receptor complexes for glial cell line-derived 
neurotrophic factor (GDNF) family ligands (GFLs), which belong to the TGF-beta superfamily 
(Baloh et al. 2000; Saarma 2000). The interaction between the GFLs and RET is mediated by 
glycosylphosphatidylinositol (GPI)-linked cell-surface glycoproteins, called GFR alpha 1–4 
(Airaksinen et al. 1999). Among the signaling pathways activated by RET are the MAP kinase 
(MAPK) and the PI3-K pathway (van Weering and Bos 1998). As is the case for other RTKs, 
phosphorylated tyrosine (Tyr) residues in RET are critical for the formation of docking sites for 
intracellular adaptor and effector signaling molecules (de Graaff et al. 2001). 
1.2 
Tumors with RET Abnormalities and Current Treatment Options  
Genetic alterations in the RET gene are implicated in the pathogenesis of several human cancers 
affecting both adult and pediatric patient populations. RET can be oncogenically activated by two 
primary mechanisms: (1) chromosomal rearrangements, producing cytoplasmically localized 
oncogenic hybrid proteins that fuse the RET kinase domain with a partner protein dimerization 
domain (e.g., CCDC6/PTC1, KIF5B, NCOA4/PTC3), thus endowing the kinase with ligand-
independent, constitutive activity; and (2) point mutations that directly or indirectly activate the 
kinase. The oncogenic potential of RET was first identified as a result of its ability to transform 
NIH 3T3 cells through deoxyribonucleic acid (DNA) rearrangement (Takahashi, Ritz et al. 
1985). Since its oncogenic potential was first discovered, the identification of additional, 
activating RET gene alterations in several different tumor types clearly implicates RET in the 
pathogenesis of human cancers. RET gene fusions have been identified in ~6% of sporadic 
papillary thyroid cancers (PTCs) (Fusco, Grieco et al. 1987, Cancer Genome Atlas Research 
2014) and at even higher frequency in radiation-induced PTCs (Ito, Seyama et al. 1994, 
Fugazzola, Pilotti et al. 1995, Bounacer, Wicker et al. 1997, Nikiforov, Rowland et al. 1997). In 
patients with PTC, RET gene fusions are associated with adverse prognostic features (Prasad, 
Vyas et al. 2016, Su, He et al. 2016). In addition, activating RET gene mutations occur at high 
frequency in medullary thyroid cancer (> 90% hereditary, ~50–60% sporadic) (Donis-Keller, 
Dou et al. 1993, Mulligan, Kwok et al. 1993, Carlson, Dou et al. 1994, Eng, Smith et al. 1994, 
Hofstra, Landsvater et al. 1994, Agrawal, Jiao et al. 2013, Ji, Oh et al. 2015).  
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Highly selective tyrosine kinase inhibitors (TKIs) that inhibit RET are lacking, but several 
multikinase inhibitors (MKIs) with some degree of anti-RET activity are already in the clinic, 
and two MKIs, cabozantinib and vandetanib, have received regulatory approval for advanced 
medullary thyroid cancer (MTC) (irrespective of the presence or absence of a RET mutation), 
with tumor response rates of 28% and 45% and progression-free survival (PFS) improvements 
(over placebo) of 7.2 and 11.2 months, respectively (Wells, Robinson et al. 2012, Elisei, 
Schlumberger et al. 2013). The different degree of benefit observed in each study was most 
likely due to the eligibility requirement for recent tumor progression in the cabozantinib study, 
but not the vandetanib study (Chuk et al, 2018). In subset analyses of both studies, patients 
whose tumors harbored RET activating mutations derived greater benefit than RET mutation 
negative patients (Wells, Robinson et al. 2012, Sherman, Clary et al. 2016).  
The efficacy of these MKIs is ultimately limited by incomplete inhibition of RET in tumors in 
patients, significant toxicity from stronger inhibition of other targets (e.g., KDR/VEGFR2, 
EGFR, MET) and poor pharmacokinetics (PK) (i.e., significant drug accumulation and long half-
life contributing to toxicity, but not efficacy) in patients. As a result, the majority of patients 
treated with these agents experience significant toxicities requiring dose interruptions, reductions 
and/or treatment cessation.  
1.3 
Role of RET in Pediatric Cancers  
The application of next-generation sequencing (NGS) approaches to a large collection of human 
tumors has led to the identification of RET gene in a fraction of other tumor types, including 
infantile myofibromatosis (IM), infantile fibrosarcoma, and chronic myeloproliferative 
neoplasms (Ballerini, Struski et al. 2012, Ju, Lee et al. 2012, Kohno, Ichikawa et al. 2012, 
Lipson, Capelletti et al. 2012, Takeuchi, Soda et al. 2012, Bossi, Carlomagno et al. 2014, 
Stransky, Cerami et al. 2014).  
The high-frequency alterations in a less-prevalent cancer like MTC and the potential additional 
role of RET in other rare and/or pediatric cancers indicates that a significant number of patients 
with advanced, RET-fusion and/or RET-mutant cancers could benefit from potent and selective 
RET kinase inhibition.  
Available evidence indicates that 7 to 10% of all thyroid malignancies occur in children and 
young adults. 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. Standard of care treatment for non-metastatic MTC in young patients is total 
thyroidectomy, which is associated with long-term sequelae of hypothyroidism and the need for 
continuous thyroid hormone replacement. Patients with a family history of hereditary MTC, 
harboring a germline RET mutation are treated with prophylactic total thyroidectomy after 
reaching the age of 5 in an effort to prevent the development of MTC. Anti-RET multikinase 
inhibitors cabozantinib and vandetanib have proven anti-tumor activity in adult patients with 
MTC and have demonstrated preliminary anti-tumor activity in young children with MTC (Fox 
et al. 2013).  
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Case reports of patients with IM and infantile myofibroblastic tumors (IMT) indicate that RET 
mutations may be a primary oncogenic driver for a subset of these cancers. There have been no 
clinical trials due to the rarity of these diseases, and most treatment approaches have been 
published as single case reports. The most common therapeutic intervention is surgery, although 
this is not a viable option for many patients due to tumor location. Additionally, patients with IM 
or IMT may receive cytotoxic chemotherapy typically including an alkylating agent. These 
regimens (such as vincristine, actinomycin-D and cyclophosphamide) are not well tolerated and 
lead to side effects including pain, neuropathy, infection, renal/hepatic dysfunction, cardiac 
toxicity, delayed achievement of growth and neurologic milestones, infertility, and secondary 
malignancies. Given the short and long-term toxicities associated with multiagent chemotherapy, 
there is a need for effective targeted therapies with improved short-term and long-term toxicity 
profiles in pediatric patients with IM and IMT (Rosenzweig et al. 2016).  
Cabozantinib and vandetanib, small molecule inhibitors of multiple kinases including RET, have 
been approved for adults with advanced, progressive and/or symptomatic MTC (Fox et al. 2013). 
Many patients require dose reduction due to significant toxicities. A Phase 1/2 clinical trial of 
vandetanib in 12 pediatric or adolescent patients with MTC demonstrated an objective response 
rate of 47% with diarrhea as the most common dose-limiting toxicity (DLT). Recently, 
cabozantinib was studied in a Phase 1 dose escalation pediatric study. While the authors reported 
that a maximum tolerated dose (MTD) was not reached, 3 patients discontinued therapy due to 
DLTs. While the study was conducted as an all-comer population study, 2 patients with MTC 
achieved partial responses (PRs). All patients with MTC had a decrease in calcitonin within the 
first cycle (Chuk et, al. 2018). 
Patients with RET fusion-positive cancers (IM, congenital mesoblastic nephroma tumors [CMN], 
thyroid, and others) and RET-mutated cancers (MTC) represent populations with high unmet 
clinical need. In IM and CMN, chemotherapy is associated with significant short-term and long-
term toxicities in pediatric patients. Anti-RET multikinase inhibitors are moderately effective 
and associated with significant toxicities in both adult and pediatric/adolescent patients. 
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.  
1.4 
Rationale  
Selpercatinib is a highly potent and specific inhibitor of the RET RTK, with minimal inhibition 
of other kinase and non-kinase targets, and therefore may be of benefit to patients with tumors 
(such as MTC, PTC, IM, CMN) that harbor RET alterations and/or depend on RET activity. This 
Phase 1/2 study of selpercatinib is required to understand the PK, safety, and MTD for 
selpercatinib in pediatric patients, and to permit the preliminary assessment of efficacy. 
Additional information is provided in the Selpercatinib Investigator’s Brochure (IB). 
1.5 
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 
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causes dose-dependent inhibition of tumor growth in multiple, biologically relevant 
RET-dependent tumor models in vitro and in vivo, including NSCLC, MTC, and colorectal 
cancer cells and tumors harboring KIF5B-RET and non-KIF5B-RET fusions, with and without 
the RET V804M gatekeeper mutation and activating RET mutations found in MTC. 
Selpercatinib was selective for 98% of 329 non-RET kinases tested in a large in vitro screen. 
This high degree of selectivity was maintained in additional enzyme and cell-based assays. 
Selpercatinib at clinically and toxicologically relevant concentrations had no significant effects 
on a range of other targets and receptors.  
Additional information is provided in the Selpercatinib IB.  
Figure 1-1 
Effect of Selpercatinib on RET Fusions and Mutations In Cells  
 
Figure 1-1. LOXO-292 = selpercatinib. Concentration-dependent inhibition of phosphorylated RET levels with 
selpercatinib was demonstrated in NIH 3T3 cells engineered to express four oncogenic RET proteins: KIF5B-RET, 
RET-M918T (left), KIF5B-RET-V804L and KIF5B-RET V804M (right). Cell lines were treated with a dose range 
of selpercatinib or cabozantinib and vandetanib as controls, and cellular phosphorylated RET levels were determined 
by in Cell Western assay. Data are shown as mean ± standard error of the mean. 
Selpercatinib caused dose-dependent inhibition of tumor growth in multiple, biologically 
relevant RET-dependent tumor models, including: 1) allografts of NIH 3T3 cells engineered to 
express the KIF5B-RET fusion protein (-/+ V804M) found in human NSCLC; 2) xenografts of 
human cancer cell lines harboring endogenous RET gene alterations found in human lung cancer 
(CCDC6-RET fusion) and MTC (RET mutation encoding C634W); and 3) patient-derived 
xenografts (PDXs), including tumors harboring the challenging V804M anticipated acquired 
resistance mutation. In contrast, the MKIs cabozantinib and ponatinib were much less active 
against RET fusions with a V804M substitution (Figure 1-2). 
K I F 5 B - R E T / R E T  M
9 1 8 T
0 . 0 1
0 . 1
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
0
2 5
5 0
7 5
1 0 0
D r u g  C o n c e n t r a t i o n  ( n M
)
p R E T  ( %
 o f   C o n t r o l )
L O X O - 2 9 2  K I F 5 B - R E T
C a b o z a n t i n i b  K I F 5 B - R E T
V a n d e t a n i b  K I F 5 B - R E T
L O X O - 2 9 2  R E T  M
9 1 8 T
K I F 5 B - R E T  V 8 0 4 L / M
0 . 0 1
0 . 1
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
0
2 5
5 0
7 5
1 0 0
D r u g  C o n c e n t r a t i o n  ( n M
)
p R E T  ( %
 o f   C o n t r o l )
V a n d e t a n i b  V 8 0 4 M
C a b o z a n t i n i b  V 8 0 4 L
L O X O - 2 9 2  V 8 0 4 L
V a n d e t a n i b  V 8 0 4 L
C a b o z a n t i n i b  V 8 0 4 M
L O X O - 2 9 2  V 8 0 4 M
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Figure 1-2 
Effect of Selpercatinib on RET Fusions and Mutations In Vivo  
0
5
10
15
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1000
NIH 3T3
KIF5B-RET
Day
Tumor Volume
(mean  SEM, mm3)
0
5
10
15
0
500
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2500
NIH 3T3
KIF5B-RET V804M
Day
Tumor Volume
(mean  SEM, mm3)
Vehicle
10 mg/kg BID LOXO-292
30 mg/kg BID LOXO-292
0
4
7 11 14 18 21 25 28
0
500
1000
PDX
CCDC6-RET
Day
Tumor Volume
(mean  SEM, mm3)
0
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9 13 16 20 23 26 28
0
500
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1500
2000
PDX
CCDC6-RET V804M
Day
Tumor Volume
(mean  SEM, mm3)
30 mg/kg BID LOXO-292
Vehicle
10 mg/kg BID LOXO-292
40 mg/kg cabozantinib
20 mg/kg ponatinib
0
5
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     TT Medullary Thyroid Cancer
RET C634W
Day
Tumor Volume
(mean  SEM, mm3)
0
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0
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LC-2/ad Lung Cancer
CCDC6-RET
Day
Tumor Volume
(mean  SEM, mm3)
Vehicle
3 mg/kg BID LOXO-292
10 mg/kg BID LOXO-292
30 mg/kg BID  LOXO-292
Figure 1-2. LOXO-292 = selpercatinib. Selpercatinib inhibits tumor growth in six RET-fusion/mutant allograft, 
xenograft or patient-derived xenograft (PDX) models. Upper Allograft: NIH 3T3-KIF5B-RET (left), NIH 3T3-
KIF5B-RET V804M (right); Middle Xenograft: TT (RET C634W, MTC, left), LC-2/a (CCDC6-RET, NSCLC, 
right); Lower PDX: Parental (CCDC6-RET, colorectal cancer, left), Resistant (CCDC6-RET V804M, colorectal 
cancer, ponatinib-resistant, right, derived from Parental by continuous treatment of animals with ponatinib). Percent 
changes from baseline tumor volume in nude mice (n = 8–10/group) that were injected subcutaneously with tumor 
cells and treated with vehicle (control) or the indicated daily doses of selpercatinib are shown. For the PDCs, the 
effects of cabozantinib or ponatinib are also shown for comparison. 
Finally, selpercatinib demonstrated potent anti-tumor activity against a RET-fusion 
patient-derived xenograft (PDX) implanted directly into the brain (Figure 1-3). 
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Figure 1-3 
Inhibition of Tumor Growth in a RET Fusion-Dependent Patient 
Derived Xenograft (PDX) Tumor Model Implanted into the Brain  
 
Figure 1-3. LOXO-292 = selpercatinib. Tumor suspensions of the CCDC6-RET fusion PDX were orthotopically 
injected into the brains of nude mice (Ncr:Nu/Nu). Seven days after implantation, mice were randomized (10 mice 
per group) and were dosed orally with selpercatinib (30 mg/kg twice daily [BID]), ponatinib (20 mg/kg once daily 
[QD], as a reference compound) or vehicle. Animals were evaluated daily for clinical status and were sacrificed if 
they exhibited central nervous system toxicity (e.g., unsteady gait, ataxia), discomfort, 20% or more body weight 
loss or if their clinical condition otherwise deteriorated. All vehicle-treated animals had to be sacrificed between 
Day 16 and Day 47 (median survival equal to 21 days). In contrast, both selpercatinib and ponatinib significantly 
prolonged survival up to 51 days after treatment initiation (median survival equal to 100% for each). To determine 
whether survival could be maintained with lower doses, the doses of each agent were lowered by the same fraction 
of the starting dose on Day 52 (e.g., selpercatinib from 30 mg/kg BID to 3 mg/kg BID, ponatinib from 20 mg/kg QD 
to 2 mg/kg QD). Following these dose adjustments, all but 1 ponatinib-treated animal had to be sacrificed by Day 84 
(median survival equal to 19 additional days after the dose reduction). In contrast, 9/10 selpercatinib-treated animals 
survived to the end of the experiment on Day 84. 
1.5.1 
Pharmacokinetics  
The pharmacokinetics of selpercatinib have been evaluated in both healthy volunteers and cancer 
patients, including, 4 pediatric single-patient protocol studies. 
These data show that selpercatinib is well absorbed after oral administration to patients, with a 
median Tmax of approximately 2 hours. AUC0-12 increases approximately 3-fold with repeated 
dosing. Doses of selpercatinib from 20 mg QD to 240 mg BID show approximately linear to 
slightly supra-proportional pharmacokinetics.  
A dose of 160 mg BID in adult cancer patients resulted in a 
 
 
 Accumulation from single to steady state dose is approximately 3.4-fold, 
  
0
20
40
60
80
100
0
50
100
Days
Percent survival
Vehicle Control
LOXO-292
Ponatinib
PDX CCDC6-RET BRAIN
Dose lowered
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Pediatric dose has been selected as 92 mg/m2, with a maximum dose of 160 mg BID, 
 
 
 
 
 
 
Selpercatinib has high permeability such that once it dissolves, selpercatinib can be absorbed 
readily from the gastrointestinal tract. Selpercatinib is a substrate for P-gp and BCRP in vitro, 
however these transporters do not appear to limit the oral absorption of selpercatinib, as its 
absolute oral bioavailability is 
 and its exposure was increased only minimally by 
co-administration of a P-gp inhibitor in a clinical study (increase of approximately 
 
 in selpercatinib AUC0-24 and Cmax, respectively). 
Selpercatinib has pH-dependent solubility, being more soluble in an acidic environment than 
a neutral one. This pH-dependent solubility led to a 
 in selpercatinib AUC when 
selpercatinib was given under fasted conditions to subjects treated with the acid-reducing agent 
omeprazole. The presence of food appears to mitigate the pH-dependent reduction in exposure.  
In vitro, selpercatinib is metabolized essentially exclusively by CYP3A4 and therefore the effect 
a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the PK of selpercatinib was 
evaluated. The strong CYP3A4 inhibitor itraconazole caused in an increase of approximately 
130% and 30% in selpercatinib AUC and Cmax, respectively, compared to selpercatinib alone and 
multiple doses of the strong CYP3A4 inducer rifampin resulted in a decrease of approximately 
87% and 70% in selpercatinib AUC and Cmax, respectively, compared to selpercatinib alone. 
These data confirmed that strong CYP3A4 inhibitors and inducers can affect the PK of 
selpercatinib. The effect of other strong and moderate inhibitors and moderate inducers of 
CYP3A4 was evaluated with a PBPK model, which predicted 148%, 118%, and 283% increases 
in AUC with the concomitant use of the moderate and strong CYP3A4 inhibitors fluconazole, 
diltiazem, and clarithromycin, and a 47% and 36% reduction in AUC with the concomitant use 
of moderate CYP3A4 inducers bosentan and modafinil, respectively. 
In vitro selpercatinib showed no significant inhibition of CYP1A2, CYP2B6, CYP2C19, 
CYP2D6, and CYP3A4, but showed weak competitive inhibition of CYP2C8 and weak time-
dependent inhibition of CYP3A4. Inhibition of CYP1A2, CYP2B6, CYP2C9, CYP2C19, 
or CYP2D6 at clinically relevant exposures of selpercatinib was considered unlikely based on in 
vitro data. Clinical drug interaction studies were conducted with a sensitive CYP2C8 probe 
(repaglinide) and a CYP3A4 probe (midazolam) to determine the potential for selpercatinib to 
inhibit these enzymes. Multiple-dose steady-state administration of 160 mg BID selpercatinib 
resulted in an increase of approximately 54% and 39% in midazolam AUC0-inf and Cmax, 
respectively, compared to midazolam alone and an increase of approximately 188% and 91% 
in repaglinide AUC0-inf and Cmax, respectively, compared to repaglinide alone.  
A study in healthy volunteers has demonstrated that the 160 mg selpercatinib 
 is 
bioequivalent to the 2 × 80 mg capsule with no new safety findings. 
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1.5.2 
Safety Pharmacology  
As part of the development program for selpercatinib, three stand-alone safety pharmacology 
studies were conducted. Additionally, individual safety pharmacology endpoints (cardiovascular 
and CNS) were included in the study designs of the 28-day repeat-dose toxicity studies in the rat 
and minipig, and ECGN>were evaluated in the 91-day study in minipigs.  
In the GLP human ether á-go-go-related gene (hERG) assay, selpercatinib had an IC50 value of 
, which is approximately 7-fold higher than the maximum unbound concentration at the 
clinical dose of 160 mg BID. In a stand-alone safety pharmacology study in minipigs, no 
cardiovascular effects were observed after single doses up to 12 mg/kg, the highest dose 
evaluated. In the 28-day minipig repeat-dose study, there were no ECG changes at doses up to 
12 mg/kg, the highest dose evaluated. In the 91-day minipig repeat-dose study, females 
administered 5 mg/kg exhibited a non-adverse increase in QTc prolongation of approximately 
12% and 7 %, relative to controls and pre-dose values, respectively. The dose of 5 mg/kg/day 
corresponded to a mean Cmax approximately 0.2 times the human geometric mean maximum 
concentration at the clinical dose of 160 mg BID. 
 
Respiratory function was assessed in a stand-alone safety pharmacology study in rats. 
Selpercatinib had no effects at single doses up to 45 mg/kg, the highest dose evaluated. 
Neurobehavioral function was assessed in the 28-day repeat-dose study in rats with no definitive 
findings. Decreased locomotor activity, decreased mean forelimb grip strength, and lower values 
for fine movements or rearing were observed at the high dose :97D,9/,??=4-@?0/?:?30,948,7>N
poor general condition. 
1.5.3 
Toxicology  
Repeat-dose studies up to 91 days in duration were conducted in rats and minipigs to 
characterize toxicity in support of clinical development. Target organs of toxicity common to the 
rat and minipig were hematopoietic system, lymphoid tissues, tongue, pancreas, epiphyseal 
growth plate, and testes. In general, these toxicities in these organs were reversible; the exception 
was the testicular toxicity. Reversible toxicity was observed in the ovaries and gastrointestinal 
tract in minipigs only; at high doses, gastrointestinal toxicity caused morbidity in minipigs. 
Exposures in minipigs were generally lower than exposures determined in humans at the 
recommended dose. Target organs of toxicity observed only in rats were incisor teeth, liver, 
vagina, lungs, and =@990=N>27,9/; also, multiple tissues were affected with mineralization 
associated with hyperphosphatemia. These toxicities only occurring in these organs in rats were 
reversible.  
Selpercatinib is not mutagenic and is not genotoxic at therapeutic doses. 
An embryo-fetal development study indicated that selpercatinib is a selective developmental 
toxicant, due to embryo lethality noted at all dose levels.  
In a fertility study in male rats, there were no effects of selpercatinib on mating or fertility. 
However, at all doses, germ cell depletion and spermatid retention in the testes and increased 
cellular debris in the epididymis were observed dose-dependently. At the high dose only, these 
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effects were associated with reduced organ weights, reduced sperm motility, and an increase in 
the number of abnormal sperm.  
In a fertility and early embryonic study in female rats, there were no effects of selpercatinib on 
mating or fertility. At the high dose only, a reduction in the number of estrous cycles with an 
increase in the pre-coital interval was observed, and there was an increase in the number of dead 
embryos, increased postimplantation loss, and a reduction in the number of live embryos. 
Preliminary juvenile rat toxicology studies have been conducted with selpercatinib. These studies 
indicate that juvenile rats are less tolerant of selpercatinib than adult rats.  
Additional details regarding the nonclinical toxicology studies are available in the IB.  
1.5.4 
Benefit/Risk  
The preclinical data indicate that selpercatinib is a highly potent and specific inhibitor of the 
RET RTK, with minimal inhibition of other kinase and non-kinase off targets. Since 
selpercatinib is an experimental medicine in the pediatric population, it is possible that 
unforeseen, unknown or unanticipated drug reactions and toxicities may occur. However, the 
clinical protocol is designed to mitigate risks to patients through a detailed plan for careful safety 
monitoring and management, systematic review of adverse events (AEs), serious adverse events 
(SAEs), PK, and active pharmacovigilance review to assess for safety signals or trends.  
Pediatric patients with RET-fusion cancers (papillary thyroid, soft tissue sarcoma, others) and 
RET-mutated cancer represent populations with high unmet need. As discussed in Section 1.2 
and Section 1.3 available therapies for these patients provide short-term palliation (i.e., 
chemotherapy), may be less effective in cancers driven by kinase fusions (i.e., immunotherapy) 
and/or are very toxic (i.e., MKIs). Therefore, there is an urgent need to identify new targeted 
therapies that potently inhibit RET in tumors, while sparing other kinase and non-kinase off-
targets that contribute to significant toxicity. 
These considerations indicate the benefit/risk ratio for selpercatinib in this study to be favorable. 
1.5.5 
Clinical Experience  
As of 16 December 2019, a total of 702 patients have been treated with selpercatinib at doses 
ranging from 20 mg QD to 240 mg BID in Study LOXO-RET-17001 (LIBRETTO-001). Patients 
were initially enrolled in a dose escalation (3 × 3 design). During dose escalation, the dose of 
160 mg BID was chosen as the dose for Phase 2, and subsequently, eligible and/or participating 
patients were dosed at 160 mg BID. Ninety-five percent (n = 667) of patients received at least 
one dose of the selpercatinib 60 mg, the majority of whom started treatment with a dose of 
160 mg BID (n = 609 patients). All 702 patients were included in the safety analysis. RET 
alterations were documented in 686 (97.7%) of all patients. 
At the time of this data cutoff, treatment is continuing in 548 of 702 (78.1%) patients, and 
treatment has been discontinued in 154 (21.9%) patients. The median age of patients was 
59.0 years and ranged from 15 to 92 years. The majority of patients (n = 337, 48.0%) were 45 to 
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64 years of age; 239 (34.0%) patients were H 65 years, 123 (17.5%) were 18 to 44 years, and 
3 (0.4%) were under the age of 18 years. 
As of 17 June 2019, Loxo Oncology has initiated  pediatric single patient protocols (SPPs), 
Special Access Scheme, or Temporary Authorization Use (ATU) cases to provide access to 
selpercatinib for patients with clinical need not meeting eligibility criteria for the ongoing 
clinical study. 
Please refer to the selpercatinib IB for the most current summary of clinical experience, 
including anticipated risks and dose modification plans for specific AEs.  
1.5.6 
Known and Anticipated Risks  
As of a clinical data cut-off (May 8, 2022) for the LIBRETTO-001 FIH dose-finding study, the 
following AEs of special interest include: 
F 
Dry mouth (48.7% total; 38.4% related) 
F 
Hypertension (41.5% total; 28.7% related) 
F 
AST increased (37.8% total; 28.8% related) 
F 
ALT increased (36.2% total; 29.1% related) 
F 
Electrocardiogram QT prolonged (20.5% total; 16.1% related) 
Additional details on the safety profile of selpercatinib are provided in the selpercatinib IB. 
1.5.7 
Rationale for Selection of the Starting Dose  
As outlined in Section 1.5.5, selpercatinib has been studied in an adult/adolescent Phase 1/2 trial 
(LOXO-RET-17001, LIBRETTO-001) where a recommended Phase 2 dose (RP2D) of 160 mg 
BID has been established with no MTD established. 
As of August 24, 2018, preliminary steady-state PK data (
) were available from 
141 patients enrolled in the Phase 1 LOXO-RET-17001 study (Table 1-1). These data show that 
selpercatinib is absorbed after oral administration with a median Tmax of approximately 2 hours 
(Figure 1-4). Although the plasma half-life could not be calculated with certainty because of the 
limited sampling interval (0-8 hours), based on an approximate 
 
 Low concentrations of selpercatinib were 
recovered as unchanged drug in urine indicates that the kidney does not contribute to overall 
clearance. Steady-state PK profiles of selpercatinib in cancer patients are shown in Figure 1-4. 
Of note, 
 
 
 
 
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Lee and colleagues reviewed cytotoxic chemotherapy Phase 1 trials in pediatric patients 
conducted between 1990 and 2004 (Lee JCO 2005). These authors reported that the MTD in 
children ranged between 80% and 160% compared to the adult MTD. Paoletti and colleagues 
(Paoletti et al. 2013) reviewed the dose-finding trials of 15 molecularly targeted agents in 
pediatric patients. The results of this meta-analysis revealed that the pediatric RP2D was 90%-
130% of the adult RP2D in 70% of these agents. More importantly, the authors concluded that 
63% of patients did not receive an optimal dose. A review of pediatric oncology studies revealed 
that when the pharmacokinetic/pharmacodynamic profile of the drug is not expected to be that 
different from adults, and when no cumulative toxicity is expected, it is reasonable to start by 
giving 80-100% of the body surface area (BSA)-adjusted adult dose to children, (Doussau et al. 
2016).  
In addition, as of 17 June 2019,  pediatric patients have been treated with selpercatinib through 
a compassionate use program.  
LOXO-RET-18027 is an SPP which explored the use of selpercatinib in a 10-year old male with 
an expected RET-mutant MTC. The patient was dosed at 160 mg BID with the suspension 
formulation. 
 The patient 
discontinued therapy C1D10 when further genomic profiling did not confirm a RET-alteration. 
The patient tolerated therapy with no Grade 3 or 4 events reported (Data on File, Loxo 
Oncology).  
Data from the  patients with confirmed RET fusions are summarized in Table 1-2. 
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Characteristic 
Patient 
LOXO-
RET-18018 
Patient  
LOXO-RET-
18019 
Patient 
LOXO-RET-
18058 
Patient 
LOXO-RET-
19060 
Patient 
LOXO-RET 
19067 
Country 
 
 
 
Gender 
Female 
Female 
Female 
Age at diagnosis 
7 months 
2 months 
Birth 
Age at enrollment 
13 months 
21 months 
21 months 
Diagnosis 
Infantile 
myofibroma/he
mangio-
pericytoma 
Congenital 
mesoblastic 
nephroma, 
infantile 
fibrosarcoma 
Lipo-
fibromatosis 
Primary tumor 
location 
Paraspinal and 
retroperitoneal 
Kidney, lung 
Left foot 
Presence of 
metastases 
n/a 
Lung, brain 
n/a 
RET alteration 
MYH10-RET 
SPECC1L-RET 
NCOA4-RET 
Dose 
90 mg/m2 (44 
mg) BID 
90 mg/m2 (42 
mg) BID 
90 mg/m2 
(48 mg) BID 
AUC0-24 (ng*h/mL)  
 
 
 
Prior therapy 
Chemotherapy, 
multikinase 
inhibitor 
Chemotherapy, 
surgery 
None 
Best RECIST 
response to 
selpercatinib 
PR 
PR 
PR 
Duration of 
treatment 
(months) a  
 
9  
 
Abbreviations: AE = adverse event; AUC0-24 = area under the curve time 0 to 24 hours; BID = twice daily; NA = 
 
 
 
Selpercatinib PK data are available for  pediatric patients (Table 1-3): The estimated steady-
state AUC0-24 in these patients was similar to that of adults treated with 160 mg BID 
selpercatinib (Figure 1-5). Note there is wide range of exposure in adults treated with 160 mg 
BID and the steady-state exposure of the pediatric patients is well within the range of exposures 
in adults given 160 mg BID. 
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Based on the known safety and PK profile in adults, the anticipation of similar toxicities, and 
prior experience in  pediatric patients, the starting dose for evaluation in the Phase 1 dose 
escalation is the BSA-adjusted adult RP2D dose (92 mg/m2). 
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2 
STUDY OBJECTIVES  
Study objectives and endpoints are outlined below for Phase 1 (Section 2.1) and Phase 2 
(Section 2.2). 
2.1 
Phase 1 Study Objectives  
The objectives for the Phase 1 patient population (pediatric patients with an advanced cancer 
harboring an activating RET alteration) are as follows: 
Primary 
The primary objective is to determine the safety profile, including DLTs, of the oral RET 
inhibitor selpercatinib. 
Secondary 
 To characterize the PK properties of selpercatinib  
 To identify the MTD and/or the RP2D and/or the appropriate dose of selpercatinib for further 
clinical investigation  
 To describe the antitumor activity of selpercatinib  
2.2 
Phase 2 Study Objectives  
The objectives for the Phase 2 patient population (pediatric patients with an advanced cancer 
harboring an activating RET alteration) are as follows: 
Primary 
To determine the objective response rate (ORR) as determined by an Independent Review 
Committee (IRC) and measured by the proportion of patients with best overall confirmed 
response of complete response (CR) or partial response (PR) by RECIST v1.1 or RANO criteria, 
as appropriate, following treatment with selpercatinib. 
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Secondary 
 To determine the following: 
o "%%-,>0/:9?30?=0,?4929A0>?42,?:=N>=0>;:9>0,>>0>>809?@>492RECIST v1.1 or 
RANO criteria, as appropriate to tumor type 
o DOR in patients with best overall response of CR or PR as determined by 1) an IRC and 
2) the treating Investigator 
o Duration of PFS following initiation of selpercatinib by 1) an IRC and 2) the treating 
Investigator 
o OS following initiation of selpercatinib 
o CBR based on the proportion of patients with best overall response of CR, PR, or stable 
disease (SD) lasting 16 or more weeks following initiation of selpercatinib as determined 
by 1) an IRC and 2) the treating Investigator 
 To assess the safety profile and tolerability of selpercatinib  
 To characterize the PK properties of selpercatinib in pediatric patients 
 To evaluate the concordance of prior molecular profiling that detected an activating RET 
,7?0=,?4:9B4?349?30;,?409?Ns tumor with diagnostic test(s) being evaluated by the Sponsor 
 To characterize post-operative staging and surgical margin status in patients who have 
definitive surgery following treatment with selpercatinib  
 To evaluate change from baseline in patient-reported pain at BOR visit as assessed by the 
Wong-Baker Faces Scale.  
 To assess the acceptability and palatability of selpercatinib 
 
 in patients under age 18 
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3 
INVESTIGATIONAL PLAN  
3.1 
Phase 1  
3.1.1 
Study Design  
This is a multicenter, open-label, Phase 1/2 study in pediatric patients with advanced solid or 
primary CNS tumors harboring an activating RET alteration. Selpercatinib will be administered 
in oral liquid suspension or capsule(s)/
 form BID, with the dose escalation according to 
evaluations of safety, efficacy, and PK with a BSA-based dose in all cohorts. 
The starting dose level used in this study was based on a dose, 160 mg BID, which has been 
previously tested in adults and pediatrics. The dose frequency may be changed (e.g., QD dosing) 
based on the observed PK profile in pediatric patients.  
The starting dose level is the current adult RP2D. Planned dose levels are listed in Table 3-1. 
BSA will be determined by the Mosteller (= Ҁ height (cm) × weight (kg) / 3600 = BSA). 
A minimum of  patients will enroll in Dose Levels 1, and 2, also referred to as Dose Cohorts 1 
and 2 respectively. The dose will be increased incrementally until a MTD or RP2D is identified. 
Increase or decrease in dose level if indicated, will follow the Table 3-1 dose levels listed, to the 
next appropriate dose. 
Table 3-1 
Planned Selpercatinib Dose Escalation Cohorts  
Dose Level 
Dose 
Estimated Equivalent Adult Dose 
-2 
-1 
1a 
2a 
3a,b 
Abbreviation: BID = twice daily. 
a The Dose Levels listed, i.e., Dose Levels 1, 2, and 3, correspond to the Dose Cohorts 1, 2, and 3, respectively. 
b Additional dose escalation may be considered based on the cumulative data (PK, safety, and efficacy) the actual 
dose determined by the SRC, not to exceed approximately 50% of the prior dose and taking into account capsule 
doses and capsule burden.  
3.1.1.1 
General Treatment Procedures  
Patients will begin to receive the assigned selpercatinib dose on Day 1 (BID in accordance with 
the cohort assignment). Each cycle will consist of 28 days of continuous dosing; for patients who 
reach 2 years of study treatment, cycles may be extended to 84 days in length. The maximum 
dose (regardless of BSA calculation) will be no higher than the equivalent adult dose associated 
with the BSA-based dosing, i.e., patients in Dose Cohort 1 will receive a dose no higher than 160 
mg BID, patients in Dose Cohort 2 will receive a dose no higher than 200 mg BID. 
Individual patients will continue daily selpercatinib dosing until progressive disease (PD), 
unacceptable toxicity, or other reason for treatment discontinuation, as outlined in 
Section 5.3.4.4. Patients with PD may be allowed to continue selpercatinib if, in the opinion of 
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the Investigator, the patient is deriving clinical benefit from continuing study drug, and 
continuation of treatment is approved by the Sponsor.  
Patients with locally advanced disease who achieve a radiologic confirmed PR (or better) by 
RECIST v1.1 may interrupt treatment beginning 1 year from confirmation of response. Such 
patients may undergo optional biopsy/optional positron emission tomography/computerized 
tomography (PET/CT) scan at the time of dose cessation for the purposes of more accurately 
quantifying the response to treatment. After interrupting treatment, such patients will be followed 
every 3 months with radiologic response assessment (computerized tomography [CT] or 
magnetic resonance imaging [MRI]) for up to 2 years, unless there is withdrawal of consent, 
initiation of new anti-cancer therapy, or the study ends. After 2 years, radiographic assessments 
will occur every 6 months. In addition, patients may undergo response assessment 1 month after 
interrupting selpercatinib at the discretion of the Investigator. Patients may re-start selpercatinib 
if there is evidence of PD after discontinuation of study drug (refer to Section 6). 
Patients who undergo surgical resection for local control after treatment with selpercatinib (refer 
to Section 5.3.4.5 below for details of allowed surgeries) may continue to receive selpercatinib if 
a compelling clinical rationale is provided by the Investigator and approved by the Sponsor. 
Patients who undergo surgical treatment should have selpercatinib interrupted for 7 days prior to 
surgery and resumed 14 days after surgery. If the resection surgery results in negative margins 
(an R0 surgery) and study drug is interrupted, disease assessments, as described in Section 7.13, 
should be performed every 3 months following the last dose of study drug. These patients are 
permitted to restart study drug if they experience PD after discussion with the &;:9>:=N>medical 
monitor. 
All treated patients will undergo a safety follow-up visit at 28 days (+ 7 days) after the last dose 
of study treatment and long-term follow-up visits at 3-month intervals (± 1 month) and until the 
study is officially closed. 
Patients who have an Ommaya Reservoir or are undergoing a routine diagnostic or staging 
lumbar puncture (LP) will have cerebral spinal fluid (CSF) in addition to a blood sample 
collected for PK assessment,
 
 
3.1.1.2 
Dose Escalation Scheme and Assessment of Dose-Limiting Toxicity  
The study employs a 
 dose escalation 
 
patients will be enrolled in each dose cohort, also referred to as dose levels. Each patient will 
participate in only 1 dose cohort. The total number of patients to be enrolled in the dose 
escalation phase is dependent upon the observed safety profile, which will determine the number 
of patients per dose cohort, as well as the number of dose escalations required to achieve the 
MTD. 
Escalation will proceed through the planned dose levels, or until the MTD is reached, or until the 
Sponsor, in agreement with the SRC, determines that a suitable dose has been achieved based on 
an overall assessment of safety, PK and toxicity. All patients in a given dose escalation cohort 
must have completed safety assessments through Cycle 1 Day 28 (C1D28) and must have 
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received a minimum of 75% of the planned total dose in Cycle 1 (unless due to toxicity) to be 
eligible for the assessment of a DLT. If a dose level is evaluated for MTD/RP2D and the Sponsor 
and Safety Review Committee (SRC) declare that dose level as the RP2D, and the enrolled 
patient population does not contain at least 2 patients aged 6 months to < 2 years, then the Phase 
2 expansion can continue for patients greater than 2 years of age. Up to 2 patients aged 6 months 
to < 2 years will be over-enrolled in the dose level and evaluated to ensure this age group also 
meets the MTD/RP2D safety determination. Once this milestone has been achieved, patients 
aged 6 months to < 2 years may be eligible to enroll in Phase 2. Over-enrollment to these cohorts 
may occur in order to meet this requirement. An SRC may be convened for each cohort dose 
escalation but will only be required to convene prior to a cohort escalation if there is a DLT 
reported in a cohort.  
1
 patients within a cohort experience a DLT, then the dose escalation will cease. In 
order for the MTD/RP2D to be determined, the SRC will evaluate whether the previous lower 
dose level will be considered the MTD, whether an intermediate dose level should be evaluated, 
and/or whether additional patients need to be evaluated if the DLTs seen at this dose level are 
considered to be not serious or equivocal with regard to causal relationship to selpercatinib.  
After completion of the 28-day DLT window in Cycle 1, patients may undergo intra-patient dose 
escalation to dose level(s) previously declared safe by the SRC if a compelling clinical rationale 
for dose escalation is provided by the Investigator and approved by the Sponsor.  
3.1.1.3 
Dose-Limiting Toxicity Definition  
A DLT is defined as any of the TEAEs (a TEAE is defined as an AE that starts on or after the 
first administration of study medication) listed below, as defined by the National Cancer 
9>?4?@?0N>:88:9'0=849:7:2D=4?0=4,1:=/A0=>0A09?>A0=>4:9.0 (NCI CTCAE v5.0), 
occurring during the first 28 days of treatment, provided that the participant has received at least 
75% of planned doses and the AE ,9/9:?=0,>:9,-7D,??=4-@?0/?:;,?409?N>@9/0=7D492/4>0,>0:=
other medical condition and deemed by the Investigator to be related to selpercatinib as assessed 
in accordance with CTCAE v5.0:  
 Any Grade 3 or higher nonhematologic toxicity, with the exception of Grade 3 fatigue, 
nausea, tendon reflex decrease, or weight gain attributable to normal growth and 
development. 
 Grade 3 vomiting or diarrhea will be considered DLT only if it persists > 48 hours 
despite standard of care treatment. Admission to the hospital of patients < 1 year of age 
with Grade 3 vomiting or diarrhea is recommended until these events resolve to Grade 1. 
 Grade 4 vomiting or diarrhea will be considered DLT regardless of duration. Admission 
to the hospital of patients < 1 year of age with Grade 4 vomiting or diarrhea is 
recommended until these events resolve to Grade 1. 
 Any toxicity, regardless of the NCI CTCAE v5.0 grade, resulting in discontinuation or 
dose reduction of treatment (with the exception of symptoms related to PD). 
 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with Grade 1 or higher 
bleeding. 
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 Grade 4 anemia lasting > 8 days, despite supportive therapy, not explained by underlying 
condition (transfusions are allowed during Cycle 1), and persists beyond the initial 
transfusion. 
 Grade 4 neutropenia, lasting > 8 days, despite supportive therapy (growth factor support 
during Cycle 1 not allowed for prophylaxis). 
 Grade 3 uncomplicated febrile neutropenia will not be considered a DLT. 
3.1.1.4 
Number of Patients  
A minimum of  patients are required to be enrolled in order to define the MTD/RP2D of 
selpercatinib. The safety of the patients enrolled is ensured with careful monitoring and rules for 
escalation so that an excessive number of patients are not unnecessarily exposed to a dose level 
that exceeds the MTD. Over-enrollment may occur in the dose escalation cohorts as previously 
described (Section 3.1.1.2). 
If an eligible patient is identified after  patients have been enrolled to the current dose cohort 
and prior to clearance of the DLT window for these patients, the patient may be enrolled to a 
previous cohort that has been determined safe ,1?0=/4>.@>>4:9B4?3?30&;:9>:=N> 0/4.,7
Monitor. If this occurs during the DLT window for Dose Level 1, patients may be enrolled to 
Dose Level -1. Following clearance of the current dose level, the patient(s) enrolled to a previous 
level may have the dose escalated to a higher level that has been determined safe after discussion 
with the &;:9>:=N>Medical Monitor. 
Across Phase 1 and Phase 2 portion of the study,
 
 
In the Phase 2 portion of the study, additional patients may be enrolled to better characterize the 
safety and efficacy of the selpercatinib RP2D for further study. The Phase 2 portion will enroll 
approximately 
 patients into Cohorts 1 and 2 (refer to Table 3-2 and Section 9.3); The 
total sample size for Phase 2 will not exceed 
. 
3.2 
Phase 2 Dose Expansion Cohort  
The Phase 2 portion of the study will open to enrollment when the MTD/ RP2D is confirmed and 
will enroll patients into one of 4 cohorts (refer to Table 3-2). To enroll in Cohorts 1 to 3, patients 
must have measurable disease. To be eligible for enrollment in Cohort 4, patients can have 
measurable or non-measurable disease. The expansion cohort will follow the same schedule of 
assessments as the dose escalation cohorts.  
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Table 3-2 
Disease Criteria for Enrollment: Cohorts 1 to 4  
Cohort 
Disease Criteria 
Cohort 1 
RET fusion-positive solid tumor (excluding CNS primary) with measurable disease 
Cohort 2 
RET-mutant MTC with measurable disease 
Cohort 3 
RET fusion-positive primary CNS tumor with measurable disease 
Cohort 4 
Any patient with RET mutation/alteration not fitting Cohort 1 to 3 criteria (i.e., RET 
alterations via plasma cfDNA or non-CLIA certified test, measurable or non-measurable 
disease) 
Abbreviations: cfDNA = circulating free DNA; CNS = central nervous system; MTC = medullary thyroid cancer. 
3.3 
General Treatment Procedures  
Patients will receive selpercatinib on Day 1 in accordance with the Phase 1/2 cohort assignment. 
Each cycle will consist of 28 days of continuous dosing; for patients who reach 2 years of study 
treatment, cycles may be extended to 84 days in length. 
Individual patients will continue daily selpercatinib dosing until PD, unacceptable toxicity, or 
other reason for treatment discontinuation, as outlined in Section 3.1.1.1. Patients who 
experience radiologic PD by RECIST v1.1 or RANO may be allowed to continue selpercatinib 
beyond PD if, in the opinion of the Investigator, the patient is deriving clinical benefit from 
continuing study drug, and continuation of treatment is approved by the Sponsor.  
Patients with locally advanced disease with RECIST v1.1 confirmed response of CR/PR may 
interrupt treatment in a “wait and see” approach 1 year from confirmation of response after 
discussion with the Sponsor’s Medical Monitor (see Section 5.2.5 for additional information). 
These patients may undergo an optional tissue biopsy and/or additional imaging (e.g., PET/CT) 
at the time of consideration of treatment discontinuation. The purpose of these additional studies 
is to provide additional pathologic/radiographic information about disease status (e.g., presence 
or absence of tumor). Following treatment discontinuation, these patients will continue to be 
followed with radiologic assessment every 3 months for 2 years, and then every 6 months 
thereafter, using the same imaging modality(ies) as during treatment. An optional radiographic 
disease assessment may be performed 1 month after the interruption of selpercatinib at the 
discretion of the Investigator. If a patient in this “wait and see” period is noted to have evidence 
of radiographic PD, the patient may re-start selpercatinib. At the time of selpercatinib re-
initiation, the patient will start assessments per protocol as delineated for patients on active 
treatment. Patients who re-initiate selpercatinib treatment are permitted to have their 
selpercatinib treatment held again. 
Patients who undergo surgical resection for local control may continue to receive selpercatinib 
after surgical recovery and discussion between the Investigator and the Sponsor. These patients 
should have selpercatinib held for 7 days prior to surgery and resumed 14 days after surgery. If 
the resection surgery results in negative margins and study drug is interrupted, disease 
assessments, as described in Section 7.13, should be performed every 3 months following the last 
dose of study drug. These patients are permitted to restart study drug if they experience PD after 
discussion with the Sponsor’s medical monitor. 
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Patients under age 18 may be given an alternate formulation of selpercatinib for a defined 
duration for assessment of acceptability and, if appropriate, palatability.  
All treated patients will undergo a safety follow-up visit at 28 days (+7 days) after the last dose 
of study treatment and long-term follow-up visits at 3-month intervals (± 1 month) and until the 
study is officially closed. 
3.4 
Investigational Sites  
Approximately 25 institutions will be recruited to enroll patients.  
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4 
SELECTION OF STUDY POPULATION  
Potential patients and/or their parents must sign an Informed Consent Form (ICF) and Pediatric 
Assent Form, where applicable, before any study-specific Screening tests may be conducted.  
4.1 
Inclusion Criteria  
Patients must meet all of the following criteria to be eligible for enrollment in the study: 
1. Pediatric patients  6 months of age and  21 years of age at Cycle 1 Day 1 (C1D1) with a 
locally advanced or metastatic solid or primary CNS tumor that has relapsed, progressed or 
was nonresponsive to available therapies and for which no standard or available systemic 
curative therapy exists.  
a) Patients with locally advanced disease who would require, in the opinion of the 
Investigator, disfiguring surgery or limb amputation to achieve a complete surgical 
resection, are also eligible.  
b) In geographies where a selective RET-inhibitor is approved, patients may enroll 
without prior systemic treatment. 
2. Evidence of an activating RET gene alteration in tumor and/or blood (e.g., gene 
rearrangement and/or mutation, excluding synonymous, frameshift, or nonsense mutations) 
as identified through molecular assays, as performed for clinical evaluation; refer to 
Appendix J for examples of RET-activating mutations.  
a) The RET alteration result should be generated from a laboratory with CLIA, ISO/IEC, 
CAP, or other similar certification as per local guidelines including but not limited to in 
vitro diagnostic regulation compliance as applicable. In cases where such certification 
is not clearly demonstrated to determine eligibility, the Sponsor should be contacted to 
discuss laboratory test results.  
b) A positive germline test for a RET mutation is acceptable for patients with MTC.  
c) In addition to RET fusion-positive solid tumors and RET-mutant MTC, MTC syndrome 
spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine 
features/differentiation, or poorly differentiated thyroid cancers with other RET 
alteration/activation may be allowed with prior Sponsor approval.  
3. Patients with primary CNS tumors or cerebral metastasis: 
a) Must be neurologically stable based on stable neurologic exam for 7 days prior to 
enrollment. 
b) Must have not required increasing doses of steroids within the 7 days prior to 
enrollment to manage CNS symptoms. 
4. Imaging study must be performed within 28 days of C1D1 while on stable dose steroid 
medication (if needed) for at least 7 days immediately before the imaging study. 
5. Histologic verification of malignancy at original diagnosis or relapse, except in patients with 
intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and 
elevations of CSF or serum tumor markers including alpha-fetoprotein or beta-human 
chorionic gonadotropin (HCG). 
6. Must have measurable or non-measurable but evaluable disease. 
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7. Karnofsky (patients 16 years and older) or Lansky (patients younger than 16 years) 
performance score of at least 50. 
8. Must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy 
to CTCAE (v5.0) Grade ≤ 2. 
a) Myelosuppressive chemotherapy: Start of selpercatinib must be at least 21 days after 
the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). 
b) Investigational agent or anticancer therapy other than chemotherapy: Not within 
2 weeks prior to planned start of selpercatinib or 5 half-lives, whichever is shorter. Full 
recovery of clinically significant toxicities from that therapy must be evident. Prior 
MKIs with anti-RET activity are allowed. Refer to Appendix I for examples of MKIs 
with anti-RET activity. Patients who have previously received selpercatinib are not 
eligible. 
c) Radiation therapy (XRT): Start of selpercatinib must be at least 14 days after local 
palliative radiation (small port); at least 42 days must have elapsed before start of 
selpercatinib if other substantial bone marrow radiation, including prior radio-iodized 
metaiodobenzylguanidine (131I-MIBG) therapy. 
d) Stem cell infusion (ASCT, Allogenic or CAR-T) without total body irradiation (TBI): 
No evidence of active graft versus host disease and at least 56 days must have elapsed 
before start of selpercatinib after transplant or stem cell infusion. 
e) Hematopoietic growth factors: Start of selpercatinib must be at least 14 days after the 
last dose of a long-acting growth factor (e.g., pegfilgrastim); or 7 days for short-acting 
growth factor.  
9. An archival (FFPE or fresh frozen) or fresh tumor tissue sample must be available (refer to 
Section 7.5). If archival tumor tissue sample is not available, a fresh biopsy (at a primary or 
metastatic site) should be performed. If an archival or fresh sample cannot be obtained safely, 
the patient may still be eligible with documented Sponsor approval.  
10. Adequate hematologic status, defined as: 
a) Absolute neutrophil count (ANC) ≥ 1.0  109/L not requiring growth factor support for 
at least 7 days prior to treatment. 
b) Platelet count ≥ 75  109/L not requiring transfusion support for at least 7 days prior to 
treatment.  
c) Hb ≥ 8 mg/dL not requiring transfusion support or erythropoietin for at least 7 days 
prior to treatment.  
11. Adequate hepatic / pancreatic function, defined as: 
a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5  the 
upper limit of normal (ULN) or ≤5  ULN with documented liver involvement (such 
as liver metastasis or a primary biliary tumor), and 
b) Total bilirubin ≤1.5  ULN or ≤3  ULN with documented liver involvement (patients 
with Gilbert’s Disease may be enrolled with prior Sponsor approval). 
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12. Adequate renal function, defined as:  
a) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 based on local institutional 
practice for determination, or a maximum serum creatinine by age and gender as 
presented in Table 4-1. 
Table 4-1 
Serum Creatinine by Age and Gender  
 
Maximum Serum Creatinine 
(mg/dL) 
Maximum Serum Creatinine 
(µmol/L) 
Age 
Male 
Female 
Male 
Female 
6 months to < 1 year 
0.5 
0.5 
44 
44 
1 to < 2 years 
0.6 
0.6 
53 
53 
2 to < 6 years 
0.8 
0.8 
71 
71 
6 to < 10 years 
1 
1 
88 
88 
10 to < 13 years 
1.2 
1.2 
106 
106 
13 to < 16 years 
1.5 
1.4 
132 
124 
≥ 16 years 
1.7 
1.4 
150 
124 
 
13. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits 
for the duration of study participation. 
14. Willingness of male and female patients with reproductive potential to utilize double 
effective birth control methods, defined as one used by the patient and another by his/her 
partner, for the duration of treatment and for 1 month following study completion. 
For male patients with a non-pregnant female partner of child-bearing potential, and woman 
of child-bearing potential, one of the following highly effective birth control methods (with a 
failure rate of less than 1% per year when used consistently and correctly) are recommended: 
a) Combined estrogen and progestogen containing hormonal contraception associated 
with inhibition of ovulation given orally, intravaginally, or transdermally 
b) Progestin-only hormonal contraception associated with inhibition of ovulation given 
orally, by injection, or by implant 
c) Intrauterine device (IUD) 
d) Intrauterine hormone-releasing system (IUS) 
e) Bilateral tubal occlusion 
f) Vasectomized partner 
g) Sexual abstinence: considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the 
duration of the study and to the usual lifestyle of the patient. 
Birth control methods unacceptable for this clinical trial are: 
a) Periodic abstinence (calendar, sympto-thermal, or post-ovulation methods) 
b) Withdrawal (coitus interruptus) 
c) Spermicide only 
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d) Lactational amenorrhea method 
15. Ability to swallow capsules, liquid suspension, or gastric access via a naso- or gastric tube. 
16. The patient and, when applicable, the parent/guardian of child or adolescent patient has the 
ability to understand, agree to, and sign the study Informed Consent Form (ICF) and 
applicable Pediatric Assent Form before initiation of any protocol-related procedures; patient 
has the ability to give assent, as applicable, at the time of parental/guardian consent. 
17. [removed] 
4.2 
Exclusion Criteria  
Patients meeting any of the following criteria are to be excluded from study participation: 
1. Major surgery within 2 weeks prior to C1D1. 
2. Clinically significant active cardiovascular disease or history of myocardial infarction within 
6 months prior to C1D1; ongoing cardiomyopathy; or current prolonged QT interval 
corrected for heart rate (QTc) interval > 440 milliseconds for patients ≤ 15 years old and > 
470 milliseconds for patients > 15 years old. For patients ≤ 15 years old, Bazett’s Formula 
will be utilized to determine QTc. For patients > 15 years old, either method, Fridericia or 
Bazett’s Formula may be applied. 
3. Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the 
Investigator makes the risk: benefit ratio for the patient to participate in the trial unfavorable. 
Screening for chronic conditions is not required. 
4. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal absorption of the study drug. 
5. Pregnancy or lactation. 
6. Uncontrolled hypotension or hypertension ≥ Grade 3 CTCAE (v5.0). 
7. Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e., the patient required 
a modification to current thyroid medication in the 7 days before start of selpercatinib). 
8. Uncontrolled symptomatic hypercalcemia or hypocalcemia. 
9. [Removed] 
10. Known hypersensitivity to any of the components of the investigational agent, selpercatinib 
or Ora-Sweet® SF and OraPlus®, for patients who will receive selpercatinib suspension. 
11. [Removed] 
12. [Removed] 
4.3 
Enrollment Procedures  
For all patients, a copy of the anonymized/redacted Molecular Pathology Report, or other 
report(s) describing tumor RET (and/or other) mutation analysis should be submitted to the 
Sponsor or designee during Screening/prior to eligibility for review prior to patient enrollment. 
As part of pre-screening, it is advised to provide this upon patient identification for the study.  
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A representative from the investigational site will contact the Sponsor or designee when a 
potential study candidate is identified, a patient number will be assigned that will be used 
throughout both Screening and study participation. Once Screening procedures have been 
completed for the patient, a completed enrollment form will be submitted to the Sponsor or 
designee to confirm eligibility.  
Patients who are determined to be screen failures can be re-screened. Re-screened patients will 
be provided a new patient number.  
The enrollment form will be returned to the site with the cohort assignment (if applicable) and 
must be received by the site before treatment may commence. Refer to the Study Manual for 
enrollment form, contact numbers, and other details of enrollment.  
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5 
TREATMENT  
5.1 
Investigational Product  
Selpercatinib will be provided as a liquid suspension with a concentration of 
, capsules 
in strengths of 40 mg and 80 mg, or 
 in strength of 40 mg and 160 mg.  
The capsules and 
 will be provided to the sites for distribution to the patient for outpatient 
administration. The site personnel will dispense investigational product to the patient in an 
amount necessary to allow for outpatient administration at the assigned dose level.  
Selpercatinib liquid suspension is provided as selpercatinib powder, which consists of the drug 
substance filled into a glass bottle or other suitable container with a child-resistant closure. It is 
compounded in the pharmacy 
 
 
 
 
 
 
The prepared selpercatinib liquid suspension is to be stored at 
 
Intervention Namea 
Selpercatinib 
Dosage Level(s) 
Liquid suspension 
 mg/mL 
40 mg and 80 mg capsules 
40 mg and 160 mg 
 
Authorized as defined by EU 
Clinical Trial Regulation 
Not authorized in EU 
Authorized and not used 
according to EU 
authorization 
Not authorized in EU 
a Study intervention is defined as any medicinal product(s) or medical device(s) intended to be administered to or 
used by a study participant according to the study protocol. 
Additional details regarding the investigational product are provided in the Pharmacy Manual 
and the Selpercatinib IB. 
Packaging and labeling 
Study drug 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. 
5.2 
Selpercatinib Administration  
5.2.1 
General Dosing Instructions  
Dosing for an individual should be at a consistent time each day and BID dosing will be 
separated by approximately 12 hours.  
Liquid suspension or 
 will be administered orally, or enterally via a nasogastric or 
gastrostomy feeding tube with a dosing syringe. For patients taking proton pump inhibitors 
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(PPIs), selpercatinib should be taken with a meal. Otherwise, there is no food restriction relative 
to the dosing time of selpercatinib (capsules, 
 or liquid suspension).  
If the patient spits out all of the liquid suspension immediately, they should be given another 
dose. If, after two attempts, the patient does not swallow the dose, it will be considered a 
L84>>0/M/:>0If this occurs during the time period the drug diary is required, record the missed 
/:>049?30/4,=D,>L84>>0/M and note next to the entry that the patient Lspit out the dose.M 
If the patient swallows the liquid suspension or 
 and vomits after ingesting it, 
another dose should not be given at that time. If the patient vomits the capsule(s)/
 and 
they are still recognizable, then the patient can be re-dosed. If the patient vomits 
capsule(s)/
 contents and the capsule/
 is not recognizable, the patient or parent 
should be instructed to call the Study doctor or nurse to discuss if they should take any additional 
capsules/
.  
Late doses (i.e., 4 or more hours after the scheduled time) should be noted in the diary (if diary 
required during that cycle). Doses that are late by > 6 hours should be skipped and recorded in 
the dosing diary (if diary required during that cycle) as missed. The patient, or the patientNs 
parent or legal guardian, will keep a daily diary to record dosing compliance during Cycles 1-3 
and as directed. Compliance will also be assessed at each clinic visit by means of a capsule/
 
count in the returned bottle, or liquid level verification in the suspension bottle(s).  
Since selpercatinib absorption from the GI tract may be impacted by stomach acidity, agents 
which may alter stomach pH require additional considerations for administration. Instructions for 
taking PPIs, histamine-2 (H2) blocking agents and antacids, if clinically indicated, are provided 
in Section 5.3.4.1 and 5.3.4.2. Refer to Appendix G for examples of PPIs and for additional 
information. Patients taking these agents are encouraged to record the time of each dose in 
relationship to each dose of selpercatinib in the dosing diary (when diary is in use; inaccurate 
recording will not be considered a protocol violation) (refer to Section 5.2.1). Any questions 
regarding dose rounding should be directed to the Sponsor. 
Patients will begin BID dosing on C1D1 according to the assigned cohort. Serial blood samples 
for PK monitoring will be collected as outlined in Section 7.12 and Appendix B. The blood 
volume collected should not exceed institutional guidelines. 
Selpercatinib dose rounding rules are provided in Appendix H. Any questions regarding dose 
rounding should be directed to the Sponsor and Medpace medical monitors. 
All patients will start treatment with capsule or liquid suspension, as appropriate, and will 
continue that formulation at least through the end of Cycle 3. After Cycle 3, 
 or 
 
 as an alternate formulation of selpercatinib may be given to patients less than 18 years of 
age for a defined duration (e.g., one 28 day cycle) for assessment of the acceptability and 
palatability, as individually directed by the Sponsor. Dosing diary will also be completed during 
the alternate formulation period. 
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5.2.2 
Cycle 1  
Patients will begin BID dosing on C1D1 according to the assigned cohort. Serial blood samples 
for PK monitoring will be collected and the patient will be monitored for safety as outlined in 
Section 7. The blood volume collected should not exceed institutional guidelines. Cycle length is 
28 days during both Phase 1 and Phase 2; the DLT treatment/observation period during Phase 1 
will consist of Days 1 to 28. 
5.2.3 
Cycles 2 and Higher  
In accordance with the assigned dose level, each patient will receive selpercatinib in continuous 
28-day or 84-day cycles until treatment discontinuation. Serial blood samples for PK monitoring 
will be collected and the patient will be monitored for safety as outlined in Section 7.12 and 
Appendix B. 
5.2.4 
Dose Modifications  
Table 5-1 outlines toxicities that may require dose modification. Patients who experience a 
clinically significant (> Grade 2 [i.e., Grade 3 or 4] or a 1 grade change from baseline when 
baseline is abnormal at Grade 2 or higher) hematologic or non-hematologic AE should have 
selpercatinib dosing interrupted for no longer than 28 days to evaluate the AE and to allow for 
recovery (to Grade 1 or baseline level). Upon recovery of the AE unrelated to the dose level of 
selpercatinib and/or symptoms associated with the AE, dosing may be restarted at the same dose.  
If the AE is considered related to the dose level of selpercatinib, but has returned to baseline 
level within 28 days, then the dose may be reduced to the next lower dose level. The number of 
times that a dose may be reduced is dependent upon the starting dose that the patient received. 
Patients who have been dose reduced for treatment-related AEs may be dose re-escalated after 
resolution of the AE and demonstration that they have tolerated study drug at the reduced dose 
for at least 1 full treatment cycle, after discussion with and approval from the sponsor. 
Additional guidance is found in the IB. Patients who miss 7 or more days of dosing in Cycle 1 
for reasons other than study drug-related toxicity are not evaluable for the DLT window and will 
be replaced. If a patient is tolerating selpercatinib without evidence of PD, after Cycle 1, the 
patient may have the dose increased to a dose that has already been established as tolerable by 
the SRC, and with the agreement of the Sponsor’s Medical Monitor. 
If a dose interruption includes Day 1 of the next cycle, the next cycle will start with resumption 
of study drug. If a dose interruption does not include Day 1 of the next cycle, the cycle should 
remain 28 days in length. All dose interruptions and dose modifications and the reasons for those 
changes will be recorded in the electronic Case Report Form (eCRF). 
The National Cancer Institute (NCI)-developed CTCAE should be used when evaluating 
toxicities. According to the NCI-CTCAE (version 5), adverse reactions are reported by grade 
(level of severity) on the scale of Grades 1 to 5. Generally, the descriptions for adverse reactions 
by grade level (scale of Grades 1 to 5) follow the guidelines outlined below in Section 8.1, 
Table 8-1.  
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Table 5-1 
Toxicities Requiring Dose Modification  
Toxicity 
Dose Modification 
Interstitial Lung 
Disease/Pneumonitis 
For Grade 2: Withhold selpercatinib until resolution. Resume at next lower 
dose. Discontinue selpercatinib for recurrent interstitial lung disease 
/pneumonitis. 
For Grade 3 or 4, discontinue selpercatinib.  
Increased ALT or AST, 
Grade 3 or 4 
Suspend dose until toxicity resolves to baseline or Grade 1. 
Resume selpercatinib at the second dose reduction twice daily. If after at 
least 2 weeks selpercatinib is tolerated without recurrent increased ALT or 
AST, selpercatinib dosing can be increased to the first dose reduction. If 
selpercatinib is tolerated at the first dose reduction for at least 4 weeks 
without increased ALT or AST, dosing can be increased to dose taken 
prior to the onset of Grade 3 or 4 increased ALT or AST. 
Permanently discontinue selpercatinib if Grade 3 or 4 increased ALT or 
AST recur despite dose modifications. 
Hypersensitivity 
Suspend dose until toxicity resolves and start steroid treatment. 
Resume selpercatinib at 40 mg twice daily while continuing steroid 
treatment. 
If after at least 7 days selpercatinib is tolerated without recurrent 
hypersensitivity, incrementally increase the selpercatinib dose to 80 mg 
twice daily for 7 days, followed by 120 mg twice daily for 7 days. For 
patients with an originally prescribed dose of 160 mg twice daily, if 
selpercatinib is tolerated at the 120 mg twice daily dose for 7 days, 
subsequently increase the dose to 160 mg twice daily.  
Prior to dose increase, always ensure that selpercatinib is tolerated for at 
least 7 days. 
Start steroid tapering after selpercatinib has been tolerated for at least 
7 days at the final dose. 
Discontinue selpercatinib for recurrent clinically significant 
hypersensitivity. 
QT Interval Prolongation 
Suspend dose for QTcF intervals >500 ms until the QTcF returns to 
<470 ms. 
Resume selpercatinib treatment at the next lower dose level.  
Permanently discontinue selpercatinib if QT prolongation remains 
uncontrolled after 2 dose reductions or if the patient has signs or 
symptoms of serious arrhythmia. 
Hypertension, Grade 3 or 4 
Baseline blood pressure values should be ≤140/90 mmHg (or <95th 
percentile for age for children) before starting selpercatinib. 
Temporarily suspend selpercatinib for severe hypertension until controlled 
with medical management.  
Resume dosing at the next lower dose if clinically indicated. 
Other clinically significant 
AE 
For Grade 3 or Grade 4 AE, or 1 grade change from baseline when 
baseline is abnormal at Grade 2 or higher: 
Hold dosing for up to 28 days to allow recovery (to Grade 1 or baseline) 
 If unrelated to study drug, restart at same dose 
 
If related to study drug, reduce to lower dose (refer to Table 5-2) 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase. 
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Additional information regarding the management of AEs (e.g., chylothorax, hemorrhage, etc.) 
can be found in the IB. 
Table 5-2 
Dose Level Reductions for Selpercatinib  
Dose Level a 
Dose 
Estimated 
Equivalent 
Adult Dose 
Dose of Selpercatinib 
Starting Dose (1) 
160 mg BID 
Originally assigned dose level  
First Dose Reduction (-1) 
120 mg BID 
Reduce dose by at least one dose level  
Second Dose Reduction (-2) b 
80 mg BID 
Reduce dose by at least one additional 
dose level  
a The Dose Levels listed, i.e., Dose Levels 1, -1, and -2, correspond to the Starting Dose, First Dose Reduction, 
and Second Dose Reduction, respectively. 
b If a third dose reduction is required the Investigator must contact the Sponsor to discuss the best dosing strategy 
for the patient depending on the reason for dose reduction and clinical benefit. 
5.2.5 
Drug Treatment Holiday  
If requested by Investigators, patients with durable (i.e., at least 24 months) radiographic and 
clinical disease control may be approved for a drug treatment holiday and remain in observation 
on trial. The duration of the holiday will be determined by Investigator and Sponsor before 
initiation of the holiday. Patients will continue to follow the Schedule of Assessments as per the 
long-term follow-up schedule with additional evaluations as appropriate for the standard of 
care/Investigator discretion. If patients experience disease progression during drug treatment 
holiday, they may resume selpercatinib starting with the next subsequent cycle number and 
assessments from the date of the initiation of the drug treatment holiday. 
5.3 
Prior and Concomitant Medications  
5.3.1 
General  
All medications that were used from 14 days prior to first dose through the Safety Follow-up 
visit will be recorded in the eCRF. These are to include prescription and nonprescription 
medications, transfusions, vitamins and nutritional supplements, and other remedies. Refer to 
Section 5.3.3 for information regarding prior medications that are excluded via eligibility 
criteria.  
5.3.2 
Allowed Concomitant Medications  
Standard supportive medications may be used in accordance with institutional guidelines and 
Investigator discretion. These may include hematopoietic growth factors to treat neutropenia or 
thrombocytopenia in accordance with American Society for Clinical Oncology (ASCO) and/or 
European Society for Medical Oncology guidelines, transfusions, anti-emetics and 
anti-diarrheals, and glucocorticoids (up to 10 mg dexamethasone or 50 mg of prednisone or 
equivalent), including short courses to treat asthma, chronic obstructive pulmonary disease 
(COPD), or other systemic, chronic diseases that are normally treated with short courses of 
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glucocorticoids. As selpercatinib is a substrate of CYP3A4, patients should avoid inhibitors or 
inducers of CYP3A4 if possible as they could alter the drug’s PK. Continuation of standard of 
care or supportive care medications that the patient has been on for the previous 28 days are 
allowed. 
Higher doses of glucocorticoids (e.g., dexamethasone) may be administered to primary brain 
tumor patients to reduce peritumoral edema and improve neurological deficits. However, patients 
should remain on a stable dose (i.e., same daily dose) in the 7 days prior to, and on the day of, all 
protocol-defined MRI scans (including the Screening MRI). Anti-seizure medications should be 
used as indicated. 
Enzyme-inducing anti-epileptic drugs (EIAEDs) and dexamethasone for CNS tumors or 
metastases, on a stable dose, are allowed. If, for unavoidable clinical reasons (i.e., severe 
allergies, toxicities), a patient’s anti-epileptic drug is changed, the following guidelines must be 
followed: 
 Patients who were previously on a non-EIAED and need to change anticonvulsants 
should be started on another non-EIAED if at all possible. No delays in treatment would 
be required. 
 Patients who were previously on a non-EIAED and were inadvertently and temporarily 
changed to an EIAED should immediately be started on another non-EIAED. The patient 
may continue the current treatment dose selpercatinib while a non-EIAED is re-started. 
 Patients who were previously on a non-EIAED and need to permanently change 
anticonvulsants, but who cannot change to another non-EIAED, must be discussed with 
the Sponsor. 
 Patients who were previously on an EIAED and need to permanently change or stop 
anticonvulsants, but who cannot change to another EIAED must be discussed with the 
Sponsor. 
5.3.3 
Prohibited Concomitant Medications  
5.3.3.1 
Chemotherapeutic Agents or Hematopoietic Growth Factors  
In addition, except as indicated in Section 5.3.2, patients are not allowed to receive other 
chemotherapeutic agents, hematopoietic growth factors for prophylaxis in Cycle 1, anti-cancer 
monoclonal antibodies, radiation therapy (other than palliative radiation, refer to 
Section 5.3.4.4), drugs with immunosuppressant properties administered systemically 
(topical/local applications, e.g. for atopic dermatitis, are allowed), or any other investigational 
agents besides selpercatinib. No new, alternative anticancer therapy is allowed prior to 
documentation of PD in accordance with protocol-specified disease response criteria.  
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5.3.4 
Concurrent Medications, Therapy, or Surgery  
5.3.4.1 
H2 Blockers  
When concurrent use of an H2 blocking agent is necessary, e.g., ranitidine, famotidine, or 
cimetidine, it must be administered only between 2 and 3 hours after the dose of selpercatinib. If 
not taken during this time, the dose of H2 blocking agents should not be taken again until 2 to 3 
hours after the next dose of selpercatinib.  
5.3.4.2 
PPIs  
When concurrent use of a PPI cannot be avoided, e.g., omeprazole, it must be administered with 
food. When selpercatinib is given in the fasted state with gastric pH modification by omeprazole, 
the exposure (Cmax and AUC) is reduced. The presence of food mitigates the omeprazole-induced 
reduction in exposure; when selpercatinib is given with a low-fat or high-fat meal to subjects 
treated with omeprazole, there was no significant change in selpercatinib exposure. 
5.3.4.3 
Antacids  
When concurrent use of an antacid is necessary, e.g., aluminum hydroxide/magnesium 
hydroxide/simethicone or calcium carbonate, the antacid must be administered 2 or more hours 
before and/or 2 or more hours after the dose of selpercatinib. 
5.3.4.4 
Palliative Radiotherapy  
Palliative radiotherapy to specific sites of disease is permitted if considered medically necessary 
by the treating physician. Selpercatinib should be held for 3 days before and 3 days after 
treatment. Selpercatinib may be held for a shorter time if a compelling clinical rationale (e.g., 
risk of disease flare) is provided by the Investigator and approved by the Sponsor. In general, 
target lesions being used to measure response should not be irradiated without discussion with 
the Sponsor Monitor, and may be reason for the patient to be removed from study for PD. 
Irradiated lesions will be considered not evaluable for response, but still can be used to assess 
PD. The intensities, number, and dates of doses received for allowed palliative radiotherapy 
should be recorded on the appropriate eCRF. 
5.3.4.5 
Elective Surgery or Surgical Resection  
Although selpercatinib is not expected to significantly affect wound healing, any unusual 
findings should be recorded as potential AEs. In the event of a major surgery requiring general 
anesthesia (elective or not) during study participation, it is recommended that selpercatinib be 
held 7 days before surgery and resumed 14 days after surgery, or later if wound healing is 
delayed. 
For patients who receive selpercatinib prior to attempted surgical resection, selpercatinib should 
be continued in a tumor deemed responsive to selpercatinib, until tumor resectability is possible. 
Patients may undergo surgical resection when, in the opinion of the treating Investigator, the 
tumor is resectable without mutilating surgery or limb amputation. If the resection surgery results 
in negative margins and study drug is held, disease assessments, as described in Section 7.13, 
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should be performed every 3 months following the last dose of study drug. These patients are 
permitted to restart study drug if they experience PD after discussion with the Sponsor’s Medical 
Monitor. Long-term follow-up will occur as outlined in Section 7.19.  
Patients who receive selpercatinib and go on to an attempted surgical resection will be re-staged 
just prior to surgery. Staging will be defined per tumor appropriate radiographic assessment and 
aligned with the radiographic method set at Screening. Patients who undergo surgical local 
control may -resume selpercatinib after recovery and discussion between the Investigator and the 
Sponsor. If the resection results in negative margins or otherwise considered curative and study 
drug is held, clinical and disease assessments, as described in Section 7.13, should be performed 
every 3 months following the last dose of study drug. These patients are permitted to restart 
study drug if they experience PD after discussion with the Sponsor’s Medical Monitor. 
5.3.4.6 
Inhibitors or Inducers of CYP3A4  
As selpercatinib is a substrate of CYP3A4, patients should avoid strong or moderate inhibitors or 
inducers of CYP3A4 as they could alter the drug’s PK. This includes herbal products such as St 
John’s wort, grapefruit, and grapefruit juice, which may decrease the levels of selpercatinib. 
Refer to Appendix D for lists of example inhibitors and inducers of CYP3A4. In discussion with 
the sponsor, dose reduction may be allowed for patients who cannot avoid concurrent strong 
CYP3A4 inhibitors. 
5.4 
Duration of Treatment  
It is anticipated that a patient on this study will receive treatment with open-label selpercatinib 
until the patient meets criteria requiring discontinuation of treatment (refer to Section 6.1 
Removal of Patients from Therapy or Assessment), or if the patient has chosen to withdraw from 
the study. Upon commercial availability in each patient’s respective country, there may be 
additional options for the patient to continue to receive selpercatinib once the regulatory 
requirements are satisfied. These may include but are not limited to a rollover trial, patient 
assistance (should the patient qualify), or commercial selpercatinib. The study may be terminated 
if selpercatinib does not obtain marketing approval or the development of selpercatinib is no 
longer being pursued by the Sponsor. The Sponsor also reserves the right to discontinue the 
study for clinical or administrative reasons at any time.  
Patients 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 patient is still on study 
treatment when study completion occurs. Sponsor will notify investigators when the continued 
access period begins. 
Patients 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 patient’s continued access to study intervention will end when a criterion for discontinuation 
is met (Section 6). Continued access follow-up will begin the day after the participant and the 
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investigator agree to discontinue study intervention and lasts approximately 30 days following 
the last dose of study drug. Follow-up procedures will be performed as shown in the Continued 
Access SoA (Appendix KAppendix KAppendix KAppendix K). 
Participants who are in safety follow-up when the continued access period begins will continue 
in short-term follow-up until the 28-day safety follow-up visit is completed.  
In all cases, no follow-up procedures will be performed for a participant who withdraws 
informed consent unless he or she has explicitly provided permission and consent. 
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6 
DISCONTINUATION / WITHDRAWAL CRITERIA  
6.1 
Removal of Patients from Therapy or Assessment  
Patients will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Investigator and/or the Sponsor may withdraw a patient from treatment 
for any of the reasons listed below: 
 Disease progression (PD), except: 
 if in the opinion of the Investigator, the patient is deriving clinical benefit from 
continuing study drug, and continuation of treatment is approved by the Sponsor, OR 
in the occurrence of PD during a planned drug treatment holiday and resumption of 
study treatment is considered in the best interest of the patient by the Investigator. 
 Adverse Events  
 Intercurrent illness compromising ability to fulfil protocol requirements 
 Requirement for alternative treatment in the opinion of the Investigator 
 Significant noncompliance to protocol 
 Pregnancy 
 Withdrawal of consent or assent by the patient 
 Lost to follow-up 
 Death 
 Complete surgical resection (removal from therapy, but not further assessment) 
Patients who undergo surgical resection for local control may continue to receive selpercatinib 
after surgical recovery and discussion between the Investigator and the Sponsor. These patients 
should have selpercatinib held for 7 days prior to surgery and resumed 14 days after surgery. If 
the resection surgery results in negative margins and study drug is held, disease assessments, as 
described in Section 7.13, should be performed every 3 months following the last dose of study 
drug. These patients are permitted to restart study drug if they experience PD after discussion 
with the Sponsor’s medical monitor. 
When a patient stops treatment, all safety data normally required at the end of treatment (EOT) 
visit will be obtained if possible, as outlined in Section 7.17. 
6.2 
Reasons for End of Study  
Reasons for end of study could be: 
 Withdrawal of consent or assent by the patient  
 Lost to follow-up 
 Death  
 Study terminated by Sponsor 
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 Completed the last visit where the patient completed the SFU visit, or completes any 
applicable continued access follow-up 
A clinical trial is to be discontinued or terminated in case of an unacceptable risk, any relevant 
toxicity, or a negative change in the risk/benefit assessment. This might include the occurrence 
of AEs in which character, severity or frequency is new in comparison to the existing risk 
profile. An unacceptable toxicity will be considered a treatment emergent adverse event that is ≥ 
Grade 3 or intolerable Grade 2 and considered related to study drug and that continues despite 
protocol allowed dose reduction. In addition, any data deriving from other clinical trials or 
toxicological studies which negatively influence the risk/benefit assessment may cause 
discontinuation or termination of the study. 
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7 
STUDY PROCEDURES AND ASSESSMENTS  
Descriptions of assessments are provided in Sections 7.1 through 7.19, below. Specific timing 
requirements for study procedures and assessments are provided in Appendix A, Table 11-1, and 
are described in more detail in the following subsections. 
Routine laboratories, for example serum chemistries, hematology, and urinalysis, will be 
performed locally. Special assessments such as PK and correlative studies will be performed 
centrally or as individually indicated. For each MTC patient, tests for calcitonin and CEA should 
be performed in the same laboratory to minimize intra-patient, lab-to-lab variability in their 
measurement. Additional information on the handling and processing of these special samples is 
provided in the separate Laboratory Manual. 
7.1 
Informed Consent / Pediatric Assent  
Patients must be able to provide written informed consent (or pediatric assent, when applicable) 
and meet eligibility criteria prior to enrollment. Separate ICFs will be required for patients 
enrolling in Phase 1 and in Phase 2. Additional details are provided in Section 10.1.3. 
7.2 
Screening  
The Screening procedures must be conducted within 28 days of C1D1, unless otherwise noted. 
Patients who cannot complete the procedures within the Screening window may be rescreened, 
and certain Screening procedures may not need to be repeated, including certain procedures that 
were obtained as part of the patient’s standard care prior to providing informed consent for this 
study, with documented Sponsor approval. Screening tests that are completed in the 48 hours 
prior to start of study drug administration and that duplicate C1D1 tests according to the 
Schedule of Assessments (Table 11-1) will be accepted as fulfilling the C1D1 assessments; 
repeat testing on C1D1 is not necessary for this scenario, and results should be recorded in the 
Screening set of eCRFs. 
7.3 
Enrollment  
Enrollment procedures will be conducted in accordance with the Schedule of Assessments 
(Table 11-1). Patients who meet eligibility criteria outlined in Section 4 will be enrolled in this 
study. A patient may be enrolled in either Phase 1 or Phase 2 of the study, but not both. In both 
Phase 1 and 2, the Investigator may repeat qualifying laboratory tests and vital signs/ ECGs prior 
to enrollment if a non-qualifying finding is considered an error, and/or if an acute finding is 
likely to meet eligibility criteria on repeat testing.  
7.4 
Medical History and Malignancy History  
All conditions ongoing and relevant past surgical and medical history should be collected in 
accordance with the Schedule of Assessments (Table 11-1). Medical, surgical, and malignancy 
history, including histologic confirmation of solid tumor, primary and metastatic diagnosis dates, 
prior treatments for the malignancy, etc. should be recorded on the appropriate eCRF. 
Demographics including age, gender, race, and ethnicity will be recorded.  
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7.5 
Tissue Biopsy  
Tissue biopsies should be collected in accordance with the Schedule of Assessments (Table 11-1). 
Availability of tissue biopsy is required following the most recent progression. If tissue meeting 
this criterion is not available, a tissue sample obtained prior to most recent progression is 
acceptable. If neither of these samples are available for submission, then a fresh tumor biopsy is 
requested if it can be safely obtained. If no tissue is available, the patient may still be eligible for 
enrollment following conversation with the Sponsor. Tissue biopsy collected at the EOT visit is 
optional. Additional biopsies may be requested on a case-by-case basis in patients re-starting 
study drug following a “drug holiday” and disease recurrence. All specimens will be deidentified 
and stored at a secure facility designated by the sponsor for up to 15 years from the date of 
receipt.  
7.6 
Physical Examination  
Physical examinations will be conducted in accordance with the Schedule of Assessments 
(Table 11-1) and will include review of systems (breast/chest, extremities, genitourinary, 
head/ears/eyes/nose/throat, lymph nodes, musculoskeletal, pulmonary, and skin), thorough 
neurologic assessment, body weight, and height during Screening. Symptom-directed physical 
examination and neurological examinations, including measurement of weight and height, may 
be performed at other time points after Screening in accordance with the Schedule of 
Assessments (Table 11-1). 
7.6.1 
Karnofsky or Lansky Performance Status Scales  
Karnofsky or Lansky Performance Status Scales will be conducted in accordance with the 
Schedule of Assessments (Table 11-1). The Karnofsky score should be assessed for patients 
16 years old or older, or the Lansky score should be assessed for patients younger than 16 years 
(refer to Appendix C). 
7.6.2 
Vital Signs  
Vital signs will be measured pre-dose in accordance with the Schedule of Assessments 
(Table 11-1) and should include systolic and diastolic blood pressure, heart rate, respiratory rate, 
height, weight, and body temperature (to be collected in an age appropriate fashion, e.g., orally, 
axillary, auricularly, etc.).  
At PK time points, vital signs should be assessed as indicated in the Schedule of Assessments 
(Table 11-1), prior to actual PK blood sampling at these time points. 
7.7 
Electrocardiograms  
Twelve-lead resting ECGs will be performed in accordance with the Schedule of Assessments 
(Table 11-1). To minimize variability, it is important that patients are in a resting position for at 
least 5 minutes prior to each ECG evaluation. Body position should be consistently maintained 
for each ECG to prevent changes in heart rate. ECGs for each patient should be obtained from 
the same machine whenever possible. When ECGs coincide with PK draw days, ECGs should be 
performed before the PK blood draw. Any clinically significant changes in ECGs that occur 
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during the study should be reported as an AE in the eCRF. If the machine generated ECG results 
include a prolonged QTc interval, the ECG should be interpreted by a qualified health care 
provider. Electrolytes should be monitored and repletion prescribed as needed (potassium should 
be ≥4 mEq/L and < ULN and magnesium and calcium should be within normal limits). 
7.8 
Growth Plate Evaluation  
Patients who have not yet obtained full adult height will undergo either X-ray or MRI of the right 
knee at baseline and every 6 months during participation in the study while the growth plate 
remains open. Premature closure of the growth plate after study baseline will be captured as an 
AE. 
If it is unclear that a patient has obtained full adult height, a pre-treatment tibial X-ray (anterior 
posterior and lateral views) or MRI of the right knee should be obtained. Either tibial X-ray or 
MRI (same modality as baseline) will be performed if the growth plate remains open, every 6 
months during participation in the study until the growth plate closes.  
7.9 
Dental Evaluation  
Patients aged 5 years and older, without a full set of permanent teeth, will undergo a dental 
evaluation at baseline and every 6 months during participation in the study. Patients who enroll 
prior to their 5th birthday will start dental assessments at the cycle visit closest to their 5th 
birthday. Detrimental changes in tooth development considered significant after study baseline 
will be captured as an AE, and will require dentist evaluation. 
Patients who enroll with a full set of permanent teeth will not need to undergo dental evaluations. 
7.10 
Pubertal Maturation Evaluation  
Patients aged 7 years and older will be assessed for pubertal maturation every 6 months during 
participation in the study based on the Tanner Scale. Patients who enroll prior to their 7th 
birthday will start assessment at the cycle visit closest to their 7th birthday. Delays to pubertal 
maturity (according to the Tanner Scale) after study baseline will be captured as an AE. 
Patients who have completed puberty according to the Tanner Scale at enrollment will not 
undergo evaluation. 
7.11 
 Laboratory Tests   
For all laboratory testing, institutional guidelines for the use of anesthetics prior to venipuncture 
and maximum number of attempts may be implemented. Age specific maximum blood volume 
will be adhered to for patients enrolled, per guidance and individual institutional practice. 
Laboratory normal ranges by age group and by individual institutional reference will guide 
individual laboratory result assessments.  
 
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7.11.1 
Pregnancy Test  
Pregnancy testing (serum or urine) should be conducted in accordance with the Schedule of 
Assessments (Table 11-1). Pregnancy reporting information is provided in Section 8.5. Urine or 
serum pregnancy test are required for female participants of child-bearing potential (surgically 
sterilized females or those who have not experienced menses for at least 2 years are not required 
to be tested). If any urine pregnancy test is positive, study treatment will be delayed until the 
patient pregnancy status is confirmed by a serum pregnancy test. If serum pregnancy test is 
positive, the patient will be permanently discontinued from study treatment. 
7.11.2 
Hematology  
Hematology should be assessed in accordance with the Schedule of Assessments (Table 11-1) 
and should include assessment of the following: Hemoglobin, hematocrit, RBC count, WBC 
count with differential (neutrophils [absolute count and percent] and lymphocytes, monocytes, 
eosinophils, basophils [percent]) and platelet count.  
7.11.3 
Serum Chemistries  
Serum chemistries (non-fasting) should be assessed in accordance with the Schedule of 
Assessments (Table 11-1) and should include assessment of the following: alkaline phosphatase, 
albumin, ALT, AST, BUN or urea, creatinine, glucose, LDH, total and direct bilirubin, total 
protein, phosphorus, sodium, potassium, chloride, calcium, magnesium, and bicarbonate.  
7.11.4 
Urinalysis  
Urinalysis should be conducted in accordance with the Schedule of Assessments (Table 11-1). 
Dipstick evaluation may be used if allowed per local standards, but if abnormal, it should be 
followed up with a complete urinalysis, including color, specific gravity, pH, glucose, bilirubin, 
ketones, occult blood, protein, leukocytes, nitrites and urobilinogen. If +2 protein is observed; a 
24-hour urine collection or urine protein: creatinine (UPC) ratio will be taken to quantify 
proteinuria.  
7.11.5 
Calcitonin, Thyroglobulin and Carcinoembryonic Antigen  
In patients with MTC, calcitonin, thyroglobulin, and CEA should be assessed in accordance with 
the Schedule of Assessments (Table 11-1). For each patient, all tests for calcitonin and CEA 
should be performed in the same laboratory to minimize intra-patient, lab-to-lab variability in 
their measurement. 
7.11.6 
Cortisol and Adrenocorticotropic Hormone  
In patients with MTC or other cancer patients with Cushing’s disease only, serum cortisol, serum 
adrenocorticotropic hormone (ACTH) should be assessed in accordance with the Schedule of 
Assessments (Table 11-1).  
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7.11.7 
Thyroid Function  
Hypothyroidism was reported in patients receiving selpercatinib in clinical trials. Monitor 
patients for hypothyroidism and treat as medically appropriate. Baseline laboratory measurement 
of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism 
should be treated as per standard medical practice prior to the start of selpercatinib treatment. All 
patients should be observed closely for signs and symptoms of thyroid dysfunction during 
selpercatinib treatment. Thyroid function should be monitored periodically throughout treatment 
with selpercatinib and patients who develop thyroid dysfunction should be treated as per 
standard medical practice. However, patients could have an insufficient response to substitution 
with levothyroxine (T4) as selpercatinib may inhibit the conversion of levothyroxine to 
liothyronine (T3) and supplementation with liothyronine may be needed.  
7.12 
Pharmacokinetic Samples: Blood (and Cerebrospinal Fluid, if Appropriate)  
Blood plasma samples for PK assessments (Phase 1 and Phase 2) will be collected in accordance 
with the Schedule of Assessments (Table 11-1) and the Schedule of Pharmacokinetic Sampling 
(Table 11-2). The dose of selpercatinib should be taken in the clinic on PK sampling 
 
 Samples will be collected and handled as outlined in 
the Laboratory Manual. The PK data collected 
 will be used to determine 
parameters such as area under the concentration versus time curve from time 0 to t (AUC0-t) and 
plasma terminal elimination half-life (T1/2). As noted in Table 11-2, PK samples will also be 
collected for patients participating in the optional alternate formulation assessment. 
If patients have an Ommaya Reservoir or are undergoing diagnostic LP, CSF will also be 
collected for 
 For 
patients undergoing diagnostic LP, a peripheral blood sample should be taken at the same time as 
the CSF collection. It is preferred, but not required, that the 
 
  
7.13 
Disease Assessment  
7.13.1 
Tumor Measurements  
Disease assessment should be conducted in accordance with the Schedule of Assessments 
(Table 11-1) and the Imaging Manual Tumor(s) will be assessed by radiographic tumor 
measurements using standard of care imaging modalities (CT and/or PET) or MRI of chest, 
abdomen, and pelvis, and any other areas with suspected disease involvement. Patients with a 
history of, or clinical suspicion of, CNS metastases should additionally have a head CT (or CT / 
PET) or MRI scan performed at each tumor assessment. Patients with locally advanced disease 
should have an MRI or CT (or CT / PET) of the site of disease and a CT (or CT / PET) or X-Ray 
of the chest, plus any other areas of disease involvement. A CT (or CT / PET) or MRI of the 
chest/abdomen/pelvis should be repeated yearly (or more frequently for clinical concerns) if 
there is no evidence of disease at baseline. Patients with neuroblastoma will be followed with 
MIBG scans, anatomic imaging, and bilateral bone marrow aspirates and biopsies. Patients with 
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MIBG non-avid disease may undergo fluorodeoxyglucose-PET assessment instead of MIBG per 
International Neuroblastoma Response Criteria guidelines and with sponsor approval. 
Investigators should use the same method consistently for an individual patient throughout the 
study. Disease assessments will utilize RECIST v1.1 (refer to Appendix E, Table 11-7 and 
Table 11-8); additional details are provided at www.recist.com/). Assessments of brain disease 
will be made using the current version of RANO Criteria (Appendix F, Table 11-9).  
Tumor measurements are to be performed for all patients during Screening. Tumor will be 
assessed by CT or CT / PET or MRI of chest, abdomen/pelvis, as indicated. Patients enrolled 
with a history of CNS metastases should additionally have a head CT (or CT / PET) or MRI scan 
performed at each tumor assessment. Thereafter, tumor measurements and disease response 
assessments are to be performed for patients known to have measurable disease on Day 1 of 
every other cycle, starting in Cycle 3 through Cycle 12; thereafter tumor measurements and 
disease response assessments should be performed on Day 1 (or within 1 week prior) of every 
third cycle (prior to Day 1 of Cycle 14, 17, 20, etc.). In addition, there is an optional assessment 
on Day 1 of Cycle 2. Such assessments also are to be performed at the End of Treatment visit if 
they had not been performed within the previous 2 cycles. Subsequent assessments should use 
the same radiographic methods as used during Screening. 
Anatomical measurements (summed across target lesions) will be documented during Screening 
and each subsequent evaluation. When possible, the same qualified physician will interpret 
results to reduce variability. Radiographic images should be maintained at the study center and 
?0>?=0>@7?>,9/9A0>?42,?:=N>149/492>B477-01470/49?30;,?409?N>>:@=.0/:.@809?> 
During Screening, tumor lesions are to be categorized as measurable versus non-measurable and 
target versus non-target, as follows. 
7.13.1.1 
Collection of Radiographic Studies for Independent Review  
Baseline Screening radiographic studies and all subsequent radiographic studies with any clinical 
information imperative to accurate radiographic assessment of disease will be collected and 
stored for future independent radiological review. Independent radiology review for this trial is 
used to assess the objectives of the study and any unexpected medical findings identified during 
subsequent independent radiologic review. Identification of radiographic findings which may 
impact patient management or outcomes during the course of patient participation in the study 
are the responsibility of the treating physician. 
7.13.2 
Correlative studies: 
  
At the time of relapse, 
 samples may be obtained, if possible, 
 
Whole blood for analyses of 
 should be 
obtained in accordance with the Schedule of Assessments (Table 11-1) (within 7 days following 
radiologic disease assessment, except for baseline/Screening when it may be obtained any time 
prior to treatment on C1D1) and with the Laboratory Manual. Whole blood for 
 
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should be obtained at the EOT visit even if radiologic disease assessment is not performed. Sites 
may draw fewer tubes based on local institutional policy for maximal blood draws in patients. 
The sample collection must be captured on the appropriate eCRF and requisition page(s). Refer 
to the Laboratory Manual for detailed sample collection, storage and shipment information. All 
specimens will be deidentified and stored at a secure facility designated by the sponsor for up to 
15 years from the date of receipt.  
7.13.3 
Pain and Health-Related Quality of Life: Wong-Baker Faces Scale and 
PedsQL-Core  
Pain and HRQoL assessments should be obtained in accordance with the Schedule of 
Assessments (Table 11-1). For assessment of pain, patients 3 year of age or older will be 
assessed using the Wong-Baker Faces Scale. For assessment of HRQoL, all patients will be 
assessed using the PedsQL-Core for the patient or their parent/caregiver. Each questionnaire 
should be performed before the patient learns the results of his or her restaging. 
7.13.4 
Telephone Follow-up  
The site will contact the patient by telephone in accordance with the Schedule of Assessments 
(Table 11-1) to assess for tolerability, continuation of study drug, and whether the patient needs 
to return to clinic earlier than planned. If not tolerating the drug well, the patient should be seen 
at least every 14 days to assess AEs, and the patient should be contacted regularly to assess AE 
status. 
7.13.5 
Survival Status  
Patients will be followed for survival status, date of progression, and subsequent anticancer 
therapy(ies) by telephone or other method. 
7.14 
Study Drug Administration and Dosing Diary  
Study drug should be administered in accordance with the Schedule of Assessments (Table 11-1) 
and Section 5.  
BSA should be calculated on Day 1 of each cycle to confirm dose. Dose should be increased for 
any change in BSA conferring a greater than 10% change in dose (for all cohorts). The 
maximum dose (regardless of BSA calculation) will be no higher than the recommended adult 
dose associated with the BSA-based dosing, i.e., patients in Dose Cohort 1 will receive a dose no 
higher than 160 mg BID, patients in Dose Cohort 2 will receive a dose no higher than 200 mg 
BID. 
Completion of the outpatient dosing diary will include recording of selpercatinib dosing, 
H2 blockers, and antacids. The diary will be required during Cycles 1-3 and as otherwise 
instructed (during alternative formulation assessment),and may be used in additional cycles if 
helpful to the patient/caregiver.  
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7.14.1 
Formulation Acceptability and Palatability Assessments  
During the assigned 
 dosing period for selected study subjects (participants) and/or 
caregivers who give consent, responses to questions designed to assess the acceptability of the 
 formulation (Kozarewicz 2014) will be collected. The questionnaire for the 
 
 will assess the participants ability to swallow the drug product as intended.  
The acceptability questionnaire for the 
 
 will assess 
 
 
The appropriate questionnaire(s) will be administered within approximately 30 minutes of dosing 
after the first dose of the 
 formulation and again after approximately 2-4 weeks of dosing 
the 
 formulation.  
The questionnaire will be completed by caregivers (proxy) for participants aged <6 years. For 
participants H6 years old to <12 years old, both participant and caregiver will complete the 
questionnaires. For participants H12 years old, the questionnaire will be self-completed. In the event 
a participant aged H6 years old cannot complete the questionnaire (i.e., limited capability), the 
caregiver may complete the questionnaire for the participant (only one questionnaire would need to 
be submitted for participants H6 to <12 years old in this case). This will not be a protocol deviation. 
Similarly, if the caregiver is the one preparing the 
, the caregiver and participant should 
both complete the questionnaire (two questionnaires would be submitted for participants H12 years 
old in this case). 
7.15 
Concomitant Medication  
Concomitant medications should be recorded in accordance with the Schedule of Assessments 
(Table 11-1). 
All medications that were used from 14 days prior to enrollment through the end of study 
treatment will be recorded in the eCRF. These are to include prescription and nonprescription 
medications, transfusions, vitamins and nutritional supplements, and other remedies. Excluded 
prior medications are excluded via the eligibility criteria (Section 4.2). Additional guidance 
regarding concomitant medications is provided in Section 5.3. 
7.16 
Adverse Events/Serious Adverse Events  
Adverse events (AEs) should be recorded in accordance with the Schedule of Assessments 
(Table 11-1) and Section 7.20.  
7.17 
End of Treatment Visit  
End of treatment (EOT) is defined as Day 28 (±7 days) of the final cycle of treatment (or time of 
premature discontinuation of treatment). The EOT assessments and procedures will be conducted 
in accordance with the Schedule of Assessments (Table 11-1) unless withdrawal of consent 
occurs prior to scheduled EOT visit. 
An optional tumor tissue sample from patients who experienced PD is requested; tissue biopsy 
collected at EOT visits is optional. 
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7.18 
Safety Follow-up Visit  
The safety follow-up assessments will be conducted in accordance with the Schedule of 
Assessments (Table 11-1). Safety follow-up procedures may be performed as part of the EOT 
visit if the latter was performed at least 28 days after final dose of the last cycle. 
Serum chemistries and urinalysis should be assessed only if treatment-emergent abnormalities 
were seen at EOT. 
Status of unresolved AEs should be assessed and may be done by phone if patient is not able to 
return to clinic. 
7.19 
Long-Term Follow-up  
The LTFU assessments and procedures will be conducted in accordance with the Schedule of 
Assessments (Table 11-1). After treatment discontinuation, LTFU will occur approximately 
every 3 months (±1 month) until the patient experiences PD, withdraws consent for further 
participation, is lost to follow-up, has died, or close of the study. The site will contact the patient 
follow-up assessments that may include: Date of PD, subsequent anticancer therapy(ies) and 
survival status. SAEs reported by patients that the Investigator considers related to study drug 
and that occurred in the follow-up period must be reported to the Sponsor until the patient 
discontinues from the study (for any reason) or the study closes. LTFU may be conducted by 
phone. For any patient who is lost to follow-up, the study site will attempt to ascertain survival 
information via public database search. If survival status still cannot be ascertained, patients will 
be considered lost to follow-up and will be censored appropriately. 
Special considerations: Patients who receive study drug in a pre-surgical fashion and then hold 
study drug due to histologically negative margins at resection (as is permitted by this protocol) 
may be considered for re-start of study drug if there is disease recurrence. Therefore, these 
patients should continue radiographic and/or clinical assessment of disease response utilizing the 
same modality used at baseline imaging. These response assessments should be collected and 
reported every 3 months. End of treatment, Safety Follow-up and Long-Term Follow-up visit(s) 
requirements will be conducted as described in Sections 7.17, 7.18, and 7.19. If disease 
recurrence is suspected and the Investigator wishes to consider the patient for a re-start of 
selpercatinib, a conversation with the Sponsor will be required prior to initiation of study drug. 
If a patient discontinues study treatment for reasons other than PD, lost to follow-up, withdrawal 
of consent or initiation of a new anticancer therapy(ies), the patient is required to undergo 
disease assessment by imaging (utilizing the same modality[ies] used for the baseline imaging 
assessment) as specified in Section 7.13.1 until PD (even if PD occurs after 2 years), lost to 
follow-up, withdrawal of consent, or initiation of a new anticancer therapy(ies). 
7.20 
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. 
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8 
ADVERSE EVENTS  
An AE is any unfavorable medical occurrence in a patient administered an investigational 
product, which does not necessarily have a causal relationship with the treatment. 
Events meeting the AE definition include medication error, misuse, or abuse of IMP, including 
signs, symptoms, or clinical sequelae.  
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of the investigational product, whether or not considered related to the 
investigational product. 
All AEs, complaints, or symptoms that occur from the time informed consent is signed until the 
SFU are to be recorded on the appropriate eCRF (events that occur prior to consent are 
considered medical history). Documentation must be supported by an entry in the patient’s 
source medical records. Laboratory test abnormalities considered by the Investigator to be 
clinically relevant should be reported in the eCRF as an AE. Each AE is to be evaluated for 
duration, severity, and causal relationship with the investigational product or other factors. 
Disease progression of the primary tumor in and of itself is captured as an efficacy assessment 
and should not be captured as an AE (including fatal AEs) unless the disease progression is 
assessed as related to study treatment. If toxicities due to disease progression exist and are new 
or worsened from baseline, these should be reported as AEs. If a new primary malignancy 
appears, it will also be considered an AE. 
8.1 
Grading and Intensity of Adverse Events  
The Investigator will grade the severity of each AE using, when applicable, the NCI-CTCAE, 
version 5. In the event of an AE for which no grading scale exists, the Investigator will classify 
the AE as mild, moderate, severe, life-threatening/debilitating, or fatal, as defined below. 
Table 8-1 
NCI-CTCAE Definitions of Severity for Adverse Reactions  
Toxicity 
Grade / Details 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no 
interventions required  
(an event that is usually transient in nature and generally not interfering with normal 
activities) 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; some limitation of 
activities  
(an event that is sufficiently discomforting to interfere with normal activities) 
Grade 3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization required; disabling; limitation of patient's ability to care for 
him/herself 
(an event that is incapacitating with inability to work or do usual activity, or inability to work 
or perform normal daily activity) 
Grade 4 
Life-threatening consequences; urgent intervention required  
(an event that puts the patient at immediate or potential risk of death, requires 
hospitalization, or which drastically impacts a patient’s well-being) 
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Toxicity 
Grade / Details 
Grade 5 
Death related to adverse event (fatal) 
Abbreviations: NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events. 
8.2 
Relationship to Study Drug  
The Investigator will categorize each AE as to its potential relationship to investigational product 
using the categories of Yes (causally related) and No (unrelated) as defined below. The 
assessment of the relationship of an AE to the administration of investigational product is a 
clinical decision based on all available information at the time. 
No: 
The time course between the administration of study drug and the occurrence or worsening of the 
AE rules out a causal relationship and another cause (concomitant medications, therapies, 
complications, comorbidities, etc.) is suspected. 
Yes: 
The time course between administration of investigational product and the occurrence or 
worsening of the AE is consistent with a causal relationship and no other cause (concomitant 
drugs, therapies, complications, comorbidities, etc.) can be identified. 
The following factors should also be considered: 
 Temporal sequence from treatment 
 Underlying, concomitant, or intercurrent diseases 
 Concomitant medications 
 Clinical and/or preclinical data regarding whether a particular response is a class effect 
 Pharmacology and PK of the investigational product 
An unexpected AE is an experience not previously reported or an AE that occurs with 
specificity, severity, or frequency that is not consistent with the current Selpercatinib IB. 
8.3 
Serious Adverse Event Reporting  
An SAE is any untoward medical occurrence at any dose that: 
 Results in death. 
 Is life-threatening. 
 Requires hospitalization or prolongation of existing hospitalization. 
 Results in disability/incapacity. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event. 
 (Note: Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
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life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious.) 
All SAEs occurring from the time the ICF and Pediatric Assent Form, where applicable, are 
signed through 28 days after the last dose should be reported immediately but in no more than 24 
hours of the knowledge of the occurrence (this refers to any AE that meets any of the 
aforementioned serious criteria) to Medpace Clinical Safety. All SAEs that the Investigator 
considers related to study drug occurring after the 28-day follow-up period must be reported to 
the Sponsor until the patient discontinues the study (for any reason) or the study closes. 
To report the SAE, complete the paper SAE form located in the Study Binder. Fax the completed 
paper SAE form to Medpace (the fax number is listed below) within 24 hours of awareness.  
Safety Contact Information: 
Medpace Clinical Safety: U.S. and Asia/Pacific 
SAE Reporting Number: Telephone: 
 
Safety Fax: 
  
e-mail: 
 
Medpace Clinical Safety Europe / non-U.S.: 
SAE Reporting Number: 
 
Safety Fax: 
 
e-mail: 
 
Within 24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (e.g., patient discharge summary or autopsy reports), should be faxed 
or emailed as noted above. 
The Investigator will be requested to supply detailed information regarding the event. SAEs 
should be reported to the Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Independent Ethics Committee (IEC)/Human Research Ethics Board (HREC) and a copy 
of that report must be retained at the investigative site and filed in the Investigator Site File in 
accordance with the requirements of that institution. 
Although not considered an AE per se, the Sponsor must be notified of any patient or patientN>
partner (after obtaining the necessary signed informed consent from the pregnant female partner 
directly) who becomes pregnant during a clinical study. 
Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded as an 
SAE under this criterion, nor will hospitalization for a procedure scheduled or planned before 
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signing of the informed consent. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 
seriousness. Admission to the hospital for social or situational reasons (i.e., no place to stay, live 
too far away to come for hospital visits) will not be considered inpatient hospitalizations. In the 
event of an accidental or intentional overdose by a patient, the site staff must immediately inform 
Medpace Clinical Safety. The eCRF must be updated to reflect this information. In the event that 
the overdose is associated with an SAE, the two events should be linked. In the event of an AE 
associated with an overdose, an SAE report form must be completed detailing the AE and the 
overdose details.  
Disease progression (PD) of the primary tumor in and of itself is captured as an efficacy 
assessment and should not be captured as an AE or an SAE (refer to Section 7.20). 
SAE Regulatory Reporting: 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will evaluate the reported SAEs, including confirmation of relatedness and assessment 
of expectedness. The sponsor has processes for safety reports for identification, recording, and 
expedited reporting of SUSARs according to local regulatory requirements. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
8.4 
Serious Adverse Event Follow-up  
For all SAEs occurring during the study, the Investigator must submit follow-up reports to the 
Sponsor regarding the status of the SAE and the patient’s subsequent course until the SAE has 
resolved, or until the condition stabilizes or is deemed chronic (in the case of persistent 
impairment), or the patient dies. 
8.5 
Pregnancy Reporting  
If the patient, or the partner of a patient (after obtaining the necessary signed informed consent 
from the pregnant female partner directly) participating in the study becomes pregnant during the 
study or within 28 days of discontinuing study drug, the Investigator should report the pregnancy 
to Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero Form to the Investigator for completion. 
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The patient or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
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death, or congenital anomaly), the Investigator should follow the procedures for reporting an 
SAE.  
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9 
PLANNED ANALYSES  
A full Statistical Analysis Plan will provide specific details on the analytical methods and data 
displays. 
9.1 
Study Endpoints  
9.1.1 
Phase 1 Study Endpoints  
9.1.1.1 
Primary  
The primary endpoint for Phase 1 is the frequency, severity and relatedness of TEAEs and SAEs, 
including DLTs in pediatric patients receiving selpercatinib. 
9.1.1.2 
Secondary  
The secondary endpoints for Phase 1 are: 
 Plasma concentrations of selpercatinib and PK parameters, including, but not limited to area 
under the concentration versus time curve from time 0 to 24 hours (AUC0-24), maximum drug 
concentration (Cmax), time to maximum plasma concentration (Tmax), degree of accumulation, 
and other characterizations 
 The MTD and/or the RP2D of selpercatinib in pediatric patients 
 ORR and CBR based on RECIST 1.1 or RANO as appropriate to tumor type as determined 
by an IRC and treating investigator 
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9.1.2 
Phase 2 Study Endpoints  
9.1.2.1 
Primary  
The primary endpoint for Phase 2 is the ORR based on RECIST v1.1 or RANO in pediatric 
patients with tumors harboring an activating RET alteration as appropriate to tumor type 
determined by IRC. 
9.1.2.2 
Secondary  
The secondary endpoints for Phase 2 are: 
 ORR based on RECIST v1.1 or RANO as appropriate to tumor type per the treating 
9A0>?42,?:=N>=0>;:9>0,>>0>>809? 
 DOR (IRC and treating Investigator) 
 PFS (IRC and treating Investigator) 
 OS  
 CBR (IRC and treating Investigator) 
 Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood 
chemistry values, and assessments of physical examinations, vital signs, and ECGs 
 Plasma concentrations of selpercatinib and PK parameters, including, but not limited to 
AUC0-24, Cmax, Tmax, degree of accumulation, and other characterizations 
 The percent positive agreement between prior molecular profiling that detected a RET 
,7?0=,?4:9B4?349?30;,?409?N>?@8:=B4?3/4,29:>?4.?0>?(s) being evaluated by the Sponsor 
 Post-operative staging and surgical margin status in patients who have definitive surgery 
following treatment with selpercatinib  
 Change from baseline in patient-reported pain at BOR visit as assessed by the Wong-Baker 
Faces Scale. 
 Assessment of 
 including palatability (if applicable) 
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9.2 
Analysis Populations  
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
Safety Analysis Set (SAS) 
The SAS will be used primarily for the analysis of safety data and will consist of all enrolled 
patients who receive at least 1 dose of selpercatinib. The SAS will also be used for the analysis 
of efficacy data unless otherwise specified.  
9.3 
Determination of Sample Size  
9.3.1 
Phase 1  
A minimum of  patients would be required to be enrolled into a dose escalation cohort in order 
to define the MTD or RP2D of selpercatinib. The actual number of patients enrolled is dependent 
on the number of patients enrolled in each dose escalation cohort, the number of cohorts 
enrolled, and when DLTs occur before declaring an MTD or RP2D. The safety of the patients 
enrolled is ensured with careful monitoring and rules for escalation so that an excessive number 
of patients are not unnecessarily exposed to a dose level that exceeds the MTD. 
If an investigative site identifies a patient with a known RET alteration, the patient may be 
enrolled to a previous cohort that has been determined safe ,1?0=/4>.@>>4:9B4?3?30&;:9>:=N>
Medical Monitor. If a patient with a RET alteration is identified after  patients have been 
enrolled on Dosing Cohort 1, and prior to clearance of the DLT window, that patient will be 
enrolled to Dose Level -1. Following clearance of Dose Level 1, the patient(s) enrolled to Dose 
Level -1 may be escalated to Dose Level 1 upon discussion between the Investigator and the 
Spons:=N> 0/4.,7 :94?:=Patients who miss 7 or more days of dosing in Cycle 1 for reasons 
unrelated to study drug toxicity will be considered to have inadequate study drug exposure to 
support dose escalation and will be replaced. 
9.3.2 
Phase 2  
The number of patients planned for each Phase 2 cohort was determined largely by feasibility 
considerations owing to the extreme rarity of pediatric with an advanced cancer harboring an 
activating RET alteration. Cohorts 1 and 2 may enroll approximately 10-20 patients. Although 
the planned sample size is limited, it is anticipated that the objective response rate may be high 
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(≥ 50%) for each cohort evaluated. For Cohorts 1 and 2, a sample size of 20 patients is estimated 
to provide approximately 75% power to achieve a lower boundary of a two-sided 95% exact 
binomial confidence interval (CI) about the estimated ORR that exceeds 20%. Ruling out a lower 
limit of 20% is considered clinically meaningful in patients who have limited treatment options 
for their advancing disease. Cohorts 3-4 are anticipated to enroll too few patients to be powered 
for a formal statistical testing. 
9.4 
Demographics and Baseline Characteristics  
Descriptive summaries of demographic and baseline characteristics for all enrolled patients will 
be presented by study phase. For the Phase 1 portion, tabulations will be provided by dose cohort 
and overall as appropriate. For Phase 2, tabulations will be provided by cohort and overall as 
appropriate. 
9.5 
Safety Analyses  
Safety will be assessed by clinical review of all relevant parameters including AEs, SAEs, 
laboratory values, and vital signs. Unless specified otherwise, the safety analyses will be 
conducted for the safety population defined in Section 9.2. Tabulations will be provided by dose 
cohort and overall summary across both Phase 1 and Phase 2. 
9.5.1 
Assessment Committee  
The Sponsor will appoint an Assessment Committee (AC) to include, a global principal 
investigator, an external physician, the sponsor’s project physicians and the sponsor’s compound 
lead statistician. The AC will determine whether the study should continue as planned, or 
whether modifications, such as protocol amendments for example to change enrollment, or 
patient monitoring are warranted. The first AC meeting will be performed after 10 patients have 
been enrolled and had the opportunity to be treated for 2 cycles. The AC will then meet and 
review safety data approximately every 6 months subsequently, until enrollment closure, then 
annually. 
9.5.2 
Safety Review Committee  
A Safety Review Committee (SRC), separate and in addition to the AC, will be established to 
oversee the safety aspects of the Phase 1 portion of the study, and to render dose escalation 
decisions. Specifically, the SRC will perform ongoing review and adjudication of SAEs and 
other safety trends throughout the conduct of the study. The SRC membership will consist of the 
Sponsor’s Medical Monitor, a Clinical Operations representative, and the Principal Investigator 
(or clinically qualified designee) from each active clinical site contributing patients to that 
cohort. The SRC will be convened for each cohort dose escalation decision or at a minimum of 
every 6 months (or more frequently depending on enrollment or observed safety profile). 
Decisions will be documented in written minutes.  
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9.5.3 
Treatment Emergent Adverse Events  
Summary tables and listings will be provided for all reported TEAEs, defined as AEs that start 
on or after the first administration of study drug. The reported AE term will be assigned a 
standardized preferred term using the Medical Dictionary for Regulatory Activities (MedDRA), 
version 21.1 or later. 
TEAEs will be summarized based on the number and percentage of patients experiencing the 
event by MedDRA System Organ Class and Preferred Term. The causal relationship between the 
occurrence of an AE and study drug will be judged by the Investigator based on the conventions 
described in Section 8.3. In the event a patient experiences repeat episodes of the same AE, then 
the event with the highest severity grade and strongest causal relationship to study drug will be 
used for purposes of incidence tabulations. 
Tabular summaries will be provided for: 
 TEAEs by any grade, and Grade 3/4/5 
 Drug-related TEAEs by any grade, and Grade 3/4/5 
 TEAEs with action of study drug delayed/interrupted or dose reduced 
 TEAEs with action of study drug discontinued 
 Treatment-emergent SAEs 
 Drug-related treatment-emergent SAEs 
 Fatal/Grade 5 TEAEs 
9.5.4 
Dose-Limiting Toxicity  
The observed DLT rate in each dose cohort will be calculated by the crude proportion of patients 
who experience DLT. Multiple concurrent AEs leading to DLT will be considered a single DLT. 
The estimate of the DLT rate will be accompanied by a 2-sided 95% exact binomial confidence 
interval (CI). 
9.5.5 
Deaths  
All deaths on study should be reported and recorded. All deaths that occur on study will (to the 
best of the Sponsor’s ability) be reported in a patient listing and will include the primary cause of 
death and the number of days between the date of the last dose of study drug and death.  
9.5.6 
Laboratory Values  
Laboratory values will be assigned toxicity grades when available using the NCI-CTCAE, 
version 5. Directional shifts in laboratory toxicity grades (comparing baseline grade with worst 
postbaseline grade) will be analyzed using standard shift tables, presenting number and 
proportion of patients and their maximum grade shift. For analytes without a toxicity grading 
scale, the shift table will present directional shifts from baseline to above or below the laboratory 
standard normal range using the maximum increase and/or decrease observed throughout the 
course of treatment/observation. 
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Hematology and serum chemistries will be summarized in a descriptive manner by calculating 
the mean, standard deviation, median, and range as follows: 
 Baseline value 
 Minimum postbaseline value 
 Maximum postbaseline value 
 Average postbaseline value 
 Last postbaseline value 
9.5.7 
Vital Signs  
All patients will have pretreatment baseline vital signs and pre-dose measurements on Day 1 of 
each cycle. The results for each vital sign will be summarized in a descriptive manner by 
calculating the mean, standard deviation, median, and range by time point in the same manner 
described for laboratory values. For these analyses, the minimum, maximum, average, and last 
postbaseline value will be determined relative to the baseline vital sign measurements only. 
9.5.8 
Concomitant Medications  
Prior and concomitant medications will be coded to the generic term using World Health 
Organization (WHO) Drug Dictionary version September 2018 or later and will be summarized 
by generic term and listed by patient. 
9.6 
Efficacy Analyses  
The efficacy analyses will be conducted on the SAS unless otherwise specified. The efficacy 
outcomes for patients enrolled in the Phase 1 and Phase 2 will be summarized by cohort or by 
tumor type, and overall, as appropriate. 
ORR and CBR will be estimated using disease-specific response criteria (e.g., RECIST v1.1 for 
patients with solid tumor or RANO for patients with primary CNS tumors). The ORR will be 
calculated as the proportion of patients with best overall response (BOR) of complete response 
(CR) or PR. The CBR will be calculated as the proportion of patients with BOR of CR, PR, or 
SD lasting 16 or more weeks following initiation of selpercatinib. All responses will be 
confirmed by a second scan  28 days after the initial response. The estimate of the ORR and 
CBR will be accompanied by 2-sided 95% CI. The primary analysis of ORR will be based on the 
responses determined by an IRC. A secondary analysis of ORR will be based on the treating 
Investigator’s assessment. CBR will also be analyzed based on the IRC and the treating 
investigator as a secondary endpoint. 
DOR will be calculated for patients who achieve CR or PR. For such patients, DOR is defined as 
the number of months from the start date of CR or PR (whichever response status is observed 
first) and subsequently confirmed, to the first date that recurrence or PD is objectively 
documented. If a patient dies, irrespective of cause, without documentation of recurrent or PD 
beforehand, then the date of death will be used to denote the response end date. 
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PFS is defined as the number of months from the date of the first dose of study drug to the 
earliest of documented PD or death with or without evidence of prior progression. PFS events 
occurring during a Sponsor-approved drug holiday will be included as events for PFS and DOR 
(will not be censored). 
OS is defined as the number of months from the date of the first dose of study drug to the date of 
death (due to any cause). 
Time-to-event (TTE) endpoints (DOR, PFS and OS) will be summarized descriptively using the 
Kaplan-Meier method. The Kaplan-Meier estimate with 95% CI calculated using Brookmeyer 
and Crowley method will be provided for the median. The event-free rate with the 95% CI 
.,7.@7,?0/@>492=009B::/N>1:=8@7,B477-0;=:Aided for selected time points. Median follow-
up for each endpoint will be estimated according to the Kaplan-Meier estimate of potential 
follow-up (Schemper and Smith 1996).  
For DOR and PFS, patients who meet one or more of the following conditions will be 
right-censored as follows: 
 Patients with no baseline or postbaseline disease assessments unless death occurred prior to 
the first planned assessment (in which case the death will be considered an event). 
 Patients who initiate subsequent anticancer therapy in the absence of documented 
progression. 
 Patients who die or have PD after missing 2 or more consecutively scheduled disease 
assessment visits. 
 Patients who are last known to be alive and progression-free on or before the data cut-off 
date. 
For such patients, the progression or censoring date will be determined based on described 
conventions (Food and Drug Administration 2007). Detailed censoring scheme is described in 
the SAP. 
9.7 
Pharmacokinetic Analyses  
Plasma and CSF concentrations of selpercatinib will be determined with a validated bioanalytical 
assay. Refer to Section 7.12. 
PK parameters such as Cmax and AUC will be calculated when feasible. Summary statistics will 
be generated by dose cohort and across cohorts as appropriate. Samples of plasma may also be 
analyzed for the presence of metabolites of selpercatinib; if such analyses are conducted, they 
will be reported separately by the Sponsor. Additionally, the 
 
 
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9.8 
Pain and Health Related Quality of Life  
Quality of completion will be assessed at each study visit based on the number of completed 
assessments divided by the number of expected assessments, defined as the number of patients 
eligible to complete each patient-reported outcome instrument at that visit.  
In patients 3 years of age or older, pain will be assessed by the Wong-Baker Faces Scale. 
 
 Change from 
baseline in patient-reported pain will be calculated at the BOR visit. 
 
 
The HRQoL assessment will be based on the PedsQL-Core for the patient or their 
parent/caregiver.
 
 
 
 
  
 
 
 
 will be reported 
along with 95% CI by Clopper-Pearson. 
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10 
STUDY ADMINISTRATION  
10.1 
Regulatory and Ethical Considerations  
10.1.1 
Regulatory Authority Approval  
This study will be conducted in accordance with the standard of Good Clinical Practices (GCP), 
an international ethical and scientific quality standard for designing, conducting, recording, and 
reporting studies that involve human patients. All applicable country and local regulations will 
also be observed. Compliance with these standards provides assurance that the rights, safety, and 
well-being of study patients are protected, consistent with the principles in the Declaration of 
Helsinki, and that the clinical study data are credible.  
10.1.2 
Ethics Approval  
It is the responsibility of the Investigator to ensure that the appropriate IRB/REB/IEC/HREC has 
reviewed and approved this protocol prior to initiating the study. The Investigator must provide 
the Sponsor or Sponsor’s representative with current and revised IRB/REB/IEC/HREC 
membership rosters that include the members’ occupations and qualifications or provide a copy 
of the United States Department of Health and Human Services Assurance Number. 
The IRB/REB/IEC/HREC must also review and approve the clinical site’s ICF, Pediatric Assent 
Form, other written information provided to the patient, and all advertisements that may be used 
for patient recruitment. The Investigator will provide the study monitor with copies of these 
documents and of dated IRB/REB/IEC/HREC approval(s) prior to the start of the study. 
The IRBs/REBs/IECs/HREC are required to determine if child assents are appropriate for all 
studies that include pediatric patients. The IRB/REB/IEC/HREC may opt to waive assent if the 
patients are not capable of understanding (e.g., based on level of intellectual development or 
maturity) or if the study is in the best interest of the patient (i.e., strong possibility of benefit and 
no other alternatives are available). If an IRB/REB/IEC/HREC chooses to waive assent, this 
must be documented in the IRB/REB/IEC/HREC approval letter.  
If the protocol or the ICF or Pediatric Assent Form is amended during the study, the Investigator 
is responsible for ensuring that the IRB/REB/IEC/HREC has reviewed and approved these 
amended documents. Approval of the amended documents must be obtained from the 
IRB/REB/IEC/HREC before implementation and before new patients are consented to 
participate in the study using the amended version of the ICF/Pediatric Assent Form. The 
Investigator must provide the Sponsor with the dated IRB/REB/IEC/HREC approval of the 
amended documents as soon as available. 
10.1.3 
Patient Informed Consent and Pediatric Assent  
The Investigator and designated site staff who will perform the consent/assent process are 
responsible for knowing country-specific regulations and other local requirements with regard to 
child assent to ensure that the assent process is conducted in accordance with those requirements. 
Prior to study entry, the Investigator or designee will explain the nature, purpose, benefits, and 
risks of participation in the study to each patient, patient’s legally acceptable representative, legal 
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guardian, or impartial witness. Written informed consent and pediatric assent, where applicable, 
must be obtained prior to the patient entering the study (before initiation of any study-related 
Screening procedure). In pediatric cases, where applicable and according to local regulations, 
both parents may be required to sign informed consent. Sufficient time will be allowed to discuss 
any questions raised by the patient. The ICF/Pediatric Assent Form, which will contain all 
International Conference on Harmonisation (ICH)-required elements and local privacy 
authorization information in a language that is understandable to the patient, must be signed by 
all patients, or by the patient's legal representative. The process of obtaining the ICF and 
Pediatric Assent Form, where applicable, will be in compliance with all applicable local and 
country regulations and ICH requirements. 
The Pediatric Assent Form must have a date and signature line for the child. Regional laws differ 
in their requirements for patients who have not reached the legal age of majority and 
IRBs/REBs/IECs/HRECs are responsible for following their local regulations. Use of an assent 
is not a substitute for parental permission. Parents/guardians must receive a full ICF to review 
and sign.  
If the ICF and Pediatric Assent Form, where applicable, is amended during the study, the 
Investigator must follow all applicable regulatory requirements pertaining to 
IRB/REB/IEC/HREC approval of the amended form. The clinical site must use the amended 
ICF/ Pediatric Assent Form for all new patients and repeat the consent/assent process with the 
amended form for any ongoing patients. 
An initial ICF (for adult patients or parent/guardian of child/adolescent patients) and Pediatric 
Assent Form (for child/adolescent patients, as applicable) will be provided to the Investigator to 
prepare the ICF and assent documents to be used at the PI’s site. The sample ICFs/Pediatric 
Assent Forms prepared by the Sponsor are provided in the Study Manual. 
10.1.4 
Investigator Reporting Requirements  
In accordance with applicable regulatory requirements, the Investigator is solely obligated to 
inform the IRB/REB/IEC/HREC of progress of the study and notify the IRB/REB/IEC/HREC of 
study closure. The Investigator must also provide the Sponsor with copies of all 
IRB/REB/IEC/HREC correspondence that relate to study approvals, updates, or changes. The 
Investigator is also responsible for forwarding to the IRB/REB/IEC/HREC reports of any SAEs 
from other studies conducted with the same investigational product that were provided by the 
Sponsor. 
The investigator will be responsible for reporting to the sponsor or designee significant issues 
related to participant safety, participant rights, or data integrity. 
10.2 
Data Management  
Data will be recorded at the site on source documents and reviewed by the Sponsor’s monitor 
during periodic visits, who will verify data recorded on the eCRFs within the Clinical Database 
Management System (CDMS) in accordance with source documents. All updates, corrections or 
changes made to study data must be appropriately tracked in an audit trail in the CDMS. The 
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eCRFs will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for. Additional instructions on eCRF completion are provided in the eCRF 
Completion Guidelines.  
All eCRFs must be reviewed and patient casebooks signed by the Investigator according to 
CDMS specifications. 
10.2.1 
Data Protection  
Participants will be assigned a unique identifier by the sponsor to protect the participant’s 
personal data. Any participant information, such as records, datasets or tissue samples that are 
transferred to the sponsor will contain the identifier only. Participant names or any information 
which would make the participant identifiable will not be transferred. 
The participant must be informed that the participant’s personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. This is done by the site personnel through the informed 
consent process. 
The participant must be informed through the informed consent by the site personnel that their 
medical records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
The sponsor has processes in place to ensure information security, data integrity, and data 
protection. These processes address management of data transfer, and prevention and 
management of unauthorized access, disclosure, dissemination, alteration or loss of information 
or personal data. These processes include appropriate contingency plan(s) for appropriate and 
timely response in the event of a data security breach. 
The transfer of personal data is subject to appropriate safeguards through contractual agreements 
and processes. The sponsor’s processes are compliant with local privacy laws and relevant 
legislations including the General Data Protection Regulation (GDPR). 
10.3 
Study Monitoring  
Prior to the start of the study, the Sponsor’s monitor or designee will contact the clinical site to 
discuss the protocol and data collection procedures and conduct applicable training of site 
personnel. The Sponsor and its designees will also periodically contact the clinical site during the 
conduct of the study (which will include on-site visits) in accordance with applicable regulations 
and GCP. During these contacts, the monitoring activities will include: 
 Checking and assessing the progress of the study 
 Reviewing study data collected to date for completeness and accuracy 
 Conducting source document verifications by reviewing each patient’s CRF against source 
documents 
 Identifying any issues and addressing resolutions 
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 Recording and reporting protocol deviations not previously reported to the Sponsor 
 Confirming that SAEs have been properly reported to the Sponsor and submitted to the 
IRB/REB/IEC/HREC if appropriate 
These activities will be done in order to verify that the data are authentic, accurate, and complete; 
that the safety and rights of the patient are being protected; and that the study is conducted in 
accordance with the currently approved protocol, GCP, and all applicable regulatory 
requirements. Additionally, to ensure compliance with GCP and all applicable regulatory 
requirements, the Sponsor or designee may conduct a quality assurance audit. 
10.4 
Termination  
Upon completion of the study, the following activities, when applicable, must be conducted by 
the study monitor and the Investigator: 
 Submission of all study data to the Sponsor 
 Completion of all data clarifications and/or resolutions 
 Reconciliation and final disposition of investigational product 
 Review of site study files for completeness 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely terminate this 
study for any reason. 
If the study is suspended or terminated for safety reasons, the Sponsor will promptly inform the 
Investigator, and will also inform the IRB/REB/IEC/HREC with the reasons for the action. In the 
event of prematurely termination, all study data must be submitted to the Sponsor. In addition, 
the clinical site must document final disposition of all unused investigational product in 
accordance with the Sponsor’s procedures. 
Communication of Suspended or Terminated Dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible. It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete 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 
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will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
10.5 
Records Retention  
Patient records, source documents, monitoring visit logs, investigational product inventory, 
regulatory documents, and other correspondence pertaining to the study must be maintained in 
the appropriate site study files. These records will be retained for the period required by the 
institution or site policy. Prior to transfer or destruction of these records, the Sponsor must be 
notified in writing. 
10.6 
Confidentiality of Information  
Patient names will remain confidential and will not be supplied to the Sponsor or its designee. 
The Investigator will maintain a personal patient identification list (patient and treatment 
numbers with the corresponding patient names) to enable records to be identified. 
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11 
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van Weering, D.H. and Bos, J.L. (1998) "Signal transduction by the receptor tyrosine kinase 
Ret." Recent Results Cancer Res. 154: 271-281.  
Wells, S. A., Jr., S. L. Asa, H. Dralle, R. Elisei, D. B. Evans, R. F. Gagel, N. Lee, A. Machens, J. 
F. Moley, F. Pacini, F. Raue, K. Frank-Raue, B. Robinson, M. S. Rosenthal, M. Santoro, M. 
Schlumberger, M. Shah, S. G. Waguespack and C. American Thyroid Association Guidelines 
Task Force on Medullary Thyroid (2015). "Revised American Thyroid Association guidelines 
for the management of medullary thyroid carcinoma." Thyroid 25(6): 567-610. 
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Wells, S. A., Jr., B. G. Robinson, R. F. Gagel, H. Dralle, J. A. Fagin, M. Santoro, E. Baudin, R. 
Elisei, B. Jarzab, J. R. Vasselli, J. Read, P. Langmuir, A. J. Ryan and M. J. Schlumberger (2012). 
"Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a 
randomized, double-blind phase III trial." J Clin Oncol 30(2): 134-141. 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated 
response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology 
Working Group. Journal of Clinical Oncology 2010 28:11, 1963-1972. 
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Appendix A 
Study Assessments  
Table 11-1 
Schedule of Assessments  
Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- Term 
Follow-Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 7 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Informed Consent/Pediatric Assent 
X 
K 
K 
K 
K 
K 
K 
Medical, surgical, and malignant history  
X 
K 
K 
K 
K 
K 
K 
Urine or serum pregnancy test (if 
applicable)* 
X 
X 
X 
X 
K 
K 
 
Tissue biopsy a 
X 
K 
K 
K 
X 
K 
K 
Physical examination and Karnofsky or 
Lansky b 
X 
Days 1, 8, 15 
Day 1 
Day 1v 
X 
X 
K 
Vital signs c 
X 
Days 1, 8, 15, 
pre-dose 
Day 1 pre-dose 
Day 1 
pre-dosev 
X 
X 
X 
 
 
 
 
 
 
 
12-lead ECG e 
X 
Day 1, 8 
Day 1 
Day 1v 
X 
X 
K 
Hematology f 
X 
Days 1, 8, 15 
Day 1 
Day 1v 
X 
X 
K 
Serum chemistries g 
X 
Days 1, 8, 15 
Day 1, Day 15 
(Cycles 2-4) 
Day 1 (Cycles 
5-12) 
Day 1v 
X 
[X] r 
K 
Urinalysis h 
X 
Day 1 
Day 1 
Day 1u,v 
X 
[X] r 
K 
Thyroid Hormone (TSH and T4 or free 
T4 per local standard) 
X 
 
Day 1 of odd 
cycles 
beginning with 
C3 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13v 
 
 
 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- Term 
Follow-Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 7 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Patients with MTC ONLY: Calcitonin, 
thyroglobulin, CEA 
X 
Day 1, 8, 15 
Day 1 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13v 
Day 1 
—  
Day 1 
Patients with MTC (or other cancer 
patients with Cushing’s disease): Serum 
cortisol, serum ACTH 
X 
Day 1 
Day 1 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13v 
—  
—  
—  
Growth plate evaluation i 
X 
 
q 6 months (if 
patent) 
q 6 months 
(if patent) 
q 6 months 
(if patent) 
q 6 months 
 (if patent) 
q 6 
months 
(if patent) 
Dental evaluation j 
X 
 
q 6 months (if 
no full set of 
permanent 
teeth) 
q 6 months 
(if no full set 
of permanent 
teeth) 
q 6 months (if 
no full set of 
permanent 
teeth) 
q 6 months 
(if no full 
set of 
permanent 
teeth) 
 q 6 
months 
(if no full 
set of 
permanen
t teeth) 
Pubertal maturation evaluation k 
X 
 
q 6 months until 
pubertal 
maturity  
q 6 months 
until pubertal 
maturity  
q 6 months 
until pubertal 
maturity  
q 6 months 
until 
pubertal 
maturity  
q 6 
months 
until 
pubertal 
maturity 
Menarche (female patients only) 
Collect date 
of menarche 
as medical 
history, if 
applicable 
Collect date of menarche if occurs during the course of the study. 
Disease assessment l 
X 
—  
Day 1 (±7 days) 
Cycle 2 
(optional) and 
odd cycles 
Day 1 
(±7 days) 
every third 
[X] s 
—  
X t 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- Term 
Follow-Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 7 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
cycle starting 
at Cycle 14 
Telephone follow-up 
K 
Day 22 
K 
K 
K 
K 
K 
Pain 
  
X 
Day 1 pre-dose 
Day 1 pre-dose 
Day 1 
pre-dose v 
X 
X 
K 
Whole blood for
  
 
Day 1, 15 
Day 1 odd 
cycles to 
coincide with 
disease 
assessment 
Every 12 
cycles 
(approx. 
annually) 
starting at 
Cycle 14 to 
coincide with 
disease 
assessment 
X 
K 
K 
Whole blood for genomic 
 
 
X 
K 
K 
K 
K 
K 
K 
Selpercatinib administration 
K 
 
 
 
A 
K 
K 
Patient dosing diaryw 
K 
 
 
 
 
K 
K 
Patient palatability questionnairex 
(
) 
K 
K 
As directed during alternate 
formulation assessment 
K 
K 
K 
Patient acceptability questionnairex 
(
) 
K 
K 
As directed during alternate 
formulation assessment 
K 
K 
K 
Adverse events p 
 
 
 
 
 
 
K 
Concomitant medications 
 
 
 
 
 
 
K 
Abbreviations for Table 11-1 and Footnotes: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUC0-24 = area under 
the curve time 0 to 24 hours; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CEA = carcinoembryonic antigen;
 
CNS = central nervous system; CSF = cerebrospinal fluid; CT = computerized tomography; DLTs = dose-limiting toxicities; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; EOT = end of treatment; h = hour; 
 LDH = lactate dehydrogenase; LTFU = long-term 
follow-up; MIBG = meta-iodobenzylguanidine; MRI = magnetic resonance imaging; PedsQL-Core = Pediatrics Quality of Life - Core Module; PET = positron 
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emission tomography; PK = pharmacokinetics; RBC = red blood cell; UPC = urine protein: creatinine ratio; WBC = white blood cell; SAE = serious adverse 
event. 
Footnotes for Schedule of Assessments: 
a 
Availability of tissue biopsy is required following the most recent progression. If tissue meeting this criterion is not available, a tissue sample obtained prior 
to most recent progression is acceptable. If neither of these samples are available for submission, then a fresh tumor biopsy is requested if it can be safely 
obtained. If no tissue is available the patient may still be eligible for enrollment following conversation with the Sponsor. Tissue biopsy collected at the EOT 
visit is optional. Additional biopsies may be requested on a case-by-case basis in patients re-starting study drug following a "drug holiday" and disease 
recurrence. 
b Physical examination includes review of systems: breast/chest, extremities, genitourinary, head/ears/eyes/nose/throat, lymph nodes, musculoskeletal, 
pulmonary, and skin, thorough neurologic assessment, body weight, and height during Screening. Symptom-directed physical and neurological 
examinations, including measurement of weight and height, will be performed as part of vital signs. Karnofsky should be assessed for those 16 years old or 
older, or Lansky should be assessed for those younger than 16 years. 
c 
Vital signs on Day 1 should be predose. Vital signs on Day 8 should be predose and at 
 
 Vital signs on Day 15 should be Pre-dose. Vital signs in Cycles 2 and beyond should be predose. During LTFU, only height and weight are 
to be recorded. 
d 
Blood for PK will be collected as outlined in Appendix B.  
e 
ECGs should be resting 12-lead ECG performed during Screening and during Cycle 1 at the following time points: pre-dose (±10 minutes, up to 4 hours pre-
dose), C1D1 pre-dose and 2 and 4 hours post-dose (±10 minutes), C1D8 pre-dose and 2 and 4 hours post-dose (±10 minutes. In addition, ECGs should be 
obtained pre-dose and 2 hours post-dose (±10 minutes) on C2D1 and pre-dose Cycles 3-EOT (during cycles when ECG is required). Additional ECGs may 
be performed if clinically indicated. For intra-patient dose escalation, ECGs should be performed pre-dose (up to 4 hours pre-dose) on Day 1 and 8 of the 
;,?409?N>90B/:>0 at pre-dose, 2 and 4 hours post-dose (±10 minutes). 
f 
Hematology will include Hb, hematocrit, RBC count, WBC count with differential (neutrophils [absolute count and percent] and lymphocytes, monocytes, 
eosinophils, basophils [percent]), and platelet count. 
g Serum chemistries (non-fasting) will include alkaline phosphatase, albumin, ALT, AST, BUN/urea, creatinine, glucose, LDH, total and direct bilirubin, total 
protein, phosphorus, sodium, potassium, chloride, calcium, magnesium and bicarbonate.  
h If performed by dipstick, abnormal results should be followed by a complete urinalysis, including color, specific gravity, pH, glucose, bilirubin, ketones, 
occult blood, protein, leukocytes, nitrites and urobilinogen. If +2 protein is observed; a 24-hour urine collection or UPC ratio will be taken in order to 
quantify proteinuria. 
i 
Patients who have not yet obtained full adult height will undergo imaging (anterior posterior and lateral views) of the right knee at baseline and every 
6 months during participation in the study while the growth plate remains patent. If it is unclear that a patient has obtained full adult height, a pre-treatment 
tibial imaging (anterior posterior and lateral views) of the right knee should be obtained. If the growth plate remains patent, the patient will have imaging 
(anterior posterior and lateral views) performed every 6 months during participation in the study until the growth plate is no longer patent. 
j 
Patients aged 5 and older, without a full set of permanent teeth, will undergo a dental evaluation at baseline and every 6 months during participation in the 
study. Patients who enroll prior to their 5th birthday will start dental assessments at the cycle visit closest to their 5th birthday. Changes in tooth development 
after baseline will be captured as an AE. Patients who enroll with a full set of permanent teeth will not need to undergo dental evaluations. 
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k Patients aged 7 and older will be assessed for pubertal maturation every 6 months during participation in the study based on the Tanner Scale. Patients who 
enroll prior to their 7th birthday will start assessment at the cycle visit closest to their 7th birthday. Delays to pubertal maturity (according to the Tanner Scale) 
after baseline will be captured as an AE. Patients who completed puberty according to the Tanner Scale at enrollment will not undergo evaluation. 
l 
Tumor will be assessed by standard of care imaging modalities (CT and/or PET) or MRI of chest, abdomen, and pelvis, any other areas with suspected 
disease involvement. Patients enrolled with a history of CNS metastases should additionally have a head CT or MRI scan performed at each tumor 
assessment. Patients with locally advanced infantile fibrosarcoma should have an MRI or CT of the site of disease and a CT or X-Ray of the chest, plus any 
other areas of disease involvement. Patients with neuroblastoma will be followed with MIBG scans, anatomic imaging, and bilateral bone marrow aspirates 
and biopsies. 
m 
 will be collected
. In patients 3 year of age or older, pain will be assessed by the Wong-Baker Faces Scale. 
 
. 
n Whole blood for 
 should be obtained within 7 days following radiologic disease assessment, except for baseline/Screening when it may be 
obtained any time prior to treatment on C1D1. Whole blood for 
 should be obtained at the EOT visit even if radiologic disease assessment is 
not performed. Patients less than 5 years of age will have 1×10 mL Streck tube drawn. Patients older than 5 years of age will have 2×10 mL Streck tube 
drawn. Sites may draw fewer tubes based on local institutional policy for maximal blood draws in patients. 
o Whole blood for 
 should be obtained any time during Screening prior to beginning treatment. Patients greater than 5 years of age will have one 
PAXGene tube (8.5 mL) drawn. Patients less than 5 years of age will not have any PAXGene tube drawn. Sites may draw fewer tubes based on local 
institutional policy for maximal blood draws in patients. 
p 
Adverse event (AE) reporting should include the reporting of all AEs occurring for 28 days after the last dose of study drug regardless of cause of 
discontinuation. The reporting of SAEs should occur, according to SAE reporting criteria, until the patient discontinues the study, or the study is closed. 
Refer to Section 9 Adverse Events. 
q 
During Cycle 1, observations will be performed prior to selpercatinib dosing on that day. Unless otherwise indicated, C1D1 evaluations may be performed 
either on Day -1 or predose on C1D1; if an evaluation is performed on Day -1, it need not be repeated on C1D1. Routine clinic visits performed within 
± 2 days of the nominal visit day will not be considered protocol deviations.  
r 
Repeat the assessment only if the EOT result showed treatment-emergent abnormalities. 
s 
Assessment should be performed if no disease assessment was performed in last 2 cycles. 
t 
Date of progression, as assessed by treating Investigator and survival status (may be conducted by phone). Refer to Section 7.19. Patients following LTFU 
procedures during Drug Holiday (Section 5.2.5) should also have standard of care imaging procedures every 12 weeks. 
u Perform only as clinically indicated. 
v Perform at least every 12 weeks after 2 years on treatment. Align with disease assessment visits. 
w Dosing diary will be required during Cycles 1-3 and during the cycle of alternative formulation (
) administration.  
x 
Questionnaires will be administered within approximately 30 minutes of dosing after the first dose of the 
 formulation and again after approximately 2 
to 4 weeks of alternative formulation (
) administration and returned at the following clinic visit. 
* Perform more frequently if required by local regulations. 
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Schedule of On-Study Treatment Activities 
For all Cycles: 
The changes to procedures described below are temporary measures intended to be used only 
during specific time periods as directed by the Sponsor in partnership with the Investigator (see 
Appendix L). 
If there is a concern during a remote visit that suggests on-site visit is necessary, the participant 
should have an on-site follow-up visit as soon as possible. 
The following should occur at the investigative site:  
 All visits and procedures in Cycle 1 
 
 
 ECG at C2D1 and C3D1  
 Serum chemistries at C2D1 and C3D1 
 Growth plate evaluation 
 Dental evaluation  
 Pubertal maturation evaluation 
 Disease assessment, and 
 Whole blood for 
 
In exceptional circumstances, procedures not listed above may be conducted remotely (see 
Appendix L). Remote visits should include a virtual visit with the study Investigator (including 
video) and mobile healthcare in accordance with local regulations if written approval is provided 
by the Sponsor and according to the preferences of the participant and study site. 
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Appendix C 
Karnofsky and Lansky Performance Status Scales  
Table 11-3 
Karnofsky Performance Score (≥ 16 years old)  
Score 
Karnofsky Description 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
(Karnofsky and Burchenal 1949) 
 
Table 11-4 
Lansky Performance Score (< 16 years old)  
Score 
Lansky Description 
100 
Fully active, normal 
90 
Minor restrictions in strenuous physical activity 
80 
Active, but tired more quickly 
70 
Greater restriction of plan and less time spent in play activity 
60 
Up and around, but active play minimal; keeps busy by being involved in quieter activities 
50 
Lying around much of the day, but gets dressed; no active playing, participates in all quiet play and 
activities 
40 
Mainly in bed; participates in quiet activities 
30 
Bed bound; needing assistance even for quiet play 
20 
Sleeping often; play entirely limited to very passive activities 
10 
Doesn't play; doesn't get out of bed 
0 
Unresponsive 
(Lansky, List et al. 1987) 
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Appendix D 
Inhibitors and Inducers of CYP3A4  
Table 11-5 
Inhibitors of CYP3A4  
Strong Inhibitors a 
Moderate Inhibitors b 
Boceprevir 
Amprenavir 
Clarithromycin 
Aprepitant 
Conivaptan 
Atazanavir 
grapefruit / grapefruit juice 
Ciprofloxacin 
Indinavir 
Darunavir 
Itraconazole 
Diltiazem 
Ketoconazole 
Erythromycin 
Lopinavir 
Fluconazole 
Mibefradil 
Fosamprenavir 
Nefazodone 
Imatinib 
Nelfinavir 
Verapamil 
Posaconazole 
 
Ritonavir 
 
Saquinavir 
 
Telaprevir 
 
Telithromycin 
 
Voriconazole 
 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A = cytochrome P450 3A enzyme.  
a 
Increases the AUC of the substrate by ≥5-fold. 
b 
Increases the AUC of the substrate by 2- to 5-fold. 
 
 
Table 11-6 
Inducers of CYP3A  
Strong Inducers a  
Moderate Inducers b 
Avasimibe 
Bosentan 
Carbamazepine 
Efavirenz 
Phenytoin 
Etravirine 
Rifampin 
Modafinil 
St John’s wort 
Nafcillin 
Abbreviations: AUC = area under the concentration versus time curve; CYP3A = cytochrome P450 3A enzyme.  
a 
Decreases the AUC of the substrate by ≥ 80%. 
b 
decreases the AUC of the substrate by 50–80%. 
 
Note: The above lists are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm 
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Appendix E 
Tumor Measurements and Assessment of Disease Response: RECIST, 
Version 1.1  
Measurable versus Non-Measurable 
 Measurable: lesions that could accurately be measured in at least one dimension as 
 10 mm by CT scan or caliper measurement by clinical examination or  20 mm by 
chest X-ray; the longest diameter is to be recorded. 
 Non-Measurable: all other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥10 to < 15 mm short axis) and truly non-measurable 
lesions. 
Target versus Non-Target 
 Target: all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and 
measured and recorded at Screening. Target lesions are to be selected on the basis of their 
size (i.e., those with the longest diameter) and suitability for accurate repeated 
measurement. The sum of the longest diameter for all target lesions is to be calculated 
and recorded in the CRF as the baseline sum longest diameter. 
 Non-Target: all other lesions not classified as target lesions (or sites of disease) are to be 
identified as non-target lesions and are to be recorded in the CRF. Measurement of non-
target lesions is not required. 
Disease response in target and non-target lesions will be assessed by the Investigator using 
RECIST, version 1.1, according to the categories and criteria described in Table 11-7. The best 
overall response for each patient will be reported as the best response documented over the 
sequence of objective statuses recorded using the categories and criteria in Table 11-8. 
Table 11-7 
Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines 
for Tumor Response  
Disease Response Criteria for Target and Nontarget Lesions 
Evaluation of Target lesions 
Complete Response (CR): 
Disappearance of all target lesions. 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions. 
Evaluation of Nontarget lesions 
Complete Response (CR): 
Disappearance of all nontarget lesions and normalization of tumor 
marker level. 
Incomplete Response/ Stable Disease 
Persistence of one or more nontarget lesion(s) or/and maintenance 
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(SD): 
of tumor marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
Abbreviation: LD = longest diameter. 
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. Available at: 
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
Table 11-8 
Overall Response Criteria  
Patients with Target and Nontarget Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR / Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Patients with Nontarget Lesions Only 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / 
Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR= partial response; SD 
= stable disease. 
Source: (Eisenhauer, Therasse et al. 2009). Available at : New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. Also available at: 
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
 
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Appendix F 
Response Assessment in Neuro-Oncology (RANO) Criteria for Primary 
CNS Malignancies  
The RANO criteria (Wen 2010: https://ascopubs.org/doi/pdf/10.1200/jco.2009.26.3541) were 
developed to evaluate efficacy of investigational agents in glioblastoma clinical trials and have 
been more broadly utilized for lower grade primary CNS malignancies. These criteria were 
developed in part to address issues faced when assessing some lesions based on MacDonald 
criteria, particularly lesions with central necrosis and with a T2 component. 
Table 11-9 
RANO Response Criteria Incorporating MRI and Clinical Factor  
RESPONSE CATEGORY 
CRITERIA 
Complete Response 
Disappearance of all measurable and non-measurable enhancing 
disease 
Stable or improved non-enhancing FLAIR/T2 lesions 
No new lesions 
Clinically stable or improved with no reliance on corticosteroids 
(except for physiological replacement) 
Partial Response 
≥50% decrease from baseline of all measurable enhancing lesions 
No progression of non-measurable disease 
Stable or improved non-enhancing FLAIR/T2 lesions 
No new lesions 
Clinically stable or improved, with stable or reduced 
corticosteroids compared to baseline 
Progressive Disease 
≥25% increase from baseline in enhancing lesions despite stable or 
increasing steroid dose 
Significant increase in non-enhancing FLAIR/T2 lesions not 
attributable to other non-tumor causes 
Any new lesions 
Clinical deterioration no attributable to other non-tumor causes and 
not due to steroid decrease 
Stable Disease 
Does not meet other criteria for response or progression 
Stable non-enhancing FLAIR/T2 lesions 
Clinically stable with stable or reduced corticosteroids compared to 
baseline 
Abbreviations: FLAIR/T2 = T2-weighted fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; 
RANO = Response Assessment in Neuro-Oncology. 
 
A measurable lesion is evaluated by contrast-enhancing MRI and:  
 Has clearly defined margins 
 Is visible on two or more axial slices, preferably < 5 mm thick 
 Is at least 10 mm in size if slice thickness is < 5 mm (or 2 × slice thickness if > 5 mm) 
 Does not measure a cystic cavity 
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Non-measurable lesions are those that do not fit the criteria above, and specifically lesions that 
are cystic, necrotic, or include a surgical cavity should not be considered measurable. 
Measurements are calculated by summing the products of perpendicular diameters of all 
measurable enhancing lesions. 
If there are multiple contrast-enhancing lesions, a minimum of the two largest lesions should be 
measured. However, emphasis should be placed on selecting lesions that allow reproducible 
repeated measurements. For patients who have multiple lesions for which only one or two are 
increasing in size, the enlarging lesions should be considered the target lesions for evaluation of 
response. 
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Appendix G 
Proton Pump Inhibitors (PPIs)  
Concomitant use of proton pump inhibitors (PPIs) should be avoided. For patients unable to 
discontinue use of PPIs, selpercatinib must be administered with a meal. 
The information in this table is provided as guidance to investigators and is not considered 
exhaustive. 
Table 11-10 Examples of Proton Pump Inhibitors (PPIs)  
Omeprazole 
Esomeprazole 
Lansoprazole 
Pantoprazole 
Rabeprazole 
Dexlansoprazole 
 
 
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Appendix I 
Examples of Multikinase Inhibitors with Anti-RET Activity  
Table 11-12 Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity  
Multikinase Inhibitors 
cabozantinib 
vandetanib 
lenvatinib 
alectinib 
ponatinib 
regorafenib 
sunitinib 
sorafenib 
motesanib 
RXDX-105 
sitravatinib (MGCD516) 
 
 
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Appendix J 
Examples of RET-Activating Mutations  
Table 11-13 Examples of RET-Activating Mutations  
Exon 
RET mutation 
5 
V292M, G321R 
8 
A510V, E511K, C515S, C531R, G533C 
10 
V591I, R600Q, K603E/Q, Y606C, C609F/G/R/S/W/Y, C611F/G/R/S/W/Y, 
C618F/G/R/S/W/Y, C620F/G/R/S/W/Y 
11 
C630R/Y, D631Y, E632K, C634F/G/R/S/W/Y, S649L, K666E/M 
13 
E768D, R770Q, N777S, V778I, Q781R, L790F, Y791F/N 
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. 
(Dvorakova, Vaclavikova et al. 2008, Agrawal, Jiao et al. 2013, Krampitz and Norton 2014, Ji, Oh et al. 2015, 
Wells, Asa et al. 2015, Heilmann, Subbiah et al. 2016, Romei, Casella et al. 2016, Kato, Subbiah et al. 2017). 
 
 
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Appendix K 
Continued Access  
Table 11-14 Schedule of Continued Access Procedures  
Continued Access Schedule of Activities 
 
Study 
Treatment 
Follow-Upa 
 
Visitb 
 
 
 
Procedure 
 
 
Instructions 
AE Collection 
X 
X 
Grading via CTCAE, Version 5.0. As part of AE 
collection, monitor vital signs and perform standard 
laboratory tests at the same frequency as during the study 
treatment period. All laboratory tests during the continued 
access period will be performed in the local laboratories 
only. Tumor evaluation will be performed per local 
standards. 
Administer 
selpercatinib 
X 
 
Administer according to Section 5.2 
Long-term safety for 
select patients 
X 
X 
Height, weight, and Tanner staging (until patient reaches 
sexual maturity) every 12 weeks and date of menarche 
(for females, if occurs) for patients 12-17 and up to 
5 years from treatment start date. 
Abbreviations: AE = adverse event; CTCAE = common terminology criteria for adverse events (NCI 2018); NCI = 
National Cancer Institute.  
 
a Continued-access follow-up begins when the participant and the investigator agree that the participant will no 
longer continue treatment in the continued access period and lasts approximately 30 days following the last dose 
of study drug. In all cases, no follow-up procedures will be performed for a participant who withdraws informed 
consent unless he or she has explicitly provided permission and consent. 
b Patient visits during continued access should continue at a minimum of every 84 ± 7 days for IP dispensing.  
Where allowed by local regulations, patients may alternate visits between the study site and remote visits with 
sponsor approval.  Additional visits may be performed as clinically indicated. 
 
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Appendix L 
Provisions for Changes in Study Conduct during Exceptional 
Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the Sponsor in partnership with the 
Investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
Investigators or participants, or both, to attend on-site visits or to conduct planned study 
procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the Sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the Sponsor grants written approval for changes in study conduct, the Sponsor will also 
provide additional written guidance, if needed. 
In exceptional circumstances, the flexibility measures outlined in the Schedule of Assessments 
(Table 11-1) and this appendix may be considered for Cycles 2 and higher visits after 
consultation with and prior approval by the Sponsor. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliant with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
 
 
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Informed consent 
Additional consent/assent from the participant will be obtained for the below items, as required 
by Ethical Review Boards and local regulations. Minor participants must be re-consented if they 
reach the age of majority during the course of study, in order to continue participating for 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period  
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in how study conduct will be performed (e.g., virtual vs at the 
investigative site) will not be considered protocol deviations. Every effort should be made for the 
participant to return to on-site visits as soon as reasonably possible, while ensuring the safety of 
the participant and investigational site staff.  
Remote visits 
In source documents and the CRF, the study site should capture the method of visit (e.g., virtual, 
in-person), with a specific explanation for any data missing because of missed in-person site 
visits. Remote visits may include a combination of telemedicine, local physician assessments, or 
mobile healthcare as appropriate, according to the investigator’s discretion and written approval 
by the Sponsor.  
Assessments may be completed by a combination of video conference (telemedicine), local 
physician assessments, or mobile healthcare for Cycles 2 and higher visits. 
Applicable assessments include physical examination and Karnofsky or Lansky, vital signs, 
patient PROs, and patient diaries. Other assessments, such as applicable blood draws for local 
labs, urinalysis, pregnancy tests, and 12-lead ECG (only for Cycles 7 and higher) may be 
completed remotely according to local regulations at a local clinic without video conference at 
the investigator’s discretion. If there is a concern during the remote visit, the participant should 
have an on-site follow-up visit as soon as possible.  
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. 
 
Mobile healthcare: Healthcare visits may be performed at locations other than the study site (for 
example, participant’s home or at a local clinic) when participants cannot travel to the site due to 
an exceptional circumstance. Such visits will be performed by a mobile healthcare provider 
trained on the study. 
 
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Other alternative locations: Other procedures that may be done at an alternate location in 
exceptional circumstances 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the Sponsor to determine appropriate actions. These actions may 
include 
 asking the participant, parent, or guardian to go to the site and receive study supplies 
from site staff without completion of a full study visit  
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, or 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator or Sponsor, or both, should ensure oversight of 
the shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
If the screening period lasts for more than 35 days due to exceptional circumstances, the 
participant must be discontinued because of screening interruption. This is documented as a 
screen fail in the CRF. The participant can reconsent and be rescreened as a new participant with 
a new participant number. 
Any screening procedures that fall outside of the required windows per the JZJJ Protocol 
Schedule of Screening Activities (Protocol Section 7.2) must be repeated. 
 
 
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Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities. To maximize the possibility that these visits 
can be conducted as on-site visits, the windows for visits may be adjusted, upon further guidance 
from the Sponsor. This minimizes missing data and preserves the intended conduct of the study. 
 
This table describes the allowed adjustments to visit windows. 
 
Visit Number 
Tolerance 
Cycle 1 
through Cycle 
6, Safety 
Follow-Up, 
and Long-
Term 
Follow-Up 
No adjustment from windows described in Table 11-1. 
Cycles 7 and 
higher 
Window of timing may be extended to ±7 days. 
 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
 
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Appendix M 
Country-specific Requirements  
This section describes protocol changes applicable for participants in study sites within 
Germany, France, UK, Canada, EU, and Japan. 
The revised text in the following sections show the changes applicable for study participants 
within Germany, France, UK, Canada, EU, and Japan. Additions are identified by underline. 
Deletions are identified by strikethrough format.
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EU: 
Section 3.3 General Treatment Procedures 
Patients with locally advanced disease with RECIST v1.1 confirmed response of CR/PR may 
interrupt treatment in a “wait and see” approach 1 year from confirmation of response after 
discussion with the Sponsor’s Medical Monitor. These patients may undergo an optional tissue 
biopsy and/or additional imaging (e.g., PET/CT) at the time of consideration of treatment 
discontinuation. The purpose of these additional studies is to provide additional 
pathologic/radiographic information about disease status (e.g., presence or absence of tumor). 
Following treatment discontinuation, these patients will continue to be followed with radiologic 
assessment every 3 months for 2 years, and then every 6 months thereafter, using the same 
imaging modality(ies) as during treatment. An optional radiographic disease assessment may be 
performed 1 month after the interruption of selpercatinib at the discretion of the Investigator. If a 
patient in this “wait and see” period is noted to have evidence of radiographic PD, the patient 
may re-start selpercatinib. At the time of selpercatinib re-initiation, the patient will start 
assessments per protocol as delineated for patients on active treatment. Patients who re-initiate 
selpercatinib treatment are permitted to have their selpercatinib treatment held again. 
Patients who undergo surgical resection for local control may continue to receive selpercatinib 
after surgical recovery and discussion between the Investigator and the Sponsor. These patients 
should have selpercatinib held for 7 days prior to surgery and resumed 14 days after surgery. If 
the resection surgery results in negative margins and study drug is interrupted, disease 
assessments, as described in Section 7.13, should be performed every 3 months following the last 
dose of study drug. These patients are permitted to restart study drug if they experience PD after 
discussion with the Sponsor’s medical monitor. 
All treated patients will undergo a safety follow-up visit at 28 days (+7 days) after the last dose 
of study treatment and long-term follow-up visits at 3-month intervals (± 1 month) and until the 
study is officially closed. 
Section 4.1 Inclusion Criteria 
11. Adequate hepatic / pancreatic function, defined as: 
a.) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5  the 
upper limit of normal (ULN) or ≤5  ULN with documented liver involvement (such 
as liver metastasis or a primary biliary tumor) 
b.) Total bilirubin ≤1.5  ULN or ≤3  ULN with documented liver involvement 
(patients with Gilbert’s Disease may be enrolled with prior Sponsor approval), and 
c.) Pancreatic lipase ≤1.5  ULN (or Sponsor’s approval). 
Section 7.11.3 Serum Chemistries  
Serum chemistries (non-fasting) should be assessed in accordance with the Schedule of 
Assessments (Table 11-1) and should include assessment of the following: alkaline phosphatase, 
albumin, ALT, AST, BUN or urea, creatinine, glucose, LDH, total and direct bilirubin, 
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pancreatic lipase, total protein, phosphorus, sodium, potassium, chloride, calcium, magnesium, 
and bicarbonate. 
Appendix A Study Assessments 
g 
Serum chemistries (non-fasting) will include alkaline phosphatase, albumin, ALT, AST, 
BUN/urea, creatinine, glucose, LDH, total and direct bilirubin, pancreatic lipase, total protein, 
phosphorus, sodium, potassium, chloride, calcium, magnesium and bicarbonate. 
Germany: 
Implementation of this Appendix L 
The changes to procedures described in this appendix Appendix L are temporary measures 
intended to be used only during specific time periods as directed by the Sponsor in partnership 
with the Investigator. In Germany, Appendix L is only applicable for exceptional circumstances 
related to COVID-19. 
Spain: 
Remote visits 
Where allowed by local regulations, patients may alternate visits between the study site and 
remote visits with sponsor approval.
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France: 
Section 5.3.4.7 Substrates of BCRP and P-gp 
Selpercatinib is an inhibitor of BCRP and P-gp. Substrates of BCRP and P-gp with narrow 
therapeutic index should be used with caution. 
Table 11-1 Schedule of Assessments 
e ECGs should be resting 12-lead ECG performed during Screening (in triplicate) and during 
Cycle 1 at the following time points: pre-dose (triplicate, ±10 minutes, up to 4 hours pre-dose), 
C1D1 pre-dose and at 2 and 4 hours post-dose, (triplicate, ±10 minutes) and on C1D8 pre-dose 
and at 2 and 4 hours post-dose, (triplicate, ±10 minutes). In addition, ECGs should be obtained 
pre-dose and 2 hours post-dose (±10 minutes) on C2D1 and pre-dose Cycles 3-EOT. In addition, 
triplicate ECGs should be obtained 2 hours (± 10 minutes) post selpercatinib dosing on C2D1, 
C3D1, C4D1, C5D1, and C6D1. Thereafter, ECGs should be obtained (in triplicate) every 12 
weeks at 2 hours (± 10 minutes) post selpercatinib dosing. Additional ECGs may be performed if 
clinically indicated. If 2 of the 3 ECGs demonstrate QTc 481-500 msec, perform additional ECG 
(in triplicate) at 4 hours (± 10 minutes) post dosing. If 2 of the 3 ECGs demonstrate QTc > 500 
msec, repeat the ECG (triplicate) and manually review to confirm accuracy. If QTc > 500 msec 
is confirmed on 2/3 ECGs, hold selpercatinib and assess for alternative causes (concomitant 
medications, electrolyte abnormalities). Selpercatinib may be resumed at one reduced dose level 
when QTc has returned to baseline value, and with continued ECG monitoring as noted in the 
assessment schedule. Additional ECGs may be performed if clinically indicated. For intra-patient 
dose escalation, triplicate ECGs should be performed pre-dose (up to 4 hours pre-dose) and at 2 
hours post-selpercatinib-dose (±10 minutes) on Day 1 and 8 of the patient’s new dose, and at 
pre-dose, 2 and 4 hours post-selpercatinib-dose (triplicate, ±10 minutes) on Day 8 of the patient’s 
new dose. For patients ≤ 15 years old, Bazett’s Formula will be utilized to determine QTc. For 
patients > 15 years old, either method, Fridericia or Bazett’s Formula may be applied. 
Remote visits 
Where allowed by local regulations, patients may alternate visits between the study site and 
remote visits with sponsor approval.
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UK: 
This section describes protocol changes applicable for participants in study sites in UK. 
This table describes the changes and provides a rationale for the changes 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Dose limiting toxicity 
definition updated. 
Updated Inclusion Criterion 
14 and exclusion criterion 6 
Correction 
Section 3.1.1.1. Dose-
Limiting Toxicity Definition 
Dose limiting toxicity 
definition updated. 
Correction 
Section 4.1. Inclusion Criteria Contraception guidance in 
criterion 14 updated  
Per country-specific 
amendment 
Section 4.2. Exclusion 
Criteria 
Criterion number 6 updated 
Clarification 
Section 5.3.2. Prior and 
Concomitant Medications 
Information about 
selpercatinib substrate for 
CYP3A4 removed 
Per country-specific 
amendment 
Section 5.4. Duration of 
Treatment 
Treatment duration with 
selpercatinib modified 
Clarification 
Section 7.1. Informed 
Consent/Pediatric Assent 
Information about fertility 
preservation for patients and 
phototoxicity due to 
selpercatinib added 
Per country-specific 
amendment 
Study Assessments 
Section number for Adverse 
events has been updated 
Specified in the last footnote 
that the screening pregnancy 
test must be a serum sample 
For clarification 
 
Per country-specific 
amendment 
 
 
 
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SECTION PROTOCOL SYNOPSIS 
STUDY DESIGN: 
Dose-Limiting Toxicity Definition 
 Grade 3 uncomplicated febrile neutropenia lasting >48 hours is will not be considered a 
DLT 
ELIGIBILITY CRITERIA: 
Inclusion Criteria 
14. Willingness of male and female patients with reproductive potential to utilize double 
effective birth control methods, defined as one used by the patient and another by his/her partner, 
for the duration of treatment and for 3 1 month following study completion. 
For mMale patients with a non-pregnant female partner of child-bearing potential or female 
patients of child-bearing potential with a male partner and woman of child-bearing potential, one 
of the following highly effective birth control methods (with a failure rate of less than 1% per 
year when used consistently and correctly) are recommended must agree to use 
contraception/barrier as detailed below: 
 Agree to use a male condom (if not vasectomized) AND 
 Agree to use of an additional highly effective birth control method with a failure rate 
<1% per year (such as combination oral contraceptives, implanted contraceptives, or 
intrauterine device, as listed below) 
Highly effective birth control methods include: 
a) Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally 
b) Progestin-only hormonal contraception associated with inhibition of ovulation given 
orally, by injection, or by implant 
c) Intrauterine device (IUD) 
d) Intrauterine hormone-releasing system (IUS) 
e) Bilateral tubal occlusion 
f) Vasectomized partner 
g) Sexual abstinence: considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of 
the study and to the usual lifestyle of the patient. 
According to CTFG guidelines, the definition to of a female of child-bearing potential is as 
follows: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
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 
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to confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Exclusion Criteria 
6.Uncontrolled hypotension or hypertension ≥ >140/90 mm Hg Grade 3 CTCAE (v5.0). 
Section 3.1.1.3 Dose-Limiting Toxicity Definition 
 Grade 3 uncomplicated febrile neutropenia lasting >48 hours is will not be considered a 
DLT. 
SECTION 4. SELECTION OF STUDY POPULATION 
Section 4.1 Inclusion Criteria 
14. Willingness of male and female patients with reproductive potential to utilize double 
effective birth control methods, defined as one used by the patient and another by his/her partner, 
for the duration of treatment and for 3 1 months following study completion. 
For mMale patients with a non-pregnant female partner of child-bearing potential, or female 
patients of child-bearing potential with a male partner and woman of child-bearing potential, one 
of the following highly effective birth control methods (with a failure rate of less than 1% per 
year when used consistently and correctly) are recommended must agree to use 
contraception/barrier as detailed below: 
 Agree to use a male condom (if not vasectomized) AND 
 Agree to use of an additional highly effective birth control method with a failure rate 
<1% per year (such as combination oral contraceptives, implanted contraceptives, or 
intrauterine device, as listed below) 
Highly effective birth control methods include: 
a) Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally 
b) Progestin-only hormonal contraception associated with inhibition of ovulation given 
orally, by injection, or by implant 
c) Intrauterine device (IUD) 
d) Intrauterine hormone-releasing system (IUS) 
e) Bilateral tubal occlusion 
f) Vasectomized partner 
g) Sexual abstinence: considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of 
the study and to the usual lifestyle of the patient. 
 
According to CTFG guidelines, the definition to of a female of child-bearing potential is as 
follows: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
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menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
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 post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Birth control methods unacceptable for this clinical trial are: 
a) Periodic abstinence (calendar, sympto-thermal, or post-ovulation methods) 
b) Withdrawal (coitus interruptus) 
c) Spermicide only 
d) Lactational amenorrhea method 
Section 4.2 Exclusion Criteria 
6. Uncontrolled hypotension or hypertension ≥ >140/90 mm Hg. Grade 3 CTCAE (v5.0). 
Section 5.3 Prior and Concomitant Medications 
Section 5.3.2 Allowed Concomitant Medications 
Standard supportive medications may be used in accordance with institutional guidelines and 
Investigator discretion. These may include hematopoietic growth factors to treat neutropenia or 
thrombocytopenia in accordance with American Society for Clinical Oncology (ASCO) and/or 
European Society for Medical Oncology guidelines, transfusions, anti-emetics and anti-
diarrheals, and glucocorticoids (up to 10 mg dexamethasone or 50 mg of prednisone or 
equivalent), including short courses to treat asthma, chronic obstructive pulmonary disease 
(COPD), or other systemic, chronic diseases that are normally treated with short courses of 
glucocorticoids. As selpercatinib is a substrate of CYP3A4, patients should avoid inhibitors or 
inducers of CYP3A4 if possible as they could alter the drug’s PK. Continuation of standard of 
care or supportive care medications that the patient has been on for the previous 28 days are 
allowed. 
Patients receiving selpercatinib should avoid concomitant use of CYP2C8-sensitive substrates. If 
coadministration of a CYP2C8-sensitive substrate cannot be avoided, monitor patients for 
increased adverse reactions of these drugs. 
Coadministration 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. If coadministration of a sensitive CYP3A4 substrate 
cannot be avoided, follow recommendations for modified dosing of these substrates in their 
approved product labeling and monitor for increased adverse reactions of these drugs.   
Section 5.4 Duration of Treatment 
It is anticipated that a patient on this study will receive treatment with open-label selpercatinib 
until the patient is able to obtain commercially available selpercatinib in their respective country, 
the patient does not meet criteria requiring discontinuation of treatment (refer to Section 6.1 
Removal of Patients from Therapy or Assessment), and the patient’s participation in the study 
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has not ended. Upon commercial availability in each patient’s respective country, there may be 
additional options for the patient to continue to receive selpercatinib once the regulatory 
requirements are satisfied. These may include but are not limited to a rollover trial, patient 
assistance (should the patient qualify), or commercial selpercatinib. The study may be terminated 
if selpercatinib does not obtain marketing approval or the development of selpercatinib is no 
longer being pursued by the Sponsor. The Sponsor also reserves the right to discontinue the 
study for clinical or administrative reasons at any time.  
Section 7.1 Informed Consent/Pediatric Assent 
Patients must be able to provide written informed consent (or pediatric assent, when applicable) 
and meet eligibility criteria prior to enrollment. Separate ICFs will be required for patients 
enrolling in Phase 1 and in Phase 2. Additional details are provided in Section 10.1.3. 
Based on findings for potential toxicity from animal studies, patients should be counseled to 
consider fertility preservation prior to initiation of study treatment.  
As no data are available on the potential for phototoxicity with use of selpercatinib, patients 
should be counseled to minimize exposure to UV light during treatment and for one month 
following the completion of treatment. 
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Study Assessments 
Table 11-1 
Schedule of Assessments(for UK only) 
Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- 
Term 
Follow-
Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Informed Consent/Pediatric Assent 
X 
K 
K 
K 
K 
K 
K 
History of current malignancy  
X 
K 
K 
K 
K 
K 
K 
Urine or serum pregnancy test (if 
applicable)* 
X 
X 
X 
X 
K 
K 
 
Tissue biopsy a 
X 
K 
K 
K 
X 
K 
K 
Physical examination and Karnofsky or 
Lansky b 
X 
Days 1, 8, 15 
Day 1 
Day 1v 
X 
X 
K 
Vital signs c 
X 
Days 1, 8, 15, 
pre-dose 
Day 1 pre-dose 
Day 1 
pre-dosev 
X 
X 
K 
 
  
 
 
 
 
 
 
 
 
 
12-lead ECG e 
X 
Day 1, 8 
Day 1 
Day 1v 
X 
X 
K 
Hematology f 
X 
Days 1, 8, 15 
Day 1 
Day 1v 
X 
X 
K 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- 
Term 
Follow-
Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Serum chemistries g 
X 
Days 1, 8, 15 
Day 1, Day 15 
(Cycles 2-4) 
Day 1 (Cycles 
5-12) 
Day 1v 
X 
[X] r 
—  
Urinalysis h 
X 
Day 1 
Day 1 
Day 1u,v 
X 
[X] r 
—  
Thyroid Hormone (TSH and T4 or free 
T4 per local standard) 
X 
 
Day 1 of odd 
cycles 
beginning with 
C3 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13v 
 
 
 
Patients with MTC OR OTHER 
THYROID CARCINOMA ONLY: TSH  
X 
Day 15 
Day 1 of odd 
cycles 
beginning with 
C3 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13 
 
 
 
Patients with MTC ONLY: Calcitonin, 
thyroglobulin, CEA 
X 
Day 1, 8, 15 
Day 1 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13 
Day 1 
—  
Day 1 
Patients with MTC (or other cancer 
patients with Cushing’s disease): Serum 
cortisol, serum ACTH 
X 
Day 1 
Day 1 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13 
—  
—  
—  
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- 
Term 
Follow-
Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Growth plate evaluation i 
X 
 
q 6 months (if 
patent) 
q 6 months 
(if patent) 
q 6 months 
(if patent) 
q 6 months 
 (if patent) 
q 6 
months 
(if patent) 
Dental evaluation j 
X 
 
q 6 months (if 
no full set of 
permanent 
teeth) 
q 6 months 
(if no full set 
of permanent 
teeth) 
q 6 months (if 
no full set of 
permanent 
teeth) 
q 6 months 
(if no full 
set of 
permanent 
teeth) 
 q 6 
months 
(if no full 
set of 
permanen
t teeth) 
Pubertal maturation evaluation k 
X 
 
q 6 months until 
pubertal 
maturity  
q 6 months 
until pubertal 
maturity  
q 6 months 
until pubertal 
maturity  
q 6 months 
until 
pubertal 
maturity  
q 6 
months 
until 
pubertal 
maturity 
Menarche (female patients only) 
Collect the 
date of 
menarche as 
medical 
history, if 
applicable 
Collect the date of menarche if it occurs during the course of the study. 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- 
Term 
Follow-
Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Disease assessment l 
X 
K 
Day 1 (±7 days) 
Cycle 2 
(optional) and 
odd cycles 
Day 1 
(±7 days) 
every third 
cycle starting 
at Cycle 14 
[X] s 
K 
X t 
Telephone follow-up 
K 
Day 22 
K 
K 
K 
K 
K 
Pain 
  
 
 
 
 
 
 
 
 
Whole blood for
  
 
Day 1, 15 
Day 1 odd 
cycles to 
coincide with 
disease 
assessment 
Day 1 every 
12 cycles 
starting at 
Cycle 14 to 
coincide with 
disease 
assessment 
X 
K 
K 
Whole blood for genomic 
  
X 
K 
K 
K 
K 
K 
K 
Selpercatinib administration 
K 
 
 
 
 
K 
K 
Patient dosing diary 
K 
 
 
 
 
K 
K 
Patient palatability questionnairex 
(
) 
K 
K 
As directed during alternate 
formulation assessment 
K 
K 
K 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- 
Term 
Follow-
Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Patient acceptability questionnairex 
(
) 
K 
K 
As directed during alternate 
formulation assessment 
K 
K 
K 
Adverse events p 
 
 
 
 
 
 
K 
Concomitant medications 
 
 
 
 
 
 
K 
Abbreviations for Table 11-1 and Footnotes: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUC0-24 = area under 
the curve time 0 to 24 hours; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CEA = carcinoembryonic antigen; 
 
CNS = central nervous system; CSF = cerebrospinal fluid; CT = computerized tomography; DLTs = dose-limiting toxicities; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; EOT = end of treatment; h = hour; 
 LDH = lactate dehydrogenase; LTFU = long-term 
follow-up; MIBG = meta-iodobenzylguanidine; MRI = magnetic resonance imaging; PedsQL-Core = Pediatrics Quality of Life - Core Module; PET = 
positron emission tomography; PK = pharmacokinetics; RBC = red blood cell; UPC = urine protein: creatinine ratio; WBC = white blood cell; SAE = 
serious adverse event. 
Footnotes for Schedule of Assessments: 
a 
Availability of tissue biopsy is required following the most recent progression. If tissue meeting this criterion is not available, a tissue sample obtained 
prior to most recent progression is acceptable. If neither of these samples are available for submission, then a fresh tumor biopsy is requested if it can be safely 
obtained. If no tissue is available the patient may still be eligible for enrollment following conversation with the Sponsor. Tissue biopsy collected at the EOT 
visit is optional. Additional biopsies may be requested on a case-by-case basis in patients re-starting study drug following a "drug holiday" and disease 
recurrence. 
b 
Physical examination includes review of systems: breast/chest, extremities, genitourinary, head/ears/eyes/nose/throat, lymph nodes, musculoskeletal, 
pulmonary, and skin, thorough neurologic assessment, body weight, and height during Screening. Symptom-directed physical and neurological examinations, 
including measurement of weight and height, will be performed as part of vital signs. Karnofsky should be assessed for those 16 years old or older, or Lansky 
should be assessed for those younger than 16 years. 
c 
Vital signs on Day 1 should be predose. Vital signs on Day 8 should be predose and at 
 
 Vital signs on Day 15 should be Pre-dose. Vital signs in Cycles 2 and beyond should be predose. 
d 
Blood for PK will be collected as outlined in Appendix B.  
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e 
ECGs should be resting 12-lead ECG performed during Screening and during Cycle 1 at the following time points: pre-dose (±10 minutes, up to 4 hours 
pre-dose), C1D1 pre-dose and 2 and 4 hours post-dose (±10 minutes), C1D8 pre-dose and 2 and 4 hours post-dose (±10 minutes). In addition, ECGs should be 
obtained pre-dose and 2 hours post-dose (±10 minutes) on C2D1 and pre-dose Cycles 3-EOT. Additional ECGs may be performed if clinically indicated. For 
intra-patient dose escalation, ECGs should be performed pre-dose (up to 4 hours pre-/:>0:9,D,9/:1?30;,?409?N>90B/:>0,?;=0-dose, 2 and 4 hours 
post-dose (±10 minutes). 
f 
Hematology will include Hb, hematocrit, RBC count, WBC count with differential (neutrophils [absolute count and percent] and lymphocytes, 
monocytes, eosinophils, basophils [percent]), and platelet count. 
g 
Serum chemistries (non-fasting) will include alkaline phosphatase, albumin, ALT, AST, BUN/urea, creatinine, glucose, LDH, total and direct bilirubin, 
total protein, phosphorus, sodium, potassium, chloride, calcium, magnesium and bicarbonate.  
h 
If performed by dipstick, abnormal results should be followed by a complete urinalysis, including color, specific gravity, pH, glucose, bilirubin, ketones, 
occult blood, protein, leukocytes, nitrites and urobilinogen. If +2 protein is observed; a 24-hour urine collection or UPC ratio will be taken in order to quantify 
proteinuria. 
i 
Patients who have not yet obtained full adult height will undergo imaging (anterior posterior and lateral views) of the right knee at baseline and every 
6 months during participation in the study while the growth plate remains patent. If it is unclear that a patient has obtained full adult height, a pre-treatment 
tibial imaging (anterior posterior and lateral views) of the right knee should be obtained. If the growth plate remains patent, the patient will have an imaging 
(anterior posterior and lateral views) performed every 6 months during participation in the study until the growth plate is no longer patent. 
j 
Patients aged 5 and older, without a full set of permanent teeth, will undergo a dental evaluation at baseline and every 6 months during participation in 
the study. Patients who enroll prior to their 5th birthday will start dental assessments at the cycle visit closest to their 5th birthday. Changes in tooth development 
after baseline will be captured as an AE. Patients who enroll with a full set of permanent teeth will not need to undergo dental evaluations. 
k 
Patients aged 7 and older will be assessed for pubertal maturation every 6 months during participation in the study based on the Tanner Scale. Patients 
who enroll prior to their 7th birthday will start assessment at the cycle visit closest to their 7th birthday. Delays to pubertal maturity (according to the Tanner 
Scale) after baseline will be captured as an AE. Patients who completed puberty according to the Tanner Scale at enrollment will not undergo evaluation. 
l 
Tumor will be assessed by standard of care imaging modalities (CT and/or PET) or MRI of chest, abdomen, and pelvis, any other areas with suspected 
disease involvement. Patients enrolled with a history of CNS metastases should additionally have a head CT or MRI scan performed at each tumor assessment. 
Patients with locally advanced infantile fibrosarcoma should have an MRI or CT of the site of disease and a CT or X-Ray of the chest, plus any other areas of 
disease involvement. Patients with neuroblastoma will be followed with MIBG scans, anatomic imaging, and bilateral bone marrow aspirates and biopsies. 
m 
 
 
n 
Whole blood for 
 should be obtained within 7 days following radiologic disease assessment, except for baseline/Screening when it may 
be obtained any time prior to treatment on C1D1. Whole blood for 
 should be obtained at the EOT visit even if radiologic disease assessment is 
not performed. Patients less than 5 years of age will have 1×10 mL Streck tube drawn. Patients older than 5 years of age will have 2×10 mL Streck tube drawn. 
Sites may draw fewer tubes based on local institutional policy for maximal blood draws in patients. 
o 
Whole blood for 
 should be obtained any time during Screening prior to beginning treatment. Patients greater than 5 years of age will 
have one PAXGene tube (8.5 mL) drawn. Patients less than 5 years of age will not have any PAXGene tube drawn. Sites may draw fewer tubes based on local 
institutional policy for maximal blood draws in patients. 
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p 
Adverse event (AE) reporting should include the reporting of all AEs occurring for 28 days after the last dose of study drug regardless of cause of 
discontinuation. The reporting of SAEs should occur, according to SAE reporting criteria, until the patient discontinues the study or the study is closed. Refer to 
Section 8 9 Adverse Events. 
q 
During Cycle 1, observations will be performed prior to selpercatinib dosing on that day. Unless otherwise indicated, C1D1 evaluations may be 
performed either on Day -1 or predose on C1D1; if an evaluation is performed on Day -1, it need not be repeated on C1D1. Routine clinic visits performed 
within ± 2 days of the nominal visit day will not be considered protocol deviations.  
r 
Repeat the assessment only if the EOT result showed treatment-emergent abnormalities. 
s  
Assessment should be performed if no disease assessment was performed in last 2 cycles. 
t  
Date of progression, as assessed by treating Investigator and survival status (may be conducted by phone). Refer to Section 7.19. 
u 
Perform only as clinically indicated 
v 
Perform every 12 weeks after 2 years on treatment. 
x 
Questionnaires will be administered within approximately 30 minutes of dosing after the first dose of the 
 formulation and again after 
approximately 2 to 4 weeks of alternative formulation (
) administration and returned at the following clinic visit. 
* 
Perform more frequently if required by local regulations. The screening pregnancy test must be a serum sample. 
 
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Canada: 
This section describes protocol changes applicable for participants in study sites in Canada. 
This table describes the changes and provides a rationale for the changes. 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis 
Table names specified for 
Table 3-1 
Updated age of pediatric 
patients for Criterion 1, and 
pancreatic lipase statement 
added in Inclusion 
Criterion 11. 
Updated Table 2 in Criterion 
12. 
Table and section number 
specified in Planned Sample 
Size. 
Sample Size Considerations 
phrase added in Statistical 
methods 
Clarification 
 
As per country-specific 
amendment 
 
 
 
 
Clarification 
Section 1.5.5 Clinical 
Experience 
Section number specified for 
anticipated risks and Adverse 
Events. 
Clarification 
Section 3.3 General 
Treatment Procedures 
Information about patients 
undergoing optional tissue 
biopsy and imaging removed 
Information about patients 
undergoing surgical resection 
removed 
As per country-specific 
amendment 
Section 4.1 Inclusion Criteria 
Age modified for Criterion 1 
Gilbert’s disease and 
pancreatic lipase statement 
added in Criterion 11 
Criterion 17 removed. 
Age and criteria updated in 
Table 4-1 
As per country-specific 
amendment 
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Section 5.2.4.1 Management 
Guidelines for Specific 
Adverse Events 
Information about adverse 
reactions to selpercatinib 
added 
As per country-specific 
amendment 
Section 7.7 
Electrocardiograms 
Information about more than 
one ECG tracing added 
For clarification 
Section 7.9 Dental Evaluation Statement about patients 
enrolling before 5th birthday 
removed 
As per country-specific 
amendment 
Section 7.10 Pubertal 
Maturation Evaluation 
Statement about patients 
enrolling before 7th birthday 
removed 
As per country-specific 
amendment 
Section 7.11.3 Serum 
Chemistries 
Pancreatic lipase added 
As per country-specific 
amendment 
Section 9.3.1 Phase 1 
Statement added about a 
maximum of 15 patients 
being enrolled onto dosing 
cohort 
As per country-specific 
amendment 
References 
Reference for hepatotoxicity 
added 
As per country-specific 
amendment 
Study Assessments 
Age criteria for patients 
undergoing dental evaluation, 
tanner scale assessment, and 
DNA updated  
As per country-specific 
amendment 
 
Section PROTOCOL SYNOPSIS 
STUDY DESIGN: 
Phase 1 Dose Escalation 
1
 patients within a cohort experience a DLT, then the dose escalation will stop. In 
order for the MTD/RP2D, the Safety Review Committee (SRC) will evaluate whether the 
previous lower dose level will be considered the MTD  (Synopsis Table 3-1 shows example 
doses), whether an intermediate dose level should be evaluated, and/or whether additional 
patients need to be evaluated if the DLTs seen at this dose level are considered to be not serious 
or equivocal with regard to causal relationship to selpercatinib.  
 
 
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Table 3-1 
Planned Selpercatinib Dose Escalation Cohorts  
Dose Level 
Dose 
Estimated Equivalent Adult Dose 
-2 
-1 
1a 
2a 
3a,b 
Abbreviation: BID = twice daily. 
a The Dose Levels listed, i.e., Dose Levels 1, 2, and 3, correspond to the Dose Cohorts 1, 2, and 3, respectively. 
b Additional dose escalation may be considered based on the cumulative data (PK, safety, and efficacy) the actual 
dose determined by the SRC, not to exceed approximately 50% of the prior dose and taking into account capsule 
doses and capsule burden.  
Phase 2 Expansion Cohorts 
Additional patients may be enrolled to better characterize the safety and efficacy of the 
selpercatinib dose recommended for further study. Patients may enroll into each of the 4 cohorts 
below, depending on disease characteristics (refer to Synopsis Table 1).  
Synopsis Table 1: Disease Criteria for Enrollment for Cohorts 1 to 4 
Cohort 
Disease Criteria 
Cohort 1 
RET fusion-positive solid tumor (excluding CNS primary) with measurable 
disease 
Cohort 2 
RET-mutant MTC with measurable disease 
Cohort 3 
RET fusion-positive primary CNS tumor with measurable disease 
Cohort 4 
Any patient with RET mutation/alteration not fitting Cohort 1 to 3 criteria 
(i.e., RET alterations via plasma cfDNA or non-CLIA certified test, non-
measurable (i.e., only evaluable) disease 
Abbreviations: cfDNA = circulating free DNA; CNS = central nervous system; MTC = medullary thyroid cancer. 
ELIGIBILITY CRITERIA: 
Inclusion Criteria 
1. Pediatric patients H H6 months 2 years of age and G21 years of age at Cycle 1 Day 1 (C1D1) 
with a locally advanced or metastatic solid or primary CNS tumor that has relapsed, 
progressed or was nonresponsive to available therapies and/or for which no standard or 
available systemic curative therapy exists.  
11. 
Adequate hepatic / pancreatic function, defined as: 
a) 
7,9490,849:?=,9>10=,>0',9/,>;,=?,?0,849:?=,9>10=,>0&'G	× the 
@;;0=7484?:19:=8,7(!:=G× ULN with documented liver involvement (such as 
liver metastasis or a primary biliary tumor) 
b) 
':?,7-474=@-49G× (!:=G
× ULN with documented liver involvement or 
47-0=?N>4>0,>0;,?409?>B4?347-0=?N>4>0,>08,D-009=:770/B4?3;=4:=&;:9>:=
approval), and 
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c.) 
Pancreatic lipase ≤1.5 × ULN (or Sponsor’s approval). 
12. Adequate renal function, defined as:  
a. Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 based on local institutional 
practice for determination, or a maximum serum creatinine by age and gender as 
presented in Synopsis Table 2. 
Synopsis Table 2: Serum Creatinine by Age and Gender for 2 years and above 
 
Maximum Serum 
Creatinine (mg/dL) 
Maximum Serum 
Creatinine 
(µmol/L) 
Age 
Male 
Female 
Male 
Female 
6 months to < 1 year 
0.5 
0.5 
44 
44 
1 to < 2 years 
0.6 
0.6 
53 
53 
2 to <6 years 
0.8 
0.8 
71 
71 
6 to <10 years 
1 
1 
88 
88 
10 to <13 years 
1.2 
1.2 
106 
106 
13 to <16 years 
1.5 
1.4 
132 
124 
≥16 years 
1.7 
1.4 
150 
124 
17. removed 
PLANNED SAMPLE SIZE: 
In the Phase 2 portion of the study, additional patients may be enrolled to better characterize the 
safety and efficacy of the selpercatinib RP2D. The Phase 2 portion will enroll approximately 10 
to 20 patients into Cohorts 1 and 2 (refer to Table 3-2 and Section 9.3). The total sample size for 
Phase 2 will not exceed 60 patients. 
Table 3-2 
Disease Criteria for Enrollment: Cohorts 1 to 4  
Cohort 
Disease Criteria 
Cohort 1 
RET fusion-positive solid tumor (excluding CNS primary) with measurable disease 
Cohort 2 
RET-mutant MTC with measurable disease 
Cohort 3 
RET fusion-positive primary CNS tumor with measurable disease 
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Cohort 4 
Any patient with RET mutation/alteration not fitting Cohort 1 to 3 criteria (i.e., RET 
alterations via plasma cfDNA or non-CLIA certified test, measurable or non-
measurable disease) 
Abbreviations: cfDNA = circulating free DNA; CNS = central nervous system; MTC = medullary thyroid cancer. 
STATISTICAL METHODS: 
Sample Size Considerations: 
1.5.5 Clinical Experience 
Please refer to for the most current the selpercatinib IB for a summary of clinical experience, 
including anticipated risks and dose modification plans for specific AEs.  
3 INVESTIGATIONAL PLAN 
3.1.1 Study Design 
Increase or decrease in dose level if indicated, will follow the Table 3-1 dose levels listed, to the 
next appropriate lower dose. 
3.1.1.2 Dose Escalation Scheme and Assessment of Dose-Limiting Toxicity 
No more than 15 patients will be enrolled into a Dose Escalation cohort. 
3.3 General Treatment Procedures 
Patients with locally advanced disease with RECIST v1.1 confirmed response of CR/PR may 
interrupt treatment in a “wait and see” approach 1 year from confirmation of response after 
discussion with the Sponsor’s Medical Monitor. These patients may undergo an optional tissue 
biopsy and/or additional imaging (e.g., PET/CT) at the time of consideration of treatment 
discontinuation. The purpose of these additional studies is to provide additional 
pathologic/radiographic information about disease status (e.g., presence or absence of tumor). 
Following treatment discontinuation, these patients will continue to be followed with radiologic 
assessment every 3 months for 2 years, and then every 6 months thereafter, using the same 
imaging modality(ies) as during treatment. An optional radiographic disease assessment may be 
performed 1 month after the interruption of selpercatinib at the discretion of the Investigator. If a 
patient in this “wait and see” period is noted to have evidence of radiographic PD, the patient 
may re-start selpercatinib. At the time of selpercatinib re-initiation, the patient will start 
assessments per protocol as delineated for patients on active treatment. Patients who re-initiate 
selpercatinib treatment are permitted to have their selpercatinib treatment held again. Additional 
information is outlined in Section 3.1.1.1.  
Patients who undergo surgical resection for local control may continue to receive selpercatinib 
after surgical recovery and discussion between the Investigator and the Sponsor. These patients 
should have selpercatinib held for 7 days prior to surgery and resumed 14 days after surgery. If 
the resection surgery results in negative margins and study drug is interrupted, disease 
assessments, as described in Section 7.13, should be performed every 3 months following the last 
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dose of study drug. These patients are permitted to restart study drug if they experience PD after 
discussion with the Sponsor’s medical monitor. 
All treated patients will undergo a safety follow-up visit at 28 days (+7 days) after the last dose 
of study treatment and long-term follow-up visits at 3-month intervals (± 1 month) and until the 
study is officially closed. 
4.1 Inclusion Criteria 
1. Pediatric patients ≥6 months 2 years of age and 21 years of age at Cycle 1 Day 1 (C1D1) 
with a locally advanced or metastatic solid or primary CNS tumor that has relapsed, 
progressed or was nonresponsive to available therapies and for which no standard or 
available systemic curative therapy exists.  
a) Patients with locally advanced disease who would require, in the opinion of the 
Investigator, disfiguring surgery or limb amputation to achieve a complete surgical 
resection, are also eligible. 
b) In geographies where a selective RET-inhibitor is approved, patients may enroll 
without prior systemic treatment. 
11. Adequate hepatic / pancreatic function, defined as: 
a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × the 
upper limit of normal (ULN) or ≤5 × ULN with documented liver involvement (such 
as liver metastasis or a primary biliary tumor) 
b) Total bilirubin ≤1.5 × ULN or ≤3 × ULN with documented liver involvement or 
Gilbert’s disease (patients with Gilbert’s Disease may be enrolled with prior Sponsor 
approval), and 
c) Pancreatic lipase ≤1.5 x ULN (or Sponsor’s approval). 
Table 4-1 
Serum Creatinine by Age and Gender for age 2 and above  
 
Maximum Serum Creatinine (mg/dL) 
Maximum Serum 
Creatinine (µmol/L) 
Age 
Male 
Female 
Male 
Female 
6 months to < 1 year 
0.5 
0.5 
44 
44 
1 to < 2 years 
0.6 
0.6 
53 
53 
2 to <6 years 
0.8 
0.8 
71 
71 
6 to <10 years 
1 
1 
88 
88 
10 to <13 years 
1.2 
1.2 
106 
106 
13 to <16 years 
1.5 
1.4 
132 
124 
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≥16 years 
1.7 
1.4 
150 
124 
5.2.4.1 Management Guidelines for Specific Adverse Events  
Hypersensitivity Reactions to Selpercatinib 
Drug hypersensitivity reactions to selpercatinib have been reported. Rare patients developed a 
constellation of symptoms and findings characterized by a maculopapular rash, often preceded 
by fever, with associated arthralgias or myalgias during the patient’s initial weeks of treatment, 
which were then followed by at least one of the following:  
more commonly: platelet decrease and AST/ALT increase 
less commonly: blood pressure decrease, tachycardia, and creatinine increase 
If selpercatinib drug hypersensitivity is suspected, study drug should be held and treatment with 
steroids at 1 mg/kg prednisone (or equivalent) should be initiated. Upon resolution, selpercatinib 
may be resumed at a reduced dose of 40 mg (23 mg/m2) BID while continuing steroids at the 
same dose. Hypersensitivity has recurred in some patients, typically at 3-6 hours following drug 
administration. If recurrence is severe, selpercatinib should again be held; patients with mild 
recurrence (e.g., isolated instances of rash or myalgias or low-grade fever) have been able to 
cautiously continue treatment with supportive therapy (e.g., topical treatments, ibuprofen). 
After a minimum of 7 days, and in the absence of clinically significant recurrent drug 
hypersensitivity, the dose of selpercatinib may be escalated sequentially to 80 mg (46 mg/m2) 
BID, 120 mg (70 mg/m2) BID, and 160 mg (92 mg/m2) BID. Once the patient has tolerated 
treatment for a minimum of 7 days at the final dose, steroids may be tapered slowly. If the 
patient experiences a clinically significant recurrence of drug hypersensitivity at the initial 
re-exposure dose of 40 mg (23 mg/m2) BID, selpercatinib should be discontinued. 
To understand further the mechanism of this AE, the Sponsor recommends assessment of serum 
IL-6, tumor data currently available, it may be appropriate to limit such testing to IL-6, which 
necrosis factor, and immunoglobulin E levels with each occurrence of hypersensitivity, at 3 
hours after initial drug re-exposure, and at 3 hours after each dose escalation. Based on the 
limited may be used as a measure of reaction severity and increasing tolerance with re-exposure.  
Liver Function Test Abnormalities with Selpercatinib 
LFT laboratory testing (AST, ALT, total bilirubin, and ALP) should be performed every 2 weeks 
through C4D1 and then D1 of every subsequent treatment cycle. If a patient experiences ≥Grade 
3 elevated LFT increases, study drug should be held and evaluation for potential alternative 
causes should be conducted (e.g., history of other hepatotoxic medications/substances, viral 
serologies, and liver imaging). LFTs should be monitored at least weekly until resolution to 
normal/baseline (depending on the clinical situation, resolution to Grade 1 if baseline is normal 
may be permitted with prior Sponsor approval). If the LFT abnormalities do not begin to resolve 
(or worsen) within 5 days of the AE, a hepatology consultation should be considered to evaluate 
the need for a liver biopsy. Some but not all patients were previously treated with immune 
checkpoint inhibitors (ICIs), and increased hepatotoxicity has been previously associated with 
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sequential ICI therapy and TKIs in NSCLC (Lin et al. 2018). Therefore, prior ICIs may be a 
potential contributing factor in these patients; for some, concomitant treatment with steroids 
correlated with improvement in persistent LFT abnormalities. Therefore, in patients in whom 
there is thought to be an immune component to the LFT abnormalities observed, i.e., prior ICI 
exposure or liver biopsy results demonstrating an immune infiltrate, treatment with steroids may 
be added to the dose interruption recommendations below. Patients previously treated with ICIs 
remain eligible for the study. 
Upon resolution, selpercatinib may be resumed at a reduced dose of 80 mg (46 mg/m2) BID with 
weekly LFT monitoring. In the absence of recurrent LFT abnormalities, the dose of selpercatinib 
may be escalated sequentially to 120 mg (70 mg/m2) BID after a minimum of 2 weeks at 80 mg 
(46 mg/m2) BID, and again to 160 mg (92 mg/m2) BID, and after a minimum of 4 weeks at 120 
mg (70 mg/m2) BID. Once the patient has been treated at a stable dose of selpercatinib for a 
minimum of 4 weeks without recurrent LFT abnormalities, the frequency of LFT monitoring 
may be decreased (e.g., every 2 weeks for 2 months and then monthly thereafter). For patients 
who experience ≥Grade 3 elevated LFTs on a different dose than 160 mg (92 mg/m2) BID, the 
Sponsor should be contacted for additional guidance regarding dose modification. If the patient 
experiences ≥Grade 3 elevated LFTs at a dose of 40 mg (23 mg/m2) BID, selpercatinib should be 
discontinued. 
Thrombocytopenia with Selpercatinib 
A complete blood count (CBC) should be performed during Screening, C1D1, C1D15, and Day 
1 of every subsequent cycle. If a patient is discovered to have thrombocytopenia ≥Grade 3, study 
drug should be held and the patient should be evaluated for alternative causes 
(medications/substances, viral studies). A hematology consultation may be considered as 
necessary to understand the etiology and to consider a role for concomitant steroid therapy. The 
patient should undergo weekly CBC testing until the event has recovered to normal/baseline. 
Upon recovery, the patient should resume selpercatinib at a reduced dose (e.g., 120 mg 
[70 mg/m2] BID or 80 mg [46 mg/m2] BID) with weekly CBC surveillance for 1 full cycle. The 
Sponsor should be notified for consideration of concomitant steroid therapy and for further dose 
re-escalation. 
Hypertension with Selpercatinib 
All investigators should consider optimizing patients’ blood pressure to an ideal reading of 
≤140/90 mmHg (if necessary) prior to initiation of study drug. If hypertension, defined as a 
sustained increase in blood pressure from baseline on ≥2 readings on ≥2 separate occasions, or a 
clinically significant elevation requiring acute treatment, occurs, study drug may be interrupted 
at the discretion of the investigator while considering initiation of a new anti-hypertensive 
medication regimen, or alteration of a preexisting regimen is optimized to improve BP control, 
ideally to a reproducible reading of ≤140/90 mmHg. If study drug is interrupted, it may be 
resumed at the same or a lower dose at the discretion of the Investigator. In all cases, the patient 
should continue to undergo regular blood pressure monitoring to ensure adequate blood pressure 
control. If the patient experiences uncontrolled ≥Grade 3 hypertension despite anti-hypertensive 
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regimen optimization and study drug dose reduction to 40 mg (23 mg/m2) BID, selpercatinib 
should be discontinued. 
QTcF Prolongation with Selpercatinib 
All patients should have a QTcF interval of ≤470 msec prior to initiating therapy with 
selpercatinib. If more than 1 ECG tracing is captured at any given time point during screening or 
on study, an average of the QTcF values should be used. Concomitant medications known to 
prolong the QTc interval should be avoided. ECGs should be collected and monitored, as 
indicated in the protocol, during Cycle 1 on Days 1 and 8, then monthly through Cycle 6 and 
every 12 weeks thereafter. During this time, electrolytes should be monitored and repletion 
prescribed as needed (potassium should be ≥4 mEq/L and <ULN and magnesium and calcium 
should be within normal limits).  
Pleural Effusions and Abdominal Ascites with Selpercatinib 
If a patient develops a pleural effusion and/or abdominal ascites 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 rare patients receiving selpercatinib have been 
reported to have effusions and/ or ascites which have subsequently been found to be chylous in 
nature. Distinguishing chylous fluid from malignant (as well as other causes such as infectious) 
may impact management significantly (e.g., presumption of disease progression with premature 
discontinuation of therapy). Additionally, a diagnosis of chylous effusions and/or ascites may 
reveal a role for conservative measures, such as fluid replacement, dietary alteration, and/or a 
trial of medical therapy (e.g., somatostatin analogue) prior to consideration of more invasive 
measures. Selpercatinib interruption and dose modification should follow the general strategy as 
outlined in study-specific protocols based upon severity and causality of the event. 
7.7 Electrocardiograms 
If more than one ECG tracing is captured at any given time point during screening or on study, 
an average of the QTcF or QTcB (as applicable) values should be used. Concomitant 
medications known to prolong the QTc interval should be avoided. ECGs should be collected 
and monitored during Cycle 1 on Days 1 and 8 and then monthly through Cycle 6 and every 
12 weeks thereafter. During this time, electrolytes should be monitored and repletion prescribed 
as needed (potassium should be ≥4.0 mEq/L and <ULN, and magnesium and calcium should be 
within normal limits).  
7.9 Dental Evaluation 
Patients aged 5 years and older, without a full set of permanent teeth, will undergo a dental 
evaluation at baseline and every 6 months during participation in the study. Patients who enroll 
prior to their 5th birthday will start dental assessments at the cycle visit closest to their 5th 
birthday. Detrimental changes in tooth development considered significant after study baseline 
will be captured as an AE, and will require dentist evaluation. 
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7.10 Pubertal Maturation Evaluation 
Patients aged 7 years and older will be assessed for pubertal maturation every 6 months during 
participation in the study based on the Tanner Scale. Patients who enroll prior to their 7th 
birthday will start assessment at the cycle visit closest to their 7th birthday. Delays to pubertal 
maturity (according to the Tanner Scale) after study baseline will be captured as an AE. 
7.11.3 Serum Chemistries 
Serum chemistries (non-fasting) should be assessed in accordance with the Schedule of 
Assessments (Table 11-1) and should include assessment of the following: alkaline phosphatase, 
albumin, ALT, AST, BUN or urea, creatinine, glucose, LDH, total and direct bilirubin, 
pancreatic lipase, total protein, phosphorus, sodium, potassium, chloride, calcium, magnesium, 
and bicarbonate.  
9.3 Determination of Sample Size 
9.3.1 Phase 1 
If an investigative site identifies a patient with a known RET alteration, the patient may be 
enrolled to a previous cohort that has been determined safe after discussion with the Sponsor’s 
Medical Monitor. If a patient with a RET alteration is identified after 6 patients have been 
enrolled on Dosing Cohort 1, and prior to clearance of the DLT window, that patient will be 
enrolled to Dose Level -1. Following clearance of Dose Level 1, the patient(s) enrolled to Dose 
Level -1 may be escalated to Dose Level 1 upon discussion between the Investigator and the 
Sponsor’s Medical Monitor. Patients who miss 7 or more days of dosing in Cycle 1 for reasons 
unrelated to study drug toxicity will be considered to have inadequate study drug exposure to 
support dose escalation and will be replaced. A maximum of 15 patients will be enrolled into a 
dosing cohort. 
11. REFERENCES 
Lin, J.J., Chin, E., Yeap, B.Y., Ferris, L.A., Kamesan, V., Lennes, I.T., Sequist, L.V., Heist, 
R.S., Mino-Kenudson, M., Gainor, J.F., Shaw, A.T. (2019). “Increased hepatotoxicity associated 
with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small 
cell lung cancer.” J Thorac Oncol 14(1):135-140. 
 
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Study Assessments 
Table 11-1 
Schedule of Assessments (for Canada only) 
Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- Term 
Follow-Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Informed Consent/Pediatric Assent 
X 
K 
K 
K 
K 
K 
K 
History of current malignancy  
X 
K 
K 
K 
K 
K 
K 
Urine or serum pregnancy test (if 
applicable)* 
X 
X 
X 
X 
K 
K 
 
Tissue biopsy a 
X 
K 
K 
K 
X 
K 
K 
Physical examination and Karnofsky or 
Lansky b 
X 
Days 1, 8, 15 
Day 1 
Day 1v 
X 
X 
K 
Vital signs c 
X 
Days 1, 8, 15, 
pre-dose 
Day 1 pre-dose 
Day 1 
pre-dosev 
X 
X 
K 
 
  
 
 
 
 
 
 
 
 
 
12-lead ECG e 
X 
Day 1, 8 
Day 1 
Day 1v 
X 
X 
K 
Hematology f  
X 
Days 1, 8, 15 
Day 1 
Day 1v 
X 
X 
K 
Serum chemistries g 
X 
Days 1, 8, 15 
Day 1, Day 15 
(Cycles 2-4) 
Day 1 (Cycles 
5-12) 
Day 1v 
X 
[X] r 
K 
Pancreatic lipase 
X 
Day 1 
Day 1 (Cycles 
2-12) 
Every 3rd 
cycle starting 
at Cycle 13v 
X 
 
 
Urinalysis h 
X 
Day 1 
Day 1 
Day 1u,v 
X 
[X] r 
K 
Thyroid Hormone (TSH and T4 or free 
T4 per local standard) 
X 
 
Day 1 of odd 
cycles 
beginning with 
C3 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13v 
 
 
 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- Term 
Follow-Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
Patients with MTC OR OTHER 
THYROID CARCINOMA ONLY: TSH  
X 
Day 15 
Day 1 of odd 
cycles 
beginning with 
C3 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13 
 
 
 
Patients with MTC ONLY: Calcitonin, 
thyroglobulin, CEAv 
X 
Day 1, 8, 15 
Day 1 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13 
Day 1 
—  
Day 1 
Patients with MTC (or other cancer 
patients with Cushing’s disease): Serum 
cortisol, serum ACTHv 
X 
Day 1 
Day 1 
Day 1 of 
every 3rd 
cycle starting 
at Cycle 13 
—  
—  
—  
Growth plate evaluation i 
X 
 
q 6 months (if 
patent) 
q 6 months 
(if patent) 
q 6 months 
(if patent) 
q 6 months 
 (if patent) 
q 6 
months 
(if patent) 
Dental evaluation j 
X 
 
q 6 months (if 
no full set of 
permanent 
teeth) 
q 6 months 
(if no full set 
of permanent 
teeth) 
q 6 months (if 
no full set of 
permanent 
teeth) 
q 6 months 
(if no full 
set of 
permanent 
teeth) 
 q 6 
months 
(if no full 
set of 
permanen
t teeth) 
Pubertal maturation evaluation k 
X 
 
q 6 months until 
pubertal 
maturity  
q 6 months 
until pubertal 
maturity  
q 6 months 
until pubertal 
maturity  
q 6 months 
until 
pubertal 
maturity  
q 6 
months 
until 
pubertal 
maturity 
Menarche (female patients only) 
Collect the 
date of 
menarche as 
medical 
Collect the date of menarche if it occurs during the course of the study. 
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Evaluation 
Screening 
28-Day Cycles 
End of 
Treatment 
(EOT) 
Safety 
Follow-Up 
Long- Term 
Follow-Up 
(LTFU) 
Cycle 1q 
Cycles 2 
through 12 
Cycles 13 
and Higher 
Visit Window 
(Day -28 to 
Day 0) 
± 2 Days 
± 3 Days 
± 7 Days 
± 3 Days 
Day 28 +7 
days 
Every 
3 months 
± 1 
month 
history, if 
applicable 
Disease assessment l 
X 
K 
Day 1 (±7 days) 
Cycle 2 
(optional) and 
odd cycles 
Day 1 
(±7 days) 
every third 
cycle starting 
at Cycle 14 
[X] s 
K 
X t 
Telephone follow-up 
K 
Day 22 
K 
K 
K 
K 
K 
Pain 
  
 
 
 
 
 
 
 
 
Whole blood for 
  
 
Day 1, 15 
Day 1 odd 
cycles to 
coincide with 
disease 
assessment 
Day 1 every 
12 cycles 
starting at 
Cycle 14 to 
coincide with 
disease 
assessment 
X 
K 
K 
Whole blood for 
 
 
X 
K 
K 
K 
K 
K 
K 
Selpercatinib administration 
K 
 
 
 
 
K 
K 
Patient dosing diary 
K 
 
 
 
 
K 
K 
Patient palatability questionnairex 
(
) 
K 
K 
As directed during alternate 
formulation assessment 
K 
K 
K 
Patient acceptability questionnairex 
(
) 
K 
K 
As directed during alternate 
formulation assessment 
K 
K 
K 
Adverse events p 
 
 
 
 
 
 
K 
Concomitant medications 
 
 
 
 
 
 
K 
Abbreviations for Table 11-1 and Footnotes: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUC0-24 = area under 
the curve time 0 to 24 hours; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CEA = carcinoembryonic antigen; 
 
CNS = central nervous system; CSF = cerebrospinal fluid; CT = computerized tomography; DLTs = dose-limiting toxicities; DNA = deoxyribonucleic acid; 
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ECG = electrocardiogram; EOT = end of treatment; h = hour; 
LDH = lactate dehydrogenase; LTFU = long-term 
follow-up; MIBG = meta-iodobenzylguanidine; MRI = magnetic resonance imaging; PedsQL-Core = Pediatrics Quality of Life - Core Module; PET = positron 
emission tomography; PK = pharmacokinetics; RBC = red blood cell; UPC = urine protein: creatinine ratio; WBC = white blood cell; SAE = serious adverse 
event. 
Footnotes for Schedule of Assessments: 
a 
Availability of tissue biopsy is required following the most recent progression. If tissue meeting this criterion is not available, a tissue sample obtained prior to 
most recent progression is acceptable. If neither of these samples are available for submission, then a fresh tumor biopsy is requested if it can be safely obtained. 
If no tissue is available the patient may still be eligible for enrollment following conversation with the Sponsor. Tissue biopsy collected at the EOT visit is 
optional. Additional biopsies may be requested on a case-by-case basis in patients re-starting study drug following a "drug holiday" and disease recurrence. 
b Physical examination includes review of systems: breast/chest, extremities, genitourinary, head/ears/eyes/nose/throat, lymph nodes, musculoskeletal, 
pulmonary, and skin, thorough neurologic assessment, body weight, and height during Screening. Symptom-directed physical and neurological examinations, 
including measurement of weight and height, will be performed as part of vital signs. Karnofsky should be assessed for those 16 years old or older, or Lansky 
should be assessed for those younger than 16 years. 
c 
Vital signs on Day 1 should be predose. Vital signs on Day 8 should be predose and at 
 
 Vital signs on Day 15 should be Pre-dose. Vital signs in Cycles 2 and beyond should be predose. 
d 
Blood for PK will be collected as outlined in Appendix B.  
e 
ECGs should be resting 12-lead ECG performed during Screening and during Cycle 1 at the following time points: pre-dose ( ±10 minutes, up to 4 hours pre-
dose), C1D1 pre-dose and at 2 and 4hours post-dose (±10 minutes) , C1D8 at 2 hours post-dose, ±10 minutes. On C2D1 through C6D1 visits, perform ECG at 2 
hours (± 10 minutes) post selpercatinib dosing. Thereafter, From Cycle 3 through Cycle 6 and beyond , ECGs should be obtained pre-dose. From Cycle 6 and 
beyond, ECGs should be obtained pre-dose every 12 weeks. and every 12 weeks at 2 hours post dose (±(± 10 minutes) on C2D1 and pre-dose Cycles 3 EOT. 
Post selpercatinib dosing During this time, electrolytes should be monitored and repletion prescribed as needed (potassium >3:@7/-0H8<,9/(!,9/
magnesium and calcium should be within normal limits). Additional ECGs may be performed if clinically indicated. If any ECG demonstrates QTc 481-500 
msec, perform an additional ECG at 4 hours (± 10 minutes) post dosing. If any ECG demonstrates QTc > 500 msec, repeat the ECG twice (triplicate in total) 
and manually review to confirm accuracy. If QTc > 500 msec is confirmed on 2/3 ECGs, hold selpercatinib and assess for alternative causes (concomitant 
medications, electrolyte abnormalities). LOXO-292 may be resumed at one reduced dose level when QTc has returned to baseline value, and with continued 
ECG monitoring as noted in the assessment schedule. For intra-patient dose escalation, ECGs should be performed predose (up to 4 hours pre-dose) on Day 1 of 
?30;,?409?N>90B/:>0,9/	3:@=>;:>?-selpercatinib-dosing (±10 minutes) on Days 1 ,9/:1?30;,?409?N>90B/:>0:=;,?409?>GD0,=>:7/,E0??N>
Formula will be utilized to determine QTc. For patients >15 years old, ei?30=80?3:/=4/0=4.4,:=,E0??N>:=8@7,8,D-0,;;740/ 
f 
Hematology will include Hb, hematocrit, RBC count, WBC count with differential (neutrophils [absolute count and percent] and lymphocytes, monocytes, 
eosinophils, basophils [percent]), and platelet count. 
g Serum chemistries (non-fasting) will include alkaline phosphatase, albumin, ALT, AST, BUN/urea, creatinine, glucose, LDH, total and direct bilirubin, total 
protein, phosphorus, sodium, potassium, chloride, calcium, magnesium, and bicarbonate.  
h If performed by dipstick, abnormal results should be followed by a complete urinalysis, including color, specific gravity, pH, glucose, bilirubin, ketones, occult 
blood, protein, leukocytes, nitrites, and urobilinogen. If +2 protein is observed; a 24-hour urine collection or UPC ratio will be taken in order to quantify 
proteinuria. 
i 
Patients who have not yet obtained full adult height will undergo imaging (anterior posterior and lateral views) of the right knee at baseline and every 6 months 
during participation in the study while the growth plate remains patent. If it is unclear that a patient has obtained full adult height, a pre-treatment tibial imaging 
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(anterior posterior and lateral views) of the right knee should be obtained. If the growth plate remains patent, the patient will have an imaging (anterior posterior 
and lateral views) performed every 6 months during participation in the study until the growth plate is no longer patent. 
j 
Patients aged 5 and older, without a full set of permanent teeth, will undergo a dental evaluation at baseline and every 6 months during participation in the 
study. Patients who enroll prior to their 5th birthday will start dental assessments at the cycle visit closest to their 5th birthday. Changes in tooth development 
after baseline will be captured as an AE. Patients who enroll with a full set of permanent teeth will not need to undergo dental evaluations. 
k Patients aged 7 and older will be assessed for pubertal maturation every 6 months during participation in the study based on the Tanner Scale. Patients who 
enroll prior to their 7th birthday will start assessment at the cycle visit closest to their 7th birthday. Delays to pubertal maturity (according to the Tanner Scale) 
after baseline will be captured as an AE. Patients who completed puberty according to the Tanner Scale at enrollment will not undergo evaluation. 
l 
Tumor will be assessed by standard of care imaging modalities (CT and/or PET) or MRI of chest, abdomen, and pelvis, any other areas with suspected disease 
involvement. Patients enrolled with a history of CNS metastases should additionally have a head CT or MRI scan performed at each tumor assessment. Patients 
with locally advanced infantile fibrosarcoma should have an MRI or CT of the site of disease and a CT or X-Ray of the chest, plus any other areas of disease 
involvement. Patients with neuroblastoma will be followed with MIBG scans, anatomic imaging, and bilateral bone marrow aspirates and biopsies. 
m Pain and HRQoL assessments will be collected every cycle. In patients 3 years of age or older, pain will be assessed by the Wong-Baker Faces Scale. For all 
patients HRQoL will be assessed using the PedsQL-Core for the patient or their parent/caregiver. 
n Whole blood for 
 should be obtained within 7 days following radiologic disease assessment, except for baseline/Screening when it may be 
obtained any time prior to treatment on C1D1. Whole blood for 
 should be obtained at the EOT visit even if radiologic disease assessment is not 
performed. Patients less than 5 years of age will have 1×10 mL Streck tube drawn. Patients older than 5 years of age or older will have 2×10 mL Streck tube 
drawn. Sites may draw fewer tubes based on local institutional policy for maximal blood draws in patients. 
o Whole blood for 
 should be obtained any time during Screening prior to beginning treatment. Patients less than 5 years of age will not have this 
sample drawn. Patients 5 years of age or older will have one PAXGene tube (8.5 mL) drawn. Patients less than 5 years of age will not have any PAXGene tube 
drawn. Sites may draw fewer tubes based on local institutional policy for maximal blood draws in patients. 
p 
Adverse event (AE) reporting should include the reporting of all AEs occurring for 28 days after the last dose of study drug regardless of cause of 
discontinuation. The reporting of SAEs should occur, according to SAE reporting criteria, until the patient discontinues the study or the study is closed. Refer to 
Section 8 Adverse Events. 
q 
During Cycle 1, observations will be performed prior to selpercatinib dosing on that day. Unless otherwise indicated, C1D1 evaluations may be performed 
either on Day -1 or predose on C1D1; if an evaluation is performed on Day -1, it need not be repeated on C1D1. Routine clinic visits performed within ± 2 days 
of the nominal visit day will not be considered protocol deviations.  
r 
Repeat the assessment only if the EOT result showed treatment-emergent abnormalities. 
s 
Assessment should be performed if no disease assessment was performed in last 2 cycles. 
t 
Date of progression, as assessed by treating Investigator and survival status (may be conducted by phone). Refer to Section 7.19. 
u Perform only as clinically indicated 
v Perform at least every 12 weeks after 2 years on treatment. Align with disease assessment visits. 
x Questionnaires will be administered within approximately 30 minutes of dosing after the first dose of the 
 formulation and again after approximately 2 to 4 
weeks of alternative formulation (
) administration and returned at the following clinic visit. 
* Perform every 12 weeks after 2 years on treatment Perform more frequently if required by local regulations. 
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Japan: 
This section describes protocol changes applicable for participants in study sites in Japan 
This table describes the changes and provides a rationale for the changes. 
Section # and Name 
Description of Change 
Brief Rationale 
Section Synopsis 
Information about 
selpercatinib administration as 
capsule or liquid suspension 
added. 
Information about subject 
hospitalization and not 
enrolled in phase 1 dose 
escalation removed 
Information about Japan 
participants added 
As per regulatory 
requirement 
Section 3.2 Phase 2 Dose 
Expansion Cohort 
Information about subject 
hospitalization and not 
enrolled in phase 1 dose 
escalation removed 
Information about Japan 
participants added 
As per regulatory 
requirement 
Section 4.1 Inclusion Criteria 
Information mentioned about 
contraception methods not 
applicable in Japan 
As per regulatory 
requirement 
Study Assessments 
Information about subject 
hospitalization and not 
enrolled in phase 1 dose 
escalation removed 
Information about Japan 
participants added 
As per regulatory 
requirement 
Section Synopsis 
STUDY DESIGN: 
Phase 2 Expansion Cohorts 
Selpercatinib is administered in oral capsule or liquid suspension. Each cycle consists of 28 days.  
 
 
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JAPAN ONLY: 
Subjects in Japan will be hospitalized during Cycle 1 in Phase 1.  
If a subject in Japan has not been enrolled in Phase 1 Dose Escalation, at least 1 subject in 
Phase 2 is required to be monitored by hospitalization during Cycle 1 and will be assessed 
by SRC to confirm the subject’s PK, AE, DLT and tolerability before enrolling additional 
subjects in Phase 2.  
Patients 12 years of age and older, with the exception of thyroid cancer and medullary 
thyroid cancer, and patients under 12 years of age regardless of cancer diagnosis, in 
principle and at investigator discretion, will be hospitalized during Cycle 1. 
Section 3.2 Phase 2 Dose Expansion Cohort 
Table 3-2 
Disease Criteria for Enrollment: Cohorts 1 to 4  
Cohort 
Disease Criteria 
Cohort 1 
RET fusion-positive solid tumor (excluding CNS primary) with 
measurable disease 
Cohort 2 
RET-mutant MTC with measurable disease 
Cohort 3 
RET fusion-positive primary CNS tumor with measurable disease 
Cohort 4 
Any patient with RET mutation/alteration not fitting Cohort 1 to 3 criteria 
(i.e., RET alterations via plasma cfDNA or non- CLIA certified test, 
measurable or non-measurable disease) 
Abbreviations: cfDNA = circulating free DNA; CNS = central nervous system; MTC = 
medullary thyroid cancer; RET = rearranged during transfection. 
JAPAN ONLY:  
Subjects in Japan will be hospitalized during Cycle 1 in Phase 1.  
If a subject in Japan has not been enrolled in Phase 1 Dose Escalation, at least 1 subject in Phase 
2 is required to be monitored by hospitalization during Cycle 1 and will be assessed by SRC to 
confirm the subject’s PK, AE, DLT and tolerability before enrolling additional subjects in Phase 
2.  
Patients 12 years of age and older, with the exception of thyroid cancer and medullary thyroid 
cancer, and patients under 12 years of age regardless of cancer diagnosis, in principle and at 
investigator discretion, will be hospitalized during Cycle 1. 
Section 4.1 Inclusion Criteria 
14. Willingness of male and female patients with reproductive potential to utilize double 
effective birth control methods, defined as one used by the patient and another by his/her partner, 
for the duration of treatment and for 1 month 3 months following study completion. 
For male patients with a non-pregnant female partner of child-bearing potential, and woman 
of child-bearing potential, one of the following highly effective birth control methods (with a 
failure rate of less than 1% per year when used consistently and correctly) are recommended: 
a) Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally*, or transdermally* 
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b) Progestin-only hormonal contraception associated with inhibition of ovulation given 
orally*, by injection*, or by implant* 
c) Intrauterine device (IUD) 
d) Intrauterine hormone-releasing system (IUS) 
e) Bilateral tubal occlusion 
f) Vasectomized partner 
g) Sexual abstinence: considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the 
duration of the study and to the usual lifestyle of the patient. 
Birth control methods unacceptable for this clinical trial are: 
e) Periodic abstinence (calendar, sympto-thermal, or post-ovulation methods) 
f) Withdrawal (coitus interruptus) 
g) Spermicide only 
h) Lactational amenorrhea method 
* These methods are not approved for use in Japan. 
Study Assessments(for Japan only) 
JAPAN ONLY: 
Subjects in Japan will be hospitalized during Cycle 1 in Phase 1.  
If a subject in Japan has not been enrolled in Phase 1 Dose Escalation, at least 1 subject in Phase 
2 is required to be monitored by hospitalization during Cycle 1 and will be assessed by SRC to 
confirm the subject’s PK, AE, DLT and tolerability before enrolling additional subjects in Phase 
2.  
Patients 12 years of age and older, with the exception of thyroid cancer and medullary thyroid 
cancer, and patients under 12 years of age regardless of cancer diagnosis, in principle and at 
investigator discretion, will be hospitalized during Cycle 1. 
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Appendix N 
Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Protocol Synopsis. 
Amendment [10] (09 October 2024) 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The purpose of this amendment is to  
 add instructions for IP dispensing during Continued Access 
 decrease frequency of Assessment Committee meetings 
 minor corrections and edits for clarity.  
 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Investigational 
Product 
Removed columns for vehicles, 
 
from 
the intervention table 
As no longer applicable 
7.13.1 Tumor 
Measurements 
//0/L:=MRIM,9/Lor CT / 
PET)M is in all sections of 
Section 7.13.1 where appropriate 
For correction and to maintain 
consistency in including an MRI 
or CT (or CT / PET)  
imaging techniques for the 
baseline tumor assessment 
9.5.1 Assessment 
Committee 
Decreased frequency of Assessment 
Committee review meetings 
Due to amount of safety data 
accrued in selpercatinib 
development program 
Appendix K Continued 
Access 
Added footnote L-M for instructions 
for IP dispensing during Continued 
Access 
To provide clear instruction and 
ensure patients continue to receive 
the necessary treatment without 
interruption 
Appendix M 
Country-specific 
Requirements 
For France appendix, added Section 
5.3.4.7 Substrates of BCRP and P-gp 
To comply with France 
requirements for precautions of 
use with the BCRP and P-gp 
substrates with narrow therapeutic 
index. 
For patients enrolled in the UK and 
Canada, added assessment for 
thyroid function tests, menarche, and 
 palatability and acceptability in 
the Schedule of Assessments in the 
Canada and UK appendix, 
respectively 
Correction for inadvertently 
missed assessments that should be 
collected as per the global 
Schedule of Assessments in 
Appendix A 
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 
Section # and 
Name 
Description of Change 
Brief Rationale 
For Canada appendix, strikethrough 
language that is not applicable for 
Inclusion Criteria Number 1  
Correction 
For Canada appendix, in “Synopsis 
Table 2: Serum Creatinine by Age 
and Gender for 2 years and above” 
added rows for patients aged 2 to <6 
years and 6 to <10 years 
Correction for content that was 
inadvertently omitted 
For Canada appendix, in Synopsis 
Table 2 and Table 4-1 for “Serum 
Creatinine by Age and Gender for 2 
years and above” changed from 12 to 
<13 years to 10 to <13 years in the 
age column 
Correction 
 
Amendment [9] (15 August 2023) 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the safety or the rights of the study participants. 
Overall Rationale for the Amendment: 
The purpose of this amendment is to update as per the latest Investigator Brochure and to align 
with EU Clinical Trial Regulation (EU-CTR) requirements. 
Section # and Name 
Description of Change 
Brief Rationale 
PROTOCOL SYNOPSIS 
Added 
 Regulatory Agency Identifier Numbers 
 Ethical Considerations of Benefit/Risk 
Compliance with EU-CTR 
LIST OF 
ABBREVIATIONS AND 
DEFINITION OF TERMS 
Added  
 
abuse 
 
GDPR 
 
IMP 
 
medication error 
 
misuse 
 
SUSAR 
Compliance with EU-CTR 
5.1. Investigational Product 
Updated authorization as defined by 
EU-CTR for selpercatinib and the 
definition for study intervention 
Added a statement on packaging and 
labeling 
Compliance with EU-CTR 
5.2.4. Dose Modifications 
Updated dose modification guidance for 
specific AEs 
As per updated Investigator Brochure 
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Section # and Name 
Description of Change 
Brief Rationale 
Table 5-1 Toxicities 
Requiring Dose 
Modification 
7.11.7. Thyroid Function 
Added new section for thyroid function 
As per updated Investigator Brochure 
8. ADVERSE EVENTS 
Updated events meeting the AE 
definition 
Updated regulatory reporting of SAEs 
Compliance with EU-CTR 
9.2. Analysis Populations 
Added a statement on handling of 
missing, unused, and spurious data 
Compliance with EU-CTR 
10.1.4. Investigator 
Reporting Requirements 
Added reporting to the sponsor or 
designee significant issues related to 
participant safety, participant rights, or 
data integrity 
Compliance with EU-CTR 
10.2.1. Data Protection 
Added required language on data 
protection 
Compliance with EU-CTR 
10.4. Termination 
Added required language for 
communication of suspended or 
terminated dosing and time frame for 
posting of summary of results as 
specified by local law or regulation 
Compliance with EU-CTR 
Appendix A Study 
Assessments 
Table 11-1. Schedule of 
Assessments 
%0A4>0/0A,7@,?4:91:=LPatients with 
MTC OR OTHER THYROID 
CARCINOMA ONLY: TSHM?: 
LThyroid Hormone (TSH and T4 or free 
T4 per local standard)Mand removed the 
timepoint assessment at Cycle 1 
Alignment with Section. 7.11.7 
Thyroid Function 
Throughout 
Minor editorial and document formatting 
revisions 
These are minor changes; therefore, 
they have not been summarized. 
 
Amendment [8] (30 June 2023) 
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: 
The purpose of this amendment is to 
 add the evaluation of a 
 formulation 
 add the option of treatment holiday for patients with prolonged disease control, and 
 include minor edits and correction. 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis 
Exploratory objectives updated in Phase 1 
For adding evaluation of 
 
formulation 
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Section # and Name 
Description of Change 
Brief Rationale 
Secondary and exploratory objectives 
updated in Phase 2 
Statement added under Inclusion Criterion 8 
that patients having received selpercatinib 
previously are not eligible 
 added under INVESTIGATIONAL 
DRUG 
 
For clarification 
 
 
For adding evaluation of 
 
formulation 
1.3 Role of RET in 
Pediatric Cancers 
Cancer has been removed from statement 
regarding anti-RET multikinase inhibitors 
For clarification 
1.5.1 Pharmacokinetics 
Data about bioequivalence in healthy 
volunteers added and prior data updated 
Updated per new information 
1.5.6 Known and 
Anticipated Risks 
Adverse events updated 
As per updated Investigator Brochure 
1.5.7 Rationale for 
Selection of the Starting 
Dose 
Table 1-2 and 1-3 updated 
Pharmacokinetic parameters revised 
2.1 Phase 1 Study 
Objectives 
Exploratory objectives updated 
For adding evaluation of 
 
formulation 
2.2 Phase 2 Study 
Objectives 
Secondary and exploratory objectives 
updated 
For adding evaluation of 
 
formulation  
3.1.1 Study Design 
Statement about selpercatinib being 
administered as 
 form added 
For adding evaluation of 
 
formulation 
3.3 General Treatment 
Procedures 
Information about alternate formulation of 
selpercatinib added for patients under 18 
years of age 
For adding evaluation of 
 
formulation 
4.1 Inclusion Criteria 
Statement added in Criterion 8 that patients 
who have received selpercatinib previously 
are not eligible 
For clarification 
5.1 Investigational 
Product 
Information about 
 added and 
information about suspension removed 
For adding evaluation of 
 
formulation 
5.2.1 General Dosing 
Instructions 
Information about 
 and drug diary 
added 
For consistency across all sections of 
protocol 
5.2.4 Dose 
Modifications 
Table 5-1 Toxicities Requiring Dose 
Modification updated to include Interstitial 
Lung Disease/Pneumonitis Adverse Event 
As per updated Investigator Brochure 
5.2.5 Drug Treatment 
Holiday 
Information about drug treatment holiday 
added 
As per investigator feedback 
6.1 Removal of Patients 
from Therapy or 
Assessment 
Information about disease progression 
during drug treatment holiday added 
As per rationale of the amendment 
7.12 Pharmacokinetic 
Samples: Blood (and 
Cerebrospinal Fluid, if 
Appropriate) 
Information added cycles of PK data added 
For consistency across all sections of 
protocol 
7.13.1 Tumor 
Measurements 
Information about patients with MIBG 
non-avid disease to undergo assessments 
added 
For clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
7.14 Study Drug 
Administration and 
Dosing Diary 
Diary information added 
For consistency across all sections of 
protocol 
7.14.1 Formulation 
Acceptability and 
Palatability 
Assessments 
Information about acceptability and 
palatability questionnaires added 
For adding evaluation of 
 
formulation 
7.14.1 Formulation 
Acceptability and 
Palatability 
Assessments 
Questionnaire for 
 acceptability 
assessment added for patients 
For adding the evaluation of 
 
formulation 
7.17 End of Treatment 
Visit 
Window period updated 
For clarification 
9.1.2.2 Secondary 
Endpoint about 
 assessment and 
palatability added 
For adding evaluation of 
 
formulation 
9.1.1.3 and 9.1.2.3 
Exploratory 
Exploratory endpoints updated 
For consistency across all sections of 
protocol 
9.6 Efficacy Analyses 
Information about patients experiencing 
disease progression during drug holiday 
added 
For consistency across all sections of 
protocol 
9.7 Pharmacokinetic 
Analyses 
Pharmacokinetic of 
 added 
For adding the evaluation of 
 
formulation 
9.8 Pain 
 
 
Logistic regression added 
For clarification 
Appendix A Study 
Assessments 
Table 11-1 Schedule of Assessments 
updated with following: 
 
Duration of window period for End 
of Treatment 
 
Vital signs added at long-term 
follow up visit. 
 
Menarche date collection for 
female patients added 
 
Patient palatability and 
acceptability questionnaires added 
 
Footnote t revised to add 
information about drug holiday 
For safety assessment clarification 
Appendix B 
Pharmacokinetic 
Sample Collection 
Information about 
 formulation added 
For adding evaluation of 
 
formulation 
Appendix H 
Selpercatinib Oral 
Suspension Dose 
Rounding 
 dose rounding included 
For adding evaluation of 
 
formulation 
Appendix K Continued 
Access 
Information about long term safety for select 
patients added 
For clarification 
Appendix M 
Country-specific 
Requirements 
Requirements for UK, Canada, and Japan 
added 
For EU CTR consolidation 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document formatting 
revisions. 
These are minor changes; therefore, 
they have not been summarized. 
 
 
 
 
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