A Phase 2 Study of Oral Selpercatinib (LOXO-292) in Patients With Advanced Solid Tumors, Including Rearranged in Transfection (RET) Fusion-Positive Solid Tumors, Medullary Thyroid Cancer and Other Tumors With RET Activation
Phase: PHASE2
Conditions: Solid Tumor, Medullary Thyroid Cancer
Sponsor: Eli Lilly and Company

J2G-GH-JZJK Protocol(b) 
 
A Phase 2 Study of Oral Selpercatinib (LOXO-292) in Patients with Advanced Solid Tumors, 
Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors 
with RET Activation 
 
NCT04280081 
 
Approval Date: 01-Feb2021 

J2G-GH-JZJK Clinical Protocol(b)
1
LY3527723
A Phase 2 Study of Oral Selpercatinib (LOXO-292) in 
Patients with Advanced Solid Tumors, Including RET 
Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, 
and Other Tumors with RET Activation 
Investigational Product:
Selpercatinib (LOXO-292)
(LY3527723)
Protocol Number:
J2G-GH-JZJK, LIBRETTO-321
Amendment Number
b
Development Phase:
2
Sponsor:
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Version 1.0 (China)
Approval date below
Confidential Information
The information contained in this protocol 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 (LOXO-292/LY3527723), unless such 
persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially 
confidential information exempt from public disclosure.  Eli Lilly and Company requests consultation 
regarding release/redaction prior to any public release.  In the United States, this document is subject to 
Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated 
without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Electronically Signed and Approved by Lilly:  30 July 2019
Amendment (a) Electronically Signed and Approved by Lilly:  20 July 2020
Amendment (b) Electronically Signed and Approved by Lilly:  approval date provided 
below
Approval Date: 01-Feb-2021 GMT

J2G-GH-JZJK Clinical Protocol(b)
2
LY3527723
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment a
20-Jul-2020
Protocol J2G-GH-JZJK
30-Jul-2019
Amendment (b)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
9.4.5 Interim 
Analyses and Data 
Monitoring
Added interim analyses section
An interim analysis is 
planned to assess the 
early efficacy of 
selpercatinib
Synopsis, 2.3 
Exploratory 
Objectives, and 9.1.3 
Exploratory Endpoints
An exploratory objective was added
To estimate the time 
from initial PD (PD1) to 
subsequent PD (PD2) to 
explore whether 
patients continue to 
benefit from study 
treatment after disease 
progression
6.2.3 Cycles 2 and 
Higher and Table 7-1 
Schedule of Activity 
(SoA) note e
Added reconsent information for patients 
continuing treatment beyond PD 
Clarification
Table 7-1 Schedule of 
Activity (SoA)
Revised screening period from ‘Day -28 to 
Day -1’ to ‘Up to 28 days prior to first 
dose’
Clarification
Table 7-1 Schedule of 
Activity (SoA) and 
note w
Clarified disease assessment to be 
performed based on “week”, rather than 
“cycle”, and added post scan frequency 
after initial PD in note w
Clarification
Table 7-1 Schedule of 
Activity (SoA)
Separately displayed the visit window for 
intensive PK and PopPK
Clarification
Throughout the 
protocol
Minor formatting and editorial changes 
Minor, therefore not 
detailed

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
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S y n o psis
TI T L E: 
A P h ase 2 St u d y of Oral Sel percati ni b ( L O X O - 2 9 2) i n Patie nts wit h A d va nce d S oli d T u m ors, I ncl u di n g Rearra n ge d 
i n tra nsfecti o n (R E T ) F usi o n -P ositi ve S oli d T u m ors, Me d ullar y T h y r oi d Ca ncer a n d Ot her T u m ors wit h R E T
Acti vati o n
P R O T O C O L N U M B E R: 
J 2 G-G H -J ZJ K
S T U D Y SI T E S : 
A p pr o xi matel y 4 0 i nstit uti o ns i n C hi na are pla n ne d f or partici pati o n i n t his st u d y.
P H A S E:
2 
O B J E C TI V E S:
Pri m ar y O bjecti ve:

T o assess t he a nti -t u m or acti vit y of sel percati ni b b y deter mi ni n g o bjecti ve res p o nse rate ( O R R ) usi n g 
R E CI S T v 1. 1 , as assesse d b y i n de pe n de nt re vie w c o m mittee (I R C). 
Sec o n d ar y O bjecti ves:

T o assess, f or eac h c o h ort, t he a nti -t u m or acti vit y of sel percati ni b b y deter mi ni n g: 
a.
O R R base d o n R E CI S T v 1. 1 as assesse d b y I n vesti gat or; 
b.
D urati o n of res p o nse ( D O R) as assesse d b y I R C a n d I n vesti gat or; 
c.
Ce ntral ner v o us s yste m ( C N S) O R R base d o n R E CI S T v 1. 1 as assesse d b y I R C (f or patie nts wit h 
br ai n metastases);
d.
C N S D O R as assesse d b y I R C (f or patie nts wit h brai n metastases);
e.
Ti me t o res p o nse ( T T R) base d o n R E CI S T v 1. 1 as assesse d b y I R C a n d I n vesti gat or;
f.
Ti me t o best res p o nse ( T T B R) base d o n R E CI S T v 1. 1 as assesse d b y I R C a n d I n vesti gat or;
g.
Cli nical be nefit rate ( C B R) base d o n t he pr o p orti o n of patie nts wit h best o verall res p o nse of 
c o m plete res p o nse ( C R), partial res p o nse ( P R), or sta ble disease ( S D) lasti n g 1 6 or m ore wee ks 
f oll o wi n g i nitiati o n of sel percati ni b as assesse d b y I R C a n d I n vest i gat or;
h.
Pr o gressi o n -free s ur vi val ( P F S) as assesse d b y I R C a n d I n vesti gat or;
i.
O verall s ur vi val ( O S) f oll o wi n g i nitiati o n of sel percati ni b.

T o c haracterize t he safet y pr ofile a n d t olera bilit y of sel percati ni b.

T o c haracterize t he p har mac o ki netics ( P K ) pr o perties of sel percati ni b.
E x pl or at or y O bjecti ves:

T o deter mi ne t he relati o ns hi p bet wee n P K a n d dr u g effects, i ncl u di n g efficac y a n d safet y.

T o e val uate t he ser u m t u m or mar kers carci n oe m br y o nic a nti ge n ( C E A) a n d calcit o ni n (f or patie nts wit h 
M T C ), t h yr ogl o b uli n (f or patie nts wit h n o n -M T C t h yr oi d ca ncer, u nless n ot meas ura ble d ue t o prese nce of 
a nti -t h yr ogl o b uli n a nti b o dies), a n d a dre n oc ortic otr o pic h or m o ne ( A C T H)/c ortis ol (f or patie nts wit h 
C us hi n g’s disease relate d t o t heir ca ncer), bef ore, d uri n g, a n d at t he e n d of treat me nt ( E O T) wit h 
sel percati ni b.

T o c ollect patie nt -re p orte d o utc o mes ( P R O) data t o e x pl ore disease-relate d s y m pt o ms a n d healt h-relate d 
q ualit y  of life ( H R Q o L).

T o esti mate t he ti me fr o m i nitial pr o gr essi ve disease ( P D1) t o s u bse q ue nt P D ( P D 2) t o e x pl ore w het her 
patie nts c o nti n ue t o be nefit fr o m st u d y treat me nt after disease pr o gressi o n .

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
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L Y 3 5 2 7 7 2 3
S T U D Y D E SI G N:
T his is a n o pe n la bel, m ulti -ce nter P hase 2 st u d y i n patie nts wit h a d va nce d s oli d t u m ors, i ncl u di n g R E T f usi o n-
p ositi ve s oli d t u m ors (e. g., n o n -s mall cell l u n g ca ncer [ N S C L C], t h yr oi d, pa ncreas, c ol orectal), R E T -m uta nt 
M T C, a n d ot her t u m ors wit h R E T acti vati o n (e. g., m utati o ns i n ot her t u m or t y pes or ot her e vi de nce of R E T
acti vati on). Patie nts wit h R E T alt erati o ns i n t u m or a n d/ or bl o o d will be i de ntifie d t hr o u g h m olec ular assa ys. 
T he R E T alterati o n res ult s h o ul d be ge nerate d fr o m a la b orat or y wit h certificati o n b y C hi na Nati o nal 
Accre ditati o n Ser vice f or C o nf or mit y Assess me nt ( C N A S), E xter nal Q ualit y Asses s me nt ( E Q A), Cli nical 
La b orat o r y I m pr o ve me nt A me n d me nts ( C LI A), C olle ge Of A merica n Pat h ol o gists ( C A P) or ot her si milar 
certificati on. T he S p o ns or s h o ul d be c o ntacte d t o disc uss test res ults t o e ns ure trial eli gi bilit y. 
At least 2 0 patie nts f or C o h orts 1 a n d 2 a n d u p t o 2 5 patie nts i n C o h ort 3 har b ori n g a R E T ge ne alterati o n i n 
t u m or a n d/ or bl o o d (e. g., ge ne f usi o ns a n d/ or m utati o ns, e xcl u di n g s y n o ny m o us, fra mes hift, or n o nse nse 
m utati o ns) will be e nr olle d t o o ne of t hree c o h orts (refer t o t he St u d y Sc he ma ) as n ote d bel o w. F or C o h orts 1
a n d 2, e vi de nce of a R E T ge ne alterati o n i n t u m or (i.e., n ot j ust bl o o d) as defi ne d i n S y n o psis Ta ble 1 ) is 
re q uire d (a p ositi ve ger mli ne test f or a R E T m utati o n is acce pta ble f or patie nts wit h M T C). 
E nr oll me nt will be base d o n t u m or t y pe, t y pe of R E T alterati o n, a n d pri or treat me nt: 
1.
C o h ort 1: R E T -f usi o n-p ositi ve s oli d t u m or pr o gresse d o n or i nt olera nt t o ≥1 pri or sta n dar d t hera p y , or  
patie nts w h o decl i ne d or n ot s uita ble f or sta n dar d first li ne t hera p y i n t he o pi ni o n of t he i n vesti gat or. F or
l u n g ca ncer, o nl y patie nts har b ori n g R E T -KI F 5 B, R E T -C C D C 6, R E T -N C O A 4 ca n be e nr olle d i n C o h ort 1. 
F or ot her s oli d t u m or, patie nts wit h a n y R E T f usi o n ca n be e nr oll e d i n C o h ort 1 (at least 2 0 patie nts);
2.
C o h ort 2: R E T -m uta nt M T C wit h or wit h o ut pri or s yste matic t hera p y (at least 2 0 patie nts);
3.
C o h ort 3 ( u p t o 2 5 patie nts):

C o h orts 1 -2 wit h o ut meas ura ble disease;

Ot her R E T -altere d s oli d t u m or or ot her R E T alterati on/acti vati o n n ot meeti n g t he re q uire me nts f or 
C o h orts 1 o r 2;M T C s y n dr o me s pectr u m ca ncers (e. g. M T C, p he oc hr o m oc yt o ma) wit h ne ur oe n d ocri ne 
feat ures/ differe ntiati o n or p o orl y differe ntiate d t h yr oi d ca ncers wit h ot her R E T alterati o n/acti vati o n ma y 
be all o we d wit h pri or s p o ns or a p pr o val;

K n o w n  cf D N A p ositi ve f or a R E T ge ne alterati o n n ot k n o w n t o be prese nt i n a t u m or sa m ple ma y be 
all o we d wit h s p o ns or a p pr o val ;

Fl u oresce nce i n s it u h ybr i dizati o n ( FI S H) p ositi ve i n t u m or wit h o ut p ol y merase c hai n reacti o n ( P C R )/
ne xt ge nerati o n se q ue nci n g ( N G S) res ult ma y be all o we d wit h s p o ns or’s a p pr o val.
S y n o psis T a ble 1: Defi niti o n of R E T Alter ati o ns
R E T m ut ati o n *
Pre vi o usl y re p orte d acti vati n g R E T ge ne m utati o n, e xcl u di n g s y n o n y m o us, fra mes hift or 
n o nse nse m utati o ns. Refer t o A p pe n di x B f or e xa m ples.
F or M T C, R E T ge ne m utati o n n ot k n o w n t o be acti vati n g m a y be e nr olle d wit h s p o ns or’s
a p pr o val, t o C o h ort 3.
R E T f usi o n *
B y P C R or N G S ( FI S H as t he o nl y m olec ular res ult is acce pta ble f or C o h ort 3, b ut n ot C o h ort 1).
R E T m ut ati o n or R E T f usi o n *
N o ot her k n o w n vali date d dri ver alterati o n(s). Refer t o A p pe n di x C f or e xa m ples.
*  Acc or di n g t o la b orat or y wit h C N A S , E Q A , C LI A, C A P or si milar certificati o n, s o l o n g as a writte n 
M olec ular Pat h ol o g y Re p ort is a vaila ble a n d clearl y asserts t he prese nce o f t he refere nce d R E T alterati o n.
A b bre viati o ns: FI S H -Fl u oresce nce I n Sit u H y bri dizati o n; M T C -Me d ullar y T h yr oi d Ca ncer; N G S -Ne xt Ge nerati o n 
Se q ue nci n g; P C R -P ol y merase C hai n Reacti o n.
St u d y Sc he m a

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
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L Y 3 5 2 7 7 2 3
Pri m ar y e n d p oi nt: O R R per R E CI S T v 1. 1 b y i n de pe n de nt re vie w c o m mittee
Sec o n d ar y e n d p oi nt: O R R per R E CI S T v 1. 1 b y  i n vesti gat or, D O R, C N S O R R, C N S D O R, C B R, T T R, T T B R, P F S, O S, 
P K, safet y
A b bre viati o ns: BI D -t wice dail y; M T C-me d ullar y t h yr oi d ca ncer; cf D N A -circ ulati n g free t u m or de o x yri b o n ucleic aci d.
D O R - d urati o n of res p o nse , C N S O R R- ce ntral ner v o us s yste m o bjecti ve res p o nse rate, C N S D O R- ce ntral ner v o us s yste m 
d urati o n of res p o nse , C B R- cli nical be nefit rate, T T R- ti me t o res p o nse, T T B R- ti me t o best res p o nse, P F S-pr o gressi o n -free 
s ur vi val, O S- o verall s ur vi val , P K- p har mac o ki netic
E LI GI BI LI T Y C RI T E RI A :
I ncl usi o n Criteri a:
1.
Patie nts wit h a l ocall y a d va nce d or metastatic s oli d t u m or w h o:

ha ve pr o gresse d o n or are i nt olera nt t o sta n dar d t hera p y, or

n o sta n dar d t hera p y e xists, or i n t he o pi ni o n of t he I n vesti gat or, are n ot ca n di dates f or or w o ul d be 
u nli kel y  t o t olerate or deri ve si g nifica nt cli nical be nefit fr o m sta n dar d t hera p y, or 

decli ne sta n dar d t hera p y.
2.
Pri o r M KIs wit h a nti-R E T acti vit y are all o we d. Refer t o A p pe n di x A f or e xa m ples of M KIs wit h a nti-R E T 
acti vit y. H o we ver, pri or treat me nt wit h a selecti ve R E T i n hi bit or(s) (i ncl u di n g i n vesti gati o nal selecti ve R E T 
i n hi bit or(s), s uc h as B L U-6 6 7, R X D X - 1 0 5) is pro hi bite d. T he s pecific a ge nt(s), d urati o n of treat me nt, 
cli nical be nefit, a n d reas o n f or disc o nti n uati o n (e. g., P D, dr u g t o xicit y, or i nt olera nce) s h o ul d be 
d oc u me nte d f or all ki nase i n hi bit ors t he patie nt has bee n e x p ose d t o.
3.
E vi de nce of a R E T ge ne altera ti on i n t u m or a n d/ or bl o o d (e. g., ge ne rearra n ge me nt a n d/ or m utati o n, 
e xcl u di n g s y n o n y m o us, fra mes hift, or n o nse nse m utati o ns), as i de ntifie d t hr o u g h m olec ular assa ys, as 
perf or me d f or cli nical e val uati o n. T he R E T alterati on res ult s h o ul d be ge nerate d fr o m a la b orat or y wit h 
certificati on b y  C N A S, E Q A, C LI A, C A P or  ot her si milar certificati o n. T he S p o ns or s h o ul d be c o ntacte d t o 
disc uss test res ults fr o m la bs w here s uc h certificati o n is n ot clearl y de m o nstrate d t o deter mi ne eli gi bilit y. 
4.
Meas ura ble or n o n -mea s ura ble disease as deter mi ne d b y R E CI S T v 1. 1.
5.
At least 1 8 years of a ge. 
6.
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us sc ore of 0, 1, or 2, wit h n o s u d de n 
deteri orati o n 2 wee ks pri or t o t he first d ose of st u d y treat me nt.
7.
Life e x pecta nc y of a t least 3 m ont hs.
8.
Arc hi ve d t u m or tiss ue sa m ple a vaila ble f or C o h or t 1 a n d 2. 
9.
A de q uate he mat ol o gic stat us, defi ne d as:

A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 0 1 0 9/ L n ot re q uiri n g gr o wt h fact or s u p p ort f or at least 7 da ys 
pri or t o treat me nt, a n d

Platelet c o u nt ≥7 5 1 0 9/ L n ot re q uiri n g tra nsf usi o n s u p p ort f or at least 7 da y s pri or t o treat me nt, a n d

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
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
He m o gl o bi n ( H b) ≥9 g/ d L n ot re q uiri n g tra nsf usi o n s u p p ort or er yt hr o p oieti n f or at least 7 da ys pri or t o 
treat me nt.
1 0. A de q uate he patic f u ncti o n, defi ne d as:

Ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T) ≤2. 5 t he u p per li mit of n or mal 
( U L N) or ≤5 U L N wit h d oc u me nte d li ver i n v ol ve me nt (s uc h as li ver metastasis or a pri mar y biliar y 
t u m or) a n d

T otal bilir u bi n ≤1. 5 U L N or ≤3 U L N wit h d oc u me nte d li ver i n v ol ve me nt ( patie nts wit h Gil bert’s 
Disease ma y be e nr olle d wit h pri or S p o ns or a p pr o val).
1 1. A de q uate re nal f u ncti o n, wit h esti mate d gl o mer ular filtrati o n rate (e G F R) ≥3 0 m L/ mi n ute. Sites ca n use 
t heir o w n cli nical sta n dar d f or e G F R. If n o cli nical sta n dar d, bel o w M o dificati o n of Diet i n Re nal Disease 
( M D R D) st u d y e q uati o n ca n be use d: eG F R ( m L/ mi n/ 1. 7 3 m²) = 1 7 5 × ( S cr/ 8 8. 4)-1. 1 5 4 × ( A ge) -0. 2 0 3 × ( 0. 7 4 2 
if fe male) × ( 1. 2 1 2 if Africa n A merica n) ( SI u nits). < <
1 2. A bilit y t o s wall o w ca ps ules a n d c o m pl y wit h o ut patie nt treat me nt, la b orat or y m o nit ori n g, a n d re q uire d 
cli nic visits f or t he d urati o n of st u d y partici pati o n.
1 3. Willi n g ness of me n a n d w o me n of re pr o d ucti ve p ote ntial t o o bser ve c o n ve nti o nal a n d effecti ve birt h c o ntr ol 
f or t he d urati o n of treat me nt a n d f or 3 m o nt hs f oll o wi n g t he last d ose of st u d y treat me nt; t his ma y i ncl u de 
barrier met h o ds s uc h as a c o n d o m or dia p hra g m wit h s per mici dal gel. Male st u d y partici pa nts s h o ul d refrai n 
fr o m s per m d o nati o n d uri n g st u d y treat me nt a n d u p t o 6 m o nt hs f oll o wi n g t he last d ose of sel percati ni b.
1 4. Writte n
i nf or me d c o nse nt a n d a n y l ocal re q uire d a ut h orizati o n (e. g., Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y Act i n t he U S, E ur o pea n U ni o n [ E U] Data Pri vac y Directi ve i n t he E U) o btai ne d fr o m t he 
patie nt/le gal re prese ntati ve pri or t o perf or mi n g a n y pr ot oc ol -relate d pr oce d ures, i ncl u di n g scree ni n g 
e val uati o ns.
1 5. C o h orts 1 a n d 2: faile d or i nt olera nt t o sta n dar d of care; see S y n o psis Ta ble 2 for  E xa m ples.
S y n o psis T a ble 2: St a n d ar d of C are T her a pies f or C o h ort 1 a n d 2 
A b bre viati o ns : E G F R -e pi der mal gr o wt h fact or rece pt or; H E R 2 -h u ma n e pi der mal gr o wt h fact or rece pt or 2; M T C -me d ullar y
t h yr oi d ca ncer; N S C L C-n o n -s mall cell l u n g ca ncer; P D- 1-pr o gra m me d cell deat h pr otei n 1; P D -L 1 -pr o gra m me d deat h -li ga n d 
1; V E G F -vasc ular e n d ot helial gr o wt h fact or.
1 6. C o h orts 1- 2: e nr oll me nt will be restricte d t o patie nts wit h e vi de nce of a R E T ge ne alterati o n i n t u m or 
(i.e., n ot j ust bl o o d) as defi ne d i n S y n o psis Ta ble 1 . H o we ver, a p ositi ve ger mli ne D N A test f or a R E T ge ne 
m utati o n as defi ne d i n A p pe n di x B ( Ta ble 1 1 - 2) is acce pta ble i n t he a bse nce of t u m or tiss ue testi n g f or 
patie nts wit h M T C.
1 7. C o h orts 1- 2: at least o ne meas ura ble lesi o n as defi ne d b y R E CI S T v 1. 1 a n d n ot pre vi o usl y irra diate d ( u nless 
P D f or t he irra diate d lesi o n[s] has bee n ra di o gra p hicall y d oc u me nte d). 
1 8. C o h ort 2: ra di o gra p hic P D wit hi n t he pre vi o us 1 4 m o nt hs f or s yste matic treat me nt naï ve patie nt.
C O H O R T
T H E R A P Y
C o h ort 1: R E T F usi o n -P ositi ve 
S oli d T u m or 
N S C L C: plati n u m -base d c he m ot hera p y ( or ot her c he m ot hera p y if n ot eli gi ble f or 
plati n u m) or P D -1/ P D -L 1 i m m u n ot hera p y or b ot h
T h yr oi d: s orafe ni b, patie nts m ust als o be ra di oacti ve i o di ne-refract or y as 
a p pr o priate
C ol orectal : fl u or o p yri mi di ne-base d c he m ot hera p y, wi t h or wit h o ut a nti-V E G F -
directe d t hera p y or a nti -E G F R -directe d t hera p y as a p pr o priate f or t he disease
Pa ncreas: fl u or o p yri mi di ne-base d, ge mcita bi ne -base d, or S -1 c he m ot hera p y 
Breast : a nt hrac ycli ne, ta xa ne, H E R 2 -directe d t hera p y a n d/ or h or m o nal t hera p y or 
ot her sta n dar d t hera p y a p pr o priate f or t he disease
Ot her : pri or sta n dar d t hera p y f or t he disease 
C o h ort 2: R E T -m uta nt M T C 
N o a p pr o ve d S O C

J2G-GH-JZJK Clinical Protocol(b)
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Exclusion Criteria:
19. Cohorts 1-2, an additional validated oncogenic driver that could cause resistance to selpercatinib treatment if 
known. See Appendix C (Table 11-3) for examples.
20. Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor(s), such as 
BLU-667, RXDX-105, etc.).
21. Are currently enrolled in any other clinical study involving an investigational product or any other type of 
medical research judged not to be scientifically or medically compatible with this study.
22. Investigational agent or anticancer therapy within 5 half-lives or 2 weeks (whichever is shorter) prior to 
planned start of selpercatinib. In addition, no concurrent investigational anti-cancer therapy is permitted.
23. Major surgery (excluding placement of vascular access or biopsy) within 4 weeks prior to planned start of 
selpercatinib.
24. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, 
with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field 
of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment.
25. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 except where otherwise noted in 
this eligibility criteria at the time of starting study treatment with the exception of alopecia and Grade 2, prior 
platinum therapy-related neuropathy.
26. Symptomatic primary CNS tumor, symptomatic CNS metastases, leptomeningeal carcinomatosis, or 
untreated spinal cord compression.
Exception: Patients are eligible if neurological symptoms and CNS imaging are stable and steroid dose is 
stable for 14 days prior to the first dose of selpercatinib and no CNS surgery or radiation has been 
performed for 28 days, 14 days if stereotactic radiosurgery [SRS].
Note: All prior local treatments for CNS disease (e.g. surgery, whole brain radiation [WBRT], SRS), the 
start and stop dates for each prior local therapy, the specific lesions treated (if SRS and/or surgery), whether 
the patient developed intracranial progression after the last prior local treatment, and which lesions 
progressed since completion of the local therapy must be documented.
27. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior 
to planned start of selpercatinib or prolongation of the QT interval corrected for heart rate using Fridericia’s 
formula (QTcF) > 470 msec. Correction of suspected drug-induced QTcF prolongation may be attempted at 
the investigator’s discretion if clinically safe to do so.
28. History of Human Immunodeficiency Virus (known HIV 1/2 antibodies positive); patients with unknown 
HIV status do not need to be tested.
29. History of active hepatitis B (known positive hepatitis B surface antigen [HbsAg] and quantitative hepatitis B 
DNA greater than the upper limit of detection of the assay) or C (known positive hepatitis C antibody and 
quantitative hepatitis C RNA greater than the upper limit of detection of the assay); patients with unknown 
hepatitis B/hepatitis C status do not need to be tested.
30. Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing intercurrent illness, such 
as hypertension or diabetes, despite optimal treatment. Screening for chronic conditions is not required.
31. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal 
absorption of the study drug.
32. Uncontrolled symptomatic hyperthyroidism or hypothyroidism.
33. Uncontrolled symptomatic hypercalcemia or hypocalcemia.
34. Concurrent use of drugs known to prolong QTc (refer to Appendix D of the main protocol)
35. Pregnancy or lactation. Breast-feeding should be interrupted when selpercatinib is started; breast-feeding can 
be resumed 3 months after discontinuation of selpercatinib.
36. Active second malignancy other than minor treatment of indolent cancers with prior sponsor approval.
PLANNED SAMPLE SIZE:
The study will enroll approximately 75 patients in total.
INVESTIGATIONAL PRODUCT:

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Selpercatinib will be provided in a capsule in 40 mg and 80 mg dose strengths. The capsules will be provided to 
the sites for distribution to the patient for outpatient administration at the assigned dose level. Dosing is intended 
to be fixed (i.e., not weight-based or body surface area [BSA]-based).
TREATMENT PROCEDURES:
Patients will begin dosing on Cycle 1 Day 1 (C1D1) according to the assigned cohort with cycle length of 28 
days. Individual patients will continue selpercatinib 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, the patient is deriving clinical benefit from 
continuing study treatment and continuation of treatment is approved by the Sponsor.
STUDY ASSESSMENTS:
Safety observations include physical examinations, body weight, ECOG score, clinical AEs, laboratory variables 
(hematology, serum chemistries, and urinalysis), electrocardiogram (ECG), vital signs, and thyroid function. 
Efficacy assessments include tumor evaluation every 8 weeks beginning with Cycle 3 Day 1 (C3D1) (±7 days) 
through C13D1, and approximately every 12 weeks thereafter. In addition, Investigators may conduct an initial 
tumor evaluation on C2D1 (±7 days) and a confirmatory tumor evaluation a minimum of 4 weeks (i.e., 28 days) 
after the first tumor evaluation that shows a CR or PR by RECIST v1.1, if consistent with local regulatory 
authority requirements. In fusion-positive solid tumors, patients with a history of CNS metastases, brain 
metastases at baseline, or other clinically syndrome required brain imaging, the baseline and subsequent serial 
scans will be performed. All scans will be collected and stored at a central facility to permit central reviewer 
assessment, for the purpose of confirming PD if not occurring on study, subsequent anticancer therapy(ies), and 
survival. Long-term follow-up (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.  Patients who 
discontinue study treatment for reasons other than PD, withdrawal of consent or initiation of a new anticancer 
therapy(ies), may (but for practical reasons and to minimize patient inconvenience, are not required to) undergo 
disease assessment by imaging (as specified above) until PD, withdrawal of consent or initiation of a new 
anticancer therapy(ies).
Serial blood samples for intensive PK monitoring will be collected on C1D1 and C1D8 for a total of 12 patients, 
blood samples for population pharmacokinetic (PopPK) will be collected for all enrolled patients. 
Archived tumor tissue will be obtained for patients if available and stored by the Sponsor. Patients who do not 
have adequate archival tumor tissue available should undergo a fresh tumor biopsy, if it is considered safe to 
perform, prior to treatment. If archived tumor tissue is not available and a fresh biopsy cannot be safely 
performed, the patient may still be eligible with prior Sponsor approval. Additionally, optional fresh tumor 
biopsies should be obtained prior to treatment with selpercatinib if archived tumor tissue was obtained prior to 
progression on the last MKI with anti-RET activity and at progression.
HRQoL instruments (European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 [EORTC QLQ-C30] will be administered pre-dose on C1D1 and subsequent assessments 
will occur at the same cycle visits as disease assessments until EOT. For MTC patients with diarrhea present at 
baseline, bowel assessments will be collected pre-dose C1D1, weekly for the first cycle, and at D1 of each cycle 
until EOT.
STUDY ENDPOINTS:
Primary Endpoint:

ORR based on RECIST v1.1 assessed by IRC.
Secondary Endpoints: 

Parameters of anti-tumor activity/clinical benefit, including: ORR (by Investigator), DOR (by IRC and 
Investigator), CNS ORR (by IRC), CNS DOR (by IRC), TTR (time to response), TTBR (time to best 
response by IRC and Investigator), CBR (by IRC and Investigator), PFS (by IRC and Investigator), and OS.

Frequency, severity, and relatedness of treatment-emergent adverse events (TEAEs) and Serious Adverse 
Events (SAEs), changes in hematology and blood chemistry values, assessments of physical examinations, 
vital signs, and ECGs.

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
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L Y 3 5 2 7 7 2 3

Plas ma c o nce ntrati o ns of sel percati ni b a n d P K para meters, i ncl u di n g, b ut n ot li mite d t o, A U C 0- 2 4, Cma x , a n d 
T ma x.
E x pl or at or y E n d p oi nts:

Differe nces i n efficac y a n d safet y base d o n sel percati ni b P K para meters.

C ha n ges i n C E A a n d calcit o ni n (f or patie nts wit h M T C), t h yr o gl o b uli n ( n o n -M T C patie nts), A C T H a n d 
c ortis ol ( patie nts wit h C us hi n g’s disease relate d t o t heir ca ncer) wit h sel percati ni b treat me nt.

C ha n ges fr o m baseli ne i n disease -relate d s y m pt o ms a n d H R Q o L, as meas ure d b y E O R T C Q L Q -C 3 0 
(a d ults), a n d patie nt b o wel diaries ( M T C patie nts o nl y).

Ti me fr o m P D 1 t o P D2 f or patie nts w h o c o nti n ue t o recei ve st u d y treat me nt be y o n d disease pr o gressi o n.
S T A TI S TI C A L M E T H O D S:
S afet y A n al yses:
T he safet y p o p ulati o n will c o nsist of all e nr olle d patie nts w h o recei ve at least o ne d ose of sel percati ni b. 
A baseli ne meas ure me nt a n d at least o ne la b orat or y or ot her safet y -relate d meas ure me nt o btai ne d after treat me nt 
of st u d y dr u g ma y be re q uire d f or i n cl usi o n i n t he a nal ysis of a s pecific safet y para meter.
Effic ac y A n al yses:
T he efficac y a nal ysis will be c o n d ucte d o n all treate d patie nts e nr olle d i n C o h ort 1 a n d 2 w h o ha ve c o nfir me d 
R E T f usi o n p ositi ve s oli d t u m or or R E T m uta nt M T C b y ce ntral la b, res pe cti vel y.
O R R will be esti mate d base d o n t he o bser ve d pr o p orti o n of patie nts w h ose best o verall res p o nse is c o nfir me d 
C R or P R as deter mi ne d b y I R C a n d b y t he treati n g I n vesti gat or. T he esti mates of t he O R R will be acc o m pa nie d 
b y a 2 -si de d 9 5 % e xact bi n o mia l c o nfi de nce i nter val ( CI). Waterfall pl ots will be use d t o de pict gra p hicall y t he 
ma xi m u m decrease fr o m baseli ne i n t he s u m of dia meters of tar get lesi o ns. T he d urati o n of res p o nse, P F S, a n d 
O S will be s u m marize d descri pti vel y f or eac h c o h ort usi n g t he Ka pla n -Meier met h o d.
P h ar m ac o ki netic A n al yses:
Plas ma c o nce ntrati o ns of sel percati ni b will be deter mi ne d wit h a vali date d bi oa nal ytical assa y. T he f oll o wi n g 
P K para meters will be calc ulate d fr o m plas ma c o nce ntrati o ns deter mi ne d o n C ycle 1 D a y 1 a n d Da y  8: Cm a x, 
T ma x , area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me 0 t o t ( A U C0 –t), area u n der t he c o nce ntrati o n ti me 
c ur ve fr o m ti me 0 t o i nfi nit y ( A U C 0 – ∞), a p pare nt oral cleara nce ( C L/ F), a p pare nt v ol u me of distri b uti o n ( Vz/ F), 
a n d ter mi nal eli mi nati o n h alf-life ( T1/ 2). S u m mar y statistics will be ge nerate d b y c o h ort as a p pr o priate.

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Table of Contents
Protocol Amendment Summary of Changes Table ......................................................................2
Synopsis......................................................................................................................................3
Table of Contents......................................................................................................................10
List of Tables............................................................................................................................13
List of Figures...........................................................................................................................14
List of Appendices ....................................................................................................................15
List of Abbreviations and Definition of Terms ..........................................................................16
1
Introduction ......................................................................................................................21
1.1
Tumors with RET Abnormalities and Current Treatment Options ................................21
1.2
Study Rationale............................................................................................................23
1.3
Selpercatinib Pre-clinical Data Summary .....................................................................23
1.4
Determination Starting Dose ........................................................................................24
1.5
Clinical Experience ......................................................................................................24
1.6
Benefit and Risk Assessment........................................................................................26
1.6.1
Known and Anticipated Risks ..............................................................................26
1.6.2
Potential Drug Interactions...................................................................................27
2
Study Objectives...............................................................................................................30
2.1
Primary Objective ........................................................................................................30
2.2
Secondary Objectives...................................................................................................30
2.3
Exploratory Objectives.................................................................................................30
3
Investigational Plan...........................................................................................................32
3.1
Study Design................................................................................................................32
3.2
Length of Study and End of Study................................................................................32
3.2.1
Length of Study ...................................................................................................32
3.2.2
End of Study........................................................................................................33
3.3
General Treatment Procedures......................................................................................33
3.4
Investigational Plan......................................................................................................34
3.5
Definition of RET Alterations.......................................................................................36
3.6
Number of Patients.......................................................................................................36
3.7
Investigational Sites .....................................................................................................36
4
Selection of Study Population ...........................................................................................37
4.1
Inclusion Criteria..........................................................................................................37
4.2
Exclusion Criteria ........................................................................................................40
5
Enrollment Procedures......................................................................................................42
6
Treatment..........................................................................................................................43

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6.1
Investigational Product.................................................................................................43
6.1.1
Capsules...............................................................................................................43
6.2
Selpercatinib Administration........................................................................................43
6.2.1
General Dosing Instructions.................................................................................43
6.2.2
Cycle 1.................................................................................................................44
6.2.3
Cycles 2 and Higher.............................................................................................44
6.2.4
Dose Delays and Modifications............................................................................44
6.3
Concomitant Medications.............................................................................................49
6.3.1
General ................................................................................................................49
6.3.2
Allowed Concomitant Medications ......................................................................49
6.3.3
Other Concomitant Medications...........................................................................50
6.3.4
Contraindications .................................................................................................51
6.4
Discontinuation of Study Intervention..........................................................................51
6.4.1
Discontinuation of Inadvertently Enrolled Patients...............................................52
6.5
Discontinuation/ Withdraw from the Study...................................................................53
6.6
Lost to Follow-Up........................................................................................................53
7
Tests and Evaluations........................................................................................................54
7.1
Screening Period ..........................................................................................................61
7.2
Cycle 1.........................................................................................................................62
7.3
Cycles 2 and Higher.....................................................................................................65
7.4
End of Treatment Visit (All Patients) ...........................................................................66
7.5
Safety Follow-up Visit (SFU).......................................................................................67
7.6
Long-term Follow-up (LTFU)......................................................................................68
7.7
Procedures for Special Tests.........................................................................................68
7.7.1
Tumor Measurements...........................................................................................68
7.7.2
Central Collection of Radiographic Studies..........................................................69
7.7.3
Pharmacokinetics .................................................................................................69
7.7.4
Collection of EORTC QLQ-C30 and Bowel Diary...............................................69
7.7.5
Correlative Studies...............................................................................................70
8
Study Assessments and Procedures ...................................................................................72
8.1
Efficacy Assessments...................................................................................................72
8.1.1
Imaging................................................................................................................72
8.2
Safety Assessments ......................................................................................................73
8.2.1
Electrocardiograms ..............................................................................................73
8.2.2
Clinical Safety Laboratory Assessments...............................................................74
8.2.3
Adverse Events and Serious Adverse Events........................................................75
8.3
Treatment of Overdose.................................................................................................79
8.4
Pharmacokinetics .........................................................................................................79

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8.5
Pharmacodynamics ......................................................................................................80
8.6
Biomarker ....................................................................................................................80
8.7
Medical Resource Utilization and Health Economics ...................................................81
9
Statistical Considerations ..................................................................................................83
9.1
Study Endpoints...........................................................................................................83
9.1.1
Primary Endpoint.................................................................................................83
9.1.2
Secondary Endpoints............................................................................................83
9.1.3
Exploratory Endpoints..........................................................................................83
9.2
Analysis Populations....................................................................................................83
9.3
Determination of Sample Size ......................................................................................84
9.4
Statistical Methods.......................................................................................................85
9.4.1
Demographics and Baseline Characteristics..........................................................85
9.4.2
Safety Analyses....................................................................................................85
9.4.3
Efficacy Analyses ................................................................................................86
9.4.4
Pharmacokinetic Analyses....................................................................................87
9.4.5
Interim Analyses and Data Monitoring.................................................................87
10
Study Administration ........................................................................................................88
10.1
Regulatory and Ethical Considerations .........................................................................88
10.2
Informed Consent Process............................................................................................88
10.3
Data Management ........................................................................................................89
10.3.1
Data Protection ....................................................................................................89
10.3.2
Committees Structure...........................................................................................89
10.3.3
Dissemination of Clinical Study Data...................................................................89
10.3.4
Data Quality Assurance........................................................................................89
10.3.5
Data Capture System............................................................................................90
10.3.6
Source Documents ...............................................................................................91
10.4
Study Monitoring .........................................................................................................91
10.5
Termination..................................................................................................................92
10.6
Records Retention........................................................................................................92
10.7
Confidentiality of Information......................................................................................92
11
Appendices .......................................................................................................................93
12
References ......................................................................................................................117

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List of Tables
Table 3-1
Definition of RET Alterations.................................................................36
Table 4-1
Standard of Care Therapies for Cohort 1 and 2 .......................................39
Table 6-1
Suggested Toxicity Management for all Parts of this Study ....................46
Table 7-1
Schedule of Activity (SoA).....................................................................55
Table 9-1
Lower bounds of 2-sided exact 95% confidence intervals based on 
different sample size and observed ORR.................................................84
Table 11-1
Examples of Multikinase Inhibitors (MKIs) with Anti-RET 
Activity ..................................................................................................93
Table 11-2
Examples of RET Activating Mutations..................................................94
Table 11-3
Examples of Validated Oncogenic Drivers .............................................95
Table 11-4
Examples of Inhibitors of CYP3A4 ........................................................96
Table 11-5
Examples of Inducers of CYP3A4 ..........................................................96
Table 11-6
Examples of Proton Pump Inhibitors (PPIs)............................................99
Table 11-7
Eastern Cooperative Oncology Group (ECOG) Performance Scale.......100
Table 11-8
Response Evaluation Criteria in Solid Tumors (RECIST version 
1.1) Guidelines for Tumor Response.....................................................104
Table 11-9
Overall Response Criteria: Time Point Response..................................105

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List of Figures
Figure 3-1
Study Schema.........................................................................................35

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List of Appendices
Appendix A
Examples of Multikinase Inhibitors (MKIs) with Anti-RET 
Activity ..................................................................................................93
Appendix B
Examples of RET Activating Mutations..................................................94
Appendix C
Examples of Validated Oncogenic Drivers .............................................95
Appendix D
Inhibitors and Inducers of CYP3A4........................................................96
Appendix E
Proton Pump Inhibitors (PPIs)................................................................99
Appendix F
Performance Scales ..............................................................................100
Appendix G
Tumor Measurements and Assessment of Disease Response using 
RECIST version 1.1..............................................................................101
Appendix H
Clinical Laboratory Tests......................................................................107
Appendix I
Contraceptive Guidance and Collection of Pregnancy Information .......109
Appendix J
European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and 
Bowel Diary.........................................................................................112
Appendix K
Protocol Amendment History ...............................................................113

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
1 6
L Y 3 5 2 7 7 2 3
List of A b bre vi ati o ns a n d Defi niti o n of Ter ms
A b bre vi ati o n 
or Ter m
Defi niti o n
A E
a d verse e ve nt
A C T H
a dre n oc ortic otr o pic h or m o ne
A L K
a na plastic l y m p h o ma ki nase
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
a nti-P D 1
a nti-pr o gra m me d cell deat h pr otei n 1
A S T
as partate a mi n otra nsferase
A T P
a de n osi ne tri p h os p hate
A U C
ar ea u n der t he c o nce ntrati o n vs ti me c ur ve
A U C 0 – ∞
ar ea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y
A U C 0-t
ar ea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me 0 t o t
A U C 0- 2 4
ar ea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me 0 t o 2 4 h o urs
A U C t au
ar ea u n der t he c o nce ntrati o n vers us ti me c ur ve calc ulate d d uri n g t he d osi n g i nter val 
at stea d y state
BI D
t wice dail y
B U N
bl o o d urea nitr o ge n
B S A
b o d y s urface area
C
C ycle
C 1 D 1
C ycle 1 Da y 1
C A P
C olle ge of A merica n Pat h ol o gists
C B R
cli nical be nefit rate
C D M S
Cli nical Data Ma na ge me nt S yste m
C E A
carci n oe m br y o nic a nti ge n
cf D N A
circ ulati n g free de o x yri b o n ucleic aci d
CI
c o nfi de nce i nter val
C L/ F
a p pare nt oral cleara nce of dr u g
C ma x
ma xi m u m  dr u g c o nce ntrati o n
C mi n
mi ni m u m dr u g c o nce ntrati o n
C N A S
C hi na Nati o nal Accre ditati o n Ser vice f or C o nf or mit y Assess me nt
C N S
ce ntral ner v o us s yste m
C R
c o m plete res p o nse
C T
c o m p uterize d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts

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Abbreviation 
or Term
Definition
CYP
cytochrome P450
D
Day
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate 
EGFR
epidermal growth factor receptor
EORTC
European Organization for Research and Treatment of Cancer 
EORTC QLQ-
C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
EOT
end of treatment
ER
estrogen receptor
FAS
Full Analysis Set
FGFR
fibroblast growth factor receptor
FISH
Fluorescence in Situ Hybridization
FLAIR/T2
T2-weighted fluid-attenuated inversion recovery
GALT
gastrointestinal associated lymphoid tissues
GCP
Good Clinical Practices
GI 
gastrointestinal
GLP
Good Laboratory Practice
GnRH
gonadotropin-releasing hormone
5-HT3
serotonin type 3
H2
histamine-2
Hb
Hemoglobin
hERG
Human ether-à-go-go related gene
HRQoL
Health-Related Quality of Life
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
ICH GCP
International Conference on Harmonisation-Good Clinical Practices

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Abbreviation 
or Term
Definition
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRC
independent review committee
ISO/IEC
International Organization for Standardization/ Independent Ethics Committee
IUD
intrauterine device 
IUS
intrauterine hormone-releasing system
IV
Intravenous
KRAS
Kirsten rat sarcoma virus oncogene
LDH
lactate dehydrogenase
LFTs
liver function tests
LHRH
luteinizing hormone-releasing hormone
LOXO-292
investigational product (selpercatinib)
LTFU
Long-term Follow-up
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MHC-I
Major Histocompatibility Complex class I
MKIs
multikinase inhibitors
MRI
magnetic resonance imaging
MTC
medullary thyroid cancer
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease 
PD1
initial progressive disease
PD2
subsequent progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PedsQL
Pediatric Quality of Life Inventory-Core Module
PET
positron emission tomography
PFS
progression-free survival
P-gp
p-glycoprotein
PK
pharmacokinetic 

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Abbreviation 
or Term
Definition
PO
per os (oral)
PopPK
population pharmacokinetic
PP
Per-protocol Analysis Set
PPI
proton pump inhibitors
PR
partial response
PRO
patient-reported outcomes
PTC
papillary thyroid cancer
QD
once daily
QTcF
QT interval corrected for heart rate (Fridericia's formula)
QTcI
individual animal heart rate corrected QT intervals
RBC
red blood cell(s)
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase 2 dose
RTK 
receptor tyrosine kinase
SAD
short axis diameter
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SERDs
selective estrogen receptor degraders 
SERMs
selective estrogen receptor modulators
SFU
safety follow-up
SOC
system organ class
SOD
sum of the diameters
SRC
Safety Review Committee
SRS
stereotactic radiosurgery
SUSARs
suspected unexpected serious adverse reactions
T1/2
terminal elimination half-life
FT3
Free triiodothyronine
FT4
Free thyroxine
TBD
to be determined
TBL
total bilirubin level
TEAE
treatment-emergent adverse event
TKIs
tyrosine kinase inhibitors
Tmax
time to maximum plasma concentration
TSH
thyroid stimulating hormone

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Abbreviation 
or Term
Definition
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution
WBC
white blood cell
WBRT
whole brain radiation therapy

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1
Introduction
1.1
Tumors with RET Abnormalities and Current Treatment 
Options
Rearranged in transfection (RET) is a receptor tyrosine kinase (RTK) with critical roles in normal 
organogenesis and in the maintenance of several adult tissue types, including neural, 
neuroendocrine, hematopoietic, and male germ cell (Mulligan 2014). Genetic alterations in the 
RET gene are implicated in the pathogenesis of several human cancers. RET can be oncogenically 
activated by two primary mechanisms: (1) chromosomal rearrangements, producing 
cytoplasmically localized oncogenic hybrid proteins that fuse the RET kinase domain with a 
partner protein dimerization domain (e.g., CCDC6/PTC1, KIF5B, NCOA4/PTC3), thus endowing 
the kinase with ligand-independent, constitutive activity; and (2) point mutations that directly or 
indirectly activate the kinase. The oncogenic potential of RET was first identified as a result of its 
ability to transform NIH 3T3 cells through deoxyribonucleic acid (DNA) rearrangement 
(Takahashi, Ritz et al. 1985). Since its oncogenic potential was first discovered, the identification 
of additional, activating RET gene alterations in several different tumor types clearly implicates 
RET in the pathogenesis of human cancers. RET gene fusions have been identified in ~6% of 
sporadic papillary thyroid cancers (PTCs) (Fusco, Grieco et al. 1987, Cancer Genome Atlas 
Research 2014) and at even higher frequency in radiation-induced PTCs (Ito, Seyama et al. 1994, 
Fugazzola, Pilotti et al. 1995, Bounacer, Wicker et al. 1997, Nikiforov, Rowland et al. 1997). In 
patients with PTC, RET gene fusions are associated with adverse prognostic features (Prasad, Vyas 
et al. 2016, Su, He et al. 2016). In addition, activating RET gene mutations occur at high frequency 
in human medullary thyroid cancer (MTC) (>90% hereditary, ~50–60% sporadic) (Donis-Keller, 
Dou et al. 1993, Mulligan, Kwok et al. 1993, Carlson, Dou et al. 1994, Eng, Smith et al. 1994, 
Hofstra, Landsvater et al. 1994, Agrawal, Jiao et al. 2013, Ji, Oh et al. 2015). The application of 
NGS approaches to a large collection of human tumors has led to the identification of RET gene 
fusions in a small fraction (1 to 2%) of non-small cell lung cancers (NSCLC; adenocarcinomas) 
and in an even smaller fraction of other tumor types, including colorectal cancer, breast cancer and 
chronic myeloproliferative neoplasms (Ballerini, Struski et al. 2012, Ju, Lee et al. 2012, Kohno, 
Ichikawa et al. 2012, Lipson, Capelletti et al. 2012, Takeuchi, Soda et al. 2012, Bossi, Carlomagno 
et al. 2014, Stransky, Cerami et al. 2014). 

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In addition to direct, mutation-mediated activation of RET, increased RET expression in the 
absence of RET mutation may contribute to the growth and survival of some human cancers. For 
example, RET has been shown to be a direct transcriptional target of the estrogen receptor (ER) 
(Boulay, Breuleux et al. 2008, Wang, Mayer et al. 2012), a finding that is consistent with 1) 
possible ER-mediated increased RET expression in tumors from rare families with MTC (Smith, 
Read et al. 2016); 2) increased RET expression in some ER-positive breast cancers that have 
acquired resistance to anti-estrogens (Plaza-Menacho, Morandi et al. 2010, Spanheimer, Park et 
al. 2014); and 3) re-sensitization to anti-estrogen treatment through RET inhibition (Plaza-
Menacho, Morandi et al. 2010, Morandi, Martin et al. 2013, Spanheimer, Park et al. 2014). Finally, 
a recent study identified RET as a strong negative regulator of Major Histocompatibility Complex 
class I (MHC-I) expression in several human cancer cell lines of diverse histologies (Brea, Oh et 
al. 2016). This finding suggests a possible role for RET inhibition in upregulating the anti-cancer 
immune response.
The combination of low-frequency alterations in a highly prevalent cancer like NSCLC, high-
frequency alterations in a less-prevalent cancer like MTC and potential additional roles for RET 
in other contexts indicates that a significant number of patients with advanced, RET-fusion 
NSCLC, RET-mutant MTC, and other cancers with RET activation could benefit from potent and 
selective RET kinase inhibition. 
Several multikinase inhibitors (MKIs) with some degree of anti-RET activity are already in the 
clinic and two MKIs, cabozantinib and vandetanib, have received regulatory approval for 
advanced MTC (irrespective of the presence or absence of a RET mutation), with tumor response 
rates of 28% and 45% and progression-free survival (PFS) improvements (over placebo) of 7.2 and 
11.2 months, respectively (Wells, Robinson et al. 2012, Elisei, Schlumberger et al. 2013). The 
different degree of benefit observed in each study was most likely due to the eligibility requirement 
for recent tumor progression in the cabozantinib study, but not the vandetanib study. In subset 
analyses of both studies, patients whose tumors harbored RET activating mutations derived greater 
benefit than RET mutation-negative patients (Wells, Robinson et al. 2012, Sherman, Clary et al. 
2016). Preliminary data suggests similar, moderate activity for MKIs with anti-RET activity in 
RET-fusion-positive lung cancer, with response rates of 16%-53% (depending on the specific MKI 

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and patient population), but PFS times of only 3.6 to 7.3 months, in several ongoing Phase 2 studies 
(Drilon, Rekhtman et al. 2016, Lee 2016, Velcheti 2016, Yoh, Seto et al. 2016).
The efficacy of these MKIs is ultimately limited by incomplete inhibition of RET in tumors, 
significant toxicity from stronger inhibition of other targets (e.g., KDR/VEGFR2, EGFR, MET), 
and poor pharmacokinetics (PK) (i.e., significant drug accumulation and long half-life contributing 
to toxicity, but not efficacy) in patients. As a result, the majority of patients treated with these 
agents experience significant toxicities requiring dose interruptions, reductions, and/or treatment 
cessation. 
Patients with RET-fusion-positive cancers (NSCLC, PTC, colon, others) and RET-mutant cancers 
(such as MTC) represent populations with high unmet need. Combination chemotherapy has short-
term palliative potential in advanced NSCLC(Borghaei, Paz-Ares et al. 2015, Rizvi, Hellmann et 
al. 2015, Gainor, Shaw et al. 2016, Herbst, Baas et al. 2016). Chemotherapy is ineffective for MTC 
and PTC. Therefore, there is an urgent need to identify new targeted therapies that potently inhibit 
RET in tumors, while sparing other kinase and non-kinase off-targets that contribute to significant 
toxicity. 
1.2
Study Rationale
Selpercatinib is a highly potent and specific inhibitor of the RET RTK, with minimal inhibition of 
other kinase and non-kinase targets, and therefore may be of benefit to patients with tumors (such 
as NSCLC, MTC, PTC, and colon or breast carcinomas) that harbor RET alterations and/or depend 
on RET activation. This Phase 2 study of selpercatinib is required to understand the preliminary 
assessment of efficacy for selpercatinib in Chinese patients and further determine the safety profile 
and PK properties of selpercatinib.
1.3
Selpercatinib Pre-clinical Data Summary
Selpercatinib is a small molecule designed to block the adenosine triphosphate (ATP) binding site 
of the RET RTK; there is no evidence of covalent or irreversible binding. Selpercatinib causes 
dose-dependent inhibition of tumor growth in multiple, biologically relevant RET-dependent 
tumor models in vitro and in vivo, including NSCLC, MTC, and colorectal cancer cells and tumors 
harboring KIF5B-RET and non-KIF5B-RET fusions, with and without the RET V804M gatekeeper 
mutation and activating RET mutations found in MTC. 

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Selpercatinib was selective for 98% of 329 non-RET kinases tested in a large in vitro screen. This 
high degree of selectivity was maintained in additional enzyme and cell-based assays. 
Selpercatinib at clinically and toxicologically relevant concentrations had no significant effects on 
a range of other targets and receptors.
Selpercatinib was absorbed and bioavailable in five animal species tested. 
Selpercatinib produced a 50% inhibitory concentration (IC50) value of 1.1 µM in the Good 
Laboratory Practices (GLP) in vitro human ether-a-go-go (hERG) channel assay; no drug-related 
changes in any cardiovascular endpoint, including individual animal heart rate corrected QT 
intervals (QTcI) at doses up to 12 mg/kg in the cardiovascular study using conscious minipigs.
The toxicity of selpercatinib was evaluated in rats and minipigs in 14- and 28-day repeat dose, 
nonclinical studies. Dose groups were comprised of a vehicle control and low, medium, and high 
doses of selpercatinib. Rats and minipigs were chosen as appropriate test species for all in vivo 
toxicology studies based on PK and metabolic considerations. 
Additional information on the nonclinical pharmacology, PKs, and toxicity of selpercatinib are 
provided in the selpercatinib Investigator’s Brochure (IB).
1.4
Determination Starting Dose
The dose of 160 mg twice daily (BID) was selected as the recommended Phase 2 dose (RP2D) 
based on the safety data (N=82) and preliminary efficacy data in 64 evaluable patients treated at 
doses from 20 mg once daily (QD) through 240 mg BID (Drilon 2018). Additional information is 
provided in the selpercatinib IB.
1.5
Clinical Experience
As of a data cutoff of December 16, 2019, efficacy of selpercatinib was evaluated in patients with 
RET fusion-positive NSCLC, RET-mutant MTC, and RET fusion-positive thyroid cancer treated 
on LIBRETTO-001.
Efficacy was evaluated in 105 patients with RET fusion-positive NSCLC previously treated with 
platinum chemotherapy. In these patients, the objective response rate (ORR) was 64% (95% CI 
54, 73) by Independent Review Committee (IRC) assessment. The median duration of response 

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
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( D O R) b y IR C was 1 7. 5 m o nt hs ( 9 5 % CI: 1 2. 0, n ot esti ma ble [ N E]). I n 3 9 patie nts wit h treat me nt-
nai ve R E T f usi on- p osi ti ve N S C L C, t he O R R was 8 5 % ( 9 5 % CI: 7 0, 9 4) b y I R C assess me nt. T he 
me dia n D O R b y  I R C was n ot reac he d ( 9 5 % CI: 1 2. 0, N E).
Efficac y was e val uate d i n 5 5 patie nts wit h R E T -m u ta nt M T C pre vi o usl y treate d wit h ca b oza nti ni b 
or va n deta ni b. I n these pat ient s, t he O R R was 6 9 % ( 9 5 % CI: 5 5, 8 1) b y I R C assess me nt. T he 
me dia n D O R b y I R C assess me nt was n ot reac he d ( 9 5 % CI: 1 9. 1, N E). I n 8 8 pati e nts wi t h R E T -
m uta nt M T C w h o were ca b oza nt i ni b a n d va n deta ni b treat me nt-naï ve, t he O R R was 7 3 % ( 9 5 % CI: 
6 2, 8 2) b y  I R C assess me nt. T he me dia n D O R b y I R C assess me nt was 2 2. 0 m o nt hs ( 9 5 % CI: N E, 
N E). I n 1 9 patie nts wit h pre vi o usl y treate d R E T f usi on- p osi tive t h yr o i d ca ncer, t he O R R was 7 9 % 
( 9 5 % CI: 5 4, 9 4) b y I R C. T he me dia n D O R b y I R C was 1 8. 4 m o nt hs ( 9 5 % CI: 7. 6, N E).
As of  Marc h 3 0, 2 0 2 0, a t otal of 7 3 4 of  the 7 4 4 pati e nts ( 9 8. 7 %) treate d i n LI B R E T T O - 0 0 1 
e x perie nce d at least 1 T E A E (re gar dless of  relat i ons hi p t o st u d y dr u g) of an y gra de. T he T E A Es 
were c o de d acc or di n g t o t he Me dical Dict i onar y f or Re g ul at or y Act i vities ( Me d D R A) s yste m 
or ga n class ( S O C). Acr oss 9 d ose levels ra n gi n g fr om 2 0 m g Q D t o 2 4 0 m g BI D i n t hese 7 4 4 
pati e nts, T E A Es occ urri n g i n ≥1 5 % patie nts were: dr y  mo ut h ( 3 9. 7 % t otal; 3 5. 2 % relate d), 
di arr hea ( 3 8. 2 % t otal; 2 1. 8 % relate d), h y perte nsi o n ( 3 6. 3 % t otal; 2 5. 1 % relate d), A S T i ncrease d 
( 3 1. 9 % t otal; 2 5. 9 % r elate d), A L T i ncrease d ( 3 1. 5 % t otal; 2 5. 9 % r elate d), fati g ue ( 3 0. 8 % t otal; 
1 9. 2 % relate d), c o nsti pati o n ( 2 6. 6 % t otal; 1 2. 8 % relate d), e de ma p eri p heral ( 2 5. 3 % t otal; 1 4. 1 % 
r elate d), na usea ( 2 3. 3 % t otal; 1 0. 1 % r elate d), hea dac he ( 2 3. 3 % t otal; 8. 6 % relate d), bl o o d 
creati ni ne i ncrease d ( 2 0. 2 % t otal; 1 1. 6 % relate d), a b d omi nal pai n ( 1 9. 5 % t otal; 5. 9 % r elate d), ras h 
( 1 8. 1 % t otal; 1 1. 3 % r elate d), electr ocar di o gra m Q T pr ol o n ge d ( 1 7. 5 % t otal; 1 3. 6 % r elate d), c o u g h 
( 1 5. 9 % t otal; 1. 1 % relate d), v o miti n g ( 1 5. 9 % t otal; 4. 3 % relate d), a n d d ys p nea ( 1 5. 2 % t otal; 1. 6 % 
r elate d).
A t otal of 44 1 ( 5 9. 3 %) pati e nts acr oss all d ose levels i n LI B R E T T O - 0 0 1 ha d Gra de 3- 4 T E A Es. 
Gra de 3 -4 T E A Es t hat were c o nsi dere d t o be relate d t o stu d y dr u g were re p orte d i n 2 3 9 ( 3 2. 1 %) 
pati e nts acr oss all d ose levels. T E A E s i ncl u de d h y perte nsi o n ( 1 9. 0 %; 1 2. 1 % relate d), A L T 
i ncrease d ( 9. 8 %; 8. 1 % relate d), A S T i ncrease d ( 7. 8 %; 6. 0 % relate d), h y p o natre mia ( 5. 8 %; 0. 4 % 
r elate d), E C G Q T pr ol o n ge d ( 4. 0 %; 2. 8 % relate d), l y m p h o pe nia ( 4. 0 %; 1. 1 % relate d), diarr hea 
( 3. 5 %; 1. 6 % relate d), t hr o m b oc yt o p e nia ( 2. 8 %; 2. 0 % relate d), a n d p ne u m o nia ( 2. 8 %; n o ne 

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r elate d), d ys p nea ( 2. 6 %; n o ne relate d), ne utr o pe nia ( 2. 4 %; 1. 5 % relate d), a ne mia a n d 
h y p ocalce mia (eac h 2. 2 %, eac h 0. 4 % relate d), a n d h y p o p h os p hate mia ( 2. 2 %, 0. 1 % relate d). All 
ot her Gra de 3- 4 T E A Es occ urre d i n less t ha n 2 % of  patie nts o verall. O verall , 3 2 ( 4. 3 %) p atie nts 
ha ve die d wit hi n 2 8 da ys of t he last d ose of st u d y dr u g, a n d n o deat hs ha ve bee n attri b ute d t o st u d y 
dr u g.
A d dit i onal details are pr o vi de d i n t he sel percati ni b I B.
1. 6
B e n efit a n d Ri s k A s s e s s m e nt
W he n vie we d as a w h o le, t he precli nical data i n dicate t hat selpercat i ni b is a hi g hl y  pot e nt a n d 
s pecific i n hi bit or of  the R E T R T K, wit h mi ni mal i n hi biti on of  ot her ki nase a n d n o n- ki nase off 
tar gets. Si nce sel percati ni b is a n e x peri me ntal me di ci ne, it is p ossi ble t hat u nf oresee n, u n k n o w n, 
or u na ntici pate d dr u g reacti o ns a n d t o x icities ma y occ ur. H o we ver, as detaile d bel o w, t his cli nical 
pr ot oc ol  is desi g ne d t o mit i gate ris ks t o patie nts t hr o u g h a detaile d pl a n f or caref ul safety 
m o nit ori n g, s yste mat ic re vie w of  ad verse e ve nts ( A Es), serio us A Es ( S A Es), a n d P K, a n d acti ve 
p har mac o vi gila nce re vie w t o assess f or safet y sig nals or tre n ds. 
P ati e nts wi t h R E T -f usi on- p osi tive ca ncers ( N S C L C, P T C, c o l on, ot hers) a n d R E T -m ut a nt M T C 
re prese nt p o p ul at i ons wi t h hi g h u n met nee d. As disc usse d i n Sect i on 1. 1 , a vaila ble t hera pies f or 
t hese pati e nts pr o vi de s h ort-t er m palliat i on (i.e., c he m ot hera p y) t hat ma y be less effect i ve i n 
ca ncers dri ve n b y ki nase f usio n s (i.e., i m m u n ot hera p y) a n d/ or are ver y  to xi c (i.e., M KIs). 
T heref ore, t here is a n ur ge nt nee d t o ide nt if y ne w tar gete d t hera pies t hat p ote ntl y i n hi bit R E T i n 
t u mors, w hile s pari n g ot h er ki nase a n d n o n-ki nase off -tar gets t hat c o ntri b ute t o si gnifica nt t o xicit y.
T hese c o nsi derati o ns s u p p ort e val uat i on of sel percati ni b i n t he pr o p ose d patie nt p o p ulati o n.
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, S A Es a n d reas o na bl y a nt ici pate d 
A Es of sel percati ni b are t o be f o u n d i n t he I B.
1. 6. 1
K n o w n a n d A nti ci p at e d Ri s k s 
As of  a cli ni c al d at a c ut-off ( Marc h 3 0, 2 0 2 0) f or t he LI B R E T T O - 0 0 1 first-i n-h u ma n ( FI H) d ose 
fi n di n g st u d y, t he f oll owi n g T E A Es occ urre d i n ≥1 5 % of  patie nts (re gar dless of  attri b uti on t o 
st u d y dr u g): 

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
Dry mouth (39.7% total; 35.2% related)

Diarrhea (38.2% total; 21.8% related)

Hypertension (36.3% total; 25.1% related)

AST increased (31.9% total; 25.9% related)

ALT increased (31.5% total; 25.9% related)

Fatigue (30.8% total; 19.2% related)

Constipation (26.6% total; 12.8% related)

Edema peripheral (25.3% total; 14.1% related)

Nausea (23.3% total; 10.1% related)

Headache (23.3% total; 8.6% related)

Blood creatinine increased (20.2% total; 11.6% related)

Abdominal pain (19.5% total; 5.9% related)

Rash (18.1% total; 11.3% related)

Electrocardiogram QT prolonged (17.5% total; 13.6% related)

Cough (15.9% total; 1.1% related)

Vomiting (15.9% total; 4.3% related)

Dyspnea (15.2% total; 1.6% related)
Additional details are provided in the selpercatinib IB.
1.6.2
Potential Drug Interactions
Selpercatinib has pH-dependent solubility and its PK can be affected by agents that modify gastric 
pH, such as proton pump inhibitors (PPIs) (e.g., omeprazole). Coadministration with multiple daily 
doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax by 69% and 88%, 
respectively when selpercatinib was administered fasting. Coadministration with multiple daily 
doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when 
selpercatinib was administered with food.
No clinically significant differences in selpercatinib PK were observed when coadministered with 
multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after 
the selpercatinib dose (administered fasting). The effect of antacids that contain aluminum, 

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magnesium, calcium, simethicone, or buffered medicines on the PK of selpercatinib has not been 
specifically studied.
Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the 
selpercatinib AUC0-INF by 133% and Cmax by 30%; coadministration of multiple doses of diltiazem, 
fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib 
AUC by 60 to 99% and Cmax by 46 to 76%; coadministration of multiple doses of rifampin (strong 
CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%; coadministration 
of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease 
the selpercatinib AUC by 40 to 70% and Cmax by 34 to 57%; coadministration of multiple doses 
of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and 
Cmax by 26%. Therefore, coadministration of selpercatinib with strong and moderate CYP3A 
inhibitors, strong and moderate CYP3A inducers, and CYP2C8 and CYP3A substrates should be 
avoided.
Coadministration of selpercatinib with repaglinide (sensitive CYP2C8 substrate) increased the 
repaglinide AUC0-INF by 188% and Cmax by 91%. Avoid coadministration of selpercatinib with 
sensitive CYP2C8 substrates.
Coadministration of selpercatinib with midazolam (sensitive CYP3A) increased the midazolam 
AUC0-INF by 54% and Cmax by 39%. Therefore, selpercatinib can be considered a weak inhibitor 
of CYP3A4. Coadministration of selpercatinib with sensitive CYP3A4 substrates may increase 
their plasma concentrations, which may increase the incidence or severity of adverse reactions. 
Avoid coadministration of selpercatinib with sensitive CYP3A4 substrates.
Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at 
clinically relevant concentrations.
Selpercatinib inhibits MATE1, P-gp, and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, 
OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib 
may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of 
MATE1. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, 
OATP1B1, OATP1B3, MATE1, or MATE2-K. Selpercatinib may increase serum creatinine by 
decreasing renal tubular secretion of creatinine via inhibition of MATE1. Consider alternative 
markers of renal function if persistent elevations in serum creatinine are observed. The potential 

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for selpercatinib inhibition of P-gp or BCRP in the intestine cannot be ruled out. If 
coadministration of a sensitive P-gp or BCRP substrate cannot be avoided, patients should be 
monitored for increased adverse reactions of these drugs.
Additional details are provided in the selpercatinib IB.

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2
Study Objectives
2.1
Primary Objective 

To assess the anti-tumor activity of selpercatinib by determining ORR using 
RECIST v1.1 as assessed by IRC. 
2.2
Secondary Objectives 

To assess the anti-tumor activity of selpercatinib by determining
o
ORR based on RECIST v1.1 as assessed by Investigator;
o
Duration of response (DOR) as assessed by IRC and Investigator; 
o
Central nervous system (CNS) ORR based on RECIST v1.1 as appropriate to 
tumor type, as assessed by IRC (for patients with brain metastases);
o
CNS DOR as assessed by IRC (for patients with brain metastases);
o
Time to response (TTR) based on RECIST v1.1 as appropriate to tumor type, as 
assessed by IRC and Investigator;
o
Time to best response (TTBR) based on RECIST v1.1 as appropriate to tumor 
type, as assessed by IRC and Investigator;
o
Clinical Benefit Rate (CBR) based on the proportion of patients with best overall 
response of complete response (CR), partial response (PR), or stable disease (SD) 
lasting 16 or more weeks following initiation of selpercatinib, as assessed by IRC 
and Investigator;
o
Progression-free survival (PFS) as assessed by IRC and Investigator;
o
Overall survival (OS) following initiation of selpercatinib.

To determine the safety profile and tolerability of selpercatinib.

To characterize the PK properties of selpercatinib.
2.3
Exploratory Objectives 

To determine the relationship between PK and drug effects, including efficacy and 
safety.

To evaluate the serum tumor markers, carcinoembryonic antigen (CEA) and 
calcitonin (for patients with MTC), thyroglobulin (for patients with non-MTC 
thyroid cancer, unless not measurable due to presence of anti-thyroglobulin 
antibodies), and adrenocorticotropic hormone (ACTH)/cortisol (for patients with 
Cushing’s disease related to their cancer), before, during, and at the end of 
treatment (EOT) with selpercatinib. 

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
To collect patient-reported outcomes (PRO) data to explore disease-related 
symptoms and health-related quality of life (HRQoL).

To estimate the time from initial progressive disease (PD1) to subsequent PD (PD2) 
to explore whether patients continue to benefit from study treatment after disease 
progression.

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3
Investigational Plan
3.1
Study Design
This is an open-label, multi-center Phase 2 study in patients with advanced solid tumors, including 
RET fusion-positive solid tumors (e.g., NSCLC, thyroid, pancreas, colorectal), RET-mutant MTC, 
and other tumors with RET activation (e.g., mutations in other tumor types or other evidence of
RET activation).
Patients with RET alterations in tumor and/or blood will be identified through molecular assays. 
The RET alteration results should be generated from a laboratory with certification by China 
National Accreditation Service for Conformity Assessment (CNAS), External Quality Assessment 
(EQA), Clinical Laboratory Improvement Amendments (CLIA), College Of American 
Pathologists (CAP) or other similar certification. The Sponsor should be contacted to discuss test 
results to ensure trial eligibility.
The Schedule of Assessments (refer to Table 7-1) consists of a screening period, a treatment period 
including an End of Treatment (EOT) visit, a Safety Follow-up (SFU) visit, and Long-term 
Follow-up (LTFU). Ongoing safety, and disease assessments (for patients without PD), disease 
status, survival, and subsequent anticancer therapy(ies) will be assessed during LTFU.
Selpercatinib will be administered in oral form BID. Dosing will be fixed as total milligram (mg; 
as opposed to weight-based or body surface area [BSA]-based).
3.2
Length of Study and End of Study
3.2.1
Length of Study
It is anticipated that a patient on this study will receive treatment with open-label selpercatinib
until the patient is able to obtain commercially available selpercatinib in China, if the patient does 
not meet criteria requiring discontinuation of treatment (refer to Section 6.4 Discontinuation of 
Study Intervention), and the patient’s participation in the study has not ended. 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.

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3.2.2
End of Study
The end of study is defined as the date when the last remaining patient has:

Completed the last visit where the patient completed the SFU visit, or

consent has been withdrawn, or

is lost to follow-up, or

has died, or

has transferred to a separate study to received further medication.
3.3
General Treatment Procedures
Patients will receive 160 mg BID selpercatinib on Cycle (C) 1 Day (D) 1 in accordance with the 
cohort assignment. Cycles are measured in 28-day increments.  
Individual patients will continue daily selpercatinib dosing until PD, unacceptable toxicity, 
or other reasons for treatment discontinuation, as outlined in Section 6.4. Twenty-eight days after 
the last dose of study drug (+7 days), all treated patients will undergo an SFU visit. Patients with 
documented PD may be allowed to continue selpercatinib if the patient is tolerating treatment and, 
in the opinion of the Investigator, the patient is deriving clinical benefit from continuing study 
treatment, and continuation of treatment is approved by the Sponsor.
After treatment discontinuation, all patients will enter the LTFU part of the study until death, 
withdrawal of consent, lost to follow-up or the Sponsor makes a decision to close the study. LTFU 
will include follow up for survival status, which may be conducted by telephone. During LTFU, 
for practical reasons and to minimize patient inconvenience, continued disease assessments by 
imaging until disease progression are optional. 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. 

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3. 4
I n v e sti g ati o n al Pl a n
F or t his C hi na-s pecific pr ot oc ol , it is e x pecte d t hat at least 2 0 patie nts i n eac h C o h ort 1 a n d C o h ort 
2, a n d u p t o 2 5 patie nts i n C o h ort 3 wit h a d va nce d s oli d t u mors wi t h evi de nce of  a R E T ge ne 
alt er atio n i n t u mor a n d/ or bl o o d (e. g., ge ne rearra n ge me nt f usi ons a n d/ or m ut atio ns, e xcl u di n g 
s y n o n y m o us, fra mes hift, or n o nse nse m ut atio ns) will be e nr olle d t o o ne of  three c o h orts 
(Fi g ure 3- 1 ) as n ote d bel o w t o better c haracterize t he safety a n d efficac y of  sel percati ni b i n patient s 
wi t h s pecific a b n or malities i n R E T . F or C o h ort 1 a n d 2, e vi de nce of a R E T ge ne alterati o n i n t u m or 
(i.e., n ot j ust bl o o d) as defi ne d i n Ta ble 3- 1 is re q uire d (a p ositi ve ger mli ne test f or a R E T m ut atio n 
is acce pta ble f or patie nts wit h M T C). 
E nr oll m e nt will be base d o n t u m or t yp e, t y pe of R E T alt eratio n, a n d pri or treat m e nt:
C o h ort 1: A d va nce d R E T f usi on -p osi tive s o li d t u m or pr o gresse d o n or i nt olera nt t o ≥1 pri or 
sta n dar d t hera p y, or patie nts w h o decli ne d or n ot s uita ble f or sta n dar d first li ne t he r a p y in 
t he o pini o n of t he I n vest i gat or (refer t o Ta ble 4 - 1 f or sta n dar d t hera pies). F or l u n g ca ncer, 
o nl y  patie nts har b ori n g R E T -KI F 5 B, R E T -C C D C 6, R E T -N C O A 4 ca n be e nr olle d i n C o h ort 
1. F or ot her s oli d t u m ors, patie nts wit h a n y R E T f usio ns ca n be e nr o lle d i n C o h ort 1.
C o h ort 2: A d va nce d R E T -m ut a nt M T C wit h or wit ho ut pri or s y st e mat ic t hera p y 
C o h ort 3: A d va nce d R E T alt ere d s oli d t u m or 
o
C o h orts 1 -2 wi t ho ut m eas ura ble disease;
o
Ot her R E T -alt ere d s oli d t u m or or ot her R E T alt erati o n/act i vati on n ot m eet i n g t he 
re q uire me nts f or C o h orts 1 or 2;
o
M T C s y n dr o me s pectr u m ca ncers (e. g. M T C, p he oc hr o m o c yt o ma) wi t h ne ur oe n d ocri ne 
feat ures/ differe ntiati on or p o orl y differe nt iate d t h yr oi d ca ncers wit h ot h er R E T
alt er atio n/act i vati on ma y be all o we d wi t h prior S p o ns or a p pr o val;
o
K n o w n cf D N A p ositi ve f or a R E T ge ne alterati o n a n d n ot a ble t o be deter mi ne d i n t u m or 
or FI S H p osit i ve i n t u mor wi t ho ut P C R/ N G S res ult ma y be all o we d wit h pri or S p o ns or 
a p pr o val.
S elpercat i ni b will be a d mi nistere d i n oral f or m at 1 6 0 m g BI D. Eac h c ycle will c o nsist of 2 8 da ys. 

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Primary endpoint: ORR per RECIST 1.1 by independent review committee.
Secondary endpoint: ORR per RECIST 1.1 by investigator, DOR, CNS ORR, CNS DOR, CBR, TTR, TTBR, CBR, PFS, 
OS, PK, safety 
Abbreviations: BID-twice daily, MTC-medullary thyroid cancer, DOR- duration of response, CNS ORR- central nervous 
system objective response rate, CNS DOR- central nervous system duration of response, CBR- clinical benefit rate, TTR- time 
to response, TTBR- time to best response, PFS-progression-free survival, OS- overall survival, PK- pharmacokinetic
Figure 3-1
Study Schema

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3.5
Definition of RET Alterations
The specific RET gene alterations required for enrollment to Cohort 1 and 2 are defined in Table 
3-1. RET mutations and fusions will be identified from a laboratory with CNAS, EQA, CLIA, CAP
or similar certification, so long as a written Molecular Pathology Report is available and clearly 
asserts the presence of the referenced RET alteration. 
Table 3-1
Definition of RET Alterations
RET mutation*
Previously reported activating RET gene mutation excluding synonymous, frameshift, or nonsense mutations. 
Refer to Appendix B (Table 11-2) for examples.
For MTC, RET gene mutation not known to be activating may be enrolled with Sponsor approval to Cohort 2. 
RET fusion*
By PCR or NGS (FISH as the only molecular result is acceptable for Cohort 3, but not Cohort 1).
RET mutation* or RET fusion*
No other known validated driver alteration(s). Refer to Appendix C for examples.
* According to laboratory with CNAS, EQA, CLIA, CAP or similar certification, so long as a written 
Molecular Pathology Report is available and clearly asserts the presence of the referenced RET alteration.
Abbreviations: CNAS-China National Accreditation Service for Conformity Assessment; EQA; CLIA-Clinical 
Laboratory Improvement Amendments; CAP-College Of American Pathologists; FISH-Fluorescence in Situ 
Hybridization;  MTC-medullary thyroid cancer; NGS-next generation sequencing; PCR-polymerase chain reaction.
3.6
Number of Patients
Approximately 75 patients will be enrolled. 
A statistical justification of sample/cohort size is provided in Section 9.3.
3.7
Investigational Sites
Approximately 40 institutions will be recruited to enroll patients.

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4
Selection of Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. Potential patients age 18 and older must sign an 
informed consent form before any study-specific screening tests may be conducted. 
4.1
Inclusion Criteria 
1. Patients with a locally advanced or metastatic solid tumor who:
have progressed on or are intolerant to standard therapy, or
no standard therapy exists, or in the opinion of the Investigator, are not candidates for or 
would be unlikely to tolerate or derive significant clinical benefit from standard therapy, 
or 
decline standard therapy.
2. Prior MKIs with anti-RET activity are allowed. Refer to Appendix A for examples of MKIs 
with anti-RET activity. However, prior treatment with a selective RET inhibitor(s) 
(including investigational selective RET inhibitor(s), such as BLU-667, RXDX-105) is 
prohibited. The specific agent(s), duration of treatment, clinical benefit, and reason for 
discontinuation (e.g., PD, drug toxicity, or intolerance) should be documented for all kinase 
inhibitors the patient has been exposed to.
3. Evidence of a 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. The RET alteration result should be 
generated from a laboratory with certification by CNAS, EQA, CLIA, CAP or other similar 
certification. The Sponsor should be contacted to discuss test results from labs where such 
certification is not clearly demonstrated to determine eligibility. 
Notes: 
A positive germline test for a RET mutation is acceptable for patients with MTC.
Local testing in a CNAS, EQA, CLIA, CAP or other similar certified laboratory is 
sufficient.
In all cases, a redacted/coded Molecular Pathology Report or other report(s) describing 
tumor and/or blood RET (and other) alternation analysis should be submitted to the 
Sponsor or designee during/prior to eligibility.
4. Measurable or non-measurable disease as determined by RECIST v1.1.
5. At least 18 years of age. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, with 
no sudden deterioration 2 weeks prior to the first dose of study treatment.
7. Life expectancy of at least 3 months.
8. Archived tumor tissue sample available for Cohort 1 and 2. 

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N otes:

P ati e nts w h o d o n ot ha ve a de q uate arc hi val t u m or tiss ue a vaila ble (refer t o s pecific 
arc hi val t iss ue re q uire me nts i n Secti on 7. 7. 5. 1 ) ma y u n der g o a fres h t u m or bi o ps y, if it is 
c o nsi dere d safe t o perf or m, pri or t o treat me nt. 

If arc hi ve d t u m or tiss ue was o btai ne d pri or t o pr o gressi on o n t he last M KI wit h a nt i-R E T 
acti vit y,  t he patie nt s h o ul d u n der g o a fres h t u m or bi o ps y, if it is c o nsi dere d safe t o 
perf or m , prior t o treat m e nt ( o ptio nal ). 
9.
A de q uate he mat ol o gic stat us, defi ne d as :

A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 0 1 0 9/ L n ot re q uiri n g gr o wt h fact or s u p p ort f or at 
least 7 da ys pri or t o treat me nt, a n d

Pl at elet c o u nt ≥7 5 1 0 9/ L n ot re q uiri n g tra nsf usi on s u p p ort f or at least 7 da ys pri or t o 
treat me nt, a n d

H e m o gl o bi n ( H b) ≥9 g/ d L n ot re q uiri n g tra nsf usi o n s u p p ort or er y t hr o p oieti n f or at least 
7 d a y s prior t o treat me nt .
1 0. A de q uate he pat ic f u ncti o n, defi ne d as:

Ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( AS T) ≤2. 5 t he u p per 
li mit of n or mal ( U L N) or ≤5 U L N wit h d oc u me nte d li ver i n v o l ve me nt (s uc h as li ver 
metastasis or a pri mar y biliar y t u m or) a n d

T ot al  bilir u bi n ≤1. 5 U L N or ≤3 U L N wi t h d oc u me nte d li ver i n v ol ve me nt ( patie nts 
wi t h Gil bert’s Disease ma y be e nr olle d wit h prior S p o ns or a p pr o val).
1 1. A de q uat e re nal f u nct i on, wi t h esti mate d gl omer ular filtrati o n rate ≥3 0 m L/ mi n ute . Si tes ca n 
use t heir o w n cli nical sta n dar d f or e G F R. If n o cli nical sta n dar d, bel o w M D R D st u d y  
e q uatio n ca n be use d: eG F R ( m L/ mi n/ 1. 7 3 m ²) = 1 7 5 × ( Scr/ 8 8. 4)-1. 1 5 4 × ( A ge) -0. 2 0 3 × ( 0. 7 4 2 
if fe male) × ( 1. 2 1 2 if Africa n A merica n) ( SI u nits).
1 2. A bilit y t o s wallo w ca ps ules a n d c o m pl y wi t h o ut patie nt treat me nt, la b orat or y mo ni t ori n g, 
a n d re q uire d cli nic visit s for t he d urati o n of  st u d y p artici pat i on.
1 3. Willi n g ness of
me n a n d w o me n of re pr o d ucti ve p ote ntial t o o bser ve c o n ve nt i onal a n d 
effect i ve birt h c o ntr ol f or t he d urati o n of treat me nt a n d f or 3 m o nt hs f oll owi n g t he l ast d ose 
of  st u d y tr e at me nt; t his ma y incl u de barrier m et h o ds s uc h as a c o n d o m or dia p hra g m wit h 
s permici dal gel.
N otes:

A p ost m e n o pa usal w o ma n will be defi ne d as ha vi n g n o me nses f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use. Male sterilit y will be defi ne d as o nl y me n sterilize d s ur gicall y. 
F or m ale pat ient s wit h a pre g na nt part ner, a c o n d o m s h o ul d be use d f or c o ntrace pti o n. F or 
male pat ient s wit h a n o n-pre g na nt fe male part ner of c hil d -beari n g p ote ntial a n d w o ma n o f 
c hil d-beari n g p ote ntial o ne of t he f o ll owi n g bi rt h c o ntr ol met h o ds wit h a fail ure rate of 
less t ha n 1 % per year w he n use d c o nsiste nt l y an d c orrectl y  are rec o m me n de d:
a. C o m bi ne d estr o ge n a n d pr o gester o ne c o ntai ni n g h or m o nal c o ntrace pti o n ass ociate d 
wi t h in hi bit i on of o v ulati o n gi ve n orall y, i ntra va gi nall y, or tra ns der mall y
b. Pr o gester o ne -o nl y  hor m o nal  c o ntrace ptio n ass oci ate d wit h i n hi biti on o f o v ul at i on 
gi ve n orall y, b y i nject i on, or b y  im pla nt

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c. Intrauterine device (IUD)
d. Intrauterine hormone-releasing system (IUS)
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Sexual abstinence
Birth control methods unacceptable for this clinical trial are:
a. Periodic abstinence (calendar, symptothermal, or post-ovulation methods)
b. Withdrawal (coitus interruptus)
c. Spermicide only
d. Lactational amenorrhea method
Male study participants should refrain from sperm donation during study treatment and up 
to 6 months following the last dose of selpercatinib.
14. Written informed consent and any local required authorization (e.g., Health Insurance 
Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive 
in the EU) obtained from the patient/legal representative prior to performing any protocol-
related procedures, including screening evaluations.
15. Cohorts 1 and 2: failed or intolerant to standard of care; see Table 4-1 for Examples.
Table 4-1
Standard of Care Therapies for Cohort 1 and 2 
Abbreviations: EGFR-epidermal growth factor receptor; HER2-human epidermal growth factor 
receptor 2; MTC-medullary thyroid cancer; NSCLC-non-small cell lung cancer; PD-1-
programmed cell death protein 1; PD-L1-programmed death-ligand 1; VEGF-vascular 
endothelial growth factor.
Cohort
Therapy
Cohort 1: RET Fusion-
Positive Solid 
Tumor
NSCLC: platinum-based chemotherapy (or other chemotherapy if 
not eligible for platinum) or PD-1/PD-L1 immunotherapy or both
Thyroid: sorafenib, patients must also be radioactive iodine-
refractory as appropriate
Colorectal: fluoropyrimidine-based chemotherapy, with or without 
anti-VEGF-directed therapy or anti-EGFR-directed therapy as 
appropriate for the disease
Pancreas: fluoropyrimidine-based, gemcitabine-based, or S-1 
chemotherapy
Breast: anthracycline, taxane, HER2-directed therapy and/or 
hormonal therapy or other standard therapy appropriate for the 
disease
Other: prior standard therapy for the disease
Cohort 2: RET-mutant 
MTC
No approved SOC

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16. Cohorts 1-2: enrollment will be restricted to patients with evidence of a RET gene alteration 
in tumor (i.e., not just blood) as defined in Synopsis Table 1 . However, a positive germline 
DNA test for a RET gene mutation as defined in Appendix B (Table 11-2) is acceptable in 
the absence of tumor tissue testing for patients with MTC.
17. Cohorts 1-2: at least one measurable lesion as defined by RECIST v1.1 and not previously 
irradiated (unless PD for the irradiated lesion[s] has been radiographically documented). 
18. Cohort 2: radiographic PD within the previous 14 months for systematic treatment naïve 
patient.
Note:
Patients otherwise eligible for Cohort 2 who do not demonstrate radiographic PD within the 
previous 14 months may be enrolled to Cohort 3 if a compelling rationale is provided by the 
Investigator and approved by the Sponsor.
4.2
Exclusion Criteria
19. Cohorts 1-2, an additional validated oncogenic driver that could cause resistance to 
selpercatinib treatment if known. See Appendix C (Table 11-3) for examples.
20. Prior treatment with a selective RET inhibitor(s) (including investigational selective RET 
inhibitor(s), such as BLU-667, RXDX-105, etc.) 
21. Are currently enrolled in any other clinical study involving an investigational product or any 
other type of medical research judged not to be scientifically or medically compatible with 
this study
22. Investigational agent or anticancer therapy within 5 half-lives or 2 weeks (whichever is 
shorter) prior to planned start of selpercatinib. In addition, no concurrent investigational anti-
cancer therapy is permitted.
Notes:
Refer to Section 6.3.2 of the main protocol for allowable concurrent therapies. 
Selpercatinib may be started within less than 5 half-lives or 2 weeks of prior therapy if 
considered by the Investigator to be safe and within the best interest of the patient, with 
prior sponsor approval.
23. Major surgery (excluding placement of vascular access or biopsy) within 4 weeks prior to 
planned start of selpercatinib.
24. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of 
study treatment, with the exception of patients receiving radiation to more than 30% of the 
bone marrow or with a wide field of radiation, which must be completed at least 4 weeks 
prior to the first dose of study treatment.
25. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 except where 
otherwise noted in this eligibility criteria at the time of starting study treatment with the 
exception of alopecia and Grade 2, prior platinum therapy-related neuropathy.
26. Symptomatic primary CNS tumor, symptomatic CNS metastases, leptomeningeal 
carcinomatosis, or untreated spinal cord compression.

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Exception: Patients are eligible if neurological symptoms and CNS imaging are stable and 
steroid dose is stable for 14 days prior to the first dose of selpercatinib and no CNS surgery 
or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery [SRS].
Note:
All prior local treatments for CNS disease (e.g. surgery, whole brain radiation [WBRT], 
SRS), the start and stop dates for each prior local therapy, the specific lesions treated (if 
SRS and/or surgery), whether the patient developed intracranial progression after the last 
prior local treatment, and which lesions progressed since completion of the local therapy 
must be documented.
27. Clinically significant active cardiovascular disease or history of myocardial infarction within 
6 months prior to planned start of selpercatinib or prolongation of the QT interval corrected 
for heart rate using Fridericia’s formula (QTcF) > 470 msec. Correction of suspected drug-
induced QTcF prolongation may be attempted at the investigator’s discretion if clinically safe 
to do so.
28. History of Human Immunodeficiency Virus (known HIV 1/2 antibodies positive); patients 
with unknown HIV status do not need to be tested.
29. History of active hepatitis B (known positive hepatitis B surface antigen [HbsAg] and 
quantitative hepatitis B DNA greater than the upper limit of detection of the assay) or C 
(known positive hepatitis C antibody and quantitative hepatitis C RNA greater than the upper
limit of detection of the assay); patients with unknown hepatitis B/hepatitis C status do not 
need to be tested.
30. Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing 
intercurrent illness, such as hypertension or diabetes, despite optimal treatment. Screening for 
chronic conditions is not required.
31. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal absorption of the study drug.
32. Uncontrolled symptomatic hyperthyroidism or hypothyroidism.
33. Uncontrolled symptomatic hypercalcemia or hypocalcemia.
34. Concurrent use of drugs known to prolong QTc (refer to Appendix D of the main protocol)
35. Pregnancy or lactation. Breast-feeding should be interrupted when selpercatinib is started; 
breast-feeding can be resumed 3 months after discontinuation of selpercatinib.
36. Active second malignancy other than minor treatment of indolent cancers with prior sponsor 
approval.

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5
Enrollment Procedures
For all patients, a copy of the redacted Molecular Pathology Report, or other report(s) describing 
tumor RET (and/or other) alteration analysis must be submitted to the Sponsor or designee during 
Screening for review prior to patient enrollment. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened, only after discussion with and permission from the Lilly CRP or designee. Patients may 
be eligible for re-screening up to 2 times in any of the following circumstances:

Patients who have become eligible to enroll in the study as the result of a protocol 
amendment.

Patients whose status has changed such that the eligibility criterion that caused the patient 
to screen fail would no longer cause the patient to screen fail again.

Patients who complete screening and meet all inclusion and exclusion requirements but are 
unable to be enrolled due to extenuating circumstances (such as severe weather, or child 
illness).
Each time re-screening is performed, the individual must sign a new informed consent form (ICF) 
and will be assigned a new identification number. If a target gene positive result was obtained for 
an individual under their first patient number, this result can be linked to their new number in an 
effort to preserve patient tissue. If a target gene result was not successfully obtained for an 
individual under their first patient number, then a new sample for this individual (as well as one 
repeat if needed) can be submitted to the central lab with the new patient number. Repeating of 
laboratory tests during the screening period does not constitute re-screening. 
This is an open-label study, and all patients who meet all criteria for enrollment will receive 
selpercatinib treatment. Dispensing and tracking selpercatinib treatment will be accomplished 
using an interactive Web/voice response system (IxRS).

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6
Tr e at m e nt
6. 1
I n v e sti g ati o n al Pr o d u ct
S elpercat i ni b will be pr o vi de d i n a ca ps ule i n 4 0 m g a n d 8 0 m g d ose stre n gt hs. 
6. 1. 1
C a p s ul e s
S elpercat i ni b will  be pr o vi de d i n a ca ps ule i n 4 0 m g a n d 8 0 m g d ose stre n gt hs. T he 4 0 m g ca ps ules 
will be pr o vi de d t o t he si tes i n b ottles of 6 0 ca ps ules/ b ottle. T h e 8 0 mg ca ps ul es will be pr o vid e d 
t o t he sites i n b ottles of 1 2 0 ca ps ules/ b ottle. T he site p har macist will dis pe nse b ottles t o t he patie nt 
i n a n a m o u nt necessar y t o all o w f or o ut patie nt a d mi nistrati o n at t he assi g ne d d ose le vel. D osi n g is 
i nte n de d t o be fi xe d (i.e., n ot wei g ht -base d or b o d y s urface area - base d). 
S elpercat i ni b gelat i n ca ps ules are t o be st ore d at c o ntr olle d r o o m te m perat ure i n acc or da nce wit h 
t he la bele d st ora ge c o n diti ons . 
A d dit i onal details re gar di n g t he i n vest i gati onal pr o d uct are pr o vi de d i n t he selpercat i ni b P h ar mac y 
Ma n ual a n d t he sel percati ni b I B.
6. 2
S el p er c ati ni b A d mi ni str ati o n
6. 2. 1
G e n er al D o si n g I n str u cti o n s
S elpercat i ni b d oses will be a d mi nistere d at a p pr o xi matel y t he sa me times o n eac h da y a n d BI D 
d osi n g will  be se parate d b y a p pr o xi matel y 1 2 h o urs (a mi ni m u m of 6 h o urs bet wee n c o nsec uti ve 
d oses).  
T he patie nt will kee p a dail y diar y  t o rec or d d osi n g c o m p lia nce, w hic h will als o be assesse d at 
eac h cli nic visit b y mea ns of  a ca ps ule c o u nt i n t he ret ur ne d b ottle(s). Late d oses (i.e., 4 or m o re 
h o urs after sc he d ule d t i me) s h o ul d be n ote d i n t he diar y. D oses t hat are late b y more t ha n 6 h o ur s 
s h o uld be s kip pe d a n d rec or de d i n t he d osi n g di ar y as misse d. V o mit i n g after d osi n g s h o uld b e 
n ote d i n t he diar y  a n d a v o mite d d ose s h o uld n ot be re -d ose d or re place d. 
S el percat i ni b ma y be gi v e n wi t h or wit ho ut f o o d, u nless t he pati e nt re q uires treat me nt wit h P PIs, 
H 2 rece pt or a nta g o nists, or l ocall y-act i n g a ntaci ds. A d dit i onal g ui da nce is pr o vi de d i n Secti o n
6. 3. 3 .

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
4 4
L Y 3 5 2 7 7 2 3
P ati e nts ta ki n g t hese a ge nts are e nc o ura ge d t o rec or d t he ti me of eac h d ose i n relat i ons hi p t o eac h 
d ose of  sel percati ni b i n t he d osi n g di ar y (i nacc urate rec or di n g will n ot be c o nsi dere d a pr ot oc ol 
vi o lati on). 
6. 2. 2
C y cl e 1
P ati e nt s will be gi n d osi n g o n C 1 D 1. Serial bl o o d sa mples f or i nte nsi ve P K  mo ni t orin g will be 
c ollecte d f or a t otal of 1 2 patie nts , bl o o d sa m ples f or p o p ul at i on p har mac o ki netic ( Po p P K ) will be 
c ollecte d f or all e nr o lle d pat ient s, a n d t he pat ient  will be m onit ore d f or safet y as o utli ne d i n Sect i on
7. 2 C ycle le n gt h is 2 8 da ys f or all pat ient s. 
6. 2. 3
C y cl e s 2 a n d Hi g h er
P ati e nts will recei ve sel percati ni b 1 6 0 m g BI D i n c o nti n u o us 2 8-d a y  cycles u nt il P D, u nacce pta ble 
t o xicit y, or ot her reas o ns f or treat me nt disc o nt i n uati o n. Pati e nts wi t h doc u m e nte d P D ma y be 
all o we d t o c o nt i n ue sel percati ni b if t he pat ient  is t olerat i n g treat me nt a n d, in t he o pi ni o n of  the 
I n vesti gat or, t he patie nt is deri vi n g c li nical be nefi t fr o m c o nti n ui n g st u d y treat me nt, a n d 
c o nti n uat i on of  treat me nt is a p pr o ve d b y t he S p o ns or. A d dit i onall y , t he pat ient  must rec o nse nt 
pri or t o c o nti n ui n g t o recei ve st u d y  treat me nt .
6. 2. 4
D o s e D el a y s a n d M o difi c ati o n s
C ycles are 2 8 d a y s i n d urat i on re gar dless of  dose i nterr u pti o n u nless to xicit y rec o ver y perio d 
bef ore e nteri n g n e xt c ycle i ncl u des D a y  1 of t he ne xt c ycle. F or patie nts wi t h dose i nterr u pti o n,
ne xt c ycle will st art wit h res u m ptio n of  st u d y dr u g. I n t his sit u atio n, disease assess me nts s h o uld 
c o nti n ue t o f o ll ow t he ori gi nal sc he d ule.
F or all parts of  this st u d y, t o xicities s uc h as na usea, v o mit i n g, or diarr hea or dizzi ness or 
de h y drat i on relate d t o t hese s y m pt o ms, ma y be ma na ge d wi t h i ncrease d s u p p orti ve care, i ncl u di n g 
h y drat i on, electr ol yt e re pletio n a n d t he use of  ant i-e metics s uc h as ser ot o ni n t ype 3 ( 5-H T 3) 
a nta g o nists a n d/ or a nti-di arr heals s uc h as lo pera mi de as a p pr o priate.
Treat me nt f or t he first c ycle s h o uld c o m me nce o nl y if all t he i ncl usi on a n d e xcl usio n  crit eri a ar e 
met. S u bse q ue nt l y, t he sel percati ni b d ose ma y be d el a ye d/ mo difie d if t he pat ient  ex peri e nces a 
Gra de 3 or greater cli nical A E c o nsi dere d t o be at least p ossi bl y relate d t o selpercat i ni b.

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
4 5
L Y 3 5 2 7 7 2 3
D ose re d ucti o ns s h o ul d be ma de acc or di n g t o t h e fol l owi n g para meters usi n g t he d ose re d ucti on 
ta ble belo w. 

I nterr u pt d osi n g f or C T C A E v 5. 0 Gra de 3 or greater a d verse e ve nts or Gra de 2 a d verse 
e ve nts n ot res olve d wi t hi n 4 8 h o urs wi t h ap pr o pri ate s u p p ortive care (e. g., na usea n ot 
i m pr o ve d wit h a ntie metics) a n d c o nsi dere d i nt olera ble b y t he patient  or t he i n vesti gat or. 

F or sel percati ni b relate d s pecific a d verse e ve nts (h y perse nsit i vity, li ver f uncti o n test 
a b n or malities, t hr o m b oc yt o p e nia, a n d h y perte nsi o n) , see d ose a dj ust me nt s bel o w i n 
Secti o ns 6. 2. 3 (a n y co ncer ns of  t hese rec o m me n de d acti o ns i n cli nical pract ice s h o uld b e 
di sc usse d wit h t he S p o ns or, w h o ma y per mi t a djust a cti o ns) .

D os e m o dificati o ns f or E C G c ha n ges are descri be d i n Secti o n 8. 2. 1 . If a p atie nt recei vi n g 
sel percati ni b e x perie nces Q T C F > 5 0 0 ms ec des pite t wo d ose re d uctio ns a n d if t h e 
i n vesti gat or dee ms it in t he best i nterest of t he patie nt, t he patie nt ma y c o nti n ue treat me nt 
wi t h st u d y dr u g wi t h CR P/ C R S a p pr o val. I n a d ditio n , Lill y ma y re q uest a c o p y of the E C Gs 
f or a dju dicat i on.

U p o n res ol ut i on ( or ret ur n t o pati e nt’s baseli ne) of a d verse e ve nts at least p ossi bl y relate d 
t o treat me nt, re d uce t he d ose as f oll ows: 
o
If pre vi o usl y recei vi n g d ose le vel 1, res u me treat me nt at d ose le vel -1 
o
If pre vi o us recei vi n g d ose le vel -1, res u m e treat me nt at  d ose le vel -2  
o
If pre vi o usl y  recei vi n g d ose le v el -2, res u me treat me nt at t he sa m e d os e le vel. If a 
sec o n d A E re q uiri n g d ose m o dificat i on occ urs at d ose level -2, disc o nti n ue st u d y 
treat me nt. 
o
F or A Es clearl y u nrelate d t o st u d y treat me nt t hat res olve o r ret ur n t o patie nt’s 
baseli ne i n ≤1 4 da ys, d ose re d ucti o n is n ot re q uire d. 
o
Re -escalat i on t o a pri or d ose le vel after a d ose re d ucti o n is n ot per mitte d ( ot her t ha n 
h y perse nsit i vity , li ver test a b n or malities, t hr o m b oc yt o pe nia, a n d h y perte nsi o n ).
P er m a ne nt l y disc o nt i n ue treat me nt f or a n y of : mali g na nt h y perte nsi o n, h y perte nsi ve crisis, or 
persiste nt u nc o ntr olle d h y perte nsi o n des pite o pti mal  me dical ma na ge me nt.  Patie nts wit h cli nical 
be nefit w h o e x perie nce rec urre nt h y perse ns iti vity reacti on or rec urre nt A S T or A L T i ncrease 
des pite d ose re d uctio ns s h o uld be disc usse d wi t h t he C R S/ C R P a n d ma y be allo we d t o co nti n ue 
treat me nt wit h m o re t ha n 2 d ose re d ucti o ns if c o nti n uat i on is c o nsi dere d t o be safe a n d i n t heir 
best i nterest.

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Before the start of each cycle, Grade 3 hematologic toxicity possibly related to selpercatinib must 
resolve to either baseline or at least Grade 2. If a patient experiences Grade 4 hematologic toxicity 
possibly related to selpercatinib, then dosing must be suspended (until the toxicity resolves to 
either baseline or at least Grade 2) and the dose of selpercatinib must be reduced as outlined in
Table 6-1. 
Before the start of each cycle, nonhematologic toxicity (except AEs with no immediate medical 
consequence that can be controlled with adequate treatment (e.g. pain, alopecia, neuropathy 
fatigue, nausea, vomiting, diarrhea, Grade 2 hypothyroidism, or Grade 2 hypertension).   ) possibly 
related to selpercatinib must resolve to either baseline or at least Grade 1. If a patient experiences 
persistent or recurrent Grade 2 nonhematologic toxicity possibly related to selpercatinib that does 
not resolve with maximal supportive measures within 7 days to either baseline or Grade 1, then 
dosing may be suspended (until the toxicity resolves to either baseline or at least Grade 1) and the 
dose of selpercatinib may be reduced as outlined in Table 6-1.
Treatment may be delayed for a maximum of 28 days to allow a patient sufficient time for recovery 
from selpercatinib-related toxicity. If a patient does not recover from the toxicity within 28 days 
from the time of last treatment, the patient must be discontinued from selpercatinib. In rare 
circumstances, a delay >28 days may be permitted before discontinuing the patient from treatment, 
as long as the patient demonstrates clinical benefit without objective progression and is recovering 
from the toxicity. Such circumstances should be discussed between Sponsor and Investigator and 
documented.
Table 6-1
Suggested Toxicity Management for all Parts of this Study
Dose Level
Dose of Selpercatinib
Starting Dose
160 mg BID
First Dose Reduction
120 mg BID*
Second Dose Reduction
80 mg BID*
Third Dose Reduction and Beyond
Only permitted if there is a compelling clinical rationale articulated by 
the Investigator and approved by the Sponsor.
Abbreviations: AE-adverse events; BID-twice daily; LFT-liver function test.

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
4 7
L Y 3 5 2 7 7 2 3
* F or t he s pecific A Es of h y perse nsiti vit y reacti o ns, L F T i ncreases, t hr o m b oc yt o pe nia a n d h y perte nsi o n, t he S p o ns or 
m a y  rec o m me n d a l o wer starti n g d ose (i.e. 4 0 m g BI D f or h yperse nsiti vit y reacti o ns a n d 8 0 m g BI D f or certai n 
L F T i ncreases, 1 2 0 m g BI D f or t hr o m b oc yt o pe nia ) u p o n res u m pti o n of st u d y dr u g treat me nt , wit h s u bse q ue nt d ose 
escalati o n if t olerate d wit h o ut cli nicall y si g nifica nt rec urre nce of t he A Es. Occ urre nce of t hese A Es s h o ul d be 
disc usse d wit h t he S p o ns or.
All d ose i nterr u pti o ns a n d d ose m o dificat i ons a n d t he reas o ns f or t h ose c ha n ges will be rec or de d 
i n t he electr o nic Case Re p ort F or m (e C R F).
G ui d a nce f or I n vesti g at or o n S pecific A d verse E ve nts
D ose M o dific ati o ns f or S el perc ati ni b Hy perse nsitivity
Pl ease r efer t o t he I B f or t he m o st c urre nt g ui da nce o n ma na ge me nt of  sel percati ni b
h y perse nsit i vity react i ons. Rec o m me n de d act i ons are s h o w n bel o w. 
If sel percati ni b dr u g h y perse nsit i vity is s us pecte d, st u d y dr u g s h o uld be wi t h h eld a n d treat me nt 
wi t h st er oids at 1 m g/ k g pre d nis o ne ( or e q ui vale nt) s h o ul d be i nit iate d.  U p o n res ol uti on, 
sel percati ni b ma y be res u me d at a re d uce d d ose of 4 0 m g BI D w hile c o nt i n ui n g ster oi ds at t he 
sa me d ose.  N ote t hat t his d ose re d ucti o n d oes n ot re q uire s p ons or a p pr o val.  H y perse nsi tivit y 
has rec urre d i n s o me pat ient s, t ypicall y  at 3 t o 6 h o urs f oll o wi n g dr u g a d mi nistrati o n.  F oll o w t he 
g ui deli nes bel o w if h y perse nsit i vity rec urs: 

If rec urre nce is se vere, selpercat i ni b s h o uld a gai n be wit h hel d. 

If rec urre nce is mil d (e. g., is olate d i nsta nces of ras h or m yal gias or l o w -gra de fe ver), 
sel percati ni b ma y be c o nti n ue d ca ut i ousl y, t o get her wit h treat me nt wit h s u p p orti ve 
t hera p y (e. g., t o pical treat me nts, i b u pr ofe n). 

If t he patie nt e x perie nces a cli nicall y si g nifica nt rec urre nce of dr u g h y perse nsiti vity at t he 
i nitial re-e x p os ure d ose of 4 0 m g BI D, sel percati ni b s h o ul d be disc o nti n ue d.
After a mi ni m u m of 7 da ys a n d i n t he a bse nce of cli nicall y si g nifica nt rec urre nt dr u g 
h y perse nsit i vity, t he d ose of sel percat i ni b m a y be escalate d se q ue nt iall y t o 8 0 m g BI D, 1 2 0 m g 
BI D, a n d 1 6 0 m g BI D. O nce t he patie nt has t olerate d treat me nt f or a mi ni m u m o f 7 da ys at t he 
fi nal d ose, ster oi ds ma y be ta pere d slo wl y .
D ose M o dific ati o ns f or S el perc ati ni b Rel ate d Liver F u ncti o n Test A b n or m alities

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If a patient experiences ≥Grade 3 elevated liver function tests (LFTs; including AST, ALT, ALP 
and total and direct bilirubin), study drug should be withheld and evaluation for potential 
alternative causes should be conducted (e.g., history of other hepatotoxic medications/
substances, viral serologies, liver imaging). A repeated value 3 to 5 days after the initial finding 
of elevation of LFTs should be obtained to confirm the abnormality and to confirm if it is 
increasing or decreasing. Thereafter, LFTs should be monitored at least weekly until resolution 
to normal/baseline (depending on the clinical situation, resolution to Grade 1 if baseline is 
acceptable but waiting until normalization is preferable). If the LFT abnormalities do not begin 
to resolve (or worsen) within 5 days of the AE, a hepatology consultation should be considered 
to evaluate the need for a liver biopsy.
Upon resolution, for patients who received 160 mg BID or 120 mg BID, the selpercatinib dose 
should be reduced by 2 dose levels (80 mg BID or 40 mg BID, respectively) with weekly LFTs
monitoring. In the absence of recurrent LFT abnormalities, the dose of selpercatinib may be 
escalated sequentially to the next highest dose (120 mg BID or 80 mg BID, respectively) after a 
minimum of 2 weeks and again to the original dose and after a minimum of an additional cycle.  
Once the patient has been treated at a stable dose of selpercatinib for a minimum of 1 cycle
without recurrent LFT abnormalities, the frequency of LFTs monitoring may be decreased (e.g., 
midcycle for 2 cycles and then at the start of every cycle thereafter). 
For patients who experience ≥Grade 3 elevated LFTs at 80 mg 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 BID, selpercatinib should be discontinued. Please refer to 
Section 8.2.2 for additional monitoring that may need to be initiated. 
Dose Modifications for Thrombocytopenia
If a patient is discovered to have thrombocytopenia ≥Grade 3, study drug should be withheld, 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 complete 
blood count (CBC) testing until the event resolves and CBC level returns to normal/baseline.  Upon 
recovery, the patient should resume selpercatinib with a dose reduction of at least 1 level with 
weekly CBC surveillance for 1 full cycle. 

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Dose Modifications for Hypertension
Hypertension is defined as:

a sustained increase in blood pressure from baseline, as evidenced by ≥2 readings on ≥2 
separate occasions, or 

a clinically significant elevation requiring acute treatment.
If hypertension occurs, study drug may be interrupted at the discretion of the investigator while:

a new antihypertensive medication regimen is initiated, or 

a preexisting regimen is optimized to a reproducible reading of ≤140/90 mmHg.
If study drug is interrupted, it may be resumed at the same or a lower dose at the discretion of the 
investigator.  In all cases, the patient should continue to undergo regular blood pressure 
monitoring to ensure adequate blood pressure control.  Dose re-escalation to the patient’s 
original dose can be considered once adequate blood pressure (BP) control has been obtained; 
with clinically appropriate monitoring.  
6.3
Concomitant Medications
6.3.1
General
All medications that were used from the time that written informed consent has been obtained 
through the SFU visit (at least 28 days [±7 days] after the last dose of study drug) will be recorded 
in the eCRF. These are to include prescription and nonprescription medications, transfusions, 
vitamins, and nutritional supplements, and other remedies. Additional prior excluded medications 
are indicated in the Exclusion Criteria (Section 4.2). 
6.3.2
Allowed Concomitant Medications
Standard supportive medications may be used in accordance with institutional guidelines and 
Investigator discretion. These may include hematopoietic growth factors to treat neutropenia, 
anemia or thrombocytopenia (in countries where hematopoietic growth factors are approved for 
use) in accordance with American Society for Clinical Oncology guidelines (but not for 
prophylaxis in C1); RBC and platelet transfusions, anti-emetic, analgesic and antidiarrheal 
medications; electrolyte repletion (e.g., calcium and magnesium) to correct low electrolyte levels;
conditional use of steroids treatment as indicated in Section 6.3.3; thyroid replacement therapy for 

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hypothyroidism; and bisphosphonates, denosumab; and other medications for the treatment of 
osteoporosis, prevention of skeletal-related events from bone metastases, and /or 
hypoparathyroidism. Continuation of standard of care medications, including adjuvant hormonal 
therapy for patients with prostate cancer (e.g., gonadotropin-releasing hormone [GnRH] or 
luteinizing hormone-releasing hormone [LHRH] agonists) and breast cancer (e.g., GnRH/LHRH 
agonists, aromatase inhibitors, selective estrogen receptor modulators [SERMs] or degraders 
[SERDs]), that the patient has been on for the previous 28 days, are allowed, provided they are not 
on the list of prohibited concomitant medications (refer to Section 6.3.3 and Appendix D). 
Local treatment while receiving selpercatinib (e.g., palliative radiation therapy or surgery for bone 
metastases) is permitted with Sponsor approval; however, the Sponsor recommends holding 
selpercatinib for approximately 5 half-lives (approximately 2 to 3 days) before and after radiation 
therapy or surgery. Any concern for disease flare due to a prolonged period off from selpercatinib
should be discussed with the Sponsor, who may permit holding selpercatinib for a shorter period 
of time.
6.3.3
Other Concomitant Medications
As selpercatinib is a substrate of CYP3A4, patients should avoid taking strong or moderate
inhibitors or inducers of CYP3A4 as they could alter the drug’s PK. If concomitant use of strong 
and moderate CYP3A inhibitors cannot be avoided, reduce the selpercatinib dosage and monitor 
the QT interval with ECGs more frequently.
Since selpercatinib is more soluble in an acidic environment than a neutral one, absorption may be 
impacted by stomach acidity, and concomitant use of pH altering agents require additional 
instructions. The concomitant use of PPIs should be avoided, and patients must take selpercatinib 
with food (at least 400 calories) when coadministered with a PPI if concomitant use cannot be 
avoided (refer to Appendix E).
When concurrent use of an H2 blocking agent is necessary, e.g., ranitidine (Zantac®), famotidine 
(Gaster®), or cimetidine (Tagamet®), it must be administered only 10 hours before or 2 hours after 
the dose of selpercatinib. 

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When concurrent use of an antacid is necessary, e.g., aluminum hydroxide/magnesium 
hydroxide/simethicone (Maalox®) or calcium carbonate (TUMS®), it must be administered 2 hours
before and/or 2 hours after the dose of selpercatinib.
Chronic treatment (>7 days) with steroids is not permitted except to treat symptoms from an 
immune-related AE or brain metastases. Intermittent use of inhaled steroids for asthma or local 
steroid injections is allowed. Similarly, limited use of systemic corticosteroids (≤7 days) is 
permitted where it is considered SOC (e.g., as premedication for contrast allergy or for chronic 
obstructive pulmonary disease exacerbation). Replacement doses of steroids (e.g., prednisone 10 
mg daily) are permitted while on study.
In addition, except as indicated in Section 6.3.2, patients are not allowed to receive concomitant 
systemic anti-cancer agents (including herbal products with anti-cancer activity), hematopoietic 
growth factors for prophylaxis in C1, therapeutic monoclonal antibodies, radiation therapy 
(palliative radiation therapy is permitted with Sponsor approval), drugs with immunosuppressant 
properties, or any other investigational agents besides selpercatinib. No new, alternative systemic 
anticancer therapy is allowed prior to documentation of PD in accordance with protocol-specified 
disease response criteria. If during the study, patients require initiation of treatment with strong 
inhibitors or inducers of CYP3A4 for clinical reasons, then the Sponsor should be consulted to 
determine whether selpercatinib should be stopped, and therefore whether the patient should be 
removed from the study. Strong and moderate inhibitors or inducers of CYP3A4 should be taken 
with caution. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, 
reduce the selpercatinib dosage and monitor the QT interval with ECGs more frequently. Any 
exceptions to the above must be approved by the Sponsor.
6.3.4
Contraindications 
Selpercatinib is contraindicated in patients with known hypersensitivity to any of its capsule 
components.
6.4
Discontinuation of Study Intervention 

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Patients will be advised that they are free to discontinue study treatment at any time and that they 
will be followed for survival after discontinuing treatment (refer to Section 7.6). Over the course 
of the study, the Investigator and/or the Sponsor should remove a patient from treatment for any 
of the reasons listed below:

PD
Exception: Patients with documented PD who are tolerating treatment and, in the opinion 
of the Investigator, are deriving clinical benefit from continuing study treatment, may 
continue treatment with prior Sponsor approval.

Unacceptable toxicity

Intercurrent illness compromising ability to fulfill protocol requirements

Pregnancy

Requirement for alternative treatment in the opinion of the Investigator, unless such 
treatment is temporary (e.g., local radiation or surgery for disease that does not meet the 
definition of PD)

Significant noncompliance with protocol

Withdrawal of consent by the patient

Lost to follow-up

Death

Study terminated by Sponsor
Participants discontinuing from the investigational product for any reason should complete 
adverse event per Table 7-1 (Schedule of Activities), Section 8.2 (Safety Assessments) of the 
protocol.
At the time a patient discontinues treatment, all safety data normally required at the EOT visit will 
be obtained if possible, as outlined in Section 7.4. Patients will enter LTFU where they may be 
required to undergo disease assessments (refer to Section 7.6).
6.4.1
Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study. If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without study drug.  Patients who 
are discontinued from study drug will have follow-up procedures performed as shown in the 
Schedule of Activities (Table 7-1).

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6.5
Discontinuation/ Withdraw from the Study
Discontinuation from the Study and reasons for end of study could be:

Withdrawal of consent by the patient

Lost to follow up

Death

Study terminated by Sponsor
Patients who are discontinued from the study will have follow-up procedures performed as shown 
in the Schedule of Activities.
6.6
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.
Study site personnel, or an independent third party, will attempt to collect the survival status for 
all enrolled patients who are lost to follow-up, including enrolled patients who do not receive study 
drug, within legal and ethical boundaries. Public sources may be searched for survival status 
information.  If the patient’s survival status is determined, the survival status will be documented, 
and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect survival status information.

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7
Tests and Evaluations
All required observations and their schedules are summarized in Table 7-1 and are described in 
more detail in the following subsections. 
RET alternation from Cohort 1 and 2 will be confirmed centrally. Special assessments, such as 
PK, will be performed centrally. Additional information regarding handling and processing of 
these special samples is provided in the separate Laboratory Manual.
Routine laboratories, for example serum chemistries, hematology, and urinalysis, will be 
performed locally. For each thyroid cancer patient, tests for calcitonin and CEA (MTC patients) 
and thyroglobulin (non-MTC thyroid cancer patients) should be performed in the same laboratory 
to minimize intra-patient, lab-to-lab variability in their measurement. 
Unless otherwise noted, the routine laboratories and procedures will be performed prior to dosing 
as noted, and routine evaluations performed within -2 days of the visit day will not be considered 
protocol deviations.
During the conduct of this study, the Sponsor must be notified of the collection of samples outside 
of this protocol for separate institutional investigations. 

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
5 5
L Y 3 5 2 7 7 2 3
Ta ble 7- 1
Sc he d ule of Act i vity ( S o A)
Visit Wi n d o w
Scree ni n g
C ycle 1
C ycle 2 -hi g her
S F U b
L T F U
c
U p t o 2 8 d a ys 
pri or t o first 
d ose
D 1
± 2 D a ys
D 8
± 2 D a ys
D 1 5
± 2 D a ys
D 2 2
d
± 2 D a ys
± 2 D a ys
E O T a
≤
7 
d a ys
D 2 8 
± 7 
d a ys
I nf or me d 
C o nse nt
e
X
I ncl usi o n/e xcl us
i o n criteria
X
Me dical, 
s ur gical, 
mali g na nc y 
hist or y
X
M olec ular 
Pat h ol o g y 
Re p ort(s) 
descri bi n g R E T 
a n d ot her 
alterati ons f
X
Arc hi ve d t u m or 
tiss ue or fres h 
bi o ps y g
X
P h y sical 
e xa mi nati o n a n d 
E C O G h
X  
X  
X  
X
D 1 C 2, 3, 4, 5, etc.
X  
X
Vital si g ns
i
X  
X
j
X
j
X
j
D 1 C 2, 3, 4, 5, etc.
X  
X
1 2 -lea d E C G k
X  
X  
X
D 1 C 2 -6 a n d e ver y 1 2 wee ks
X  
X
l
Ur i ne or ser u m 
pre g na nc y test m
X 
X
D 1 C 2, 3, 4, 5, etc.
He mat ol o g y n
X  
X  
X  
X
D 1 C 2, 3, 4, 5, etc.
X  
X
Ser u m 
c he mistries o
X  
X  
X  
X
D 1 C 2, 3, 4, 5, etc.
X  
X
Li ver f u ncti o n 
tests p
C 2 D 1 5 a n d C 3 D 1 5

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
5 6
L Y 3 5 2 7 7 2 3
Visit Wi n d o w
Scree ni n g
C ycle 1
C ycle 2 -hi g her
S F U b
L T F U
c
U p t o 2 8 d a ys 
pri or t o first 
d ose
D 1
± 2 D a ys
D 8
± 2 D a ys
D 1 5
± 2 D a ys
D 2 2
d
± 2 D a ys
± 2 D a ys
E O T a
≤
7 
d a ys
D 2 8 
± 7 
d a ys
C oa g ulati o n
q
X  
X
T h y r oi d pa nel r
X
X
D 1 of o d d c ycles be gi n ni n g wit h C 3 ( C 3, 5, 7, 
etc.)
Ur i nal ysis s
X
X
D 1 C 2, a n d as cli nicall y i n dicate d.
X  
X
Calcit o ni n, 
C E A ( M T C 
o nl y ) t
X  
X
X
D 1 C 2 a n d o d d -n u m bere d c ycles, starti n g wit h 
C 3 t hr o u g h C 1 3. E ver y 1 2 wee ks t hereafter ( ± 7 
da y s of eac h ra di ol o gic disease assess me nt)
X
T h y r ogl o b uli n 
( n on- M T C 
t h yr oi d ca ncers 
o nl y ) u
X  
X
X
D 1 C 2 a n d o d d -n u m bere d c ycles, starti n g wit h 
C 3 t hr o u g h C 1 3. E ver y 1 2 wee ks t hereafter ( ± 7 
da y s of eac h ra di ol o gic disease assess me nt)
X
Bl o o d c ortis ol, 
A C T H, 2 4 -
h o ur uri ne f or 
free c ortis ol v
X  
X
X
D 1 C 2 a n d o d d -n u m bere d c ycles, starti n g wit h 
C 3 t hr o u g h C 1 3. E ver y 1 2 wee ks t hereafter ( ± 7 
da y s of eac h ra di ol o gic disease assess me nt)
X
Disease 
assess me nt w
X
Perf or m assess me nts at wee k 4 ( ± 7 da ys, 
o pti o nal) a n d wee k 8 ( ± 7 da ys) a n d t he n e ver y 8 
wee ks ( ± 7 da ys) u ntil wee k 4 8 f oll o wi n g C 1 D 1 
a n d t he n e ver y 1 2 wee ks ( ± 7 da ys)
X
x
X
y
C o nfir mat or y 
disease 
assess me nt z
At least 4 wee ks p ost 1 st P R
Bl o o d sa m ple 
f or i nte nsi ve P K
aa
X  
X
Bl o o d sa m ple 
f or P o p P K b b
X
D 1 of eac h c ycle
Pre d ose sa m ple t o be dra w n
E O R T C Q L Q -
C 3 0
cc
X
E ver y 8 wee ks ( ± 7 da y s) starti n g wit h D 1 C 3 
t hr o u g h D 1 C 1 3. E ver y 1 2 wee ks ( ± 7 da ys) 
t hereafter
X

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
5 7
L Y 3 5 2 7 7 2 3
Visit Wi n d o w
Scree ni n g
C ycle 1
C ycle 2 -hi g her
S F U b
L T F U
c
U p t o 2 8 d a ys 
pri or t o first 
d ose
D 1
± 2 D a ys
D 8
± 2 D a ys
D 1 5
± 2 D a ys
D 2 2
d
± 2 D a ys
± 2 D a ys
E O T a
≤
7 
d a ys
D 2 8 
± 7 
d a ys
Dis pe nse 
sel percati ni b
X
D 1 of eac h c ycle
Sel percati ni b 
a d mi nistrati o n
Patie nt d osi n g 
diar y
Patie nt b o wel 
diar y  ( M T C 
o nl y ) d d
X  
X  
X  
X
D 1 C 2, 3, 4, 5, etc.
X
A d verse e ve nts
ee
C o nc o mita nt 
me dicati o ns
ff
S ur vi val g g
X  
X
A b bre viati o ns (f or Ta ble 7 -1 a n d F o ot n otes): A C T H -a dre n oc ortic otr o pic h or m o ne; A E -a d verse e ve nt; A L P -al kali ne p h os p hatase; A L T -ala ni ne a mi n otra nsferase; 
A S T -as partate a mi n otra nsferase; B U N bl o o d urea nitr o ge n; C -c ycle; C E A carci n oe m br y o n ic a nti ge n; C R c o m plete res p o nse; C T-c o m p ute d t o m o gra p h y; D -da y ; 
E C G electr ocar di o gra m; E C O G -Easter n C o o perati ve O nc ol o g y Gr o u p; E O R T C Q L Q -C 3 0 -E ur o pea n Or ga nizati o n f or Res earc h a n d Treat me nt of Ca ncer Q ualit y 
of Life Q uesti o n naire -C ore 3 0; E O T -E n d of Treat me nt; I V i ntra ve n o us; L D H lactate de h y dr o ge nase; L T F U l o n g -ter m f oll o w u p; M T C me d ullar y t h yr oi d ca ncer; 
M RI ma g netic res o na nce i ma gi n g; P D-pr o gr essi ve disease; P K p har maco ki netics; P R partial res p o nse; R B C-re d bl o o d cell; S A E-seri o us a d verse e ve nt; S F U safety 
f oll o w-u p; T S H -t h yr oi d-sti m ulati n g h or m o ne; T 3-free trii o d ot h yr o ni ne; T 4-free t h yr o xi ne; W B C w hite bl o o d cell. 
a.
E n d of Treat me nt ( E O T): + 7 da ys of t he last d ose or t h e decisi o n t o ter mi nate treat me nt .  If la b testi n g is perf or me d ≤7 da ys pri or t o E O T, re peat testi n g d oes 
n ot nee d t o occ ur o n E O T.
b.
Safet y F oll o w -U p ( S F U): 2 8 da y s (± 7 da ys) after last d ose of st u d y dr u g.
c.
L o n g -Ter m F oll o w -U p ( L T F U): a p pr o xi matel y e ver y 3 m o nt hs ( ± 1 m o nt h) f or u p t o t w o years after t he last d ose of st u d y dr u g.
d.
Tele p h o ne c o ntact f or safet y. 
e.
Patie nt m ust rec o nse nt pri or t o c o nti n ui n g t o recei ve st u d y treat me nt be y o n d pr o gressi o n.
f.
F or all patie nts, re dacte d re p ort(s) t o be s u b mitte d t o S p o ns or or  desi g nee d uri n g Scree ni n g / pri or t o e nr oll me nt.
g.
A de q uate a vaila bilit y of arc hi ve d t u m or tiss ue s h o ul d be c o nfir me d, eit her t u m or bl oc k ( preferre d) or ~ 1 0 × 5 m u nstai ne d sli des s h o ul d be pr o vi de d . 
Patie nts w h o d o n ot ha ve s ufficie nt arc hi val t u m or tiss ue a vaila ble s h o ul d u n der g o a n o pti o nal fres h t u m or bi o ps y, if it is c o nsi dere d safe t o perf or m, pri or t o 

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol( b)
5 8
L Y 3 5 2 7 7 2 3
treat me nt. If s ufficie nt arc hi ve d t u m or tiss ue is n ot a vaila ble a n d a fres h bi o ps y ca n n ot be safel y perf or me d, t he patie nt may still be eli gi ble wit h pr i or 
S p o ns or a p pr o val. 
h.
P h y sical e xa mi nati o n of a n d re vie w of rele va nt s yste ms at Scree ni n g, b o d y wei g ht, a n d hei g ht. S y m pt o m-directe d p h ysical e xa mi nati o ns, i ncl u di n g 
meas ure me nt of wei g ht ma y be perf or me d at ot her ti me p oi nts.
i.
S y st olic a n d diast olic bl oo d press ure, heart rate, res pirat or y rate, a n d b o d y te m perat ure.
j.
Vital si g ns s h o ul d be c o n d ucte d as f oll o ws:

C 1 D 1, C 1 D 8: pre -d ose ( u p t o 4 h o urs pre -d ose, as cl ose t o d osi n g as p ossi ble is preferre d) a n d p ost -d ose at 2 h o urs ( ± 3 0 mi n utes). Vital si g ns 
s h o ul d be perf or me d pri or t o c ollecti o n of P K bl o o d sa m ple dra w n at t hat ti me p oi nt.

C 1 D 1 5 , Da y 1 of C 2-hi g her: pre -d ose ( u p t o 4 h o urs pre -d ose, as cl ose t o d osi n g as p ossi ble is preferre d); 
k.
O btai n a si n gle pre -d ose E C G d uri n g Scree ni n g a n d a gai n o n C 1 D 1. If t he C 1 D 1 pre-d ose Q Tc F > 4 7 0 msec ( Q Tc F = Q T ( msec)/ R R 1/ 3), w here R R ( msec) 
= 6 0 * 1 0 0 0/ B P M), t he S p o ns or s h o ul d be n otifie d pri or t o d osi n g t o deter mi ne w het her t he patie nt re mai ns eli gi ble. O n C 1 D 8 , C 2 D 1 a n d t hereafter, perf or m 
a si n gle E C G at 2 h o urs ( ± 1 0 mi n utes) p ost -sel percati ni b d osi n g. O n C 1 D 8 P K c ollecti o n, a n e xtra E C G s h o ul d be ti me d pri or t o t he P K sa m ple bei n g 
dra w n. D ose patie nts i n t he visit t o e ns ure acc urac y of ti mi n g. If a n y E C G de m o nstrates Q Tc F 4 8 1-5 0 0 msec, perf or m a n a d diti o nal E C G at t he sa me da y, 
s pecific ti me j u d ge d b y i n vesti gat or. If a n y E C G de m o nstrates Q Tc F > 5 0 0 msec, re peat t he E C G t wice (tri plicate i n t otal) at t he sa me da y, s pecific ti me 
j u d ge d b y i n vesti gat or, a n d ma n uall y re vie w t o c o nfir m acc urac y. If Q Tc F > 5 0 0 msec is c onfir me d o n 2/ 3 E C Gs, h ol d sel percati ni b a n d assess f or 
alter nati ve ca uses (c o nc o mita nt me dicati o ns, electr ol yte a b n or malities). P otassi u m s h o ul d be > 4 m E q/ L a n d < U L N a n d ma g nesi u m a n d calci u m s h o ul d be 
wit hi n n o r mal li mits. sel percati ni b ma y be res u me d a t o ne re d uce d d ose le vel w he n Q Tc F has ret ur ne d t o baseli ne val ue, a n d wit h c o nti n ue d E C G 
m o nit ori n g as n ote d i n t he assess me nt sc he d ule. 
l.
Re peat o nl y if E O T rea di n g s h o we d treat me nt -e mer ge nt a b n or malities.
m.
F or w o me n of c hil d beari n g p ote ntial: Ser u m pre g na n c y  test at Scree ni n g, ser u m or uri ne pre g na nc y test at Da y 1 of e very c ycle (-2 da y s) (s ur gicall y 
sterilize d fe males or t h ose w h o ha ve n ot e x perie nce d me nses f or at least 2 years are n ot re q uire d t o be teste d i.e., p ost -me n o pa usal w o me n w h o ha ve n ot ha d 
me nses wit hi n t he last 1 2 m o nt hs b ut ha ve ha d me nses wit hi n t he last 2 4 m o nt hs will be re q uire d t o ha ve a ser u m pre g na nc y tes t perf or me d.). If scree ni n g 
testi n g is perf or me d ≤7 da ys pri or t o C 1 D 1, re peat testi n g d oes n ot nee d t o occ ur o n C 1 D 1.
n.
He m o gl o bi n, he mat ocrit, R B C c o u nt, W B C c o u nt wit h differe ntial ( ne utr o p hils [c o u nt a n d perce nt] a n d l y m p h oc ytes, m o n oc ytes, e osi n o p hils, bas o p hils 
[ perce nt]), a n d platelet c o u nt). Patie nts f o u n d t o ha ve treat me nt-e mer ge nt he mat ol o gic t o xicit y of Gra des 3 or 4 will be m o nit ore d at least wee kl y u ntil 
res ol uti o n. If scree ni n g testi n g is perf or me d ≤7 da ys pri or t o C 1 D 1, re peat testi n g d oes n ot nee d t o occ ur o n C 1 D 1.
o.
Detaile d s er u m c he mistries ( n o n -fasti n g) please see a p pe n di x H. N ote n u m ber: ≤1 4 da ys bef ore pre -d ose o n scree ni n g peri o d. If scree ni n g testi n g is 
perf or me d ≤7 da ys pri or t o C 1 D 1, re peat testi n g d oes n ot nee d t o occ ur o n C 1 D 1.  Patie nts f o u n d t o ha ve treat me nt -e mer ge nt la b orat or y t o xicit y of Gra des 3 
or  4 will be m o nit ore d at least wee kl y u ntil res ol uti o n.
p.
C ollect A S T, A L T, A L P, a n d t otal a n d direct bilir u bi n o n C 2 D 1 5 a n d C 3 D 1 5 ( ± 2 da ys).
q.
A d diti o nal assess me nts ma y be o btai ne d at t he discreti o n of t he i n vesti gat or. If scree ni n g testi n g is perf or me d ≤7 da ys pri or t o C 1 D 1, re peat testi n g d oes 
n ot nee d t o occ ur o n C 1 D 1.
r.
If scree ni n g testi n g is perf or me d ≤7 da ys pri or t o C 1 D 1, re peat testi n g d oes n ot nee d t o occ ur o n C 1 D 1. T h yr oi d -sti m ulati n g h or m o ne ( T S H), free 
trii o d ot h yr o ni ne (F T 3), a n d free t h yr o xi ne ( F T 4).
s.
If scree ni n g testi n g is perf or me d ≤7 da ys pri or t o C 1 D 1, re peat testi n g d oes n ot nee d t o occ ur o n C 1 D 1.  Detaile d ur i nal ysis please see a p pe n di x H.

J2G-GH-JZJK Clinical Protocol(b)
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t.
If screening testing is performed ≤7 days prior to C1D1, repeat testing does not need to occur on C1D1. Calcitonin and CEA only for patients with a 
diagnosis of MTC. These should be performed in the same laboratory to minimize intra-patient, lab-to-lab variability in their measurement.
u.
If screening testing is performed ≤7 days prior to C1D1, repeat testing does not need to occur on C1D1. Thyroglobulin only for patients with non-MTC 
thyroid cancers (unless not measurable due to the presence of anti-thyroglobulin antibodies). These should be performed in the same laboratory to minimize 
intra-patient, lab-to-lab variability in their measurement.
v.
If screening testing is performed ≤7 days prior to C1D1, repeat testing does not need to occur on C1D1. Optional for MTC or other cancer patients with 
Cushing’s disease related to their cancer. If performed, urine collection should begin pre-dose. If blood cortisol, ACTH cannot be measured locally, central 
laboratory will be used to perform the test.
w.
Baseline disease assessment with radiographic tumor measurements using CT or MRI of chest, abdomen, and pelvis; And any other areas with suspected 
disease involvement within 28 days of C1D1 as clinically indicated. Brain imaging is required at baseline for all RET fusion-positive patients, patients with a 
history of CNS metastases, or other patients if clinically indicated and subsequent serial scans if brain metastases are present at baseline (MRI preferred, 
CT with contrast is acceptable if MRI contraindicated). Required only for patients with nonmeasurable bone disease identified at baseline or if clinically 
indicated. For each modality, IV and oral contrast should be utilized unless there is a clear contraindication (e.g., decreased renal function or allergy that 
cannot be addressed with standard prophylactic treatments). In the absence of known or suspected disease involvement, head and neck CT/MRI scans are not 
required for malignancies other than those originating in the head and neck region. Other areas of scanning may also differ depending on disease type. Post-
baseline scans should be performed every 8 weeks (±7 days) until week 48 and every 12 weeks (±7 days) thereafter, including imaging of the chest, 
abdomen, and pelvis, using the same modality(ies) as used for baseline imaging assessment until PD, withdrawal of consent, or initiation of a new anticancer 
therapy(ies). Additionally, any studies performed at baseline that are positive for sites of disease should be repeated at all post-baseline assessments. 
Additional studies can also be performed as clinically indicated. In addition, Investigators may conduct an initial tumor evaluation on week 4 (±7 days) and a 
confirmatory tumor evaluation a minimum of 4 weeks (i.e., 28 days) after the first tumor evaluation that shows a CR or PR by RECIST 1.1, if consistent 
with local regulatory authority requirements. In addition, an initial post baseline assessment on week 4 (±7 days) is encouraged if consistent with regulatory 
guidelines. If a scan is performed on week 4, the next scan should continue according to the schedule above (beginning at week 8). For patients who 
continue to receive study treatment beyond progression, post PD scans to determine tumor disease assessment should be performed within 8 weeks (±7 days) 
of initial PD (PD1) and every 8 weeks (±7 days) thereafter until subsequent PD (PD2), withdrawal of consent, or initiation of a new anticancer therapy(ies). 
Additional scans can be performed as needed. All scans (including any unscheduled scans performed during the study) will be collected and stored at a 
central facility to permit central reviewer assessment. Please see the Site Imaging Manual for guidelines on how the various imaging studies should be 
performed.
x.
If not performed within the last 8 weeks.
y.
Patients who discontinue study drug for reasons other than PD (e.g., AE, noncompliance, etc.) may (but for practical reasons and to minimize patient 
inconvenience, are not required to) undergo additional disease assessment by imaging (as specified above until PD, withdrawal of consent or initiation of a 
new anticancer therapy(ies)).
z.
Confirmatory scans: Minimum of 4 weeks (e.g., 28 days) after the first tumor evaluation showing a CR or PR by RECIST 1.1, if permitted by regulatory 
authorities. The next scan should continue according to the schedule above.
aa. For 12 subjects in intensive PK testing, PK test performed on C1D1: Up to pre-dose, and post-dose 1 hour (±15 minutes), 2 hours (±15 minutes), and 4 hours 
(±15 minutes), 8 hours (±30 minutes) and 12 hours (±30 minutes), C1D8: Up to pre-dose, and post-dose 1 hour (±15 minutes), 2 hours (±15 minutes), and 4 
hours (±15 minutes) and 8 hours (±30 minutes).
bb. For all enrolled subjects in PopPK testing, PK test performed on each cycle D1 predose.

J2G-GH-JZJK Clinical Protocol(b)
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cc. EORTC QLQ-C30. The questionnaires should be answered by the subject to the best of his/her ability, prior to receiving drug on C1D1 and preferably prior 
to learning the results of the radiologic disease assessment for subsequent cycles.
dd. Only for patients with a diagnosis of MTC and diarrhea at baseline. Two patient bowel diary cards will be dispended on C1D15. The questionnaires should 
be answered by the subject to the best of his/her ability.
ee. AEs and SAEs should be recorded from the time that written informed consent has been obtained through the SFU Visit. 
ff.
Concomitant, ongoing medication(s) plus those administered within 14 days prior to the planned start of treatment.
gg. Patients will be followed for survival status, date of progression, and subsequent anticancer therapy(ies) by telephone or other method.

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7.1
Screening Period
The following procedures must be obtained within 28 days of C1D1 unless otherwise noted. 
Patients who cannot complete the procedures within the screening window may be rescreened, and 
certain screening procedures, in investigator’s opinion, may not need to be repeated, including 
certain procedures that were obtained as part of the patient’s standard care prior to providing 
informed consent for this study (provided the patient provides informed consent), with the 
approval of the Sponsor. 

Informed Consent.

Medical, surgical, and malignancy history, including histologic confirmation of solid 
tumor, primary and metastatic diagnosis dates, prior treatments for the malignancy, etc. 

Submission of redacted Molecular Pathology Report(s) describing RET and other 
alterations, to Sponsor or designee.

Confirmation of availability of archived tumor tissue to be submitted, either tumor 
block (preferred) or ~10 × 5m unstained slides. If archived tumor tissue is not 
available or is of insufficient quantity or quality, a fresh tumor biopsy could be obtained 
prior to selpercatinib. If patients cannot provide sufficient tumor tissue sample, patients 
still can be enrolled after discussion between sponsor and investigator and get sponsor’s 
approval. Physical examination, including relevant review of systems, body weight and 
height, and ECOG performance status (refer to Appendix F).

Vital signs, including systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature.

Obtain a single ECG during Screening.

Serum pregnancy test for women of childbearing potential (surgically sterilized females 
or those who have not experienced menses for at least 2 years are not required to be 
tested i.e., post-menopausal women who have not had menses within the last 12 
months, but have had menses within the last 24 months will be required to have a serum 
pregnancy test performed.).

Hematology, details described in Appendix H.

Serum chemistries (non-fasting), details described in Appendix H.

Coagulation: (as described in Section 7.1).

Thyroid panel, including thyroid stimulating hormone (TSH), free triiodothyronine
(FT3), and free thyroxine (FT4).

Urinalysis, details described in Appendix H.

Calcitonin, CEA: for patients with MTC only. For each patient, all tests for calcitonin 
and CEA should be performed in the same laboratory to minimize intra-patient, lab-to-
lab variability in their measurement.

Thyroglobulin: for patients with non-MTC thyroid cancers only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 

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thyroglobulin should be performed in the same laboratory to minimize intra-patient, lab-
to-lab variability in their measurement.

Blood cortisol, adrenocorticotropic hormone (ACTH), 24-hour urine for free cortisol: 
optional for patients with Cushing’s disease related to their cancer. 

Baseline disease assessment with radiographic tumor measurements using:
o
All patients: computerized tomography (CT) or magnetic resonance imaging (MRI) 
of chest, abdomen, and pelvis, and any other areas with suspected disease 
involvement, within 28 days of C1D1.
Note: Accurate documentation of prior irradiation including exact locations/sites 
must be provided.
o
All fusion-positive solid tumor patients, patients with a history of CNS metastases, or 
other patients if clinically indicated: brain imaging, MRI with and without contrast is 
preferred, CT with and without contrast is acceptable if MRI is medically 
contraindicated, within 28 days of C1D1.
o
For each modality, intravenous (IV) and oral contrast should be utilized where 
applicable unless medically contraindicated.
o
If CT/positron emission tomography (PET) is utilized, the CT component of CT/PET 
must be of the same quality as a dedicated diagnostic CT scan, i.e., with IV and oral 
contrast and 5 mm or less slice thickness.
o
Bone scan required only for patients with nonmeasurable bone disease identified at 
baseline or if clinically indicated. 
Notes:

In patients with thyroid and other head and neck cancers, imaging of the relevant 
areas (e.g., neck, skull base) is required at baseline; other areas of scanning may 
differ depending on disease type. Refer to the separate Imaging Manual that will 
be distributed to the sites for details.

Additional scans can be performed as needed to evaluate potential sites of disease.

Disease assessments will utilize RECIST 1.1  (refer to Section 7.7.1).

Guidelines on the technical parameters of how scans should be performed will be 
provided in the Imaging Manual

Concomitant, ongoing medications plus those administered within 14 days prior to the 
planned start of treatment.
7.2
Cycle 1
The procedures listed below will be performed at the indicated intervals. Observations, routine 
laboratory tests, and HRQoL assessments will be performed prior to selpercatinib dosing on that 
day unless otherwise indicated. Routine clinic visits and C1D1 evaluations performed within -
2 days of the nominal visit day will not be considered protocol deviations, with the exception of 
ECGs, PKs, and vital signs, which must be performed relative to the dose of selpercatinib on that 
day as indicated below. 

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Day 1 

Symptom-directed physical examination, weight, and ECOG.

Vital signs: pre-dose (up to 4 hours pre-dose, as close to dosing as possible is preferred) 
and 2 hours post-dose (±30 minutes). Vital signs should be performed prior to collection 
of PK blood sample drawn at that time point.

Resting 12-lead ECG: pre-dose (up to 4 hours pre-dose). 

Serum or urine pregnancy test for women of childbearing potential (surgically sterilized 
females or those who have not experienced menses for at least 2 years are not required 
to be tested i.e., post-menopausal women who have not had menses within the last 12 
months, but have had menses within the last 24 months will be required to have a serum 
pregnancy test performed).

Hematology (as described in Appendix H).

Serum chemistries (as described in Appendix H).

Blood sample of intensive PK (2 mL whole blood) for a total 12 subjects: pre-dose, and 
post-dose at 1 hour (±15 minutes), 2 hours (±15 minutes), and 4 hours (±15 minutes), 8 
hours (±30 minutes) and 12 hours (±30 minutes). Exact clock time (24h format) of 
sample collection and of dose administration should be recorded. 

Blood sample of PopPK (2 mL whole blood) for all enrolled subjects: each cycle D1 
predose.

Coagulation (as described in Section 7.1).

Calcitonin, CEA: for patients with MTC only. For each patient, all tests for calcitonin 
and CEA should be performed in the same laboratory to minimize intra-patient, lab-to-
lab variability in their measurement.

Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, lab-
to-lab variability in their measurement.

Blood cortisol, ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer. If done, urine collection should begin pre-
dose.

Dispense selpercatinib.

Selpercatinib administration.

Outpatient diaries for recording daily selpercatinib dosing, H2 blockers and antacids.

AEs.

Concomitant medications.

Patient-reported outcomes to be completed pre-dose:
o
For MTC patients with diarrhea present at baseline: bowel diary.
o
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30).
Day 8

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
Symptom-directed physical examination, weight, and ECOG.

Vital signs: pre-dose (up to 4 hours pre-dose, as close to dosing as possible is preferred) 
and 2 hours post-dose (±30 minutes). Vital signs should be performed prior to collection 
of PK blood sample drawn at that time point.

Resting 12-lead ECG: perform a single ECG at 2 hours (± 10 minutes) post-
selpercatinib dosing. On C1D8 PK collection, an extra ECG should be timed prior to the 
PK sample being drawn. If any ECG demonstrates QTcF 481-500 msec, perform an 
additional ECG at the same day, specific time judged by investigator. If any ECG 
demonstrates QTcF > 500 msec, repeat the ECG twice (triplicate in total) at the same 
day, specific time judged by investigator, and manually review to confirm accuracy.

Hematology (as described in Appendix H).

Serum chemistries (as described in Appendix H).

Blood sample of intensive PK (2 mL whole blood) for a total 12 subjects: pre-dose, and 
post-dose at 1, 2 and 4 hours (±15 minutes), and 8 hours (±30 minutes). Exact clock 
time (24h format) of sample collection and of dose administration should be recorded. 

Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids.

AEs.

Concomitant medications.

For MTC patients with diarrhea present at baseline: bowel diary.
Day 15

Symptom-directed physical examination, weight, and ECOG.

Vital signs: pre-dose (up to 4 hours pre-dose, as close to dosing as possible is 
preferred). 

Hematology (as described in Appendix H).

Serum chemistries (as described in Appendix H).

Thyroid panel, including TSH, FT3, and FT4.

Urinalysis.

Calcitonin, CEA: for patients with MTC only. For each patient, all tests for calcitonin 
and CEA should be performed in the same laboratory to minimize intra-patient, lab-to-
lab variability in their measurement.

Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, lab-
to-lab variability in their measurement.

Blood cortisol, ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer. If done, urine collection should begin pre-
dose.

Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids.

AEs.

Concomitant medications.

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
F or M T C patie nts wit h diarr hea prese nt at baseli ne: b o wel diar y . T w o pati e nt b o wel 
di ar y car ds will b e dis pe n de d o n C 1 D 1 5, a n ot her car d will be use d o n C 1 D 2 2.
D a y  2 2

T el e p h o ne c o ntact f or safet y. 
7. 3
C y cl e s 2 a n d Hi g h er
T he f oll owi n g pr oce d ures will be p erf or m e d pri or t o d osi n g as n ote d. R o uti ne cli nic visit s 
perf or m e d wit hi n ±2 da ys o f t he n o mi nal visit da y  will n ot be c o nsi dere d pr ot oc ol  de viati ons.

S y m pt o m -di recte d p h ysical e xa mi nati on, wei g ht, a n d E C O G: Da y  1 eac h c ycle starti n g 
wi t h C 2.

Vi t al si g ns: u p t o 4 h o urs pre -d ose o n Da y  1 eac h c ycle starti n g wit h C 2.

Rest i n g 1 2-lea d E C G ( 2 h o urs [ ± 1 0 mi n utes] p ost-d ose o n C 2 D 1, C 3 D 1, C 4 D 1, C 5 D 1 
a n d C 6 D 1 a nd e ver y  1 2 wee ks t hereafter). A d dit i onal E C Gs ma y  be perf or me d if 
cli nicall y i n dicate d.

Bl o o d sa m ple of p o p ul at i on P K ( 2 m L w h o le bl o o d) f or all e nr olle d s u bjects: eac h c ycle 
D 1 pre d ose.

S er u m  or uri ne pre g na nc y t est for w o m e n of c hil d beari n g p ote ntial (s u r gicall y sterilize d 
fe males or t h ose w h o ha ve n ot e x perie nce d me nses f or at least 2 years are n ot re q uire d 
t o be teste d): Da y 1 eac h c ycle starti n g wit h C 2. 

H e m at olo g y : (as descri be d i n Secti on 7. 1 ).Da y 1 eac h c ycle starti n g wit h C 2. 
N ote: Patie nts f o u n d t o ha ve treat me nt -e mer ge nt he mat olo gi c t o xicit y of Gra des 3 or 
4 will be m o nit ore d at least wee kl y u nt il res ol uti on.

S er u m  c he mistries (as descri bed i n A p pe n di x H ): Da y 1 eac h c ycle starti n g with C 2. 
N ote: Patie nts f o u n d t o ha ve treat me nt -e mer ge nt la b orat or y t o xicit y of Gra des 3 or 4 
will be m o nit ore d at l east wee kl y u ntil res olut i on.

L F T s, i ncl u di n g A S T, A L T, A L P, a n d t otal a n d di rect bilir u bi n: C 2 D 1 5 a n d C 3 D 1 5.

T h y r oid pa nel: Da y  1 of o d d-n u m bere d c ycles, starti n g wit h C 3. 

Uri nal ysis: D 1 C 2 , a n d as cli nicall y i n dicate d.

Di s pe nse sel percati ni b.

S el percat i ni b a d mi nistrati o n.

O ut pati e nt diaries for rec or di n g dail y sel percat i ni b d osi n g, H 2 bl oc kers a n d a ntaci ds.

A Es.

C o nc o mita nt me dicat i ons.

P ati e nt -re p orte d o utc o mes: 
o
F or M T C patie nts wit h diarr hea prese nt at baseli ne: b o wel diar y , Da y 1 eac h c ycle 
starti n g wit h C 2.
o
E O R T C Q L Q -C 3 0, c o m plete d at t he sa me c ycle visits as disease assess me nts u nt il 
E O T.

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The following procedures will be performed as planned even if cycles are delayed. As a result, 
the following procedures may not always occur at the beginning of a cycle. 

Calcitonin, CEA: for patients with MTC only; Day 1 of C2 and odd-numbered cycles, 
starting with C3 through C13, and every 12 weeks thereafter (±7 days of each 
radiologic disease assessment). For each patient, all tests for calcitonin and CEA should 
performed in the same laboratory to minimize intra-patient, lab-to-lab variability in their 
measurement.

Thyroglobulin: for patients with non-MTC thyroid cancer only, unless not measurable 
due to presence of anti-thyroglobulin antibodies): Day 1 of C2 and odd-numbered 
cycles, starting with C3 through C13, and every 12 weeks thereafter (±7 days of each 
radiologic disease assessment). For each patient, all tests for thyroglobulin should be 
performed in the same laboratory to minimize intra-patient, lab-to-lab variability in their 
measurement.

Blood cortisol, ACTH, 24-hour urine for free cortisol: for patients with Cushing’s 
disease related to their cancer. Day 1 of C2 and odd-numbered cycles, starting with C3 
through C13, and every 12 weeks thereafter (±7 days of each radiologic disease 
assessment). If done, urine collection should begin pre-dose.

Radiographic disease assessment: every 8 weeks (±7 days) beginning with C3D1 
through C13D1, and every 12 weeks (±7 days) thereafter until PD, withdrawal of 
consent, or initiation of a new anticancer therapy(ies), including imaging of the chest, 
abdomen, and pelvis, utilizing the same modality(ies) as used for the baseline imaging 
assessment. Additionally, any studies performed at baseline that are positive for sites of 
disease should be repeated at all post baseline assessments. Additional studies can also 
be performed as clinically indicated. Please refer to the Imaging Manual for guidelines 
on how the various imaging studies should be performed.
Notes: 

Patients who discontinue study drug for reasons other than PD (e.g., AE, 
noncompliance, etc.) may (but, for practical reasons and to minimize patient 
inconvenience, are not required to) have scans performed and collected as defined 
above. 

Post-baseline imaging of the brain using the same modality as at baseline should be 
performed for patients with evidence of CNS disease at baseline and if clinically 
indicated.

If consistent with local regulatory guidelines, an initial post-baseline assessment after 
4 weeks of treatment (±7 days) is encouraged. If this scan is performed, the next scan 
should continue according to the schedule above (beginning at C3D1).

If consistent with local regulatory guidelines, confirmatory imaging a minimum of 
4 weeks (e.g., 28 days) after the first imaging studies that demonstrate a tumor CR or 
PR by RECIST 1.1 is encouraged. If this scan is performed, the next scan should 
continue according to the schedule above.
7.4
End of Treatment Visit (All Patients)

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Within 7 days of last dose of study drug or at the time of premature discontinuation of treatment, 
the following procedures will be performed at the EOT visit:

Scheduling of tumor tissue biopsy from patients who experience PD (optional and if it 
can be safely performed in the judgement of the Investigator).

Symptom-directed physical examination, weight, and ECOG.

Vital signs.

Resting 12-lead ECG.

Hematology.

Serum chemistries.

Urinalysis. 

Calcitonin, CEA: for patients with MTC only. For each patient, these should be 
performed in the same laboratory as prior testing to minimize intra-patient variability in 
measurement.

Thyroglobulin: for patients with non-MTC thyroid cancer only (unless not measurable 
due to presence of anti-thyroglobulin antibodies). For each patient, all tests for 
thyroglobulin should be performed in the same laboratory to minimize intra-patient, lab-
to-lab variability in their measurement.

Blood cortisol, ACTH, 24-hour urine for free cortisol: optional for patients with 
Cushing’s disease related to their cancer.

Radiographic disease assessment (if not performed within the last 2 cycles). Patients 
who have an ongoing CR or PR and discontinue study drug for reasons other than PD 
(e.g., AE, noncompliance, etc.), may (but, for practical reasons and to minimize patient 
inconvenience, are not required to) have scans collected ~ every 8-12 weeks as outlined 
above until documented PD.

Return unused selpercatinib.

Outpatient diaries for recording daily selpercatinib dosing, H2 blockers, and antacids.

AEs.

Concomitant medication(s).

Patient-reported outcomes: 
o
For MTC patients with diarrhea present at baseline: bowel diary.
o
EORTC QLQ-C30.
7.5
Safety Follow-up Visit (SFU)
Twenty-eight (28) days (+7 days) after the final dose of study drug (may be performed as part of 
the EOT visit if the latter was performed at least 28 days after final dose of the last cycle), the 
following will be performed:

Symptom-directed physical examination, weight, and ECOG.

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
Vital signs.

Resting 12-lead ECG: only if prior ECG reading showed treatment-emergent 
abnormalities.

Hematology.

Serum chemistries.

Urinalysis.

Status of unresolved SAEs (if unresolved SAEs exist at the time of this visit, subsequent 
assessment for resolution may be conducted by phone if patient is not able to return to 
clinic).

AEs.

Concomitant medications.
7.6
Long-term Follow-up (LTFU)
After treatment discontinuation, for patients who remain on study, LTFU will occur approximately 
every 3 months (±1 month), until the patient has withdrawn consent for further participation, is 
lost to follow-up, has died or the Sponsor makes a decision to close the study. Assessments may 
include: subsequent anticancer therapy(ies) and survival status. Long-term follow up 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.
If a patient discontinues study treatment for reasons other than PD, withdrawal of consent, lost to 
follow-up or initiation of a new anticancer therapy(ies), the patient may (but, for practical reasons 
and to minimize patient inconvenience, is not required to) undergo disease assessment by imaging 
as specified in Section 7.3 until PD, withdrawal of consent, lost to follow-up or initiation of a new 
anticancer therapy(ies) utilizing the same modality(ies) used for the baseline imaging assessment.
7.7
Procedures for Special Tests
7.7.1
Tumor Measurements
Tumors will be assessed by the Investigator according to the guidelines provided in Section 7 and 
the Imaging Manual. Investigators should use the same method consistently for an individual 
patient throughout the study. Assessments of both measurable and non-measurable disease will be 
made by the Investigator using RECIST 1.1 (refer to Appendix G);  as appropriate to tumor type;
or a comparable assessment method depending on location of tumor.

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7. 7. 2
C e ntr al C oll e cti o n of R a di o gr a p hi c St u di e s
Baseli ne scree ni n g r a dio gra p hic st u dies a n d all su bse q ue nt r a dio gra p hi c st u dies (incl u di n g a n y 
u nsc he d ule d sca ns p erf or m e d f or a n y cli nical reas o ns) a n d t heir ass ociate d re p orts will be c o llecte d 
a n d st ore d f or f ut ure i n de pe n de nt ra di ol o gical re vie w.
7. 7. 3
P h ar m a c o ki n eti c s
Pl as ma sa m ples will be o btai ne d f or p at ient s as o utli ne d i n S o A. A d di tio nal  P K assess me nts ma y 
be c o n d ucte d i n patie nts w he n c o nsi dere d necessar y b y t he I n vest i gat or t o u n dersta n d e x p os ure i n 
r elat i ons hi p t o p ossi ble s afet y or efficac y fi n di n gs or if t here is a c ha n ge t o t he f or mulat i on of  
sel percati ni b a d mi nistere d. S a m ples will be c o llecte d a n d ha n dle d as o utli ne d i n t he La b orat or y 
Ma n ual, a n d c o nce ntrati o ns of  sel percati ni b will be deter mi ne d wi t h a vali date d bi oa nal yt ical 
met h o d. T hese data will be use d t o deter mi ne p ar a m eters s uc h as A U C 0-t a n d pl as ma ter mi nal 
eli mi nat i on half -life ( T1/ 2). T he 0- 8-h o ur d urati o n of  sa m ple c ollectio n will be s ufficie nt t o c o ver 
a sig nifica nt fract i on of t he area u n der t he plas ma c o nce ntrati o n vers us t i me c ur ve.
S eri al blo o d s a m ples f or i nte nsi ve P K m o nit ori n g will  be c ollecte d o n C 1 D 1 a n d C 1 D 8 f or a t otal 
of  1 2 patie nts, blo o d sa m ples f or P o p P K will be c ollecte d f or all e nr olle d pati e nts. P K para meters 
calc ulate d fr o m t he dr u g c o nce ntrati o ns i n t hese sa mples will be use d t o co m pare t he area u n der 
t he c o nce ntr at i on vers us ti me c ur ve fr om time 0 t o infi nit y ( AU C 0- ∞) o n D 1 wi t h t he area u n der 
t he c o nce ntratio n vers us ti me c ur ve calc ulate d d uri n g t he d osi n g i nter val at st e a d y state ( A U Cta u) 
a n d detect a n y a ut o-i n hi biti on or a ut o -i n d ucti on of t he p har mac o ki net ics of selpercat i ni b ( n o ne is 
e x pecte d). E x pl orat or y  anal yses t o deter mi ne t he prese nce a n d str uct ures of  meta b olit es of 
sel percati ni b ma y als o be c o n d ucte d a n d t he res ults of t hese a nal yses, if c o n d ucte d, will be re p orte d 
se paratel y b y t he S p o ns or.
7. 7. 4 C oll e cti o n of E O R T C Q L Q -C 3 0 a n d B o w el Di ar y
Pa per Q ualit y of  Life ( Q o L) i nstr u me nts will be a d mi nistere d pre -d ose o n C 1 D 1. 
T he E O R T C Q L Q -C 3 0 a n d a b o wel diar y (f or M T C patie nts o nl y) will be use d (refer t o A p pe n di x 
J) a n d s h o uld be i m ple me nte d f or ne wl y e nr olle d pat ient s. O nl y p atie nts w h o ha ve c o m plete d t he 
q uesti o n naire at baseli ne s h o uld c o m p lete s u bse q ue nt q uesti o n naires at t he s pecifie d f oll ow- u p 
p eri o ds.

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For EORTC QLQ-C30, subsequent assessments will occur at the same cycle visits as disease 
assessments until EOT. Each assessment should be performed before the subject learns the results 
of his or her restaging.
For MTC patients, the bowel diary assessments will be collected weekly on Cycle 1, and on Day 
1 of every cycle thereafter through EOT. Inaccurate recording will not be considered a protocol 
violation.
7.7.5
Correlative Studies
7.7.5.1
Tumor Samples 
Archived tumor samples prior to treatment with selpercatinib are required if available for 
participation in the trial. Tissue blocks are preferred, otherwise ~10 × 5m unstained slides should
be provided. If sufficient quantity or quality of tissue cannot be provided, patients can undergo a 
fresh tumor biopsy, if it is considered safe to perform, prior to treatment (refer to Section 7.7.5.2). 
If patients cannot provide sufficient tumor tissue sample, patients still can be enrolled after 
discussion between sponsor and investigator and get sponsor’s approval. The samples will be used 
for identification or confirmation of molecular abnormalities in RET gene. Samples (including 
tumor sample and derivatives such as DNA and RNA) will be retained at a facility selected by 
Lilly for a maximum of 4 years after the last patient visit for the study, or for a shorter period if 
local regulations and/or ethical review boards (ERBs)/investigational review boards (IRBs) 
impose shorter time limits.  This retention period enables response to regulatory questions related 
to selpercatinib, after which they will be destroyed. 
The sample collection must be captured on the appropriate eCRF and requisition page(s). Refer to 
the Laboratory Manual for detailed sample collection, storage, and shipment information.
7.7.5.2
Fresh Tumor Biopsies
Fresh tumor samples will be used for identification or confirmation of molecular abnormalities in 
RET and other genes. Fresh tumor biopsies are strongly encouraged when the Investigator feels it 
is appropriate and safe to do so.

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Prior to Selpercatinib Treatment
Required: A fresh tumor biopsy must be obtained prior to selpercatinib for all patients who do not 
have archival tumor tissue available (or who have insufficient tissue quantity or quality—refer to 
Section 7.7.5.1) and for whom, in the opinion of the Investigator, a fresh tumor biopsy can be 
safely performed. 
Optional: If archived tumor tissue was obtained prior to progression on the last MKI with anti-
RET activity, a fresh biopsy of a lesion may be obtained if the patient provides informed consent 
and it can be safely performed. The purpose of the fresh tumor biopsy is to identify genetic 
alterations related to progression after the previous MKI(s). 

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8
Study Assessments and Procedures
Table 7-1 provides the Schedule of Activities for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or laboratory 
certification standards.

Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed by the investigator to 
confirm that potential participants meet all eligibility criteria.  The investigator will 
maintain a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count, scans, RET testing) and obtained before signing of the ICF may be utilized 
for screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
8.1
Efficacy Assessments
8.1.1
Imaging
To evaluate PFS, tumor assessments will be performed for each patient at the times shown in the 
Schedule of Activities (Table 7-1) or whenever clinically indicated.  Radiologic assessments 
obtained previously as part of routine clinical care may be used as baseline assessment provided 
they are of diagnostic quality and were done no more than 28 days before the first dose of study 
drug. 
Computed tomography (CT) scans, including spiral CT, are the preferred methods of measurement 
(CT scan thickness recommended to be £5 mm); however, magnetic resonance imaging (MRI) is 
also acceptable in certain situations, such as when body scans are indicated or if there is a concern 

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a b o ut ra diati on e x p os ure ass ociate d wi t h CT.  Int ra ve n o us a n d or al  co ntrast is re q uire d u nless 
me dicall y c o nt rai n dicate d.
T he C T p orti o n of  a posi tr o n e missi o n t o mo gra p h y  (P E T) -C T sca n ma y be use d as a met h o d of 
res p o nse assess me nt if t he sit e ca n d oc u m e nt t hat t he C T is of  ide nt ical dia g n ost ic q ualit y t o a 
di a g n ostic C T ( wit h i ntra ve n o us a n d oral c o ntrast).  A P E T sca n al o ne or as part of a P E T -C T ma y 
be p erf or m e d f or a d ditio nal  a nal yses b ut ca n n ot be use d t o assess res p o nse acc or di n g t o R E CI S T 
1. 1 ( Eise n ha uer et al. 2 0 0 9).
T he m et h o d of t u mor assess me nt use d at baseli ne m ust be use d c o nsiste nt l y t hr o u g h o ut t he st u d y.  
Ra di ol o gi c sca n of  the t hora x, a b d o me n, a n d pel vis is re q uire d, as well as a n y ot her areas wi t h 
s us pecte d disease i n v o l ve me nt. A baseli ne i ntracra nial e val uati on wi t h C T or M RI is re q uir e d for 
pati e nts wit h k n o w n C N S lesi ons. A baseli ne b o ne sci nti gra p h y ( preferre d) or P E T sca n or P E T 
c o mp o ne nt of  PE T/ C T sca n is re q uire d f or patie nts wit h k n o w n n o n meas ura ble b o ne lesi ons 
(incl u de ne w c o nfir me d lesi ons i n scree n p eri o d). It is allo we d t o s kip b o ne sci nti gra p h y or P E T 
sca n or P E T c o m p o ne nt of P E T/ C T sca n at s u bse q ue nt t u m or assess me nts, u n der t he circ u msta nce 
w here ot her i ma gi n g met h o ds c o ver t he b o ne lesi o n(s). Ot her wise, b o ne sci nt i gra p h y or P E T sca n 
or P E T c o mp o n e nt of  PE T/ C T sca n ma y be o btai ne d e ver y 2 4 wee ks ( ± 7 da ys) or m or e of te n if 
cli nicall y i n dicate d. Please see t he Site I ma gi n g Ma n ual f or g ui deli nes o n h o w t he var i ous i ma gi n g 
st u dies s h o uld be perf or m e d a n d tra ns mitte d f or ce ntral re vie w.
8. 2
S af et y A s s e s s m e nt s
8. 2. 1
El e ctr o c ar di o gr a m s
E C G m o nit ori n g s h o uld be p erf or m e d as o utli ne d i n t he S o A (Ta ble 7- 1 ).  The act i ons bel o w 
s h o uld be ta ke n if t he tri plicate a vera ge Q Tc F is greater t ha n 5 0 0 msec.  
Ma n uall y  re vie w t o c o nfir m acc urac y
Assess f or alter nat i ve ca uses (c o nc omit a nt me dicati o ns, electr ol yte a b n or malit ies, 
prese nce of pace ma ker).  P otassi u m s h o ul d be ≥4 m E q / L a n d < U L N a n d ma g nesi u m a n d 
calci u m s h o uld be wi t hi n n or mal li mits.
I nstituti o nal  g ui deli nes or S O C meas ures f or ma n a g e m e nt of Q Tc F i nter val > 5 0 0 msec 
a n d/ or ass ociate d arr h yt h mias s h o uld be i ni tiate d.  
Cli nical c he mistr y  s h o uld be assesse d a n d if electr ol y tes are a b n or mal, t he y s h o uld be 
re peate d as i n dicate d.

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If a patie nt e x perie nces a Q Tc F i nter val > 5 0 0 msec a n d if t he i n vesti gat or dee ms it i n t he best 
i nterest of t he patie nt, t he patie nt ma y c o nti n ue treat me nt wit h st u d y dr u g ( wit h a d ose 
re d uctio n).  
8. 2. 2
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s

I n vesti gat or sites ma y use l ocal la b orat ories t o deter mi ne patie nt eli gi bility a n d 
treat me nt decisio n s. 

I n a d diti on, bl o o d will be c ollecte d, 
o
See A p pe n di x H f or t he list of cli nical la b orat or y tests t o be perf or me d a n d Ta ble 7- 1
( Sc he d ule of Acti vities) for t he ti mi n g a n d fre q ue nc y .
o
T he i n vest i gat or s h o ul d re vie w a n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs
a n d assess rele va nce t o patie nt care.  If t he la b orat or y fi n di n gs are cli nicall y 
sig nifica nt, t he i n vest i gat or s h o ul d d oc u me nt t he fi n di n gs as a n a d verse e ve nt i n t he 
case re p ort f or m.  T he la b orat or y re p orts must be file d wit h t he s o urce d oc u me nts.  
Cli n icall y si g nifica nt a b n or mal la b orat or y fi n di n gs are base d o n i n vesti gat or 
j u d ge me nt.

Re gar dless of w het her or n ot ce ntral or l ocal la b orat or y  tests are use d t o deter mi ne 
pati e nt care decisio n s, all la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nific a ntl y 
a b n or mal d uri n g partici pat i on i n t he st u d y or u ntil c o mplet i on of S F U s h o uld be 
re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger c o nsi dere d 
cli nicall y si g nifica nt b y t he i n vestig at or.
o
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a perio d of  ti me j u d ge d 
reas o na ble b y t he i n vesti gat or, t he eti ol og y  s h o uld be i de ntifie d, a n d t he s p o ns or 
n otifie d.
o
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x H , must be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual  a n d t he S o A.
8. 2. 2. 1
H e p ati c S af et y M o nit ori n g
If a stu d y  partici pa nt e nr olle d wi t h baseli ne A L T/ A S T < 1. 5 X U L N e x perie nces ele vate d A L T / A S T
≥3 X U L N a n d ele vate d t otal bilir u bi n le vel (T B L ) ≥2 X U L N, or A L T / A S T ≥5 X U L N , L F Ts (A S T, 
A L T, A L P a n d t otal an d di r e ct bilir u bi n ) s h o uld be re peate d wit hi n 3 t o 5 da ys t o c o nfir m t h e 
a b n or malit y an d t o deter mi ne if it is i ncreasi n g or decreasi n g.  If t he a b n or malit y persists or 
w orse ns, cli nical a n d la b orat or y mo ni t ori n g s h o uld be i nit iate d b y t he i n vesti gat or a n d i n 
c o ns ult atio n wit h t he st u d y C R P/ C R S.  M o nit ori n g of L F Ts s h o uld c o nt i n ue u ntil le vels n or malize 
or ret ur n t o a p pr o xi mate baseli ne le vels. 

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol ( b)
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If a st u d y particip a nt e nr olle d wi t h baseli ne A L T/ A S T ≥1. 5 X U L N e x p erie nces ele vate d 
A L T/ A S T ≥ 3 X baseli ne or A L T/ A S T ≥2 X baseli ne a n d T B L ≥2 X U L N, L F T s s h o uld be re peate d 
wi t hi n 3 t o 5 da ys t o c o nfir m t he a b n or mality a n d t o deter mi ne if it is i ncreasi n g or decreasi n g.  If 
t he a b n or malit y per sists or w orse ns, cli nical a n d la b orat or y m o nit ori n g a n d e val uati o n f or p ossi ble 
ca uses of a b n or mal li ver tests s h o ul d be i nitiate d b y t he i n vest i gat or i n c o ns ultati on wit h t he st u d y 
C R P/ C R S.  Mo ni t ori n g of  L F T s s h o uld c o nt i n ue u nt il le vels n or m alize or r e t ur n t o a p pr o xi mate 
baseli ne le vels.
He pati c data s h o ul d be c o llecte d i n t he e ve nt that o ne ( or m ore) of t he f o ll owi n g c o n dit i ons is met  
f or t he patie nt d urin g t he c o urse of t he st u d y : 

I n patie nts e nr olle d wit h baseli ne A L T / A S T ( < 1. 5 U L N) t he t hres h ol d f or 
clos e m o ni t ori n g is as f oll o ws: 
a.
Ele vate d A L T / AS T ≥3 X U L N a n d ele vate d T B L ≥2 X U L N 
b.
A L T/ A S T ≥5 X U L N o n 2 c o nsec ut i ve tests

I n patie nts e nr olle d wit h ele vate d baseli ne A L T / A S T (≥1. 5 X U L N) (re gar dless of 
w het her or n ot t he y  ha ve he pat ic met astasis) t he t hres h o l d f or clos e m o ni t ori n g is: 
a.
Ele vate d A L T / AS T ≥2 X baseli ne a n d ele vate d T B L ≥2 X U L N
b.
Ele vate d A L T / AS T ≥3 X baseli ne o n 2 c o nsec ut i ve tests 

All patie nts
a.
di sc o nti n uati on fr om st u d y treat me nt d ue t o a he patic e ve nt or 
a b n or malit y of li ver tests
b.
occ urre nce of a he pat ic e ve nt c o nsi dere d t o be a S A E
8. 2. 3
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of partici pa nts w h o ha ve e ntere d t his st u d y 
a n d f or alert i n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y b e 
c o nsi dere d a n u na nti ci pate d be nefit t o t he partic i pa nt.  The i n vesti gat or is res p o nsi ble f or t he 
a p pr o priate me dical care of partici pa nts d uri n g t he st u d y. 
T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, A Es 
t hat are seri o us or ot her wise me dicall y i m p orta nt , c o nsi dere d relate d t o t he i n vesti gati onal pr o d uct 
or t he st u d y, or t hat  ca use d t he partici pa nt t o disc o nti n ue t he i n vesti gati onal pr o d uct bef ore 
c o mplet i n g t he st u d y.  T he partici pa nt s h o uld be f oll o we d u ntil t he e ve nt res ol ves, sta bilizes wit h 
a p pr o priat e dia g n ostic e val uat i on, or is ot her wise e x plai ne d. T he fre q ue nc y of  fol l ow -u p 

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evaluations of the AE is left to the discretion of the investigator.  Lack of drug effect is not an AE 
in clinical studies, because the purpose of the clinical study is to establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via case report 
form (CRF) the occurrence and nature of each participant’s preexisting conditions, including 
clinically significant signs and symptoms of the disease under treatment in the study.  In addition, 
site personnel will record any change in the condition(s) and any new conditions as AEs.  The 
investigator should provide AE verbatim terms and then the terms will be mapped by Lilly or its 
designee to corresponding terminology within the Medical Directory for Regulatory Activities 
(MedDRA) Lower level term (LLT) dictionary.  The investigator will use CTCAE v5.0 to assign 
AE severity grades. 
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure or investigational product, via CRF.  The investigator will interpret and document 
whether or not an AE has a reasonable possibility of being related to study treatment, or a study 
procedure, taking into account the disease, concomitant treatment, or pathologies.  A “reasonable 
possibility” means that there is a cause and effect relationship between the investigational product, 
and/or study procedure and the AE. The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a participant’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF, clarifying if possible, the circumstances leading 
to any dosage modifications, or discontinuations of treatment. 
Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

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
important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria.  
The SAE reporting to the sponsor begins after the participant has signed the ICF and has received 
investigational product.  However, if an SAE occurs after signing the ICF, but prior to receiving 
investigational product, the SAE should be reported to the sponsor as per SAE reporting 
requirements and timelines (see Section 8.2.3.1) if it is considered reasonably possibly related to 
study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they are 
to be immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.  
Participants with a serious hepatic adverse event should have additional data collected using the 
CRF (see Section 8.2.2.1).
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
Suspected Unexpected Serious Adverse Reactions (SUSARs)
Lilly has procedures that will be followed for the identification, recording and expedited reporting 
of SUSARs that are consistent with global regulations and the associated detailed guidances.
Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements.

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Patients will be instructed to contact the investigator as soon as possible if he or she has a complaint 
or problem with the investigational product so that the situation can be assessed.
8.2.3.1
Time Period and Frequency for Collecting AE and SAE Information
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to Lilly begins after the patient has signed the ICF and has received study drug.  
However, if an SAE occurs after signing the ICF, but prior to receiving study treatment, it needs 
to be reported ONLY if it is considered reasonably possibly related to study procedures.  
AEs that begin before the start of study intervention but after obtaining informed consent will be 
recorded on the AE CRF, not the Medical History CRF.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of investigator awareness.  The investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available.  Serious adverse events, 
including death, caused by disease progression should not be reported unless the investigator 
deems them to be possibly related to study treatment.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
8.2.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs, will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in SoA).

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8.2.3.3
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation.  The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.2.3.4
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and until 
the completion of SFU.

If a pregnancy is reported, the investigator should inform the sponsor within 24 
hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix I.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.

Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix I.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
8.2.3.5
Cardiovascular and Death Events
Not applicable.
8.3
Treatment of Overdose
Refer to the IB and/or product label of selpercatinib for available information on the signs, 
symptoms, and treatment of overdose.
8.4
Pharmacokinetics

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At the visits and times specified in the Schedule of Activities (Table 7-1), blood samples of 
approximately 2 mL each will be collected to determine the plasma concentrations of selpercatinib. 
A maximum of 6 samples may be collected at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling and prior dose will be recorded.  
For 12 subjects in intensive PK testing, PK test performed on C1D1: Up to pre-dose, and post-
dose 1 hour (±15 minutes), 2 hours (±15 minutes) , and 4 hours (±15 minutes),8 hours (±30 
minutes) and 12 hours (±30 minutes), C1D8: Up to pre-dose, and post-dose 1 hour (±15 minutes), 
2 hours (±15 minutes), and 4 hours (±15 minutes) and 8 hours (±30 minutes). For all enrolled 
subjects in PopPK testing, PK test performed on each cycle D1. Exact clock time (24h format) of 
sample collection and of dose administration should be recorded. Time of previous 3 doses should 
also be recorded.
Additional PK may also be assessed in patients when considered necessary by the Investigator to 
understand exposure in relationship to possible safety. 
PK samples will be retained at a facility selected by Lilly for a maximum of 4 years after the last 
patient visit for the study.
8.5
Pharmacodynamics
Not applicable.
8.6
Biomarker
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, variability of participant response (including safety), and clinical outcome. Sample 
collection is incorporated into clinical studies to enable examination of these questions through 
measurement of biomolecules including deoxyribonucleic acid (DNA), ribonucleic acid (RNA).
Tissue samples for biomarker research will be collected at the times specified in the Schedule of 
Activities (Section 1.3) where local regulations allow.  It is possible that biomarker data for 
patients in the study has already been generated from samples that were collected and analyzed 

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prior to enrolling in this study.  This may include pathology reports and data generated from 
genetic analyses.  If available, these data may be requested from medical records for use. In 
addition, for all patients, an anonymized/redacted Molecular Pathology Report or other report(s) 
describing tumor RET (and other) alteration analysis should be submitted to the Sponsor, designee, 
or central laboratory.
All samples will be coded with the participant number.  These samples and any data generated can 
be linked back to the participant only by the investigator site personnel.  
Archived tumor tissue should be submitted for Cohort 1 and 2, either via tumor block (preferred) 
or ~10 × 5m unstained slides. We may have extracted DNA and RNA that be obtained from the 
tissue samples for central lab RET eligibility testing or RET alteration confirmation.  Lilly has a 
right to retain a portion of the submitted tissue.  Archival blocks will be sectioned and returned to 
the study site or patients.  Slides and tissue samples collected on-study will not be returned.  If 
patients cannot provide sufficient tumor tissue sample, patients still can be enrolled after 
discussion between sponsor and investigator and get sponsor’s approval. Patients who do not have 
sufficient archival tumor tissue available may undergo a fresh tumor biopsy, if it is considered safe 
to perform, prior to treatment.  
Samples (including tumor sample and derivatives such as DNA and RNA) will be retained at a 
facility selected by Lilly for a maximum of 4 years after the last patient visit for the study, or for a 
shorter period if local regulations and ERBs impose shorter time limits.  This retention period 
enables response to regulatory questions related to selpercatinib.
8.7
Medical Resource Utilization and Health Economics
Patient-reported questionnaires will be collected via a paper source document according to the 
Schedule of Activities
EORTC QLQ-C30
Health-related quality of life will be assessed with the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30; 
Aaronson et al. 1993).

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The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 items covered by 1 
of 3 dimensions:

global health status/quality of life (2 items)

functional scales (15 total items addressing either physical, role, emotional, 
cognitive, or social functioning)

symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, diarrhea, or financial impact)
Bowel Diary (for MTC patients only)
Bowel Diary adapted and modified from patient-reported questionnaire (STIDAT) by Michelle 
Lui et al., Development and validation of a patient-reported questionnaire assessing systemic 
therapy induced diarrhea in oncology patients, HEALTH AND QUALITY OF LIFE OUTCOMES 
15:249 (2017). Copyright © 2017 Michelle Lui, Daniela Gallo-Hershberg and Carlo DeAngelis 
(Lui, Gallo-Hershberg et al. 2017). STIDAT distributed as-is and as-available, with no warranties, 
under 
the 
Creative 
Commons 
Attribution 
4.0 
International 
License 
(https://creativecommons.org/licenses/by/4.0/legalcode).

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9
Statistical Considerations
A full Statistical Analysis Plan (SAP) will provide specific details on the analytical methods and 
data displays.
9.1
Study Endpoints
9.1.1
Primary Endpoint 

ORR using RECIST v1.1 as assessed by independent review committee (IRC). 
9.1.2
Secondary Endpoints 

Parameters of anti-tumor activity/clinical benefit, including: ORR (by Investigator), 
DOR (by IRC and Investigator), CNS ORR (by IRC), CNS DOR (by IRC), time to any 
and best response (by IRC and Investigator), CBR (by IRC and Investigator), PFS (by 
IRC and Investigator), and OS 

Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and 
blood chemistry values, and assessments of physical examinations, vital signs, and 
ECGs

Plasma concentrations of selpercatinib and PK parameters, including, but not limited to, 
AUC0-24, Cmax, and Tmax
9.1.3
Exploratory Endpoints 

Differences in efficacy and safety based on selpercatinib PK parameters

Changes in CEA and calcitonin (patients with MTC), thyroglobulin (non-MTC thyroid 
cancer patients), and ACTH and cortisol (patients with Cushing’s disease related to their 
cancer) with selpercatinib treatment

Changes from baseline in disease-related symptoms and HRQoL, as measured by 
EORTC QLQ-C30, and patient bowel diaries (MTC patients only)

Time from PD1 to PD2 for patients who continue to receive study treatment beyond 
disease progression
9.2
Analysis Populations
Enrolled population: will include all enrolled patients.
Treated population will include all enrolled patients who received at least one dose of 
selpercatinib. This population will be used for safety analysis and efficacy analysis other than 
primary efficacy analysis.
Primary efficacy analysis population: will include all treated patients enrolled in Cohort 1 and 
2 who have confirmed RET fusion positive solid tumor or RET mutant MTC by central lab, 
respectively. The primary efficacy analysis will be conducted on this population. 

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Pharmacokinetic population will include all treated patients with baseline and at least one 
postbaseline evaluable PK sample.
9.3
Determination of Sample Size
For Cohort 1-2, at least 20 patients will be targeted for enrollment in each cohort. The main 
objective is to provide for a preliminary assessment of the antitumor activity of selpercatinib in 
Chinese patients with RET alterations. Table 9-1 presents the lower bounds of 2-sided exact 95% 
confidence intervals based on different choice of sample size and observed ORR. If the observed 
ORR is high (i.e., exceeds 45%) within a cohort of 20 patients, then the corresponding lower limit 
of a 2-sided exact 95% confidence interval will exclude true response rates that are considered 
marginal or uninteresting.
Up to 25 patients will be enrolled into Cohort 3 based on clinical considerations. 
In addition, with an overall sample size of 75, the probability of observing one or more instances
of a specific AE with a true incidence rate of 2% and 5% is approximately 80% and 98%, 
respectively.  
Table 9-1
Lower bounds of 2-sided exact 95% confidence intervals based on different sample 
size and observed ORR
n         ORR
0.4
0.45
0.5
0.55
0.6
0.65
10
0.12
0.15
0.19
0.22
0.26
0.3
20
0.19
0.23
0.27
0.32
0.36
0.41
25
0.21
0.25
0.30
0.34
0.39
0.44
30
0.23
0.27
0.31
0.36
0.41
0.46
40
0.25
0.29
0.34
0.38
0.43
0.48
50
0.26
0.31
0.36
0.40
0.45
0.50
60
0.28
0.32
0.37
0.42
0.47
0.52

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9.4
Statistical Methods
9.4.1
Demographics and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics for all enrolled patients will 
be tabulated. Patients will be tabulated by cohort and overall. 
9.4.2
Safety Analyses
Safety will be assessed by clinical review of all relevant parameters including AEs, SAEs, 
laboratory values, vital signs, ECG results, concomitant medications, and thyroid function. Unless 
specified otherwise, the safety analyses will be conducted for the safety population defined in 
Section 8.2 from all cohorts. Tabulations will be provided by cohort and overall. 
Summary tables and listings will be provided for all reported TEAEs, defined as AEs that start on 
or after the first administration of study drug. The reported AE term will be assigned standardized 
coding using MedDRA; the MedDRA version shall be specified in study documents. 
TEAEs will be summarized based on the number and percentage of patients experiencing the event 
by MedDRA System Organ Class (SOC) and preferred term (PT). 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 8.2. In the event a patient experiences repeat episodes of the same AE, then 
the event with the highest severity grade and strongest causal relationship to study drug will be 
used for purposes of incidence tabulations.
Tabular summaries will be provided for:

All TEAEs.

TEAEs by relationship (yes, no) to underlying disease, other medical conditions or 
concomitant medications, and maximum severity grade.

TEAEs with action of study drug delayed/interrupted or treatment reduced.

TEAEs with action of study drug discontinued.

All SAEs.

SAEs by relationship (yes, no) to underlying disease, other medical conditions, or 
concomitant medications.
All deaths including on-study death that occur within 28 days of treatment discontinuation will be 
reported in a patient listing, which will include the primary cause of death and the number of days 

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between the date of the last dose of study drug and death. A summary of the anticancer therapies 
received after discontinuation of study drug will be provided.
Hematology and serum chemistries will be summarized in a descriptive manner by calculating the 
mean, standard deviation, median, and range.
9.4.3
Efficacy Analyses
The efficacy analyses will be conducted on the efficacy population unless otherwise specified. 
Tumor response will be assessed using RECIST 1.1 (Table 11-8).  The objective response rate 
(ORR) is defined as the number of patients who achieve a best overall response of complete 
response (CR) or partial response (PR) that are confirmed divided by the total number of efficacy 
analysis population. ORR, accompanied by 2-sided 95% exact binomial CIs, will be summarized. 
The analysis of ORR will be conducted both by the responses determined by IRC and investigator.
Waterfall plots will be used to depict graphically the maximum decrease from baseline in the sum 
diameters of target lesions. 
DOR will be calculated for patients who achieve CR or PR. For such patients, DOR is defined as 
the number of months from the start date of CR or PR (whichever response status is observed first) 
and subsequently confirmed, to the first date that PD is objectively documented. If a patient dies, 
irrespective of cause, without documentation of PD beforehand, then the patient’s date of death 
will be used to denote the response end date.
PFS will be derived for each patient as the number of months from the date of the first dose of 
study drug to the earlier of documented PD or death due to any cause. Patients who are alive and 
without documented PD as of a data analysis cutoff date will be right-censored. 
OS will be derived for each patient as the number of months from the date of the first dose of study 
drug to the date of death, irrespective of cause. Patients who are alive or lost to follow-up as of a 
data analysis cutoff date will be right-censored. The censoring date will be determined from the 
last date the patient was known to be alive or data analysis cutoff date, whichever occurs first.
The detailed censoring rule for lifetime data such as DOR, PFS and OS will be specified in SAP. 
DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method with 95% 

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CIs. Me dia n f o ll ow- u p f or eac h e n d p o i nt will be esti mate d acc or di n g t o t he Ka pla n-Meier esti mate 
of  p ote ntial fol l ow- u p ( Sc he m per a n d S mit h 1 9 9 6 ). 
A nal yses of ot her sec o n dar y  a n d e x pl orat or y e n d p oi nts will be pr o vi de d i n t he S A P.
9. 4. 4
P h ar m a c o ki n eti c A n a l y s e s
Pl as ma c o nce ntrati o ns of  sel percati ni b will be deter mi ne d wi t h a vali date d bi oa nal yt ical assa y. 
T he f o ll owi n g P K para meters will be calc ulate d fr o m plas ma c o nce ntrati o ns deter mi ne d o n C 1 D 8: 
C ma x, T ma x , area u n der t he c o nce ntratio n vers us time c ur ve fr o m ti me 0 t o t ( AU C 0– t), A U C 0 – ∞, 
a p pare nt oral cleara nce ( C L/ F), a p pare nt v ol u me of distri b ut i on ( V z/ F), a n d T1/ 2.
S u m mar y  statistics will be ge nerate d b y c o h orts as a p pr o priate. 
9. 4. 5
I nt eri m A n al y s e s a n d D at a M o nit ori n g
A n i nteri m a nal ysis is pla n ne d t o trig ger earl y  int eractio n wi t h re g ulat or y a ut h orities. T he data 
c ut off date is deter mi ne d s uc h t hat a p pr o xi matel y half o f e nr olle d pat ient s will ha ve recei ve d at 
least o ne p ost-baseli ne t u m or assess me nt.
T he pri mar y  a nal ysis will be perf or me d after all e nr olle d patie nts ha ve bee n f oll o we d u p f or a
s ufficie nt a m o u nt of ti me, defi ne d as wit h at least t w o p ost-baseli ne t u m or assess me nts. T he 
pri mar y  a nal ysis ma y be u p date d u p o n re q uest fr o m re g ulat or y a ut h orities.

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10
Study Administration
10.1 Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.  
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
10.2 Informed Consent Process

The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 

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Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.3 Data Management
10.3.1
Data Protection

Participants will be assigned a unique identifier by the investigator.  Any participant 
records or datasets 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 his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law.  The level of disclosure 
must also be explained to the participant.

The participant must be informed that his/her 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.
10.3.2
Committees Structure
The primary endpoint ORR will be assessed by IRC. Independent central review will consist of 
independent radiologists to perform response assessments and determination of disease progression per 
RECIST 1.1.
10.3.3
Dissemination of Clinical Study Data
Dissemination of study data will be performed according to all applicable Lilly and international 
policies.
10.3.4
Data Quality Assurance
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following:

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
provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors 
In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site.  The study may be audited by the 
sponsor or its representatives and/or regulatory agencies at any time.  Investigators will be given 
notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
10.3.5
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment (COA) data (questionnaires) will be collected by the 
subject, via a paper source document and will be transcribed by the investigator site personnel 
into the EDC system.
Data collected via the sponsor-provided data capture system will be stored at third-party.  The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and results will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.

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Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.3.6
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.   Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
10.4 Study Monitoring
Prior to the start of the study, the Sponsor’s monitor will contact the clinical site to discuss the 
protocol and data collection procedures and conduct applicable training of site personnel. The 
Sponsor and its designees will also periodically contact the clinical site during the conduct of the 
study (which will include on-site visits) in accordance with applicable regulations and GCP. 
During these contacts, the monitoring activities will include:

Checking and assessing the progress of the study.

Reviewing study data collected to date for completeness and accuracy.

Conducting source document verifications by reviewing each patient’s eCRF against source 
documents.

Identifying any issues and addressing resolutions.

Recording and reporting protocol deviations not previously reported to the Sponsor.

Confirming that SAEs have been properly reported to the Sponsor and submitted to the 
IRB/IEC if appropriate.
These activities will be done in order to verify that the data are authentic, accurate, and complete; 
that the safety and rights of the patient are being protected; and that the study is conducted in 
accordance with the currently approved protocol, ICH GCP, and all applicable regulatory 
requirements. Additionally, to ensure compliance with ICH GCP and all applicable regulatory 
requirements, the Sponsor or designee may conduct a quality assurance audit. 

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10.5 Termination
Upon completion of the study, the following activities, when applicable, must be conducted by the 
site monitor and the Investigator:

Submission of all study data to the Sponsor.

Completion of all data clarifications and/or resolutions.

Reconciliation and final disposition of investigational product.

Review of site study files for completeness.

In addition, the Sponsor reserves the right to temporarily suspend or prematurely terminate 
this study for any reason.
If the study is suspended or terminated for safety reasons, the Sponsor will promptly inform the 
Investigator and will also inform the IRB/IEC with the reasons for the action. In the event of 
prematurely termination, all study data must be submitted to the Sponsor. In addition, the clinical 
site must document final disposition of all unused investigational product in accordance with the 
Sponsor’s procedures.
10.6 Records Retention
Patient records, source documents, monitoring visit logs, investigational product inventory, 
regulatory documents, and other correspondence pertaining to the study must be maintained in the 
appropriate site study files according to ICH GCP and applicable regulatory requirement(s). These
records will be retained for the period required by the institution or site policy. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing.
10.7 Confidentiality of Information
Patient names will remain confidential and will not be supplied to the Sponsor or its designee. The 
Investigator will maintain a personal patient identification list (patient and treatment numbers with 
the corresponding patient names) to enable records to be identified.

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11
Appendices
Appendix A
Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity
Table 11-1
Examples of Multikinase Inhibitors (MKIs) with Anti-RET Activity
Multikinase Inhibitors
Cabozantinib
Vandetanib
Alectinib
Lenvatinib
Ponatinib
Regorafenib
Sunitinib
Sorafenib
Motesanib
sitravatinib (MGCD516)
Anlotinib
Apatinib

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Appendix B
Examples of RET Activating Mutations
Table 11-2
Examples of RET Activating Mutations
Exon
RET Mutation
5
V292M, G321R
8
A510V, E511K, C515S, C531R, G533C
10
V591I, R600Q, K603E/Q, Y606C, C609F/G/R/S/W/Y, C611F/G/R/S/W/Y, 
C618F/G/R/S/W/Y, C620F/G/R/S/W/Y
11
C630R/Y, D631Y, E632K, C634F/G/R/S/W/Y, S649L, K666E/M
13
E768D, R770Q, N777S, V778I, Q781R, L790F, Y791F/N
14
V804L, V804M, Y806C, E818K, 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.
References: (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 C
Examples of Validated Oncogenic Drivers
Table 11-3 provides examples of oncogenic drivers that may cause resistance to selpercatinib.
Table 11-3
Examples of Validated Oncogenic Drivers
Tumor Type
Oncogenic Driver(s)
NSCLC
Targetable mutation in EGFR or MET, targetable rearrangement involving 
ALK or ROS1, or activating mutation in KRAS
Thyroid 
(non-MTC)
Targetable mutation in BRAF or activating mutation in RAS genes
MTC
Targetable rearrangement involving ALK or activating mutation in RAS
genes
Pancreatic
Activating mutation in KRAS
Colorectal
Targetable mutation in BRAF or PIK3CA or activating mutation in RAS
genes
Breast
Targetable mutation in PIK3CA or alteration in HER2
Other
Targetable mutation/rearrangement known to occur in the specific disease 
type
Abbreviations: MTC = medullary thyroid cancer. NSCLC = non-small cell lung cancer.

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Appendix D
Inhibitors and Inducers of CYP3A4
Note: Avoid concomitant use of strong and moderate CYP3A inhibitors or inducers with 
selpercatinib. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, 
reduce the selpercatinib dosage and monitor the QT interval with ECGs more frequently.
Table 11-4
Examples of Inhibitors of CYP3A4
Strong inhibitors a
Moderate inhibitors b
Boceprevir
amprenavir
Clarithromycin
aprepitant
Conivaptan
atazanavir
grapefruit juice
ciprofloxacin
Indinavir
darunavir
Itraconazole
diltiazem
Ketoconazole
erythromycin
Lopinavir
fluconazole
Mibefradil
fosamprenavir
Nefazodone
imatinib
Nelfinavir
verapamil
Posaconazole
Ritonavir
saquinavir
telaprevir
telithromycin
voriconazole
Abbreviations: CYP3A4 = cytochrome P450 3A4.
a Increases the area under the curve (AUC) of the substrate by ≥5-fold.
b Increases the AUC of the substrate by 2- to 5-fold.
Table 11-5
Examples of Inducers of CYP3A4
Strong inducers a
Moderate inducers b
avasimibe
Bosentan
carbamazepine
Efavirenz
enzalutamide
Etravirine
phenytoin
Modafinil
rifampin
Nafcillin
St John’s wort
Abbreviations: CYP3A4 = cytochrome P450 3A4.

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a Increases the area under the curve (AUC) of the substrate by ≥5-fold.
b Increases the AUC of the substrate by 2- to 5-fold.
Note: The above lists are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio
nslabeling/ucm093664.htm.
http://www.jp-orangebook.gr.jp/cgi-bin/search/search_e.cgi.

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Examples of Agents Known to Cause QTc Prolongation
amiodarone
ibogaine 
anagrelide
ibutilide
azithromycin
levofloxacin
chloroquine
levomepromazine (methotrimeprazine) 
chlorpromazine
levosulpiride 
cilostazol
methadone
ciprofloxacin
moxifloxacin
citalopram
ondansetron
clarithromycin
papaverine HCl (intracoronary)
cocaine
pentamidine
disopyramide
pimozide
dofetilide
procainamide
domperidone 
propofol
donepezil
quinidine
dronedarone
roxithromycin 
droperidol
sevoflurane
erythromycin
sotalol
escitalopram
sulpiride 
flecainide
sultopride 
fluconazole
terlipressin 
halofantrine 
terodiline 
haloperidol
thioridazine
hydroquinidine, dihydroquinidine 
Note: The above list is not exhaustive. Please refer to www.crediblemedicines.com for a 
current list of agents known to cause QTc prolongation as well as agents with a possible or 
conditional risk. 

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Appendix E
Proton Pump Inhibitors (PPIs)
Patients should avoid concomitant use of a PPI with selpercatinib. If concomitant use cannot 
be avoided, take selpercatinib with food when coadministered with a PPI.
Table 11-6
Examples of Proton Pump Inhibitors (PPIs)
omeprazole (Omepral®)
esomeprazole (Nexium®)
lansoprazole (Takepron®)
pantoprazole (Protonix®)
rabeprazole (Pariet®)
dexlansoprazole (Dexilant®)
Abbreviations: PPI = proton pump inhibitor

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Appendix F
Performance Scales
Table 11-7
Eastern Cooperative Oncology Group (ECOG) Performance Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead

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Appendix G
Tumor Measurements and Assessment of Disease Response using RECIST version 1.1
Tumor measurements are to be performed for all patients during Screening, as follows 
(as summarized in Section 7.1): 
Baseline disease assessment: radiographic tumor measurements using CT) or MRI of chest, 
abdomen, and pelvis, and any other areas with suspected disease involvement, and CT or 
MRI of brain within 28 days of C1D1. For brain imaging, MRI without and with 
contrast is preferred, CT without and with contrast is acceptable if MRI is medically 
contraindicated. For each modality, IV and oral contrast should be utilized where 
applicable unless medically contraindicated. If CT/PET is utilized, the CT component of 
CT/PET must be of the same quality as a dedicated diagnostic CT scan, i.e., with IV and 
oral contrast, and 5 mm or less slice thickness.
Notes:

In patients with thyroid and other head and neck cancers, imaging of the relevant 
areas (e.g., neck, skull base) is required at baseline; other areas of scanning may differ 
depending on disease type. Refer to the Imaging Manual for details.

Additional scans can be performed as needed to evaluate potential sites of disease.

Disease assessments will utilize RECIST 1.1 as appropriate to tumor type (refer to 
Section 7.7.1).

Guidelines on the technical parameters of how scans should be performed will be 
provided in a separate Imaging Manual that will be distributed to the sites.
Thereafter, tumor measurements and disease response assessments are to be performed as 
follows (as summarized in Section 7.3):
Radiographic disease assessment: every 8 weeks (±7 days) beginning with Cycle 3 Day 1 
through Cycle 13 Day 1 and every 12 weeks (±7 days) (thereafter until PD, withdrawal 
of consent, or initiation of a new anticancer therapy(ies), including imaging, of the chest, 
abdomen, and pelvis, utilizing the same modality(ies) as used for the baseline imaging 
assessment. Additionally, any studies performed at baseline that are positive for sites of 
disease should be repeated at all post baseline assessments. Additional studies can also 
be performed as clinically indicated. Please refer to the Site Imaging Manual for 
guidelines on how the various imaging studies should be performed. 
Notes: 

Patients who have an ongoing CR or PR and discontinue study drug for reasons other 
than PD (e.g., AE, noncompliance, etc.) may (but for practical reasons and to 
minimize patient inconvenience, are not required to) have scans collected as defined 
above. 

Post-baseline imaging of the brain using the same modality as at baseline should be 
performed for patients with evidence of CNS disease at baseline, and if clinically 
indicated.

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
If c o nsiste nt wit h l ocal re g ulat or y g uideli nes, a n i nit ial p ost-baseli ne assess me nt after 
4 wee ks of treat me nt ( ± 7 da ys) is e nc o ura ge d . If t his sca n is perf or me d, t he ne xt sca n 
s h o uld c o nt i n ue acc or di n g t o t he sc he d ule a b o ve ( be gi n ni n g at C ycle 3 Da y 1).

If c o nsiste nt wit h l ocal re g ulat or y g uideli nes, c o nfir mat or y i ma gi n g a mi ni m u m of 
4 wee ks (e. g., 2 8 da ys) after t he first i ma gi n g st u dies t hat de m o nstrate a t u mor C R or 
P R b y  R E CI S T 1. 1 as a p pr o priate t o t u m or t ype, is e nc o ura ge d. If t his sca n is 
perf or m e d, t he ne xt sca n s h o ul d c o nti n ue acc or di n g t o t he sc he d ule a b o ve.
S uc h assess me nts als o are t o be perf or me d at t he E O T visit if t he y ha d n ot bee n p erf or m e d 
wi t hi n t he pre vi o us 2 c ycles. 
A nat o mical 
meas ure me nts 
(s u m me d acr oss tar get lesi ons) will 
be d o c u m e nte d d uri n g 
Scree ni n g a n d eac h s u bse q ue nt e val uat i on. W he n p ossi ble, t he sa me q ualifie d p h ysicia n will 
i nter pret res ults t o re d uce varia bilit y. Ra di o gra p hic i ma ges will be mai ntai ne d at t he st u d y site 
a n d se nt t o a ce ntral i ma ge c ollect i on ware h o use. Ce ntral  rea di n g of  so m e or all  of t he sca ns 
ma y be p erf or m e d b y a t hird- part y  ve n d or w h o has e x pertise i n e val uat i n g i ma ge data. Test 
res ults a n d I n vesti gat or’s fin di n gs will be file d i n t he pat ient ’s s o urce d oc u me nts.
D uri n g Scree ni n g, t u mor lesi ons are t o be cate g orize d as meas ura ble vers us n o n -me as ura ble 
a n d tar get vers us n o n-tar get, as f oll o ws. 
Me as ur a ble vers us n o n -me as ur a ble
Meas ura ble: Lesi o ns t hat c o ul d acc uratel y  b e meas ure d i n at least o ne di me nsi o n, t he 
l on gest di a meter i n t he pla ne o f meas ure me nt t o be rec or de d as:
o
T u m or lesi o n s: 1 0 m m b y C T sca n 
o
Mali g na nt l y m p h n o des: T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, 
t he n o de m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y C T sca n. At baseli ne a n d i n 
f oll ow u p, o nl y  t he s h ort a xis will be meas ure d a n d f oll o we d. N o des t hat ha ve a s h ort 
a xis < 1 0 m m  are c o nsi dere d n o n-pat h o l ogi cal a n d s h o uld n ot be rec or de d or 
f oll owe d. 
N o n -meas ura ble: All ot her lesio n s, i ncl u di n g s mall lesi ons (l o n gest dia meter < 1 0 m m or 
pat h ol o gi cal l y m p h n o des wit h ≥1 0 t o < 1 5 m m s h ort a xis), a n d tr ul y n o n- meas ura ble 
lesio ns. 
T ar get vers us n o n -t ar get
Tar get: All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d 5 lesi ons i n 
t otal, re prese ntati ve of all i n v ol ve d or ga ns, are t o be i de ntifie d as tar get lesi ons a n d 
meas ure d a n d rec or de d at Scree ni n g. Tar get lesi o ns are t o be selecte d o n t he basis of 
t heir size (i.e., t h ose wit h t h e lo n gest di a meter) a n d s uita bilit y fo r acc urate re peate d 
meas ure me nt. L y m p h n o des ma y  be selecte d as tar get lesi o ns; t he y  must be defi ne d as 
meas ura ble, a n d o nl y t he s h ort a xis of t he n o de will c o ntri b ute t o t he baseli ne s u m. All 

J 2 G-G H -J ZJ K Cli nical Pr ot oc ol ( b)
1 0 3
L Y 3 5 2 7 7 2 3
ot her pat h ol o gic n o des wit h s h ort a xis ≥1 0 m m , b ut < 1 5 m m s h o ul d be c o nsi dere d 
n o n- tar get lesio ns. 
N o n -t ar get: All ot her lesi ons n ot classifie d as tar get lesi o ns ( or sites of disease) are t o be 
i de ntifie d as n o n-tar get lesio n s a n d are t o be rec or de d i n t he e C R F. Meas ure me nt of 
n o n- tar get lesio ns is n ot re q ui re d.
T h e s u m of t he di a meters (lo n gest f or n o n- n o dal  lesio n s a n d s h ort a xis f or n o dal lesi ons) f or 
all tar get lesi o ns i s t o be calc ulate d a n d rec or de d i n t he e C R F as t he baseli ne s u m dia meters. 
Di sease res p o nse i n t ar get a n d n o n- tar get lesi ons will be assesse d b y t he I n vesti gat or usi n g 
R E CI S T 1. 1, acc or di n g t o t he cate g ories a n d criteria descri be d i n Ta ble 1 1- 8 . T he best o verall 
res p o nse f or eac h patie nt will be re p orte d as t he best res p o nse d oc u me nte d o ver t he se q ue nce 
of  o bject i ve stat uses rec or de d usi n g t he cate g ories a n d criteria i n Ta ble 1 1- 9.

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Table 11-8
Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) 
Guidelines for Tumor Response
Disease Response Criteria for Target and Non-Target Lesions
Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions. Any pathologic nodes 
(whether target or non-target lesions) must have a reduction in 
short axis diameter (SAD) to less than 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of the diameters (SOD) (LD 
for non-nodal lesions and SAD for nodal lesions) of target 
lesions, taking as reference the baseline sum LD.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started.
Progressive Disease (PD):
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest sum on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5.0 mm. (Note: the 
appearance of one or more new lesions is also considered 
progression).
Evaluation of Non-Target Lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of 
tumor marker level.
Incomplete Response/ Stable Disease 
(SD):
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.
Abbreviations: LD = longest diameter.
Source: (Eisenhauer, Therasse et al. 2009). Available at: 
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf.

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Table 11-9
Overall Response Criteria: Time Point Response
Patients with Target and Non-Target Lesions
Target Lesions
Non-Target Lesions
New Lesions
Overall 
Response
CR
CR
No
CR
CR
Non-CR / Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall 
Response
CR
No
CR
Non-CR / Non-PD
No
Non-CR / 
Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Best overall response when confirmation of CR and PR required
Overall response first time 
point
Overall response subsequent 
time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PR
CR
SD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for 
SD duration met, otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD

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PR
NE
SD provided minimum criteria for 
SD duration met, otherwise, NE
NE
NE
NE
Abbreviations: CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial 
response; SD = stable disease.
Source: (Eisenhauer, Therasse et al. 2009). Available at: 
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf. 

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Appendix H
Clinical Laboratory Tests

All the clinical laboratory testing showed in Appendix H will be performed in local 
laboratory.

If there is an abnormal laboratory value or abnormal value for any other diagnostic or 
screening test (for example, blood pressure increased, neutrophils decreased, etc.) and it 
is known to be related to a diagnosis (for example, hypertension, neutropenia, etc.) this 
should be reported into the CRF as an AE.  Do not enter the test abnormality, enter the 
disease diagnosis or categorical term.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations and clinically significant findings 
should be reported in the CRF as an AE.

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Clinical Laboratory Tests
Hematologya,b
Leukocytes (WBC)
Basophils
Neutrophils
Erythrocytes (RBC)
Lymphocytes
Hemoglobin (HGB)
Monocytes
Hematocrit (HCT)
Eosinophils
Platelets (PLT)
Coagulationa
PT/INR
PTT/aPTT
Clinical chemistry
Serum concentrations of: 
Alanine aminotransferase (ALT)
Chloride
Albumin
Creatinine
Alkaline phosphatase
Glucose (random)
Aspartate aminotransferase (AST)
Magnesium
Bilirubin, direct
Potassium
Bilirubin, total
Protein
Blood urea nitrogen (BUN) or blood urea
Sodium
Calcium
Urinalysisc
Blood
Protein
Glucose
Specific gravity
Ketones
Urine leukocyte esterasec
pH
Pregnancy Testd
Urine pregnancy test
Serum pregnancy test
Thyroid panelb
Free triiodothyronine (FT3)
Thyroid stimulating hormone (TSH)
Free thyroxine (FT4)
a
Local or investigator-designated laboratory.
b
Treatment and enrollment decisions are all based on local laboratory results.
Note: Neutrophils reported by automated differential hematology instruments include both segmented and band forms.  
When a manual differential is needed to report the neutrophils, the segmented and band forms should be added together 
and reported on the CRF, unless the CRF specifically provides an entry field for bands.
c
Urine microscopy may be used in the place of the urine leukocyte esterase assessment to test for the presence of WBCs.
d
For female patients of childbearing potential.
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CRF = case 
report form; FT3 = free triiodothyronine; FT4 = free thyroxine; HCT = hematocrit; HGB = hemoglobin; PLT = platelets; 
PT/INR = prothrombin time/international normalized ratio; PTT = partial thromboplastin time; RBC = red blood cells; TSH = 
thyroid-stimulating hormone; WBC = white blood cells.

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Appendix I
Contraceptive Guidance and Collection of Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered WOCBP:
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).  However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance:

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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner

(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days.)
Highly Effective Methodsb That Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc
o
oral
o
intravaginal
o
transdermal
o
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
o
oral
o
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.)
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly.  Typical use failure rates differ from those 
when used consistently and correctly.
c.) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study.  Male condom and female condom should not be used together (due to risk of failure with friction)
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study.  This 
applies only to male participants who receive selpercatinib.

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
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy.  The female 
partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to the sponsor.  Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date.  Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female Participants Who Become Pregnant

The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study.  Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the sponsor.  Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.  Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such.  Any post-study 
pregnancy related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor as described in Section 8.3.2.  While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.

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Appendix J
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) and Bowel Diary
EORTC QLQ-C30
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. 
It is a copyrighted instrument, which has been translated and validated in over 100 languages and 
is used in more than 3,000 studies worldwide. This study is utilizing version 3.0, and the study 
manual should be consulted for instructions on implementing and scoring.
References:
EORTC website: http://groups.eortc.be/qol/eortc-qlq-c30
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376 (Aaronson, Ahmedzai et al. 1993). 
Bowel Diary
References:
Bowel Diary adapted and modified from patient-reported questionnaire (STIDAT) by Michelle 
Lui et al., Development and validation of a patient-reported questionnaire assessing systemic 
therapy induced diarrhea in oncology patients, HEALTH AND QUALITY OF LIFE OUTCOMES 
15:249 (2017). Copyright © 2017 Michelle Lui, Daniela Gallo-Hershberg and Carlo DeAngelis 
(Lui, Gallo-Hershberg et al. 2017). STIDAT distributed as-is and as-available, with no warranties, 
under 
the 
Creative 
Commons 
Attribution 
4.0 
International 
License 
(https://creativecommons.org/licenses/by/4.0/legalcode).

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Appendix K
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Protocol J2G-GH-JZJK
30-Jul-2019
Amendment [a]: (20 July 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
Synopsis, and 3.4 
Investigational Plan
Enrollment in Cohort 1 was clarified as “For 
lung cancer, only patients harboring RET-
KIF5B, RET-CCDC6, RET-NCOA4 can be 
enrolled in Cohort 1. For other solid tumor, 
patients with any RET fusion can be enrolled 
in Cohort 1”. Added inclusion criteria to 
Cohort 3 as “Other RET-altered solid tumor or 
other RET alteration/activation not meeting the 
requirements for Cohorts 1 or 2”.
Clarification
Synopsis, and 4.1 
Inclusion Criteria
Add additional information to clarify 
calculation of eGFR.
Clarification
Synopsis, and 4.2 
Exclusion Criteria
Metastases was clarified as symptomatic CNS 
metastases in exclusion criterion 26. “Lower 
limit of detection of the assay” was updated to 
“upper limit of detection of the assay” in 
Exclusion Criterion 29; removed exclusion 
criterion 34 and 35.
Clarification
1.1 Tumors with RET
Abnormalities and 
Current Treatment 
Options, 1.4 
Determination Starting 
Dose
Updated related contents per latest IB.
To be consistent 
with IB version 7.0 
1.5 Clinical Experience
Updated new data of LIBRETTO-001 study.
To be consistent 
with IB version 7.0 
1.6.1 Known and 
Anticipated Risks
Replaced risks based on animal studies with
risks based on clinical studies.
To be consistent 
with IB version 7.0 

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Section # and Name
Description of Change
Brief Rationale
1.6.2 Potential Drug 
Interactions, 6.3.3 
Other Concomitant 
Medications, Appendix 
D and Appendix E
Updated drug interaction part and concomitant 
medication guidance per latest IB.
To be consistent 
with IB version 7.0 
4.1 Inclusion Criteria
Removed “requirement may be waived with 
Sponsor approval” for archived tumor tissue 
sample notes. 
Clarification
6.2.1 General Dosing 
Instructions, 6.2.4 Dose 
Delays and 
Modifications
Added additional information when re-
escalation to a prior dose level after a dose 
reduction is permitted. Add additional 
information for dose modifications for 
hypersensitivity, LFT abnormalities, 
thrombocytopenia, and hypertension. 
Clarification and to 
be consistent with 
IB version 7.0 
6.2.4 Dose Delays and 
Modifications, and 
8.2.2.1 Hepatic Safety 
Monitoring
Clarified LFTs included AST, ALT, ALP, and 
total and direct bilirubin; modified dose 
modification guidance for special adverse 
events, including hypersensitivity, liver 
function test abnormalities, thrombocytopenia, 
and hypertension.
To be consistent 
with IB version 7.0 
Table 6-1 Suggested 
Toxicity Management 
for all Parts of this 
Study
The starting dose for thrombocytopenia was 
updated from 80 mg to 120 mg.
Clarification
6.3.3 Other 
Concomitant 
Medications
Clarified herbal products were with anti-
cancer activity; added language for concurrent 
use of steroids.
Clarification; to be 
consistent with IB 
version 7.0 
7 Tests and Evaluations
Added additional information for timing of 
routine laboratories and procedures and 
clarified “routine evaluations performed 
within -2 days of the visit day will not be 
considered protocol deviations”.
Clarification
Table 7-1 Schedule of 
Activity (SoA) 
Added Serum chemistries in C1D8±2 Days, 
Survival in SFU (D28±7 days).
Clarification
Table 7-1 Schedule of 
Activity (SoA) note “a”
The duration of ±7 days was updated to +7 
days in the explanation of EOT, and added 
additional information for lab testing 
performed ≤7 days prior to EOT.
Clarification

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Section # and Name
Description of Change
Brief Rationale
Table 7-1 Schedule of 
Activity (SoA) note 
“h”
Added respiratory rate to vital signs.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“i”, 7.2 Cycle 1, and 
7.3 Cycles 2 and 
Higher
C1D15 was updated to C1D15, Day 1 of C2-
higher, and clarified vital signs should be 
performed prior to PK collection. Removed 
tests in Day 1 of C2-C6 and all other clinic 
visits when neither PK nor ECGs are being 
collected. 
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“j”, and 7.2 Cycle 1
C1D8 and thereafter was updated to C1D8, 
C2D1 and thereafter for ECG test, and 
clarified an extra ECG should be timed prior 
to PK collection on C1D8.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note “l”
Added a window of -2 days to Day 1 of every 
cycle, and added additional information for 
screening testing performed ≤7 days prior to 
C1D1.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“o”, 7.2 Cycle 1
Added a window of -2 days to C2D15 and 
C3D15.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“p”
Added additional information for coagulation 
testing to avoid repeat testing.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“v”, 7.1 Screening 
Period, and Appendix 
G. Tumor 
Measurements and 
Assessment of Disease 
Response using 
RECIST version 1.1
Removed “chest CT does not require IV 
contrast” for IV and oral contrast.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“z”, and 8.4 
Pharmacokinetics
Added hours (±15 minutes) to 1 and 2.
Clarification
Table 7-1 Schedule of 
Activity (SoA) note 
“bb”
Patient bowel diary was clarified to be 
answered by the subject to the best of his/her 
ability
Clarification

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Section # and Name
Description of Change
Brief Rationale
7.1 Screening Period
Removed repeated information in Screening 
Period.
Clarification
7.2 Cycle 1
Clarified ECG testing should be performed 
before PK collection on C1D8.
To be consistent 
with Table 7-1 
notes “j”
7.3 Cycles 2 and 
Higher
Clarified urinalysis to be performed D1 C2, 
and as clinically indicated; Adjusted order of 
safety part.
To be consistent 
with Table 7-1; 
Clarification
7.4 End of Treatment 
Visit (All Patients)
Removed limitations to “Resting 12-lead 
ECG”.
Clarification
7.5 Safety Follow-up 
Visit (SFU)
Added limitations to “Resting 12-lead ECG” 
with “only if prior ECG reading showed 
treatment-emergent abnormalities”.
Clarification
8.1.1 Imaging
Added descriptions for bone scan. 
Clarification
8.2.2.1 Hepatic Safety 
Monitoring
Added AST testing instead of ALT only, and 
added language for participants with baseline 
ALT/AST ≥1.5X ULN; removed Appendix H 
in brackets.
To be consistent 
with IB version 
7.0; the content is 
not available in 
Appendix H.
8.7 Medical Resource 
Utilization and Health 
Economics
Replaced electronic versions of the 
questionnaires with paper source document, 
and removed related language.
Clarification
10.3.2 Committees 
Structure
Deleted “blinded” for independent central 
review.
Clarification
Appendix H. Clinical 
Laboratory Tests
Clarified all safety related laboratory tests 
were performed in local labs, and made minor 
formatting/ editorial changes.
Clarification
Throughout
Updated the name of LOXO-292 to 
selpercatinib
Clarification
Throughout
Updated all T3 and T4 to FT3 and FT4, 
respectively.
Clarification

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12
References
Aaronson, N. K., S. Ahmedzai, B. Bergman, M. Bullinger, A. Cull, N. J. Duez, A. Filiberti, H. 
Flechtner, S. B. Fleishman, J. C. de Haes and et al. (1993). "The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
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