An Open-Label, Multicenter, Phase 1a/1b Study of Olaratumab (LY3012207) Plus Pembrolizumab (MK3475) in Patients With Unresectable Locally Advanced or Metastatic Soft Tissue Sarcoma (STS) Who Have Failed Standard Treatments
Phase: PHASE1
Conditions: Soft Tissue Sarcoma
Sponsor: Eli Lilly and Company

 
 
 
Protocol: I5B-MC-JGDQ(c) 
 
 
An Open-Label, Multicenter, Phase 1a/1b Study of Olaratumab (LY3012207) 
Plus Pembrolizumab (MK3475) in Patients with Unresectable Locally 
Advanced or Metastatic Soft Tissue Sarcoma Who Have Failed Standard 
Treatments 
 
 
NCT03126591 
 
 
Approval Date: 19 Sep 2018 

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1
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1. P r ot o c ol I 5 B-M C -J G D Q ( c)
A n  O p e n-L a b el, M ulti c e nt er, P h a s e 1 a/ 1 b St u d y  of 
O l ar at u m a b ( L Y 3 0 1 2 2 0 7) Pl u s P e m br oli z u m a b ( M K 3 4 7 5) i n 
P ati e nt s wit h U nr e s e ct a bl e L o c all y  A d v a n c e d or M et a st ati c 
S oft Ti s s u e S ar c o m a W h o H a v e F ail e d St a n d ar d 
Tr e at m e nt s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
L Y 3 0 1 2 2 0 7 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y 
a n d C o m p a n y or  it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s :  t hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e .  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e .  I n
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.   
O l ar at u m a b ( L Y3 0 1 2 2 0 7 )
T hi s P h a s e 1 st u d y i s a n o p e n -l a b el, m ulti c e nt er, n o nr a n d o mi z e d, d o s e -e s c al ati o n st u d y 
f oll o w e d b y c o h ort e x p a n si o n of i ntr a v e n o u s L Y3 0 1 2 2 0 7 pl u s i ntr a v e n o u s p e m br oli z u m a b
( M K 3 4 7 5) i n p ati e nt s wit h u nr e s e ct a bl e l oc all y a d v a n c e d or m et a st ati c s oft ti s s u e s ar c o m a 
w h o h a v e f ail e d st a n d ar d tr e at m e nt s.
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 7 O ct o b er 2 0 1 6
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 7 F e br u ar y 2 0 1 7.
A m e n d m e nt ( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 3 0 N o v e m b er 2 0 1 7.
A m e n d m e nt ( c ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w .
A p pr o v al D at e: 1 9- S e p- 2 0 1 8 G M T

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2. Synopsis
This Phase 1a/1b study is an open-label, multicenter, nonrandomized, dose-escalation study that 
includes a dose-expansion component to evaluate intravenous (IV) olaratumab (LY3012207) 
plus pembrolizumab (MK3475) in patients with unresectable locally advanced or metastatic soft 
tissue sarcoma (STS) who have failed standard treatments.

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Clinical Protocol Synopsis:  Study I5B-MC-JGDQ(b)
Name of Investigational Product:  Olaratumab (LY3012207) 
Title of Study: An Open-Label, Multicenter, Phase 1a/1b Study of Olaratumab (LY3012207) Plus Pembrolizumab 
(MK3475) in Patients with Unresectable Locally Advanced or Metastatic Soft Tissue Sarcoma (STS) Who Have 
Failed Standard Treatments
Number of Planned Patients: Approximately 37
Phase 1a:
Entered: 14
Enrolled: 12
Phase 1b:
Entered: 28
Enrolled: 25
Phase of Development:  1a/1b
Length of Study: 2 years
Planned first patient visit: June 2017
Planned last patient visit:  June 2019
Phase 1a planned interim analysis: Data will be reviewed on a cohort-by-cohort basis during dose escalation for 
evaluation of safety and determination of recommended Phase 2 dose.
Phase 1b planned interim analyses: Two interim analyses may be planned.  The first will occur once all patients 
enrolled in the cohort have completed approximately 3 months of treatment; the second will occur once all patients 
enrolled in the cohort have completed approximately 6 months of treatment.  These interim analyses will evaluate 
preliminary antitumor activity and may be combined with ongoing trial-level or annual safety review. 
Objectives:  
Phase 1a (dose escalation) primary objective:

To confirm the safety and tolerability of the combination of olaratumab plus pembrolizumab in 
patients with unresectable locally advanced or metastatic STS who have failed standard treatments
and determine the recommended dose of olaratumab in combination with pembrolizumab for 
evaluation in Phase 1b.
Phase 1a secondary objectives:

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of olaratumab when 
administered in combination with pembrolizumab 

To determine the immunogenicity of olaratumab when administered in combination with 
pembrolizumab 

To document any antitumor activity of olaratumab when administered in combination with 
pembrolizumab as assessed by: 
o
Objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST)
v1.1 and immune-related RECIST (irRECIST)
o
Disease control rate (DCR) using RECIST v1.1 and irRECIST
o
Duration of response (DOR) using RECIST v1.1 and irRECIST
o
Progression-free survival (PFS) using RECIST v1.1 and irRECIST
o
Overall survival (OS)
Phase 1b (dose expansion) primary objective:

The primary objective of the Phase 1b portion of the study is to confirm the safety and tolerability of 
olaratumab at the recommended dose in combination with pembrolizumab in patients with 
unresectable locally advanced or metastatic STS who have failed standard treatments.  
Phase 1b secondary objectives:

To document any antitumor activity of olaratumab at the recommended dose when administered in 
combination with pembrolizumab as assessed by: 
o
ORR using RECIST v1.1 and irRECIST
o
DCR using RECIST v1.1 and irRECIST

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
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o
D O R usi n g R E CI S T v 1. 1 a n d ir R E CI S T
o
P F S usi n g R E CI S T v 1. 1 a n d ir R E CI S T
o
O S 

T o c haracterize t he P K a n d P D of olarat u ma b at t he rec o m me n de d d ose w h e n a d mi nistere d i n 
c o m bi nati o n w it h pe m br oliz u ma b 

T o deter mi ne t he i m m u n o ge nicit y of olarat u ma b at t he rec o m me n de d d ose w h e n 
a d mi nistere d i n c o m bi nati o n wit h pe m br oliz u ma b 
St u d y Desi g n: St u d y J G D Q is a n o pe n -la bel, m ultice nter, n o nra n d o mize d, P hase 1a/ 1 b d ose-escalati o n st u d y 
f oll o we d b y c o h ort e x pa nsi o n of I V olarat u ma b pl us pe m br oliz u ma b i n p atie nts wit h u nresecta ble l ocall y a d va nce d 
or  metastatic S T S w h o ha ve faile d sta n dar d treat me nts.  I n t he P hase 1a d ose-escalati o n p orti o n of t he st u d y, 
eli gi ble patie nts will recei ve olarat u ma b 1 5 m g/ k g (starti n g d ose) or 2 0 m g/ k g o n Da y 1 a n d Da y 8 pl us 
pe m br oliz u ma b 2 0 0 m g I V (fi xe d d ose) o n Da y 1 of a 2 1-da y c ycle.  Patie nts will e nr oll i n a 3 + 3 fas hi o n u ntil 
d ose -li miti n g t o xicit y ( D L T) is o bser ve d or t he ma xi m u m t olerate d d ose is ac hie ve d.  Patie nts i n a n y c o h ort w h o 
d o n ot c o m plete C ycle 1 treat me nt f or reas o ns ot her t ha n a D L T will be re place d.  A mi ni m u m of 6 patie nts will be 
e nr olle d t o t he hi g hest t olerate d d ose i n eac h c o h ort i n P hase 1a.  U p o n deter mi nati o n of a rec o m me n de d d ose f or 
olarat u ma b , a n e x pa nsi o n c o h ort i n t he P hase 1 b p orti o n of t he st u d y will o pe n.  Eli gi ble patie nts will recei ve t he 
rec o m me n de d d oses of olarat u ma b pl us pe m br oliz u ma b i n a 2 1- da y  c ycle.  
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Di a g n osis a n d M ai n Criteri a f or I ncl usi o n a n d E xcl usi o ns:
I ncl usi o n:
[ 1]
Ha ve hist ol o gicall y c o nfir me d dia g n osis of u nresecta ble l ocall y a d va nce d or metastatic S T S, n ot 
a me na ble t o c urati ve treat me nt a n d after a vaila ble sta n dar d t hera pies ha ve faile d t o pr o vi de cli nical 
be nefit, or ha ve bee n dee me d i na p pr o priate ca n di dates f or a d diti o nal sta n dar d treat me nts b y t he 
i n vesti gat or.
[ 2]
Is ≥1 8 years of a ge.
[ 3]
Are willi n g a n d a ble t o perf or m writte n i nf or me d c o nse nt f or t he trial a n d are a me na ble t o c o m plia nce 
wit h pr ot oc ol sc he d ules a n d testi n g.
[ 4]
Ha ve meas ura ble or n o n meas ura ble b ut e val ua ble disease as defi ne d b y Res p o nse E val ua ti o n Criteria i n 
S oli d T u m ors ( R E CI S T versi o n 1. 1).
[ 5]
Ha ve a de q uate or ga n f u ncti o n, wit h all scree ni n g la bs perf or me d wit hi n 1 4 da ys of first d ose of st u d y 
treat me nt.
[ 6]
Ha ve a n Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us ( E C O G P S) sc ore of 0 or 1 at t he ti me 
of e nr oll me nt.
[ 7]
Ha ve s ufficie nt a vaila ble material fr o m arc hi ve d f or mali n -fi xe d paraffi n-e m be d de d t u m or tiss ue o btai ne d 
wit hi n 6 m o nt hs of st u d y e nr oll me nt f or 
  
 
[ 8]
Ha ve res ol uti o n, e xce pt w here ot her wise state d i n t he i ncl usi o n criteria, of all cli nicall y si g nifica nt t o xic 
effects of pri or s yste mic ca ncer t hera p y, s ur ger y, or ra di ot hera p y t o Gra de ≤1 b y Nati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E), Versi o n 4. 0.
[ 9a]
If male, t he patie nt is sterile (i ncl u di n g vasect o m y) or a grees t o use a n effecti ve met h o d of birt h c o ntr ol 
a n d t o n ot d o nate s per m d uri n g t he st u d y a n d f or at least 1 2 0 da ys f oll o wi n g t he last d ose of st u d y 
treat me nt.  
[ 9b]
If fe male, is n ot of c hil d beari n g p ote ntial d ue t o s ur gical sterilizati o n c o nfir me d b y me dical hist or y or 
me n o pa use.  If fe male a n d of c hil d beari n g p ote ntial, has a ne gati ve ser u m or uri ne pre g na nc y test wit hi n 
7 2 h o urs pri or t o t he first d ose of st u d y me dicati o n, a grees t o use a hi g hl y effecti ve met h o d of birt h 
c o ntr ol d uri n g t he st u d y a n d f or u p t o 1 2 0 da ys f oll o wi n g t he last d ose of t he st u d y dr u gs, a n d is n ot 
br eastfee di n g. 
[ 1 0]
Ha ve a n a ntici pate d life e x pecta nc y of ≥3 m o nt hs.
[ 1 1]
I ncl usi o n C riteri o n [ 1 1] has bee n delete d.
E xcl usi o n:
[ 12]
Ha ve disease t hat is s uita ble f or l ocal t hera p y a d mi nistere d wit h c urati ve i nte nt.
[ 13]
Ha ve recei ve d a n y pre vi o us s yste mic t hera p y (i ncl u di n g i n vesti gati o nal a ge nts) tar geti n g P D -1/ P D L -1 o r 
P D -1/ P D L -2 si g nali n g pat h wa ys (i ncl u di n g pr e vi o us partici pati o n i n Merc k M K -3 4 7 5 trials ).  Pri or 
treat me nt wit h olarat u ma b is all o we d.  Pr i or t hera p y with ot her i m m u ne c hec k p oi nt i n hi bit ors, i ncl u di n g 
b ut n ot li mite d t o, a nti -C D 1 3 7 a nti b o d y or a nti -c yt ot o xic T -l y m p h oc yte-ass ociate d a nti ge n -4 ( C T L A -4) 
a nti b o d y, is n ot per mitte d.  
[ 14]
Ha ve ha d c he m ot hera p y, tar gete d s mall m olec ule t hera p y, or ra diati o n t he ra p y wit hi n 2 wee ks a n d/ or 
m o n ocl o nal a nti b o d y treat me nt wit hi n 4 wee ks pri or t o st u d y Da y 1 or w h o ha ve n ot rec o vere d fr o m t he 
effects of pre vi o usl y a d mi nistere d a ge nts. 
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[15]
Exclusion Criterion [15] has been deleted.
[16]
Have known active central nervous system (CNS) metastasis and/or carcinomatous meningitis.  Patients 
with treated CNS metastases are eligible for this study if they have not received corticosteroids and/or 
anticonvulsants within 7 days of study treatment, and their disease is asymptomatic and radiographically 
stable for at least 60 days.
[17]
Have a history or current evidence of any serious medical condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation for the full duration of 
the trial, or not be in the best interest of the patient to participate, in the opinion of the treating 
investigator.
[18]
Have received a live-virus vaccine within 30 days prior to planned treatment start.
[19]
Have received transfusion of blood products or administration of colony stimulating factors within 2 
weeks prior to study Day 1.
[20]
Have histologically or cytologically confirmed Kaposi’s sarcoma or gastrointestinal stromal tumor 
(GIST).
[21]
Have received treatment within 28 days of the initial dose of study drug with an investigational product or 
non-approved use of a drug (other than the study drug used in this study) or are concurrently enrolled in 
any other type of medical research judged not to be scientifically or medically compatible with this study.
[22]
Have inflammatory bowel disease for which the patient has used immunosuppressive agents within the 
last 2 years. 
[23]
Have had an allogenic tissue/solid organ transplant.
Test Product, Dosage, and Mode of Administration:  
Olaratumab will be administered at 15 mg/kg or 20 mg/kg as an approximately 60 (± 5)-minute IV infusion on 
Day 1 and Day 8 of a 21-day cycle.  Pembrolizumab will be administered as a 200-mg fixed dose IV over 30 
minutes on Day 1 of a 21-day cycle.
Reference Therapy, Dose, and Mode of Administration:
Not applicable.
Planned Duration of Treatment: The planned duration of treatment with pembrolizumab is a maximum of 
35 cycles (approximately 2 years).  The planned duration of treatment for olaratumab is not fixed; all patients will 
remain on study until confirmed progressive disease, unacceptable toxicity, or they fulfill one of the other criteria 
for study treatment discontinuation
30-day and 90-day safety follow-up (postdiscontinuation): Upon discontinuation of study treatment, patients will 
receive short-term follow-up assessments approximately 30 and 90 days later.
Long-term follow-up (postdiscontinuation): Once the 90-day safety follow-up is complete, patients will enter the 
long-term follow-up period where they will continue to be followed every 6 weeks until progressive disease and 
approximately every 2 months thereafter (for survival) until death or overall study completion. Continued access:
All patients remaining on study treatment without disease progression following study completion (at least 60 days 
after the last patient has discontinued treatment with pembrolizumab and after all study objectives are met) will be 
able to enter the continued access period of the study, where patients on study treatment who continue to 
experience clinical benefit and no undue risks may continue to receive study treatment until disease progression, 
death, unacceptable toxicity, or start of new anticancer treatment.  

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Criteri a f or E v al u ati o n
Efficac y:   R E CI S T v 1. 1 a n d ir R E CI S T
Safet y:   N CI -C T C A E v 4. 0
I m m u n o ge nicit y: V ali date d assa y i nter nall y de vel o pe d b y Lill y a n d desi g ne d t o detect a nti -dr u g a nti b o dies ( A D A) 
i n t he prese nce of olarat u ma b a n d b y e xter nal assa y f or detecti o n of a nti -Galact ose -al p ha -1, 3 -galact ose 
i m m u n o gl o b uli n (I g)E a nti b o dies.
P har mac o ki netics:   Ser u m c o nce ntrati o ns of olarat u ma b o btai ne d at differe nt ti me p oi nts will be s u m marize d b y 
descri pti ve statistics a n d n o nc o m part m e n tal a nal ysis.  A d diti o nal a nal ysis utilizi n g t he p o p ulati o n P K a p pr oac h 
m a y  als o be c o n d ucte d.
 
 
 
 
 
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St atistic al Met h o ds:
Efficac y:   I n di vi d ual best o verall res p o nse ( B O R) usi n g R E CI S T versi o n 1. 1 criteria, D O R , P F S, a n d O S will be 
liste d a n d s u m marize d.  Rates i ncl u di n g O R R a n d D C R will be c o m p ute d a n d esti mates re p orte d wit h e xact 9 5 % 
c o nfi de nce i nter vals ( CIs) .  Ti me-t o-e ve nt varia bles, i ncl u di n g P F S, D O R , a n d O S will be a nal yze d usi n g t he 
Ka pla n -Meier met h o d.  S ur vi val c ur ves will be use d t o s u m marize t he data.  If data are s ufficie ntl y mat ure, 
me dia ns will be re p orte d wit h t he 9 5 % CIs.  I n a d diti o n, f or eac h ti me -t o-e ve nt varia ble, s ur vi val rates at a de q uate 
ti me p oi nts will be re p orte d.  I n di vi d ual c ha n ges i n t he t u m or size o ver ti me will be prese nte d gra p hicall y usi n g 
li ne pl ots.  T he c ha n ge i n t u m or size c orres p o n di n g t o t he best res p o nse base d o n tar get lesi o ns f or eac h patie nt will
be re prese nte d i n waterfall pl ots b y c o h ort.
Safet y:   All patie nts w h o recei ve at least 1 d ose of a n y st u d y t hera p y will be e val uate d f or safet y a n d t o xicit y .  
T he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) versi o n 1 6. 1 ( or hi g her) will be use d w he n re p orti n g 
A Es b y  Me d D R A ter ms.  Me d D R A L o wer Le vel Ter m  will be use d i n t he treat me nt-e mer ge nt c o m p utati o n.  
Treat me nt -e mer ge nt a d verse e ve nts will be s u m marize d b y S yste m Or ga n Class a n d b y decreasi n g fre q ue nc y of 
Preferre d Ter ms) wit hi n S yste m Or ga n Class ( S O C ).  Safet y a nal yses will i ncl u de s u m maries of t he f oll o wi n g:  
D L Ts at eac h d ose le vel; a d verse e ve nts ( A Es), i ncl u di n g se verit y a n d p ossi ble relati o ns hi p t o st u d y dr u g; seri o us 
a d verse e ve nts ( S A Es), i ncl u di n g p ossi ble relati o ns hi p t o st u d y dr ug; A E s lea di n g t o d ose a dj ust me nts; 
disc o nti n uati o ns fr o m st u d y treat me nt d ue t o A E s or deat h; treat me nt-e mer ge nt a b n or mal c ha n ges i n la b orat or y 
val ues; treat me nt -e mer ge nt a b n or mal c ha n ges i n vital si g ns .  
I m m u n o ge nicit y: I m m u n o ge nicit y data will be s um marize d b y d ose, dr u g c o nce ntrati o ns, a n d ti me fr o m d ose.  If 
warra nte d, e val uati o n of i m m u n o ge nicit y a n d A E s ma y be c o n d ucte d. A listi n g will be pr o vi de d of all a vaila ble 
i m m u n o ge nicit y data.  A d diti o nall y, a listi n g of i m m u n o ge nicit y data fr o m t h ose patie nts wit h at least o ne p ositi ve 
A D A at a n y  ti me p oi nt will be pr o vi de d.  T he fre q ue nc y of patie nts wit h at least o ne p ositi ve A D A assess me nt, a n d 
fre q ue nc y of patie nts w h o de vel o p A D A after a ne gati ve baseli ne assess me nt will be pr o vi de d.  
P har mac o ki net ics: Ser u m olarat u ma b c o nce ntrati o ns at differe nt ti me p oi nts will be s u m marize d b y descri pti ve 
statistics.  A d diti o nal a nal yses utilizi n g t he p o p ulati o n P K a p pr oac h ma y als o be c o n d ucte d if dee me d a p pr o priate.  
P K a n d P D data will be a nal yze d wit h a p pr o priate sta n dar d n o nli near a nal ytic s oft ware.  P K para meter esti mates 
f or olarat u ma b will be calc ulate d b y sta n dar d n o nc o m part me ntal met h o ds of a nal ysis.  T he pr i mar y para meters f or 
a nal ysis will be ma xi m u m plas ma c o nce ntrati o n ( C ma x ) a n d area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C[ 0-tlast], 
A U C [ 0-∞]) of olarat u ma b.  Ot her n o nc o m part me ntal para meters, s uc h as ti me of half-life (t1/ 2), a p pare nt cleara nce 
( C L/ F), a n d a p pare nt v ol u me of distri b uti o n ( V/ F) ma y be re p orte d.  A d diti o nal e x pl orat or y a nal yses will be 
perf or me d if warra nte d b y data a n d ot her vali date d P K s oftware pr o gra ms (f or e xa m ple, N O N M E M) ma y be use d 
if a p pr o priate a n d a p pr o ve d b y Gl o bal PK ma na ge me nt.  
 
 
 
 
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3. Table of Contents
Section
Page
1.
Protocol I5B-MC-JGDQ(b)  An Open-Label, Multicenter, Phase 
1a/1b Study of Olaratumab (LY3012207) Plus Pembrolizumab 
(MK3475) in Patients with Unresectable Locally Advanced or 
Metastatic Soft Tissue Sarcoma Who Have Failed Standard 
Treatments..........................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................16
5.
Introduction ......................................................................................................................21
5.1.
Rationale and Justification for the Study ......................................................................21
5.1.1.
Rationale for Amendment (a)...............................................................................23
5.1.2.
Rationale for Amendment (b)...............................................................................25
5.2.
Objectives ....................................................................................................................26
5.2.1.
Phase 1a:  Dose Escalation...................................................................................26
5.2.1.1.
Primary Objective...........................................................................................26
5.2.1.2.
Secondary Objectives .....................................................................................26
5.2.2.
Phase 1b:  Dose Expansion...................................................................................27
5.2.2.1.
Primary Objective...........................................................................................27
5.2.2.2.
Secondary Objectives .....................................................................................27
5.2.3.
Exploratory Objectives.........................................................................................27
5.3.
General Introduction to Olaratumab and Pembrolizumab..............................................27
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................28
5.3.1.1.
Olaratumab.....................................................................................................28
5.3.1.2.
Pembrolizumab...............................................................................................28
5.3.2.
Nonclinical and Clinical Pharmacokinetics...........................................................28
5.3.2.1.
Olaratumab.....................................................................................................28
5.3.2.2.
Pembrolizumab...............................................................................................29
5.3.3.
Nonclinical Toxicology........................................................................................29
5.3.3.1.
Olaratumab.....................................................................................................30
5.3.3.2.
Pembrolizumab...............................................................................................30
5.4.
Rationale for Selection of Dose....................................................................................30
5.4.1.
Rationale for Selection of Olaratumab Dose.........................................................30
5.4.2.
Rationale for Selection of Pembrolizumab Dose...................................................31
6.
Investigational Plan...........................................................................................................34
6.1.
Study Population..........................................................................................................34

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6.1.1.
Inclusion Criteria .................................................................................................34
6.1.2.
Exclusion Criteria ................................................................................................37
6.2.
Summary of Study Design............................................................................................39
6.2.1.
Study Completion and End of Trial......................................................................40
6.2.2.
Continued Access Period......................................................................................40
6.3.
Discontinuations ..........................................................................................................41
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................41
6.3.2.
Discontinuation of Patients from Study or Study Drugs........................................41
6.3.2.1.
Discontinuation of Study Therapy after Complete 
Response ........................................................................................................42
6.3.3.
Patients Lost to Follow-Up...................................................................................42
6.3.4.
Discontinuation of Study Sites .............................................................................43
6.3.5.
Discontinuation of the Study................................................................................43
7.
Treatment..........................................................................................................................44
7.1.
Materials and Supplies .................................................................................................44
7.1.1.
Olaratumab ..........................................................................................................44
7.1.2.
Pembrolizumab ....................................................................................................44
7.2.
Study Drug Administration ..........................................................................................45
7.2.1.
Dosing Schedule ..................................................................................................45
7.2.2.
Phase 1a Dose Escalation.....................................................................................46
7.2.2.1.
Olaratumab Dose-Escalation Rules.................................................................46
7.2.2.2.
Dose-Limiting Toxicity Determination ...........................................................47
7.2.3.
Phase 1b Dose Expansion.....................................................................................48
7.2.4.
Dose Adjustments and Delays..............................................................................49
7.2.4.1.
Olaratumab.....................................................................................................49
7.2.4.1.1.
Hematologic Toxicity ...............................................................................49
7.2.4.1.2.
Nonhematologic Toxicity..........................................................................49
7.2.4.2.
Pembrolizumab...............................................................................................50
7.3.
Method of Assignment to Treatment ............................................................................54
7.4.
Blinding .......................................................................................................................54
7.5.
Concomitant Therapy...................................................................................................54
7.5.1.
Supportive Care Guidelines for Olaratumab .........................................................55
7.5.1.1.
Infusion-Related Reactions.............................................................................55
7.5.2.
Supportive Care Guidelines for Pembrolizumab...................................................56
7.5.2.1.
Pneumonitis....................................................................................................57
7.5.2.2.
Diarrhea/Colitis ..............................................................................................57
7.5.2.3.
Type 1 Diabetes Mellitus or Hyperglycemia ...................................................57
7.5.2.4.
Hypophysitis ..................................................................................................58

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7.5.2.5.
Hyperthyroidism or Hypothyroidism ..............................................................58
7.5.2.6.
Hepatic Injury.................................................................................................58
7.5.2.7.
Renal Failure or Nephritis...............................................................................59
7.5.2.8.
Pembrolizumab Infusion-Related Reactions....................................................59
7.6.
Treatment Compliance .................................................................................................61
7.6.1.
Evaluable Patients................................................................................................61
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................63
8.1.
Safety Evaluations........................................................................................................63
8.1.1.
Safety Data Collection and Review ......................................................................63
8.1.2.
Adverse Events ....................................................................................................64
8.1.2.1.
Serious Adverse Events ..................................................................................65
8.1.2.2.
Notable Adverse Events..................................................................................66
8.1.2.2.1.
Adverse Events of Special Interest for Olaratumab ...................................66
8.1.2.2.2.
Events of Clinical Interest for Pembrolizumab ..........................................66
8.1.2.3.
Adverse Event and Serious Adverse Event Reporting .....................................67
8.1.2.3.1.
Prior to Administration of Study Drug(s) ..................................................67
8.1.2.3.2.
On-Study Treatment .................................................................................67
8.1.2.3.3.
Follow-Up Visits ......................................................................................67
8.1.2.4.
Suspected Unexpected Serious Adverse Reactions..........................................68
8.1.2.5.
Summary of AE/SAE Reporting Guidelines ...................................................68
8.1.3.
Other Safety Measures .........................................................................................70
8.1.3.1.
Electrocardiograms.........................................................................................70
8.1.4.
Safety Monitoring ................................................................................................70
8.1.5.
Complaint Handling.............................................................................................71
8.2.
Sample Collection and Testing.....................................................................................71
8.2.1.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................71
8.2.2.
Samples for Pharmacogenetics Research..............................................................72
8.2.3.
Samples for Pharmacodynamics and Biomarkers .................................................72
8.2.3.1.
Blood Samples for Biomarker Research..........................................................73
8.2.3.2.
Tissue Samples for Biomarker Research.........................................................73
8.2.4.
Samples for Immunogenicity Research.................................................................74
8.3.
Efficacy Evaluations ....................................................................................................75
8.4.
Procedure/Sampling Compliance..................................................................................77
9.
Data Management Methods...............................................................................................78
9.1.
Data Quality Assurance................................................................................................78
9.2.
Data Capture Systems ..................................................................................................78

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9.2.1.
Case Report Form ................................................................................................78
9.2.2.
Ancillary Data......................................................................................................78
10.
Data Analyses ...................................................................................................................80
10.1. General Considerations ................................................................................................80
10.1.1.
Sample Size Determination ..................................................................................80
10.1.2.
Populations for Analyses......................................................................................81
10.2. Patient Disposition .......................................................................................................82
10.3. Patient Characteristics ..................................................................................................82
10.4. Safety Analyses............................................................................................................82
10.5. Pharmacokinetic Analyses............................................................................................82
10.6. Biomarker Analyses.....................................................................................................83
10.7. Immunogenicity...........................................................................................................83
10.8. Efficacy........................................................................................................................83
10.9. Interim Analyses ..........................................................................................................84
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................85
11.1. Informed Consent.........................................................................................................85
11.2. Ethical Review.............................................................................................................85
11.3. Regulatory Considerations ...........................................................................................85
11.3.1.
Investigator Information.......................................................................................86
11.3.2.
Protocol Signatures ..............................................................................................86
11.3.3.
Final Report Signature .........................................................................................86
12.
References ........................................................................................................................87

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List of Tables
Table
Page
Table JGDQ.1.
Olaratumab Phase 2 Dosing Exposure-Response Modeling and Phase 3 
Dosing Projections.........................................................................................31
Table JGDQ.2.
Phase 1a and 1b Study Drug Administration..................................................46
Table JGDQ.3.
General Guidelines for Dose Modification Due to Nonhematologic 
Toxicities Related to Olaratumab...................................................................50
Table JGDQ.4.
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs Associated with Pembrolizumab................................................51
Table JGDQ.5.
Olaratumab Infusion-Related Reaction Treatment Guidelines........................56
Table JGDQ.6.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines..................60
Table JGDQ.7.
Adverse Event and Serious Adverse Reporting Guidelines for Study 
JGDQ ............................................................................................................69
Table JGDQ.8.
Estimated Incidence Rate and Its 2-Sided 95% CI..........................................81

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List of Figures
Figure
Page
Figure JGDQ.1. Study design overview for Study I5B-MC-JGDQ. .........................................40

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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Study Schedule..............................................................................................90
Attachment 2.
Clinical Laboratory Tests.............................................................................102
Attachment 3.
Hepatic Monitoring Tests for Treatment Emergent Abnormality..................103
Attachment 4.
Pharmacokinetic, Biomarker, Pharmacogenetics, and Immunogenicity 
Sampling Schedules.....................................................................................104
Attachment 5.
Recommendations for Reporting Serious Adverse Events............................107
Attachment 6.
ECOG Performance Status...........................................................................108
Attachment 7.
Creatinine Clearance Formula......................................................................109
Attachment 8.
RECIST 1.1 and irRECIST..........................................................................110
Attachment 9. 
Protocol Amendment I5B-MC-JGDQ(c) Summary .....................................119

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4. Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event (AE) can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not related to the medicinal 
(investigational) product.
AESI
adverse event(s) of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
BOR
best overall response
CI
confidence interval
CL/F (or CL)
apparent systemic clearance
Cmax
maximum plasma concentration
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.

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confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
continued access 
period
The period between study completion and end of trial during which patients on 
study treatment who continue to experience clinical benefit and no undue 
risks may continue to receive study treatment until one of the criteria for 
discontinuation is met. 
CR
complete response
CRF/eCRF
case report form/electronic case report form:  Sometimes referred to as clinical 
report form, a printed or electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
CRP
clinical research physician
CRS
clinical research scientist
CSF
colony-stimulating factor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DLET
dose-limiting equivalent toxicity
DLT
dose-limiting toxicity
DOR
duration of response
DP
drug product
DS
drug substance
ECG
electrocardiogram
ECI
event(s) of clinical interest
ECOG
Eastern Cooperative Oncology Group
end of trial
End of study (trial) is defined as the date of the last visit or last scheduled 
procedure at the last site shown in the Study Schedule for the last active patient 
in the study.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least one dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives.

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ERB/IRB
ethical review board/institutional review board:  A board or committee 
(institutional, regional, or national) composed of medical and nonmedical 
members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical study are protected.
GCP
good clinical practice
GI
gastrointestinal
GIST
gastrointestinal stromal tumor
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form.
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.
investigational 
product (IP)
A pharmaceutical form of an active substance or placebo being tested or used as 
a reference in a clinical trial.  Investigational product includes a product with a 
marketing authorization when:

used or assembled (formulated or packaged) in a way different 
from the authorized form

used for an unauthorized indication or

used to gain further information about the authorized form
investigator
A person responsible for the conduct of the clinical study at a study site.  If a 
study is conducted by a team of individuals at a study site, the investigator is the 
responsible leader of the team and may be called the principal investigator.
IRR
infusion-related reaction
irRECIST
immune-related Response Evaluation Criteria In Solid Tumors
IV
intravenous

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legal 
representative
An individual, judicial, or other body authorized under applicable law to 
consent on behalf of a prospective patient, to the patient’s participation in the 
clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system.
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local SOPs (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed 
consent document, any other written information provided to subjects, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations. 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
objective response rate
OS
overall survival
patient
A subject with a defined disease.
PD
progressive disease
PDGF
platelet-derived growth factor
PFS
progression-free survival
PI
package insert
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PR
partial response

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PS
performance status
PSA
prostate-specific antigen
PVC
polyvinyl chloride
Q2W
every 2 weeks
Q3W
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
re-screen
to screen a patient who was previously declared a screen failure for the same 
study
RP2D
recommended Phase 2 dose
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial.
SmPC
Summary of Product Characteristics
sponsor
The party who takes responsibility for the initiation, management, and/or 
financing of a clinical study.
STS
soft tissue sarcoma
study completion
This study will be considered complete after the final analysis for overall 
survival is performed. 
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
tmax
time of maximal plasma concentration
TPO
third-party organization
ULN
upper limit of normal
UPS
undifferentiated pleomorphic sarcoma
US
United States
V/F (or V)
apparent volume of distribution

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An Open-Label, Multicenter, Phase 1a/1b Study of 
Olaratumab (LY3012207) Plus Pembrolizumab (MK3475) in 
Patients with Unresectable Locally Advanced or Metastatic 
Soft Tissue Sarcoma Who Have Failed Standard Treatments
5. Introduction
5.1.
Rationale and Justification for the Study
Sarcomas remain one of the most devastating solid tumors for children and adults.  The rare 
nature of the disease and the heterogeneity within the tumor make it difficult to develop novel 
therapies. There are approximately 50 different histological tumor subtypes of soft tissue 
sarcomas (STS).  STS is a rare type of cancer comprising approximately 1% of adult cancers,
with an annual incidence of approximately 3300 and 12,000 newly diagnosed cases in the United 
Kingdom (UK) (Soft tissue sarcoma statistics page [WWW] 2010) and United States (US) (ACS
2016), respectively.  Treatment of localized disease is usually with curative intent using surgical 
resection with or without radiotherapy and chemotherapy.  STS recurs frequently as locally 
inoperable or metastatic disease and systemic therapy plays a prominent role.  The mainstay 
therapy for treating advanced-stage STS has been cytotoxic chemotherapy.  More recently,
targeted agents have shown promising activity (that is, agents targeting platelet-derived growth 
factor [PDGF]).
Olaratumab (LY3012207; hereafter, olaratumab), is a recombinant human immunoglobulin G 
subclass 1 (IgG1)-type monoclonal antibody (mAb) that binds to PDGFRα.  This antibody 
possesses high affinity binding for PDGFRα and blocks PDGF-AA, -BB, and -CC from binding 
to the receptor.  Recently, the randomized Phase 2 portion of Study I5B-IE-JGDG ([JGDG; 
[IMCL CP15-0806]; olaratumab plus doxorubicin versus doxorubicin alone in patients with 
advanced STS) met its primary progression-free survival (PFS) endpoint.  Olaratumab plus 
doxorubicin resulted in a significant improvement in overall survival (OS) relative to the control 
arm (doxorubicin alone) (Tap et al. 2016). 
Single-agent olaratumab has consistently been well tolerated, with no dose-limiting toxicities 
(DLTs) observed up to a dose of 20 mg/kg administered every 2 weeks and up to a dose of 
15 mg/kg administered on Days 1 and 8 of a 21-day cycle. In randomized studies of olaratumab 
plus chemotherapies, a generally well-tolerated safety profile was observed for olaratumab.  
There were modest increases in known toxicities of the chemotherapy agent(s) when combined 
with olaratumab relative to chemotherapy alone.  In Study JGDG in patients with STS, although 
there was a higher incidence of some known doxorubicin toxicities such as mucositis, 
nausea/vomiting, and diarrhea, these were monitorable, predominantly Grade ≤2, and did not 
lead to a higher incidence of treatment discontinuation.  Overall, these toxicities were consistent 
with the toxicity profile of the combination agents used and are considered monitorable and 
acceptable for the patient populations studied.  As with other monoclonal antibodies, 
hypersensitivity reactions (including fatal reactions) have been reported with olaratumab 
administration. Most infusion-related reactions (IRRs) were mild in severity.  The common 

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signs and symptoms of IRRs were chills, flushing, pyrexia, dyspnea, and urticaria. More severe 
IRRs (Grade ≥3) can present within minutes of olaratumab infusion as severe hypersensitivity 
reactions or anaphylaxis, which may necessitate immediate treatment.
Immune checkpoint inhibition with antibodies has made a significant therapeutic impact in a 
variety of tumors. Pembrolizumab (MK-3475, Keytruda®) is a potent humanized 
immunoglobulin G4 (IgG4) mAb with high specificity of binding to the programmed cell death 1 
(PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy 
for advanced malignancies. KeytrudaTM (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. For more details on specific indications refer to the 
Investigator Brochure. 
Information on the most common adverse events observed with pembrolizumab can be found in 
the most current version of the pembrolizumab Investigator’s Brochure or the KeytrudaTM
package insert.
Although there is limited clinical data with PD-L1 inhibitors in sarcoma, sarcomas have been 
linked to the immune system as early as the 1800s when William Coley noted a relationship 
between infection and regression of sarcoma (McCarthy 2006).
This study, I5B-MC-JGDQ (Study JGDQ) will evaluate the safety and efficacy of the 
combination of olaratumab with pembrolizumab in patients with unresectable locally advanced 
or metastatic STS who have failed standard treatments. 
Immunotherapies, and particularly immune checkpoint inhibitors such as agents targeting the 
PD-1/PD-L1 signaling pathway, have been an area of interest and have shown activity in a 
variety of tumor types to date.  Though these therapies are providing new treatment options, 
recent trial results are showing that the use of checkpoint inhibitors in combination with other 
therapies may be able to improve the efficacy observed for single agent checkpoint inhibitor use
(Dammeijer et al. 2017).
Soft tissue sarcomas (STS) are a heterogeneous group of cancers originating from mesenchymal-
derived soft tissues.  Treatment beyond first line chemotherapy based regimens in metastatic STS 
has been characterized by relatively low response rates and limited improvements in OS to date
(Comandone et al. 2017).
To date, there has been limited success with the use of immune checkpoint inhibitors in STS.  
Recently, data from several early studies of immune checkpoint inhibitors in STS have shown 
limited benefit to patients: A recent Phase 2 study of nivolumab in uterine leiomyosarcoma had 
no responses among the initial 12 patients (Ben-Ami et al. 2017); a retrospective review of 
nivolumab use in patients with metastatic STS or bone sarcomas showed 3 partial responses 
among 28 patients (Paoluzzi et al. 2016); and a study of pembrolizumab in prespecified 
histologic subtypes of STS showed responses varied between subtypes (Tawbi et al. 2017). In 

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this trial (SARC-028) pembrolizumab was studied in patients with bone sarcomas or STS 
evaluated patients with 4 types of STS (leiomyosarcoma, poorly differentiated/de-differentiated 
liposarcomas, undifferentiated pleomorphic sarcomas [UPS], and synovial sarcomas;
approximately 10 patients per group).  Objective response rate (ORR) of 40% (1 CR and 3 PR in 
10 patients) was observed in the undifferentiated pleomorphic sarcoma subtype.  In the poorly 
differentiated/dedifferentiated liposarcoma and synovial sarcoma groups, 2 and 1 PRs, 
respectively, were observed (N=10 for both groups).  In the leiomyosarcoma group, 0 of 10 
patients achieved a PR or better (Tawbi et al. 2017). .
There is a growing understanding of the tumor microenvironment and the interplay of immune 
components and the microenvironment.  A recent report by Pollack et al. (2017) suggests that the 
highly mutated (UPS) subtype elicits a more clonal T-cell population and greater tumor 
infiltrating lymphocytes, which may explain the higher response rate observed in the previously 
mentioned study for UPS.  However, Pollack et al. also showed that other subtypes present 
immunogenic antigens but may be limited in antigen presentation and/or T-cell infiltration.
The recent results for olaratumab plus doxorubicin in STS demonstrated improvement in median 
overall survival (26.5 vs 14.7 months for doxorubicin alone) (Tap et al. 2016).  In this study, 
median PFS also favored the olaratumab plus doxorubicin treatment arm (6.6 vs 4.1 months).  
The magnitude of improvement reported in median OS was greater than the observed 
improvement in median PFS suggesting that the inhibitory effects of olaratumab on PDGFRα 
have a persisting effect that extends beyond the immediate treatment period.  The ability of 
olaratumab to inhibit PDGFRα signaling, which can contribute to the stromal tumor 
microenvironment in STS, as well as the recent results in Study JGDG for olaratumab in STS,
suggest a longer lasting effect whereby one possible mechanism is the disruption of some of the 
stroma and/or stromal signaling of the tumor microenvironment.  As noted above, among STS 
subtypes that have shown responses to checkpoint inhibitors, there are subtypes with potentially 
immunogenic antigen presentation that may have limited response. Olaratumab may alter the 
tumor microenvironment in a manner which allows checkpoint blockade via pembrolizumab to 
elicit more robust immune response to tumor cells in STS than previously demonstrated in 
studies of monotherapy checkpoint inhibitors. Combining olaratumab, shown to work in 
combination with doxorubicin in STS, with pembrolizumab in STS may enhance anti-tumor 
activity of checkpoint inhibitors.  
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.1.1. Rationale for Amendment (a)
The original JGDQ study protocol, together with an Investigational New Drug application (IND) 
was submitted to the US Food and Drug Administration (FDA) in October of 2016.  Following 
review, the FDA requested the following changes to the protocol, to which Lilly agreed and has 
implemented in this amendment:

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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LY3012207

Addition of a 3-hour monitoring period for IRRs following pembrolizumab 
administration in Cycles 1 and 2.

Delay in the start of the study Continued Access Period from 1 year after the 
last patient entered treatment to until after all patients have discontinued 
pembrolizumab treatment.

Extension of the adverse event (AE) collection period following the end of 
study treatment (or initiation of a new anticancer therapy) from 30 days to 90 
days.

Elaboration on the safety data to be considered by Lilly in determining 
whether or not to enroll further patients to a cohort or to advance to the Phase 
1b portion of the study.

Elaboration on the criteria for continuing treatment after initial radiographic 
evidence of progression per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1.

Removal of a statement that electrocardiograms (ECGs) would be evaluated in 
the determination of study eligibility.

Wording changes regarding the number of patients to be enrolled at the 
highest tolerated dose.

Inclusion of wording that addresses expected adverse reactions for olaratumab 
and pembrolizumab.
Concurrent with these FDA-requested changes, Lilly made a business decision to remove a 
parallel treatment arm investigating the combination of the Lilly Notch inhibitor compound 
(LY3039478) plus pembrolizumab from the study.  Amendment (a) reflects the removal of this 
arm from the study.  
Lastly, Lilly elected to make the following additional changes to the protocol:

In collaboration with Merck & Co, updates to Section 5.1 to reflect the most 
current language regarding pembrolizumab mechanism of action and the
approved indications for pembrolizumab.

Correction of the minimum olaratumab concentration for infusion solutions.

Addition of a requirement to permanently discontinue pembrolizumab in the 
event of recurrent Grade 2 pneumonitis based on a French Health Authority 
request to Merck & Co.

Revisions to the olaratumab dose-escalation rules to clarify the 
conduct/progression of the study.

Addition of a note on the Study Schedule to clarify that radiologic images are 
to be sent to and stored at a central vendor.

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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
Removal of the requirements for mean platelet volume and hemoglobin A1c
testing from Attachment 2 (Clinical Laboratory Tests) and a change in the 
coagulation testing from central collection to performance at the local 
laboratory.

Addition of a Cycle 4 Day 1 olaratumab pharmacokinetic (PK) sample to 
Attachment 4, as well as minor edits for clarity.

Minor editorial revisions for clarity throughout the protocol.
The amended JGDQ(a) protocol will be the first version of the protocol operationalized at 
investigative sites.
5.1.2. Rationale for Amendment (b)
As of 21 September 2017, 2 of 4 patients enrolled in Cohort 1 had asymptomatic lipase increases 
(Grade 4) without any clinical or radiographic signs of pancreatitis.  Asymptomatic lipase and 
amylase increases have been reported in patients treated with immuno-oncology agents (Postow 
2015; Villadolid and Amin 2015; Bender et al. 2016).  A 2015 review showed Grade ≥3 lipase 
increases were reported in multiple studies of immuno-oncology agents, ranging from an 
incidence of 1% to up to 13% (Naidoo et al. 2015).  This review included a total of 16 patients 
with Grade ≥3 lipase increases, while other studies not included in this review provide further 
reports of lipase increases (Bender et al. 2016; Hamid et al. 2017). Based on observations of
patients with ≥ Grade 3 asymptomatic lipase and amylase elevations, recently published 
recommendations suggest that no modification to treatment is indicated in such patients and that 
these laboratory parameters should not even be routinely tested due to lack of clinical 
consequence  (Postow 2015; Fay et al. 2016; Hofmann et al. 2016).
However, per Study JGDQ protocol version (a), these Grade 4 lipase elevations qualified as 
DLTs, resulting in 2 patients with DLTs out of 4 enrolled and enrollment was, therefore, stopped. 
Following discussions with the investigators and with Merck, this amendment revises the 
treatment modification guidelines to allow patients with clinically non-significant, treatable, or 
reversible lipase or amylase elevations to continue to receive study treatment.  In addition, the 
DLT criteria have been updated to reflect the most current wording for pembrolizumab protocols 
including that non-hematologic laboratory elevations that are deemed clinically non-significant 
or are treatable/reversible would not be considered a DLT, nor in certain situations Grade 3 rash 
and Grade 3 fatigue are not considered DLTs. The rationale for this change regarding non-
hematologic laboratory abnormalities is discussed above in this section; the revised DLT criteria 
are described in Section 7.2.2.2 and the revised dose modifications are described in Section 7.2.4.  
Based upon these protocol revisions, Lilly intends to enroll 1 to 3 additional patients at the first 
dose level to adequately determine the safety of the combination at this dose level.  
In addition, minor editorial changes have been made throughout the protocol to improve clarity 
and practicability of the protocol, secure alignment with the intended study design, and update 
information available for study drugs.

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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5.1.3. Rationale For Amendment (c)
Protocol Amendment (c) for Study JGDQ adds the ability for pembrolizumab to be supplied for 
the study as an aqueous solution in addition to the lyophilized powder formulation.  
The amendment also adds an exclusion criterion for patients that have had an allogenic tissue or 
solid organ transplant, consistent with other pembrolizumab clinical trials. Moreover, it clarifies 
data collection requirements intended for the follow-up period.
Amendment (c) also includes an update to the olaratumab premedication instructions.  
Minor editorial changes have been made throughout the protocol to improve clarity and
practicability of the protocol, secure alignment with the intended study design, and update
information available for study drugs. 
5.2. Objectives
5.2.1. Phase 1a:  Dose Escalation
5.2.1.1. Primary Objective
The primary objective of the Phase 1a portion of the study is to confirm the safety and 
tolerability of the combination of olaratumab plus pembrolizumab in patients with unresectable 
locally advanced or metastatic STS who have failed standard treatments and determine the
recommended dose of olaratumab in combination with pembrolizumab for evaluation in 
Phase 1b.
5.2.1.2. Secondary Objectives
The secondary objectives of the Phase 1a portion of the study are:

To characterize the PK and pharmacodynamics (PD) of olaratumab when 
administered in combination with pembrolizumab 

To determine the immunogenicity of olaratumab when administered in 
combination with pembrolizumab 

To document any antitumor activity of olaratumab when administered in 
combination with pembrolizumab as assessed by: 
o
Objective response rate (ORR) using Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 and immune-related RECIST (irRECIST)
o
Disease control rate (DCR) using RECIST v1.1 and irRECIST
o
Duration of response (DOR) using RECIST v1.1 and irRECIST
o
Progression-free survival (PFS) using RECIST v1.1 and irRECIST
o
Overall survival (OS)

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 7
L Y 3 0 1 2 2 0 7
5. 2. 2.
P h a s e 1 b:  D o s e E x p a n si o n
5. 2. 2. 1. Pri m ar y O bj e cti v e
T he pri mar y  o bjecti ve of t he P hase 1 b p orti o n of t he st u d y is t o c o nfir m t he safet y a n d 
t olera bilit y of o larat u ma b at t he rec o m me n de d d ose i n c o m bi nat i on wi t h pe m br oliz u ma b i n 
pati e nts wit h u nresecta ble l ocall y a d va nce d or metastatic S T S w h o ha ve faile d st a n dar d 
treat me nts.
5. 2. 2. 2. S e c o n d ar y O bj e cti v e s
T he sec o n dar y  o bjecti ves of t he P hase 1 b p orti o n of t he st u d y are:

T o d oc u me nt a n y  a ntit u mor acti vit y of o larat u ma b at t he rec o m me n de d d ose
w he n a d mi nistere d i n c o m bi nat i on wi t h pe m br oliz u ma b as assesse d b y: 
o
O R R usi n g R E CI S T v 1. 1 a n d ir R E CI S T
o
D C R usi n g R E CI S T v 1. 1 a n d ir R E CI S T
o
D O R usi n g R E CI S T v 1. 1 a n d ir R E CI S T
o
P F S usi n g R E CI S T v 1. 1 a n d ir R E CI S T
o
O S 

T o c haracterize t he P K a n d P D of olarat u ma b at t he rec o m me n de d d ose w he n 
a d mi nistere d i n c o m bi nati on wi t h pe m br oliz uma b 

T o deter mi ne t he i m m u n o ge nicit y of  olar at u ma b at t he rec o m me n de d d ose
w he n a d mi nistere d i n c o m bi nat i on wi t h pe m br oliz u ma b 
5. 3.
G e n er al I ntr o d u cti o n t o Ol ar at u m a b a n d P e m br oli z u m a b
M ore i nf or m at i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks a n d reas o na bl y a nt ici pate d A Es 
f or ol arat u ma b ma y be f ou n d i n t he olarat u m a b I n vestigat or’s Br oc h ure (I B) .  I nf or mati on o n 
A Es e x pecte d t o be relate d t o t his i n vesti gati onal pr o d uct ma y be f o u n d i n Sect i on 7 
( Devel o p me nt C ore Safet y I nf or mat i on) of t he I B.  I nf or mati o n o n seri o us a d verse e ve nts 
( S A Es) e x pecte d i n t he st u d y p o p ulatio n i n de pe n de nt of dr u g e x p os ure a n d t hat will be assesse d 
b y t he s p o ns or i n a g gre gate, peri o dicall y  d uri n g t he c o urse of t he st u d y, ma y be f ou n d i n 
Secti o n 6 ( Effects i n H u ma ns) of t he I B.
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 8
L Y 3 0 1 2 2 0 7
M ore detaile d 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 a n d ris ks of pe m br o liz u ma b 
ma y be f o u n d i n t he Ke ytr u d a Pac ka ge I nsert ( PI) a n d S u m mar y of Pr o d uct C haracterist ics
( S mP C) .
5. 3. 1.
M e c h a ni s m of A cti o n a n d I n Vitr o/I n Vi v o A cti vit y
5. 3. 1. 1. Ol ar at u m a b
O larat u ma b is a rec o m bi na nt h u ma n i m m u n o gl o b uli n G s u bclass 1 (I g G 1)-t yp e m A b t hat bi n ds 
t o P D G F R α.  T his a nti b o d y p ossesses hi g h affi nity bi n di n g f or P D G F R α a n d bl oc ks P D G F -A A, 
-B B, a n d -C C fr o m bi n di n g t o t he rece pt or.  I n a d diti on t o bl oc ki n g li ga n d -i n d uce d cell 
mit o ge nesis a n d rece pt or a ut o p h os p h or ylat i on, ol ar at u ma b i n hi bits l i ga n d-i n d uce d 
p h os p h or ylat i on of t he d o w nstrea m si g nali n g m o lec ules A kt a n d mit o ge n-act i vate d pr otei n 
ki nase ( M A P K).  Precli nical st u dies c o n d ucte d wit h olarat u ma b ha ve de m o nstrate d a nti mit otic 
acti vit y i n cell li nes a n d a ntitu m or gr o wt h acti vit y i n h u ma n 
 
 
 
  O larat u ma b d oes n ot cr oss -react wit h P D G F R β or wit h m uri ne 
P D G F R α.  T heref ore, i n vi v o e x peri me nts i n mice beari n g h u ma n t u m or xe n o grafts treate d wit h 
ol ar at u ma b ma y u n derest i mate t he p ote ntial a ntica ncer acti vity of  olar at u ma b beca use 
ol ar at u ma b ca n n ot react wit h m o use str o ma, or re g ulate ca ncer -ass ociate d vasc ulat ure i n t hese 
m o dels ( S ha h et al . 2 0 1 0).  
5. 3. 1. 2. P e m br oli z u m a b
Bi n di n g of t he P D -1 li ga n ds, P D -L 1 a n d P D -L 2 , t o t he P D-1 rece pt or f o u n d o n T cells, i n hi bit s T 
cell pr oliferat i on a n d c yt o ki ne pr o d ucti o n. U pre g ulat i on of P D -1 li ga n ds occ urs i n s o me t u m ors 
a n d si g nali n g t hr o u g h t his pat h wa y ca n c o ntri b ute t o i n hi biti on of act i ve T-cell i m m u ne 
s ur veilla nce of t u m ors.  Pe m br o liz u ma b is a m A b t hat bi n ds t o t he P D-1 rece pt or a n d bl oc ks its 
i nteract i on wi t h P D-L 1 a n d P D -L 2, rel easi n g P D-1 pat h wa y -me diate d i n hi bit i on of t he i m m u ne 
res p o nse, i ncl u di n g t he a nti-t u mor i m m u ne res p o nse.  I n s y n ge neic m o use t u m or m o dels, 
bl oc ki n g P D -1 acti vit y res ulte d i n decrease d t u mor gr o wt h ( Merc k 2 0 1 6).
5. 3. 2.
N o n cli ni c al a n d Cli ni c al P h ar m a c o ki n eti c s
5. 3. 2. 1. Ol ar at u m a b
A p har mac o ki net ic ( P K) pr ofile of o larat u ma b c o nsiste nt wit h t hat e x pecte d f or a mA b was 
o bser ve d i n b ot h mice a n d m o n ke ys base d o n assess me nts of half -life (t½ ), cleara nce, a n d v o l ume 
of  distri b uti on.  I n mice, t he half -life was 7. 4 d a y s after i ntra perit o neal a d mi nistrati o n, w hic h 
s u p p orte d t he t wice wee kl y d osi n g strate g y t hat was e mpl o ye d t o e val uate olarat u ma b act i vity i n 
xe n o graft m o dels.  S y ste mic e x p os ure t o olarat u ma b i ncrease d wit h i ncreasi n g d ose i n b ot h mice 
a n d m o n ke ys.  N o c o nsiste nt se x -relate d differe nces i n e x p os ure were o bser ve d i n m on ke ys o ver 
3 9 wee ks a n d olarat u ma b acc u m u late d b y a fact or of 1. 4 t o 2. 4 bet wee n t he first a n d last d ose i n 
t he 3 9-wee k t o xicit y st u d y.  Olarat u ma b a nt i dr u g a nti b o dies ( A D A) were detecte d i n se veral 
ser u m sa m ples i n re peat-d ose t o xicit y st u di es; h o we ver, assess me nt of A D A was o fte n 
C CI

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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confounded by high circulating concentrations of olaratumab.  A direct correlation between 
immunogenicity response and the rapid drug clearance exhibited by some animals was clearly 
demonstrated in the 39-week toxicity study.
The pharmacokinetics of olaratumab were studied in 171 patients who received doses of either 
15 mg/kg on Days 1 and 8 of a 21-day cycle, or 20 mg/kg on Day 1 of a 14-day cycle.  Based on 
population pharmacokinetic analysis, the mean clearance for olaratumab is 0.56 L/day and the 
volume of distribution at steady state is 7.7 L.  This corresponds to a terminal half-life of 
approximately 11 days, and a time to steady state of approximately 7 weeks.
5.3.2.2. Pembrolizumab
The pharmacokinetics of intravenously administered pembrolizumab have been extensively 
studied in Cynomolgus monkeys through single-dose and repeat-dose studies across a wide range 
of dose levels and different dosing regimens. The single-dose study investigated 0.3, 3.0, and 
30-mg/kg doses. The repeat-dose studies investigated 6-, 40-, and 200-mg/kg doses, as well as 
weekly and bi-weekly dosing regimens. The PK profile of pembrolizumab exhibited multiphasic 
kinetics, with greater than dose-proportionality exposure at the lower single doses (0.3 and 
3.0 mg/kg) and dose-proportional exposure at the higher repeat-dose levels (6 to 200 mg/kg).  In 
repeat-dose studies, neutralizing anti-pembrolizumab antibodies were detected in the lower dose 
groups (6 and 40 mg/kg), but no neutralizing ADA were detected in the highest dose group (200 
mg/kg). Detection of neutralizing ADA corresponded with significantly lower pembrolizumab 
concentrations in the test animals. The terminal half-life of pembrolizumab in ADA-negative 
animals ranged from approximately 16 to 22 days in the repeat-dose studies. Repeat dosing 
resulted in accumulation of pembrolizumab that was dependent on dose and dosing frequency as 
expected. Steady-state of pembrolizumab was achieved by Day 71, which is consistent with 
approximately 3.5 terminal half-lives of the drug. In all the repeat-dose studies, systemic 
exposure of pembrolizumab was independent of sex.
The pharmacokinetics of pembrolizumab was studied in 2195 patients with various cancers who 
received doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on 
population pharmacokinetic analyses in patients with solid tumors, the geometric mean [% 
coefficient of variation (CV%)] for clearance (CL), steady-state volume of distribution, and 
terminal half-life were 202 mL/day (38%), 7.38 L (19%) and 27 days (38%), respectively.
Steady-state concentrations of pembrolizumab were reached by 19 weeks of repeated dosing 
with an every 3-week regimen and the systemic accumulation was 2.2-fold. The peak 
concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus 
time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose 
range of 2 to 10 mg/kg every 3 weeks.
5.3.3. Nonclinical Toxicology
Combination toxicology studies with olaratumab and pembrolizumab have not been conducted, 
as these studies are not warranted to support combination clinical trials intended to treat patients 
with advanced cancer (Nonclinical Evaluation for Anticancer Pharmaceuticals, ICH S9).  The 
toxicity of olaratumab and pembrolizumab have been characterized individually in both clinical 

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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and nonclinical studies and have a clinically manageable safety profile.  The target organs 
identified in single-agent studies of each agent do not appear to overlap (see below).  Based on 
this nonclinical data and the intended testing strategy, the combination of olaratumab and 
pembrolizumab is expected to have increased effectiveness when combined, without any 
potential additive toxicity.
5.3.3.1. Olaratumab
In repeat-dose monkey toxicity studies, the no-observable-adverse-effects levels (NOAEL) were 
established as the highest test doses:  50 mg/kg in the 5-week study and 75 mg/kg (Human 
Equivalent Dose of 24 mg/kg) in the 13- and 39-week studies.  There were no olaratumab-related 
findings on the reproductive system in either gender or on the cardiovascular, respiratory, central 
nervous system (CNS), immune system, or effects on the gastrointestinal (GI) or hematopoietic 
systems.  The exposure (area under the plasma or serum concentration-time curve [AUC]) 
following the last infusion of 75 mg/kg in the 39-week monkey study (284976 hr•μg/mL) was 
approximately 4-fold greater than exposures (AUC) of olaratumab that are needed for antitumor 
activity in humans (Study JGDG, 15 mg/kg).  
5.3.3.2. Pembrolizumab
Pembrolizumab was evaluated in repeat-dose toxicology studies of one- and six-months duration 
in the monkey. In the one-month study, animals received a total of 5 IV doses of pembrolizumab 
at dose levels of 0, 6, 40 and 200 mg/kg/week. There were no effects on survival, clinical signs, 
body weight, food consumption, cardiovascular measurements, or clinical pathology endpoints. 
Histopathology data obtained in the 1-month study indicated a tendency toward increased 
monocytic and/or lymphocytic infiltration of tissues, many of which are known autoimmune 
target organs in humans; however, the severity scores were generally low in magnitude.
In the 6-month study, animals received a total of 12 biweekly IV doses of pembrolizumab at 
dose levels of 0-, 6-, 40-, and 200-mg/kg dose. Histological changes in this study were similar in 
character to those observed in the 1-month study, and included an increased incidence of 
monocytic and/or lymphocytic tissue infiltration; however, the magnitude and/or severity was 
similar across studies and did not exhibit a tendency toward increasing severity with increasing 
duration of exposure.  These changes are consistent with the pharmacologic activity of the 
antibody:  blocking signaling through the immunoinhibitory PD-1 pathway. In addition, in both 
monkey studies, exposure of pembrolizumab at all dose levels tested exceeded that measured in 
humans at the intended clinical dose and schedule of 2 mg/kg once every 3 weeks. 
Please see the pembrolizumab IB for additional information.
5.4.
Rationale for Selection of Dose
5.4.1. Rationale for Selection of Olaratumab Dose
The olaratumab dose-selection strategy for this study is based on the integrated safety, efficacy, 
and PK data for olaratumab across previous Phase 1 and Phase 2 studies.  In 2 Phase 1 dose-
escalation trials in patients with solid tumors (Studies I5B-IE-JGDC and I5B-IE-JGDF) and in 
the 2 Phase 2 monotherapy studies (Studies I5B-IE-JGDE [glioblastoma] and I5B-IE-JGDH

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[GIST]), single-agent olaratumab has consistently been well-tolerated, with no dose-limiting 
toxicities (DLTs) observed up to a dose of 20 mg/kg administered every 2 weeks and up to a 
dose of 15 mg/kg administered on Days 1 and 8 of a 21-day cycle.  When used in combination 
with liposomal doxorubicin in Study I5B-IE-JGDA (olaratumab dose of 20 mg/kg every 2 
weeks), and with paclitaxel plus carboplatin in Study I5B-IE-JGDB (olaratumab dose of 15 
mg/kg Days 1 and 8 every 3 weeks), a higher rate of toxicities such as neutropenia and infections 
was observed versus the comparator agents.  In Study JGDG, although there was a higher 
incidence of some known doxorubicin toxicities such as mucositis, nausea/vomiting, and 
diarrhea, these were monitorable, predominantly Grade ≤2, and did not lead to a higher incidence 
of treatment discontinuation.  Overall, these toxicities were consistent with the toxicity profile of 
the combination agents used and are considered monitorable and acceptable for the patient 
populations studied.
The starting dose of olaratumab in the dose-escalation portion of this study (15 mg/kg given on 
Days 1 and 8 of a 21-day cycle) is the dose of olaratumab used in combination with doxorubicin 
in Study JGDG, where olaratumab plus doxorubicin met the primary study endpoint for PFS and 
demonstrated a significant improvement in OS above doxorubicin alone.  
As above, in studies of olaratumab plus cytotoxic chemotherapy, some additional 
myelosuppression was observed upon the addition of olaratumab to the chemotherapy.  As the 
addition of pembrolizumab is unlikely to result in significant myelosuppression, exploration of a 
higher dose of 20 mg/kg given on Day 1 and Day 8 of a 21-day cycle is warranted.  The AE 
profile of olaratumab to date suggests there is no significant overlap in toxicities with the known 
AE profile of pembrolizumab.  A loading dose of 20 mg/kg in Cycle 1 has been safely
administered in several ongoing studies (Studies JGDJ, JGDI, and JGDK) in combination with 
doxorubicin.  Exposure-response modeling from the recently completed Phase 2 Study JGDG 
indicated patients in the lowest quartile of exposure in Cycle 1 were below the identified target 
therapeutic concentrations and may benefit from higher exposures (Table JGDQ.1).  The loading 
dose was intended to increase the proportion of patients above the therapeutic threshold in Cycle
1, thus providing rationale for the exploration of a 20-mg/kg dose in this study.  
Table JGDQ.1.
Olaratumab Phase 2 Dosing Exposure-Response Modeling and 
Phase 3 Dosing Projections
Phase 2 Study JGDG
(15-mg/kg dose for all doses)
Predicted exposures with loading 
dose in Phase 3 Study JGDJ
Cycle 1
Steady State
Cycle 1
Steady State
Percentage of patients below ECmin150
45
23
24
22
Abbreviations:  ECmin150 = trough concentration (Cmin) in Cycle 1 that induces 50% of the maximum effect; kg = 
kilogram; mg  = milligrams.
5.4.2. Rationale for Selection of Pembrolizumab Dose
The dose of pembrolizumab planned to be studied in this trial is 200 mg every 3 weeks (Q3W).  
The dose recently approved in the US and several other countries for treatment of patients with 

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melanoma and NSCLC is 2 mg/kg Q3W. Information on the rationale for selecting 200 mg 
Q3W is summarized below.  
In KEYNOTE-001, an open-label Phase 1 clinical trial, conducted to evaluate the safety, 
tolerability, PK and PD, and anti-tumor activity of pembrolizumab when administered as 
monotherapy. The dose-escalation portion of this trial evaluated 3 dose levels, 1 mg/kg, 
3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) and dose-expansion cohorts 
evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in patients with advanced solid tumors. All dose 
levels were well tolerated and no DLTs were observed. This first-inhuman study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels. No MTD has been identified. In addition, 2 randomized cohort 
evaluations of melanoma patients receiving pembrolizumab at a dose of 2 mg/kg versus 
10 mg/kg Q3W have been completed, and one randomized cohort evaluating 10 mg/kg Q3W 
versus 10 mg/kg Q2W has also been completed. The clinical efficacy and safety data 
demonstrate a lack of clinically important differences in efficacy response or safety profile 
across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W. Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in patients 
with melanoma in the range of doses between 2 mg/kg and 10 mg/kg. Exposures for 200 mg 
Q3W are expected to lie within this range and will be close to those obtained with 2-mg/kg Q3W 
dose.
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a low clearance and a 
limited volume of distribution. The distribution of exposures from the 200-mg fixed dose are 
predicted to considerably overlap those obtained with the 2-mg/kg dose and importantly will 
maintain individual patient exposures within the exposure range established in melanoma as 
associated with maximal clinical response. Pharmacokinetic properties of pembrolizumab, and 
specifically the weight dependency in clearance and volume of distribution are consistent with 
no meaningful advantage to weight-based dosing relative to fixed dosing.
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a direct 
interaction with tumor cells, rendering it independent of the specific tumor type. In addition, 
available PK results in patients with melanoma, NSCLC, and other tumor types support a lack of 
meaningful difference in pharmacokinetic exposures obtained at tested doses among tumor types. 
Thus the 200-mg Q3W fixed-dose regimen is considered an appropriate fixed dose for other 
tumor indications as well.
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed-dosing scheme will also reduce complexity in the 

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logistical chain at treatment facilities and reduce wastage. The existing data suggest 200 mg 
Q3W as the appropriate dose for pembrolizumab.

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6. Investigational Plan
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened once.  Repeating laboratory tests during the screening period, after a patient has not met 
requisite criteria does not constitute re-screening. 
Screening laboratory tests may not be repeated more than twice in order to meet eligibility 
during the screening period. If a repeat laboratory value meets eligibility, it is recommended that 
the test is rechecked to confirm stability.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Study Population
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to the first dose of study drug.
[1]
Have histologically confirmed diagnosis of unresectable locally advanced or 
metastatic STS, not amenable to curative treatment and after available standard 
therapies (per local guidelines) have failed to provide clinical benefit, or been 
deemed inappropriate candidates for additional standard treatments by the 
investigator.  
Patients with a diagnosis of Grade 1 liposarcoma (atypical lipomatous neoplasms) 
are eligible if there is histological or radiographic evidence of evolution to more 
aggressive disease. 
[2]
Is ≥18 years of age.
[3]
Are willing and able to perform written informed consent for the trial and are 
amenable to compliance with protocol schedules and testing.
[4]
Have measurable or nonmeasurable but evaluable disease as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST version 1.1 [v1.1]; Eisenhauer et al. 
2009). 

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 3 5
L Y 3 0 1 2 2 0 7
[ 5]
Ha ve a de q uate or ga n f u nct i on, as defi ne d i n t he ta ble bel o w, wit h all scree ni n g la bs 
perf or m e d wit hi n 1 4 da ys of first d ose of st u d y treat me nt.
S yste m
L a b or at or y V al ue
He m at ol o gic al
A bs ol ute ne utr o p hil c o u nt ( A N C)
≥1. 5 x 1 0 9/ L
Platelets
≥1 0 0 x 1 0 9/ L ( platelet tra nsf usi o ns are 
n ot all o we d wit hi n 2 wee ks pri or t o 
St u d y Da y 1, see E xcl usi o n Criteri o n 
[ 2 0])
He m o gl o bi n
≥9 g/ d L or ≥5. 6 m m ol/ L ( pac ke d re d 
bl o o d cell tra nsf usi o ns are n ot all o we d 
wit hi n 2 wee ks pri or t o St u d y Da y 1, see 
E xcl usi o n Criteri o n [ 2 0])
Re n al
Creati ni ne or
Meas ure d or calc ulate d
a cr eati ni ne cleara nce ( Cr Cl)
( G F R ma y be use d i n place of creati ni ne or Cr Cl) 
(Attac h me nt 7 )
≤1. 5 x U L N or ≥6 0 m L/ mi n
He p atic
T otal bilir u bi n
≤1. 5 x U L N
A S T ( S G O T) a n d A L T ( S G P T)
≤2. 5 x U L N or
≤5 x U L N f or patie nts wit h li ver 
metastases
C o a g ul ati o n
T he patie nt has a n a de q uate c oa g ulati o n f u ncti o n as defi ne d b y I nter nati o nal N or malize d Rati o 
≤1. 5 x U L N or pr ot hr o m bi n ti me ≤1. 5 x U L N, a n d partial t hr o m b o plasti n ti me ≤1. 5 x U L N if 
n ot recei vi n g a ntic oa g ulati o n t hera p y.
F or patie nts recei vi n g a ntic oa g ula nts, e xce pti o ns t o t hese c oa g ulati o n para meters are all o we d 
if t he y are wit hi n t he i nte n de d or e x pecte d ra n ge f or t heir t hera pe utic use. Patie nts m ust ha ve 
n o hist or y of acti ve blee di n g ( defi ne d as wit hi n 1 4 da ys of first d ose of st u d y dr u g) or 
pat h ol o gical c o n diti o n t hat carries a hi g h ris k of blee di n g (e. g., t u m or i n v ol vi n g maj or vessels 
or  k n o w n es o p ha geal varices).
a
Creati ni ne cleara nce s h o ul d be calc ulate d per i nstit uti o nal sta n dar d .
[ 6]
Ha ve a n Easter n C o o perati ve O nc o l og y  Gr o u p Perf or ma nce Stat us ( E C O G P S) 
sc ore of 0 or 1 at t he ti me of e nr oll me nt (refer t o Attac h me nt 6 ).
[ 7]
Ha ve s ufficie nt a vaila ble material fr o m arc hi ve d f or mali n -fi xe d paraffi n-e m be d de d 
t u mor ti ss ue o btai ne d withi n 6 m o nt hs of st u d y  e nr oll me nt 
 
 
 
 
 
C CI

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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[8]
Have resolution, except where otherwise stated in the inclusion criteria, of all 
clinically significant toxic effects of prior systemic cancer therapy, surgery, or 
radiotherapy to Grade ≤1 by National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0 (v 4.0).
[9a] If male, the patient is sterile (including vasectomy) or agrees to use an effective 
method of birth control (for example, male condom with spermicide) and to not 
donate sperm during the study and for at least 120 days following the last dose of 
study treatment.  
[9b] If female, is not of childbearing potential due to surgical sterilization confirmed by 
medical history (at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy or tubal ligation) or menopause.
Menopausal women include women with either: 
1) spontaneous amenorrhea for at least 12 months, not induced by a 
medical condition such as anorexia nervosa, and not taking medications 
during the amenorrhea that induced the amenorrhea (for example, oral 
contraceptives, hormones, gonadotropin-releasing hormone, antiestrogens, 
selective estrogen receptor modulators, or chemotherapy), or
2) spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone level >40 mIU/mL. 
If female and of childbearing potential, has a negative serum or urine pregnancy 
test within 72 hours prior to the first dose of study medication, agrees to use a 
highly effective method of birth control during the study and for up to 120 days 
following the last dose of the study drugs, and is not breastfeeding.  If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
A highly effective method of birth control is defined as one that results in 
a low failure rate (that is, <1% incidence of pregnancy per year) when 
used consistently and correctly, such as contraceptive implants, 
injectables, combined oral estrogen or progestogen-only contraceptives 
associated with inhibition of ovulation, some intrauterine contraceptive 
devices (IUDs), sexual abstinence, or a vasectomized partner.  For patients 
using a hormonal contraceptive method, information regarding the study 
drugs under evaluation and their potential effect on the contraceptive 
should be addressed.
Abstinence as a method of birth control is acceptable if it is the established 
and preferred method of contraception for the patient.
[10] Have an anticipated life expectancy of ≥3 months.
[11] Inclusion Criterion [11] has been deleted.

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6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[12]
Have disease that is suitable for local therapy administered with curative intent.
[13]
Have received any previous systemic therapy (including investigational agents) 
targeting PD-1/PDL-1 or PD-1/PDL-2 signaling pathways (including previous 
participation in Merck MK-3475 trials).  Prior treatment with olaratumab is 
allowed.  Prior therapy with other immune checkpoint inhibitors, including but 
not limited to, anti-CD137 antibody or anti-cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) antibody, is not permitted.  
[14]
Have had chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks and/or monoclonal antibody treatment within 4 weeks prior to 
study Day 1 or who have not recovered (that is, to ≤ Grade 1 or baseline) from the 
effects of previously administered agents.  

Neuropathy (≤ Grade 2) or nonserious and nonlife-threatening 
toxicities, such as alopecia, altered taste, or nail changes, are an 
exception to this criterion.
Note:  If patient received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting 
therapy.  
[15]
Exclusion Criterion [15] has been deleted.
[16]
Have known active CNS metastasis and/or carcinomatous meningitis (screening 
not required). Patients with treated CNS metastases are eligible for this study if 
they have not received corticosteroids and/or anticonvulsants within 7 days of 
study treatment, and their disease is asymptomatic and radiographically stable for 
at least 60 days.  This exception does not include carcinomatous meningitis,
which is excluded regardless of clinical stability.
[17]
Have a history or current evidence of any serious medical condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with 
the patient’s participation for the full duration of the trial, or not be in the best 
interest of the patient to participate, in the opinion of the treating investigator. 
Serious medical condition(s) include, but are not limited to, the following:

Diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the 
first dose of study treatment.  

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
Active autoimmune disease that has required systemic treatment in past 
2 years from first dose of study treatment (that is, with use of disease-
modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (for example, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.

History of (non-infectious) pneumonitis that required steroids or current
pneumonitis. 

Known human immunodeficiency virus (HIV) infection (HIV 1/2 
antibodies) or acquired immunodeficiency syndrome (AIDS)-related 
illness (screening not required).

History of interstitial lung disease.

Known active Hepatitis A, B (for example, HBsAg reactive) or C (for 
example, HCV RNA [qualitative] is detected) infection (screening not 
required).

Liver cirrhosis at a level of Child-Pugh B (or worse).

Liver cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis.  Clinically 
meaningful ascites is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.

Active or uncontrolled clinically serious infection requiring systemic 
therapy.

Known psychiatric or substance abuse disorders that, in the opinion of the 
investigator, may prevent the patient from participating in the clinical trial.

Known allergy or hypersensitivity reaction to olaratumab or any of its
components.

Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients.

History of prior or second concurrent primary malignancies that, in the 
judgment of the investigator and Lilly, may affect the interpretation of 
results. Patients with carcinoma in situ of any origin and patients with 
prior malignancies who are in remission and whose likelihood of 
recurrence is very low (such as basal cell carcinoma), as judged by the 
investigator in consultation with Lilly CRP/CRS, are eligible for this 
study. 
[18]
Have received a live-virus vaccine within 30 days prior to planned treatment start.  
Examples of live vaccines include, but are not limited to:  measles, mumps, 
rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, Bacillus 

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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Calmette-Guérin (BCG), and typhoid vaccine.  Seasonal flu vaccines that do not 
contain live virus are permitted.
[19]
Have received transfusion of blood products (including platelets or red blood 
cells) or administration of colony stimulating factors (including granulocyte 
colony stimulating factors [G-CSF], GM-CSF or recombinant erythropoietin) 
within 2 weeks prior to study Day 1.
[20]
Have histologically or cytologically confirmed Kaposi’s sarcoma or 
gastrointestinal stromal tumor (GIST).
[21]
Have received treatment within 28 days of the initial dose of study drug with an 
investigational product or non-approved use of a drug (other than the study drug 
used in this study) or are concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this study. 
Patients participating in surveys or observational studies are eligible to participate 
in this study.
[22]
Have inflammatory bowel disease for which the patient has used 
immunosuppressive agents within the last 2 years.
[23]
Have had an allogenic tissue/solid organ transplant.
6.2. Summary of Study Design
Study JGDQ is an open-label, multicenter, nonrandomized, Phase 1a/1b dose-escalation study
followed by cohort expansion of IV olaratumab plus pembrolizumab in patients with
unresectable locally advanced or metastatic STS.  Treatment cycles will be 21 days (± 3 days).
In the Phase 1a dose-escalation portion of the study, eligible patients will receive olaratumab
15 mg/kg (starting dose) or 20 mg/kg on Day 1 and Day 8 plus pembrolizumab 200 mg IV (fixed 
dose) on Day 1 of a 21-day cycle. Patients will enroll in a 3+3 fashion, according to the dose-
escalation rules outlined in Section 7.2.2.  No intrapatient dose escalation is permitted.  Patients 
in any cohort who do not complete Cycle 1 treatment for reasons other than a DLT will be 
replaced.  A minimum of 6 patients will be enrolled to the highest tolerated dose in Phase 1a.  
There will be a 2-week observation of the first patient at each dose level before additional 
patients in that cohort can be enrolled.
Upon determination of a recommended dose for olaratumab, a Phase 1b expansion cohort will 
open.  Eligible patients will receive the recommended Phase 2 dose (RP2D) of olaratumab plus 
pembrolizumab in a 21-day cycle.  In the Phase 1b portion, approximately 25 patients will be 
enrolled.
Figure JGDQ.1 illustrates the design of the trial.
The planned duration of treatment with pembrolizumab is a maximum of 35 cycles 
(approximately 2 years).  The planned duration of treatment for olaratumab is not fixed; all 
patients will remain on study until confirmed progressive disease, unacceptable toxicity, or they 
fulfill one of the other criteria for study treatment discontinuation (Section 6.3).  

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The treatment period of the study includes a 30-day, 90-day, and a long-term follow-up period.  
The 30-day safety follow-up period begins 1 day after the patient and the investigator agree that 
the patient will no longer continue treatment and lasts approximately 30 days. The 90-day safety 
follow-up period begins 1 day after the 30-day safety follow-up period ends and lasts 
approximately 60 days. Thereafter, patients will enter the long-term follow-up period as detailed 
in the Study Schedule (Attachment 1).
Abbreviations:  D = day; DLT = dose-limiting toxicity; IV = intravenous; olara = 
olaratumab; pembro = pembrolizumab.
Figure JGDQ.1.
Study design overview for Study I5B-MC-JGDQ.
6.2.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete) at a 
date determined by Lilly at least 60 days after the last patient has discontinued treatment with 
pembrolizumab and after all study objectives are met. 
The end of trial occurs after study completion and after the last patient has discontinued all study 
treatment and completed any applicable continued access follow-up.
6.2.2. Continued Access Period
All patients remaining on study treatment (that is, with olaratumab only) without disease 
progression following study completion (at least 60 days after the last patient has discontinued 
treatment with pembrolizumab and after all study objectives are met) will be able to enter the 
continued access period of the study.  The continued access period begins after study completion 
and ends at the end of trial.  During the continued access period, patients on study treatment who 
continue to experience clinical benefit and no undue risks may continue to receive study 
treatment until disease progression, death, unacceptable toxicity, or start of new anticancer 
treatment.  The continued access period includes a follow-up visit.  The follow-up visit begins 1 
day after the patient and the investigator agree that the patient will no longer continue treatment 

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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in the continued access period and lasts approximately 30 days.  If it is deemed to be in the best 
interest of the patient to start a new anti-cancer treatment prior to the scheduled end of the 
follow-up visit, the follow-up visit duration may be shortened. In this case, the follow-up 
assessments should be completed prior to the initiation of the new therapy.
Lilly will notify investigators when the continued access period begins.
During the continued access period, all AEs, SAEs, and any study drug dose adjustments will be 
collected on the case report form (CRF). 
Serious adverse events will also be reported to Lilly Global Patient Safety and collected in the 
pharmacovigilance system (Section 8.1.2.5).  In the event that an SAE occurs, additional 
information (such as local laboratory results, concomitant medications, and hospitalizations) may 
be requested by Lilly in order to evaluate the reported SAE. 
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.
6.3. Discontinuations
The reason for and date of treatment discontinuation will be collected for all patients.  The date 
of discontinuation (for any reason) from study treatment is to be reported on the CRF.  
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal, consistent with the original authorization.
6.3.1. Discontinuation of Patients Inadvertently Enrolled
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor CRP/CRS and the investigator to determine whether the patient may continue in the 
study, with or without investigational product.  Inadvertently enrolled patients may be 
maintained in the study and on investigational product when the Lilly CRP/CRS agrees with the 
investigator that it is medically appropriate for that patient.  The patient may not continue in the 
study with or without investigational product if the Lilly CRP/CRS does not agree with the 
investigator’s determination that it is medically appropriate for the patient to continue.  The 
investigator must obtain documented approval from the Lilly CRP/CRS to allow the 
inadvertently enrolled patient to continue in the study with or without investigational product.
6.3.2. Discontinuation of Patients from Study or Study Drugs
In both the Phase 1a and 1b portions of the trial, patients for whom discontinuation of one study 
drug is necessary for safety reasons may continue to receive the other study drug at the discretion 
of the investigator.  Patients who reach the maximum number of permitted cycles of 

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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pembrolizumab (35) will be allowed to continue receiving olaratumab until discontinuation 
criteria is met.
Patients who are discontinued from all study drugs will have follow-up procedures performed as 
shown in the Study Schedule (Attachment 1).
In addition, patients will be discontinued from all study drugs and/or from the study in the 
following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drugs
o
the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication.  
Discontinuation from the study drugs should occur prior to introduction of the 
other agent

Patient Decision
o
the patient requests to be discontinued from the study or study drugs

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP

The patient has evidence of progressive disease.
o
If tumor imaging shows initial disease progression, patients may remain on study 
treatment with repeat imaging ≥4 weeks later to assess tumor response or 
confirmed progression per irRECIST.

The patient experiences unacceptable toxicity.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).
6.3.2.1. Discontinuation of Study Therapy after Complete Response
Discontinuation of treatment may be considered for patients who have attained a confirmed 
complete response (CR).  These patients must have been treated with pembrolizumab for at least 
24 weeks and had at least 2 pembrolizumab treatments beyond the date when the initial CR was 
declared.  
6.3.3. Patients Lost to Follow-Up
A patient would 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.

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6.3.4. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for any 
scientific, medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.
6.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges discontinuation of the study necessary for any scientific, medical, safety, 
regulatory, ethical, or other reasons consistent with applicable laws, regulations, and GCP.

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7. Treatment
7.1. Materials and Supplies
7.1.1. Olaratumab
Olaratumab will be supplied as a sterile preservative-free solution for IV infusion in single-use 
vials containing 500 mg/50 mL of olaratumab (10 mg/mL). Olaratumab is formulated in 10-mM 
histidine, 100-mM glycine, 50-mM sodium chloride, 75-mM mannitol, and 0.02% polysorbate-
20, pH 5.5. All excipients used in the formulation of olaratumab drug product (DP) are of
pharmacopeial grade. 
The DP must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) with protection from 
direct light.  Do not freeze and/or shake olaratumab DP.  Stability studies have demonstrated that 
the DP can withstand transient excursion to room temperature without adverse effect; however, 
storage at this temperature is not recommended.
Please refer to the Pharmacy Manual for information on preparing the olaratumab dosing 
solution for infusion. 
CAUTION:  IRRs may occur during or following olaratumab administration.  See 
Section 7.5.1.1 for instructions on the management of olaratumab IRRs.
7.1.2. Pembrolizumab
Two DP dosage forms are available for pembrolizumab: a white to off white lyophilized powder, 
50 mg/vial, and a liquid, 100 mg/vial, both in Type I glass vials intended for single use only.

Pembrolizumab Powder for Solution for Infusion, 50 mg/vial is a lyophilized powder that 
is reconstituted with sterile water for injection prior to use. It is manufactured using either 
the fully formulated drug substance (DS) or the partially formulated DS. The fully 
formulated DS uses L histidine as a buffering agent, polysorbate 80 as surfactant, and 
sucrose as stabilizer/tonicity modifier. Pembrolizumab DP using the partially formulated 
DS is formulated with L histidine as a buffering agent, polysorbate 80 as a surfactant, and 
sucrose as a stabilizer/tonicity modifier and may contain hydrochloric acid and/or sodium 
hydroxide for pH adjustment (if necessary).

Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP (manufactured using the 
fully formulated DS with L histidine as a buffering agent, polysorbate 80 as a surfactant, 
and sucrose as a stabilizer/tonicity modifier).
Both DP dosage forms are stored under refrigerated conditions (2°C to 8°C).
The lyophilized DP after reconstitution with sterile water for injection and the liquid DP are clear 
to opalescent solutions, essentially free of visible particles. The reconstituted lyophilized product 
and the liquid product are intended for IV administration. The reconstituted DP solution or the 
liquid DP can be further diluted with normal saline or 5% dextrose in the concentration range of 
1 to 10 mg/mL in IV containers made of polyvinyl chloride (PVC) or non PVC material. 
Reconstituted vials should be used immediately to prepare the infusion solution in the IV bag, 

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and the infusion solution should be administered immediately. If the diluted pembrolizumab 
solution is not used immediately, it may be stored for no more than 24 hours at 2°C to 8°C. This 
24 hour total hold from reconstitution may include up to 6 hours at room temperature (at or 
below 25°C). Any additional hold time must be at 2°C to 8°C. If refrigerated, the vials and/or IV
bags must be allowed to come to room temperature prior to use. 
The recommended dose of pembrolizumab in adults is 200 mg administered as an IV infusion 
over 30 minutes Q3W.
7.2. Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) and planned duration 
of each individual’s treatment to the site personnel or patient,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation, and collection, and
returning or destroying all unused medication to Lilly or its designee at the 
end of the study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
7.2.1. Dosing Schedule
Study drugs will be administered in both the Phase 1a and 1b portions of the trial as follows:  
7.2.1.1. Olaratumab
Olaratumab will be administered as an approximately 60 minute IV infusion on Day 1 and Day 8 
of a 21-day cycle at the doses shown in Table JGDQ.2.  Exceptions to the 60-minute duration of 
the olaratumab infusion are permitted; see Pharmacy Manual for more information. On Day 1 of 
each cycle, olaratumab should be administered prior to pembrolizumab.
7.2.1.1.1. Olaratumab Premedication
Premedicate patients prior to administration of olaratumab as below:

Premedication in Cycle 1:
Premedication is mandatory for all patients during Cycle 1 prior to each dose of 
olaratumab.  Premedicate all patients with the following (or equivalent) medications on 
Days 1 and 8 of Cycle 1: 
o
Histamine H1 antagonist (for example, diphenhydramine) 
o
Dexamethasone IV

Premedication in Cycles 2-n:
For subsequent cycles, premedication with a histamine H1 antagonist (for example, 
diphenhydramine) is recommended prior to each dose of olaratumab 
Additional premedication may be provided at the investigator’s discretion.  Premedication must 
be provided in the setting of a prior Grade 1 or 2 olaratumab IRR, as detailed in Section 7.5.1.1.  

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All premedication administered must be adequately documented in the electronic case report 
form (eCRF).  
Patients are required to be monitored for 1 hour after the olaratumab infusion in Cycles 1 and 2 
for signs or symptoms of IRRs; see Section 7.5.1.1 for full description of required olaratumab 
monitoring period in Cycles 1 and 2.  Patients should complete the required monitoring period 
prior to the start of pembrolizumab administration (when applicable). In addition, patients will 
be monitored for 3 hours following the end of the pembrolizumab infusion in Cycles 1 and 2 for 
signs and symptoms of IRRs (see Section 7.5.2.8).  
7.2.1.2. Pembrolizumab
Pembrolizumab will be administered as a 200-mg fixed dose intravenously over 30 minutes on 
Day 1 of a 21-day cycle.  Every effort should be made to ensure infusion timing is as close as 
possible to 30 minutes.  However, a window of between -5 minutes and +10 minutes is permitted 
(that is, infusion time is 30 minutes -5 min/+10 min). Patients should be monitored in Cycles 1 
and 2 for signs and symptoms of IRRs for 3 hours following the end of the pembrolizumab 
infusion.  
Table JGDQ.2.
Phase 1a and 1b Study Drug Administration
Drug
Dose Level
Dose
Route
Dosing Day
of 21-Day Dosing Period
olaratumab
Level 1
15 mg/kg
IV
Day 1 and Day 8
Level 2
20 mg/kg
IV
Day 1 and Day 8
pembrolizumab
Fixed dose
200 mg
IV
Day 1
Abbreviations:  IV = intravenous.
7.2.2. Phase 1a Dose Escalation
A 3+3 dose-escalation design will be used to assess the safety of olaratumab given in 
combination with pembrolizumab. The DLT observation period will last for 1 cycle 
(approximately 21 days) for each patient in this portion of the study.  
7.2.2.1. Olaratumab Dose-Escalation Rules
In the Phase 1a portion of the study, patients will begin olaratumab at Dose Level 1 (see Table 
JGDQ.2). The pembrolizumab dose will be fixed at 200 mg.  
If none of the initial 3 DLT-evaluable patients (defined in Section 7.6.1) treated at Dose Level 1 
develops a DLT, the study will proceed to enroll patients at the higher dose (Dose Level 2).
If 1 of the initial 3 DLT-evaluable patients treated at Dose Level 1 develops a DLT, 3 additional 
patients will be added to Dose Level 1.  If ≤1 of 6 DLT-evaluable patients develops a DLT, the 
study will proceed to enroll patients at the higher dose (Dose Level 2).  
If ≥2 DLT-evaluable patients develop a DLT at Dose Level 1, the regimen will be stopped. 

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If the study is enrolling patients at Dose Level 2 and 1 of the initial 3 DLT-evaluable patients 
develops a DLT, 3 additional patients will be added at Dose Level 2. If ≤1 of 6 DLT-evaluable 
patients develops a DLT, the Phase 1b (dose expansion) portion will start at Dose Level 2.
If the study is enrolling patients at Dose Level 2 and ≥2 of the initial 3 DLT-evaluable patients 
develops a DLT, Dose Level 2 will not be used in the Phase 1b (dose expansion) portion. 
A minimum of 6 patients will be enrolled at the highest tolerated dose.  All evaluable patients 
will be considered in deciding whether the dose is tolerated prior to expansion to Phase 1b. 
No intra-patient dose escalation is allowed.  Patients who withdraw from the study during the 
DLT observation period for reasons other than a treatment-related toxicity may be replaced 
within the same dose level.  
Safety data, in particular AEs, will be the primary criteria for the dose escalation.  No dose 
escalation can occur without prior discussion and agreement between the investigators and the
Lilly CRP/CRS; the decision will be documented in writing.  
Based on the ongoing safety reviews, modifications to the dose-escalation strategy or other 
design elements may be made via protocol amendment to ensure patient safety. 
7.2.2.2. Dose-Limiting Toxicity Determination
A DLT is defined as an AE during Cycle 1 that is possibly related to the study drug and fulfills 
any 1 of the following criteria using the NCI CTCAE v4.0:

CTCAE Grade ≥3 nonhematologic toxicity. Exceptions that will not be considered a 
DLT are:
o
Grade 3 nausea, vomiting, diarrhea, or constipation that lasts ≤72 hours and that 
can be controlled with appropriate treatment; Grade 3 fatigue that lasts ≤72 hours;
Grade 3 rash without the use of corticosteroids or anti-inflammatory agents per 
standard of care
o
Clinically non-significant, treatable, or reversible laboratory abnormalities 
including liver function tests, pancreatic enzymes, uric acid, electrolytes, etc.  
Grade 4 electrolyte disturbance lasting more than 24 hours despite appropriate 
treatment will be considered a DLT.
o
Transient (<7 days) Grade 3 elevations of alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) that are not accompanied by a Grade 2 bilirubin 
increase are considered an exception to the DLT criteria, unless there is a clear 
alternative cause (for example, worsening biliary obstruction) if agreed by the 
study investigator and Lilly CRP/CRS.
o
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the patient is asymptomatic

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o
Grade 3 inflammatory reaction attributed to a local antitumor response (for 
example, inflammatory reaction at sites of metastatic disease, lymph nodes, etc.)
o
Concurrent vitiligo or alopecia of any AE grade
o
Any infusion or hypersensitivity reactions occurring during the infusion of the 
drug are not considered dose-related and therefore will NOT be considered a DLT

Grade 4 anemia

Grade 4 neutropenia or leukopenia of >5 days duration 

Any febrile neutropenia

Grade 3 thrombocytopenia with clinically significant bleeding or Grade 4 
thrombocytopenia

Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (for example, any toxicity that is possibly related 
to the study medication that requires the withdrawal of the patient from the study during 
Cycle 1)
Investigators, together with the Lilly CRP/CRS, can declare a DLT if a patient is experiencing 
increasing toxicity during further cycles of treatment and it becomes clear that it will not be 
possible to continue on treatment without exposing the patient to excessive risk.
A dose-limiting equivalent toxicity (DLET) is an AE that meets the DLT criteria as defined 
above and occurs in any cycle other than Cycle 1 for a patient enrolled in the Phase 1a portion of 
the study.
The MTD is defined as the highest tested dose that has <33% probability of causing a DLT 
during Cycle 1.  At the time of safety assessments for each cohort, all available safety data, 
including DLTs and DLETs from later cycles of treatment, will be included.  In addition to the 
DLT assessment period in Cycle 1, safety data beyond Cycle 1 available at the time of safety 
review will also be taken into consideration prior to determining dose escalation, whether to 
enroll additional patients, or whether to proceed to the Phase 1b portion of the study.   
Toxicity that is clearly and directly related to the primary disease or to another etiology is 
excluded from the definition of DLTs.
7.2.3. Phase 1b Dose Expansion
Based on the safety profile observed during the Phase 1a portion of the trial, the sponsor will
determine the dosing regimen to be investigated in the Phase 1b portion of the study and open 
enrollment in the Phase 1b portion to further evaluate the combination therapy in this patient 
population.  
Patients enrolled to the Phase 1a portion of the study will not participate in the Phase 1b portion.  
Patients in Phase 1b portion will meet the same eligibility criteria as for Phase 1a portion of the 
study.  The purpose of Phase 1b expansion is to gather additional safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy information 
regarding the combination. 

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7.2.4. Dose Adjustments and Delays
7.2.4.1. Olaratumab
Olaratumab dose adjustments within Cycle 1 should be avoided if possible.  If a dose adjustment 
or delay is required during Cycle 1 in the dose-escalation phase of the study, the patient will be 
allowed to continue but may be replaced if deemed appropriate by the Lilly CRP/CRS and 
investigator.  
If a patient treated at a given dose level experiences a DLT (as defined in Section 7.2.2.2), then 
treatment will be suspended for that patient.  Dosing may restart after recovery from toxicity at a 
lower dose after consultation between the investigator and Lilly CRP/CRS.  If a toxicity does not 
meet the criteria for a DLT in Cycle 1 (or a DLET) but nonetheless requires omission of dose(s) 
for tolerability, then dosing may resume at the same dose or reduced dose after the toxicity 
resolves to baseline; however, the dose(s) omitted for tolerability during a cycle will not be 
replaced.  Treatment may be delayed for up to 14 days to allow a patient sufficient time for 
recovery from study drug-related toxicity.  If Day 8 dosing is delayed for approximately 14 days, 
the patient should resume treatment with Day 1 treatment for the next cycle.
The olaratumab dose for a patient should be reduced for all subsequent cycles of therapy, if the 
investigator determines that it is in the best interest of the patient or if the patient experienced at 
a DLT.  For such patients requiring a dose reduction, re-escalation to the original dose level is 
not permitted.  Patients who require more than 2 dose reductions of olaratumab will be 
discontinued from olaratumab treatment.  If a patient experiences a DLET at a reduced dose 
level, then the patient will be discontinued from study treatment.  
7.2.4.1.1. Hematologic Toxicity
Treatment should not begin on Day 1 of any cycle until the absolute neutrophil count (ANC) is 
≥1500 cells/µL and the platelet count is ≥100,000 cells/µl.
Olaratumab treatment on Day 8 of any cycle should be held until ANC is >500 cells/µL and 
platelet count is ≥75,000 cells/µL. 
7.2.4.1.2. Nonhematologic Toxicity
Specific guidelines for dose adjustments in patients who experience olaratumab IRRs may be 
found in Section 7.5.1.1.
General guidelines for dose modification for other nonhematologic toxicities related to 
olaratumab are shown in Table JGDQ.3.  If more than 2 toxicity-related olaratumab dose 
reductions are required, olaratumab will be permanently discontinued.

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Table JGDQ.3.
General Guidelines for Dose Modification Due to Nonhematologic 
Toxicities Related to Olaratumab
Reaction Grade
Required Dose Modification
Grade 1
No dose modification is required.
Grade 2
At the investigator’s discretion, the patient may continue to receive olaratumab per protocol, 
provided that the event does not pose a serious health risk or is easily treated.
Grade 3 
For a Grade 3 toxicity not adequately controlled with appropriate supportive care, the dose 
must be withheld until toxicity is ≤ Grade 1 or has returned to pretreatment baseline; then 
treatment may resume at a reduced dose of 12 mg/kg for the 15-mg/kg cohort (Phase 1a) and 
reduced dose of 15 mg/kg for the 20-mg/kg cohort.  If toxicity recurs after therapy resumes, a 
second dose reduction (second dose reduction of 10 mg/kg for the 15-mg/kg cohort and 
12 mg/kg for the 20-mg/kg cohort) is permitted.
Grade 4
The dose must be withheld until dose toxicity is ≤ Grade 1 or has returned to baseline.  
Permanent discontinuation should be considered for any patient experiencing Grade 4 
nonhematologic toxicity assessed as related to olaratumab.  However, if resumption of dosing 
is deemed appropriate by the investigator, treatment may resume only after consultation with 
the Lilly study physician, with the dose reduced to 10 mg/kg for the 15-mg/kg cohort or to 15 
mg/kg for the 20-mg/kg cohort.  If Grade 4 toxicity recurs after therapy resumes, all study 
treatment will be discontinued.
Note:  for asymptomatic Grade 3/4 laboratory abnormalities that are clinically non-significant, treatable, or 
reversible, treatment with olaratumab may continue without dose modifications at the discretion of the 
investigator.
7.2.4.2. Pembrolizumab
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of treatment and may affect more than one
body system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, and/or
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold 
or permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in
Table JGDQ.4. See Section 7.5.2 for supportive care guidelines for pembrolizumab, including 
use of corticosteroids.

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Table JGDQ.4.
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with 
Pembrolizumab
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus).
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Grade 4
Permanently 
discontinue
AST / ALT 
elevation or 
Increased 
Grade 2
Withhold
Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable

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bilirubin
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
Initiate insulin replacement therapy 
for participants with T1DM 
Administer anti-hyperglycemic in 
participants with hyperglycemia 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.  
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 
Administer corticosteroids 
(prednisone 1-2 mg/kg or equivalent) 
followed by taper.
Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 

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event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; GI = gastrointestinal; irAE = immune-related adverse event; IV = intravenous; T1DM = Type 1 diabetes mellitus.
Note: Patients who have asymptomatic or clinically non-significant Grade 3 or 4 lipase or amylase elevations (that is, not associated with clinical symptoms or 
radiological signs of pancreatitis) which are transient as demonstrated by a decrease of at least 1 CTCAE Grade within 7 days ±3 days of onset will not 
require pembrolizumab discontinuation or modification. If the elevation has not decreased at least 1 CTCAE Grade within this time window, pembrolizumab 
treatment may only continue after consultation and discussion with the Sponsor.

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7.3.
Method of Assignment to Treatment
Before a patient’s enrollment into the study, an eligibility check must be conducted between the 
investigational site and Lilly clinical research personnel to confirm that the patient meets all 
eligibility criteria.  Upon confirmation of eligibility, the sponsor will confirm the dose and 
identification number assignment for the patient.  No dose escalations (that is, to the next cohort) 
can occur without prior discussion and agreement with the responsible Lilly CRP/CRS. 
If investigators have eligible patients who have consented concurrently, more than 3 patients 
may be entered at a particular dose level provided that accrual has not ceased due to excessive 
toxicity.  This enrollment procedure is allowed because of the advanced disease state of this 
patient population and the screening involved in defining eligibility.  This event should be 
approved by the sponsor following discussions with the investigators.
7.4.
Blinding
This is an open-label study.
7.5. Concomitant Therapy
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study. The need for any form 
of radiotherapy will be cause for early discontinuation from study treatment (palliative
radiotherapy is permitted if clinically indicated, after discussion with the Lilly CRP/CRS).  In 
addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate discontinuation from study treatment.  Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the eCRF.  
Replacement hormonal therapy initiated before study entry will be allowed.
Patients should receive full supportive care with the exception that the routine use of G-CSF is 
not permitted during this study. Patients should not receive G-CSF prophylactically in any cycle.  
G-CSFs may only be used for patients who have ANC<0.5 109, neutropenic fever, or 
documented infections while neutropenic.  G-CSFs must be discontinued at least 24 hours before 
the start of the next cycle of treatment.  Should the use of hematopoietic colony-stimulating 
factors (CSFs) be necessary, follow the American Society of Clinical Oncology (ASCO) 
recommendations for the use of CSFs (Smith et al. 2006).  If clinically indicated at any time 
during the study, erythropoietin and packed red blood cell transfusions may be used according to 
ASCO guidelines (Rizzo et al. 2008). 
All concomitant medications should be recorded throughout the patient’s participation in the 
study.

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7.5.1. Supportive Care Guidelines for Olaratumab
7.5.1.1. Infusion-Related Reactions
As with other monoclonal antibodies, hypersensitivity reactions may occur during or following 
olaratumab administration.  Premedications to be given prior to olaratumab infusions are 
described in Section 7.2.1.
An approximate 1-hour observation period is required after the administration of olaratumab
during the first and second cycles of olaratumab.  Patients should complete the olaratumab 
observation period prior to starting pembrolizumab (when applicable). If there is no evidence of 
an IRR during the initial 2 cycles of olaratumab, then no observation period is required for 
subsequent treatment cycles.  In the event an IRR occurs thereafter, the 1-hour observation 
should be reinstituted.  During the observation period, patients treated with olaratumab should be 
closely monitored for signs and symptoms indicative of an infusion reaction by the medical staff 
from the start of the infusion until at least 1 hour after the end of the infusion in an area where 
emergency medical resuscitation equipment and other agents (epinephrine, prednisolone 
equivalents, etc.) are available.
Olaratumab infusion reactions will be defined according to the NCI-CTCAE Version 4.0 
definition of IRRs.
Symptoms occurring during or following infusion of investigational therapy may also be defined 
according to AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome 
(NCI-CTCAE Version 4.0 section “Immune system disorders”).  In the setting of symptoms 
occurring during or following infusion of investigational therapy, investigators are encouraged to 
use the AE term “infusion-related reaction” and any additional terms (including those not listed 
here) that best describe the event.
Treatment guidelines for olaratumab IRRs as well as premedications for subsequent infusions are 
described in Table JGDQ.5.

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Table JGDQ.5.
Olaratumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Infusions
Grade 1 or 2
Stop infusion and monitor symptoms.
Additional appropriate medical therapy  should be given 
according to standard medical practice; may include, but 
is not limited to:

Antihistamines (for example, diphenhydramine 
HCl)

Steroids (for example, dexamethasone)

Acetaminophen

Oxygen
After recovery, the infusion rate should be decreased 
50% for the duration of the infusion.  
Patients should be premedicated 
with antihistamines, steroids, 
acetaminophen, etc., as 
appropriate.
Grades 3 or 4
Stop infusion.
Administer immediate treatment.  May include, but is 
not limited to:

Epinephrine

Bronchodilators and/or glucocorticoids for 
symptomatic bronchospasm

IV fluids and/or pressors for hypotension
Treatment with olaratumab should be immediately 
and permanently discontinued.
No subsequent dosing
All attempts should be made to obtain an anti-olaratumab antibody and olaratumab PK blood samples as 
close to the onset of the event as possible, at the resolution of the event, and 30 days (±3 days) following the 
event.  The procedure for sample collection and handling is described in a separate procedural manual.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
Abbreviations:  HCl = hydrochloride; IV = intravenous; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events.
7.5.2. Supportive Care Guidelines for Pembrolizumab
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined below.  Where appropriate, these guidelines include the use 
of oral or IV treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several courses of 
steroid tapering may be necessary, as symptoms may worsen when the steroid dose is decreased.  
For each disorder, attempts should be made to rule out other causes, such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab.

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Note:  If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below).  Refer to Section 7.2.4 for dose 
modification guidelines.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
7.5.2.1. Pneumonitis
Grade 2 immune-mediated pneumonitis events should be treated with systemic corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
Pembrolizumab should be permanently discontinued in patients who experience recurrent 
Grade 2 pneumonitis.
Grade 3 or 4 events should be immediately treated with IV steroids. Administer additional anti-
inflammatory measures, as needed.
Prophylactic antibiotics for opportunistic infections should be added in the case of prolonged 
steroid administration.
7.5.2.2. Diarrhea/Colitis
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  
All patients who experience diarrhea/colitis should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted 
via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis.
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
For Grade 3 or 4 diarrhea/colitis, treat with IV steroids followed by high-dose oral steroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
7.5.2.3. Type 1 Diabetes Mellitus or Hyperglycemia
The following are recommendations for management of Type 1 diabetes mellitus (if new onset, 
including diabetic ketoacidosis [DKA]) or Grade ≥3 hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA):

Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3
or 4 hyperglycemia associated with metabolic acidosis or ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 

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Grade 2 events should be treated with corticosteroids.  When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks.  Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
Grade 3 or 4 events should be treated with an initial dose of IV corticosteroids followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over at least 4 weeks.  Replacement of appropriate hormones may be required as the 
steroid dose is tapered.
7.5.2.4. Hypophysitis
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
For Grade 3 to 4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered.
7.5.2.5. Hyperthyroidism or Hypothyroidism
Thyroid disorders can occur at any time during treatment.  Patients should be monitored for 
changes in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Grade 2 hyperthyroidism events (and Grade 2 to 4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (for example, propranolol) are suggested 
as initial therapy.  

In hypothyroidism, thyroid hormone replacement therapy with levothyroxine or 
liothyronine is indicated per standard of care.  
Grade 3 or 4 hyperthyroidism:

Treat with an initial dose of IV corticosteroid followed by oral corticosteroids.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.  Replacement of appropriate hormones may be required as the 
steroid dose is tapered.
7.5.2.6. Hepatic Injury
For Grade 2 immune-mediated hepatitis, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).  Treatment with IV or oral corticosteroids should
be considered.
For Grade 3 or 4 immune-mediated hepatitis, treat with IV corticosteroids for 24 to 48 hours.
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks.

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7.5.2.7. Renal Failure or Nephritis
In the case of Grade 2 events, treatment with corticosteroids is recommended.
Patients that experience Grade 3 or 4 events should be treated with systemic corticosteroids.
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
7.5.2.8. Pembrolizumab Infusion-Related Reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.
A 3-hour observation period is required after the administration of pembrolizumab during the 
first and second cycles.  During the observation period, patients treated with pembrolizumab
should be closely monitored for signs and symptoms indicative of an infusion reaction by the 
medical staff from the start of the infusion until at least 3 hours after the end of the infusion.
Table JGDQ.6 shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab.

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Table JGDQ.6.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤24 hrs.
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (for example, from 100 mL/hr to 50 
mL/hr).  Otherwise, dosing will be held 
until symptoms resolve and the patient 
should be premedicated for the next 
scheduled dose.
Patients who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Patient may be premedicated 
1.5 hr (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).

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Pembrolizumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:  Prolonged (that is, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (for example, renal 
impairment, pulmonary infiltrates)
Grade 4:  Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids

Epinephrine
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Patient is permanently discontinued 
from further trial treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
Abbreviations:  IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAIDs = non-steroidal anti-inflammatory drugs; po = by mouth.
7.6. Treatment Compliance
Olaratumab and pembrolizumab will be administered intravenously at the investigational site, 
under the direction of the investigator.  As a result, a patient’s compliance with study drug 
administration is ensured.  Patients should attend scheduled clinic visits and must comply with 
study criteria under their control.  Deviation(s) from the prescribed dosage regimen should be 
recorded on the CRF.  
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for the assessment of a dose level.
In the Phase 1a portion of the study, any patient who is discontinued from study treatment before 
completing 1 cycle of treatment will be deemed non-evaluable for assessment of a dose level, 
unless they experience a DLT prior to withdrawal. 

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Non-evaluable patients may be replaced to ensure that enough patients complete 1 cycle of 
therapy at each dose level, unless accrual to that cohort has stopped due to a DLT.
Patients who are not evaluable for pharmacokinetics, but who complete 1 cycle of therapy, may 
be replaced upon consultation with the investigator(s) and the Lilly CRP/CRS to ensure adequate 
PK data, unless accrual to that cohort has stopped due to a DLT.

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8.
Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of olaratumab have been assessed in nonclinical toxicology studies,
and the results from these studies are detailed in the olaratumab IB (Lilly 2016). The safety and 
tolerability of pembrolizumab has been assessed in nonclinical and clinical studies; the results 
from these studies are detailed in the Keytruda PI and SmPC. This Phase 1 study contains 
detailed safety monitoring that will permit initial characterization of the safety profile of 
olaratumab in combination with pembrolizumab in patients.  Study procedures and their timing, 
including collection of blood, urine, and tumor tissue samples, are described in the Study 
Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, coagulation, and urinalysis panels, 
will be performed.  All standard laboratory tests will be analyzed centrally, with the exception of 
urinalyses and pregnancy tests.  Central or local laboratory results will be used to determine 
patient eligibility at baseline and local laboratory results may be used for on-study dosing 
decisions; if so, testing must still be performed by the central laboratory.  These central 
laboratory results will be used for subsequent safety analyses.  In the event of minor 
discrepancies between local and central laboratory results, the investigator may use the local 
results for treatment decisions, and the central laboratory results will remain part of the safety 
database. Other clinical laboratory tests will also be collected.  Attachment 2 lists the specific 
tests that will be performed for this study.
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JGDQ.7 presents a summary of AE and SAE reporting guidelines.  Table JGDQ.7 also 
shows which database or system is used to store AE and SAE data.

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8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital sign measurements, and so on that occur should also be reported to Lilly or its designee as 
an AE.  
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect. Progression of the cancer under study is not considered an AE. 
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE v 4.0.
The NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms. All AEs observed 
will be graded using CTCAE v 4.0.  Any minor version of CTCAE v 4.0 (for example, version 
4.0) may be used for this study.  Minor CTCAE v 4.0 updates from the NCI will not necessitate a 
protocol amendment. For AEs without matching terminology within the NCI-CTCAE v 4.0 
criteria, the investigator will be responsible for selecting the appropriate system organ class and 
assessing severity grade based on the intensity of the event.  Note that both CTCAE term (actual 
or coded) and severity grade must be selected by study site personnel and collected on the CRF.  
This collection is in addition to verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breastfeeding should be collected, if feasible, for regulatory 
reporting and drug safety evaluation. Upon documentation of pregnancy, the patient must be 
removed from study treatment immediately.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition,
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment. 

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Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure or study drug via eCRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment 
and the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment 
and the AE has not been demonstrated at this time and is not probable, but is 
also not impossible.

Unrelated:  without question, the AE is definitely not associated with the 
study treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1. Serious Adverse Events
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs.  Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study treatment or other protocol-required 
procedure) should not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious 
per ICH definition, are reportable to the sponsor in the same timeframe as SAEs to meet certain 
local requirements.
Therefore, these events are considered serious by the sponsor for collection purposes.

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●
Is a new cancer (that is not a condition of the study)
●
Is associated with an overdose
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
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.  
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor and the SAEs will be entered in the
Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
8.1.2.2. Notable Adverse Events
Adverse events that have been identified as safety signals during preclinical or early clinical 
trials or based on class effects of similar drugs are known as adverse events of special interest 
(AESI) for olaratumab and as events of clinical interest (ECI) for pembrolizumab.  These events 
will be monitored prospectively in the clinical development program.  
8.1.2.2.1. Adverse Events of Special Interest for Olaratumab
IRRs are an AESI for olaratumab. AESIs are defined by a careful assessment and grouping of 
individual related MedDRA preferred terms.  Section 7.5.1.1 describes supportive care measures 
for olaratumab IRRs.
8.1.2.2.2. Events of Clinical Interest for Pembrolizumab
Selected non-serious and serious AEs are ECIs for pembrolizumab and must be reported to the 
sponsor. 
ECIs for pembrolizumab are:  
1) an overdose of pembrolizumab that is not associated with clinical symptoms or 
abnormal laboratory values. An overdose will be defined as ≥1000 mg (5 times 
the protocol-specified dose).  No specific information is available on the treatment 
of overdose of pembrolizumab.  In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated.

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2) an elevated AST or ALT laboratory value that is greater than or equal to 3X the 
upper limit of normal (ULN) and an elevated total bilirubin laboratory value that 
is greater than or equal to 2X the ULN, and at the same time, an alkaline 
phosphatase laboratory value that is less than 2X the ULN, as determined by way 
of protocol-specific laboratory testing or unscheduled laboratory testing.
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow-up to an ECI, that occurs to any patient must be reported within 24 hours to the 
sponsor if it causes the patient to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, or procedure.
For the time period beginning at treatment assignment through 30 days following cessation of 
treatment, any ECI or follow-up to an ECI, whether or not related to the sponsor’s product, must 
be reported to the sponsor, either by electronic media or paper.  ECIs that fulfill SAE criteria
must be reported within 24 hours.
8.1.2.3. Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.3.1. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent form (ICF).  For patients who do not 
enroll in the trial (that is, have not received at least 1 dose of any study drug), only AEs and 
SAEs related to protocol procedures are required to be collected. 
8.1.2.3.2. On-Study Treatment
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
to when he/she receives the last dose of study drug.
8.1.2.3.3. Follow-Up Visits
The study includes a 30-day and 90-day safety follow-up period.  The initial follow-up visit 
(Visit 801) begins the day after the patient and the investigator agree that the patient will no 
longer continue study treatment and lasts approximately 30 days (±7 days). The 90-day safety 
follow-up period (Visit 802) begins 1 day after the 30-day safety follow-up period ends and lasts 
approximately 60 days. At the end of the follow-up visit, the patient will be required to have 
safety assessments as outlined in Attachment 1.  All AEs and SAEs, regardless of relatedness to 
study drugs or protocol procedures, occurring during the safety follow-up visits (Visits 801 and 
802) must be reported to Lilly or its designee.
Following the safety assessments, which mark the end of the safety follow-up visit (Visits 801
and 802), if there is an ongoing AE or SAE that is possibly related to study drug, that AE or SAE
should be followed in subsequent follow-up visits (Visit 803-8XX) until the event is resolved, 

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the event is no longer considered to be drug-related, the event becomes stable or returns to 
baseline, a new treatment is initiated for the patient, the patient dies or is lost to follow-up.
After the safety follow-up visit (Visit 802), AEs are not required to be reported unless the 
investigator feels the AEs were related to either study drug or a protocol procedure.  If an 
investigator becomes aware of an SAE believed to be related to protocol procedures or study 
drug, the investigator should report the SAE to the sponsor, and the SAE will be entered in the in 
the Lilly Safety System.
If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
8.1.2.4. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
Development Core Safety Information (DCSI) or in the IB and that the investigator identifies as 
related to study drug or procedure.  The United States 21 CFR 312.32, the European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulatory regulations and the associated detailed guidances.
8.1.2.5. Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JGDQ.7.

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Table JGDQ.7.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JGDQ
Timing
Types of AEs/SAEs Reported 
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of informed 
consent and ends just before the first 
dose of study drug)
Preexisting conditions
All AEs
All SAEs regardless of relatedness 
x
x
x
x
On therapy
[Starts at first dose of study drug(s) 
and ends at last dose of study drug(s)]
All AEs
All SAEs regardless of relatedness
x
x
x
30-day follow-up (Visit 801)
(Starts the day after the patient and the 
investigator agree that the patient will 
no longer continue study treatment and 
lasts approximately 30 days (±7 days).
All AEs
All SAEs regardless of relatedness
x
x
x
90-day follow-up (Visit 802)
(Starts 1 day after the 30-day safety 
follow-up period ends and lasts 
approximately 60 days, at which time 
end-of-study safety assessments are 
completed)
All AEs
All SAEs regardless of relatedness
x
x
x
Subsequent follow-up visits, if 
necessary for patient monitoring 
Ongoing AEs possibly related to 
study drug(s) or protocol procedures
All SAEs related to protocol 
procedures or study drug
x
x
x
Long-term follow-up (Visit 803-8XX)
(Starts the day after the 90-day safety 
follow-up is completed and ends at 
death or entry into continued access 
period)
AEs related to study drug or 
protocol procedure
SAEs related to study drug or 
protocol procedure
x
x
x
Continued access period
All AEs 
All SAEs regardless of relatedness
x
x
x
Continued access period follow-up (30 
days; or sooner if patient begins new 
anticancer therapy)
All AEs 
All SAEs regardless of relatedness
x
x
x
Patient no longer on study
All SAEs related to protocol 
procedures or study drug that the 
investigator becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.

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8.1.3. Other Safety Measures
8.1.3.1. Electrocardiograms
For each patient, a 12-lead digital ECG will be collected locally according to the Study Schedule 
(Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible (ideally while the 
patient is still present) to identify any clinically relevant findings.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation. Any 
clinically significant findings that result in a diagnosis and that occur after the patient receives 
the first dose of study treatment should be reported to Lilly or its designee as an AE via eCRF.
8.1.4. Safety Monitoring
The Lilly CRP/CRS will monitor safety data throughout the course of the study. 
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical research scientist, and periodically review:

trends in safety data,

laboratory analytes,

AEs including monitoring of olaratumab AESI and pembrolizumab ECI (see Section 
8.1.2.2)

If a study patient experiences elevated ALT >5X ULN and elevated total bilirubin >2X 
ULN, clinical and laboratory monitoring should be initiated by the investigator.  For 
patients entering the study with ALT >3X ULN, monitoring should be triggered at ALT 
>2X baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 3).

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8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.  
Attachment 4 lists the schedule of pharmacokinetic, biomarker, pharmacogenetic, and 
immunogenicity samples to be collected in this study.
8.2.1. Samples for Drug Concentration Measurements 
Pharmacokinetics
Pharmacokinetics will be collected as specified in the Pharmacokinetic, Biomarker, and 
Immunogenicity Sampling Schedule (Attachment 4).  Based on the time and dates specified in 
Attachment 4, blood samples will be drawn for all patients for the assessment of olaratumab PK. 
Serum concentrations of olaratumab obtained at different time points will be summarized by 
descriptive statistics and noncompartmental analysis. Additional analysis utilizing the 
population pharmacokinetic approach may also be conducted, if deemed necessary.  
At the visits and times specified in the Pharmacokinetic Sampling Schedule (Attachment 4), 
venous blood samples of approximately 3 mL each will be collected to determine the 
concentrations of olaratumab in serum.  A maximum of 5 samples in addition to those shown in 
Attachment 4 may be collected at additional time points during the study if warranted and agreed 
upon between both the investigator and Lilly. Instructions for the collection and handling of 
blood samples will be provided by the sponsor.  It is preferred that the blood samples be obtained 
from a peripheral access point.  Blood samples can be collected via central access devices, but a 
sample drawn for PK from any type of central catheter cannot be diluted or it will not be viable 
for analysis.  If multiple samples are obtained centrally, the PK sample should be the last 
specimen drawn to reduce the potential for a diluted or improperly drawn sample.  The actual 
date and time (24-hour clock time) of each sampling will be recorded.

I 5 B-M C -J G D Q( c ) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 7 2
L Y 3 0 1 2 2 0 7
T hese s a mples will be a nal yze d at o ne or m or e lab orat or ies desi g nate d b y  t he s p o ns or.  Ser u m 
c o nce ntrati o ns of olarat u ma b will be assa ye d usi n g desi g nate d vali date d e nz y me-li n ke d 
i m m u n os or be nt assa y ( E LI S A) met h o d s.  
T he P K sa m ples will be st ore d at a facilit y desi g nate d b y  t he s p o ns or.  T he re m ai ni n g plas ma or 
ser u m fr om t he sa mples c ollecte d f or P K ma y be p o ol e d a n d use d f or e x pl orat or y meta b o lis m 
w or k as dee me d a p pr o priate.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure olarat u ma b c o nce ntratio n s will be retai ne d f or a 
ma xi m u m o f 1 y e ar fol l owi n g l ast patie nt visit for t he st u d y .
8. 2. 2.
S a m pl e s f or P h ar m a c o g e n eti c s R e s e ar c h
A w h o le bl o o d sa m ple will be c ollecte d f or p har mac o ge netic a nal ysis as s pecifie d i n At tac h me nt 
4 , w here lo c al  r e g ulat i ons all o w.
S a m ples will  not be use d t o c o n d uct u ns pecifie d disease or p o p ulat i on ge net ic researc h eit her 
n o w or i n t he f ut ure.  Sa m ples will be use d t o i n vesti gate varia ble res p o nse t o st u d y treat me nt 
a n d t o i n vesti gate ge netic varia nts t h o u g ht t o pla y a r ole i n sarc o ma.  Assess me nt of varia ble 
res p o nse ma y i ncl u de e val uati on of A Es or differe nces i n efficac y.
All sa m ples will be c o de d wit h t he patie nt n um ber.  T hese sa m ples a n d a n y data ge nerate d ca n 
be li n ke d bac k t o t he patie nt o nl y b y t he st u d y site pers o n nel.  Sa mples will  be retai ne d f or a 
ma xi m u m o f 1 5 y ears after t he last patie nt visit f or t he st u d y, or for a s h orter peri o d if l ocal 
re g ulat i ons a n d / or et hical re vie w b oar ds ( E R Bs) i m p ose s h orter ti me li mit s, at a facility selecte d 
b y Lill y .  T his rete nti o n peri o d e na bles use of ne w tec h n o l ogi es, res p o nse t o q uesti o ns fr o m 
re g ulat or y a ge ncies, a n d i n vesti gati on of varia ble res p o nse t hat ma y n ot be o bs er ve d u nt il later i n 
t he de vel o p me nt of st u d y dr u gs or after st u d y dr u gs bec o me c o m merciall y a vaila ble.
M olec ular tec h n o l ogi es are e x pecte d t o i m pr o ve d uri n g t he 1 5- ye ar st ora ge peri o d a n d t heref ore 
ca n n ot be s pecificall y na me d.  H o we ver, e xisti n g tec h n ol ogi es i ncl u de w h ole ge n o me a n d e x o me 
se q ue nci n g, ge n ome -wi de ass oci at i on st u dies, m ulti ple x assa ys, ca n di date ge ne st u dies, a n d 
e pige net ic a nal yses.  Re gar dless of t he tec h n ol o g y utilize d, data ge nerate d will be use d o nl y f or 
t he s pecific researc h sc o pe des cri be d i n t his sect i on.
8. 2. 3.
S a m pl e s f or P h ar m a c o d y n a mi c s a n d Bi o m ar k er s
C ollect i on of sa m ples f or bi o mar ker researc h is als o part of t his st u d y .  Bl o o d a n d t iss ue sa m ples 
will be c o llecte d.  
Re q ui re d sa m ples f or bio m ar ker researc h t o be c ollecte d fr o m all pat ient s i n t his st u d y are t he 
f oll owi n g:


O pti o nal  sa m ples f or bio m ar ker researc h t hat s h o ul d be c ollecte d fr o m pat ient s i n t he st u d y 
w here p ossi ble are t he f o ll owi n g:
C CI
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
 
S a m ple c ollect i on i ncl u di n g bl o o d a n d t u m or tiss ue will occ ur at s pecifie d t i me p oi nts as 
i n dicate d i n At tac h me nt 4.  
 
 
 
8. 2. 3. 1.
 
 
 
 
 
 
 
 
8. 2. 3. 2.
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
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8. 2. 4.
S a m pl e s f or I m m u n o g e ni cit y R e s e ar c h
I n t he P hase 1a a n d P hase 1 b p orti o n s of  t he trial, bl oo d sa m ples f or i m m u n o ge nicit y testi n g will 
be c o llecte d t o deter mi ne a nti b o d y pr o d ucti o n a gai nst olarat u ma b.  T o i nter pret t he res ults of 
i m m u n o ge nicity,  blo o d s a m ples will be c o llecte d at t he sa me ti me p oi nts as t he bl o o d sa m ples 
desi g nate d t o meas ure t he ser u m c o nce ntrati o ns o f ol ar at u ma b (as n ote d i n At tac h me nt 4).
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In the event of an olaratumab IRR, unscheduled blood samples will be collected for additional 
immunogenicity and PK analysis.  These additional samples will be collected as close as possible 
to the onset of the event, at the point of resolution from the event, and 30 days (± 3 days) after 
onset of the event (as noted in Section 7.5.1.1).
Immunogenicity will be assessed by a validated assay internally developed by Lilly and 
designed to detect ADA in the presence of the olaratumab.  Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of olaratumab.  
Immunogenicity may be further characterized by performing additional related assays.  
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to olaratumab.  
The duration allows the sponsor to respond to regulatory requests related to olaratumab.
8.3.
Efficacy Evaluations
A secondary objective of both the Phase 1a and 1b portions of the study is to assess the following 
efficacy endpoints:

ORR

DCR

DOR

PFS

OS 
ORR, DCR, DOR, and PFS will be assessed according to RECIST v1.1 (Eisenhauer et al. 2009).    
PFS is defined as the time from the date of study enrollment until the date of the first observed 
radiographically documented PD or death due to any cause, whichever comes first.  Overall 
survival, including 1- and 2-year survival rates, is determined from the date of first treatment 
until death due to any cause. 
Patients may continue to be treated with the combination therapy until a confirmed progression is 
documented per irRECIST.  
Following computerized axial tomography (CT) scan or magnetic resonance imaging (MRI) 
during the screening period, investigators will assess tumor response modified for confirmation 
of progression (irRECIST) every 6 weeks (± 5 working days) for up to 24 weeks.  Confirmatory 
scans will be preferably obtained at the next routine scheduled imaging time point (that is, 6 
weeks) and no earlier than 4 weeks later.  After 24 weeks, tumor assessments will be conducted 
every 12 weeks.  Additional radiologic assessments are permissible at the discretion of the 
investigator.  The method of assessment used at baseline should be used consistently for a patient 
throughout the trial. Refer to Attachment 1 for details regarding the timing of specific efficacy 
measures.  

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Immune-Related RECIST (irRECIST)
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  Standard RECIST may not provide an accurate response assessment 
of immunotherapeutic agents such as pembrolizumab (Wolchok et al. 2009).  Therefore, 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics known to 
occur with pembrolizumab treatment (irRECIST) and additionally assessed using these criteria. 
Adaptations for irRECIST are detailed in Attachment 8.
If radiologic imaging verifies initial PD, tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD with the option of continuing study treatment as described below while 
awaiting radiologic confirmation of progression.
If repeat imaging shows <20% increase in target lesion size compared to nadir, stable or 
improved previous new lesion (if identified as cause for initial PD), and stable/improved non-
target disease (if identified as cause for initial PD), treatment may be continued/resumed.
If repeat imaging confirms PD due to any of the scenarios listed below, patients will be 
discontinued from study treatment.  In determining whether or not the tumor burden has 
increased or decreased, the site study team should consider all target lesions as well as non-target 
lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains increased by ≥20% and at least a 5-mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is worse (qualitative)

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation
In patients who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a patient on study treatment until repeat imaging is obtained.  This 
clinical judgment decision should be based on the patient’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Patients may receive study 
treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria:

absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

no decline in ECOG performance status

absence of rapid progression of disease

absence of progressive tumor at critical anatomical sites (for example, cord 
compression) requiring urgent alternative medical intervention

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When feasible, patients should not be discontinued from study treatment until progression is 
confirmed.  This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some patients may have a transient tumor flare in the first few 
months after the start of immunotherapy, but subsequent disease response.  Patients who are 
deemed clinically unstable are not required to have repeat imaging for confirmation of PD.
8.4.
Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from study treatment.
The collection times of safety assessments, pharmacokinetic samples, pharmacodynamic 
samples, and efficacy measurements are given as targets, to be achieved within reasonable limits.  
The scheduled time points may be subject to minor alterations; however, the actual collection 
time must be correctly recorded on the lab requisition form.  
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and pharmacokinetic information obtained during the study.  Any major modifications that might 
affect the conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.

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9. Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
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 evaluate CRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRB/ERBs 
with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
For data handled by a data management third-party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to Lilly’s data 
warehouse, using standard Lilly file transfer processes.
For data handled by the sponsor internally, CRF data and some or all data that are related will be 
managed by the sponsor and stored electronically in the sponsor’s system.
9.2.2. Ancillary Data
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central laboratory’s database system.  Data will subsequently be transferred 
from the central vendor to the Lilly data warehouse.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  

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Data will subsequently be transferred from the central vendor to the Lilly data warehouse.  Data 
from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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10.
Data Analyses
10.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP/CRS, pharmacokineticist, and statistician.  The CRP/CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
10.1.1.Sample Size Determination
In Phase 1a portion of the study, up to approximately 12 patients may be treated and evaluated in 
order to determine the recommended dose of olaratumab for the Phase 1b portion (RP2D). In the
Phase 1b portion, approximately 25 patients will be enrolled.
The primary objective of this study is to confirm the feasibility of the RP2D and to further 
characterize the safety profile at the RP2D.  The secondary objective is to evaluate any 
preliminary efficacy signal. With 6 patients treated at the RP2D in Phase 1a (dose escalation) 
and 25 patients treated at the RP2D in Phase 1b (dose confirmation), a total of 31 patients can 
provide adequate precision for the estimated incidence rate of the following quantities of interest:
(1) patients having a specified AE, or 
(2) patients showing a response (PR/CR) to treatment 
With a total sample size of N=31, the 95% confidence interval (CI) is approximately equal to the 
observed incidence rate (± 15 to 20%). Example point estimates of incidence rates and 
corresponding 2-sided 95% CIs are summarized in Table JGDQ.8. The values are provided as a 
reference for estimation rather than a basis of any decision criteria. The RP2D may be revised 
based on the safety data obtained in Phase 1b (Iasonos and O’Quigley 2013).

I 5 B-M C -J G D Q( c ) P h a s e 1 O n c ol o g y Pr ot o c ol
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T a bl e J G D Q. 8.
E sti m at e d In ci d e n c e R at e a n d It s 2- Si d e d 9 5 % CI
N u m ber of C ases
( N = 3 1)
Est. R ate
9 5 % CI a
L o wer Li mit
U p per Li mit
0
0. 0
0. 0
0. 1 1
5
0. 1 6 
0. 0 5
0. 3 4
1 0
0. 3 2
0. 1 7
0. 5 1
1 5
0. 4 8 
0. 3 0
0. 6 7
2 0
0. 6 5
0. 4 5
0. 8 1
2 5
0. 8 1 
0. 6 3
0. 9 3
A b bre viati o ns:  CI = c o nfi de nce i nter val; Est = esti mate d; N = t otal n u m ber of patie nts.
a
9 5 % Cl o p per -Pears o n i nter val f or bi n o mial distri b uti o n wit h sa m ple size of 3 .
P ati e nts w h o are e nr olle d d uri n g d ose escalat i on b ut disc o nt i n ue treat me nt d uri n g C ycle 1 f or 
reas o ns ot her t ha n treat me nt-relate d A E s ma y be r e place d t o e ns ure t hat e n o u g h patie nts are 
e val ua ble t o deter mi ne t he R P 2 D .
St u d y  J G D Q re q uires (i ncl usi o n cri t erio n [ 7]) t he a vaila bilit y of  s ufficie nt material fr o m arc hi ve d 
t u mor ti ss ue o btai ne d withi n 6 m o nt hs of st u d y  e nr oll me nt (or , if s uc h tiss ue is n ot a vaila ble, a 
ne wl y o btai ne d bi o ps y ).  
 
 
 
 
 
 
 
 
1 0. 1. 2. P o p ul ati o n s f or A n al y s e s
T he f o ll owi n g p o p ul at i ons will be defi ne d f or t his st u d y :
S afet y p o p ul ati o n:   will i ncl u de all e nr olle d patient s w h o recei ve d a n y q ua ntity of  st u d y 
treat me nt, re gar dle ss of t heir eli gi bilit y for t he st u d y .  T he safety e val uat i on will be perf or me d 
base d o n t he first d ose of st u d y  treat me nt a patie nt act uall y recei ve d.  T he safet y p o p ulati o n will  
be use d f or all d osi n g/e x p os ure, safet y, a n d efficac y a nal yses.
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P h ar m ac o ki ne tic p o p ul ati o n:  will i ncl u de all e nr olle d patie nts w h o recei ve d at least 1 d ose of 
st u d y tr e at me nt a n d ha ve at least 1 p ost baseli ne e val ua ble P K sa m ple.
 
1 0. 2. P ati e nt Di s p o siti o n
All patie nt disc o nt i n uati ons will be d oc u me nte d, a n d t he e xte nt of eac h pat ient ’s partici pati on i n 
t he st u d y will be re p orte d.  If k n o w n, a reas o n f or t heir disc o nti n uati o n will be gi ve n.
1 0. 3. P ati e nt C h ar a ct eri sti c s
P ati e nt c haracterist ics will i ncl u de a s u m mar y of t he f oll owi n g:

P ati e nt de mo gra p hics (i ncl u di n g a ge, se x, scree ni n g hei g ht a n d wei g ht, a n d scree ni n g 
b o d y  mass i n de x [B MI ]) will be re p orte d.

Baseli ne disease c haracterist ics

Pri or disease -relate d t hera pies 

C o nc o mita nt me dicat i ons
Ot her patie nt c haracterist ics will be s u m marize d as dee me d a p pr o priate.
1 0. 4. S af et y A n al y s e s
All patie nts w h o recei ve at least 1 d ose of a n y st u d y t hera p y will  be e val uate d f or safet y a n d 
t o xicit y. 
T he Me dical Dicti o na r y for R e g ul at or y Acti vities ( Me d D R A) Versi on 1 6. 1 ( or hi g her) will be 
use d w he n re p orti n g A Es b y Me d D R A ter ms.  T he Me d D R A L o wer Le vel Ter m ( L L T) will be 
use d i n t he treat me nt -e mer ge nt c o mp ut ati o n.  Treat m e nt -e mer ge nt a d verse e ve nts will be 
s u m marize d b y S y st e m Or ga n Class ( S O C) a n d b y decreasi n g fre q ue nc y of Pr eferre d Ter ms
( P T) wit hi n S O C.
S af et y a nal yses will i ncl u de s u m maries of t he f o ll owi n g:

D L Ts at eac h d ose le vel

A E s, i ncl u di n g se verity a n d p ossi ble relat i ons hi p t o st u d y  dr u g

S A E s, i ncl u di n g p ossi ble relati o ns hi p t o st u d y dr u g

A E s lea di n g t o d ose a dj ust me nt s

di sc o nti n uati ons fr o m  st u d y tr e at me nt d ue t o A E s or deat h

treat me nt -e mer ge nt a b n or mal c ha n ges i n la b orat or y val ues

treat me nt-e mer ge nt a b n or mal c ha n ges i n vital si g ns 
1 0. 5. P h ar m a c o ki n eti c A n al y s e s
Se r u m ol ar at u ma b c o nce ntratio ns at differe nt ti me p oi nts will be s u m marize d b y descri pt i ve 
statistics.  A d dit i on al  a nal yses utilizi ng t he p o p ulati o n  p har mac o ki netic a p pr oac h ma y als o be 
c o n d ucte d if dee me d a p pr o priate.
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P K a n d P D data will be a nal yze d wit h a p pr o priate sta n dar d n o nli near a nal yt ic s oftware.  
P har mac o ki net ic para meter esti mates f or ol arat u ma b will be calc ulate d b y  sta n dar d 
n o nc o m part me nt al met h o ds of a nal ysis.
T he pri mar y  para meters f or a nal ysis will be ma xim u m c o nce ntrati o n ( C m a x ) a n d area u n der t he 
c o nce ntrati o n-ti me c ur ve ( A U C[0- tlast], A U C [0- ∞] ) of ol ar at u ma b.  Ot her n o nc o mpart me ntal  
para m eters, s uc h as ti me of half-life (t1/ 2 ), a p pare nt cleara nce ( C L/ F), a n d a p pare nt v ol ume of 
di stri b uti on ( V/ F) ma y be r e p orte d.  A d dit i onal e x pl orat or y a nal yses will be perf or me d if 
warra nte d b y  data a n d ot her vali date d p har mac o ki net ic s oftware pr o gra ms (f or e xa m ple, 
N O N M E M) m a y be use d if a p pr o priate a n d a p pr o ve d b y Glo b al P har mac o ki netic ma na ge me nt.  
T he versi o n o f a n y sof t ware use d f or t he a nal ysis will be d oc u me nte d a n d t he pr o gra m will meet 
t he Lill y re q uire me nts of s oft ware vali dati o n.
1 0. 6.
 
 
 
1 0. 7. I m m u n o g e ni cit y
I mm u n o ge nicit y data will be s u m marize d b y d ose, dr u g c o nce ntrati o ns, a n d t i me fr o m d ose.  If 
warra nte d, e val uat i on of i m m u n o ge nicit y a n d A E s ma y be c o n d ucte d.  A listi n g will be pr o vi de d 
of  all a vaila ble i m m u n o ge nicity data.  A d dit i onall y, a list i n g of i m m u n o ge nicity data fr o m t h ose 
pati e nt s wit h at least o ne p ositive A D A at a n y  ti me p oi nt will be pr o vi de d.  T he fre q ue nc y o f 
pati e nt s wit h at least o ne p ositive A D A assess me nt, a n d fre q ue nc y o f pati e nt s w h o de vel o p A D A 
after a ne gati ve baseli ne assess me nt will be pr o vi de d.  
1 0. 8. Effi c a c y
T he f o ll owi n g e n d p o i nts will be liste d a n d s u m marize d:  in di vi d ual  best o verall res p o nse (B O R )
usi n g R E CI S T versi o n 1. 1 criteria , D O R , P F S, a n d O S .  I n a d diti on, t he f o ll owi n g e n d p oi nts will 
be liste d a n d s u m marize d usi n g i r R E CI S T criteria:  B O R, D O R , a n d P F S b y ir R E CI S T.   Rates 
i ncl u di n g O R R a n d D C R will be c om p ute d a n d t he esti mates will be re p orte d wit h e xact 9 5 % 
CIs.   Ti me -t o-e ve nt varia bles i ncl u di n g P F S, D O R , a n d O S will be a nal y z e d usi n g t he Ka pla n-
Meier m et h o d ( Ka pla n a n d Meier 1 9 5 8). S ur vi val c ur ves will be use d t o s u m mari ze t he data. If 
data are s ufficie ntl y mat ure, m e dia ns will be re p orte d wit h t he 9 5 % CIs. I n a d diti on, f or eac h 
ti me-t o- e ve nt varia ble, s ur vi val rates at a de q uate ti me p oi nts will be re p orte d (f or e xa m ple, 3, 6, 
a n d 1 2 m o nt hs).
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Individual changes in the tumor size over time will be presented graphically using line plots.  
The change in tumor size corresponding to the best response based on target lesions for each 
patient will be represented in waterfall plots by cohort.
10.9. Interim Analyses
Because this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
Phase 1a portion of the study.  The purpose of these cohort-by-cohort reviews is to evaluate the 
safety data at each dose level and determine if a DLT has been observed.  The investigators and 
the Lilly study team will make the determination regarding dose escalation based upon their 
review of the safety and tolerability data as described in this protocol.  
For the Phase 1b portion of the study, 2 interim analyses are planned. The first will occur once 
all patients enrolled in the cohort have completed or had the opportunity to complete
approximately 3 months of treatment; the second will occur once all patients enrolled in the 
cohort have completed or had the opportunity to complete approximately 6 months of treatment. 
The intent of these interim analyses is to evaluate preliminary antitumor activity. The interim 
analyses may also be combined with ongoing trial-level safety review or annual safety review for 
annual safety update reporting. No independent data monitoring committee will be required for 
this study. 
This study will be considered complete (that is, the scientific evaluation will be complete) at a 
date determined by Lilly at least 60 days after the last patient has discontinued treatment with 
pembrolizumab and after all study objectives have been met. Study objectives may be 
considered as met once all enrolled patients having had opportunity for approximately 1 year 
follow-up from date of study enrollment. It is expected that at that time, enough data will have 
been obtained to assess the primary objective and the secondary objectives and allow the creation 
of a clinical study report. For PFS and OS, in the event that that the data are not mature enough 
to characterize the entire survival curve, a landmark analysis at 12 months will be done for the 
purpose of the clinical study report. All data defined in the protocol will continue to be collected 
from patients who remain on treatment in the continued access period.  These data may be 
reported separately and analyses on all patients with these data may not be performed.

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11.
Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  This includes obtaining the appropriate 
signatures and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of study drug. 
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the ICH guideline on GCP.  Documentation of ERB approval of the 
protocol and the ICF must be provided to Lilly before the study may begin at the investigative 
site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling (for example Patient Information Leaflet, Package 
Insert, or Summary of Product Characteristics) and updates during the course of the study

ICF

relevant curricula vitae
11.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
2) the ICH GCP Guideline (E6)
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the sponsor will be assigned to a TPO.

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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LY3012207
An identification code assigned (by the investigator) to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
11.3.1.Investigator Information
Site-specific contact information may be provided in a separate document.
11.3.2.Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
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.
11.3.3.Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report 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.
The investigator with the most analyzable patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

I 5 B-M C -J G D Q( c ) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 8 7
L Y 3 0 1 2 2 0 7
1 2.
R ef er e n c e s
[ A C S] A merica n Ca ncer S ociety.  Sarc o ma: a d ult s oft tiss ue ca ncer. 2 0 1 6. A vaila ble at : 
ht t p:// w w w.ca ncer. or g/acs/ gr o u ps/ci d/ d oc u me nts/ we bc o nte nt/ 0 0 3 1 3 8-p df.  Accesse d A u g ust 
2 2, 2 0 1 6. 
Be n -A mi E , Bar ysa us kas C M , S ol o m o n S , Ta hlil K , Malle y  R, H o h os M , P ols o n K, L o uc ks 
M,
Se ver g ni ni M , Patel  T, C u n ni n g ha m A , R o di g SJ , H o di F S , M or ga n J A , Merria m 
P, Wa g ner AJ , S ha pir o G , Ge or ge S . I m m u n ot hera p y wit h si n gle a ge nt ni v o l uma b f or 
a d va nce d lei om y os arc o ma of  t he uter us: Res ults of a p hase 2 st u d y . C a ncer . 2 0 1 7;
1 2 3( 1 7): 3 2 8 5 -3 2 9 0.
Be n der C, Di mitra k o p o ul o u - Stra uss A, E n k K, Hassel J C. S af et y of  t he P D-1 a nti b o d y  
pe m br o liz u ma b i n patient s wit h hi g h-gra de a d verse e ve nts u n der i pili m u ma b treat me nt . A n n 
O nc ol . 2 0 1 6; 2 7, ( 7):1 3 5 3 – 1 3 5 4.
Ca ncer T hera p y  E val uati on Pr o gra m, C o m m o n Ter mi n o l og y  Crit eria for A d verse E ve nts, 
Versi o n 4. 0, D C T D, N CI, NI H, D H H S. 2 0 0 9. P u blis h date: 2 9 Ma y  2 0 0 9.
C oc kcr oft D W, Ga ult M D. Pre dicti o n of creat i ni ne cleara nce fr om ser u m creati ni ne. Ne p hr o n . 
1 9 7 6; 1 6: 3 1 - 4 1.
C o m a n d o ne A, Petrelli F, B o gli o ne A, Bar ni S. Sal va ge thera p y i n ad va nce d ad ul t sof t tiss ue 
sarc o ma: a syste matic re vie w a n d m et a-a nal ysis of ra n d o mize d trials. O nc ol o gist. 2 0 1 7 . pii: 
t he o nc olo gi st. 2 0 1 6-0 4 7 4.
Da m meijer F, La u S P, va n Eijc k C HJ, va n der B ur g S H, Aerts J GJ V . Rati o nall y  c o m bini n g 
i m m u n ot hera pies t o i m pr o ve efficac y of i m m u ne c hec k p oi nt bloc ka de i n s oli d t u m ors.
Cyt oki ne Gr o wt h F act or Rev. 2 0 1 7 ; 3 6: 5-1 5.
D' A n gel o S P, S h o us htari A N, A gara m N P, K u k D, Qi n L X, Car vajal R D, Dic ks o n M A, 
G o u n der M, Ke o ha n M L, Sc h wartz G K, Ta p W D. Pre vale nce of t u m or -i nfiltrati n g 
l y m p h oc ytes a n d P D-L 1 e x pressi o n i n t he s oft tiss ue sarc o ma micr oe n vir o n me nt. H u m P at h ol . 
2 0 1 5; 4 6( 3): 3 5 7 - 3 6 5.
Eise n ha uer E A, T herasse P, B o gaert s J, Sc h wartz L H, Sar ge nt D, F or d R, Da nce y J, Ar b uc k S, 
G w y t her S, M o o ne y M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pla n R, Lac om be D, Ver weij J. 
Ne w res p o nse e val uat i on cri teria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( versi on 1. 1). 
E ur J C a ncer . 2 0 0 9; 4 5( 2): 2 2 8- 2 4 7.
Fa y A P, M orei ra R B, N u nes Fil h o P R S, Al b u q uer q ue C, Barri os C H. T he ma na ge me nt of 
i m m u ne-r elate d a d verse e ve nts ass ociate d wit h i m m u ne c hec k p o i nt bloc ka de. Ex pert Rev Q u al 
Life C a ncer C are . 2 0 1 6; 1( 1):8 9- 9 7.
Ha mi d O, Ba uer T M, S pira AI, S mit h D C , Olsza ns ki AJ, Tar hi ni A A, Lara P, Gaje ws ki T, 
Wasser J S, Patel S P, B or ges V F, Bal ma n o u kia n A S, Sc h mi dt E V, Z ha o Y, J o nes M M, a n d 
Ga n ga d har T C. Safet y  of e paca d ostat 1 0 0 m g bi d pl us pe m br oliz u ma b 2 0 0 m g Q 3 W i n 
a d va nce d s o li d t u m ors: P hase 2 data fr o m E C H O-2 0 2/ K E Y N O T E -0 3 7. J Cli n O nc ol. 2 0 1 7 
3 5: 1 5 _s u p pl, 3 0 1 2.
H of ma n n L, F orsc h ner A, L o q uai C, G ol di n ger S M, Zi m mer L, U g urel S, Sc h mi d ge n MI, 
G utz m er R, Utik al  J S, G ö p p ner D, Hassel J C, Meier F, Tietze J K, T h o mas I, Weis ha u pt C, 

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Leverkus M, Wahl R, Dietrich U, Garbe C, Kirchberger MC, Eigentler T, Berking C, 
Gesierich A, Krackhardt AM, Schadendorf D, Schuler G, Dummer R, Heinzerling LM.
Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. 
EurJ Cancer. 2016;60:190-209.
Iasonos A, O’Quigley J. Design considerations for dose-expansion cohorts in phase 1 trials.
J Clin Oncol. 2013;31(31):4-14-4021.
In GK, Hu JS, Tseng WW. Treatment of advanced, metastatic soft tissue sarcoma: latest 
evidence and clinical considerations. Ther Adv Med Oncol. 2017;9(8):533-550.
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Kim JR, Moon YJ, Kwon KS, Bae JS, Wagle S, Kim KM, Park HS, Lee H, Moon WS, Chung 
MJ, Kang MJ, Jang KY. Tumor infiltrating PD1-positive lymphocytes and the expression of 
PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One. 2013; 8(12):e82870.
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Corcoran E, Deevi DS, Balderes P, Bassi R, Jimenez X, Joynes CJ, Mangalampalli VR, 
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potential therapeutic target. Mol Cancer Ther. 2005;4(3):369-379.
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sarcomas. Iowa Orthop J. 2006;26:154-158.
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formula for new drugs. J Clin Oncol. 2003;21(14):2633-2635.
Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchok JD.
Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;
26(12):2375-2391.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5:649-
655.
Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, Rosen G.  
Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res. 
2016;6:24.
Pollack SM, He Q, Yearley JH, Emerson R, Vignali M, Zhang Y, Redman MW, Baker 
KK, Cooper S, Donahue B, Loggers ET, Cranmer LD, Spraker MB, Seo YD, Pillarisetty 
VG, Ricciotti RW, Hoch BL, McClanahan TK, Murphy E, Blumenschein WM, Townson 
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programmed cell death protein 1 and programmed death-ligand 1 expression in patients with 
soft tissue sarcomas. Cancer. 2017;123(17):3291-3304.

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Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol 
Educ Book. 2015:76-83.
Raj S, Bui M, Gonzales R, Letson D, Antonia SJ. Impact of PDL-1 expression on clinical 
outcomes in subtypes of sarcoma. Ann Oncol. 2014; 25(suppl 4): Abstract 1421PD.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
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Attachment 1.
Study Schedule

I 5 B-M C -J G D Q( c ) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 1
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) B a s eli n e A s s e s s m e nt s ( P h a s e 1 a a n d P h a s e 1 b)
Rel a ti ve D a y Pri or t o 
D a y 1 of C ycle 1
2 8
1 4
7
I nf or me d co nse nt 
Ra di ol o gical tu m or 
a ssess me nt
X
Me dical h ist or y
X
De m o gra p h y
X
Pri o r treat me nt th e ra pies
X
P h y sical exa m
X
Wei g ht / B S A
X
Vital si g ns 
X
E C O G p er f orma nce 
stat us
X
C o nc o mita nt 
m e dicati o ns
X
E C G 
X
He mat ol o g y 
X
Ser u m ch e mistr y  
X
T h y r oi d f u ncti on tests
X
C oa g ulati o n p r ofile
X
Ur i nal ysis 
X
Pre g na nc y test
X
T u m o r m eas ure me nt 
( pal pa ble or v isi ble)
X
C T C A E v 4. 0 g ra di n g 
( Pree xisti n g co n diti o ns)
X
C CI

I 5 B-M C -J G D Q( c ) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 2
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) B aseli ne Assess me nts ( P h ase 1 a a n d P h ase 1 b)
Rel ati ve D a y Pri or t o 
D a y 1 of C ycle 1
2 8
1 4
7
C o m me nts
A b bre viati o ns:  B S A = b o d y s urface area; C 1 D 1 = C ycle 1, Da y 1; C R P = cli nical researc h p h ysicia n ; C R S = 
cli nical researc h scie ntist; C T = c o m p ute 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; E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc o l o g y Gr o u p; M RI = ma g netic res o na nce 
i ma gi n g; S T S = s oft tiss ue sarc o ma; v = versi o n .
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 3
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) Tr e at m e nt P eri o d a n d P o st s t u d y A s s e s s m e nt s: P h a s e 1 a a n d 1 b
C ycle 1  
C ycle 2  
C ycle 3 - n
F oll o w -U p a
C o m me nts
2 1 -d a y 
c ycle
2 1- d a y 
c ycle
2 1 -d a y 
c ycle
3 0- d a y a n d 9 0 -
d a y S afet y 
F oll o w -U p b
L o n g -
Ter m c
Rel ative D ay 
Wit hi n a Cycle
d
1 
8 
1 
8 
1 
8
Visit 
8 0 1
Visit 
8 0 2
Visit 
8 0 3 -8 X X
Olarat u ma b
X  
X  
X  
X  
X  
X
Pe m br oliz u ma b
X
X
X
P h y sical e xa m
X  
X  
X  
X  
X  
X  
X  
X
Wei g ht / B S A
X
X
X
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 4
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) Tre at me nt Peri o d a n d P ostst u d y Assess me nts:  P h ase 1 a a n d 1 b
C ycle 1  
C ycle 2  
C ycle 3 - n
F oll o w -U p a
C o m me nts
2 1 -d a y 
c ycle
2 1- d a y 
c ycle
2 1 -d a y 
c ycle
3 0- d a y a n d 9 0 -
d a y S afet y 
F oll o w -U p b
L o n g -
Ter m c
Rel ative D ay 
Wit hi n a Cycle
d
1 
8 
1 
8 
1 
8
Visit 
8 0 1
Visit 
8 0 2
Visit 
8 0 3- 8 X X
Vital si g ns 
X  
X  
X  
X  
X  
X  
X  
X
E C O G 
perf or ma nce 
stat us
X
X
X
X  
X
E C G
X
X  
X
He mat ol o g y
X  
X  
X  
X  
X  
X  
X  
X
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 5
L Y 3 0 1 2 2 0 7
Ser u m c he mistr y
X  
X  
X  
X  
X  
X  
X  
X
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 6
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) Tre at me nt Peri o d a n d P ostst u d y Assess me nts: P h ase 1 a a n d 1 b
C ycle 1  
C ycle 2  
C ycle 3 - n
F oll o w -U p a
C o m me nts
2 1 -d a y 
c ycle
2 1- d a y 
c ycle
2 1 -d a y 
c ycle
3 0- d a y a n d 9 0 -
d a y S afet y 
F oll o w -U p b
L o n g -
Ter m c
Rel ative D ay 
Wit hi n a Cycle
d
1 
8 
1 
8 
1 
8
Visit 
8 0 1
Visit 
8 0 2
Visit 
8 0 3- 8 X X
T h y r oi d f u ncti on 
tests
X
X
X  
X
C oa g ulati o n 
pr ofile
X
X
Ur i nal ysis
X
X
Pre g na nc y test
X
X
X
X  
X
C T C A E v 4. 0 
gra di n g
X
X
X  
X  
X  
X
C o nc o mita nt me ds
X
X
X  
X  
X
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 7
L Y 3 0 1 2 2 0 7
P K sa m pli n g 
See 
Attac h me nt 
4 f or 
s pecific 
ti me p oi nts
See 
Attac h me nt 
4 f or 
s pecific ti me 
p o i nts
See 
Attac h me nt 
4 f or 
s pecific ti me 
p oi nts
See 
Attac h
me nt 4
f or 
s pecifi
c ti me 
p oi nts
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 8
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) Tre at me nt Peri o d a n d P ostst u d y Assess me nts:  P h ase 1 a a n d 1 b
C ycle 1  
C ycle 2  
C ycle 3 - n
F oll o w -U p a
C o m me nts
2 1 -d a y 
c ycle
2 1- d a y 
c ycle
2 1 -d a y 
c ycle
3 0- d a y a n d 9 0 -
d a y S afet y 
F oll o w -U p b
L o n g -
Ter m c
Rel ative D ay 
Wit hi n a Cycle
d
1 
8 
1 
8 
1 
8
Visit 
8 0 1
Visit 
8 0 2
Visit 
8 0 3- 8 X X
I m m u n o ge nicit y
See 
Attac h me nt 
4 f or 
s pecific 
ti me p oi nts
See 
Attac h me nt 
4 f or 
s pecific ti me 
p oi nts
See 
Attac h
me nt 4
f or 
s pecifi
c ti me 
p oi nts
P har mac o ge netics 
w h ole bl o o d 
sa m ple
X
T u m o r 
meas ure me nts 
( pal pa ble or 
visi ble )
X
X
X
C CI
C CI

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 9 9
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) Tre at me nt Peri o d a n d P ostst u d y Assess me nts:  P h ase 1 a a n d 1 b
C ycle 1  
C ycle 2  
C ycle 3 - n
F oll o w -U p a
C o m me nts
2 1 -d a y 
c ycle
2 1- d a y 
c ycle
2 1 -d a y 
c ycle
3 0- d a y a n d 9 0 -
d a y S afet y 
F oll o w -U p b
L o n g -
Ter m c
Rel ative D ay 
Wit hi n a Cycle
d
1 
8 
1 
8 
1 
8
Visit 
8 0 1
Visit 
8 0 2
Visit 
8 0 3- 8 X X
Ra di ol o gical 
t u m or assess me nt
X
X  
X  
X
C ollecti o n of 
s ur vi val 
i nf or mati o n
X  
X  
X
C ollecti o n of p ost -
st u d y-treat me nt 
a ntica ncer t hera p y 
i nf or mati o n
X  
X  
X
A b bre viati o ns:  A E = a d verse e ve nt; B P = bl o o d press ure; B S A = b o d y s urface area; C = c ycle; C R F/e C R F = case re p ort f or m/electr o nic case re p ort f or m ; C T = 
c o m p ute 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; 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; hrs = h o urs; I R R = i nf usi o n-relate d reacti o n; ir R E CI S T = i m m u ne-relate d Res p o nse E val uati o n Criteria I n S oli d T u m ors; M RI = ma g netic 
res o na nce i ma gi n g; olara = olarat u ma b; P D = pr o gr essi ve disease; pe m br o = pe m br oliz u ma b; P K = p har mac o ki ne tic; R R = res pirati o n rate; S A Es = seri o us 
a d verse e ve nts.
C CI

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
Page 100
LY3012207
I5B-MC-JGDQ(b) Treatment Period and Poststudy Assessments:  Phase 1a and 1b
a
No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
b
30-day and 90-day Safety follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and 
lasts approximately 90 days (±7 days). The date of this agreement is to be reported on the CRF as the date of discontinuation from study treatment.  Visit 801 
should occur approximately 30 days (±7 days) after the decision to discontinue treatment.  Visit 802 begins 1 day after the 30-day safety follow-up period 
ends and lasts approximately 60 days.  If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to the scheduled end of 
the follow-up visits, the visit duration may be shortened. In this case, the follow-up assessments should be completed prior to the initiation of the new 
therapy.
c
Long-term follow-up (Visits 803-8XX) begins the day after 90-day safety follow-up is completed.  
Follow-up for progression:  Patients that discontinue study treatment for reasons other than progression will be followed every 6 weeks (±7 days) until PD
or initiation of other anticancer therapy.  Additional radiologic assessments are permissible at the discretion of the investigator.
Follow-up for survival:  All patients will be followed every 2 months (±7 days) for the first 2 years, then every 6 months (±14 days) until the patient’s death 
or overall study completion.
d
A window of ±3 days will be permitted due to holidays, weekends, inclement weather or other unforeseen circumstances, including unexpected changes in 
patient schedules, and will not count as a protocol deviation.  In later cycles, longer delays may be allowed in consultation with Lilly medical representative.  

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 0 1
L Y 3 0 1 2 2 0 7
I 5 B-M C -J G D Q ( b) C o nti n u e d A c c e s s P eri o d
C o nti n ue d Access Peri o d a
Visit 5 0 1 -
5 X X
F oll o w -U p 
Visit 9 0 1 b
C o m me nts
2 1 -d a y c ycle
Rel ative D ay wit hi n a 
Cycle c
1 
8
Olarat u ma b
X  
X
D osi n g i nf or mati o n
X
P K sa m pli n g / 
I m m u n o ge nicit y
C T C A E v 4. 0 gra di n g
X
X
A b bre viati o ns :  A E = a d verse e ve nt; 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; e C R F = electr o nic case re p ort f or m; I R R = i nf usi o n -relate d 
reacti o n; P K = p har mac o ki netics; S A E = seri o us a d verse e ve nt.
a
T he c o nti n ue d access peri o d ( Visits 5 0 1-5 X X) be gi ns after st u d y c o m pleti o n a n d e n ds at t he e n d of trial (see Secti o n 6. 2. 1 ). F oll o wi n g st u d y c o m pleti o n, 
patie nts wit h o ut disease pr o gressi o n w h o c o nti n ue t o e x perie nce cli nical be nefit a n d n o u n d ue ris ks ma y c o nti n ue t o recei ve st u d y treat me nt u ntil disease 
pr o gressi o n, deat h, u nacce pta ble t o xicit y, or start of ne w a ntica ncer treat me nt.   D uri n g t his peri o d, i n vesti gat ors ma y perf or m sta n dar d pr oce d ures a n d tests 
n ot s h o w n here as nee de d t o treat a n d e val uate patie nts; h o we ver, Lill y will n ot r o uti nel y c ollect t he res ults of t hese assess me nts.
b
T he c o nti n ue d access f oll o w -u p visit ( Visit 9 0 1) be gi ns 1 da y after t he patie nt a n d t he i n vesti gat or a gree t hat t he patie nt will n o l o n ger c o nti n ue treat me nt i n 
t he c o nti n ue d access peri o d a n d lasts a p pr o xi matel y 3 0 da ys ( ± 7 da ys).  If it is dee me d t o be i n t he best i nterest of t he patie nt t o start a ne w a nti-ca ncer 
treat me nt pri or t o t he sc he d ule d e n d of t he f oll o w-u p visit, t he visit d urati o n ma y be s h orte ne d. I n t his case, t he f oll o w-u p assess me nts s h o ul d be c o m plete d 
pri or t o t he i nitiati o n of t he ne w t hera p y.
c
Dela ys of u p 7 da ys will be per mitte d d ue t o h oli da ys, wee ke n ds, i ncle me nt weat her or ot her u nf oresee n circ u msta nces a n d will n ot c o u nt as a pr ot oc ol 
de viati o n .
C CI

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Attachment 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Sodium
Hematocrit
Magnesium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT/SGPT)
Monocytes
Aspartate aminotransferase (AST/SGOT)
Eosinophils
Blood urea nitrogen
Basophils
Creatinine
Platelets
Uric acid
Calcium
Glucose, random
Coagulationb
Albumin
aPTT
Total protein
PT/INR
Chloride
Bicarbonate
Direct bilirubin
Urinalysisb
Creatinine clearance
Specific gravity
Phosphorus
pH
Lipase
Protein
Glucose
Thyroid Function Testsa
Ketones
T3 (or FT3)
Blood
FT4
Urine leukocyte esterase
Thyroid Stimulating Hormone (TSH)
pH
Serum or Urine Pregnancy Test (females only)b
Abbreviations:  aPTT = activated partial thromboplastin time; FT3 = free triiodothyronine; FT4 = free thyroxine;
PT/INR = international normalized ratio of prothrombin time; RBC = red blood cells; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; T3 = triiodothyronine; WBC = white 
blood cells.
a
Assayed by Lilly-designated central laboratory.
b
Local or investigator-designated laboratory.

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Attachment 3.
Hepatic Monitoring Tests for Treatment 
Emergent Abnormality 
Selected tests may be obtained in the event of a treatment emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = International Normalised Ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

I 5 B-M C -J G D Q( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 0 4
L Y 3 0 1 2 2 0 7
At t a c h m e nt 4.
P h ar m a c o ki n et i c, Bi o m ar k er , 
P h ar m a c o g e n eti c s, a n d I m m u n o g e ni cit y S a m pli n g 
S c h e d ul e s
C CI

I 5 B-M C -J G D Q ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 0 5
L Y 3 0 1 2 2 0 7
C CI

I 5 B-M C -J G D Q ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 0 6
L Y 3 0 1 2 2 0 7
C CI

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Attachment 5.
Recommendations for Reporting 
Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report a SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures.

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Attachment 6.
ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Activity Status
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 performance of a light or sedentary nature, for example,
light housework, office work
2
Ambulatory and capable of all selfcare but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally 
confined to bed or chair
5
Dead
Source:  Oken et al. 1982.

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Attachment 7.
Creatinine Clearance Formula
Note:  This formula is to be used for calculating CrCl from local laboratory results only.  
For serum creatinine 
concentration in mg/dL:
CrCl =
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
a age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.
-OR-
GFR(mL/min/1.73m2) = 170 x [PCr]-0.999 x [age]-0.176
x [0.762 if patient is female] x [1.18 if patient is black]
x [SUN]-0.17 x [Alb]+0.318
PCr= Plasma Creatinine, mg/dL; SUN= Serum urea nitrogen, mg/dL; Alb= Serum albumin, g/dL
Source:  Murray and Ratain 2003

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Attachment 8.
RECIST 1.1 and irRECIST 
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST):  Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009) and by the immune-related Response Evaluation 
Criteria in Solid Tumors (irRECIST).
RECIST 1.1
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis,  inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques to measure bone lesions.

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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.
Cystic lesions:  

Simple cysts should not be considered as malignant lesions (neither measurable 
nor nonmeasurable) 

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated at a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion.  
Baseline Documentation of Target and Non-Target Lesion
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Non-nodal Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements..  
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan.  All measurements are to be recorded in the case record form (CRF) in millimeters (or 
decimal fractions of centimeters [cm]).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as one liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.

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Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.  
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumor type under investigation and the anatomic location of the 
disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm.  When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.  
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following CR or 
surgical resection is an endpoint.

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Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published.  
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD). 
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment.  If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected. 
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
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 (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of one or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.

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Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response. 
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).
Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable:  When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.  
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table ATT.8.1 provides a summary of the overall response status calculation at 
each time point for patients who have measurable disease at baseline.
Table ATT.8.1.
Time Point Response: Patients with Target (Nontarget) Disease
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 all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD 
= stable disease. 

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Table ATT.8.2 is to be used when patients have nonmeasurable disease only.
Table ATT.8.2.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; NE = not evaluable; PD = progressive disease.
a
non-CR/non-PD is preferred over SD for nontarget disease. 
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment.  Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6 to 8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.  
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed.  The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur;  assessment of 
nontargets is not required.  
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from first dose.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 

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progression is observed (taking as reference for PD the smallest measurements recorded on 
study). For any patient who is not known to have died or to have had progression of disease as 
of the data inclusion cut-off date, duration of response will be censored at the date of last 
objective response assessment prior to the date of any subsequent systemic anticancer therapy.  
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).  
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.  

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Immune-related RECIST (irRECIST) Assessment of Disease
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab.  Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses.  The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.  Standard RECIST may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab.  Therefore, RECIST 
1.1 will be adapted to account for the unique tumor response characteristics seen with treatment 
of pembrolizumab (immune-related RECIST [irRECIST]).  irRECIST will be applied as detailed 
below for treatment-related decisions, and the resulting data will be included in the clinical 
database.
If radiologic imaging verifies initial PD, tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD with the option of continuing study treatment per below while awaiting 
radiologic confirmation of progression.
If repeat imaging shows <20% increase in target lesion size compared to nadir, stable or 
improved previous new lesion (if identified as cause for initial PD), and stable/improved non-
target disease (if identified as cause for initial PD), treatment may be continued / resumed.
If repeat imaging confirms PD due to any of the scenarios listed below, patients will be 
discontinued from study treatment.  
In determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains increased ≥ 20% and at least a 5-mm absolute increase compared 
to nadir

Non-target disease resulting in initial PD is worse (qualitative)

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation
In patients who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a patient on study treatment until repeat imaging is obtained.  This 
clinical judgment decision should be based on the patient’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Patients may receive study 
treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria:

absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

no decline in ECOG performance status

absence of rapid progression of disease

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
absence of progressive tumor at critical anatomical sites (for example, cord 
compression) requiring urgent alternative medical intervention
When feasible, patients should not be discontinued from study treatment until progression is 
confirmed.  This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some patients can have a transient tumor flare in the first few 
months after the start of immunotherapy, but with subsequent disease response.  Patients who are 
deemed clinically unstable are not required to have repeat imaging for confirmation of PD.
Table ATT.8.3 summarizes the guidance for imaging and treatment after the first radiologic 
evidence of PD.
Table ATT.8.3.
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging ≥4
weeks later at site 
to confirm PD
May continue 
study treatment at 
the investigator’s 
discretion while 
awaiting 
confirmatory scan
Repeat imaging ≥4 
weeks later to 
confirm PD, per 
investigator 
discretion only
Discontinue 
treatment 
Repeat tumor 
imaging confirms 
PD by irRECIST 
at the local site
No additional 
imaging required 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
sponsor)a
No additional 
imaging requiredb
N/A
Repeat tumor 
imaging shows 
SD, PR, or CR by 
irRECIST at the 
local site
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the 
investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion 
Abbreviations:  CR = complete response; irRECIST = immune-related Response Evaluation Criteria In Solid 
Tumors; N/A = not applicable; PD = progressive disease; PR = partial response; RECIST = Response Evaluation 
Criteria in Solid Tumors; SD = stable disease.
a
If a subject has confirmed radiographic progression (that is, 2 scans at least 4 weeks apart demonstrating 
progressive disease) per irRECIST, but the subject is achieving a clinically meaningful benefit, and there is no 
further increase in the tumor burden at the confirmatory tumor imaging, an exception to continue treatment may be 
considered following consultation with the sponsor. In this case, if treatment is continued, tumor imaging should 
continue to be performed following the intervals outlined in Section 8.3.
b
Patients that are deemed clinically unstable are not required to have repeat tumor imaging for confirmation.

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Attachment 9.
Protocol Amendment I5B-MC-JGDQ(c) 
Summary
Overview
Protocol I5B-MC-JGDQ, An Open-Label, Multicenter, Phase 1a/1b Study of Olaratumab 
(LY3012207) Plus Pembrolizumab (MK3475) in Patients with Unresectable Locally Advanced 
or Metastatic Soft Tissue Sarcoma Who Have Failed Standard Treatments, has been amended.  
The new protocol is indicated by Amendment (c) and will be used to conduct the study in place 
of any preceding version of the protocol.
Lilly has elected to make the following changes to this protocol; these changes are shown in the 
“Revised Protocol Sections” section below:

Added an exclusion criterion for patients that have had an allogenic tissue or solid organ 
transplant, consistent with other pembrolizumab clinical trials (Section 6.1.2).

Added the ability for pembrolizumab to be supplied for the study as an aqueous solution 
in addition to the lyophilized powder formulation (Section 7.1.2).

Updates to the management of pembrolizumab related AEs were added consistent with 
other ongoing pembrolizumab protocols (Table JGDQ.4).  

Clarified data collection requirements intended for the follow-up period (Table JGDQ.6).

Updated the olaratumab premedication instructions (Section 7.2.1.1.1).

Other minor editorial changes were made to add clarity.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.

I 5 B-M C -J G D Q ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 1
L Y 3 0 1 2 2 0 7
1. Pr ot o c ol I 5 B -M C -J G D Q( b c)
…
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 7 O ct o b er 2 0 1 6
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 7 F e b ur ar y F e br u ar y
2 0 1 7.
A m e n d m e nt ( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 3 0 N o v e m b er 2 0 1 7.
A m e n d m e nt ( c) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.
2.
S y n o p si s
…
O bjecti ves:   
…
P h ase 1 a sec o n d ar y o bjecti ves:

T o c haracterize t he p har mac o ki netics ( P K) a n d ( P K) p har mac o d y na mics ( P D) of olarat u ma b w he n 
a d mi nistere d i n c o m bi nati o n wit h pe m br oliz u ma b 
…
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n a n d E xcl usi o ns:
…
E xcl usi o n:
…
[ 2 3]
Ha ve ha d a n all o ge nic tiss ue/s oli d or ga n tra ns pla nt.
…
Criteri a f or E v al u ati o n
…
I m m u n o ge nicit y: Vali date d assa y i nter nall y de vel o pe d b y Lill y a n d desi g ne d t o detect a nti -dr u g a nti b o dies ( A D A) 
i n t he prese nce of olarat u ma b a n d b y e xter nal assa y f or detecti o n of a nti-Galact ose -al p ha -1, 3 -galact ose 
i m m u n o gl o b uli n (I g)E a nti b o dies.
P har mac o ki netics:   Ser u m c o nce ntrati o ns of olarat u ma b o btai ne d at differe nt ti me p oi nts will be s u m marize d b y 
descri pti ve statistics a n d n o nc o m part me ntal a nal ysis.  A d diti o nal a nal ysis utilizi n g t he p o p ulati o n p har mac o ki netic 
P K a p pr oac h ma y als o be c o n d ucte d.
 
 
 
 
 
…
…
C CI
C CI

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4. Abbreviations and Definitions
Term
Definition
…
DP
DS
drug product
drug substance
…
PVC
polyvinyl chloride
…
5. Introduction
5.1. Rationale and Justification for the Study 
…
To date, there has been limited success with the use of immune checkpoint inhibitors in STS.  
Recently, data from several early studies of immune checkpoint inhibitors in STS have shown 
limited benefit to patients: A recent Phase 2 study of nivolumab in uterine leiomyosarcoma had 
no responses among the initial 12 patients (Ben-Ami et al. 2017); a retrospective review of 
nivolumab use in patients with metastatic STS or bone sarcomas showed 3 partial responses
among 28 patients (Paoluzzi et al. 2016); and a study of pembrolizumab in prespecified 
histologic subtypes of STS showed responses varied between subtypes (Tawbi et al. 2017).  In 
this trial (SARC-028) pembrolizumab was studied in patients with bone sarcomas or STS 
evaluated patients with 4 types of STS (leiomyosarcoma, poorly differentiated/de-differentiated 
liposarcomas, undifferentiated pleopmorphic sarcomas [UPS], and synovial sarcomas;
approximately 10 patients per group).  Objective response rate (ORR) of 40% (1 CR and 3 PR in 
10 patients) was observed in the undifferentiated pleomorphic sarcoma subtype.  In the poorly 
differentiated/dedifferentiated liposarcoma and synovial sarcoma groups, 2 and 1 PRs, 
respectively, were observed (N=10 for both groups).  In the leiomyosarcoma group, 0 of 10 
patients achieved a PR or better (Tawbi et al. 2017).  .
…
5.1.3. Rationale For Amendment (c)
Protocol Amendment (c) for Study JGDQ adds the ability for pembrolizumab to be supplied for 
the study as an aqueous solution in addition to the lyophilized powder formulation.  
The amendment also adds an exclusion criterion for patients that have had an allogenic tissue or 
solid organ transplant, consistent with other pembrolizumab clinical trials. Moreover, it clarifies 
data collection requirements intended for the follow-up period.
Amendment (c) also includes an update to the olaratumab premedication instructions.  

I 5 B-M C -J G D Q ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 3
L Y 3 0 1 2 2 0 7
Mi n or e di t orial c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol t o i m pr o ve clarit y a n d 
practi ca bilit y of t he pr ot oc ol, sec ure ali g n me nt wit h t he i nte n de d st u d y desi g n, a n d u p date 
i nf or mat i on a vaila ble f or st u d y  dr u gs.  
…
5. 2. O bj e cti v e s
…
…
6. I n v e sti g ati o n al Pl a n
…
6. 1. St u d y  P o p ul ati o n
…
6. 1. 2. E x cl u si o n Crit eri a
…
[ 1 9]
Ha ve recei ve d tra nsf usi o n of bl o o d pr o d ucts (i ncl u di n g platelets or re d bl o o d 
cells) or a d mi nistrati o n of c ol o n y st i m ulati n g fact ors (i ncl u di n g gra n ul oc y t e 
c olo n y st i m ulati n g fact ors [ G-C S F ], G M-C S F or rec o m bi na nt 
er yt hr o p oeti ner yt hr o p oiet i n) wit hi n 2 wee ks pri or t o st u d y D a y 1.
…
[ 2 3]
Ha sve ha d a n all o ge nic tiss ue/s oli d or ga n tra ns pla nt.
…
7. Tr e at m e nt
7. 1. M at eri al s a n d S u p pli e s 
7. 1. 1. Ol ar at u m a b
Ol ar at u ma b will be s u p plie d as a sterile preser vat i ve-free s ol uti on f or I V i nf usi on i n si n gle-use 
vials c o ntai ni n g 5 0 0 m g/ 5 0 m L of olarat u ma b ( 1 0 m g/ m L).  Olarat u ma b is f or m ulate d i n 1 0 -m M 
C CI

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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histidine, 100-mM glycine, 50-mM sodium chloride, 75-mM mannitol, and 0.02% polysorbate-
20, pH 5.5.  All excipients used in the formulation of olaratumab drug product (DP) are of 
pharmacopeial grade. 
The drug productDP must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) with 
protection from direct light.  Do not freeze and/or shake olaratumab drug productDP.  Stability 
studies have demonstrated that the drug productDP can withstand transient excursion to room 
temperature without adverse effect; however, storage at this temperature is not recommended.
…
7.1.2. Pembrolizumab
The drug product pembrolizumab will be supplied Two DP dosage forms are available for 
pembrolizumab: a white to off white lyophilized powder, 50 mg/vial, and a liquid, 100 mg/vial, 
both in Type I glass vials intended for single use only.

Pembrolizumab Powder for Solution for Infusion, 50 mg/vial is a lyophilized powder that 
is reconstituted with sterile water for injection prior to use. It is manufactured using either 
the fully formulated drug substance (DS) or the partially formulated DS. The fully 
formulated DS uses L histidine as a buffering agent, polysorbate 80 as surfactant, and 
sucrose as stabilizer/tonicity modifier. Pembrolizumab DP using the partially formulated 
DS is formulated with L histidine as a buffering agent, polysorbate 80 as a surfactant, and 
sucrose as a stabilizer/tonicity modifier and may contain hydrochloric acid and/or sodium 
hydroxide for pH adjustment (if necessary).

Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP (manufactured using the 
fully formulated DS with L histidine as a buffering agent, polysorbate 80 as a surfactant, 
and sucrose as a stabilizer/tonicity modifier).
Both DP dosage forms are stored under refrigerated conditions (2°C to 8°C).
The lyophilized DP after reconstitution with sterile water for injection and the liquid DP are clear 
to opalescent solutions, essentially free of visible particles. The reconstituted lyophilized product 
and the liquid product are intended for IV administration. The reconstituted DP solution or the 
liquid DP can be further diluted with normal saline or 5% dextrose in the concentration range of 
1 to 10 mg/mL in IV containers made of polyvinyl chloride (PVC) or non PVC material. 
Reconstituted vials should be used immediately to prepare the infusion solution in the IV bag, 
and the infusion solution should be administered immediately. If the diluted pembrolizumab 
solution is not used immediately, it may be stored for no more than 24 hours at 2°C to 8°C. This 
24 hour total hold from reconstitution may include up to 6 hours at room temperature (at or 
below 25°C). Any additional hold time must be at 2°C to 8°C. If refrigerated, the vials and/or IV 
bags must be allowed to come to room temperature prior to use. 
The recommended dose of pembrolizumab in adults is 200 mg administered as an IV infusion 
over 30 minutes Q3W.as aA sterile, non-pyrogenic lyophilized powder for IV infusion in single-
use Type I glass vials containing 50 mg of pembrolizumab.  The product is preservative-free, 
white to off-white powder and free from visible foreign matter.  The pembrolizumab powder 

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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should be reconstituted with 2.3-mL sterile water for injection (SWFI; injected along the walls of 
the vial and not directly on the powder)  to yield a 2.4-mL solution containing 25 mg/mL of 
pembrolizumab. 
The drug product must be stored under refrigerated condition 2°C to 8°C (36°F to 46°F).  Prior 
to reconstitution, the vial of lyophilized powder can be out of refrigeration (temperatures at or 
below 25°C [77°F]) for up to 24 hours. Aa -
Following reconstitution with SWFI, pembrolizumab  infusion solutions should be prepared in 
0.9% Sodium Chloride Injection, USP (normal saline) or regional equivalent and the final 
concentration of pembrolizumab in the infusion solution should be between 1 mg/mL and 10 
mg/mL.  If normal saline is not available, 5% Dextrose Injection, USP or regional equivalent 
(5% dextrose) is permissible.  The preferred diluent is 0.9% Sodium Chloride and 5% dextrose is 
only permissible if normal saline is not available.
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 
hours.  This includes room temperature storage of reconstituted drug product solution in vials, 
room temperature storage of admixture solutions in the IV bags and the duration of infusion.  In 
addition, reconstituted vials and/or IV bags may be stored under refrigeration at 2 °C to 8 °C (36 
°F to 46 °F) for up to 20 hours.  If refrigerated, allow the vials and/or IV bags to come to room 
temperature prior to use.  
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration.  Discard the drug product vial if discoloration or extraneous particulate 
matter (other than translucent to white proteinaceous particles) is observed.
Sites should follow their SOPs for drug transport and delivery, with all possible effort to 
minimize agitation of the reconstituted and diluted drug product between the pharmacy and the 
clinic
Do not shake or freeze pembrolizumab vial(s).  Do not administer the product as an IV 
bolus.  Do not combine, dilute, or administer pembrolizumab as an infusion with other 
medicinal products.  Do not coadminister other drugs through the same infusion line.
7.2. Study Drug Administration
…
7.2.1. Dosing Schedule
…
7.2.1.1. Olaratumab
Olaratumab will be administered as an approximately 60 (± 5) minute IV infusion on Day 1 and 
Day 8 of a 21-day cycle at the doses shown in Table JGDQ.2.  Certain exceptionsExceptions to 
the 60-minute duration of the olaratumab infusion are permitted; see Pharmacy Manual for more 
information.  

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7.2.1.1.1. Olaratumab Premedication
On Day 1 of each cycle, olaratumab should be administered prior to pembrolizumab.  
Premedicate all patients with the following (or equivalent) medications:  a histamine H1 
antagonist (for example, diphenhydramine) and dexamethasone intravenously 30 to 60 minutes 
prior to the olaratumab doses on Days 1 and 8 of Cycle 1.  For subsequent cycles, premedicate 
all patients with a histamine H1 antagonist (for example, diphenhydramine) intravenously 30 to 
60 minutes prior to each dose of olaratumab.  
Premedicate patients prior to administration of olaratumab as below:

Premedication in Cycle 1:
Premedication is mandatory for all patients during Cycle 1 prior to each dose of 
olaratumab.  Premedicate all patients with the following (or equivalent) medications on 
Days 1 and 8 of Cycle 1: 
o
Histamine H1 antagonist (for example, diphenhydramine) 
o
Dexamethasone IV

Premedication in Cycles 2-n:
For subsequent cycles, premedication with a histamine H1 antagonist (for example, 
diphenhydramine) is recommended prior to each dose of olaratumab 
…
7.2.1.2. Pembrolizumab
…
7.2.4. Dose Adjustments and Delays
…
7.2.4.2. Pembrolizumab
…
Table JGDQ.4.
Dose Modification and Toxicity Management Guidelines for Immune
Related AEs Associated with Pembrolizumab
…

I5B-MC-JGDQ(c) Phase 1 Oncology Protocol
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Hypophysitis
Grade 2
Withhold
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.  
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyroinine) 
per standard of care
Monitor for signs and symptoms of thyroid 
disorders. 
…
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  

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…
7.5. Concomitant Therapy 
…
7.5.1. Supportive Care Guidelines for Olaratumab 
7.5.1.1. Infusion-Related Reactions
…
An approximately 1-hour observation period is required after the administration of olaratumab 
during the first and second cycles of olaratumab.  Patients should complete the olaratumab 
observation period prior to starting pembrolizumab (when applicable). If there is no evidence of 
an IRR during the initial 2 cycles of olaratumab, then no observation period is required for 
subsequent treatment cycles.  In the event an IRR occurs thereafter, the 1-hour observation 
should be reinstituted.  During the observation period, patients treated with olaratumab should be 
closely monitored for signs and symptoms indicative of an infusion reaction by the medical staff 
from the start of the infusion until at least 1 hour after the end of the infusion in an area where 
emergency medical resuscitation equipment and other agents (epinephrine, prednisolone 
equivalents, etc.) are available.
…
7.5.2. Supportive Care Guidelines for Pembrolizumab
…
7.5.2.8. Pembrolizumab Infusion-Related Reactions
…
Table JGDQ.6.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤24 hrs.
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics
Increase monitoring of vital signs as 
Patient may be premedicated 
1.5 hr (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).

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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (for example, from 100 mL/hr to 50 
mL/hr).  Otherwise, dosing will be held 
until symptoms resolve and the patient 
should be premedicated for the next 
scheduled dose.
Patients who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).
…
Attachment 1. Study Schedule
…
I5B-MC-JGDQ(b) Treatment Period and Poststudy Assessments:  Phase 1a and 1b
…
c
Long-term follow-up (Visits 803-8XX) begins the day after 90-day safety follow-up is completed.  
Follow-up for progression:  Patients that discontinue study treatment for reasons other than progression will be 
followed every 6 weeks (±7 days) until PD or initiation of other anticancer therapy.  Additional radiologic 
assessments are permissible at the discretion of the investigator.
Follow-up for survival:  All Patients patients will be followed every 2 months (±7 days) for the first 2 years, 
then every 6 months (±14 days) until the patient’s death or overall study completion.
…

A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 8 - S e p - 2 0 1 8  1 8 : 2 4 : 3 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 9 - S e p - 2 0 1 8  1 1 : 1 6 : 3 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D
P P D