An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination With Radiotherapy in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: EMD Serono Research & Development Institute, Inc.



M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 1 4 9
s u bsi diar y. C o p yri g ht © 2 0 1 9 b y  Merc k KG a A, Dar msta dt, Ger ma n y, or its s u bsi diar y. All ri g hts 
reser ve d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 4 9
Pr ot oc ol T a ble of C o nte nts
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 3
Ta ble of I n -Te xt Ta bles ....................................................................................................... 8
Ta ble of I n -Te xt Fi g ures ...................................................................................................... 8
List of A b bre viati o ns ........................................................................................................... 9
1
S y n o psis ..............................................................................................1 4
2
S p o ns or, I n vesti gat ors a n d Trial A d mi nistrati ve Str uct ure ................ 5 6
2. 1
I n vesti gati o nal Sites............................................................................ 5 6
2. 2
C o or di nati n g I n vesti gat or ................................................................... 5 6
2. 3
K e y  Parties a n d Ser vice Pr o vi ders...................................................... 5 7
2. 4
Trial C o or di nati o n/ M o nit ori n g ........................................................... 5 7
2. 5
Safet y  M o nit ori n g C o m mittee............................................................ 5 8
3
Bac k gr o u n d I nf or mati o n ..................................................................... 5 8
............. 5 9
............. 5 9
3. 1. 2
F or m ulati o n De vel o p me nt .................................................................. 6 0
3. 2
Trial P o p ulati o n .................................................................................. 6 1
3. 3
Rati o nale f or Trial Desi g n a n d J ustificati o n of Starti n g D ose ............ 6 1
.............................. 6 2
3. 4
Rati o nale f or Ra di ot hera p y  D ose........................................................ 6 3
3. 5
Rati o nale f or Cis plati n D ose ...............................................................6 3
3. 6
K n o w n a n d P ote ntial Ris ks a n d Be nefits t o H u ma n S u bjects ............ 6 3
4
Trial O bjecti ves .................................................................................. 6 4
4. 1
Pri mar y O bjecti ves ............................................................................. 6 4
4. 2
Sec o n dar y  O bjecti ves ......................................................................... 6 4
........................................................ 6 5
5
I n vesti gati o nal Pla n ............................................................................ 6 6
5. 1
O verall Trial Desi g n a n d Pla n ............................................................ 6 6
5. 1. 1
D ose Escalati o n R ules ........................................................................7 1
5. 1. 2
Ta blet F or m ulati o n I ntr o d ucti o n, E val uati o n, a n d S M C Decisi o n 
Ma ki n g ................................................................................................7 4
5. 2
Disc ussi o n of Trial Desi g n ................................................................. 7 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 1 4 9
5. 2. 1
I ncl usi o n of S pecial P o p ulati o ns ................................ ........................7 6
5. 3
Selecti o n of Trial P o p ulati o n ..............................................................7 6
5. 3. 1
I ncl usi o n Criteria ................................................................................ 7 6
5. 3. 2
E xcl usi o n Criteria ............................................................................... 7 8
5. 4
Criteria f or I nitiati o n of Trial Treat me nt ............................................ 8 0
5. 5
Criteria f or S u bject Wit h dra wal .......................................................... 8 0
5. 5. 1
Wit h dra wal fr o m Trial T hera p y.......................................................... 8 0
5. 5. 2
Wit h dra wal fr o m t he Trial .................................................................. 8 1
5. 6
Pre mat ure Ter mi nati o n of t he Trial .................................................... 8 1
5. 7
Defi niti o n of E n d of Trial ................................................................... 8 2
6
I n vesti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he 
Trial ..................................................................................................... 8 2
6. 1
Descri pti o n of t he I n vesti gati o nal Me dici nal Pr o d uct ........................ 8 2
6. 2
Descri pti o n of C o nc urre n t C he m ot hera py .......................................... 8 2
6. 3
D osa ge a n d A d mi nistrati o n ................................................................ 8 3
6. 3. 1
P hase Ia a n d I b Parts........................................................................... 8 3
6. 3. 2
A ncillar y  c P o P Part............................................................................. 8 8
6. 4
Assi g n me nt t o Treat me nt Gr o u ps ....................................................... 8 9
6. 5
N o ni n vesti gati o nal Me dici nal Pr o d ucts t o be Use d ............................ 8 9
6. 6
C o nc o mita nt Me dicati o ns a n d T hera pies ........................................... 8 9
6. 6. 1
Per mitte d Me dici nes ........................................................................... 8 9
6. 6. 2
Pr o hi bite d Me dici nes .......................................................................... 8 9
6. 6. 3
Ot her I nter ve nti o ns ............................................................................. 9 0
6. 6. 4
S pecial Preca uti o ns ............................................................................. 9 1
6. 6. 5
Ma na ge me nt of S pecific A d verse E ve nts or A d verse Dr u g 
Reacti o ns .............................................................................................9 1
6. 7
Pac ka gi n g a n d La beli n g of t he I n vesti gati o nal Me dici nal Pr o d uct .... 9 2
6. 8
Pre parati o n, Ha n dli n g, a n d St ora ge of t he I n vesti gati o nal 
Me dici nal Pr o d uct ...............................................................................9 2
6. 9
I n vesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y ............................. 9 2
6. 1 0
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce .........9 3
6. 1 1
Bli n di n g................................ ..............................................................9 3
6. 1 2
E mer ge nc y  U n bli n di n g.......................................................................9 4
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 1 4 9
6. 1 3
Treat me nt of O ver d ose .......................................................................9 4
6. 1 4
Me dical Care of S u bjects after E n d of Trial ....................................... 9 4
7
Trial Pr oce d ures a n d Assess me nts ...................................................... 9 4
7. 1
Sc he d ule of Assess me nts .................................................................... 9 4
7. 1. 1
Scree ni n g Peri o d ( Da y  -2 1 t o Da y  - 1)................................................ 9 4
7. 1. 2
Treat me nt Peri o d ................................................................................ 9 5
7. 1. 3
F oll o w -u p Peri o d ................................................................................ 9 9
7. 1. 4
Disc o nti n uati o n/ E n d of Trial ............................................................ 1 0 2
7. 2
De m o gra p hic a n d Ot her Baseli ne C haracteristics ............................ 1 0 2
7. 2. 1
De m o gra p hic Data ............................................................................ 1 0 3
7. 2. 2
T u m or Hist or y .................................................................................. 1 0 3
7. 2. 3
Me dical Hist or y  a n d Pre vi o us a n d C o nc o mita nt Me dicati o n........... 1 0 3
7. 2. 4
Vital Si g ns a n d P h y sical E xa mi nati o n.............................................. 1 0 3
7. 2. 5
C T or Ma g netic Res o na nce I ma gi n g Sca ns f or T u m or Assess me nt 1 0 4
7. 2. 6
Car diac Assess me nts ........................................................................ 1 0 4
7. 2. 7
Cli nical L a b orat or y Tests ................................................................. 1 0 4
7. 3
Efficac y  Assess me nts ....................................................................... 1 0 4
7. 3. 1
T u m or Res p o nse Assess me nt ........................................................... 1 0 4
7. 4
Assess me nt of Safet y ........................................................................ 1 0 5
7. 4. 1
A d verse E ve nts ................................................................................. 1 0 5
7. 4. 2
Pre g na nc y  a n d I n Uter o Dr u g E x p os ure........................................... 1 1 2
7. 4. 3
Cli nical L a b orat or y Assess me nts ..................................................... 1 1 2
7. 4. 4
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts........... 1 1 4
7. 5
P har mac o ki netics .............................................................................. 1 1 4
7. 5. 1
Sa m ple C ollecti o n .............................................................................1 1 4
7. 5. 2
P har mac o ki netic Calc ulati o ns ................................ ..........................1 1 5
.......................................................... 1 1 6
..........................................................1 1 6
..........................................................1 1 7
7. 7
Ot her Assess me nts ............................................................................1 1 8
8
Statistics ............................................................................................1 1 8
.................................................................................1 1 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 1 4 9
8. 2
Ra n d o mizati o n ..................................................................................1 2 1
8. 3
E n d p oi nts .......................................................................................... 1 2 1
8. 3. 1
Pri mar y  E n d p oi nts............................................................................ 1 2 1
8. 3. 2
Sec o n dar y  E n d p oi nts........................................................................ 1 2 2
...............................................................1 2 2
8. 4
A nal y sis Sets..................................................................................... 1 2 3
8. 5
Descri pti o n of Statistical A nal y ses ................................................... 1 2 4
8. 5. 1
Ge neral C o nsi derati o ns ..................................................................... 1 2 4
8. 5. 2
A nal y sis of Pri mar y E n d p oi nts......................................................... 1 2 5
8. 5. 3
A nal y sis of Sec o n dar y E n d p oi nts..................................................... 1 2 5
8. 5. 4
A nal y sis of Safety a n d Ot her E n d p oi nts ........................................... 1 2 6
..................................................... 1 2 7
8. 6
I nteri m A nalys is................................................................................ 1 2 7
9
Et hi cal a n d Re g ulat or y As pects ........................................................ 1 2 7
9. 1
Res p o nsi bilities of t he I n vesti gat or .................................................. 1 2 7
9. 2
S u bject I nf or mati o n a n d I nf or me d C o nse nt ..................................... 1 2 8
9. 3
S u bject I de ntificati o n a n d Pri vac y .................................................... 1 2 9
9. 4
E mer ge nc y  Me dical S u p p ort a n d S u bject Car d................................ 1 2 9
9. 5
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects ................... 1 3 0
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o nal Re vie w B oar d ........ 1 3 0
9. 7
Healt h A ut h orities ............................................................................. 1 3 0
1 0
Trial Ma na ge me nt ............................................................................. 1 3 0
1 0. 1
Case Re p ort F or m Ha n dli n g .............................................................1 3 0
1 0. 2
S o urce Data a n d S u bject Files .......................................................... 1 3 1
1 0. 3
I n vesti gat or Site File a n d Arc hi vi n g................................................. 1 3 1
1 0. 4
M o nit ori n g, Q ualit y Ass ura nce a n d I ns pecti o n b y Healt h 
A ut h orities ........................................................................................ 1 3 2
1 0. 5
C ha n ges t o t he Cli nical Trial Pr ot oc ol .............................................. 1 3 2
1 0. 6
Cli nical Trial Re p ort a n d P u blicati o n P olic y .................................... 1 3 2
1 0. 6. 1
Cli nical Trial Re p ort .........................................................................1 3 2
1 0. 6. 2
P u blicati o n ........................................................................................1 3 3
1 1
Refere nces Cite d i n t he Te xt .............................................................1 3 4
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 4 9
1 2
A p pe n dices .......................................................................................1 3 5
A p pe n di x A:
Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he Trial.................... 1 3 5
Si g nat ure Pa ge – Pr ot oc ol L ea d ....................................................................................... 1 3 6
Si g nat ure Pa ge – C o or di nati n g I n vesti gat or.................................................................... 1 3 7
Si g nat ure Pa ge – Pri nci pal I n vesti gat or ........................................................................... 1 3 8
S p o ns or Res p o nsi ble Pers o ns n ot Na me d o n t he C o ver Pa ge ......................................... 1 3 9
A p pe n di x B:
Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T v 1. 1) ....... 1 4 0
...................................................................... 1 4 5
A p pe n di x D:
O utli ne of I nte nsit y -m o d ulate d Ra di ot hera p y .................................. 1 4 7
A p pe n di x E:
C o ntrace pti ve G ui da nce a n d W o me n of C hil d beari n g P ote ntial ...... 1 4 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 1 4 9
T a ble of I n-Te xt T a bles
Ta ble 1 
Sc he d ule of Assess me nts – P hase Ia ( Ar m A): Ca ps ule C o h orts....... 2 7
Ta ble 2
Sc he d ule of Assess me nts – P hase Ia ( Ar m A): Ta blet C o h orts.......... 3 1
Ta ble 3
Sc he d ule of Assess me nts – First 3 S u bjects i n P hase I b ( Ar m A; 
N S C L C C o h ort) .................................................................................. 3 6
Ta ble 4
Sc he d ule of Assess me nts – P hase I b ( Ar m A; N S C L C C o h ort) ........ 4 0
Ta ble 5
Sc he d ule of Assess me nts – P hase Ia ( Ar m B; S C C H N C o h ort) ........ 4 3
Ta ble 6
Sc he d ule of Assess me nts – P hase I b ( Ar m B; S C C H N C o h ort) ........ 4 7
Ta ble 7
Sc he d ule of Assess me nts – A ncillar y  Cli nical Pr o of-of- Pri nci ple 
Part ...................................................................................................... 5 1
Ta ble 8
Ra di ot hera p y ( Al o ne) a n d M 3 8 1 4 + R T Sc he d ule f or t he 
A ncillar y  Cli nical Pr o of-of- Pri nci ple (c P o P) Part of t he Trial ........... 5 4
Ta ble 9
P har mac o ki netic a n d 
 Sa m pli n g Sc he d ule of 
M 3 8 1 4 d uri n g P hase
Ia, P hase I b, a n d t he A ncillar y c P o P Part of 
t he Trial...............................................................................................5 5
Ta ble 1 0
Trial A d mi nistrati ve Str uct ure ............................................................ 5 7
..6 2
Ta ble 1 2
D oses of M 3 8 1 4 i n t he A ncillar y  c P o P Part of t he Trial.................... 7 3
Ta ble 1 3
D ose M o dificati o ns f or M 3 8 1 4, Ra di ot hera p y, a n d Cis plati n 
D uri n g t he Trial ..................................................................................8 5
Ta ble 1 4
Pre d osi n g C o nsi derati o ns f or Cis plati n .............................................. 8 8
Ta ble 1 5
Re q uire d La b orat or y  Safet y Tests.................................................... 1 1 3
T a ble of I n-Te xt Fi g ures
Fi g ure 1
O ver vie w of Trial Desi g n wit h 5 Se g me nts ....................................... 6 7
Fi g ure 2
Sc he matic of Trial Desi g n .................................................................. 6 8
Fi g ure 3
Treat me nt O ver vie w ( P hase Ia Ar m A) .............................................. 6 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 4 9
List of A b bre vi ati o ns
A D M E
A bs or pti o n, distri b uti o n, meta b olis m, a n d eli mi nati o n
A E
A d verse eve nt
A D R
A d verse dr u g reacti o n
A L L 
All su bjects (a nal ys is set)
A L T
Ala ni ne a mi n otra nsferase
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
A U C 0- ∞
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o e xtra p olate d t o i nfi nit y
A U C 0-t
Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n
A U C τ
Area u n der t he c o nce ntrati o n-ti me c ur ve o ver t he d osi n g i nter val after m ulti ple 
d osi n g
B C R P
Breast ca ncer resista nce pr otei n
BI D
T wice dail y
B S A
B o d y s urface area
CI
C o nfi de nce i nter val
C L /f
Oral cleara nce
C L ss/f
Oral cleara nce at stea d y s tate
C N S
Ce ntral ner v o us s ys te m
c P o P
Cli nical p r o of-of- p ri nci ple
C R O
C o ntract researc h o r ga nizati o n
C R T
C he m ora di ot hera p y
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 eve nts
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 4 9
ct D N A
Circ ulati n g t u m or D N A
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
C Y P
C y t oc hr o me P 4 5 0
D E
D ose escalati o n (a nal ys is set)
D L T
D ose li miti n g t o xicit y
D N A -P K
De o x yri b o n ucleic aci d -de pe n de nt pr otei n ki nase
D S B
D o u ble- stra n d brea k
E C G
E lectr ocar di o gra m
E C O G P S
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 R F
Electr o nic case re p ort f or m
E O T
E n d of trial
E T T
Earl y treat me nt ter mi nati o n
F A S
F ull a nal ys is set
F D
Fracti o n d a y
FI M
First -i n-ma n
F T
Fee di n g t u be
F U
F oll o w -u p
F/ W
Fracti o ns per wee k
G C P
G o o d cli nical practice
G -C S F
Gra n ul oc y te-c ol o n y sti m ulati n g fact or
G y
Gra y  ( deri ve d u nit of i o nizi n g ra diati o n d ose)
H B V
He patitis B vir us
H C G
H u ma n c h ori o nic g o na d otr o pi n
H C V
He patitis C vir us
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 4 9
P K
P har mac o ki netic (s)
P PI
Pr ot o n p u m p i n hi bit or
P T D
P ost -treat me nt d a y
Q D
O nce dail y
Q Tc F
Fri dericia -c orrecte d Q T i nter val
R acc( A U C)
Acc u m ulati o n rati o f or area u n der t he c o nce ntrati o n-ti me c ur ve
R acc( C ma x)
Acc u m ulati o n rati o f or ma xi m u m c o nce ntrati o n
R E CI S T
Res p o nse eval uati o n criteria i n soli d tu m ors
R P 2 D
Rec o m me n de d P hase II d ose
R T
Ra di ot hera p y
S A E
Seri o us a d verse eve nt
S A F
Safet y  anal ys is set
S A P
Statistical anal y sis p la n
S C C H N
S q ua m o us cell carci n o ma hea d a n d nec k
S D
Sta n dar d de viati o n
S M C
Safet y  Mo nit ori n g C o m mittee 
S m P C
S u m mar y  of pr o d uct c haracteristics
S o C
Sta n dar d of C are
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2
A p pare nt ter mi nal half -life
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
tma x
Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n
U L N
U p per li mit of n or mal
U S A
U nite d States of A merica
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 4 9
V z/f
A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase
V ss/f
A p pare nt v ol u me of distri b uti o n at stea d y state
W O C B P  
W o ma n of c hil d beari n g p ote ntial
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 4 9
o
( Ar m B) T o deter mi ne t he M T D a n d a R P 2 D f or M 3 8 1 4
i n c o m bi nati o n wit h
c urati vel y i nte n de d c he m ora di ot hera p y ( C R T: 2 G y x 3 3 t o 3 5; 5 F/ W wit h 
c o nc urre nt cis plati n ) i n treat me nt-naï ve s u bjects wit h l ocal/l ocall y a d va nce d 
S C C H N .

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
( Ar m A) T o e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h 
fracti o nate d R T ( 2 G y  x 33 ; 5 F/ W) i n treat me nt-naï ve s u bjects wit h S ta ge III A/ B 
n o n- s mall cell l u n g ca ncer ( N S C LC) n ot eli gi ble f or c o nc urre nt c he m ora diati o n
o
( Ar m B) T o e val uate t he safet y a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h C R T 
( 2 G y x 3 3 t o 3 5; 5 F/ W wit h c o nc urre nt c is plati n) i n s u bjects wit h treat me nt-naï ve
S C C H N .
Sec o n d ar y o bjecti ves:

P hase Ia ( d ose escalati o n): 
o
T o e val uate t he safet y pr ofile a n d t olera bility of M 3 8 1 4
i n c o m bi nati o n wit h R T 
( Ar m A) a n d C R T ( Ar m B)
o
T o e x pl ore t he a ntit u m or acti vit y of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A ) a n d 
C R T (Ar m B) .

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
T o e x pl ore t he efficac y i n ter ms of o verall res p o nse rate, pr o gressi o n free s ur vi val 
( P F S) a n d o verall s ur vi val ( O S) of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A) or i n 
c o m bi nati o n wit h C R T ( Ar m B), a n d l ocal/l ocal re gi o nal t u m or c o ntr ol ( Ar m B)

P hase Ia, P hase I b, a n d t he a ncillar y c P o P part of t he trial : T o assess t he p har mac o ki netics 
( P K) of M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 4 9
Met h o d ol o g y: T his is a c o m bi ne d P hase I a/I b, o pe n la bel, d ose escalati o n a n d d ose e x pa nsi o n 
trial desi g ne d t o e x pl ore t he safety, t olera bilit y, P K a n d P D pr ofile, a n d cli nical acti vit y of 
M 3 8 1 4
i n c o m bi nati o n wit h R T / C R T, a n d t o deter mi ne t he M T D a n d a R P 2 D f or M 3 8 1 4
i n 
c o m bi nati o n wit h R T / C R T. A n a ncillar y cP o P part of t he trial will be c o n d ucte d i n p arallel 
wit h t he P hase Ia/I b c ore trial t o e x pl ore t he P D effect of M 3 8 1 4
i n c o m bi nati o n wit h R T o n 
tar get e n ga ge me nt i n t u m or tiss ue.
I n t he P hase Ia part of t he trial, pre vi o usl y treate d s u bjects wit h l ocall y a d va nce d disease (a ny 
t u m or or metastas es i ncl u di n g l ym p h o mas) l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x t hat 
is n ot a me na ble t o s ur gical t hera p y or wit h sta n dar d s yste mic t hera p y wit h a n i n dicati o n f or 
palliati ve R T ( 3 0 G y  in 1 0 fracti o ns) will be i ncl u de d i n Ar m A. After t he first d ose le vel i n 
Ar m A has bee n c o m plete d, a sec o n d d ose escalati o n ar m ( Ar m B) will be i nitiate d i n 
treat me nt-naï ve s u bjects wit h S C C H N, w h o are eli gi ble f or fracti o nate d R T ( 6 6 t o 7 0 G y  in 
3 3 t o 3 5 fracti o ns) wit h c o nc urre nt cis plati n. T he d ose escalati o n of M 3 8 1 4
deter mi ne d b y t he 
Safet y  Mo nit ori n g C o m mittee ( S M C) will be g ui de d b y  the Ba ye sia n l o gistic m o del wit h 
o ver d ose c o ntr ol.
I n t he P hase I b part, eac h ar m fr o m P hase Ia will ha ve a n e x pa nsi o n c o h ort. After esta blis h me nt 
of R P 2 D i n Ar m A, s u bjects wit h treat me nt-naï ve S ta ge III A/ B N S C L C , n ot eli gi ble f or
s ur gical resecti o n or c o nc urre nt c he m ora diati o n, will be gi ve n 6 6 G y  i n 3 3 fracti o ns. T he d ose 
of M 3 8 1 4
f or t he first 3 s u bjects will be esta blis he d fr o m t he a vaila ble data i n b ot h ar ms of
P hase Ia. I n case a R P 2 D i n Ar m B has bee n esta blis he d bef ore a R P 2 D i n Ar m A, t he n t he 
e x pa nsi o n c o h ort f or Ar m A ca n be i nitiate d at t hat d ose. I n case a R P 2 D has bee n esta blis he d 
i n Ar m A o nl y , t he n t he first 3 s u bjects i n t he e x pa nsi o n c o h ort f or Ar m A will be treate d at
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 4 9
o ne d ose le vel bel o w t he R P 2 D. T he S M C will deter mi ne if it is safe t o escalate t he d ose . T he 
e x pa nsi o n c o h ort f or Ar m B will i ncl u de treat me nt-naï ve s u bjects wit h S C C H N, as s pecifie d 
i n P hase Ia, a n d will be gi ve n t he sa me C R T ( 6 6 t o 7 0 G y i n 3 3 t o 3 5 fracti o ns wit h c o nc urre nt 
cis plati n) i n c o m bi nati o n wit h M 3 8 1 4
at t he R P 2 D esta blis he d i n P hase Ia Ar m B.
I n t he a ncillar y c P o P part of t he trial , s u bjects wit h at least 2 (s u b)c uta ne o us t u m or/ metastases 
of a n y ty pe (at least 2 c m a part) wit h a n i n dicati o n for si n gle hi g h d ose palliati ve R T will be 
i ncl u de d. T he d ose of M 3 8 1 4
will be i n t he ra n ge of 1 0 0 t o 4 0 0 m g o nce dail y  (Q D ).
T he c urre nt trial i nitiall y starte d t o i n vesti gate M 3 8 1 4 b y  use of a p o w d er-i n-ca ps ule ( Pi C) 
f or m ulati o n. W hile
t he d ose escalati o n p hase of P hase Ia was o n g oi n g , a ne w 
 ta blet 
f or m ulati o n of M 3 8 1 4 beca me a vaila ble. T he
 ta blet will be i ntr o d uce d a n d e val uate d i n 
t his trial.
Scree ni n g p eri o d
After pr o vi di n g i nf or me d c o nse nt f or t he trial a n d t he p har mac o ge netic ( P G x) a nal ysis, t he 
eli gi bilit y of trial s u bjects will be esta blis he d acc or di n g t o t he pr ot oc ol -defi ne d incl usi o n a n d 
excl usi o n criteria d uri n g a ma xi m u m 2 1- da y  Scree ni n g Peri o d (scree ni n g a n d baseli ne 
e val uati o ns). O nce all scree ni n g pr oce d ures ha ve bee n c o m plete d a n d it has bee n c o nfir me d 
t hat a s u bject meets all t he eli gi bilit y criteria, t he s u bject will be e nr olle d i nt o t he trial a n d e nter 
t he treat me nt p eri o d. 
Tre at me nt p eri o ds
T hr o u g h o ut t he treat me nt p eri o d, s u bjects i n all c o h orts will atte n d re g ular trial visits f or 
d osi n g, safet y e val uati o ns a n d bl o o d sa m pli n g f or P K a n d P D.
P hase Ia 
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, s u bjects e nr olle d i n t he 
P hase Ia part of t he trial will recei ve treat me nt wit h a ca ps ule f or m ulati o n of M 3 8 1 4
at a 
starti n g d ose of 1 0 0 m g Q D f or Ar m A a n d 5 0 m g Q D f or Ar m B, w hic h will be gi ve n 1. 5 h o urs
( ± 3 0 mi n utes) bef ore eac h R T fracti o n ( 3 G y ) f or u p t o 1 0 fracti o ns ( Ar m A) or 2 G y f or 3 3 t o 
3 5 fracti o ns ( Ar m B) .
I n b ot h ar ms, d ose escalati o n will c o nti n ue wit h t he M 3 8 1 4 
ca ps ule f or m ulati o n fr o m 
1 0 0 m g/ da y ( Ar m A) or 5 0 m g/ da y ( Ar m B) u p t o a ma xi m u m d ose of 8 0 0 m g/ da y u ntil o ne 
of t he f oll o wi n g st o p pi n g r ules a p pl y: a ma xi m u m n u m ber of 3 0 s u bjects are i ncl u de d, m ore 
t ha n t hree c o h orts are assi g ne d t o t he sa me d ose le vel or t he esti mate f or d ose li miti n g t o xicit y  
(D L T ) pr o ba bilit y  of t he M T D 
reac hes s ufficie nt precisi o n. It is a ntici pate d t hat u p t o 
3 0 e val ua ble s u bjects ( 1 0 c o h orts of 3 s u bjects) ma y  be nee de d i n eac h ar m i n or der t o 
deter mi ne t he M T D of M 3 8 1 4 .
T he ta blet will be i ntr o d uce d first i n P hase Ia Ar m A i n c o m bi nati o n wit h R T. S u bjects will 
recei ve t he ta blet at a starti n g d ose of 1 0 0 m g Q D . Safet y, t olera bilit y a n d e x p os ure data alrea d y 
ge nerate d wit h t he ca ps ule f or m ulati o n of M 3 8 1 4 i n c o m bi nati o n wit h R T will g ui de t he 
esta blis h me nt of t he R P 2 D wit h t he ta blet. I n ad diti o n, a n i ntra-i n di vi d ual c o m paris o n of 
M 3 8 1 4 P K bet wee n t he ta blet a n d ca ps ule will be perf or me d i n P hase Ia Ar m A. T hese P K 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 4 9

S h ort -ter m Safet y Foll o w -u p: A f oll o w-u p peri o d of 3 0 da y s after t he e n d of R T f or e val uati o n 
of safet y

M i d-ter m Safet y  Foll o w -u p: A safet y f oll o w-u p peri o d of 3 m o nt hs
after t he e n d of R T t o 
e val uate late si g ns of R T-i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

L o n g -ter m Safet y  F oll o w -u p : A safet y foll o w -u p peri o d u ntil 1 2 m o nt hs after e n d of R T t o 
e val uate late si g ns of R T-i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

S ur vi val F oll o w -u p : A f oll o w -u p peri o d t hat will c o nti n ue u ntil 1 2 m o nt hs after t he last s u bject 
has st o p pe d R T / C R T.
A ncillar y  c P o P part of t he trial
A f oll ow- u p peri o d of 3 0 da y s after t he e n d of t he R T/ M 3 8 1 4
f or e val uati o n of safet y. S u bjects 
will be per mitte d t o recei ve a n y  i n dicate d t hera pe utic m o dalit y as s o o n as cli nicall y i n dicate d after 
Da y 1 0.
D ose esc al ati o n
M 3 8 1 4 d ose escalati o n will n ot pr ocee d t o t he ne xt d ose le vel u ntil all s u bjects ha ve c o m plete d t he 
D L T peri o d .
P hase Ia
A Ba y esia n t w o-para meter l o gistic re gressi o n m o del wit h o ver d ose c o ntr ol will be use d t o assist 
t he S M C wit h d ose selecti o n d uri n g t he P has e Ia d ose escalati o n. C o h orts of 3 s u bjects eac h will 
be treate d at t he sa me d ose le vel ( ca ps ule starti n g d ose: 1 0 0 m g Q D f or Ar m A a n d 5 0 m g Q D f or 
Ar m B ). T he m o del 
i nc or p orates pri or i nf or mati o n (fr o m n o n cli nical data) a n d o bser ve d 
i nf or mati o n fr o m eac h c o m plete d c o h ort (a n d data fr o m all pre vi o us c o h orts) t o pr o vi de a 
rec o m me n de d d ose f or t he ne xt c o h ort. A preselecte d set of acce pta ble d oses are c o nsi dere d b y  t he 
m o del, h o we ver d oses w hic h are n ot part of t he pres pecifie d set ma y  be c h ose n as well .T he m o del 
e ns ures t hat rec o m me n de d d oses c orres p o n d t o a pr o ba bilit y  of less t ha n 2 5 % t hat t he tr ue D L T  
rate is m ore t ha n 3 5 % i n Ar m A a n d 4 5 % i n Ar m B . D ose escalati o n will st o p i n eac h ar m as s o o n 
as t he first of t he f oll o wi n g st o p pin g r ules a p ply:  a ma xi m um of 3 0 s u bjects are i ncl u de d, m ore 
t ha n t hree c o h orts are assi g ne d t o t he sa me d ose le vel, or t he esti mate of D L T pr o ba bilit y  at t he 
M T D reac hes a s ufficie nt precisi o n .
P hase I b
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, treat me nt-naï ve s u bjects wit h 
S ta ge III A/ B N S C L C e nr olle d i n t he P hase I b part of t he trial ( Ar m A e x pa nsi o n c o h ort) will 
recei ve M 3 8 1 4 , t o be gi ve n 1. 5 h o ur s ( ± 3 0 mi n utes) bef ore eac h R T fr acti o n f or 3 3 fracti o ns. T he
d ose of M 3 8 1 4
f or t he first 3 s u bjects will be esta blis he d fr o m t he a vaila ble data i n b ot h ar ms 
of t he P hase Ia part of t he trial . 
T he d ose i n t he Ar m B e x pa nsi o n c o h ort will be t he deter mi ne d R P 2 D of M 3 8 1 4 fr o m P hase Ia, 
Ar m B a n d will be gi ve n t o s u bjects wit h treat me nt-naï ve S C C H N i n c o m bi nati o n wit h t he sa me 
C R T re gi me n as i n P hase Ia ( Ar m B).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 4 9
D oses of M 3 8 1 4
i n t he a ncill ar y c P o P p art of t he tri al
A ncillar y  c P o P part
T he si n gle d ose of M 3 8 1 4
t o be a d mi nistere d o n Da y  2 of the a ncillar y c P o P part of t he trial is 
fi xe d f or s uccessi ve c o h orts as s h o w n bel o w:
D ose s of M 3 8 1 4 i n t he a ncill ar y c P o P p art of t he tri al
D ose ( m g) a
N u m ber of s u bjects i ncl u de d b
1 0 0
3 
2 0 0
3
4 0 0
3
( > 1 0 0 / < 4 0 0) c
( 3)
c P o P = cli nical pr o of -of -pri nci ple; 
=
 P K = p har mac o ki netics; R P 2 D = rec o m me n de d P hase II d ose; 
S M C = Safet y M o nit ori n g C o m mittee .
a.
A d diti o nal c o h orts of M 3 8 1 4 ( 
 f or m ulati o n) ma y be i ntr o d uce d . T he starti n g d ose a n d s u bse q ue nt d ose le vels of 
M 3 8 1 4 (
f or m ulati o n) will be defi ne d b y t he S M C base d o n P K a n d safet y data ge nerate d i n o n g oi n g cli nical 
st u dies e val uati n g t he safet y, t olera bilit y, P K, a n d p har mac o d y na mics of M 3 8 1 4 (
f or m ulati o n).
b.  
A t t he R P 2 D a n a d diti o nal 2 s u bjects will be i ncl u de d ma ki n g 5 s u bjects at t he R P 2 D .
c.  
Ad diti o nal d oses mi g ht be o pe ne d u p o n S M C decisi o n .
Pl a n ne d n u m ber of s u bjects: U p t o 1 5 5 e val ua ble s u bjects will be e nr olle d i n t his trial: 
a p pr o xi matel y 7 8 e val ua ble s u bjects i n P hase Ia part; u p t o 5 4 e val ua ble s u bjects i n P hase I b 
d ose e x pa nsi o n part; a n d a p pr o xi matel y 23 s u bjects i n t he a ncillar y c P o P part of t he trial.
C o nsi deri n g a dr o p -o ut rate of 1 0 % f or s u bjects n ot e val ua ble f or D L T assess me nt i n P hase Ia, 
a p pr o xi matel y 1 6 5 s u bjects nee d t o be incl u de d i n t he trial.
Pri m ar y e n d p oi nts: 

P hase Ia ( Ar m A): 
o
Occ urre nce of D L T u p t o 5 wee ks after t he first d ose of M 3 8 1 4
i n c o m bi nati o n wit h 
palliati ve fracti o nate d R T .

P hase Ia ( Ar m B): 
o
Occ urre nce of D L T u p t o 1 2 wee ks after t he first d ose of M 3 8 1 4
i n c o m bi nati o n wit h 
sta n dar d C R T ( wit h cis plati n) wit h c urati ve i nte nt.

P hase I b ( Ar m A) – first 3 s u bjects: 
o
Occ urre nce of D L T u p t o 1 2 wee ks after t he first d ose of M 3 8 1 4
i n c o m bi nati o n wit h 
c urati vel y i nte n de d fracti o nate d R T.

P hase I b: Safet y a n d t olera bilit y as f oll o ws:
o
Occ urre nce of treat me nt- e mer ge nt a d verse e ve nts (T E A Es ) (se verity gra d e d acc or di n g 
t o 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 ] v 4. 0 3).
o
Res ults of la b orat or y tests, vital si g ns, electr ocar di o gra ms ( E C Gs).
Sec o n d ar y e n d p oi nts: 

P hase Ia ( Ar m A a n d Ar m B): Safet y e n d p oi nts : 
o
Occ urre nce of T E A Es (se verit y gra de d acc or di n g t o t he N CI  C T C A E v 4. 0 3)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 4 9
o
Res ults of la b orat or y tests, vital si g ns, E C Gs.

Efficac y  para meters
o
Best o verall res p o nse base d o n t u m or e val uati o ns ma de b y In vesti gat or i n acc or da nce 
wit h R E CI S T ( Res p o nse e val uati o n criteria i n s oli d t u m ors) v 1. 1
o
T u m or size meas ure me nt 
base d o n I n vesti gat or assess me nt i n acc or da nce wit h 
R E CI S T v 1. 1
o
P F S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o pr o gressi ve disease 
( per R E CIS T v 1. 1) base d o n t he I n vesti gat or assess me nt or deat h fr o m a n y ca use, a n d 
l ocal/l ocal re gi o nal t u m or c o ntr ol ( P hase I b, Ar m B e x pa nsi o n c o h ort)
o
O S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o t he date of deat h fr o m 
a n y ca use.
P h ar m ac o ki netic en d p oi nt s - c a ps ule: Plas ma P K para meters of M 3 8 1 4
f or P hase Ia part: 
a.
Fracti o n D a y  1 – ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ), ti me t o reac h 
ma xi m u m o bser ve d c o nce ntrati o n (tma x ), area u n der t he c o nce ntrati o n-ti me c ur ve 
( A U C) fr o m ti me zer o t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n (A U C 0-t),
A U C fr o m ti me zer o e xtra p olate d t o i nfi nit y (A U C 0- ∞), a p pare nt ter mi nal half-life
(t1/ 2), oral cleara nce (C L /f), ap pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase
(Vz/f )
b.
Fracti o n D a y  1 0 - Cma x , tma x , A U C o ver t he d osi n g i nter val after m ulti ple d osi n g
(A U C τ), A U C 0 - ∞, t1/ 2, oral cleara nce at stea d y state ( C L ss/f), a p pare nt v ol u me of 
distri b uti o n at stea d y  state ( Vss/f), acc u m ulati o n rati o f or A U C c ur ve
( Racc[ A U C]), acc u m ulati o n rati o f or ma xi m u m c o nce ntrati o n ( Racc[ Cma x ]).
P h ar m ac o ki netic e n d p oi nts - t a blet: Plas ma P K para meters of M 3 8 1 4 f or P hase Ia part: 
a.
Fracti o n Da y  1 – Cma x , tma x , A U C0 -t, A U C0- ∞, t1/ 2, C L/f, Vz/f
b.
Fracti o n Da y  6 - Cma x , tma x , A U C 0 -t, A U C0- ∞, t1/ 2, C L/f, Vz/f
c.
Fracti o n Da y  1 0 - Cma x , tma x , A U Cτ, A U C0 - ∞, t1/ 2, C Lss/f, Vss/f, Racc[ A U C], 
R acc[ Cma x ].
P o p ulati o n P K para meters f or P hase I b a n d t he a ncillar y c P o P part of t he trial will be re p orte d 
i n a se parate P K re p ort, w hic h will n ot be part of t he Cli nical Trial Re p ort f or t his trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 / 1 4 9
Di a g n osis a n d ke y i ncl usi o n a n d e xcl usi o n criteri a: 
I ncl usi o n criteria

P h ase I a p art : a d va nce d s oli d t u m ors or metastases i ncl u di n g l ym p h o ma l ocalize d i n t he 
hea d a n d nec k re gi o n or t h ora x wit h a n i n dicati o n f or fracti o nate d palliati ve R T ( Ar m A); 
or treat me nt-naï ve S C C H N eli gi ble f or fracti o nate d c urati vel y i nte n de d R T wit h c o nc urre nt 
cis plati n ( Ar m B)

P h ase I b part : treat me nt-naï ve S ta ge III A/ B N S C L C n ot eli gi ble f or s ur gical resecti o n or
c o nc urre nt c he m ora diati o n ( Ar m A e x pa nsi o n c o h ort) or treat me nt-naï ve S C C H N eli gi ble 
f or fracti o nate d c urati vel y i nte n de d R T wit h c o nc urre nt cis plati n ( Ar m B e x pa nsi o n c o h ort)

A ncill ar y c P o P p art : a n y tu m or wit h at least 2 (s u b)c uta ne o us t u m or/ metastases at least 
2 c m a part w hic h are R T naï ve wit h a n i n dicati o n f or hi g h d ose palliati ve R T 

A vaila bilit y  of arc hi val t u m or material, eit her as a bl oc k or sli des ( P hase Ia a n d I b). If n o 
arc hi val material is a vaila ble t he n a fres h bi o ps y s h o ul d be ta ke n

Willi n g t o ha ve
t u m or bi o psies c ollecte d i n t he a ncillar y c P o P part of t he trial

Meas ura ble or e val ua ble disease b y  RE CI S T v 1. 1 ( n ot re q uire d f or t he a ncillar y c P o P part 
of t he trial )

E aster n C o o perati ve O nc ol o g y  Gr o u p p erf or ma nce stat us ( E C O G P S) ≤1

Life e x pecta nc y of ≥3 m o nt hs
( P hase Ia, Ar m A) or ≥6 m o nt hs (P hase Ia, Ar m B a n d 
P hase I b)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 / 1 4 9

Fe male s u bjects of c hil d beari n g p ote ntial a n d male s u bjects wit h fe male part ners of 
c hil d beari n g p ote ntial m ust be willi n g t o a v oi d pre g na nc y .
Mai n e xcl usi o n criteria f or P hase Ia a n d P hase I b:

C he m ot hera p y, i m m u n ot hera py, h or m o nal t hera p y, bi ol o gic t hera p y, or a n y ot her 
a ntica ncer t hera p y or I M P wit hi n 2 8 da y s of first trial dr u g i nta ke f or P hase Ia s u bjects, a n d 
a n y pri or t hera p y f or P hase I b s u bjects. F or s u bjects wit h ra pi dly gr o wi n g t u m ors l ocalize d 
i n t he hea d a n d nec k re gi o n or t h ora x w here t he treati n g p h y sicia n ca n n ot wait f or 2 8 da ys, 
i ncl usi o n ma y ta ke place if t here is n o resi d ual t o xicit y fr o m pre vi o us treat me nt ( ma xi m u m
C T C A E G ra de 1)

Pri or R T t o t he sa me re gi o n wit hi n 1 2 m o nt hs
(P hase Ia, Ar m A ; s u bjects wit h t u m ors 
l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x) or at a n y t i me pre vi o usl y ( P hase Ia, Ar m B ; 
treat me nt-naï ve s u bjects wit h S C C H N a n d P hase I b; treat me nt-naï ve s u bjects wit h Sta ge III 
A/ B N S C L C or S C C H N )

E xte nsi ve pri or R T o n ≥3 0 % of b o ne marr o w reser ve as j u d ge d b y t he I n vesti gat or or pri or 
b o ne marr o w/ste m cell tra ns pla ntati o n wit hi n 5 y ears bef ore trial start.

P o or vital or ga n f u ncti o ns defi ne d as: 
o
B o ne marr o w i m pair me nt as e vi de nce d b y  he m o gl o bi n < 1 0. 0 g/ d L , ne utr o p hil 
c o u nt < 1. 0 × 1 0 9/ L, platelets < 1 0 0 × 1 09/ L
o
Re nal i m pair me nt as e vi de nce d b y  ser u m creati ni ne > 1. 5 × u p per li mit of 
n or mal ( U L N) 
o
Li ver f u ncti o n a b n or malit y as defi ne d b y  total bilir u bi n > 1. 5 × U L N or as partate 
a mi n otra nsferase ( A S T)/ala ni ne a mi n otra nsferase ( A L T) > 2. 5 × U L N (e xce pt 
f or s u bjects wit h li ver i n v ol ve me nt, w h o ca n ha ve A S T/ A LT > 5 × U L N)

Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n or ot her c hr o nic gastr oi ntesti nal disease or 
c o n diti o ns t hat ma y  ha m per c o m plia nce a n d/ or a bs or pti o n of t he I MP, c urre nt use of 
perc uta ne o us e n d osc o pic gastr ost o m y ( P E G) t u bes

Si g nifica nt car diac c o n d ucti o n a b n or malities, i ncl u di n g a hist or y  of l o n g Q Tc s yn dr o me 
a n d/ or pace ma ker, or i m paire d car di o vasc ular f u ncti o n s uc h as Ne w Y or k Heart Ass ociati o n 
classificati o n sc ore > 2 .

S u bjects c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose of trial 
dr u g) me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors of c yt oc hr o me P 4 5 0 
( C Y P) 3 A or C Y P 2 C 1 9 ( m ust st o p at least 1 wee k pri or), p ote nt i nd ucers of C Y P 3 A or 
C Y P 2 C 1 9 ( m ust st o p at least 3 wee ks pri or), or dr u gs mai nl y meta b olize d b y  C Y P 3 A wit h 
a narr o w t hera pe utic i n de x ( m ust st o p at least o ne da y  pri or).

S u bjects c urre ntl y r ecei vi n g H 2-bl oc ker or pr ot o n p u m p i n hi bit ors ( or u na ble t o st o p at least 
5 da y s pri or t o t he first treat me nt).

If t he pla n ne d ra diati o n fiel d i ncl u des a n y part of t he es o p ha g us a n d t he s u bject has 
s ym pt o ms 
of o n g oi n g es o p ha gitis, t he s u bject is n ot eli gi ble, u nless a n es o p ha geal 
e n d osc o p y r ules o ut t he prese nce of es o p ha gitis.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 4 9
 ( 
 t a blet f or m ul ati o n of M 3 8 1 4: 
M 3 8 1 4
will be pr o vi de d as 
 ta blet f or m ulati o n of 5 0 m g, f or oral a d mi nistrati o n. D osi n g 
sc he d ule of t he ta blet f or m ulati o n f oll o ws t he descri pti o n gi ve n f or t he ca ps ule f or m ulati o n 
a b o ve. T he ta blet f or m ulati o n will be i nitiall y assesse d i n P hase Ia Ar m A ta ki n g i nt o acc o u nt 
t he a vaila ble safety, t olera bilit y a n d P K res ults fr o m t he ca ps ule. Sta n dar d 3 + 3 d ose escalati o n 
desi g n criteria will a p pl y. E val uati o n o f si n gle d ose P K data after a d mi nistrati o n of t he ta blet 
a n d t he ca ps ule i n t he sa me s u bject will su p p ort t he selecti o n of ta blet d oses i n P hase Ia Ar m B ,
t he P hase Ib parts a n d i n t he a d diti o nal c o h orts of M 3 8 1 4 i n t he a ncillar y c P o P part of t he trial .
C o nc urre nt cis pl ati n - Dose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule:
C o nc urre nt cis plati n will be a d mi nistere d i n c o m bi nati o n wit h t he I MP i n s u bjects wit h 
S C C H N i ncl u de d i n P hase Ia Ar m B a n d t he S C C H N e x pa nsi o n c o h ort i n P hase I b. T he d ose 
a n d d ose re gi me n of cis plati n is t o be a p plie d i n li ne wit h c urre nt me dical g ui deli nes ( N C C N, 
A C C P/ A S C O , a n d E S M O) wit h refere nce t o t he Sta n dar d of Care (S o C ) f or c o nc urre nt C R T 
wit h cis plati n i n t he treat me nt of s u bjects wit h S C C H N . Cis plati n will be gi ve n t wice at a d ose 
of 1 0 0 m g/ m 2 or wee kl y at a d ose of 4 0 m g/ m 2.
Pl a n ne d tri al a n d tre at me nt d ur ati o n per s u bje ct: 
Treat me nt d urati o n is e x pecte d t o be a p pr o xi matel y  2 wee ks ( Ar m A) or 7 wee ks ( Ar m B) f or 
t he P hase Ia part, 6- 7 wee ks f or t he P hase I b part, a n d 2 da y s f or t he a ncillar y c P o P part.
St atistic al met h o ds:
I n the P hase Ia part , f or eac h ar m ( A a n d B) t he sa m ple size will de pe n d o n t he n u m ber of D L T s 
o bser ve d at t he differe nt d ose le vels a n d t he n u m ber of teste d or e x pa n de d d ose le vels f or M 3 8 1 4 . 
S u bject s will be e nr olle d i n c o h orts of 3 s u bjects. 
T he P hase I b part c o nsists of o ne e x pa nsi o n c o h ort per ar m fr o m t he P hase Ia part. F or Ar m A, 
t he e x pa nsi o n c o h ort will e x pl ore t he acti vit y of M 3 8 1 4
c o m bi ne d wit h R T i n treat me nt-naï ve
s u bjects wit h S ta ge III A/ B N S C L C . T he c o h ort will e nr oll u p t o 2 7 e val ua ble s u bjects i ncl u di n g 
t he safety r u n-i n part, bri n gi n g t he a ntici pate d ma xi m u m sa m ple size f or t he P hase Ia/I b parts t o 
7 5 s u bjects f or Ar m A . A sa m ple size of 2 7 e val ua ble s u bjects will e na ble t he l o wer li mit of a 
2- si de d 9 5 % c o nfi de nce i nter val ( CI ) f or t he res p o nse rate t o e xte n d n o f urt her t ha n a n a bs ol ute 
2 0 % fr o m t he e x pecte d pr o p orti o n of 5 0 %, t here b y ens uri n g t he l o wer li mit is n o less t ha n t he 
hist orical c o ntr ol of 3 0 % i n treat me nt-naï ve s u bjects wit h Sta ge III A/ B N S C L C. 
F or Ar m B, t he a ntici pate d sa m ple size i n t he escalati o n part is 3 0 partici pa nts (t o get her f or 
ta blet a n d ca ps ule). T he e x pa nsi o n c o h ort will e x pl ore t he safety, t olera bilit y an d efficac y of 
M 3 8 1 4
c o m bi ne d wit h C R T ( wit h cis plati n) i n treat me nt-naï ve s u bjects wit h S C C H N. A 
sa m ple size of u p t o 2 7 e val ua ble s u bjects will be e nr olle d t o c o nfir m safet y a n d t olera bilit y of 
t he c o m bi nati o n . T o get her, t his bri n gs t he a ntici pate d sa m ple size f or t he P hase Ia/I b parts t o 
5 7 s u bjects f or Ar m B .
F or t he a ncillar y c P o P part of t he trial c o n d ucte d i n p arallel wit h t he P hase Ia part, a fi xe d n u m ber 
of 3 s u bjects will be e nr olle d at t he t w o l o wer fi xe d d ose le vels a n d 5 s u bjects will be e nr olle d at 
t he R P 2 D . Ass u mi n g a c orrelati o n bet wee n t he f ol d i n d ucti o n of t he mar ker a n d t he d ose is 0. 6 9, 
t he p o wer of detecti n g a li near relati o ns hi p is 8 0 % wit h a n al p ha-le vel of 5 % ( 2-si de d). I n case 
t he P D res ults d o n’t all o w detect i o n of s ufficie nt m o d ulati o n of tar get e n ga ge me nt i.e., a clear 
d ose/effect relati o ns hi p bet wee n le vels i n pre- a n d o n treat me nt t u m or bi o psies, a d diti o nal d ose 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 4 9
le vel(s) c o ul d be e x pl ore d u p o n S M C decisi o n acc or di n g t o t he fi n di n gs d uri n g t he escalati o n 
p hase i n P hase Ia. A p pr o xi matel y  12 a d diti o nal s u bjects ma y  be e nr olle d i n t he a ncillar y cP o P 
part of t he trial usi n g M 3 8 1 4 
 f or m ulati o n, t h us lea di n g t o a ma xi m u m sa m ple size i n t he 
a ncillar y c P o P part of 2 3.
T he a ntici pate d t otal n u m ber of e val ua ble s u bjects t o be i ncl u de d i n t he t hree parts of t he trial
wit h a d diti o nal c o h orts i n t he a ncillar y c P o P part of t he trial is t heref ore 1 5 5 . C o nsi deri n g a dr o p -
o ut rate of 1 0 % f or s u bjects n ot e val ua ble f or D L T assess me nt i n P hase Ia, a p pr o xi matel y 
1 6 5 s u bjects nee d t o be e nr olle d i n t he trial.
F or t he P hase Ia part , t he n u m ber a n d pr o p orti o n of s u bjects e x perie nci n g a D L T will be re p orte d 
b y f or m ulati o n a n d d ose le vel, base d o n t he o bser vati o n of D L Ts u p t o 5 wee ks ( Ar m A) or 
1 2 wee ks ( Ar m B) after t he first d ose of M 3 8 1 4
ta ki n g i nt o acc o u nt t he k n o w n t o xicities wit h
R T al o ne.
F or t he safet y r u n-i n part of P hase I b (first 3 s u bjects i n Ar m A) , t he n u m ber of s u bjects 
e x perie nci n g a D L T u p t o 1 2 wee ks after t he first d ose of M 3 8 1 4 will als o be re p orte d. S u bjects 
i ncl u de d i n t he r u n-i n part will be a nalyz e d se paratel y fro m t he re mai ni n g s u bjects of P hase I b.
All sec o n dar y  en d p oi nts will be s u m marize d b y mea n of descri pti ve statistics i ncl u di n g 9 5 % CI  
b y  d ose le vel a n d o verall, u nless ot her wise state d. Res p o nse rate will be calc ulate d, a n d P F S a n d 
O S will be e val uate d f or t he e x pa nsi o n c o h ort o nly.
A d verse e ve nts will be c o de d acc or di n g t o t he latest a vaila ble versi o n of t he Me dical Dicti o nar y 
f or Re g ulat or y Acti vities ( Me d D R A). Se verit y of A Es will be gra de d usi n g t he C T C A E (v 4. 0 3) 
t o xicit y gra des. A d verse e ve nts relate d t o t he trial me dicati o n will be defi ne d as a n y A E 
c o nsi dere d relate d t o M 3 8 1 4 . I n a d diti o n, missi n g classificati o ns c o ncer ni n g trial me dicati o n 
relati o ns hi ps will be c o nsi dere d relate d t o t he trial dr u g. S u bject s w h o ter mi nate treat me nt will 
be dis pla y e d in a b y -s u bject listi n g, a n d s u m marize d b y  pri mar y wit h dra wal reas o n f or eac h 
treat me nt gr o u p. All re p orte d deat hs d uri n g t hera p y  an d deat hs wit hi n 3 0 da y s after last d ose of 
trial treat me nt will be ta b ulate d a n d t he pri mar y ca use of deat h will be re p orte d (f or all s u bjects 
e nr olle d). La b orat or y  res ults will be classifie d b y  gra de acc or di n g t o t he C T C A E v 4. 0 3 . T he 
w orst o n -trial gra des after t he first d ose of trial treat me nt will be s u m marize d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 4 9
T a ble 1
Sc he d ule of Assess me nts – P h ase I a ( Ar m A): C a ps ule C o h orts
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  
F U
L o n g -t er m 
S af et y  F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , a n d 
3 1 2 x
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
- 
-
± 2
± 2
± 7 
± 7
± 7
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X 
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 o nl y
I nf e cti o n s cr e e n ( h e p atiti s B a n d 
C) , o pti o n al HI V t e ste
X
Vit al si g n s f
X g
X
X 
X 
X
X
X
X
X h
P h y si c al e x a mi n ati o n
X 
X
X 
X 
X
X
X
X
X i
Cli ni c al e x a mi n ati o n of bl e e di n g
X 
X
X 
X 
X
X
E s o p h a g e al e n d o s c o p y (if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n R T 
ar e a
X 
X 
X
X
X
X
X
E C O G P S
X
X 
X
P T D 3 0 o nl y
X
X
X i
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 5 6 2 1 4 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 8e 7 2 2
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 5 4 8 0 9 8 _ 4 6 2 6 0 5 9

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  
F U
L o n g -t er m 
S af et y  F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , a n d 
3 1 2 x
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
- 
-
± 2
± 2
± 7 
± 7
± 7
A d v er s e e v e nt a s s e s s m e nt
X 
X
X 
X 
X
X
X j
X j
X j
C o n c o mit a nt m e di c ati o n
X 
X
X 
X 
X
X
H e m at ol o g y k
X 
X
X 
X 
X
X
S er u m c h e mi str y a n d c o a g ul ati o n l
X 
X
X 
X 
X
X
Uri n al y si s ( di p sti c k) m
X
X 
X
P T D 3 0 o nl y
1 2 -l e a d E C G (i n cl u di n g Q T c F)n
X 
X o
X p
T u m or a s s e s s m e nt ( R E CI S T) q
X
X r
X h , r
X h
P K bl o o d s a m pl e s s
X 
X t
X 
X
Ar c hi v al t u m or m at eri al
u
X
S ur vi v al 
X y
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 5 6 2 1 4 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 8e 7 2 2
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 5 4 8 0 9 8 _ 4 6 2 6 0 5 9
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 4 9
A E = a d v er s e e v e nt ; C T = c o m p ut e d t o m o gr a p h y; 
; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s ; e C R F = el e ctr o ni c c a s e r e p ort f or m; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n ; F D = fr a cti o n d a y; 
F U = f oll o w -u p; F/ W =  fr a ctio n p er w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e 
i m a gi n g; P D = p h ar m a c o d y n a mi c s; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st -tr e at m e nt D a y; Q T c F = Fri d eri ci a - c orr e ct e d Q T i nt er v al; 
R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s ; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D) ( d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n). P o st -tr e at m e nt D a y ( P T D) ( d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er).
a.
All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or 
a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e . g., if a n e w tr e at m e nt i s st art e d, wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d 
i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s m u st b e d o n e a s pl a n n e d f or P T D 3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, 
s u bj e ct s will b e f ol l o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g .
c.
F D 1 0 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al fr o m t h e tri al d uri n g t h e tr e at m e nt p eri o d , t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit 
o n F D 1 0 s h o ul d b e p erf or m e d. I n s u c h c a s e s t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit. If F D 1 0 i s o n a Fri d a y, P K, P D, s af et y 
l a b or at or y, a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
A ll A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 2 1 t o e v al u at e t h e o c c urr e n c e of D L T s.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul ator y g ui d a n c e.
f.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
g.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
h.
O nl y r e q uir e d if s u bj e ct h a s n ot st art e d a n e w a ntit u m or tr e at m e nt. If a n e w tr e at m e nt i s st art e d, t h e d at e ( a n d r e gi m e n) m u st b e r e p ort e d i n t h e e C R F.
i.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
j.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
k.
S e e  T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
l.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
m.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s .
n. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
p. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
q.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or e v al u ati o n c a n b e u p t o 2 8 d a y s ol d 
w h e n tr e at m e nt st art s.
r.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g-t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1- 1 8 0 [ 4 a s s e s s m e nt s]) a n d d uri n g s ur vi v al F U ( e v er y 1 3 w e e k s 
d uri n g D a y 1 8 1 -3 6 5 [ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
s.
P K s a m pl e s will b e c oll e ct e d a s d et ail e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d b y t h e S M C b a s e d o n e m er gi n g d at a. S e e S e cti o n 7. 5. 1 f or 
d et ail s.
t.
Pr e d o s e o nl y .
u.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e) . If n o ar c hi v al t u m or m at eri al i s a v ail a bl e a 
fr e s h bi op s y m u st b e t a k e n.
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 5 6 2 1 4 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 8e 7 2 2
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 5 4 8 0 9 8 _ 4 6 2 6 0 5 9
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 4 9
x.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
y.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 4 9
T a ble 2
Sc he d ule of Assess me nts – P h ase I a ( Ar m A): T a blet C o h orts
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -
t er m 
S af et y  
F U
Mi d -
t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
T a bl et y
-
X
X
-
M 3 8 1 4 C a p s ul e
X
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6 z
F D 7
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 a a ,
a n d 
3 1 2 a a
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
-
-
± 2 
± 2 
± 7 
± 7
± 7
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X 
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 
o nl y
I nf e cti o n s cr e e n ( h e p atiti s B a n d C), 
o pti o n al HI V t e st e
X
Vit al si g n s f
X g
X
X
X 
X
X 
X 
X
X h
P h y si c al e x a mi n ati o n
X 
X
X
X 
X
X 
X 
X
X i
Cli ni c al e x a mi n ati o n of bl e e di n g
X 
X
X
X 
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -
t er m 
S af et y  
F U
Mi d -
t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
T a bl et y
-
X
X
-
M 3 8 1 4 C a p s ul e
X
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6 z
F D 7
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 a a ,
a n d 
3 1 2 a a
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
-
-
± 2 
± 2 
± 7 
± 7
± 7
E s o p h a g e al e n d o s c o p y (if r el e v a nt) 
X
E v al u ati o n of all ti s s u e s i n R T ar e a
X
X 
X
X 
X 
X
X
E C O G P S
X
X 
X
P T D 3 0 
o nl y
X 
X
X i
A d v er s e e v e nt a s s e s s m e nt
X 
X
X
X 
X
X 
X j
X j
X j
C o n c o mit a nt m e di c ati o n
X 
X
X
X 
X
X
H e m at ol o g y k
X 
X
X
X 
X
X
S er u m c h e mi str y a n d c o a g ul ati o n l
X 
X
X
X 
X
X
Uri n al y si s ( di p sti c k) m
X
X 
X
P T D 3 0 
o nl y
1 2 -l e a d E C G (i n cl u di n g Q T c F)n
X 
X o
X p
T u m or a s s e s s m e nt ( R E CI S T)q
X
X r
X h , r
X h
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -
t er m 
S af et y  
F U
Mi d -
t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
T a bl et y
-
X
X
-
M 3 8 1 4 C a p s ul e
X
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6 z
F D 7
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 a a ,
a n d 
3 1 2 a a
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
-
-
± 2 
± 2 
± 7 
± 7
± 7
P K bl o o d s a m pl e s s
X 
X t
X 
X t
X
Ar c hi v al t u m or m at eri alu
X
S ur vi v al 
X x
A E = a d v er s e e v e nt; C T = c o m p ut e d t o m o gr a p h y; C R T = c h e m or a di ot h er a p y ;
; D L T = d o s e li miti n g t o xi cit y; E C G = 
el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s; e C R F = el e ctr o ni c c a s e r e p ort f or m; E O T = E n d of Tri al; E T T = E arl y 
Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U = f oll o w -u p; F/ W = fr a cti o n p er w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n 
i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st- tr e at m e nt 
D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 4 9
N ot e:
Fr a cti o n D a y ( F D) ( d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n). P o st-tr e at m e nt D a y ( P T D) ( d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er). 
a.
All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or 
a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d , wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d 
i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s m u st b e d o n e a s pl a n n e d f or P T D 3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, 
s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
F D 1 0 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al fr o m t h e tri al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit 
o n F D 1 0 s h o ul d b e p erf or m e d. I n s u c h c a s e s t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit. If F D 1 0 i s o n a Fri d a y, P K, P D, s af et y 
l a b or at or y, a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
All A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 2 1 t o e v al u at e t h e o c c urr e n c e of D L T s.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
f.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
g.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
h.
O nl y r e q uir e d if s u bj e ct h a s n ot st art e d a n e w a ntit u m or tr e at m e nt. If a n e w tr e at m e nt i s st art e d, t h e d at e ( a n d r e gi m e n) m u s t b e r e p ort e d i n t h e e C R F.
i.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
j.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
k.
S e e  T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
l.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
m.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
n. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
p. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
q.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or e v al u ati o n c a n b e u p t o 2 8 d a y s ol d 
w h e n tr e at m e nt st art s.
r.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g -t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1-1 8 0 [ 4 a s s e s s m e nt s]) a n d d uri n g s ur vi v al F U ( e v er y 1 3 w e e k s 
d uri n g D a y 1 8 1 - 3 6 5 [ 2 a ss e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
s.
P K s a m pl e s will b e c oll e ct e d a s d et ail e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d by t h e S M C b a s e d o n e m er gi n g d at a. S e e S e cti o n 7. 5. 1 f or 
d et ail s.
t.
Pr e d o s e o nl y.
u.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e) . If n o ar c hi v al t u m or m at eri al i s a v ail a bl e a 
fr e s h bi o p s y m u st b e t a k e n.
x.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3
m o nt h s.
y.
S u bj e ct s tr e at e d i n t h e t a bl et t e sti n g c o h ort s of P h a s e I a Ar m A will r e c ei v e t h e t a bl et o n F D 1 -5 a n d F D 7 - 1 0 a n d a r e s p e cti v e si n gl e d o s e str e n gt h of t h e 
c a p s ul e f or m ul ati o n o n F D 6.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 4 9
z.
If F D 6 i s N O T o n a M o n d a y
t h e n it m u st b e s c h e d ul e d t o t a k e pl a c e o n t h e M o n d a y cl o s e st t o F D 6 a s w a s h- o ut o v er t h e w e e k e n d i s r e q uir e d. 
a a.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 4 9
T a ble 3
Sc he d ule of Assess me nts – First 3 S u bjects i n P h ase I b ( Ar m A; N S C L C C o h ort)
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U/ E O T a
S ur vi v al F U
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
D L T 
P eri o d / S
h ort -
t er m 
S af et y  
F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D
1 t o 3 7
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D
8, 1 5 , 2 2, 
3 7 e
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , 2 7 0,
3 1 2 x , a n d
3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
- 
- 
- 
-
-
± 2 
± 7 
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y 
t e st 
(if a p pli c a bl e)
X
P T D 2 2
o nl y
I nf e cti o n s cr e e n ( h e p atiti s 
B a n d C), o pti o n al HI V 
t e stf
X
Vit al si g n s g
X h
X
X 
X
X
X 
X
X
P h y si c al e x a mi n ati o n
X
X
X 
X
X
X 
X
X i
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X
X
X 
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U/ E O T a
S ur vi v al F U
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
D L T 
P eri o d / S
h ort -
t er m 
S af et y  
F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D
1 t o 3 7
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D
8, 1 5 , 2 2, 
3 7 e
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , 2 7 0,
3 1 2 x , a n d
3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
- 
- 
- 
-
-
± 2 
± 7 
± 7
-
E s o p h a g e al e n d o s c o p y ( if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n 
R T ar e a
X 
X
X
X 
X
X
E C O G P S
X
X
F D 3 3 o nl y
X 
X
X
A d v er s e e v e nt 
a s s e s s m e nt
X
X
X 
X
X
X 
X j
X j
C o n c o mit a nt m e di c ati o n
X
X
X 
X
X
X
H e m at ol o g y k
X
X
X 
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n l
X
X
X 
X
X
X
Uri n al y si s ( di p sti c k)m
X
X
F D 1 6 a n d 
3 3 o nl y
X
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) n
X
X o
X p
T u m or a s s e s s m e nt 
( R E CI S T)q, r
X
X
X
P K bl o o d s a m pl e s s
X 
X t
X 
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U/ E O T a
S ur vi v al F U
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
D L T 
P eri o d / S
h ort -
t er m 
S af et y  
F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D
1 t o 3 7
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D
8, 1 5 , 2 2, 
3 7 e
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , 2 7 0,
3 1 2 x , a n d
3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
- 
- 
- 
-
-
± 2 
± 7 
± 7
-
Ar c hi v al t u m or m at eri al u
X
S ur vi v al 
X y
A E = a d v er s e e v e nt; C T = c o m p ut e d t o m o gr a p h y; 
; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U = f oll o w -u p; F/ W
= fr a cti o n p er 
w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st- tr e at m e nt D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n 
S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n. P o st-tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er.
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e . g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D
3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 4 9
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
If FD 1 0 i s o n a Fri d a y, P K, P D, s af et y l a b or at or y , a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n F D 3 3
s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit.
e.
All A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 3 7 t o e v al u at e t h e o c c urr e n c e of D L T s.
f.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
g.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht . S e e S e cti o n 7. 4. 4 f or d et ail s.
h.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
i.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
j.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
k.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
l.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
m.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s .
n. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
p. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
q.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
r.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g-t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1- 1 8 0 [ 4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
s.
P K s a m pl e s f or t h e fir st 3 s u bj e ct s i n P h a s e I b will f oll o w t h e s a m pli n g f or P h a s e I a a s d et ail e d i n T a bl e 9.  S a m pli n g s c h e d ul e m a y b e c h a n g e d b y t h e 
S M C b a s e d o n e m er gi n g d at a. S e e S e cti o n 7. 5. 1 f or d et ail s.
t.
Pr e d o s e o nl y .
u.
M a n d at or y ar c hi v al t u m or m at eri a l s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e).
x.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
y.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 / 1 4 9
T a ble 4
Sc he d ule of Assess me nts – P h ase I b (Ar m A; N S C L C C o h ort)
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0v , 
2 7 0, 3 1 2 v , 
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 
o nl y
I nf e cti o n s cr e e n ( h e p atiti s B 
a n d C), o pti o n al HI V t e st e
X
Vit al si g n s f
X g
X
X
X
X
X
P h y si c al e x a mi n ati o n
X
X
X
X
X
X
X h
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X
X
X
X
X
E s o p h a g e al e n d o s c o p y (if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n R T 
ar e a
X
X
X
X
X
E C O G P S
X
-
F D 3 3 o nl y
P T D 3 0
o nl y
X
X
A d v er s e e v e nt a s s e s s m e nt
X
X
X
X
X
X i
X i
C o n c o mit a nt m e di c ati o n
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0v , 
2 7 0, 3 1 2 v , 
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
H e m at ol o g y j
X
X
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n k
X
X
X
X
X
Uri n al y si s ( di p sti c k) l
X
F D 1 6 a n d 3 3
o nl y
P T D 3 0 
o nl y
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) m
X
X n
X o
T u m or a s s e s s m e nt 
( R E CI S T)p, q
X
X
X
P K bl o o d s a m pl e s r
X
X
Ar c hi v al t u m or m at eri al s
X
S ur vi v al 
X w
C T = c o m p ut e d t o m o gr a p h y; 
; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y 
Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U
= f oll o w -u p; F/ W = fr a cti o n p er w e e k; G y = G r a y; 
H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
;  
 
; P K = p h ar m a c o ki n eti c s; P T D = P o st -tr e at m e nt D a y; Q T c F = Fri d eri ci a - c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n. P o st -tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 4 9
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s
aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D 3 6 5 . Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g .
c.
If F D 1 0 i s o n a Fri d a y, P K, P D, a n d s af et y l a b or at or y s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d , t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n F D 3 3
s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
f.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
g.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
h.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
i.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s .
j.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
k.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
l.
U ri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
m.
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
n. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
p.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1.
B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
q.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g-t er m s af et y F U (e v er y 6 w e e k s d uri n g D a y 3 1 - 1 8 0 [4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]) . T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
r.
S p ar s e P K s a m pl e s will b e c oll e ct e d a s d et ail e d i n T a bl e 9.  T h e s e s a m pli n g ti m e p oi nt s mi g ht b e r e-s c h e d ul e d b a s e d o n P K r e s ult s fr o m P h a s e I a b y t h e 
S M C.
s.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e).
If n o ar chi v al m at eri al i s a v ail a bl e t h e n a fr e s h 
bi o p s y s h o ul d b e t a k e n .
v.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s wil l b e p erf or m e d at t h e s e vi sit s.
w.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 4 9
T a ble 5
Sc he d ule of Assess me nts – P h ase I a ( Ar m B; S C C H N C o h ort)
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al 
F U
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + C i s pl ati n)
D L T P eri o d /
S h ort -t er m 
S af et y  F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D
1 t o 3 5
P T D
1 t o 9 0
P T D
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6, 3 1 a n d 
l a st F D/ E T Td
P T D
7 , 14 , 21 , 28, 
3 5 e
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0z, 
2 7 0, 3 1 2 z, a n d 
3 6 5
-
Vi sit Wi n d o w ( d a y s)
- 
- 
- 
- 
-
-
± 2
± 7
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n 
crit eri a
X 
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y 
t e st 
(if a p pli c a bl e)
X
P T D 2 8 o nl y
I nf e cti o n s cr e e n ( h e p atiti s 
B a n d C), o pti o n al HI V 
t e stf
X
H P V st at u s i n t u m or g
X
A u di o gr a m h
X
Vit al si g n s i
X j
X
X 
X
X
X
X
X
P h y si c al e x a mi n ati o n
X 
X
X 
X
X
X
X
X k
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X 
X
X 
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al 
F U
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + C i s pl ati n)
D L T P eri o d /
S h ort -t er m 
S af et y  F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D
1 t o 3 5
P T D
1 t o 9 0
P T D
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6, 3 1 a n d 
l a st F D/ E T Td
P T D
7 , 14 , 21 , 28, 
3 5 e
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0z, 
2 7 0, 3 1 2 z, a n d 
3 6 5
-
Vi sit Wi n d o w ( d a y s)
- 
- 
- 
- 
-
-
± 2
± 7
± 7
-
E s o p h a g e al e n d o s c o p y ( if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n 
R T ar e a
X 
X
X
X
X
X
E C O G P S
X
X
L a st F D o nl y
X
X
X
A d v er s e e v e nt 
a s s e s s m e nt
X 
X
X 
X
X
X
X l
X l
C o n c o mit a nt m e di c ati o n
X 
X
X 
X
X
X
H e m at ol o g y m
X 
X
X 
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n n
X 
X
X 
X
X
X
Uri n al y si s ( di p sti c k) o
X
X
F D 1 6 a n d 
l a st F D o nl y
X
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) p
X 
X q
X r
X r
X r
X r
T u m or a s s e s s m e nt 
( R E CI S T)s , t
X
X
X
P K bl o o d s a m pl e s u
X 
X v
X 
X
Ar c hi v al t u m or m at eri al w
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al 
F U
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + C i s pl ati n)
D L T P eri o d /
S h ort -t er m 
S af et y  F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D
1 t o 3 5
P T D
1 t o 9 0
P T D
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6, 3 1 a n d 
l a st F D/ E T Td
P T D
7 , 14 , 21 , 28, 
3 5 e
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0z, 
2 7 0, 3 1 2 z, a n d 
3 6 5
-
Vi sit Wi n d o w ( d a y s)
- 
- 
- 
- 
-
-
± 2
± 7
± 7
-
S ur vi v al 
X a a
A E = a d v er s e e v e nt; C T = c o m p ut e d t o m o gr a p h y; 
 D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U = f oll o w -u p; F/ W
= fr a cti o n p er 
w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; H P V = h u m a n p a pill o m a vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st- tr e at m e nt D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = 
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n ( pl u s ci s pl ati n o n F D s a s s p e cifi e d a b o v e). P o st-tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s 
of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar l at er .
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D
3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
If F D 1 0 i s o n a Fri d a y, P K, P D, s af et y l a b or at or y, a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 - 3 5 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n t h e 
l a st F D s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit.
e.
All A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 3 3 -3 5 t o e v al u at e t h e o c c urr e n c e of D L T s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 4 9
f.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
g.
I m m u n o hi st o c h e mi str y i n t u m or m at eri al.
h.
A s n e e d e d a c c or di n g t o l o c al g ui d eli n e s.
i.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
j.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
k.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
l.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
m.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
n.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
o.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
p. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
q. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
r.
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
s.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
t.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g -t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1-1 8 0 [ 4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
u.
P K s a m pl e s will f oll o w t h e s a m pli n g f or P h a s e I a a s d et ail e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d b y t h e S M C b a s e d o n e m er gi n g d at a. S e e 
S e cti o n 7. 5. 1 f or d et ail s.
v.
Pr e d o s e o nl y.
w.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e).
z.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
a a.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 / 1 4 9
T a ble 6
Sc he d ule of Assess me nts – P h ase I b (Ar m B; S C C H N C o h ort)
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + Ci s pl ati n )
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 26, 
3 1 a n d l a st 
F D / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0x , 
2 7 0, 3 1 2 x ,
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 
o nl y
I nf e cti o n s cr e e n ( h e p atiti s B 
a n d C), o pti o n al HI V t e st e
X
H P V st at u s i n t u m or f
X
A u di o gr a m g
X
Vit al si g n s h
X i
X
X
X
X
X
P h y si c al e x a mi n ati o n
X
X
X
X
X
X
X j
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X
X
X
X
X
E s o p h a g e al e n d o s c o p y ( if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n R T 
ar e a
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + Ci s pl ati n )
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 26, 
3 1 a n d l a st 
F D / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0x , 
2 7 0, 3 1 2 x ,
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
E C O G P S
X
-
L a st F D o nl y
P T D 3 0 
o nl y
X
X
A d v er s e e v e nt a s s e s s m e nt
X
X
X
X
X
X k
X k
C o n c o mit a nt m e di c ati o n
X
X
X
X
X
H e m at ol o g y l
X
X
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n m
X
X
X
X
X
Uri n al y si s ( di p sti c k) n
X
F D 1 6 a n d l a st F D
o nl y
P T D 3 0 
o nl y
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) o
X
X p
X q
X q
X q
X q
T u m or a s s e s s m e nt 
( R E CI S T)r, s
X
X
X
P K bl o o d s a m pl e s t
X
X
Ar c hi v al t u m or m at eri al
u
X
S ur vi v al 
X y
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 / 1 4 9
C T = c o m p ut e d t o m o gr a p h y; ct D N A = cir c ul ati n g t u m or D N A; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y 
Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U
= f oll o w -u p; F/ W = fr a cti o n p er w e e k; G y = G r a y; 
H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; H P V = h u m a n p a pill o m a vir u s; M RI
= m a g n eti c r e s o n a n c e i m a gi n g; P D = 
p h ar m a c o d y n a mi c s; P G x = p h ar m a c o g e n eti c s; P K = p h ar m a c o ki n eti c s; P T D = P o st -tr e at m e nt D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n ( pl u s ci s pl ati n o n F D s a s s p e cifi e d a b o v e). P o st-tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s 
of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar l at er .
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s
ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D
3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
If F D 1 0 i s o n a Fri d a y, P K, P D, a n d s af et y l a b or at or y s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 - 3 5 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n t h e 
l a st F D s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T e r mi n ati o n vi sit.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
f.
I m m u n o hi st o c h e mi str y i n t u m or m at eri al.
g.
A s n e e d a c c or di n g t o l o c al g ui d eli n e s.
h.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 for d et ail s.
i.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
j.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
k.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
l.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
m.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
n.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
o. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
p. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e.
q. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
r.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
s.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g -t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1-1 8 0 [ 4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
t.
S p ar s e P K s a m pl e s w ill b e c oll e ct e d a s d et ail e d i n T a bl e 9.  T h e s e s a m pli n g ti m e p oi nt s mi g ht b e r e- s c h e d ul e d b a s e d o n P K r e s ult s fr o m P h a s e I a b y t h e 
S M C.
u.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e). If n o ar c hi v al m at eri al i s a v ail a bl e t h e n a fr e s h 
bi o p s y s h o ul d b e t a k e n .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 4 9
w.
Pr e d o s e w h ol e bl o o d a n d pl a s m a s a m pli n g f or P G x.
x.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
y.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 / 1 4 9
T a ble 7
Sc he d ule of Assess me nts – A ncill ar y Cli nic al Pr o of -of- Pri nci ple P art
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt D ur ati o n
F U
S af et y  F oll o w u p
a n d E n d of Tri al
Tri al D a y s
D a y -2 1 t o - 1
1
2
3 t o 1 0
1 1 t o 32
M 3 8 1 4
-
-
X
-
-
R T: 1 0 -2 5 G y a
L e si o n 1
L e si o n 2
Tri al Vi sit D a y
– 2 1 t o – 1
1 b
2
1 0
3 2
Vi sit wi n d o w ( d a y s)
-
-
-
± 1
± 2
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m pr e g n a n c y t e st 
(if a p pli c a bl e)
X
I nf e cti o n s cr e e n ( h e p atiti s B a n d C ), o pti o n al 
HI V t e st c
X
Vit al si g n s d
X e
X f
X f
X
P h y si c al e x a mi n ati o n
X
E v al u ati o n of all ti s s u e s i n R T ar e a
X
X
X
X
E C O G P S
X
A d v er s e e v e nt a s s e s s m e nt
X
X
X
X
X g
C o n c o mit a nt m e di c ati o n
X
X
X
X
H e m at ol o g y h
X
X
X
S er u m c h e mi str y a n d c o a g ul ati o n i
X
X
X
Uri n al y si s ( di p sti c k)j
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt D ur ati o n
F U
S af et y  F oll o w u p
a n d E n d of Tri al
Tri al D a y s
D a y -2 1 t o - 1
1
2
3 t o 1 0
1 1 t o 32
M 3 8 1 4
-
-
X
-
-
R T: 1 0 -2 5 G y a
L e si o n 1
L e si o n 2
Tri al Vi sit D a y
– 2 1 t o – 1
1 b
2
1 0
3 2
Vi sit wi n d o w ( d a y s)
-
-
-
± 1
± 2
1 2 -l e a d E C G (i n cl u di n g Q T c F)
X
P K bl o o d s a m pl e
X m
L o c al t u m or a s s e s s m e nt ( R E CI S T) o, p
X
X
E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s ; F U = f oll o w -u p; F/ W =  fr a cti o n p er w e e k; G y = Gr a y; 
HI V = h u m a n i m m u n o d efi ci e n c y vir u s; L 1 = L e si o n 1; L 2 = L e si o n 2; P D = p h ar m a c o d y n a mi c s; P K = p h ar m a c o ki n eti c s; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; 
R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y.
a.
T o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g .
b.
F or l o gi sti c al r e a s o n s ( h a n dli n g a n d s e n di n g m at eri al s), D a y 1 m u st b e o n a W e d n e s d a y or e arli er.
c.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
d.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht.
e.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
f.
Pr e d o s e vit al si g n s .
g.
L o c al t ol er a bilit y o nl y .
h.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
i.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
j.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s .
m.
P K s a m pl e s will b e c oll e ct e d a s d e s cri b e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d i n t h e c o ur s e of t h e tri al. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 / 1 4 9
o.
L o c al t u m or a s s e s s m e nt (i n irr a di at e d l e si o n s) b y cli ni c al e x a m or i m a gi n g a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or e v al u ati o n c a n b e u p t o 2 1 d a y s ol d 
w h e n tr e at m e nt st art s.
p.
O nl y a p pli c a bl e f or a d diti o n al c o h ort s wit h M 3 8 1 4 
 f or m ul ati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 / 1 4 9
T a ble 8
R a di ot her a p y ( A l o ne) a n d M 3 8 1 4
+ R T Sc he d ule f or t he A ncill ar y 
C li nic al P r o of - of- Pri nci ple (c P o P) P art of t he Tri al
D a y 1 ( b a s eli n e) a
D a y 1
D a y 2
L e si o n 1
Bi o p s y
B 1
B 3 b
--
R T c
--
+
--
M 3 8 1 4
--
-
--
L e si o n 2
Bi o p s y
B 2
--
B 4 b
R T c
--
--
+
M 3 8 1 4
--
--
+
R T = r a di ot h er a p y .
a.
B a s eli n e bi o p s y t o b e t a k e n a n y ti m e pri or t o R T f or b ot h l e si o n s ( S cr e e ni n g t o D a y 1).
b.
C or e bi o p s y n e e d s t o b e p erf or m e d 2 t o 4 h o ur s aft er R T. D et ail e d ti m e s c h e d ul e a n d s a m pl e c oll e cti o n 
pr o c e d ur e s will b e d e s cri b e d i n t h e l a b or at or y m a n u al .
c.
R a di ot h er a p y will b e gi v e n a s a si n gl e hi g h d o s e of R T ( 1 0- 2 5 G y) . T h e d o s e of M 3 8 1 4
s h o ul d b e 
a d mi ni st er e d 1. 5 h o ur s ( ± 3 0 mi n ut e s) b ef or e r a di ot h er a p y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 4 9
T a ble 9
P h ar m ac o ki netic a n d 
 S a m pli n g Sc he d ule of M 3 8 1 4
d uri n g P h ase I a, P h ase I b , a n d t he A ncill ar y c P o P P a rt of t he Tri al
Ti m e p oi nt s
V ol u m e of 
bl o o d r e q uir e d 
p er ti m e p oi nt a
P h a s e I a
P h a s e I b b
A n cill ar y  c P o P
P K c
2 m L 
P K c
2 m L
P K c
2 m L
F D 1
Pr e d o s e
X
X
H 0. 5
X
X
H 1. 0
X
R T
1 . 5 h o ur s
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
1 0 -2 5
H 2. 0
X
X
H 4 . 0
X
X
H 6. 0
X
X
F D 2
Pr e d o s e d
X
X
H 0. 5
X
H 1. 0
X
R T
1 . 5 ho ur s
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
1 0 -2 5
H 2. 0
X
H 4. 0
X
F D 6
Pr e d o s e d
X
H 0. 5 g
X
H 1. 0 g
X
R T
1. 5 h o ur s 
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
H 2. 0 g
X
H 4. 0 g
X
H 6. 0 g
X
F D 7 g
Pr e d o s e d
X
F D 1 0 f
Pr e d o s e d
X
X
H 0. 5
X
X
H 1. 0
X
R T
1 . 5 h o ur s
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
H 2. 0
X
X
H 4. 0
X
X
c P o P = cli ni c al pr o of -of -pri n ci pl e; F D = fr a cti o n d a y; F/ W = fr a cti o n p er w e e k; G y = G r a y; N S C L C = n o n -s m all c ell l u n g 
c a n c er;
; P K = p h ar m a c o ki n eti c; R T = r a di ot h er a p y; S C C H N = s q u a m o u s c ell c ar ci n o m a 
h e a d a n d n e c k; S M C = S af et y M o nit ori n g C o m mitt e e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 4 9
M 3 8 1 4
als o tar gets PI 3 K , s pecifically t he delta is of or m, at a c o nce ntrati o n 1 5 5 -f ol d hi g her t ha n 
t hat nee de d t o o btai n a n i n hi biti o n of D N A -P K. T he c o nce ntrati o ns necessar y t o i n hi bit t he vari o us 
ot her PI 3 K is of or ms are 4 0 0 - 5 0 0 ti mes hi g her t ha n t hat nee de d t o i n hi bit D N A -P K. O ne a d diti o nal 
k n o w n off -tar get of i nterest is affecte d by M 3 8 1 4 , h u ma n c ycl o -o x y ge nase, wit h a 5 0 % i n hi bit or y  
c o nce ntrati o n of 1. 7 µ M.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 4 9
3. 1. 2
F or m ul ati o n De vel o p me nt
A p o w d er i n ca ps ule ( P i C) f or m ulati o n is use d i n t his trial; t hese ca ps ules are fille d wit h b ul k dr u g 
s u bsta nce a n d d o n ot c o ntai n a n y  exci pie n ts. H o we ver, the pr o d ucti o n pr ocess f or t he ca ps ules is 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 / 1 4 9
n ot easil y s ustai na ble f or st u dies wit h a hi g h n u m ber of s u bjects. T he dr u g pr o d uct t hat is g oi n g t o 
be use d f or P hase II s h o ul d be a f or m ulati o n ma n ufact ure d wit h acce pta ble scale-u p a bilit y  of t he 
p har mace utical pr ocess t o easil y su p pl y P hase II trials. T heref ore , fil m-c oate d 
 ta blets ha ve 
bee n de vel o pe d a n d are g oi n g t o be i n vesti gate d i n t his trial.
3. 2
Tri al P o p ul ati o n
T he trial p o p ulati o n i n P hase Ia, Ar m A, c o nsists of pre vi o usl y treate d s u bjects dia g n ose d wit h 
l ocall y a d va nce d disease (a ny t u m or i ncl u di n g l y m p h o mas) l ocalize d i n t he hea d a n d nec k re gi o n
or t h ora x t hat is n ot a me na ble t o s ur gical t hera py wit h a n i n dicati o n f or palliati ve R T ( 3 0 G y  in 
1 0 fracti o ns). P hase I a, Ar m B, c o nsists of s u bjects wit h treat me nt-naï ve s q ua m o us cell carci n o ma 
hea d a n d nec k (S C C H N ) eli gi ble f or a c o urse of c urati vel y i nte n de d R T ( 6 6 t o 7 0 G y  in 3 3 t o 
3 5 fracti o ns) wit h c o nc urre nt cis plati n. I n t he P hase I b part, t he trial p o p ulati o n is treat me nt-naï ve 
s u bjects wit h n o n- s mall cell l u n g ca ncer (N S C L C ) Sta ge III A/ B ( n ot eli gi ble f or s ur gical resecti o n 
or c o nc urre nt c he m ora diati o n) eli gi ble f or a c o urse of c urati vel y i nte n de d R T
( 6 6 G y  in 
3 3 fracti o ns) ( Ar m A) ; a f urt her trial p o p ulati o n of S C C H N s u bjects, as s pecifie d f or Ar m B i n 
P hase I a a n d usi n g t he sa me c he m ora di ot hera p y  ( C R T) re gi me n, will be i ncl u de d ( Ar m B) .
I n t he a ncillar y c P o P part of t he trial, t he trial p o p ulati o n is s u bjects wit h at least t w o
(s u b)c uta ne o us t u m or/ metastases of a ny t y p e (at least 2 c m a part) wit h a n i n dicati o n f or hi g h d ose 
palliati ve R T ( 1 0-2 5 G y  i n o ne fracti o n).
3. 3
R ati o n ale f or Tri al Desi g n a n d J ustific ati o n of St arti n g D ose
T his trial is desi g ne d i n t w o se q ue ntial parts, a n d i ncl u des o ne a ncillar y c P o P part t hat will r u n i n 
parallel wit h t he P hase I a/Ib c ore trial. T h us, t he o verall trial has 5 mai n parts (Fi g ure 1) . P hase Ia 
Ar m A
will e val uate t he safety a n d t olera bility of M 3 8 1 4
i n c o m bi nati o n wit h fracti o nate d 
palliati ve R T i n all-c o mers wit h l ocall y ad va nce d t u m ors or metastases l ocalize d i n t he hea d a n d 
nec k re gi o n or t h ora x. P hase Ia Ar m B will e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n 
c o m bi nati o n wit h fracti o nate d c urati vel y i nte n de d R T i n c o m bi nati o n wit h c o nc urre nt cis plati n i n 
s u bjects wit h treat me nt-naï ve l ocal/l ocall y  a d va nce d S C C H N. T he P hase I b part will e val uate t he 
safety a nd o verall res p o nse of M 3 8 1 4
i n c o m bi nati o n wit h fracti o nate d c urati vel y i nte n de d R T i n 
s u bjects wit h Sta ge III A/ B N S C L C a n d t he safety a n d o verall res p o nse of M 3 8 1 4
i n c o m bi nati o n 
wit h fracti o nate d c urati vel y inte n de d R T wit h c o nc urre nt cis plati n i n s u bjects wit h l ocal/l ocall y 
a d va nce d S C C H N. T he a ncillar y c P o P part of t he trial will be c o n d ucte d i n parallel wit h t he P hase 
Ia/I b c ore trial t o e x pl ore t he P D effect of M 3 8 1 4
i n c o m bi nati o n wit h R T o n tar get e n ga ge me nt 
i n t u m or tiss ue.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 4 9
3. 4
R ati o n ale f or R a di ot her a p y D ose
T he R T d oses pr o p ose d f or t he P hase Ia (Ar m A: 3 G y  x 10; 5 fracti o ns per wee k [ F/ W] a n d 
Ar m B: 2 G y  x 3 3 t o 3 5 ; 5 F/ W ) a n d P hase I b (2 G y  x 33; 5 F/ W [ N S C LC] a n d 2 G y  x 3 3 t o 3 5;
5 F/ W [ S C C H N] ) are Sta n dar d of Care ( S o C) f or palliati ve a n d c urati ve i nte n de d ra di ot hera p y i n 
t he s pecifie d areas of t he b o d y . I n t he a ncillar y c P o P part of t he trial (si n gle d ose 1 0- 2 5 G y ) t he 
l o wer li mit of 1 0 G y is set as t his is t he t hres h ol d t hat nee ds t o be gi ve n bef ore we ca n detect t he 
p har mac o d y n a mics si g nal. T he ra n ge of 1 0 t o 2 5 G y is als o t he S o C w he n hi g h d ose ra di ot hera p y 
is gi ve n as a si n gle s h ot.
3. 5
R ati o n ale f or Cis pl ati n D ose
T he d ose of cis plati n pr o p ose d f or P hase Ia, Ar m B a n d P hase I b, e x pa nsi o n c o h ort f or Ar m B 
( S C C H N) is 1 0 0 m g/ m 2 gi ve n t wice ( o n F D 1 a n d F D 3 1), or 4 0 m g/ m 2 gi ve n wee kl y, c o nc urre ntl y 
wit h R T. T he d oses are i n li ne wit h c urre nt me dical g ui deli nes ( Nati o nal C o m pre he nsi ve Ca ncer 
Ne t w or k, A merica n C olle ge of C hest P h y sicia ns/A merica n S ociet y o f Cli nical O nc ol o g y [ A S C O], 
a n d E ur o pea n S ociet y  for Me dical O nc ol o g y ) wit h refere nce t o t he S o C f or c o nc urre nt C R T wit h 
cis plati n i n t he treat me nt of s u bjects wit h S C C H N.
3. 6
K n o w n a n d P ote nti al Ris ks a n d Be nefits t o H u m a n S u bjects
T his cli nical trial will be c o n d ucte d i n c o m plia nce wit h t he I CH E 6 G C P G ui da nce,
a n d a n y 
a d diti o nal a p plica ble re g ulat or y re q uire me nts.
T he be nefit -ris k relati o ns hi p has bee n caref ull y co nsi dere d i n t he pla n ni n g of t he trial. Base d o n 
t he 
data o n M 3 8 1 4
a n d o n p u blis he d n o n cli nical a n d cli nical data s h o wi n g e vi de nce of 
cell deat h a n d t u m or s hri n ka ge after si n gle-a ge nt use i n t u m ors wit h pre -e xisti n g altere d re pair 
mec ha nis ms, t h us ill ustrati n g t he c o nce pt of s ynt hetic let halit y, t he c o n d uct of t his trial is 
c o nsi dere d j ustifia ble usi n g t he d ose(s) a n d d osa ge re gi me n(s) of t he I MP as s pecifie d i n t his 
cli nical trial pr ot oc ol [ 1, 2, 3].
It is k n o w n t hat R T ca n ca use ac ute t o xicities i n t he f or m of, f or e xa m ple, ra diati o n der matitis a n d 
m uc ositis. Defi niti ve c o nc urre nt C R T, c o nsi dere d t he S o C f or i n o pera ble l oc ore gi o nally a d va nce d 
S C C H N, is ass ociate d wit h si g nifica nt ac ute t o xicities i ncl u di n g st o matitis ( oral m uc ositis), 
s wall o wi n g dys f u ncti o n ( o d yn o p ha gia, d y s pha gia), decrease d a p petite, a n d der matitis [4, 5, 6, 7] .
F or i nc ura ble hea d a n d nec k ca ncers, R T has bee n de m o nstrate d t o be a n effecti ve palliati ve 
m o dalit y  an d m ost ac ute t o xicities are ge nerall y relate d t o m uc osal i nfla m mati o n a n d der matitis, 
e ve n t h o u g h t he se verit y an d fre q ue nc y of t hese A Es were l o wer c o m pare d wit h C R T i n t he 
c urati ve setti n g [ 8]. Late t o xicities arisi n g 3 m o nt hs or later after t he e n d of R T ca n be see n i n t he
f or m of, f or e xa m ple, xer ost o mia, es o p ha gitis, p ne u m o nitis, a n d fi br osis. Patie nts s h o ul d be 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 / 1 4 9
re mi n de d t o c o ntact t he trial site i m me diatel y in case of t o xicities w here t he y will be e val uate d a n d 
treate d as a p pr o priate acc or di n g t o i nstit uti o nal g ui deli nes . P ote ntiall y  ac ute a n d late t o xicities ca n 
be m ore se vere w he n R T is gi ve n i n c o m bi nati o n wit h M 3 8 1 4.
T his will be e val uate d o n a n 
o n g oi n g basis f or u p t o 1 2 m o nt hs after t he e n d of treat me nt .
I n this trial, t he S M C will m o nit or t he be nefit -ris k rati o o n a n o n g oi n g basis . The trial will b e 
disc o nti n ue d i n t he e ve nt of a n y ne w fi n di n gs t hat i n dicate a rele va nt deteri orati o n of t he 
be nefit -ris k rati o f or t he s u bjects, w hic h w o ul d re n der c o nti n uati o n of t he trial u nj ustifia ble.
Base d o n t he a vaila ble 
 a n d cli nical data t o date, t he c o n d uct of t he trial s pecifie d i n 
t his pr ot oc ol is c o nsi dere d j ustifia ble i n s u bjects wit h l ocall y  a d va nce d disease. 
4
Tri al O bjecti ves
4. 1
Pri m ar y O bjecti ves
T he pri mar y  o bjecti ves of t he trial are:

P hase Ia ( d ose escalati o n): 
o
( Ar m A) T o deter mi ne t he ma xi m u m t olerate d d ose (M T D)
a n d a R P 2 D f or M 3 8 1 4
i n 
c o m bi nati o n wit h fracti o nate d palliati ve R T f or t u m ors or metastases l ocalize d i n t he hea d 
a n d nec k re gi o n or t h ora x ( 3 G y x 1 0; 5 F/ W).
o
( Ar m B) T o deter mi ne t he M T D a n d a R P 2 D f or M 3 8 1 4
i n c o m bi nati o n wit h c urati vel y 
i nte n de d C R T ( 2 G y  x 3 3 t o 3 5; 5 F/ W wit h c o nc urre nt cis plati n) i n treat me nt-naï ve
s u bjects wit h l ocal/l ocall y a d va nce d S C C H N .

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
( Ar m A) T o
e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h 
fracti o nate d R T
( 2 G y  x 3 3 ; 5 F/ W) i n treat me nt-naï ve s u bjects wit h S ta ge III A/ B 
N S C L C n ot eli gi ble f or c o nc urre nt c he m ora diati o n
o
( Ar m B) T o e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h C R T
( 2 G y x 3 3 t o 3 5; 5 F/ W wit h c o nc urre nt cis plati n) i n s u bjects wit h treat me nt-naï ve
S C C H N .
4. 2
Sec o n d ar y O bjecti ves
T he sec o n dar y  o bjecti ves of t he trial are:

P hase Ia ( d ose escalati o n): 
o
T o e val uate t he safety pr ofile a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h palliati ve 
R T f or t u m ors or metastases l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x ( Ar m A) a n d 
i n c o m bi nati o n wit h c urati vel y inte n de d C R T i n treat me nt-naï ve s u bjects wit h S C C H N
( Ar m B)
o
T o e x pl ore t he a ntit u m or acti vit y of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A) a n d C R T
( Ar m B).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 4 9

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
T o e x pl ore t he efficac y i n ter ms of o verall res p o nse rate, pr o gressi o n -free s ur vi val ( P F S) 
a n d o verall s ur vi val ( O S) of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A) or i n c o m bi nati o n 
wit h C R T ( Ar m B) , a n d l ocal/l ocal re gi o nal t u m or c o ntr ol ( Ar m B)

P hase Ia , P hase I b, a n d a ncillar y c P o P parts : T o assess t he P K of M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 / 1 4 9
5
I n vesti g ati o n al Pl a n
5. 1
O ver all Tri al Desi g n a n d Pl a n
T his is a c o m bi ne d P hase Ia/I b, o pe n la bel, d ose escalati o n, a n d d ose e x pa nsi o n trial desi g ne d t o 
e x pl ore t he sa fet y, t olera bilit y, P K a n d P D pr ofile, a n d cli nical acti vit y of M 3 8 1 4 i n c o m bi nati o n 
wit h R T / C R T, a n d t o deter mi ne t he M T D a n d R P 2 D f or M 3 8 1 4
i n c o m bi nati o n wit h R T / C R T. A n 
a ncillar y cP o P part of t he trial will be c o n d ucte d i n parallel wit h t he P hase Ia/I b c ore trial t o e x pl ore 
t he P D effect of M 3 8 1 4
i n c o m bi nati o n wit h R T o n tar get e n ga ge me nt i n t u m or tiss ue.
I n t he P hase Ia part of t he trial, pre vi o usl y treate d s u bjects wit h l ocally a d va nce d disease (a ny 
t u m or or metastas es i ncl u di n g ly m p h o mas) l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x t hat is 
n ot a me na ble t o s ur gical t hera p y, or wit h sta n dar d s yste mic t hera p y wit h a n i n dicati o n f or 
palliati ve R T ( 3 0 G y i n 1 0 fracti o ns) will be i ncl u de d i n Ar m A. After t he first d ose le vel ( 1 0 0 m g 
M 3 8 1 4 ) i n Ar m A has bee n c o m plete d, a sec o n d d ose escalati o n ar m ( Ar m B) will be i nitiate d at 
a starti n g d ose of 5 0 m g M 3 8 1 4
i n treat me nt-naï ve s u bjects wit h S C C H N, w h o are eli gi ble f or 
fracti o nate d R T (6 6 t o 7 0 G y  i n 3 3 t o 3 5 fracti o ns) wit h c o nc urre nt cis plati n. I n t he P hase I b part, 
eac h ar m fr o m P hase Ia will ha ve a n e x pa nsi o n c o h ort. After esta blis h me nt of R P 2 D i n Ar m A, 
s u bjects wit h treat me nt-naï ve S ta ge III A/ B N S C L C n ot eli gi ble f or s ur gical resecti o n or
c o nc urre nt c he m ora diati o n will be gi ve n M 3 8 1 4
i n c o mbi nati o n wit h R T ( 6 6 G y  in 3 3 fracti o ns)
i n t he Ar m A e x pa nsi o n c o h ort. T he e x pa nsi o n c o h ort f or Ar m B will i ncl u de treat me nt-naï ve
s u bjects wit h S C C H N, as s pecifie d i n P hase Ia a n d will be gi ve n t he sa me C R T ( 6 6 t o 7 0 G y i n 3 3 
t o 3 5 fracti o ns wit h c o nc urre nt cis plati n) i n c o m bi nati o n wit h M 3 8 1 4
at t he R P 2 D esta blis he d i n 
P hase Ia Ar m B. I n t he a ncillar y c P o P part of t he trial, s u bjects wit h at least 2 (s u b)c uta ne o us 
t u m or/ metastases of a n y t y p e (at least 2 c m a part) wit h a n i n dicati o n f or si n gle hi g h d ose palliati ve 
R T will be i ncl u de d.
A sc he matic of t he o verall trial desi g n is s h o w n i n Fi g ure 1,  t he d ose escalati o n is s h o w n i n 
Fi g ure 2 a n d t he treat me nt o ver vie w wit h t he ta ble ts i n P hase Ia Ar m A is s h o w n i n  Fi g ure 3 . T he 
Sc he d ule of Assess me nt s is s h o w n f or the P hase Ia part of t he trial i n Ta ble 1 ( Ar m A - ca ps ule), 
Ta ble 2 ( Ar m A – ta blet), a n d Ta ble 5 ( Ar m B, S C C H N c o h ort), f or t he first 3 s u bjects i n t he
P hase I b part of t he trial (Ar m A , N S C L C c o h ort) i n Ta ble 3,  f or t he P hase I b part of t he trial i n
Ta ble 4 (Ar m A , N S C L C c o h ort) a n d Ta ble 6 (Ar m B, S C C H N c o h ort), a n d t he a ncillar y c P o P
part of t he trial i n Ta ble 7 . In a d diti o n, t he sc he d ule of trial treat me nt a n d bi o psies i n t he a ncillar y
c P o P part of t he trial are o utli ne d i n Ta ble 8.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 4 9
Fi g ure 1
O ver vie w of T ri al D esi g n wit h 5 S e g me nts
ci s = ci s pl ati n; c P o P = cli ni c al pr o of- of -pri n ci pl e; C R T = c h e m or a di ot h er a p y; G y = gr a y;  
 = 
 
N S C L C = n o n - s m all c ell l u n g c a n c er; R T = r a di ot h er a p y; S C C H N = S q u a m o u s c ell c ar ci n o m a h e a d a n d n e c k .
Ar m  A / P h a s e Ia p art
A n y t um o r or m et a st a s e s i n  
h e a d , n e c k  or t hor a x  3 G y
× 1 0
•
D o s e e s c al ati o n  in 
p a lliati v e s etti n g
•
 f or mul a ti o n to b e 
i ntr o du c e d
Ar m  A / P h a s e I b p art
N S C L C III A/ B
•
2 G y × 3 3 E x p a n s i o n   
c o h o rt f or R T co m bi n a ti o n
•
E s t a blis h  saf et y pr ofil e of 
c o m b i nati o n  in p a ti e nt s n o t 
el i gi bl e for c o n c u rr e nt 
c h e m or a d i ati o n
Ar m B / P h a s e I a p ar t
tr e at me n t-n a ï ve S C C H N
2 G y × 3 3 t o 3 5 + ci s
•
D o s e e s c al ati o n  in c u r ati ve 
s etti n g,  ini ti at e d i n US o n l y
•
C R T  wit h Ci s pl ati n
Ar m  B / P h a s e I b p ar t
tr e at me n t-n a ï v e S C C H N
2 G y × 3 3 t o 3 5 + ci s
•
E x p a n s i o n co h ort f or C R T 
c o m b i nati o n
A n ci ll ar y c P o P p art of t h e tr i al
S u bj e ct s wi t h at le a st t w o c ut a n e o u s t um o r s or m et a st a s e s. Pr e a n d 
p o st tr e at me n t bi o p si e s t a k e n  to e v al u a t e o n tar g et m o d ul a ti o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 / 1 4 9
Fi g ure 3
Tre at me nt O ver vie w ( P h ase I a Ar m A )
D L T = d o s e li miti n g t o xi cit y; F D = fr a cti o n d a y; G y = gr a y; R T = r a di ot h er a p y.
N ot e: t h e st arti n g d o s e f or t h e t a bl et i s 5 0 % of t h e c urr e nt t ol er a bl e c a p s ul e f or m ul ati o n.
Scree ni n g Per i o d
After pr o vi di n g i nf or me d c o nse nt f or t he trial a n d t he P G x a nal ysis, t he eli gi bilit y of trial s u bjects 
will be esta blis he d acc or di n g t o t he pr ot oc ol -defi ne d incl usi o n ( Secti o n 5. 3. 1 ) a n d excl usi o n 
criteria (Secti o n 5. 3. 2 ) d uri n g a ma xi m u m 2 1 -da y  Scree ni n g Peri o d (scree ni n g a n d baseli ne 
e val uati o n s). O nce all scree ni n g pr oce d ures ha ve bee n c o m plete d a n d it has bee n c o nfir me d t hat a 
s u bject meets all t he eli gi bilit y criteria, t he s u bject will be e nr olle d i nt o t he trial a n d e nter t he 
treat me nt p eri o d. 
Tre at me nt Peri o ds
I n t he P hase Ia part ( Ar ms A a n d B) , su bjects will be assi g ne d t o a d ose deter mi ne d b y  the S M C 
i n t he ne xt a vaila ble o pe n treat me nt c o h ort g ui de d b y  a Ba yesia n l o gistic re gressi o n m o del wit h 
o ver d ose c o ntr ol. O nl y  escalati o n i n t he ta blet c o h ort of Ar m A will be perf or me d acc or di n g t o a 
3 + 3 desi g n as it is n ot pla n ne d t o deter mi ne M T D, b ut rat her c o nfir m t he R P 2 D of t he ca ps ule 
f or m ulati o n. F ull details of t he d osi n g re gi me ns f or M 3 8 1 4
are pr o vi de d i n Secti o n 6. 3. All 
treat me nt wit h M 3 8 1 4
will be gi ve n i n c o m bi nati o n wit h R T o nl y i n Ar m A, a n d i n c o m bi nati o n 
wit h C R T i n Ar m B .
T hr o u g h o ut t he treat me nt peri o d , s u bjects i n all c o h orts will atte n d re g ular trial visits f or d osi n g, 
safety e val uati o ns a n d bl o o d sa m pli n g f or P K a n d P D , as descri be d i n Secti o n 7.
P hase Ia 
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, s u bjects i ncl u de d i n t he P hase Ia, 
Ar m A, part of t he trial will recei ve treat me nt wit h M 3 8 1 4
at a starti n g d ose of 1 0 0 m g  QD f or 
2 c o nsec uti ve wee ks d uri n g t he peri o d R T ( 3 G y x 1 0, 5 F/ W) is gi ve n. T he a d mi nistrati o n of 
M 3 8 1 4
will ta ke place 1 . 5 h o urs ( ± 3 0 mi n utes) bef ore t he start of R T.
I n Ar m A, the s u bjects i n t he d ose escalati o n part will recei ve t he ca ps ule f or m ulati o n of M 3 8 1 4 
t hr o u g h o ut, e xce pt f or t he s u bjects i n t he ta blet testi n g c o h orts , w h o
will recei ve t he ca ps ule 
DL T p eri o d
Tr e at m e nt a d mi nistr ati o n
( M 3 8 1 4 + 3 G y R T)
Tr i al d a y
1 2 3 4 5 6 7 8
1 5
2 2 
2 9
s af ety f oll o w-u p
Fr acti o n d a y ( F D)
1 2 3 4 5 
6 7 8 9 1 0
Tr i al w e e k
1
2 
3 
4 
5
t a bl et
c a ps ul e
Ta bl e t t esti n g c o h orts
t a bl et
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 4 9
It is pla n ne d t o e nr oll 1 1 s u bjects wit h (s u b)c uta ne o us t u m or/metastases i n t he a ncillar y c P o P part 
of t he trial usi n g M 3 8 1 4 
ca ps ule f or m ulati o n a n d a p pr o xi matel y 12 a d diti o nal s u bjects wit h 
(s u b)c uta ne o us t u m or/ metastases usi n g M 3 8 1 4 
 f or m ulati o n.
F oll o w -u p Peri o ds
P hase Ia /Ib
T he f oll o w- u p peri o d f or all s u bjects i n t he P hase Ia a n d I b part s of t he trial will c o nsist of t he 
f oll o wi n g: 

D L T Peri o d : A 5- wee k ( Ar m A) or 1 2- wee k ( Ar m B) D L T p eri o d after t he first d ose of M 3 8 1 4
f or t he e val uati o n of ‘ac ute’ s yste mic a n d l ocal t o xicit y i n all s u bjects i n P hase Ia a n d a 1 2- wee k 
D L T peri o d after t he first d ose of M 3 8 1 4
i n t he first 3 s u bjects of t he safet y ru n- i n part i n t he 
N S C L C e x pa nsi o n c o h ort d uri n g P hase I b ( Ar m A)

S h ort -ter m Safet y F oll o w -u p: A f oll o w- u p f or a peri o d of 3 0 d a y s after t he e n d of R T f or 
e val uati o n of safet y

Mi d -ter m Safety F oll o w - u p: A safet y f oll o w -u p peri o d of 3 m o nt hs after e n d of R T t o e val uate 
si g ns of R T-i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

L o n g -ter m Safet y F oll o w - u p: A safety f oll o w-u p peri o d u ntil 1 2 m o nt hs
after e n d of R T t o 
e val uate late si g ns of R T -i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

S ur vi val F oll o w - u p: A f oll o w -u p peri o d t hat will c o nti n ue u ntil 1 2 m o nt hs after t he last s u bject 
has st o p pe d R T/ C R T.
A ncillar y  c P o P part
S u bject o verall safety will be e val uate d u p t o Da y 1 0 ( F oll o w- u p Peri o d) . L ocal t olera bilit y  will 
be re p orte d o n D a y s 1 0 a n d 3 2 ( D a y s 8 a n d 3 0 after t he e n d of treat me nt, Safet y  Foll o w -u p Peri o d) . 
I n a d diti o n, o n Da y 1 0 l ocal t u m or res p o nse will be assesse d i n irra diate d lesi o ns ( o nl y a p plica ble
f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 f or m ulati o n]). S u bjects will be per mitte d t o recei ve a n y 
i n dicate d s yste mic t hera pe utic m o dalit y as s o o n as cli nicall y i n dicate d after Da y 1 0.
5. 1. 1
D ose E sc al ati o n Rules
T he criteria f or d ose escalati o n are base d o n t he occ urre nce of A Es a n d/ or D L Ts t hat are u nrelate d 
t o u n derl y i n g c o n diti o ns a n d/ or t o c o nc o mita nt me dicati o n d uri n g t he D L T peri o d i n e val ua ble 
s u bjects i n eac h c o h ort. T he D L T wi n d o w of 5 wee ks (P hase Ia, Ar m A) or 1 2 wee ks (P hase Ia, 
Ar m B a n d t he first 3 s u bjects i n t he e x pa nsi o n c o h ort f or Ar m A [ N S C L C]) after t he start of 
M 3 8 1 4 treat me nt all o ws a n e val uati o n of ac ute t o xicit y. M 3 8 1 4
d ose escalati o n will n ot pr ocee d 
t o t he ne xt d ose le vel u ntil all s u bjects i n t he pre vi o us d ose le vel ha ve bee n o bser ve d f or t he 
d urati o n of t he D L T peri o d . H o we ver, R T / C R T a n d t he c o m bi nati o n of R T / C R T a n d M 3 8 1 4
ca n 
als o gi ve rise t o later t o xicities. A 3- m o nt h mi d -ter m safet y f oll o w-u p will be perf or me d i n all 
s u bjects i n t he Phase Ia part of t he trial a n d, o nce a vaila ble, t hese data will als o g ui de s u bse q ue nt 
d ose escalati o n a n d t he esta blis h me nt of t he R P 2 D. A vaila ble P K a n d P D data will als o be ta ke n 
i nt o c o nsi derati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 4 9
D ose Esc al ati o n D uri n g P h ase I a
A Ba yesia n t w o-para meter l o gistic re gressi o n m o del wit h o ver d ose c o ntr ol will be use d t o assist 
t he S M C wit h d ose selecti o n d uri n g t he P hase Ia d ose escalati o n (ca ps ule f or m ulati o n i n Ar m A/ B, 
a n d ta blet f or m ulati o n i n Ar m B) . C o h orts of 3 s u bjects eac h will be treate d at t he sa me d ose le vel 
(ca ps ule starti n g d ose: 1 0 0 m g Q D f or Ar m A a n d 5 0 m g Q D f or Ar m B). T he m o del i nc or p orates 
pri or i nf or mati o n (fr o m n o n cli nical data) a n d o bser ve d i nf or mati o n fr o m eac h c o m plete d c o h ort 
(a n d data fr o m all pre vi o us c o h orts) t o pr o vi de a rec o m me n de d d ose f or t he ne xt c o h ort. A 
preselecte d set of acce pta ble d oses are c o nsi dere d b y t he m o del, h o we ver d oses w hic h are n ot part 
of t he pres pecifie d set ma y  be c h ose n as well . T he m o del e ns ures t hat rec o m me n de d d oses 
c orres p o n d t o a pr o ba bilit y  of less t ha n 2 5 % t hat t he tr ue D L T rate is m ore t ha n 3 5 % i n Ar m A 
a n d 4 5 % i n Ar m B . D ose escalati o n will st o p i n eac h ar m as s o o n as t he first of t he f oll o wi n g 
st o p pi n g r ules a p pl y: a ma xi m u m of 3 0 s u bjects are i ncl u de d, m ore t ha n t hree c o h orts are assi g ne d 
t o t he sa me d ose le vel, or t he esti mate of D L T pr o ba bilit y  at t he M T D reac hes a s ufficie nt precisi o n
(see Secti o n 8 f or m ore details).
Selecti o n of t he R P 2 D deter mi ne d wit h t he ca ps ule f or m ulati o n will be perf or me d i n P hase Ia Ar m 
A base d o n t he a vaila ble cli nical i nf or mati o n alrea d y ge nerate d wit h t he M 3 8 1 4 
ca ps ule at 
escalati n g d oses. T heref ore, it is a ntici pate d t hat a s maller n u m ber of d ose c oh orts a n d s u bjects 
will be re q uire d t o reassess safety, t olera bilit y an d P K of M 3 8 1 4 after d osi n g wit h t he ta blet 
f or m ulati o n i n c o m bi nati o n wit h R T b y  use of sta n dar d 3 + 3 d ose escalati o n desi g n criteria (see 
S ecti o n 5. 1. 2 f or m ore details). 
D ose Esc al ati o n D uri n g P h ase I b
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, treat me nt-naï ve s u bjects wit h 
S ta ge III A/ B N S C L C e nr olle d i n t he P hase I b part of t he trial ( Ar m A e x pa nsi o n c o h ort) will 
recei ve M 3 8 1 4 , t o be gi ve n 1. 5 h o urs ( ± 3 0 mi n utes) bef ore eac h R T fracti o n f or 3 3 fracti o ns. T he 
d ose of M 3 8 1 4
f or t he first 3 s u bjects will be esta blis he d fr o m t he a vaila ble data i n b ot h ar ms of 
the P hase Ia part of t he trial . I n cas e a R P 2 D i n A r m B has bee n esta blis he d bef ore a R P 2 D fr o m 
Ar m A, t he n t he Ar m A e x pa nsi o n c o h ort ca n be i nitiate d at t he R P 2 D i de ntifie d i n Ar m B. I n case 
a R P 2 D has bee n esta blis he d first i n Ar m A, t he first 3 s u bjects will be treate d o ne d ose le vel bel o w 
t he R P 2 D. Base d o n t he safety pr ofile, t he S M C will deci de if t he d ose ca n be escalate d t o t he 
R P 2 D i de ntifie d i n P hase Ia, Ar m A. 
T he d ose i n t he Ar m B e x pa nsi o n c o h ort will be t he deter mi ne d R P 2 D of M 3 8 1 4
fr o m P hase Ia 
Ar m B a n d will be gi ve n t o s u bjects wit h treat me nt-naï ve S C C H N i n c o m bi nati o n wit h t he sa me 
C R T re gi me n as i n P hase Ia ( Ar m B).
D oses of M 3 8 1 4
i n t he A ncill ar y c P o P P art of t he Tri al
I n the a ncillar y c P o P part of t he trial, t he d oses are fi xe d at 1 0 0 m g , 2 0 0 m g, a n d 4 0 0 m g . After 
t he t hree pla n ne d c o h orts, a d diti o nal c o h ort(s) mi g ht be o pe ne d u p o n S M C decisi o n.
T he si n gle d ose of M 3 8 1 4
t o be a d mi nistere d o n Da y  2 of t he a ncillar y c P oP part of t he trial is 
fi xe d f or s uccessi ve c o h orts as s h o wn i n Ta ble 1 2.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 / 1 4 9
t o xicities at eac h ne w d ose. T he S M C ma y deci de t o sto p d ose escalati o n at a n y d ose le vel base d 
o n safety a n d P K data.
I ntr o d ucti o n a n d e val uati o n of t he ta blet will be perf or me d i n t he P hase Ia, Ar m A part of t he trial. 
A first c o h ort of patie nts will recei ve t he ta blet f or m ulati o n at a d ose of 1 0 0 m g. Base d o n t he 
pre vi o us cli nical e x perie nce wit h t he M 3 8 1 4 ca ps ule d oses u p t o 4 0 0 m g i n t he o n g oi n g d ose 
escalati o n, a n d t he a ntici pate d ma xi mal e x p os ure after a d mi nistrati o n of t he ta blet, t he i nitial ta blet 
d ose of 1 0 0 m g i n t he first ta blet c o h ort is e x pecte d t o be safe a n d well -t olerate d.
After re vie w of t he safety, t olera bilit y, a n d P K data fr o m t his c o h ort i n relati o n t o t he data o btai ne d 
i n t he o n g oi n g d ose escalati o n, t he S M C ma y  deci de t o test f urt her ta blet d ose le vels. T he ai m is 
t o c o nfir m t he R P 2 D t hat has bee n defi ne d f or t he ca ps ule, usi n g t he ta blet f or m ulati o n. 
T he desi g n of t he ta blet testi n g c o h orts i n t he P hase Ia part of Ar m A als o i ncl u des i ntra-i n di vi d ual 
c o m paris o n of si n gle d ose P K of M 3 8 1 4 after a d mi nistrati o n of t he ta blet vers us ca ps ule. T he 
ca ps ule a d mi nistere d o n F D 6 after a 4 8- h o ur was h -o ut is n o t e x pecte d t o be i nfl ue nce d b y  th e 
pre vi o us a d mi nistrati o n of M 3 8 1 4 ta blets o n F D 1 t o F D 5, c o nsi deri n g t he me dia n ter mi nal half -life 
of 5. 5 h o urs (ra n ge 2. 0 t o 8. 8 h o urs, preli mi nar y data esti mate d i n t he 
) 
after m ulti ple dail y  dosi n g. Cli nical safety, t olera bilit y , a n d P K res ults o btai ne d i n P hase Ia Ar m A 
will deter mi ne s u bse q ue nt i ntr o d ucti o n of t he ta blet i n ot her parts of t he trial.
5. 2. 1
I ncl usi o n of S peci al P o p ul ati o ns
N ot a p plica ble.
5. 3
Selecti o n of Tri al P o p ul ati o n
O nl y s u bjects meet i n g all i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria ma y be e nr olle d i nt o 
t he trial. Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical care, 
t he I nvesti gat or will e ns ure t hat t he s u bject has pr o vi de d writte n i nf orme d c o nse nt f oll o wi n g t he 
pr oce d ure descri be d i n Secti o n 9. 2.
F or s u bjects i n P hase Ia a n d I b, arc hi val t u m or material m ust be a vaila ble, eit her as a bl oc k or 
sli des ( m ost rece nt material) . If n o arc hi val material is a vaila ble t he n a fres h bi o ps y  sh o ul d be 
ta ke n.
All s u bjects i n t he a ncillar y c P o P part of t he trial m ust a gree t o ha ve t u m or bi o psies 
c ollecte d.
5. 3. 1
I ncl usi o n Criteri a
T o be eli gi ble t he s u bject m ust f ulfil l all of t he f oll o wi n g criteria:
1.
S u bjects m ust ha ve:
a. P h ase I a p art : a d va nce d s oli d t u m ors or metastases i ncl u di n g l ym p h o ma l ocalize d i n t he
hea d a n d nec k re gi o n or t h ora x wit h a n i n dicati o n f or fracti o nate d palliati ve R T ( Ar m A); 
or treat me nt-naï ve
S C C H N eli gi ble f or fracti o nate d c urati vel y i nte n de d R T wit h 
c o nc urre nt cis plati n ( Ar m B)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 4 9
b. P h ase I b p art : treat me nt-naï ve S ta ge III A/ B N S C L C n ot eli gi ble f or s ur gical resecti o n
or c o nc urre nt c he m ora diati o n ( Ar m A e x pa nsi o n c o h ort) or treat me nt-naï ve S C C H N 
eli gi ble f or fracti o nate d c urati vel y inte n de d R T wit h c o nc urre nt cis plati n ( Ar m B 
e x pa nsi o n c o h o rt)
c. A ncill ar y c P o P p art : a n y t u m or wit h at least 2 (s u b)c uta ne o us t u m or/ metastases at least 
2 c m a part w hic h are R T naï ve wit h a n i n dicati o n f or hi g h d ose palliati ve R T
2.
Meas ura ble or e val ua ble disease acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors 
(R E CI S T ) v 1. 1 (n ot re q uire d f or t he a ncillar y c P o P part of t he trial )
3.
Male or fe male s u bjects at least 1 8 y ears of a ge 
4.
Easter n C o o perati ve O nc ol o g y  Gr o u p p erf or ma nce stat us ( E C O G P S) ≤1
5.
M ust ha ve rea d, well u n derst o o d, a n d si g ne d a n d date d t he I nf or me d C o nse nt F or m (I C F); t he 
s u bject f ull y un dersta n ds t he re q uire me nts of t he trial a n d is willi n g t o c o m pl y wit h all trial 
visits a n d assess me nts
6.
A male partici pa nt m ust a gree t o use a n d t o ha ve t heir fe male part ners t o use a hi g hl y ef fecti ve 
c o ntrac e pti o n (ie, met h o ds wit h a fail ure rate of less t ha n 1 % per year) as detaile d i n 
A p pe n di x E of t his pr ot oc ol 1 4 d a y s bef ore first d ose of trial treat me nt, duri n g t he treat me nt 
peri o d a n d f or at least 9 0 da y s after t he last d ose of trial treat me nt a n d refrai n fr o m d o nati n g 
s per m d uri n g t his peri o d
7.
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt (see A p pe n di x E ), n ot 
breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns a p plies:
a. N ot a w o ma n of c hil d beari n g p ote ntial ( W O C B P) as defi ne d i n  A p pe n di x E
O R
b. A W O C B P w h o a grees t o use a hi g hl y effecti ve c o ntrace pti o n (ie, met h o ds wit h a fail ure 
rate of less t ha n 1 % per year) , as detaile d i n A p pe n di x E of t his pr ot oc ol , 1 4 da y s bef ore 
t he start o f first d ose of trial treat me nt, d uri n g t he treat me nt peri o d a n d f or at least 9 0 d a y s
after t he last d ose of trial treat me nt
8.
L ife e x pecta nc y of ≥3 m o nt hs
( P hase Ia, Ar m A) or ≥6 m o nt hs
(P hase Ia, Ar m B a n d 
P hase I b).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 4 9
5. 3. 2
E xcl usi o n Criteri a
5. 3. 2. 1
P h ase I a/I b P arts
S u bjects are n ot eli gi ble f or t he P hase Ia or I b parts of t he trial if t he y fulfill a n y  of t he f oll o wi n g 
e xcl usi o n criteria:
1.
Pri or treat me nt c o nsisti n g of: 
a. C he m ot hera p y, i m m u n ot hera p y, h or m o nal t hera p y, bi ol o gic t hera p y, or a n y ot her 
a ntica ncer t hera p y or I M P wit hi n 2 8 da y s of first trial dr u g i nta ke ( 6 wee ks f or 
nitr os o ureas or mit o m y ci n C) f or P hase Ia, Ar m A s u bjects, a n d a n y pri or t hera p y for 
P hase I b s u bjects. F or s u bjects wi t h ra pi dl y gr o wi n g t u m ors l ocalize d i n t he hea d a n d 
nec k re gi o n or t h ora x w here t he treati n g p h y sicia n ca n n ot wait f or 2 8 d a y s, i ncl usi o n ma y  
ta ke place if t here is n o resi d ual t o xicit y fr o m pre vi o us treat me nt ( ma xi m u m 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] G ra de 1)
b. Pri or R T t o t he sa me re gi o n wit hi n 1 2 m o nt hs
( P hase Ia, Ar m A ; s u bjects wit h t u m ors 
l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x ) or at a n y ti me pre vi o usl y (P hase Ia, Ar m 
B ; treat me nt-naï ve s u bjects wit h S C C H N a n d P hase I b; treat me nt-naï ve s u bjects wit h
S ta ge III A/ B N S C LC or S C C H N )
c. E xte nsi ve pri or R T o n ≥3 0 % of b o ne marr o w reser ve as j u d ge d b y  the In vesti gat or or 
pri or b o ne marr o w/ste m cell tra ns pla ntati o n wit hi n 5 years bef ore trial start
2.
Resi d ual t o xicit y  d ue t o pri or t hera py wit h n o ret ur n t o baseli ne or ≤Gra de 1 (e xce pt al o pecia 
acc or di n g t o C T C A E v 4. 0 3)
3.
S ur gical i nter ve nti o n , i ncl u di n g bi o psies a n d de ntal r o ot s ur geries, wit hi n 2 8 da y s pri or t o t he 
first d ose of I M P a d mi nistrati o n or ha vi n g partici pate d i n a n i nter ve nti o nal cli nical trial wit hi n 
2 8 da y s pri or t o t he first d ose of I M P a d mi nistrati o n f or P hase Ia/I b. Nee dle bi o psies are n ot 
c o nsi dere d as s ur ger y .
4.
P o or vital or ga n f u ncti o ns defi ne d as: 
a. B o ne marr o w 
i m pair me nt as e vi de nce d b y  he m o gl o bi n < 1 0. 0 g/ d L
( 5. 7 µ m ol/ L) , 
ne utr o p hil c o u nt < 1. 0 × 1 0 9/L , platelets < 1 0 0 × 1 0 9/ L
b. Re nal i m pair me nt as e vi de nce d b y ser u m creati ni ne > 1. 5 × u p per li mit of n or mal ( U L N )
c. Li ver f u ncti o n a b n or malit y as defi ne d b y  total bilir u bi n > 1. 5 × U L N or as partate 
a mi n otra nsferase (A S T )/ala nine a mi n otra nsferase ( A L T ) > 2. 5 × U L N
(e xce pt f or 
s u bjects wit h li ver i n v ol ve me nt, w h o ca n ha ve A S T/ A L T > 5 × U L N )
5.
Si g nifica nt car diac c o n d ucti o n a b n or malities,i ncl u di n g a hist or y  of l o n g Q Tc s yn dr o me a n d/ or 
pace ma ker, or i m paire d car di o vasc ular f u ncti o n s uc h as Ne w Y or k Heart Ass ociati o n 
classificati o n sc ore > 2
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 4 9
6.
H y perte nsi o n u nc o ntr olle d b y  me dicati o n 
7.
K n o w n C N S metastases u nless pre vi o usl y treate d b y  RT, sta ble b y  c o m p ute d t o m o gra p hy (C T )
sca n f or at least 3 m o nt h s wit h o ut e vi de nce of cere bral e de ma a n d n o re q uire me nt f or 
c ortic oster oi ds or a ntic o n v ulsa nts
8.
K n o w n h u ma n i m m u n o deficie nc y vir us (HI V) p ositi vit y , k n o w n cli nicall y si g nifica nt hist or y 
of he patitis (e. g., He patitis B [ H B V] or He patitis C [ H C V] vir us), c urrent alc o h ol a b use, or 
cirr h osis . Scree ni n g f or HI V t o be perf or me d acc or di n g t o l ocal practice a n d l ocal re g ulat or y 
g ui da nce. Testi n g f or HI V a n d H B V/ H C V s h o ul d be re peate d if t he s u bject teste d ne gati ve f or 
t he vir uses m ore t ha n 3 m o nt hs bef ore trial e nr oll me nt
9.
O n g oi n g acti ve i nfecti o n ot her t ha n HI V, H B V or H C V , or treat me nt wit h a li ve atte n uate d 
vacci ne wit hi n 3 0 da y s of d osi n g
1 0. Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n or ot her c hr o nic gastr oi ntesti nal disease or 
c o n diti o ns t hat m a y  ha m per c o m plia nce a n d/ or a bs or pti o n of t he I MP, c urre nt use of 
perc uta ne o us e n d osc o pic gastr ost o m y ( P E G) t u bes
1 1. Hist or y  of a n y ot her si g nifica nt me dical disease s uc h as maj or gastric or s mall b o wel s ur ger y, 
rece nt drai na ge of si g nifica nt v ol u mes (as per I n vesti gat or’s j u dge me nt) of ascites or ple ural 
eff usi o n or a ps yc hiatric c o n diti o n t hat mi g ht i m pair t he s u bject’s well -bei n g or precl u de f ull 
partici pati o n i n t he trial
1 2. K n o w n h y perse nsiti vit y  t o t he trial treat me nt or t o o ne or m ore of t he e xci pie nts use d
1 3. Pre g na n c y or lactati o n peri o d
1 4. Le gal i nca p acit y or li mite d le gal ca pacit y
1 5. S u bjects c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose of trial
dr u g) me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors of C Y P 3 A or C Y P 2 C 1 9 
m ust st o p at least 1 wee k pri or t o ta ki n g M 3 8 1 4 . S u bjects recei vi n g p ote nt i n d ucers of C Y P 3 A 
or C Y P 2 C 1 9 m ust st o p at least 3 wee ks pri or t o ta ki n g M 3 8 1 4 . T h ose recei vi n g dr u gs mai nly 
meta b olize d b y  CY P 3 A wit h a narr o w t hera pe utic i n de x as j u d ge d b y  the I nvesti gat or (a n d 
after o pti o nal c o ns ultati o n wit h t he S p o ns or) m ust st o p at least o ne da y pri or t o ta ki n g M 3 8 1 4 .
1 6. S u bjects c urre ntl y recei vi n g H2-bl oc ker or pr ot o n p u m p i n hi bit ors ( P PI s) ( or u na ble t o st o p at 
least 5 da ys pri or t o t he first treat me nt).
1 7. If t he pla n ne d ra diati o n fiel d i ncl u des a ny p art of t he es o p ha g us a n d t he s u bject has s ym pt o ms 
of o n g oi n g es o p ha gitis, t he s u bject is n ot eli gi ble, u nless a n es o p ha geal e n d osc o p y rules o ut 
t he prese nce of es o p ha gitis.
1 8. S u bject s w here m ore t ha n 1 0 % of t he t otal es o p ha g us v ol u me recei ves m ore t ha n 5 0 % of t he 
prescri be d R T d ose .
O ut of ra n ge la b orat or y  val ues ma y be reteste d wit hi n t he ti mefra me of t he scree ni n g peri o d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 / 1 4 9
5. 3. 2. 2
A ncill ar y Cli nic al Pr o of -of -Pri nci ple P art
S u bjects are n ot eli gi ble f or t he a ncillar y c P o P part of t he trial if t he y fulfill a n y of t he f oll o wi n g 
e xcl usi o n criteria:
1. Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n or ot her c hr o nic gastr oi ntesti nal disease or 
c o n diti o ns t hat ma y ha m per c o m plia nce a n d/ or a bs or pti o n of t he I M P
2. Hist or y  of a n y ot her si g nifica nt me dical disease s uc h as maj or gastric or s mall b o wel s ur gery, 
rece nt drai na ge of si g nifica nt v ol u mes of ascites or ple ural eff usi o n (as per I n vesti gat or’s 
j u d ge me nt) or a ps yc hiatric c o n diti o n t hat mi g ht i m pair the s u bject’s well -bei n g or precl u de 
f ull partici pati o n i n t he trial
3. K n o w n h y perse nsiti vit y  t o t he trial treat me nt or t o o ne or m ore of t he e xci pie nts use d 
4. Pre g na n c y or lactati o n peri o d
5. Le gal i nca pacit y or li mite d le gal ca pacit y
6. S u bjects c urre ntl y recei vi ng ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose of trial
dr u g) me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors of C Y P 3 A or C Y P 2 C 1 9 
m ust st o p at least 1 wee k pri or t o ta ki n g M 3 8 1 4 . S u bjects recei vi n g p ote nt i n d ucers of C Y P 3 A 
or C Y P 2 C 1 9 m ust st o p at least 3 wee ks pri or t o ta ki n g M 3 8 1 4 . T h ose recei vi n g dr u gs mai nl y 
meta b olize d b y  CY P 3 A wit h a narr o w t hera pe utic i n de x as j u d ge d b y  the I nvesti gat or (a n d after 
o pti o nal c o ns ultati o n wit h t he S p o ns or) m ust st o p at least o ne da y  pri or t o ta ki n g M 3 8 1 4 .
5. 4
Criteri a f or I niti ati o n of Tri al Tre at me nt
T his is a n o pe n la bel trial wit h o ut ra n d o mizati o n. S u bjects w h o pr o vi de writte n i nf or me d c o nse nt 
a n d w h o meet all rele va nt eli gi ble criteria will recei ve o pe n la bel M 3 8 1 4
at t he c urre ntl y r ecr uiti n g
c o h ort d ose le vel.
5. 5
Criteri a f or S u bject Wit h dr a w al
5. 5. 1
Wit h dr a w al fr o m Tri al T her a p y
T he s u bject m ust be wit h dra w n fr o m I M P i n t he e ve nt of a ny of t he f oll o wi n g:

Occ urre nce of a n e xcl usi o n criteri o n w hic h is cli nicall y rele va nt a n d affects t he s u bject’s safety,  
if disc o nti n uati o n is c o nsi dere d necessar y by t he I n vesti gat or a n d/ or S p o ns or pri or t o treat me nt 
c o m pleti o n 

T hera pe utic fail ure re q uiri n g ur ge nt a d diti o nal dr u g (if a p plica ble)

Disc o nti n uati o n of R T

A d verse dr u g reacti o ns ( AD R s) t hat ca use R T dela y s of > 7 da y s
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 4 9

Occ urre nce of A Es, if disc o nti n uati o n of trial dr u g is desire d or c o nsi dere d necessar y  by t he 
I n vesti gat or a n d/ or t he s u bject (if a p plica ble)

Occ urre nce of pre g na nc y

Use of a n o n per mitte d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 6,  w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he I M P

Ne w sta n dar d e xisti n g t hera py t hat is c o nsi dere d m ore s uita ble acc or di n g t o t he Pri nci pal 
I n vesti gat or

N o nc o m plia nce t hat is dee me d b y t he I n vesti gat or or t he S p o ns or t o c o m pr o mise s u bject safet y 
or trial i nte grit y .
5. 5. 2
Wit h dr a w al fr o m t he Tri al
S u bjects are free t o disc o nti n ue t he trial at a n y ti me wit h o ut gi vi n g t heir reas o ns. 
A s u bject m ust be wit h dra w n i n t he e ve nt of a ny of t he f oll o wi n g:

Wit h dra wal of t he s u bject’s c o nse nt

Partici pati o n i n a n y ot her trial d uri n g t he d urati o n of t his trial ( u p t o 1 2 m o nt hs i n P hase Ia a n d 
I b parts a n d u p t o 3 2 da ys i n t he a ncillar y c P o P part)

Pre g na nc y pri or t o treat me nt c o m pleti o n or u p t o 3 0 da y s after R T.
If a s u bject has faile d t o atte n d sc he d ule d trial assess me nts, t he I n vesti gat or m ust deter mi ne t he 
reas o ns a n d t he circ u msta nces as c o m pletely a n d acc uratel y as p ossi ble.
I n case of pre mat ure wit h dra wal fr o m t he trial, assess me nts f or Fracti o n Da y  1 0 (Ar m A) or last 
Fracti o n D a y ( 3 3 t o 3 5; Ar m B) i n P hase Ia , Fracti o n Da y  3 3 (N S C L C c o h ort ) or last Fracti o n Da y 
( 3 3 t o 3 5; S C C H N c o h ort) i n P hase I b a n d t he E O T visit s h o ul d be perf or me d , if p ossi ble wit h 
f oc us o n t he m ost rele va nt assess me nts (Ta ble 1 [ P hase Ia – Ar m A
ca ps ule c o h orts ], Ta ble 2
[ P hase Ia – Ar m A ta blet c o h orts], Ta ble 3 [first 3 s u bjects i n P hase Ib – Ar m A, N S C L C c o h ort], 
Ta ble 4 [P hase I b – Ar m A, N S C L C c o h ort], Ta ble 5 [ P hase Ia: – Ar m B, S C C H N c o h ort], Ta ble 6
[ P hase I b – Ar m B, S C C H N c o h ort], a n d Ta ble 7 [a ncillar y c P o P part of t he trial]). I n an y  case, 
t he ap pr o priate electr o nic Case Re p ort F or m (e C R F) secti o n m ust be c o m plete d.
5. 6
Pre m at ure Ter mi n ati o n of t he Tri al
T he cli nical trial ma y  be ter mi nate d pre mat urel y at t he re q uest of Healt h A ut h orities or if ne w 
safety or efficac y i nf or mati o n lea ds t o a n u nfa v ora b le be nefit-ris k j u d g me nt (e. g., d ue t o e vi de nce 
of i na de q uate dr u g e x p os ure; occ urre nce of si g nifica nt pre vi o usl y  un k n o w n a d verse reacti o ns or 
u ne x pecte dl y  hi gh i nte nsit y  or i nci de nce of k n o w n a d verse reacti o ns; or o t her u nfa v ora ble safety 
fi n di n gs i n t his trial or t he FI M trial or a ny ot her trial ).
T he S p o ns or m a y  disc o nti n ue t he trial if it bec o mes u nj ustifia ble f or me dical or et hical reas o ns, 
f or p o or e nr oll me nt ma ki n g c o m pleti o n of t he trial wit hi n a n acce pta ble ti me fra me u nli kel y, or 
beca use of di sc o nti n uati o n of cli nical de vel o p me nt of M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 4 9
Healt h A ut h orities a n d I nde pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal Re vie w B oar ds (I R Bs) 
will be i nf or me d a b o ut t he disc o nti n uati o n of t he trial i n acc or da nce wit h a p plica ble re g ulati o ns.
5. 7
Defi niti o n of E n d of Tri al
T he trial will e n d after t he last s u bject i n t he P hase I b part has c o m plete d t he 1 -ye ar f oll o w-u p 
peri o d or all s u bjects i n t he a ncillar y c P o P part of t he trial ha ve c o m plete d t he 3 0- da y  foll o w u p ,
w hic he ver c o mes later.
6
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n 
t he Tri al
T he ter m “In vesti gati o nal Me dici nal Pr o d uct” refers t o a n acti ve s u bsta nce or a place b o bei n g 
teste d or use d as a refere nce t hera py i n a cli nical trial, i ncl u di n g pr o d ucts t hat ha ve a mar keti n g 
a ut h orizati o n b ut are f or m ulate d , pac ka ge d , or a d mi nistere d differe ntl y  fr o m t he a ut h orize d f or m, 
use d f or a n u na ut h orize d i n dicati o n, or use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.  
I n t his trial, t he ter m “In vesti gati o nal Me dici nal Pr o d uct” refers t o t he i n vesti gati o nal dr u g M 3 8 1 4 , 
w hic h is t he o nl y  IM P use d i n t his trial.
6. 1
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct
M S C 2 4 9 0 4 8 4 A, I nter nati o nal U ni o n of P ure a n d A p plie d C he mistr y  na me ( S)-[ 2-chl or o - 4-fl u or o-
5- ( 7-m or p h oli n -4 -yl -q ui naz oli n - 4-yl )-p he n y l]-( 6-met h o x y -p y ri dazi n- 3-yl )-met ha n ol, is s u p plie d 
as 1 0 m g (size 4, i v or y ), 5 0 m g (size 0, i v or y ), a n d 1 0 0 m g (size 0, S we dis h ora n ge) har d gelati n 
ca ps ules, as well as 5 0 m g ( bei ge t o yell o w ca plet) fil m-c oate d ta blets f or oral a d mi nistrati o n. 
Ca ps ules c o nsist of b ul k dr u g s u bsta nce fille d i nt o har d gelati n ca ps ules of differe nt size a n d/ or 
c ol or, de pe n di n g o n t he d ose stre n gt h. N o f urt her e xci pie nts are use d. Har d gelati n ca ps ule s hells 
meet t he s u p plier’s ( Ca ps u gel ®) sta n dar ds a n d gelati n is of p har mac o p oeial gra de .
Fil m -c oate d ta blets c o nsist of a ta blet c ore c o m p ose d of e xtr u date ( 2 0 % ( w/ w) dr u g s u bsta nce/ 8 0 % 
( w/ w) c o p o vi d o ne s oli d dis persi o n) a n d ot her e xci pie nts 
 
. All e xci pie nts use d i n t he ta blet f or m ulati o n 
are of c o m pe n dial gra de. S u p plier’s certificates s h o w t hat t here is n o tra ns missi ble s p o n gif or m 
e nce p hal o pat h y ris k.
M S C 2 4 9 0 4 8 4 ca ps ules a n d ta blets are pr o vi de d i n 
 a n d s h o ul d be 
st ore d
. T he ta blets s h o ul d n ot be fr oze n.
6. 2
Descri pti o n of C o nc urre nt C he m ot her a p y
C he m o t hera py will be a d mi nistere d i n c o m bi nati o n wit h t he I M P ( M 3 8 1 4 ) i n s u bjects e nr olle d i n 
Ar m B. T he c he m ot hera p y a ge nt is cis plati n w hic h is c o nsi dere d S o C f or t his i n dicati o n. T his 
c he m ot hera pe utic a ge nt is a d mi nistere d via i ntra ve n o us (i v) i nf usi o n. D ose a n d d ose re gi me n of 
cis plati n is t o be a p plie d i n li ne wit h c urre nt me dical g ui deli nes ( Nati o nal C o m pre he nsi ve Ca ncer 
Net w or k , A merica n C olle ge of C hest P h y sicia ns/ A S C O, a n d E ur o pea n S ociet y  for Me dical 
O nc ol o g y ) wit h refere nce t o t he S o C f or c o nc urre nt C R T wit h cis plati n i n t he treat me nt of s u bjects 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 4 9
wit h S C C H N. T w o cis plati n d osi n g sc he d ules are all o we d, 1 0 0 m g/ m 2 gi ve n t wice or 4 0 m g / m2
gi ve n wee kl y d uri n g t he R T treat me nt . I n ad diti o n t o me dical g ui deli nes, d osi n g of cis plati n is t o 
be 
perf or me d 
i n acc or da nce wit h 
t he pr o d uct 
la beli n g a n d cli nical site’s s pecific 
p olicies /i nstr ucti o ns. Cis plati n
will n ot be s u p plie d b y  the S p o ns or. It will be use d fr o m 
c o m merciall y a vaila ble s o urces a n d pre pare d i n acc or da nce wit h its pr o d uct la beli n g.
6. 3
D os a ge a n d A d mi nistr ati o n
6. 3. 1
P h ase I a a n d I b P arts
S u bjects wit h l ocall y ad va nce d disease , as descri be d i n t he Eli g i bilit y Criteria ( Secti o n 5. 3 ), will 
be assi g ne d t o recei ve M 3 8 1 4
at a starti n g d ose of 1 0 0 m g Q D ( Ar m A) or 5 0 m g Q D ( Ar m B)
w hic h will be gi ve n 1. 5 h o urs ( ± 3 0 mi n utes) bef ore eac h R T fracti o n f or u p t o 1 0 fracti o ns
( Ar m A) or f or 3 3 t o 3 5 fracti o ns ( Ar m B) .
I n t he P hase Ia part of t he trial a n d f or t he first 3 s u bjects i n P hase I b ( N S C L C e x pa nsi o n c o h ort) , 
t he d ose of M 3 8 1 4
will
be i ncrease d acc ordi n g t o t he d ose escalati o n r ules descri be d i n
Secti o n 5. 1. 1. N o i ntras u bject d ose escalati o n is per mitte d.
S u bjects will ta ke t heir assi g ne d d ose of M 3 8 1 4
Q D wit h a f ull glass of water (a p pr o xi matel y 
2 4 0 m L / 8 fl ui d o u nces). 
S u bjects will be i nstr ucte d as f oll o ws:

O n d a y s wit h serial P K c ollecti o ns (Fracti o n Da y s 1 a n d 1 0 ), t o fast 1. 5 h o urs pri or t o d ose 
a d mi nistrati o n a n d c o nti n ue t o fast f or 4 h o urs p ost d os e

O n all ot her Fracti o n Da y s, t o fast 1. 5 h o urs pri or t o d ose a d mi nistrati o n a n d c o nti n ue t o fast 
f or 1 h o ur p ost d os e

Ta ke t he prescri be d d ose of M 3 8 1 4
1 . 5 h o urs ( ± 3 0 mi n utes) bef ore R T is starte d

S wall o w t he ca ps ules or ta blets w h ole a n d n ot bite i nt o t he ca ps ules, brea k or o pe n t he m, or 
atte m pt t o diss ol ve t he c o nte nts i n w ater pri or t o ta ki n g t heir assi g ne d d ose

T he d oses o n Fracti o n Da y s 1, 2, 6 a n d 1 0 s h o ul d n ot be ta ke n u ntil t he pre d ose P K c ollecti o n 
has bee n c o m plete d.
If a s u bject v o mits after ta ki n g t heir d ose of M 3 8 1 4 , t he y sh o ul d be gi ve n a n a ntie metic b ut n o 
f urt her d ose wi ll be gi ve n t hat da y . Pr o p h y lactic a ntie metics s h o ul d t he n be gi ve n pri or t o 
s u bse q ue nt d oses of M 3 8 1 4 . An y  cha n ge fr o m d osi n g sc he d ule, d ose i nterr u pti o ns, or d ose 
re d ucti o ns s h o ul d be rec or de d i n t he e C R F.
T he f or mal criteria f or M 3 8 1 4 , R T , a n d cis plati n d ose m o dificati o n i n t he trial are i ncl u de d i n 
Ta ble 1 3.
I n ge neral, eac h s u bject will sta y on t he M 3 8 1 4 , R T a n d cis plati n (as a p plica ble) d ose le vel 
assi g ne d i n t he trial u nless treat me nt nee ds t o be i nterr u pte d, m o difie d or st o p pe d. I n all ot her 
sit uati o ns, if t he In vesti gat or belie ves t hat a treat me nt-e mer ge nt a d verse e ve nt (T E A E ) is d ue t o 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 4 9
cis plati n, t he d ose is t o be m o difie d acc or di n g t o t he pac ka ge i nsert / S m P C or l ocal g ui deli nes. A 
cis plati n d ose dela y  of u p t o 1 wee k is per mitte d, i n a d diti o n t o t he s pecific g ui da nce pr o vi de d 
bel o w.
M 3 8 1 4 will be pr o vi de d as ta blet f or m ulati o n of 5 0 m g f or oral a d mi nistrati o n. D osi n g sc he d ule 
of t he ta blet f or m ulati o n f oll o ws t he descri pti o n gi ve n f or t he ca ps ule f or m ulati o n a b o ve. T he 
ta blet f or m ulati o n will be i nitiall y assesse d i n P hase Ia Ar m A ta ki n g i nt o acc o u nt t he a vaila ble 
safety, t olera bilit y a n d P K res ults fr o m t he ca ps ule. Sta n dar d 3 + 3 d ose escalati o n desi g n criteria 
will a p pl y. C o m paris o n of si n gle d ose P K data bet wee n t he ta blet a n d t he ca ps ule will g ui de t o 
defi ne t he ta blet d oses i n P hase Ia Ar m B a n d i n t he P hase I b parts.
F or s u bjects in Ar m B recei vi n g cis plati n:

T here will be n o d ose escalati o n of cis plati n a b o ve t he pr ot oc ol -s pecifie d d ose . H o we ver ,
cis plati n d ose re-escalati o n after a n i nitial d ose re d ucti o n, f oll o wi n g t he ma n ufact urer’s la bel, 
is per mitte d.

D ose m o dificati o ns f or t o xicit y sh o ul d be i n de pe n de ntl y assesse d pri or t o d ose a d mi nistrati o n 
at eac h visit f oll o wi n g i nstit uti o nal g ui deli nes or Ta ble 1 3 i n t he a bse nce of s uc h g ui deli nes.

Pr o p h y lactic gra n ul oc y t e-c ol o n y sti m ulati n g fact or ( G-C S F )
m a y  be i m ple me nte d if 
ne utr o pe nia res ults i n d ose re d ucti o n or d ose dela y  at pri or d oses, as s u g geste d i n t he A S C O
g ui deli nes. T hera pe utic use of he mat o p oiet ic c ol o n y-sti m ulati n g fact ors is per mitte d f oll o wi n g 
A S C O g ui deli nes.

I n t he e ve nt a s u bject e x perie nces ne utr o pe nia ,a n d G- C S F is i nitiate d,a n d ne utr o pe nia rec o vers 
wit hi n 4 8 h o urs after be gi n ni n g treat me nt wit h G- C S F, G- C S F m a y  be i m ple me nte d i n t he 
ma na ge me nt of ne utr o pe nia i n t his s u bject t o a v oi d d ose re d ucti o ns or h ol di n g a d ose.
He m o gl o bi n m ust be ≥1 0 g/ d L at F D 1 a n d m ust be ≥9 g/ d L f or all s u bse q ue nt d oses. If 
he m o gl o bi n is <9 g/ d L t he n a p pr o priate meas ures acc or di n g t o sta n dar d cli nical practice m ust be 
ta ke n pri or t o a ny f urt her d ose a d mi nistrati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 4 9
T a ble 1 3
D ose M o dific ati o ns f or M 3 8 1 4 , R a di ot her a p y, a n d Cis pl ati n D uri n g t he Tri al
T o xi cit y
D o s e M o difi c ati o n s
M 3 8 1 4
a
R a di ot h er a p y b
Ci s pl ati n
( o nl y f or Ar m B a n d i n t h e a b s e n c e 
of i n stit uti o n al g ui d a n c e o n 
ci s pl ati n d o s e m o difi c ati o n s)
T o xi citi e s i n R a di ati o n Fi el d Gr a d e 4

M u c o siti s
( mu c o s al i nfl a m m ati o n)

R a di ati o n d er m atiti s
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt o n c e s e v erit y 
r e s ol v e s t o Gr a d e ≤3.
T e m p or aril y i nt err u pt 
tr e at m e nt. R e s u m e tr e at m e nt 
o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤3.
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt o n c e s e v erit y 
r e s ol v e s t o Gr a d e ≤3.
S y st e mi c T o xi citi e s

F e bril e n e utr o p e ni a

Gr a d e 3 t hr o m b o c yt o p e ni a wit h m e di c all y c o n c er ni n g bl e e di n g

H e m at ol o gi c T o xi citi e s: A n y Gr a d e ≥4 t o xi cit y, e x cl u di n g:

Gr a d e 4 n e utr o p e ni a l a sti n g f or ≤5 d a y s a n d n ot 
a s s o ci at e d wit h f e v er

I s ol at e d Gr a d e 4 l y m p h o c yto p e ni a wit h o ut cli ni c al c orr el at e
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt ( at t h e s a m e 
d o s e) o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤ 1 or B a s eli n e . I n c a s e of 
a s e c o n d r e c urr e n c e at t h e s a m e 
gr a d e , p er m a n e ntl y di s c o nti n u e 
I M P.
N o a cti o n t o b e t a k e n .
F e bril e n e utr o p e ni a a n d Gr a d e 3 
t hr o m b o c yt o p e ni a wit h bl e e di n g: 
p er m a n e nt 2 5 % d o s e r e d u cti o n.
If o n t h e d a y of s c h e d ul e d tr e at m e nt 
wit h ci s pl ati n A N C i s < 1 5 0 0/ m m 3 , 
h ol d tr e at m e nt u ntil A N C 
≥1 5 0 0/ m m 3 , t h e n tr e at at 1 0 0 % 
d o s e.
If o n t h e d a y of s c h e d ul e d tre at m e nt 
wit h ci s pl ati n t h e pl at el et c o u nt i s 
< 7 5, 0 0 0/ m m 3 , h ol d tr e at m e nt u ntil 
pl at el et s ar e > 7 5, 0 0 0/ m m 3, t h e n tr e at 
at 1 0 0 % d o s e.
S y st e mi c T o xi citi e s

N o n h e m at ol o gi c T o xi citi e s

A n y Gr a d e ≥3 t o xi cit y, e x cl u di n g:

Di arr h e a of Gr a d e ≥3 ( ≤3 d a y s d ur ati o n) f oll o wi n g 
a d e q u at e a n d o pti m al t h er a p y

N a u s e a a n d v o miti n g of Gr a d e ≥3 ( ≤3 d a y s d ur ati o n) 
wit h a d e q u at e a n d o pti m al t h er a p y

F ati g u e or h e a d a c h e of Gr a d e 3 ( ≤7 d a y s d ur ati o n) 
f oll o wi n g i niti ati o n of a d e q u at e s u p p orti v e c ar e

A n y ot h er si n gl e l a b or at or y v al u e s of Gr a d e ≥3 o ut of 
t h e n or m al r a n g e t h at h a v e n o cli ni c al si g nifi c a n c e, a n d 
t h at r e s ol v e t o Gr a d e ≤2 wit h a d e q u at e m e a s ur e s 
wit hi n 7 d a y s
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt ( at t h e s a m e 
d o s e) o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤ 1 or B a s eli n e . I n c a s e of 
a s e c o n d r e c urr e n c e at t h e s a m e 
gr a d e , p er m a n e ntl y di s c o nti n u e 
I M P.
I n c a s e of Gr a d e ≥3 li v er e n z y m e 
v al u e s, t h e s u bj e ct m u s t b e 
m o nit or e d at l e a st e v er y 4 d a y s 
u ntil r e c o v er y t o Gr a d e ≤2.
N o a cti o n t o b e t a k e n .
I n stit uti o n al g ui d eli n e s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 4 9

E vi d e n c e of st u d y tr e at m e nt -r el at e d h e p at o c ell ul ar i nj ur y 
f or m or e t h a n 3 d a y s, s u c h a s > 5- f ol d el e v ati o n s a b o v e 
t h e U L N of A L T or A S T ( C T C A E Gr a d e 3 or 4) wit h or 
wit h o ut el e v ati o n of s er u m t ot al bilir u bi n t o > 2 × U L N, 
wit h o ut i niti al fi n di n g s of c h ol e st a si s ( el e v at e d s er u m 
a k ali n e p h o s p h at a s e) or ot h er a p p ar e nt cli ni c al c a u s alit y.
A E = a d v er s e e v e nt; A L T = al a ni n e a mi n otr a n sf er a s e; A N C = a b s ol ut e n e utr o p hil c o u nt; A S T = a s p art at e a mi n otr a n sf er a s e; C T C A E = c o m m o n t er mi n ol o g y crit eri a f or a d v er s e e v e nt s; 
I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; R T = r a di ot h er a p y; U L N = u p p er li mit of n or m al .
N ot e: S e v erit y of A E s will b e gr a d e d u si n g t h e C T C A E ( v 4. 0 3) t o xi cit y gr a d e s.
a A s all tr e at m e nt s wit h M 3 8 1 4
wi ll b e gi v e n i n c o m bi n ati o n wit h R T, a n i nt err u pti o n i n t h e a d mi ni str ati o n of R T w o ul d l e a d t o a n i nt err u pti o n i n tr e at m e nt wit h M 3 8 1 4 .
b A m a xi m u m R T d el a y of u p t o a n d i n cl u di n g 7 d a y s i n t ot al i s all o w e d wit hi n t h e c o m pl et e tr e at m e nt p eri o d. If R T a n d M 3 8 1 4
tr e at m e nt h a v e t o b e d el a y e d b y m or e t h a n 7 d a y s, t h e 
s u bj e ct m u st b e di s c o nti n u e d fr o m M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 4 9
A s all treat me nts wit h M 3 8 1 4
will be gi ve n i n c om bi nati o n wit h R T , a n i nterr u pti o n i n t he 
a d mi nistrati o n of R T w o ul d lea d t o a n i nterr u pti o n i n treat me nt wit h I M P. See Secti o n 6. 6. 3. 1 f or 
details o n ha n dli n g R T treat me nt dela y s.
6. 3. 1. 1
D os a ge a n d A d mi nistr ati o n of C o nc urre nt Cis pl ati n
T he c urre ntl y pr o p ose d re gi me n f or treat me nt-naï ve s u bjects wit h S C C H N i n P hase Ia ( Ar m B) 
a n d P hase I b ( S C C H N e x pa nsi o n c o h ort) c o nsists of Q D a d mi nistrati o n of M 3 8 1 4
o n eac h R T 
fracti o n da y t o get her wit h t he S o C (cis plati n).
O n Fracti o n D a y s 1 a n d 3 1 f or t he 1 0 0 m g/ m 2 d ose , or wee kl y  for t he 4 0 m g/ m 2 d ose , cis plati n 
will be gi ve n acc or di n g t o i nstit uti o nal g ui deli nes.
T he ti mi n g of ra di ot hera p y after t he a d mi nistrati o n of cis plati n will als o f oll o w i nstit uti o nal 
g ui deli nes, a p plica ble f or P hase Ia, A r m B ( d ose escalati o n) a n d t he Ar m B ( S C C H N) e x pa nsi o n
c o h ort o nl y . A d mi nistrati o n of M 3 8 1 4
will ta ke place 1. 5 h o urs ( ± 3 0 mi n utes) bef ore t he start of 
ra di ot hera py (see Secti o n 6. 3. 1) .
B o d y s urface area (B S A) s h o ul d be calc ulate d base d o n a sta n dar d f or m ula , s uc h as t he M osteller 
f or m ula [9 ]:
B S A ( m²) = ([ Hei g ht (c m) × Wei g ht( k g) ]/ 3 6 0 0)½
e. g. B S A = s q uare r o ot([c m × k g] / 3 6 0 0)
or, i n i nc hes a n d p o u n ds:
B S A ( m²) = ([ Hei g ht(i n) × Wei g ht(l bs)]/ 3 1 3 1 )½
If t here is a c ha n ge i n b o d y  wei g ht of at least 1 0 perce nt, t he i n di vi d ual cis plati n d ose s h o ul d be 
recalc ulate d. Ot her wise, t he i nitial B S A s h o ul d be utilize d f or s u bse q ue nt d oses.
6. 3. 1. 1. 1
Pre d osi n g C o nsi der ati o ns f or Cis pl ati n
Cis plati n is a d mi nistere d t o S C C H N s u bjects as part of t he trial. As wit h m ost c yt ot o xic re gi me ns, 
t his dr u g is prece de d a n d acc o m pa nie d b y  su p p orti ve care. Ge neral g ui da nce o n t he use of cis plati n 
is pr o vi de d. H o we ver, In vesti gat or s are referre d t o a n d nee d t o f oll o w t he pac ka ge i nsert, t he 
s u m mar y of pr o d uct c haracteristics ( S m P C), a n d t heir l ocal p olicies /i nstr ucti o ns f or t he 
a d mi nistrati o n of cis plati n.
Mai n pre d osi n g meas ures f or cis plati n are pr o vi de d i n  Ta ble 1 4 bel o w a n d nee d t o be assesse d f or 
t he i n di vi d ual s u bject pri or t o t he first, b ut als o f or s u bse q ue nt a d mi nistrati o ns of cis plati n. N ote 
t hat s o me meas ures ma y be gi n se veral da ys bef ore act ual treat me nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 4 9
T a ble 1 4
Pre d osi n g C o nsi der ati o ns f or Cis pl ati n
I s s u e/I n di c ati o n
R e c o m m e n d e d St e p s
Pr e- e m e si s
F oll o w c urr e nt M A S C C/ E S M O a or N C C N b g ui d eli n e s f or c h e m ot h er a p y -i n d u c e d 
n a u s e a a n d v o miti n g f or a “ hi g h ri s k” r e gi m e n
H y dr ati o n/
n e p hr ot o xi cit y
P er p a c k a g e i n s ert/S m P C f or ci s pl ati n c. Ci s pl ati n c a u s e s s e v er e c u m ul ati v e 
n e p hr ot o xi cit y. A uri n e o ut p ut of 1 0 0 m L/ h o ur or gr e at er will t e n d t o mi ni mi z e 
ci s pl ati n n e p hr ot o xi cit y. A d e q u at e h y dr ati o n m u st t h er ef or e b e m ai nt ai n e d t o 
c a u s e s uffi ci e nt di ur e si s pri or t o, d uri n g a n d aft er tr e at m e nt wit h ci s pl ati n. N e xt 
t o i v i nf u si o n, f or c e d di ur e si s m a y b e r e q uir e d a n d m or e o v er s u bj e ct s ar e t o b e 
r e q u e st e d t o dri n k a p pr o pri at e q u a ntiti e s of li q ui d s f or 2 4 h o ur s aft er ci s pl ati n 
i nf u si o n t o e n s ur e a d e q u at e uri n e s e cr eti o n.
M y el o s u p pr e s si o n/
n e utr o p e ni a
R ef er t o t h e c urr e nt p a c k a g e i n s ert/ S m P C a n d l o c al g ui d a n c e f or m o difi c ati o n s 
i n d o s e a n d s c h e d ul e of ci s pl ati nc. Ci s pl ati n d o s e s h o ul d b e wit h h el d if pl at el et 
c o u nt i s l e s s t h a n 7 5, 0 0 0 c ell s/ m m 3 or n e utr o p hil c o u nt i s l e s s t h a n 
1 5 0 0 c ell s/ m m 3 .
Pri m ar y pr o p h yl a xi s wit h G - C S F i n or d er t o r e d u c e t h e ri s k of f e bril e n e utr o p e ni a 
( F N) i s n ot r e c o m m e n d e d, a c c or di n g t o A S C Od a n d E S M O g ui d eli n e s. F N i s 
d efi n e d a s or al t e m p er at ur e > 3 8. 5° C or t w o c o n s e c uti v e r e a di n g s of > 3 8° C f or 
2 h o ur s a n d a n a b s ol ut e n e utr o p hil c o u nt < 0. 5 × 1 0 9 / L, or e x p e ct e d t o f all b el o w 
0. 5 × 1 0 9 / L. S e c o n d ar y pr o p h yl a xi s wit h C S F s i s r e c o m m e n d e d f or s u bj e c t s w h o 
e x p eri e n c e d a n e utr o p e ni c c o m pli c ati o n fr o m a pr e vi o u s c y cl e of c h e m ot h er a p y 
(f or w hi c h pri m ar y pr o p h yl a xi s w a s n ot r e c ei v e d), i n w hi c h a r e d u c e d d o s e or 
tr e at m ent d el a y m a y c o m pr o mi s e di s e a s e-fr e e or O S or tr e at m e nt o ut c o m e . T h e 
s e c o n d ar y pr o p h yl a xi s s h o ul d f oll o w A S C O or E S M O or l o c al g ui d eli n e s.
T h e d o s a g e i n str u cti o n s s h o ul d f oll o w t h e l o c al g ui d eli n e s or t h e A S C O or 
E S M O g ui d eli n e s.
Ot ot o xi cit y/
n e ur ot o xi cit y
P er p a c k a g e i n s ert/ S m P C f or ci s pl ati n c. Ci s pl ati n i s pr o v e n t o b e c u m ul ati v e 
ot ot o xi c a n d n e ur ot o xi c. N e ur ol o gi c e x a mi n ati o n a n d m o nit ori n g of p ot e nti al 
ot ot o xi cit y i s t o b e p erf or m e d pri or t o e a c h ci s pl ati n d o si n g a n d d uri n g t h e 
tr e at m e nt.
A S C O = A m eri c a n S o ci et y of Cli ni c al O n c ol o g y ; C S F = c ol o n y sti m ul ati n g f a ct or ; E S M O = E ur o p e a n S o ci et y f or 
M e di c al O n c ol o g y ; F N = f e bril e ne utr o p e ni a; G -C S F = g r a n ul o c yt e-c ol o n y sti m ul ati n g f a ct or ; i v = i ntr a v e n o u s;
M A S C C = M ulti n ati o n al A s s o ci ati o n of S u p p orti v e C ar e i n C a n c er ; N C C N = N ati o n al C o m pr e h e n si v e C a n c er 
N et w or k ; S m P C = s u m m ar y of pr o d u ct c h ar a ct eri sti c s; O S = o v er all s ur vi v al.
a A n n al s of O n c ol o g y 2 1 ( S u p pl e m e nt 5): v 2 3 2 – v 2 4 3, 2 0 1 0
b N C C N G ui d eli n e s A nti e m e si s v er si o n 2/ 2 0 1 6
c htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ m e di ci n e/ 2 5 9 4 4 ( L a st U p d at e d o n e M C 0 9 J a n u ar y 2 0 1 5 )
d J Cli n O n c ol 3 3: 3 1 9 9 -3 2 1 2
6. 3. 1. 2
R a di ot her a p y
A n o ver vie w of t he R T tec h ni q ue ( inte nsit y- m o d ulate d ra di o t hera p y [IM R T] ) f or d os e escalati o n 
Ar m B ( S C C H N) i n P hase Ia a n d b ot h e x pa nsi o n c o h orts i n P hase I b is gi ve n i n A p pe n di x D .
6. 3. 2
A ncill ar y c P o P P art
S u bjects will recei ve a si n gle hi g h d ose of R T ( 1 0-2 5 G y ) gi ve n o n Lesi o n 1 o n Da y 1 . O n Da y 2, 
s u bjects will recei ve a si n gle d ose of M 3 8 1 4
i n c o m bi nati o n wit h
a si n gle hi g h d ose of R T 
( 1 0- 2 5 G y ) gi ve n o n Lesi o n 2. S u bject s will fast f or 1. 5 h o urs pri or t o d ose a d mi nistrati o n a n d 
c o nti n ue t o fast f or 1 h o ur p ost d os e. M 3 8 1 4
will be a d mi nistere d 1 . 5 h o ur ( ± 3 0 mi n utes) bef ore
t he start of R T. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 / 1 4 9
T he d ose of M 3 8 1 4
t o be a d mi nistere d t o s u bjects i n s uccessi ve c o h orts of t he a ncillar y c P o P part 
of t he trial is s h o w n i n Ta ble 1 2.
6. 4
Assi g n me nt t o Tre at me nt Gr o u ps
All eli gi ble s u bjects will be assi g ne d t o recei ve o pe n la bel M 3 8 1 4 . S u bjects will be assi g ne d t o 
treat me nt se q ue ntially. D uri n g d ose escalati o n ( P hase Ia) a n d f or t he first 3 N S C L C s u bjects i n t he 
Ar m A e x pa nsi o n c o h ort ( P hase I b) , t he ne xt d ose le vel will be o pe n f or e nr oll me nt o nl y after t he 
D L Ts i n t he c urre nt d ose le vel ha ve bee n f ully e val uate d b y t he S M C a n d a f or mal S M C decisi o n 
t o pr ocee d t o t he ne xt d ose le vel has bee n d oc u me nte d.
6. 5
N o ni n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
N ot a p plica ble.
6. 6
C o nc o mit a nt Me dic ati o ns a n d T her a pies
A ll c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m t he date of si g nat ure of 
i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he eC R F, n oti n g t he na me, d ose, 
d urati o n a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y c ha n ges t o a c o nc o mita nt 
me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he eC R F .
6. 6. 1
Per mitte d Me dici nes
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y t he cli nical trial pr ot oc ol) t hat are c o nsi dere d 
necessar y  f or t he s u bjects’ welfare a n d will n ot i nterfere wit h t he trial me dicati o n ma y be gi ve n at 
t he In vesti gat or’s discreti o n.
T he f oll o wi n g me dicati o ns are per mitte d:

L ocal, t o pical, or s h ort -ter m (i.e., < 7 da ys) of s yste mic c ortic oster oi ds

A nti -i nfecti o us dr u gs

He mat o p oietic gr o wt h fact ors, if me dicall y i n dicate d.
T he I n vesti gat or will rec or d all c o nc o mita nt me dicati o ns ta ke n b y  the s u bject a n d a n y c o nc o mita nt 
pr oce d ures pr o vi de d t o t he s u bject d uri n g t he trial, fr o m t he date of si g nat ure of i nf or me d c o nse nt, 
i n t he a p pr o priate secti o ns of t he e C R F.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he trial a n d a n y cha n ge t o 
c o nc o mita nt dr u gs m ust be rec or de d i n t he c orres p o n di n g secti on of t he e C R F, n oti n g t he na me, 
d ose, d urati o n a n d i n dicati o n of eac h dr u g.
6. 6. 2
Pr o hi bite d Me dici nes
As state d i n Secti o n 5. 3. 2 , s u bjects m ust n ot ha ve recei ve d c he m ot hera p y, i m m u n ot hera py,  
h or m o nal t hera py,  bi ol o gic t hera p y, or a n y ot her a ntica ncer t hera p y or a n y in vesti gati o nal a ge nt 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 / 1 4 9
wit hi n 2 8 da y s of t he first d ose of I M P a d mi nistrati o n ( 6 wee ks f or nitr os o ureas or mit o m yci n C), 
e xce pt f or s u bjects wit h ra pi dl y gr o wi n g t u m ors l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x 
w here t he treati n g p h y sicia n ca n n ot wait f or 2 8 d a y s. T hese t hera pies are als o pr o hi bite d d uri n g 
t he treat me nt peri o d a n d u p t o 3 0 d a y s after R T, wit h t he e xce pti o n of c o nc urre nt cis plati n i n t he 
S C C H N p o p ulati o n (Ar m B). D uri n g t he treat me nt peri o d a n d u p t o 3 0 da ys after R T , a n y ot her 
i n vesti gati o nal a ge nt, c he m ot hera p y, e x te nsi ve R T (i n v ol vi n g ≥3 0 % of b o ne marr o w) or a n y o t her 
a ntica ncer t hera p y ( bi ol o gics or ot her tar gete d t hera p y) a n d a nti ne o plastic ster oi d t hera p y are als o 
pr o hi bite d ( P hase Ia a n d P hase I b o nl y) . Use of a n y in vesti gati o nal a ge nt d uri n g t he e ntire trial 
d urati o n is n ot per mitte d. 
Me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors or i n d ucers of C Y P 3 A or 
C Y P 2 C 1 9, or dr u gs mai nl y  meta b olize d b y C Y P 3 A wit h a narr o w t hera pe utic i n de x as j u d ge d b y 
t he I n vesti gat or (a n d after o pti o nal c o ns ultati o n wit h t he S p o ns or) are p r o hi bite d (see Secti o n 6. 6. 4
f or details).
T he s ol u bilit y of M 3 8 1 4
is p H de pe n de nt; t heref ore, a ntaci d dr u gs, H 2-bl oc ker a n d P PI s mi g ht 
affect a bs or pti o n. H 2-bl oc kers or P PI s s h o ul d be st o p pe d 5 da y s pri or t o t he first treat me nt, a n d 
a v oi de d d uri n g t he e ntire treat me nt peri o d wit h I M P. A ntaci d dr u gs s h o ul d n ot be ta ke n 1 h o ur 
bef ore I M P a d mi nistrati o n u ntil 2 h o urs after I M P a d mi nistrati o n.
If t he a d mi nistrati o n of a n o n per mitte d c o nc o mita nt dr u g bec o mes necessar y d uri n g t he treat me nt 
peri o d , e. g., d ue t o A Es, t he s u bject s h o ul d be disc o nti n ue d fr o m t he trial treat me nt a n d c o m plete 
all assess me nts liste d u n der t he E T T visit .
See als o Secti o n 6. 6. 4 f or details of p ossi ble dr u g -dr u g i nteracti o ns wit h a n d b y  co nc o mita nt 
me dicati o n.
6. 6. 3
Ot her I nter ve nti o ns
T he pla n ni n g of R T will be i n acc or da nce wit h l ocal practice. 
P h ase I a: s u bjects will recei ve fracti o nate d palliati ve R T (Ar m A; 3 G y
x 1 0, 5 F/ W) or 
fracti o nate d R T (Ar m B; 2 G y  x 3 3 t o 3 5, 5 F/ W) as part of c urati vel y i nte n de d C R T ( wit h 
c o nc urre nt cis plati n) .
P h ase I b: N S C L C s u bjects will recei ve fracti o nate d R T ( 2 G y  x 3 3, 5 F/ W) ; S C C H N s u bjects will 
recei ve t he sa me C R T re gi me n as i n P hase Ia.
Misse d fracti o n(s) of R T m ust be gi ve n at t he e n d of t he sc he d ule t o e ns ure t hat t he t otal d ose is 
reac he d. T he d ose of M 3 8 1 4
s h o ul d be a d mi nistere d 1. 5 h o urs ( ± 3 0 mi n utes) bef ore R T . W her e 
a p plica ble, cis plati n s h o ul d be a d mi nistere d acc or di n g t o i nstit uti o nal g ui deli nes
(see 
Secti o n 6. 3. 1. 1) .
A ncill ar y c P o P p art : s u bjects will recei ve a si n gle hi g h d ose of R T ( 1 0-2 5 G y ) o n Da y 1 gi ve n 
o n L esi o n 1 a n d a si n gle hi g h d ose of R T ( 1 0 - 2 5 G y ) o n Da y  2 gi ve n o n Lesi o n 2.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 4 9
6. 6. 3. 1
R a di ot her a p y Tr e at me nt Del a y
T he f or mal criteria f or m o dificati o n of R T treat me nt are prese nte d i n  Ta ble 1 3 . Wit hi n t his trial, a 
ma xi m u m dela y  of u p t o a n d i ncl u di n g 7 d a y s i n t otal is all o we d wit hi n t he c o m plete treat me nt 
peri o d. If R T a n d I MP treat me nt ha ve t o be dela y e d b y  more t ha n 7 da ys , t he s u bject m ust be 
disc o nti n ue d fr o m I M P.
6. 6. 5
M a n a ge me nt 
of S pecific A d verse E ve nts or A d verse Dr u g 
Re acti o ns
At t he c urre nt sta ge of de vel o p me nt t here are n o k n o w n A D Rs or s pecific A Es . 
Earl y a n d late to xicities relate d t o R T a n d/ or M 3 8 1 4
will be ma na ge d acc or di n g t o t he l ocal 
i nstit ute’s g ui deli nes .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 4 9
O ver d os e of cis plati n ge nerall y res ults i n se vere f or ms of n or mall y occ urri n g a d verse reacti o ns. 
I n vesti gat ors are as ke d t o c hec k t he res pecti ve i nf or mati o n i n t he S m P C f or f urt her a d vice.
6. 7
P ac k a gi n g a n d L a beli n g
of t he I n vesti g ati o n al Me dici n al 
Pr o d uct
M 3 8 1 4
will be pac ka ge d as b o xes of 
 pac ks of 1 0 m g , 5 0 m g  or 1 0 0 m g ca ps ules or 5 0 m g 
ta blets. 
P ac ka gi n g a n d la beli n g will be i n acc or da nce wit h all a p plica bl e l ocal re g ulat or y re q uire me nts a n d 
a p plica ble G o o d M a n ufact uri n g P ractice G ui deli nes.
6. 8
Pre p ar ati o n, H a n dli n g , a n d St or a ge of t he I n vesti g ati o n al 
Me dici n al Pr o d uct
M 3 8 1 4
s h o ul d be st ore d at t he rec o m me n de d te m perat ure 
. A n y de viati o ns fr o m t he 
rec o m me n de d st ora ge c o n diti o ns s h o ul d be i m me diatel y re p orte d t o t he c o ntact s pecifie d i n t he 
M a n ual of O perati o ns , a n d t he trial dr u g s h o ul d n ot be use d u ntil a ut h orizati o n has bee n recei ve d 
fr o m t he S p o ns or or C R O .
T he I n vesti gat or or a trai ne d desi g nee will dis pe nse M 3 8 1 4
t o s u bjects acc or di n g t o t heir all ocate d 
d ose le vel.
Cis plati n will be st ore d acc or di n g t o t he pac ka ge i nsert a n d t he S m P C.
6. 9
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y
T he I n vesti gat or is res p o nsi ble f or e ns uri n g acc o u nta bilit y f or M 3 8 1 4, i ncl u di n g r ec o nciliati o n of 
dr u gs a n d mai nte na nce of rec or ds.

U p o n recei pt of M 3 8 1 4 , t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y  an d 
ac k n o wle d ge recei pt b y  si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me ntati o n pr o vi de d 
b y  t he S p o ns or/ C R O a n d ret ur ni n g it t o t he l ocati o n s pecifie d. A c o p y will be arc hi ve d f or t he 
I n vesti gat or Site File.

I M P dis pe nsi n g will be rec or de d o n t he a p pr o priate dr u g acc o u nta bilit y  for ms pr o vi de d b y  t he 
S p o ns or / C R O s o t hat acc urate rec or ds will be a vaila ble f or verificati o n at eac h m o nit ori n g visit.

Trial site I MP acc o u nta bilit y  rec or ds will i ncl u de t he f oll o wi n g:

C o nfir mati o n of I MP recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge

T he i n ve nt or y  of I M P pr o vi de d f or t he cli nical trial a n d pre pare d at t he site

T he use of eac h d ose b y eac h s u bject

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n use d I M P

Dates, q ua ntities, batc h n u m bers, vial n u m bers, e x pir y dates, f or m ulati o n (f or I M P pre pare d 
at t he site), a n d t he i n di vi d ual s u bject trial n u m bers.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 4 9
T he I n vesti gat or site s h o ul d mai ntai n rec or ds, w hic h
a de q uatel y d oc u me nt t hat s u bjects were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d t hat all IM Ps pr o vi de d were f ull y rec o ncile d.
U n use d I M P m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he prese nt trial. A n y I M P 
t hat has bee n dis pe nse d t o a s u bject m ust n ot be re dis pe nse d t o a differe nt s u bject.
T he S p o ns or M o nit or will peri o dicall y  collect t he I M P acc o u nta bilit y for ms a n d will c hec k all 
ret ur ns ( b ot h u n use d a n d use d c o ntai ners) bef ore a uth orizi n g t heir destr ucti o n b y  t he trial site.
6. 1 0
Assess me nt of I n vesti g ati o n al Me dici n al Pr o d uct C o m pli a nce
M 3 8 1 4
will be a d mi nistere d at t he site b y  the I n vesti gat or or desi g nate d pers o n nel . M 3 8 1 4
a d mi nistrati o n , i ncl u di n g batc h n u m bers, kit n u m bers, a n d vial n u m bers m ust be rec or de d i n t he 
e C R F, as a p plica ble.
Dr u g a d mi nistrati o n rec or ds will be use d t o assess c o m plia nce.
T he In vesti gat or is res p o nsi ble f or t he c o ntr ol of dr u gs u n der i n vesti gati o n; a de q uate rec or ds of 
t he recei pt ( e. g., Dr u g Recei pt Rec or d) a n d dis p ositi o n (e. g., Dr u g Acc o u nta bilit y  Rec or d, Dr u g 
Destr ucti o n Rec or d) of t he I M P, i ncl u di n g dates, q ua ntities, a n d use b y  su bject, m ust be 
mai ntai ne d.
All rec or ds a n d dr u g s u p plies m ust be a vaila ble f or i ns pecti o n at e ver y  m o nitori n g visit. O nce t he 
trial has bee n ter mi nate d a n d dr u g acc o u nta bilit y has bee n satisfact oril y co m plete d b y  th e 
p har macist or trial dr u g pre parer ( or desi g nee), t he use d a n d u n use d I M P (i.e., e m pt y, partiall y 
use d, a n d u n use d c o ntai ners) will be release d f or l ocal destr ucti o n f oll o wi n g t he i nter nal sta n dar d 
o perati n g pr oce d ures of t he desi g nate d facilit y. T he c o m plete d Dr u g Acc o u nta bilit y  an d Dr u g 
Destr ucti o n Rec or ds will be se nt t o t he m o nit or or its desi g nee.
T he site p har macist or trial dr u g pre parer ( or desi g nee) m ust mai ntai n rec or ds of t he deli ver y  of 
t he I MP t o t he trial site, t he i n ve nt or y at t he site, t he use b y  eac h s u bject a n d I MP destr ucti o n at 
t he cli nical site after dr u g acc o u nta bilit y has bee n perf or me d b y  the res p o nsi ble m o nit or. T he 
dr u g - dis pe nsi n g l o g m ust be ke pt c urre nt, listi n g t he i de ntificati o n of t he s u bject w h o recei ve d 
I M P al o n g wit h t he date a n d q ua ntit y of I M P dis pe nse d; it m ust be a vaila ble f or m o nit ori n g.
Rec or ds s hall als o be mai ntai ne d b y  the I n vesti gat or of t he met h o d of destr ucti o n (ta ki n g i nt o 
acc o u nt t he re q uire me nts of l ocal la w), a n d t he pers o n w h o dis p ose d of t he trial dr u g. T h e 
te m perat ure of t he st ora ge facilities will be m o nit ore d a n d d oc u me nte d.
After c o m pleti o n of t he trial, a n y IM P distri b ute d t o t he site b ut n ot a d mi nistere d or dis pe nse d t o 
or ta ke n b y  the s u bject will be destr o ye d at t he site. All u n use d me dicati o ns will be caref ull y 
rec or de d a n d d oc u me nte d bef ore destr ucti o n. T he In vesti gat or will e ns ure t hat t he trial dr u g s u p ply 
is n ot use d f or a ny p ur p ose ot her t ha n t h e c urre nt trial.
6. 1 1
Bli n di n g
T his is a n o pe n la bel trial; t heref ore, n o bli n di n g will be perf or me d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 4 9
6. 1 2
E mer ge nc y U n bli n di n g
N ot a p plica ble.
6. 1 3
Tre at me nt of O ver d ose
A n o ver d ose is de fi ne d as a n y dose greater t ha n t he hi g hest dail y d ose i ncl u de d i n a cli nical trial 
pr ot oc ol or pla n ne d f or a n i n di vi d ual s u bject e nr olle d i n t he trial. E ve n if it d oes n ot meet ot her 
criteria f or a n S A E , a n y o ver d ose m ust be rec or de d i n t he trial me dicati o n secti o n of t he e C R F a n d 
re p orte d t o Dr u g Safet y i n a n e x pe dite d ma n ner usi n g t he S A E Re p ort F or m, a n d f oll o wi n g t he 
pr oce d ure i n Secti o n 7. 4. 1. 4 . 
T here is n o esta blis he d treat me nt f or o ver d ose wit h M 3 8 1 4 . T he I n vesti gat or s h o ul d use cli nical 
j u d g me nt t o ma na ge a n y o ver d ose c o nsi deri n g t he prese nt i n g s ym pt o ms a n d sta n dar d e val uati o n 
res ults.
6. 1 4
Me dic al C are of S u bjects after E n d of Tri al
After a s u bject has c o m plete d t he trial or has wit h dra w n earl y, us ual treat me nt will be 
a d mi nistere d, if re q uire d, i n acc or da nce wit h t he trial site’s S o C a n d ge nerall y acce pte d me dical 
practice a n d de pe n di n g o n t he s u bject’s i n di vi d ual me dical nee ds.
7
Tri al Pr oce d ures a n d Assess me nts
7. 1
Sc he d ule of Assess me nts
Pri or t o perf or mi n g a n y  trial assess me nts t hat are n ot part of r o uti ne me dical care f or t he s u bject, 
t he In vesti gat or will o btai n writte n i nf or me d c o nse nt as descri be d i n Secti o n 9. 2.
C o m plete sc he d ules of assess me nts f or P hase Ia ( Ar m A – Ca ps ule a n d Ta blet ), P hase I b – f irst 
3 s u bjects (Ar m A, N S C L C c o h ort), P hase I b (Ar m A, N S C L C c o h ort), P hase Ia ( Ar m B, S C C H N 
c o h ort), P hase I b (Ar m B, S C C H N c o h ort) a n d a ncillar y c P o P part s are pr o vi de d i n Ta ble 1,  
Ta ble 2, Ta ble 3 , Ta ble 4, Ta ble 5 , Ta ble 6 a n d Ta ble 7, res pecti vely . D uri n g R T, n o visit wi n d o w 
will be all o we d. 
E ver y  eff ort s h o ul d be ma de t o perf or m assess me nts as cl ose as p ossi ble t o t he sc he d ule d ti me 
p oi nts.
7. 1. 1
Scree ni n g Peri o d ( D a y -2 1 t o D a y -1)
Base d o n t he fi n di n gs o btai ne d d uri n g t he Scree ni n g Peri o d, t he I n vesti gat or will deci de w het her 
t he s u bject is eli gi ble f or t he trial. Sc he d ule d scree ni n g assess me nts i n all s u bjects are as f oll o ws:

Pr o visi o n of writte n i nf or me d c o nse nt f or t he trial a n d P G x a nal ysis a n d re vie w of i ncl usi o n 
a n d e xcl usi o n criteria

D oc u me ntati o n of de m o gra p hics, rele va nt me dical hist or y , a n d c o nc o mita nt me dicati o ns
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 4 9

Safet y  la b orat or y (he mat ol o g y , ser u m c he mistr y, uri nal y sis, c oa g ulati o n a n d ser u m β- h u ma n 
c h ori o nic g o na d otr o pi n [ H C G] pre g na nc y  test [if a p plica ble])

I nfecti o n scree n. He patitis B a n d C testi n g t o be perf or me d u nless o btai ne d wit hi n 3 m o nt hs 
pri or t o Scree ni n g. Scree ni n g f or HI V will be perf or me d acc or di n g t o l ocal practic e a n d l ocal 
re g ulat or y g ui da nce

E val uati o n of h u ma n pa pill o ma vir us stat us i n t u m or material b y  im m u n o hist oc he mistr y
( P hase Ia, Ar m B a n d P hase I b, Ar m B e x pa nsi o n c o h ort o nl y)

A u di o gra m, as nee de d acc or di n g t o l ocal g ui deli nes ( P hase Ia, Ar m B a n d P hase I b, Ar m B 
e x pa nsi o n c o h ort o nl y)

Assess me nt of vital si g ns ( bl o o d press ure a n d hea rt rate), b o d y  wei g ht, a n d hei g ht , b o d y  
te m perat ure ( hei g ht meas ure d at Scree ni n g o nly)

Assess me nt of A Es

T u m or e val uati o n b y  ra di o gra p hic or ot her m o dalit y  (R E CI S T v 1. 1) ( P hase Ia a n d P hase I b 
o nl y ). Baseli ne t u m or e val uati o n ca n be u p t o 2 8 da ys ol d w he n treat me nt starts

E C O G P S

1 2- lea d E C G i ncl u di n g t he Fri dericia-c orrecte d Q T i nter val ( Q Tc F )

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae , i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa) ( P hase Ia a n d P hase I b o nly) .

I n case of cli nical si g ns of es o p ha gitis, a n es o p ha geal e n d osc o p y m ust be perf or me d , if t he 
ra diati o n fiel ds i n v ol ve t he es o p ha g us.
A ncillar y  c P o P part of t he trial o nl y :

E val uati o n of all tiss ues i n t he R T area

L ocal t u m or assess me nt (i n irra diate d lesi o ns) b y  cli nical e xa m or i ma gi n g acc or di n g t o 
R E CI S T v 1. 1 ( o nl y a p plica ble f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 f or m ulati o n]).
7. 1. 2
Tre at me nt Peri o d
7. 1. 2. 1
P h ase I a P art : Ar m A a n d Ar m B ( Fr acti o n D a ys 1 t o 1 0)
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da y s 1, 6 a n d 1 0; if Fracti o n Da y 1 0 is 
o n a Fri da y , P K, 
 safet y la b orat or y, a n d uri nal ysis sa m pli n g m ust be d o ne o n Fra cti o n Da y 9:

Re vie w of i ncl usi o n a n d e xcl usi o n criteria ( Fracti o n Da y  1 o nl y)

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 4 9

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area ( Fracti o n Da y  6 a n d 1 0 o nly)

E C O G P S ( Fracti o n Da y 1 0 o nl y)

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da y 1 0 o nl y)

1 2- lea d E C G i ncl u di n g Q Tc F ( Fracti o n Da y 1 a n d 1 0)

C ollecti o n of P K bl o o d s a m ples

A vaila bilit y  of arc hi val t u m or material, eit her as a bl oc k or sli des. If n o arc hi val material is 
a vaila ble t he n a fres h bi o ps y  s h o ul d be ta ke n
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da y 2:

C ollecti o n of P K bl o o d sa m ples ( pre d ose)
7. 1. 2. 2
P h ase I a P art : Ar m B ( S C C H N) ( Fr acti o n D a ys 1 6 t o 3 1)
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da y s 1 6, 2 1, 2 6, 3 1, a n d last F D/ E T T 

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area

E C O G P S ( last Fracti o n Da y  o nl y)

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 4 9

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da y 16 a n d last Fracti o n Da y o nl y )

1 2-lea d E C G i ncl u di n g Q Tc F
7. 1. 2. 3
P h ase I b P art : Ar m A ( N S C L C) E x p a nsi o n C o h ort ( Fr acti o n 
D a ys 1 t o 3 3)
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da ys 1, 6 (first 3 s u bjects o nl y), 1 0, 16 , 
2 1 , 26 a n d 3 3 ; if Fracti o n Da y 1 0 is o n a Fri da y , P K, P D, a n d safet y la b orat or y sa m pli n g m ust be 
d o ne o n Fracti o n Da y 9:

Re vie w of i ncl usi o n a n d e xcl usi o n criteria ( Fracti o n Da y  1 o nl y)

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area ( n ot perf or me d o n Fracti o n Da y  1)

E C O G P S ( Fracti o n Da y  3 3 o nl y )

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da ys 1 0 [f irst 3 s u bjects o nl y ], 1 6, a n d 3 3 o nl y )

1 2- lea d E C G i ncl u di n g Q Tc F ( Fracti o n Da y 1 a n d 1 0)

C ollecti o n of P K bl o o d sa m ples ( Fracti o n Da y s 1 a n d 1 0 o nl y)

A vaila bilit y  of arc hi val t u m or material, eit her as a bl oc k or sli des. If n o arc hi val material is 
a vaila ble t he n a fres h bi o ps y s h o ul d be ta ke n
T he f oll o wi n g assi g n me nts will be perf or me d o n Fracti o n Da y 2 (first 3 s u bjects o nl y):

C ollecti o n of P K bl o o d sa m ples ( pre d ose)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 4 9
7. 1. 2. 4
P h ase I b P art : Ar m B ( S C C H N) E x p a nsi o n C o h ort ( Fr acti o n 
D a ys 1 t o L ast Fr acti o n D a y )
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h C R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da ys 1, 6, 1 0, 1 6 , 21 , 26, 3 1 a n d t he last 
Fracti o n D a y ( 3 3 t o 3 5) ; if Fracti o n D a y 1 0 is o n a Fri da y, P K, 
 a n d safet y la b orat or y sa m pli n g 
m ust be d o ne o n Fracti o n Da y 9:

Re vie w of i ncl usi o n a n d e xcl usi o n criteria ( Fracti o n Da y  1 o nl y)

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all ti ss ues i n t he R T area ( n ot perf or me d o n Fracti o n Da y 1)

E C O G P S ( last Fracti o n Da y  o nl y)

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da y 1 6 a n d last Fracti o n Da y o nl y )

1 2-lea d E C G i ncl u di n g Q Tc F

C ollecti o n of P K bl o o d sa m ples ( Fracti o n Da y s 1 a n d 1 0 o nl y)

A vaila bilit y  of arc hi val t u m or materi al, eit her as a bl oc k or sli des. If n o arc hi val material is 
a vaila ble t he n a fres h bi o ps y  s h o ul d be ta ke n
7. 1. 2. 5
A ncill ar y c P o P P art
Eli gi ble s u bjects will recei ve a si n gle hi g h d ose of R T gi ve n o n L esi o n 1 o n Da y 1, a n d o n Da y 2, 
will recei ve M 3 8 1 4
wit h a si n gle hi g h d ose of R T gi ve n o n Lesi o n 2 .
F or l o gistical reas o ns ( ha n dli n g a n d se n di n g materials), Da y 1 m ust be o n a We d nes da y or earlier.
T he f oll o wi n g assess me n ts will be perf or me d o n Da y 1 a n d Da y 2:

Assess me nt of vital si g ns ( bl o o d press ure , heart rate , a n d b o d y te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 4 9

E val uati o n of all tiss ues i n t he R T area ( Da y  2 o nl y )

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

T u m or bi o ps y :
o
D a y  1: baseli ne bi o psy t o be ta ke n a n y t i me pri or t o R T f or b ot h lesi o ns ( Scree ni n g 
t o Da y 1) a n d 2-4 h o urs after R T f or Lesi o n 1
o
D a y  2: t o be ta ke n 2- 4 h o urs after R T f or Lesi o n 2.
7. 1. 3
F oll o w -u p Peri o d
7. 1. 3. 1
D L T Peri o d : P h ase I a, Ar m A
T he f oll o wi n g assess me nts will be perf or me d o n P T D 8 a n d 1 5 :

Assess me nt of vital si g ns ( bl o o d press ure , heart rate , a n d b o dy te m perat ure ), bo d y  wei g ht

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae , i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area 

E C O G P S

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n) 

Uri nal y sis.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 4 9
7. 1. 3. 2
D L T Peri o d /S h ort -ter m S afet y F oll o w -u p : P h ase I a, Ar m B
a n d First 3 S u bjects i n P h ase I b ( Ar m A E x p a nsi o n C o h ort i n 
N S C L C)
T he f oll o wi n g assess me nts will be perf or me d o n P T D 7, 1 4, 2 1, 2 8 a n d 3 5 ( P hase Ia, Ar m B) or 
o n P T D 8, 1 5, 2 2 a n d 3 7 (first 3 s u bjects i n P hase I b, Ar m A) :

Ser u m β -H C G pre g na nc y  test (if a p plica ble a n d o nl y  PT D 2 8 [ P hase Ia, Ar m B] or P T D 2 2
[first 3 s u bjects i n P hase I b, Ar m A] )

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y te m perat ure), b o d y wei g ht

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area 

E C O G P S

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n) 

Uri nal y sis.
7. 1. 3. 3
S h ort -ter m S afet y F oll o w -u p : P h ase I a, Ar m A a n d P h ase I b
T he f oll o wi n g assess me nts will be perf or me d o n P T D 2 2 a n d 3 0 i n P hase Ia ( Ar m A) a n d o n 
P T D 8, 1 5, 2 2 a n d 3 0 i n P hase I b :

Ser u m β -H C G pre g na nc y test (if a p plica ble a n d o nl y P T D 3 0)

Assess me nt of vital si g ns ( bl o o d press ure , heart rate , a n d b o dy te m perat ure ), bo d y  wei g ht

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g pet ec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area 

E C O G P S (P T D 3 0 o nl y )

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati on) 

Uri nal y sis (P T D 3 0 o nl y) .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 4 9
7. 1. 3. 4
Mi d -ter m S afet y F oll o w-u p : P h ase I a a n d P h ase I b
T he mi d -ter m safety f oll o w- u p will be perf or me d o n P T D 8 4. T o e val uate si g ns of R T -i n d uce d 
t o xicit y o n n or mal s urr o u n di n g tiss ues, t he f oll o wi n g assess me nts were perf or me d:

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y  wei g ht
( P hase Ia o nly)

P h y sical e xa mi nati o n

1 2- lea d E C G i ncl u di n g Q Tc F ( Ar m B S C C H N c o h ort o nl y)

E C O G P S

E val uati o n of all tiss ues i n t he R T area 

E val uati o n of o n g oi n g T E A E s
7. 1. 3. 5
L o n g -ter m S afet y F oll o w -u p : P h ase I a a n d P h ase I b
T he f oll o wi n g assess me nts will be perf or me d f or all s u bjects, e xcl u di n g s u bjects i n t he a ncillar y 
c P o P part of t he trial, o n P T D 4 2, 1 2 6, 1 6 8, a n d 1 8 0, ( P hase Ia a n d P hase I b), a n d o n P T D 2 7 0 a n d 
3 6 5 ( P ha se I b o nly) :

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y te m perat ure), b o d y wei g ht

P h y sical e xa mi nati o n 

1 2- lea d E C G i ncl u di n g Q Tc F ( Ar m B S C C H N c o h ort o nl y)

E C O G P S

E val uati o n of all tiss ues i n t he R T area 

E val uati o n of o n g oi n g T E A Es

T u m or assess me nt acc or di n g t o R E CI S T v 1. 1, o nl y  re q uire d if s u bject has n ot starte d a ne w 
a ntit u m or treat me nt. If a ne w treat me nt is starte d, t he date (a n d re gi me n) m ust be re p orte d i n 
e C R F. 
T he f oll o wi n g assess me nts will be perf or me d o n P T D 2 1 0 a n d 3 1 2:

E val uati o n of l o n g ter m R T t o xicit y (s u bject calle d b y p h o ne).
7. 1. 3. 6
S ur vi v al F oll o w -u p : P h ase I a a n d P h ase I b
T he f oll o wi n g assess me nts will be perf or me d o n P T D 2 7 0 a n d 3 6 5 ( E O T) f or patie nts i n P hase Ia, 
Ar m A :

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y  wei g ht. O nl y 
re q uire d f or P hase Ia if s u bject has n ot starte d a ne w a ntit u m or treat me nt

P h y sical e xa mi nati o n

E C O G P S
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 4 9

E val uati o n of all tiss ues i n t he R T area 

E val uati o n of o n g oi n g T E A Es

T u m or assess me nt acc or di n g t o R E CI S T v 1. 1. O nl y  re q uire d f or P hase Ia if s u bject has n ot 
starte d a ne w a ntit u m or treat me nt.
F or all patie nts, the s ur vi val f oll o w- u p peri o d will c o nti n ue u ntil 1 2 m o nt hs after t he last s u bject 
has st o p pe d R T/ C R T ( defi ne d as e n d of trial; see Secti o n 5. 7) . After c o m pleti o n of t he visit o n 
P T D 3 6 5, all s u bjects will be f oll o we d f or s ur vi val e ver y 3 mo nt hs via a p h o ne call u ntil t he e n d 
of t he trial.
7. 1. 3. 7
F oll o w -u p f o r t he A ncill ar y c P o P P art of t he Tri al
T he f oll o wi n g assess me nts will be perf or me d o n Da y  1 0 a n d Da y  32 ( 8 a n d 3 0 d a y s after e n d of 
treat me nt):

Assess me nt of vital si g ns ( bl o o d press ure , heart rate, a n d b o d y  te m perat ure), bo d y  wei g ht
( Da y 1 0 o nl y)

E val uati o n of all tiss ues i n R T area

Assess me nt of A Es (l ocal t olera bilit y 3 0 da ys after last trial dr u g a d mi nistrati o n )

D oc u me ntati o n of c o nc o mita nt me dicati o ns ( o nl y at Da y 1 0)

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

L ocal t u m or assess me nt (i n irra diate d lesi o ns) b y  cli nical e xa m or i ma gi n g acc or di n g t o
R E CI S T v 1. 1 ( o nl y at Da y 1 0 a n d o nl y a p plica ble f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 
f or m ulati o n]).
7. 1. 4
Disc o nti n u ati o n/ E n d of Tri al
F or t he P hase Ia a n d I b parts, all s u bjects w h o disc o nti n ue I MP m ust u n der g o a f ull safety 
e val uati o n at t he ti me of disc o nti n uati o n. T he assess me nts s pecifie d f or t he E T T visit s h oul d be 
perf or me d (see Ta ble 1 [ P hase Ia – Ar m A ca ps ule c o h orts ], Ta ble 2 [ P hase Ia – Ar m A ta blet 
c o h orts],
Ta ble 3
[first 3 s u bjects i n P hase I b
–
Ar m A, 
N S C L C 
c o h ort],
Ta ble 4
[ P hase I b – Ar m A, N S C L C c o h ort], Ta ble 5 [ P hase Ia – Ar m B, S C C H N c o h ort] a n d Ta ble 6
[ P hase Ib – Ar m B, S C C H N c o h ort] f or details).
A n E O T v isit will als o be perf o r me d o n P T D 3 6 5, or if t he s u bject wit h dra ws pri or t o P T D 3 6 5 . 
A ll assess me nts m ust be d o ne as pla n ne d f or t he EO T visit, see Secti o n s 7. 1. 3. 5 a n d 7. 1. 3. 6.
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
T he assess me nts a n d pr oce d ures descri be d i n t his secti o n m ust be perf or me d d uri n g t he Scree ni n g 
Peri o d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 4 9
7. 2. 1
De m o gr a p hic D at a
T he f oll o wi n g de m o gra p hic data will be rec or de d:

S u bject i de ntifier

Date of birt h

Se x

Race

Et h nicit y
7. 2. 2
T u m or Hist or y
T he f oll o wi n g i nf or mati o n will be d oc u me nte d a n d verifie d at t he S cree ni n g visit f or eac h s u bject:

All t hera py use d f or pri or treat me nt of t he t u m or (i ncl u di ng s ur ger y, R T , c he m ot hera p y, 
i m m u n ot hera p y, a n d h or m o nal or bi ol o gic t hera p y)

C urre nt ca ncer si g ns a n d s ym pt o ms a n d si de effects fr o m c urre nt a n d/ or pre vi o us a ntica ncer 
treat me nts

Date of dia g n osis a n d hist ol o g y , w he ne ver p ossi ble

Gra di n g a n d sta gi n g of t he t u m or

Date of t he first occ urre nce of disease a n d t he date of pr o gressi o n after t he first, sec o n d, a n d 
a n y s u bse q ue nt treat me nt fail ure.

H u ma n pa pill o ma vir us e val uati o n i n S C C H N t u m or material (f or P hase Ia, Ar m B a n d P hase I b, 
S C C H N e x pa nsi o n c o h ort o n l y)
7. 2. 3
Me dic al Hist or y
a n d Pre vi o us a n d C o nc o mit a nt Me dic ati o n
T o deter mi ne t he s u bject’s eli gi bilit y  f or t he trial, rele va nt me dical hist or y of eac h s u bject will be 
c ollecte d a n d d oc u me nte d d uri n g scree ni n g t hat will i ncl u de t he f oll o wi n g:

Past a n d c o nc o mit a nt n o n mali g na nt diseases a n d treat me nts

All me dicati o ns ta ke n a n d pr oce d ures carrie d o ut wit hi n 2 1 da y s pri or t o scree ni n g.
F or trial e ntr y , all s u bjects m ust f ulfill all i ncl usi o n criteria descri be d i n Secti o n 5. 3. 1 a n d n o ne of 
t he e xcl usi o n criteria descri be d i n Secti o n 5. 3. 2.
7. 2. 4
Vit al Si g ns a n d P h ysic al E x a mi n ati o n
Vital si g ns, i ncl u di n g b o d y  te m perat ure, heart rate a n d bl o o d press ure (after 5 mi n ute s rest), will 
be rec or de d at trial e ntr y .
A c o m plete p h y sical e xa mi nati o n (i ncl u di n g ge neral a p peara nce, der mat ol o gical, hea d/ nec k, 
p ul m o nar y , car di o vasc ular, gastr oi ntesti nal, ge nit o uri nar y , l ym p hatic, m usc ul os keletal s yste m, 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 4 9
e xtre mities, e yes [i ns pecti o n a n d visi o n c o ntr ol], n ose, t hr oat, a n d ne ur ol o gic stat us) will be 
perf or me d a n d t he res ults d oc u me nte d.
Cli ni cal e xa mi nati o n of blee di n g (i ncl u di n g petec hiae , i n s ki n, i n t he sclera of t he e ye, oral m uc osa)
will be perf or me d .
T he E C O G P S will be d oc u me nte d d uri n g t he Scree ni n g Peri o d.
B o d y wei g ht a n d hei g ht will be rec or de d.
7. 2. 5
C T 
or M a g netic 
Res o n a nce 
I m a gi n g Sc a ns f or T u m or 
Assess me nt
A n e n ha nce d C T sca n or e n ha nce d ma g netic res o na nce i ma gi n g ( M RI) of t he t u m or will be 
perf or me d pri or t o t he be gi n ni n g of trial treat me nt t o d oc u me nt t he baseli ne stat us of t he t u m or 
usi n g R E CI S T v 1. 1 (A p pe n di x B ). Baseli ne t u m or e val uati o n ca n be u p t o 2 8 d a y s ol d w he n 
treat me nt starts.
7. 2. 6
C ar di ac Assess me nts
Tri plicate 1 2- lea d E C Gs will be rec or de d l ocally at scree ni n g ( pred ose) after t he s u bject has bee n 
i n a s u pi ne p ositi o n breat hi n g q uietly f or at least 5 mi n utes a n d p ost d ose. T he E C G res ults will be 
use d t o e val uate t he heart rate, atrial ve ntric ular c o n d ucti o n, Q R a n d Q T i nter vals (i ncl u di n g 
Q Tc F), a n d p ossi ble arr h y t h mias.
7. 2. 7
Cli nic al L a b or at or y Tests
Bl o o d sa m ples will be c ollecte d l ocall y at scree ni n g f or cli nical la b orat or y para meter e val uati o ns. 
T hese cli nical la b orat or y test res ults will ser ve n ot o nl y  as t he baseli ne val ues f or s u bse q ue nt safety 
cli nical la b orat or y eval ua ti o ns d uri n g t he trial b ut als o as verificati o n t hat eac h e nr olle d s u bject 
f ulfills all t he trial e ntr y criteria a n d d oes n ot meet a n y of t he trial e xcl usi o n criteria f or la b orat or y 
para meters as liste d i n Secti o n 5. 3. 2 . Detaile d descri pti o n of la b orat or y assess me nts is pr o vi de d i n 
Secti o n 7. 4. 3.
7. 3
Effic ac y Assess me nts
7. 3. 1
T u m or Res p o nse Assess me nt
T u m or res p o nse will be e val uate d acc or di n g t o R E CI S T v 1. 1 (see A p pe n di x B ).
T he t u m or res p o nse assess me nt will be perf or me d as liste d acc or di n g t o t he sc he d ules of 
assess me nts (Ta ble 1 [ P hase Ia – Ar m A
ca ps ule c o h orts ], Ta ble 2 [P hase Ia – Ar m A ta blet 
c o h orts],
Ta ble 3
[first 3 
s u bjects i n P hase I b
–
Ar m A, 
N S C L C 
c o h ort],
Ta ble 4
[ P hase I b – Ar m A, N S C L C c o h ort], Ta ble 5 [ P hase Ia – Ar m B, S C C H N c o h ort] a n d Ta ble 6
[ P hase Ib – Ar m B, S C C H N c o h ort] ). T his s h o ul d i ncl u de a c o m plete assess me nt of all tar get a n d 
n o ntar get lesi o ns f or s u bjects wit h s oli d t u m ors. T his assess me nt will be perf or me d b y  CT or M RI . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 4 9
I n ge neral, lesi o ns detecte d d uri n g scree ni n g nee d t o be f oll o we d usi n g t he sa me met h o d ol o g y  an d 
prefera bl y t he sa me e q ui p me nt at s u bse q ue nt t u m or assess me nt v isits.
F or t he a ncillar y cP o P part of t he trial ( o nly a p plica ble f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 
f or m ulati o n]): T he l ocal t u m or res p o nse assess me nt i n irra diate d lesi o ns will be perf or me d as liste d 
acc or di n g t o t he sc he d ule of assess me nts (Ta ble 7) . L o cal t u m or res p o nse i n irra diate d lesi o ns will 
be e val uate d acc or di n g t o R E CI S T v 1. 1 (see A p pe n di x B ). T his assess me nt will be perf or me d 
f oll o wi n g t he i nstit uti o nal practices, eit her b y  cli nical e xa m or i ma gi n g. Lesi o ns assesse d d u ri n g 
scree ni n g nee d t o be f oll o we d b y  the sa me tec h ni q ue a n d met h o d ol o g y  of assess me nt at t he 
s u bse q ue nt t u m or assess me nt visit o n Da y 1 0. T he c uta ne o us a n d s u bc uta ne o us lesi o ns s h o ul d als o 
be d oc u me nte d b y c ol or p h ot o gra p h y (i ncl u di n g a cali per or scale ) at Baseli ne a n d o n Da y 1 0.
7. 4
Assess me nt of S afet y
T he safety pr ofile of M 3 8 1 4
will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d a nal ysis of 
baseli ne me dical c o n diti o ns, A Es , p h y sical e xa mi nati o n fi n di n gs i ncl u di n g vital si g ns a n d 
m o nit ori n g f or blee di n g, la b orat or y tests, E C O G P S , a n d 1 2- lea d E C Gs.
C o m pre he nsi ve assess me nt of a n y ap pare nt t o xicit y ex perie nce d b y  eac h s u bject will be perf or me d 
fr o m t he ti me of gi vi n g i nf or me d c o nse nt u p t o 1 2 m o nt hs after R T c o m pleti o n . T he I n vesti gat or
will re p ort a n y A Es , w het her o bser ve d b y  the I nvesti gat or or re p orte d b y  the s u bject (see 
Secti o n 7. 4. 1. 2) . T he re p orti n g peri o d f or A E s is descri be d i n Secti o n 7. 4. 1. 3 .
7. 4. 1
A d verse E ve nts
7. 4. 1. 1
A d verse E ve nt Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. A n 
A E ca n t heref ore be a n y unfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n ab n or mal la b orat or y 
fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her 
or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct. 
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ur e is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself. T he I n vesti gat or is re q uire d t o gra de t he 
se verity or t o xicit y of eac h A E .
I n vesti gat ors will refere nce t he Nati o nal Ca ncer I nstit ute ( N CI)-C T C A E, v 4. 0 3 ( p u blicati o n date: 
1 4 J u ne 2 0 1 0 ), a descri pti ve ter mi n ol o g y t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity ) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 4 9
If a partic ular A E se verit y is n ot s pecificall y gra de d b y t he g ui da nce d oc u me nt, t he I n vesti gat or is 
t o use the ge neral N CI -C T C A E ( v 4. 0 3) defi niti o ns of Gra de 1 t hr o u g h Gra de 5 f oll o wi n g his or 
her best me dical j u d g me nt.
T he 5 ge neral gra des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate ni n g

Gra de 5 or Deat h .
Acc or di n g t o t he S p o ns or’s c o n ve nti o n, a n y cli nical A E wit h se verity of Gra de 4 or 5 m ust als o 
be re p orte d as a n S A E. H o we ver, a la b orat or y a b n or malit y of Gra de 4, s uc h as a ne mia or 
ne utr o pe nia, is c o nsi dere d seri o us o nl y  if t he c o n diti o n meets o ne of t he seri o us criteria descri be d 
bel o w.
If deat h occ urs , t he pri mar y  ca use of deat h or t he e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be re c or de d as t he o utc o me of t h is s pecific e ve nt a n d deat h will 
n ot be rec or de d as a se parate e ve nt. O nl y i f n o ca use of deat h ca n be re p orte d (f or e xa m ple, s u d de n 
deat h, u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o t he trial treat me nt
usi n g t he f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E 
t o M 3 8 1 4 / R T/ C R T i ncl u de te m p oral relati o ns hi p bet wee n t he A E a n d M 3 8 1 4 / R T/ C R T, k n o w n 
si de effects of M 3 8 1 4 / R T/ C R T, me dical hist or y , c o nc o mita nt me dicati o n, c o urse of t he u n derl y i n g 
disease, trial pr oce d ures.
U nrel ate d:
N ot reas o na bly relate d t o M 3 8 1 4 / R T/ C R T treat me nt. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o M 3 8 1 4 / R T/ C R T treat me nt u n der 
st u d y in t his cli nical trial pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be 
a vaila ble.
Rel ate d:
R eas o na bl y 
relate d 
t o M 3 8 1 4 / R T/ C R T
treat me nt. A E 
c o ul d 
me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o M 3 8 1 4 / R T/ C R T treat me nt u n der 
st u d y i n t his cli nical trial pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (f or e xa m ple, o n a n 
E C G trace) s h o ul d n o t be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym pt o ms, lea d t o treat me nt disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  
t he I n vesti gat or. If a la b orat or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical c o n diti o n 
(e. g., a ne mia, i ncrease d A LT) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue itself.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 4 9
Seri o us A d verse E ve nt s
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h.

Is life-t hreate ni n g. (N ote: T he ter m “life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject is 
at ris k of deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi g ht ha ve ca used deat h 
if it was m ore se vere. )

Re q uires i n patie nt h os pitalizati o n or pr ol o n g s a n e xisti n g h os pitalizati o n.

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacity.

Is a c o n ge nital a n o maly or birt h defect.

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. ( N ote: I mp orta nt me dical e ve nts t hat ma y 
n ot res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he s u bject or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E xa m ples 
of s uc h e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y 
r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, 
or t he de vel o p me nt of dr u g de pe n de nc y or dr u g a b use. ).
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a n I M P  is als o 
c o nsi dere d a n S A E as descri be d i n Secti o n 7. 4. 1. 4.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y trial treat me nt or trial pr oce d ures (f or 
e xa m ple, a n o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera py a p plicati o n) 
are n ot c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n (e. g., u n desira ble effects of a n y a d mi nistere d treat me nt) 
m ust be d oc u me nte d a n d re p orte d as S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial trial visit t hat d o n ot w orse n i n se verit y or fre q ue nc y duri n g 
t he trial are defi ne d as Baseli ne Me dical C o n diti o ns, a n d are N O T t o be c o nsi dere d A Es.
A Es/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase Pr o gressi o n
Pr o gressi o n of t he disease/ dis or der b ei n g st u die d, assesse d b y  meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds , as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he patie nt’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he a d verse e ve nt re p orti n g peri o d (as defi ne d i n Secti o n 7. 4. 1. 3 ).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 4 9
A d verse E ve nt s of S peci al I nterest f or S afet y M o nit ori n g
N ot y et defi ne d.
D ose Li miti n g T o xicities
Eac h D L T (as defi ne d i n Secti o n 7. 4. 1. 5) , re gar dless of seri o us ness m ust be i m me diatel y rec or de d 
i n t he e C R F. I n ad diti o n, seri o us D L Ts ha ve t o re p orte d i n a n e x pe dite d ma n ner as f or S A Es as 
descri be d i n Secti o n 7. 4. 1. 4 .
7. 4. 1. 2
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts
At eac h trial visit, t he s u bject will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d , a n y u nfa v ora ble c ha n ges i n t he s u bject’s c o n diti o n will be rec or de d as A Es, 
w het her re p orte d b y t he s u bject or o bser ve d b y t he I nvesti gat or . 
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R F. 
All S A Es m ust be d oc u me nte d a d diti o nall y a n d re p orte d usi n g t he a p pr o priate f or m as descri be d 
i n Secti o n 7. 4. 1. 4.
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates [a n d ti mes w he n it is i m p orta nt t o assess t he ti me of A E o nset relati ve t o t he 
rec or de d treat me nt a d mi nistrati o n ti me]), its se verit y, its ca usal relati o ns hi p wit h t he trial 
treat me nt, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or ot her acti o n ta ke n , i ncl u di n g 
d ose m o dificati o n or disc o nti n uati o n of t he I MP, a n d its o utc o me. I n a d diti o n, seri o us cases s h o ul d 
be i de ntifie d a n d t he a p pr o priate seri o us ness criteria d oc u me nte d. If a n A E c o nstit utes a D L T t his 
has t o be d oc u me nte d acc or di n gl y.
S pecific g ui da nce ca n be f o u n d i n t he e C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d 
b y t he S p o ns or.
7. 4. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he s u bject is i nitiall y i ncl u de d i n t he 
trial ( date of first si g nat ure of i nf or me d c onse nt ) a n d c o nti n ues t hr o u g h t he trial’s p ost -treat me nt
f oll o w-u p peri o d u p t o P T D 3 6 5. 
A T E A E is defi ne d as a n y AE t hat occ urs fr o m t he d a y  of first d ose of M 3 8 1 4 (re gar dless of 
pretreat me nt or p ost -treat me nt o n first d osi n g da y ), t hr o u g h Da y 3 0 after t he e n d of R T. 
A n y  SA E assesse d as relate d t o M 3 8 1 4
m ust be re p orte d w he ne ver it occ urs irres pecti ve of t he 
ti me ela pse d si nce t he last a d mi nistrati o n of M 3 8 1 4 . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 4 9
7. 4. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse 
E ve nts of S peci al I nterest a n d D ose Li miti n g T o xiciti es
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 h o urs after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee i n writi n g. All writte n re p or ts s h o ul d be tra ns mitte d usi n g t he S A E Re p ort 
F or m, w hic h m ust be c o m plete d b y  t he I n vesti gat or f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
in t hese cases, a writ te n re p ort m ust be se nt i m me diatel y t hereafter.
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n parallel (e. g., me dical hist or y , c o nc o mita nt 
me dicati o n ). A d diti o nal d oc u me nts m a y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (f or e xa m ple, 
la b orat or y res ults, h os pital re p ort a n d a ut o ps y re p ort). In all cases, t he i nf or mati o n pr o vi de d o n t he 
S A E Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he e C R F.
T he I n vesti gat or m ust 
res p o n d t o a n y re q uest f or f oll o w- u p i nf or mati o n (e. g., a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee m a y  h ave o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of the e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us ual l y be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e x ce pti o nal 
circ u msta nces t he C R O’s Gl o bal Dr u g Safet y de part me nt ma y  c o ntact t he I n vesti gat or directly t o 
o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
D ose Li miti n g T o xicities
Eac h e ve nt meeti n g t he criteria of a D L T (see Secti o n 7. 4. 1. 5 ) m ust be rec or de d i n t he e C R F wit hi n 
2 4 h o urs after bec o mi n g a ware of t he e ve nt. Seri o us D L Ts m ust
be re p orte d i n a n e x pe dite d 
ma n ner as S A Es as o utli ne d a b o ve .
7. 4. 1. 5
D ose Li miti n g T o xicities
A
D L T is defi ne d as a n y Gra de ≥3 n o n he mat ol o gic A E or a n y Gra de ≥4 he mat ol o gic A E 
(acc or di n g t o N CI-C T C A E v ersi o n 4. 0 3) t hat is relate d t o a n y of t he st u d y treat me nts a n d occ urs 
d uri n g t he D L T peri o d of 5 wee ks ( P hase Ia, Ar m A) or 1 2 wee ks ( P hase Ia, Ar m B a n d P hase I b, 
first 3 s u bjects i n t he e x pa nsi o n c o h ort of Ar m A [ N S C L C] ) after t he first d ose of M 3 8 1 4 .
A D L T m ust be c o nfir me d b y  t he S M C.
I n a d diti o n, t he f oll o wi n g are c o nsi dere d D L Ts:
1.
Gra de 3 t hr o m b oc y t o pe nia wit h me dicall y c o ncer ni n g blee di n g
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 0 / 1 4 9
2. 
F e brile ne utr o pe nia
3.  
A n y  to xicit y  or st u dy treat me nt-relate d T E A E t hat, i n t he o pi ni o n of t he S M C , is of p ote ntial 
cli nical si g nifica nce s uc h t hat f urt her d ose escalati o n w o ul d e x p ose s u bjects t o u nacce pta ble 
ris k
4.
A n y  t o xicit y relate d t o st u d y treat me nts t hat ca uses t he s u bject t o recei ve less t ha n 8 0 % of 
t he pla n ne d R T d ose
5.
A n y  t o xicit y relate d t o st u d y treat me nts lea di n g t o a n interr u pti o n of R T l o n ger t ha n 1 wee k 
i n Ar m B
6.
E vi de nce of st u d y treat me nt-relate d he pat ocell ular i nj ur y for m ore t ha n 3 da y s, s uc h as 
> 5- f ol d ele vati o ns a b o ve t he U L N of A L T or A S T ( C T C A E Gra de 3 or 4) wit h or wit h o ut 
ele vati o n of ser u m t otal bilir u bi n t o > 2 × U L N, wit h o ut i nitial fi n di n gs of c h olestasis 
(ele vate d ser u m al kali ne p h os phatase) or ot her a p pare nt cli nical ca usalit y.
T he f oll o wi n g st u d y treat me nt-relate d A Es are e xce pti o ns t o t he a b o ve me nti o ne d D L T defi niti o n 
a n d are n ot c o nsi dere d t o be D L Ts :
1.
M uc ositis ( m uc osal i nfla m mati o n), i ncl u di n g oral m uc ositis (st o matitis) of Gr a de ≥3 lasti n g 
f or ≤4 wee ks after c o m pleti o n of t he st u d y  treat me nts
2.
St o matitis ass ociate d t o xicities (e. g., s wall o wi n g d y sf u ncti o n [ o d yn o p ha gia, d y s p ha gia], 
decrease d a p petite or wei g ht l oss d ue t o diffic ult y  or pai nf ul s wall o wi n g) of Gra de ≥3 
lastin g f or ≤4 wee ks after c o m pleti o n of t he st u d y treat me nts
3.
Diarr hea of Gra de ≥3 ( ≤3 da y s d urati o n) f oll o wi n g a de q uate a n d o pti mal t hera p y 
4.
Na usea a n d v o miti n g of G ra de ≥3 ( ≤3 da y s d urati o n) wit h a de q uate a n d o pti mal t hera p y
5.
Ra diati o n der matitis a n d ass ociate d t o xicities of Gra de ≥3 lasti n g f or ≤4 wee ks after 
c o m pleti o n of t he st u d y treat me nts
6.  
N e utr o pe nia of Gra de 4 lasti n g f or ≤5 da y s a n d n ot ass ociate d wit h fe ver
7.
Is olate d Gra de 4 ly m p h oc y t o pe nia wit h o ut cli nical c orrelate
8.
Fati g ue or hea dac he of Gra de 3 ( ≤7 d a y s d urati o n) f oll o wi n g i nitiati o n of a de q uate 
s u p p orti ve care
9.
A n y  ot her si n gle la b orat or y val ues of Gra de ≥3 o ut of t he n or mal ra n ge t hat ha ve n o cli nical 
si g nifica nce, a n d t hat res ol ve t o Gra de 2 or less wit h a de q uate meas ures wit hi n 7 da y s.
T he d urati o n of fee di n g t u be ( F T) use ( nas o gastric t u be, perc uta ne o us e n d osc o pic gastr ost o m y ) 
s h o ul d n ot defi ne t he se verity of t he t o xicit y (e. g., se vere s wall o wi n g d y sf u ncti o n, na usea, 
v o miti n g). A caref ul e val uati on of t he s u bject’s s ym pt o ms b y  the I n vesti gat or at eac h visit is 
re q uire d i n or der t o i de ntif y su bjects w h o are F T de pe n de nt (e. g., s u bjects w h o ref use/a v oi d 
s wall o wi n g, etc).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 4 9

I n t he e ve nt of se vere s wall o wi n g d y sf u ncti o n ( Gra de ≥3 d y s p ha gia or o d y n o p ha gi a) t hat 
re q uires F T place me nt a n d res ol ves t o Gra de ≤2 pri or t o t he e n d of 4 wee ks after c o m pleti n g 
st u d y treat me nts, if t he F T is still i n place f or ot her reas o ns t he n dys p ha gia or o d y n o p ha gia will 
n ot be c o nsi dere d a D L T.

I n t he e ve nt of Gra de 3 na usea or Gra de ≥3 v o miti n g t hat re q uires F T place me nt a n d res ol ves 
t o Gra de ≤2 wit hi n 3 da ys, if t he F T is still i n place f or ot her reas o ns t he n na usea or v o miti n g 
will n ot be c o nsi dere d a D L T. 
T he S M C ma y  i de ntif y as a D L T, a n y A D R t hat i m pairs dail y fu ncti o n, or a b n or malit y  occ urri n g 
i n s u bjects treate d wit h M 3 8 1 4
at a n y ti me d uri n g t he trial i ncl u di n g i n-fiel d late ra diati o n 
t o xicities.
S u bjects w h o disc o nti n ue treat me nt wit h M 3 8 1 4
beca use of a D L T s h o ul d n ot be re-e x p osed t o 
t he trial dr u g b ut o n g oi n g R T ca n c o nti n ue.
S u bjects w h o d o n ot c o m plete t he D L T o bser vati o n peri o d f or reas o ns ot her t ha n a D L T will be 
re place d.
7. 4. 1. 6
S afet y Re p orti n g t o He alt h A ut h orities, I n de pe n de nt Et hics 
C o m mittees/ I nstit uti o n al Re vie w B o ar ds a n d I n vest i g at ors
T he S p o ns or / desi g nee will 
se n d a p pr o priate safety n otificati o ns t o Healt h 
A ut h orities 
i n 
acc or da nce wit h a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es (partic ular l y deat hs) i n v ol vi n g trial s u bjects t o t he I EC/I R B t hat a p pr o ve d t he 
trial.
I n acc or da nce wit h I C H G C P, t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of “fi n di n gs t hat 
c o ul d a d versel y affect t he safety o f s u bjects, i m pact t he c o n d uct of t he trial or alter t he I EC’s/I R B’s 
a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he trial.” I n partic ular a n d i n li ne wit h res pecti ve 
re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of A Es t hat are b ot h seri o us a n d 
u ne x pecte d a n d are c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d u ne x pecte d 
seri o us a d verse reacti o ns” or S U S A Rs). T he I n vesti gat or s h o ul d place c o pies of Safet y Re p orts i n 
t he I nvesti gat or Site File. Nati o nal re g ulati o ns wit h re gar d t o Safet y Re p ort n otificati o ns t o 
I n vesti gat ors will be ta ke n i nt o acc o u nt.
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 4 9
F or trials c o vere d b y t he E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities re gar di n g 
t he re p orti n g of S A Es/ S U S A Rs/ Safet y Iss ues will be carrie d o ut i n acc or da nce wit h t hat Directi ve 
a n d wit h t he relate d Detaile d G ui da nce d oc u me nt s.
7. 4. 1. 7
M o nit ori n g of S u bjects wit h A d verse E ve nts
A d verse e ve nts are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he trial (see Secti o n 7. 4. 1. 3 ) 
a n d are assesse d f or fi nal o utc o me at t he P T D 3 6 5 v isit. All S A Es o n g oi n g at t he E O T v isit m ust 
be m o nit ore d a n d f oll o we d u p b y  the I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, 
u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p”. Reas o na ble atte m pts t o o btai n t his 
i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure 
t hat a n y necessar y a d diti o nal t hera pe utic meas ures a n d f oll o w- u p pr oce d ures are perf or me d. 
7. 4. 2
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure 
O nl y  pre g na ncies c o nsi dere d b y  the I n vesti gat or t o be relate d t o trial treat me nt (e. g., res ulti n g fr o m 
a dr u g i nteracti o n wit h a c o ntrace pti ve me dicati o n) are c o nsi dere d t o be A E s. H o we ver, all 
pre g na ncies wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n 7. 4. 1. 3 m ust 
be rec or de d b y  co n ve nti o n i n t he S A E pa ge/secti o n of t he eC R F. T he sa me r ule a p plies t o 
pre g na ncies i n fe male s u bjects a n d t o pre g na ncies i n fe male part ners of male s u bjects. T he 
I n vesti gat or m ust n otif y  the S p o ns or/ desi g nee i n a n e x pe dite d ma n ner of a n y pre g na nc y usi n g t he 
Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitte d acc or di n g t o t he sa me pr ocess as descri be d 
f or S A E re p orti n g i n Secti o n 7. 4. 1. 4.  
I n vesti gat ors m ust 
acti vel y foll o w u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he s u bjects are wit h dra w n fr o m t he trial.
T he I n vesti gat or m ust n otif y  t he S p o nsor/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y  Re p ort 
F or m . If a n a b n or mal o utc o me occ urs , t he S A E Re p ort F or m will be use d if t he s u bject s ustai ns 
a n e ve nt a n d t he Pare nt - C hil d/ Fet us A E Re p ort F or m if t he c hil d/fet us s ustai ns a n e ve nt.
A n y  ab n or mal o utc o me m ust be re p orte d i n a n e x pe dite d ma n ner as descri be d i n Secti o n 7. 4. 1. 4,  
w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da y s after deli ver y.
I n the e ve nt of a pre g na nc y  in a s u bject occ urri n g d uri n g t he c o urse of t he trial, t he s u bject m ust 
be disc o nti n ue d fr o m trial me dicati o n i m me diatel y. T he S p o ns or/ desi g nee m ust be n otifie d 
wit h o ut dela y  a n d t he s u bject m ust be f oll o we d as me nti o ne d a b o ve.
7. 4. 3
Cli nic al L a b or at or y Assess me nts
It is esse ntial t hat t he S p o ns or or desi g nee be pr o vi de d wit h a list of la b orat or y nor mal ra n ges 
bef ore s hi p me nt of trial dr u g. A n y c ha n ge i n la b orat or y nor mal ra n ges d uri n g t he trial will 
a d diti o nall y be f orwar de d t o t he S p o ns or or desi g nee.
Res ults m ust be a vaila ble pri or t o t he first d ose of I M P. T he re p ort of t he res ults m ust be retai ne d 
as part of t he s u bject’s me dical rec or d or s o urce d oc u me nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 4 9
Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he f oll o wi n g cli nical la b orat or y tests, f oll o wi n g t he 
ti mi n g n ote d i n t he Sc he d ule s of Assess me nts (Ta ble 1, Ta ble 2, Ta ble 3, Ta ble 4, Ta ble 5, Ta ble 6
a n d Ta ble 7 f or P hase Ia [ Ar m A ca ps ule c o h ort], P hase Ia [ Ar m A ta blet c o h ort], P hase I b – f irst 
3 s u bjects [Ar m A, N S C L C c o h ort], P hase I b [Ar m A, N S C L C c o h ort], P hase Ia [ Ar m B, S C C H N
c o h ort], P hase I b [Ar m B, S C C H N c o h ort] a n d a ncillar y c P o P parts , res pecti vely) . All sa m ples 
s h o ul d be clearl y i de ntifie d. Uri nal ys is (se di me nt a n d pr otei n c o nte nt) will als o be perf or me d at 
s pecifie d ti me p oi nts.
T a ble 1 5  
Re q uire d L a b or at or y S afet y Tests
S er u m C h e mi str y
H e m at ol o g y
Al b u mi n
W h it e bl o o d c ell s a n d diff er e nti al c o u nt
Al k ali n e p h o s p h at a s e
H e m o gl o bi n
Al a ni n e a mi n otr a n sf er a s e
H e m at o crit
A s p art at e a mi n otr a n sf er a s e
R e d bl o o d c ell s
Bl o o d ur e a nitr o g e n
M e a n c or p u s c ul ar v ol u m e
C al ci u m
M e a n c or p u s c ul ar h e m o gl o bi n
Cr e ati n e p h o s p h o ki n a s e
M e a n c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n
Cr e ati ni n e
R eti c ul o c yt e s
Pl at el et c o u nt
G a m m a gl ut a m yltr a n sf er a s e
A b s ol ut e l y m p h o c yt e c o u nt 
Gl u c o s e
A b s ol ut e n e utr o p hil c o u nt 
L a ct at e d e h y dr o g e n a s e
M a g n e si u m
C o a g ul ati o n
P h o s p h or o u s
I nt er n ati o n al n or m ali z e d r ati o 
P ot a s si u m
A cti v at e d p arti al t hr o m b o pl a sti n ti m e
S o di u m
T ot al bilir u bi n
I nf e cti o n s cr e e n
T ot al pr ot ei n
H e p atiti s B
Uri c a ci d
H e p atiti s C
β- h u m a n c h ori o ni c g o n a d otr o pi n i n f e m al e s u bj e ct s (if 
a p pli c a bl e)
H u m a n i m m u n o d efi ci e n c y vir u s ( a c c or di n g t o l o c al 
pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e)
F or w o me n of c hil d beari n g p ote ntial, pre g na nc y testi n g (ser u m β -H C G) will be perf or me d d uri n g 
t he Scree ni n g Peri o d a n d at t he visits s pecifie d i n t he Sc he d ule of Assess me nts . S u bjects after 
me n o pa use (a ge-relate d a me n orr hea ≥1 2 c o nsec uti ve m o nt hs) or s u bjects w h o ha ve u n der g o ne 
h y sterect o my or bilateral o o p h orect o m y are e xe m pt fr o m pre g na nc y testi n g.
Details o n t he bl o o d v ol u me t o be dra w n fr o m eac h s u bject d uri n g t he trial are prese nte d i n a 
se parate la b orat or y d oc u me nt.
F or t he P hase Ia a n d I b parts, i ncl u di n g t he bl o o d v ol u me dra w n f or researc h p ur p oses ( P K, P D
mar kers, a n d P G x ) a n d safety assess me nts, t he t otal v ol u me of bl o o d dra w n fr o m eac h s u bject 
d uri n g t he Scree ni n g P eri o d (i ncl u di n g pre d ose) will be a p pr o xi matel y 6 1 m L . D uri n g t he 
treat me nt p eri o d, D L T peri o d a n d S h ort -ter m Safet y F oll o w -u p (e xcl u di n g pre d ose), t he t otal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 4 9
v ol u me of bl o o d dra w n fr o m eac h s u bject will be a p pr o xi matel y 1 3 8 m L
( P hase Ia, Ar m A) , 
1 8 6 m L  (first 3 s u bjects i n P hase I b, Ar m A e x pa nsi o n c o h ort [ N S C LC] ), 1 7 2 m L  (P hase I b, 
Ar m A e x pa nsi o n c o h ort [ N S C LC] ), 2 1 0 m L  (P hase Ia, Ar m B) a n d 1 8 4 m L  (P hase I b, Ar m B 
e x pa nsi o n c o h ort [ S C C H N]) . T he t otal v ol u me of bl o o d dra w n fr o m eac h s u bject i n t he a ncillar y 
c P o P part of t he trial, i ncl u di n g bl o o d sa m pli n g f or mar kers, is a p pr o xi matel y 7 3 m L .
7. 4. 4
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
Vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y  wei g ht, a n d E C O G P S will be 
meas ure d as descri be d i n t he Sc he d ule of Assess me nts: (Ta ble 1,  Ta ble 3 , Ta ble 4 , Ta ble 5 , 
Ta ble 6 a n d Ta ble 7 f or P hase Ia [ Ar m A] , P hase I b – f irst 3 s u bjects [Ar m A, N S C L C c o h ort], 
P hase I b [Ar m A, N S C L C c o h ort], P hase Ia [ Ar m B, S C C H N c o h ort], P hase Ib [ Ar m B, S C C H N
c o h ort] a n d a ncillar y c P o P parts , res pecti vel y). If p ossi ble, diast olic/s y st olic bl o o d press ure s h o ul d 
be ta ke n o n t he sa me ar m at eac h visit.
P h y sical e xa mi nati o ns will be o btai ne d pre d ose a n d p ost d ose. Vital si g ns (bl o o d press ure, heart 
rate, a n d b o d y  te m perat ure) assess me nts s h o ul d be perf or me d pre d ose a n d 2 t o 3 h o urs p ost d ose .
B o d y w ei g ht will be meas ure d pre d ose o nl y. 1 2- lea d E C Gs (i n tri plicate after t he s u bject has bee n 
s u pi ne f or at least 5 mi n utes) s h o ul d be perf or me d pre d ose a n d 2 t o 3 h o urs p ost d ose o n Fracti o n 
D a y  1, a n d 2 h o urs p ost d ose o n Fracti o n Da y  1 0.
I n t he a ncillar y c P o P part of t he trial , vital si g ns a n d b o d y wei g ht s h o ul d be meas ure d pre d ose.
7. 5
P h ar m ac o k i netics
7. 5. 1
S a m ple C ollecti o n
Details of P K bl o o d sa m ple c ollecti o n a n d pr ocessi n g pr oce d ures, st ora ge, a n d tra ns p ortati o n will 
be s u m marize d i n t he la b orat or y  s pecificati o ns d oc u me nt.
F or details of P K bl o o d sa m pli n g ti me p oi nts i n t he P hase Ia, P hase I b, a n d a ncillar y c P o P parts of 
t he trial, see Ta ble 9 . 
P har mac o ki netic sa m pli n g s h o ul d be perf or me d wit hi n ± 1 5 mi n utes of t he first 3 0 mi n ute p ost d ose 
sa m ple c ollecti o ns, a n d wit hi n ± 3 0 mi n utes f or s u bse q ue nt sa m pli n g at eac h sa m pli n g d a y . T he 
pre d ose sa m ple s h o ul d be ta ke n wit hi n 1 h o ur bef ore d osi n g at eac h sa m pli n g da y. A p pr o xi matel y 
2 m L  of bl o o d s h o ul d be c ollecte d at eac h sc he d ule d ti me. T he dr u g a d mi nistrati o n, act ual date 
a n d e xact bl o o d sa m pli n g ti me m ust be rec or de d.
T he S M C ma y m o dif y  t he P K sa m pli n g sc he d ule base d u p o n P K i nf or mati o n c ollecte d d uri n g t he 
trial. T he S M C is n ot e x pecte d t o i ncrease t he o verall a m o u nt of bl o o d t o be c ollecte d f or P K 
sa m pli n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 4 9
7. 5. 2
P h ar m ac o k i netic C alc ul ati o ns
7. 5. 2. 1
N o n C o m p art me nt al A n al ysis
Ca ps ule f or m ulati o n:
T he f oll o wi n g P K para meters will be calc ulate d f or t he M 3 8 1 4
c o nce ntrati o n data o btai ne d o n 
Fracti o n D a y  1 a n d Fracti o n Da y  1 0 (if Fracti o n Da y 1 0 is o n a Fri da y, t he n t hese e val uati o ns will 
be d o ne o n Fracti o n Da y 9) i n t he P hase Ia part usi n g n o nc o m part me ntal a nal ysis a p pr oac hes as 
a p pr o priate:

C ma x

Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n (tma x )

A U C o ver t he d osi n g i nter val after m ulti ple d osi n g ( A U Cτ) (Fracti o n Da y  1 0 o nl y ) 

A U C fr o m ti me zer o t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C0-t) ( Fracti o n Da y 1 
o nl y ) A U C
fr o m ti me zer o e xtra p olate d t o i nfi nit y ( A U C0- ∞, Fracti o n Da y  1 a n d o nl y if 
mea ni n gf ul o n Fracti o n Da y  1 0)

A p pare nt ter mi nal half -life (t1/ 2)

Oral cleara nce ( C L/f) ( Fractio n Da y  1 o nly)

Oral cleara nce at stea d y s tate ( C Lss/f) ( Fracti o n Da y 1 0 o nly)

A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase ( Vz/f) ( Fracti o n Da y 1 o nly)

A p pare nt v ol u me of distri b uti o n at stea d y  state ( Vss/f) ( Fracti o n Da y 1 0 o nl y )

Acc u m ulati o n rati o f or A U C ( Racc[ A U C]) ( Fracti o n Da y 1 0 o nl y )

Acc u m ulati o n rati o f or C ma x ( Racc[ Cma x ]) ( Fracti o n Da y 1 0 o nl y ).
Ta blet f or m ulati o n:
T he f oll o wi n g P K para meters will be calc ulate d f or t he M 3 8 1 4
c o nce ntrati o n data o btai ne d o n 
Fracti o n Da y  1, 6 (if a patie nt d oes n ot start treat me nt o n a M o n da y, t he n “ F D 6” bec o mes t he F D 
t hat is cl osest t o a M o n da y. T heref ore, t here will be a was h-o ut of M 3 8 1 4 o ver t he wee ke n d) a n d 
Fracti o n D a y  10 (if Fracti o n D a y 1 0 is o n a Fri da y , t he n t hese e val uati o ns will be d o ne o n Fr acti o n 
D a y  9) i n t he P hase Ia part usi n g n o nc o m part me ntal a nalys is a p pr oac hes as a p pr o priate:

C ma x

Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n (t ma x )

A U C o ver t he d osi n g i nter val after m ulti ple d osi n g ( A U C τ) ( Fracti o n Da y 1 0 o nl y) 

A U C fr o m ti me zer o t o the ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C0-t) ( Fracti o n Day 1 
a n d Fracti o n D a y  6) A U C fr o m ti me zer o e xtra p olate d t o i nfi nit y ( A U C0- ∞, Fracti o n Da y 1 a n d 
Fracti o n Da y  6, a n d o nl y if mea ni n gf ul o n Fracti o n Da y 1 0)

A p pare nt ter mi nal half -life (t1/ 2)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 6 / 1 4 9

Oral cleara nce ( C L/f) ( Fracti o n Da y  1 a n d Fracti o n Da y 6 o nl y )

Oral cleara nce at stea d y s tate ( C Lss/f) ( Fracti o n Da y 1 0 o nly)

A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase ( Vz/f) ( Fracti o n Da y  1 a n d Fracti o n 
D a y 6 o nl y )

A p pare nt v ol u me of distri b uti o n at stea d y  state ( Vss/f) ( Fracti o n Da y 1 0 o nl y)

Acc u m ulati o n rati o f or A U C ( R acc[ A U C]) ( Fracti o n Da y 1 0 o nl y)

Acc u m ulati o n rati o f or C ma x ( Racc[ Cma x ]) ( Fracti o n Da y 1 0 o nl y).
A d diti o nal P K para meters ma y  be calc ulate d.
Plas ma c o nce ntrati o n of M 3 8 1 4
will be deter mi ne d b y  a Li q ui d c hr o mat o gra p h y- ta n de m mass 
s pectr o metr y met h o d .
7. 5. 2. 2
P o p ul ati o n P K A n al ysis a n d Si m ul ati o n
P o p ul ati o n p h ar m ac o ki netic
O bjecti ves of t he p o p ulati o n P K a nal y sis will be:

I de ntificati o n of p o p ulati o n P K m o del of M 3 8 1 4

Esti mati o n of t y pical p o p ulati o n P K para meters of M 3 8 1 4
as cleara nces, ce ntral a n d peri p heral 
v ol u mes, etc.

Esti mati o n of t he varia bilit y  of t he p o p ulati o n P K para meters

I de ntificati o n of a d diti o nal c o variates, s uc h as de m o gra p hics, c o me dicati o n or me dical hist or y, 
t hat are si g nifica nt pre dict ors of P K varia bilit y , R T d ose .
Si m ul ati o n
If re q ueste d, si m ulati o n of a n alter nati ve d osi n g re gi me n will be perf or me d i n or der t o ac hie ve a 
certai n tar get.
T he p o p ulati o n a nal ysis will be c o n d ucte d wit h s oft ware pac ka ge N O N M E M ( versi o n 7. 2. 0), 
w hile t he si m ulati o ns will be perf or me d wit h eit her N O N M E M or SI M U L X s oft ware.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 4 9
7. 7
Ot her A ssess me nts
N ot a p plica ble.
8
St atistics
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 4 9
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 4 9
8. 2
R a n d o miz ati o n
N ot a p plica ble .
8. 3
E n d p oi nts
8. 3. 1
Pri m ar y E n d p oi nts
T he p ri mar y e n d p oi nts f or t he trial are:

P hase Ia ( Ar m A): Occ urre nce of D L T u p t o 5 wee ks after first d ose of M 3 8 1 4
i n c o m bi nati o n 
wit h palliati ve fracti o nate d R T

P hase Ia ( Ar m B): Occ urre nce of D L T u p t o 1 2 wee ks after first d ose of M 3 8 1 4
i n c o m bi nati o n 
wit h sta n dar d C R T ( wit h cis plati n) wit h c urati ve i nte nt

P hase I b ( Ar m A) – first 3 s u bjects: Occ urre nce of D L T u p t o 1 2 wee ks after t he first d ose of 
M 3 8 1 4 i n c o m bi nati o n wit h c urati vel y i nte n de d fracti o nate d R T

P hase I b: Safet y a n d t olera bilit y as f oll o ws:
o
Occ urre nce of T E A Es (se verit y gra de d acc or di n g t o t he N CI  C T C A E v 4. 0 3)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 4 9
o
Res ults of la b orat or y tests, vital si g ns, E C Gs.
8. 3. 2
Sec o n d ar y E n d p oi nts
8. 3. 2. 1
S afet y E n d p oi nts

Occ urre nce of T E A Es (se verit y gra de d acc or di n g t o t he N CI  C T C A E v 4. 0 3)

Res ults of la b orat or y tests, vital si g ns, E C Gs .
8. 3. 2. 2
Effic ac y E n d p oi nts

Best o verall res p o nse base d o n t u m or e val uati o ns ma de b y  In vesti gat or i n acc or da nce wit h 
R E CI S T v 1. 1

T u m or size meas ure me nt base d o n I n vesti gat or assess me nt i n acc or da nce wit h R E CI S T v 1. 1

P F S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o pr o gressi ve disease ( per 
R E CI S T v 1. 1) base d o n t he I nvesti gat or assess me nt or deat h fr o m a n y ca use, a n d l ocal/l ocal 
re gi o nal t u m or c o ntr ol ( P hase I b, Ar m B e x pa nsi o n c o h ort)

O S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o t he date of deat h fr o m a n y c a use 
8. 3. 2. 3 
P h ar m ac o k i netic E n d p oi nts
Plas ma P K para meters of M 3 8 1 4
f or P hase Ia part (ca ps ule): 

Fracti o n Da y  1 – Cma x , tma x , A U C 0-t, A U C 0 - ∞, t1/ 2, C L /f, Vz/f

Fracti o n Da y  1 0 – Cma x , tma x , A U C τ, A U C0- ∞, t1/ 2, C L ss/f, Vss/f , Racc[ A U C], Racc[ Cma x ].
Plas ma P K para meters of M 3 8 1 4
f or P hase Ia part (ta blet): 

Fracti o n Da y  1 – Cma x , tma x , A U C0 -t, A U C0- ∞, t1/ 2, C L/f, Vz/f

Fracti o n Da y  6 – Cma x , tma x , A U C0-t, A U C0- ∞, t1/ 2, C L/f, Vz/f

Fracti o n Da y  1 0 – C ma x , tma x , A U Cτ, A U C 0- ∞, t1/ 2, C Lss/f, Vss/f, Racc[ A U C], Racc[ Cma x ].
P o p ulati o n P K para meters f or P hase I b a n d t he a ncillar y c P o P part of t he trial will be re p orte d i n 
a se parate P K re p ort, w hic h will n ot be part of t he Cli nical Trial Re p ort f or t his trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 4 9
8. 4
A n al ysis Sets
All S u bjects A n al ysis Set
T he All s u bjects (A L L ) a nal ys is set will i ncl u de all t he s u bjects w h o ha ve si g ne d t he I CFs (i.e.,
scree ni n g fail ures pl us s u bjects e nr olle d). T he A L L a nal ys is set will be use d t o s u m marize a n d 
descri be t he s u bject dis p ositi o n, a n d deat hs, u nless o t her wise state d.
F ull A n al ysis Set/ S afet y A n al ysis Set
T he F ull A nal y sis Set ( F A S)/Safet y ( S A F) a nal ysis set will i ncl u de all s u bjects w h o recei ve at 
least o ne a d mi nistrati o n of t he trial me dicati o n. T he F A S/ S A F a nal ys is set will be use d f or all 
baseli ne , safet y (e xce pt f or D L Ts a n d deat hs), a n d efficac y s u m maries, u nless ot her wise state d.
D ose Esc al ati o n A n al ysis Set
T he D ose Escalati o n ( D E) a nal ys is set will i ncl u de all s u bjects treate d i n d ose escalati o n c o h orts 
w h o recei ve at least 8 0 % of M 3 8 1 4
a n d R T pla n ne d d ose a n d c o m plete t he D LT peri o d (t hr o u g h 
5 wee ks [P hase Ia, Ar m A] or 1 2 wee ks [ P hase Ia, Ar m B a n d P hase I b, first 3 s u bjects i n t he 
e x pa nsi o n c o h ort of Ar m A - N S C L C] after start of M 3 8 1 4 treat me nt). T he D E set will als o i ncl u de 
s u bjects treate d i n d ose escalati o n c o h orts w h o e x perie nce a D L T d uri n g t he D L T peri o d re gar dless 
of t he recei ve d a m o u nt of eac h dr u g. T he D E a nal ysis set will be use d f or t he D L T s u m maries. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 4 9
P h ar m ac o ki netics A n al ysis Set
T he P K e val uati o n ( P K) a nal ys is set i n P hase Ia a n d P hase I b parts will i ncl u de s u bjects w h o ha ve 
recei ved at least t he first d ose of t he dr u g a n d pr o vi de d P K sa m ples as per pr ot oc ol f or at least 
6 h o urs f oll o wi n g first d osi n g o n Fracti o n D a y  1.
8. 5
Descri pti o n of St atistic al A n al yses
8. 5. 1
Ge ner al C o nsi der ati o ns
All a nal yses will be pre pare d b y  f or m ulati o n (ca ps ule, ta blet) a n d d ose le vel (if a p plica ble), a n d 
will be descri be d i n detail i n t he Statistical A nal y sis Pla n ( S A P). 
T he f oll o wi n g s u m mar y statistics will be use d t o s u m marize t he trial data per d ose le vel u nless 
ot her wise s pecifie d:

C o nti n u o us varia bles: n u m ber of n o n missi n g o bser vati o ns, mea n, sta n dar d de viati o n ( S D), 
me dia n, mi ni m u m, a n d ma xi m u m, 9 5 % CI s f or t he mea n, as a p pr o priate

Cate g o rical varia bles: fre q ue ncies a n d perce nta ges.
T he c ut off f or d ose escalati o n assess me nts b y  the S M C i n P hase Ia will be tri g gere d b y  th e 
c o m pleti o n of t he D L T peri o d of t he last s u bject i n t he res pecti ve c o h ort.
T he c ut off f or a nal ys is of t he sec o n dar y safet y data fr o m t he P hase Ia d ose escalati o n a n d M T D 
deter mi nati o n p hase of t he trial will be tri g gere d w he n t he last s u bject e nr olle d reac hes t he sec o n d 
p ost -treat me nt t u m or assess me nt or e x perie nces deat h or pre mat ure wit h dra wal f or a n y reas o n, 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 5 / 1 4 9
w hic he ver c o mes first. T he c ut off f or t he c P o P a nal ysis will be tri g gere d w he n t he last s u bject 
e nr olle d i n t he a ncillar y c P o P part of t he trial c o m pletes t he assess me nt at t he E O T visit. 
T he c ut off f or t he a nal ys is of t he safety a n d efficac y e n d p oi nts i n t he P hase I b e x pa nsi o n c o h ort s
(i ncl u di n g t he first 3 N S C L C s u bjects treate d at a l o wer d ose) will be tri g gere d b y  t he date w he n 
t he last e nr olle d s u bject reac hes t he sec o n d p ost -treat me nt t u m or assess me nt or e x perie nces deat h 
or pre mat ure wit h dra wal f or a n y rea s o n, w hic he ver c o mes first.
F ull details of t he pla n ne d a nal ys es will be descri be d i n t he trial S A P se paratel y for t he d ose 
escalati o n a n d t he e x pa nsi o n part of t he trial.
8. 5. 2
A n al ysis of Pri m ar y E n d p oi nts
P hase Ia a n d t he first 3 s u bjects i n P hase I b (Ar m A) : T he n u m ber a n d pr o p orti o n of s u bjects 
e x perie nci n g a D L T will be re p orte d se parately f o r eac h ar m a n d f or m ulati o n b y  d ose le vel, base d 
o n t he o bser vati o n of D L Ts u p t o 5 wee ks ( P hase Ia, Ar m A) or 1 2 wee k s (P hase Ia, Ar m B a n d 
first 3 s u bjects i n P hase I b [ Ar m A] ) after t he first d ose of M 3 8 1 4 ta ki n g i nt o acc o u nt t he k n o w n 
t o xicities wit h R T al o ne. P osteri or pr o ba bilities ( 2. 5 %, 2 5 %, 5 0 %, 7 5 % a n d 9 7. 5 % q ua n tiles) after 
t he last c o h ort will be esti mate d (if a p plica ble). T he D E a nal ys is set will be use d f o r t his a nalys is.
8. 5. 3
A n al ysis of Sec o n d ar y E n d p oi nts
8. 5. 3. 1 
P h ar m ac o k i netics
8. 5. 3. 1. 1
Descri pti ve St atistics
T he P K varia bles will be a nal yze d descri pti vel y  for eac h treat me nt se parately.  Descri pti ve 
statistics i ncl u de N, arit h metic mea n, ge o metric mea n, S D, sta n dar d err or of t he mea n, me dia n, 
mi ni m u m, ma xi m u m, c oefficie nt of variati o n ( %), a n d ge o metric c oefficie nt of variati o n . T he dr u g 
c o nce ntrati o n i n plas ma at eac h sa m pli n g ti me will be prese nte d o n t he ori gi nal scale f or all 
s u bjects w h o partici pate i n t he trial a n d pr o vi de at least 1 plas ma c o nce ntrati o n of M 3 8 1 4 . Val ues 
bel o w t he l o wer li mit of q ua ntificati o n will be ta ke n as zer o f or descri pti ve statistics of 
c o nce ntrati o ns. 
I n di vi d ual plas ma c o nce ntrati o n-ti me pr ofiles (li near a n d se mi-l o garit h mic scale) will be pl otte d 
b y  treat me nt. Mea n plas ma c o nce ntrati o ns per treat me nt will be pl otte d wit h S D b y  sc he d ule d ti me 
p oi nts. If e vi de nce is o btai ne d t hat wei g ht affects t he P K pa ra meters, t he n a nal yses will als o be 
perf or me d f or wei g ht -n or malize d P K para meters. F or mal statistical h y p ot heses are n ot set u p. All 
statistical tests will be perf or me d i n a n e x pl orat or y ma n ner. All a nal yses will be base d o n t he P K 
a nal ys is set. 
Details of t he statistical a nal y ses will be descri be d i n t he S A P. 
8. 5. 3. 1. 2
A n al ysis of D ose Pr o p orti o n alit y
Details of t he statistical a nal y ses will be descri be d i n t he S A P.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 4 9
8. 5. 3. 3
Effic ac y A n al yses
S u m mar y  statistics as descri be d i n Secti o n 8. 5. 1 will be use d f or t he s u m mar y of efficac y en d p oi nts 
b y  dose le vel a n d c o h ort. Pr o gressi o n free s ur vi val a n d O S will be calc ulate d f or t he e x pa nsi o n 
c o h ort o nl y. 
8. 5. 4
A n al ysis of S afet y a n d Ot her E n d p oi nts
8. 5. 4. 1
A d verse E ve nts
A d verse E ve nts will be c o de d acc or di n g t o t he latest a vaila ble versi o n of t he Me dical Dicti o nar y  
f or Re g ulat or y  Acti vities ( Me d D R A). Se verit y  of A Es will be gra de d usi n g t he C T C A E (v 4. 0 3) 
t o xicit y gra des. A d verse e ve nts relate d t o trial me dicati o n will be defi ne d as a n y A E c o nsi dere d 
relate d t o M 3 8 1 4 . I n a d diti o n, missi n g classificati o ns c o ncer ni n g trial me dicati o n relati o ns hi ps 
will be c o nsi dere d relate d t o t he trial dr u g. 
T he i nc i de nce a n d ty pe of t he f oll o wi n g T E A Es o bser ve d u ntil 3 0 da ys fr o m e n d of treat me nt will 
be a nal yz e d re p orti n g se paratel y t h ose relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n: 

T E A Es of a n y gra de a n d S A Es

T E A Es a n d S A Es of a n y gra de relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n

T E A Es wit h C T C A E Gra de ≥3

T E A Es relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n wit h C T C A E Gra de ≥3

A Es lea di n g t o wit h dra wal, d ose m o dificati o ns or per ma ne nt t rial treat me nt disc o nti n uati o n

A Es relate d t o M 3 8 1 4 , R T , C R T or t heir c o m bi nati o n lea di n g t o wit h dra wal, d ose m o dificati o ns 
or per ma ne nt t rial treat me nt disc o nti n uati o n

A Es lea di n g t o deat h

A Es relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n lea di n g t o deat h.
T hese will be s u m marize d acc or di n g t o Me d D R A S y ste m Or ga n Classes an d Preferre d Ter ms. 
S u bject s w h o ter mi nate treat me nt will be dis pla ye d i n a b y -s u bject listi n g, a n d s u m marize d b y 
pri mar y  wit h dra wal reas o n f or eac h treat me nt gr o u p. 
All re p orte d deat hs d uri n g t hera p y a n d deat hs wit hi n 3 0 d a y s after first a n d last d ose of trial 
treat me nt as well as reas o ns f or deat h will be ta b ulate d (f or all s u bjects e nr olle d). Deat hs wit hi n 
3 0 da y s fr o m last d ose a d mi nistrati o n a n d reas o ns f or t he m will als o be ta b ulate d. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 4 9
8. 5. 4. 2
L a b or at or y V ari a bles
La b orat or y  res ults will be classi fie d b y  gra de acc or di n g t o t he C T C A E v 4. 0 3. T he w orst o n- trial 
gra des after t he first d ose of trial treat me nt will be s u m marize d.
S hifts i n t o xicit y gra des fr o m first treat me nt t o hi g hest gra de will be dis pla y e d. Res ults f or 
varia bles t hat are n ot part of N CI -C T C A E ( v 4. 0 3) will be prese nte d as bel o w, wit hi n, or a b o ve 
n or mal li mits. O nl y  su bjects wit h p ost baseli ne la b orat or y val ues will be i ncl u de d i n t hese a nal ys es. 
8. 5. 4. 3
P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o n, i ncl u di n g vital si g ns ( b o dy t e m perat ure, heart rate, a n d bl o o d press ure), a n d 
1 2- lea d E C G rec or de d at baseli ne a n d after a d mi nistrati o n of M 3 8 1 4
will be prese nte d. Eac h E C G 
para meter will be s u m marize d b y  descri pti ve statistics per time p oi nt, a n d c ha n ges fr o m baseli ne 
will be calc ulate d. A cate g orical a nal ys is will be perf or me d f or Q Tc F data. Data will be f urt her 
a nal yz e d usi n g c o nce ntrati o n effect m o deli n g f or baseli ne -c orrecte d Q Tc F val ues o btai ne d at 
D a y 1. 
8. 6
I nteri m A n al ysi s
N o f or mal i nteri m a nal yses are pla n ne d . H o we ver , a d mi nistrati ve l o o ks i nt o t he data ma y
be 
perf or me d.
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t he I n vesti g at or
T he I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he trial t o e ns ure t hat t he trial is perf or me d i n 
acc or da nce wit h t his pr ot oc ol, t he et hical pri nci ples o utli ne d i n t he Declarati o n of Helsi n ki, I CH 
G C P , a n d a n y ot her a p plica ble re g ulati o ns. T he I n vesti gat or m ust e ns ure t hat o nl y  su bjects w h o 
ha ve gi ve n i nf or me d c o nse nt are i ncl u de d i n t he trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 4 9
Acc or di n g t o U nite d States C o de of Fe deral Re g ulati o ns Part 5 4. 2 (e), f or trials c o n d ucte d i n a n y 
c o u ntr y that c o ul d res ult i n a pr o d uct s u b missi o n t o t he U nite d States F o o d a n d Dr u g 
A d mi nistrati o n f or mar keti n g a p pr o val a n d c o ul d c o ntri b ute si g nifica ntl y  t o t he de m o nstrati o n of 
efficac y an d safet y of a n I MP ( w hic h are c o nsi dere d “c o vere d cli nical trials” b y  the F D A), t he 
I n vesti gat or a n d all s u bIn vesti gat ors are o bli ge d t o discl ose a n y f i na ncial i nterest w hic h t he y, t heir 
s p o uses or t heir de pe n de nt c hil dren m a y  ha ve i n t he S p o ns or or t he S p o ns or’s pr o d uct u n der st u d y. 
T his i nf or mati o n is re q uire d d uri n g t he trial a n d f or 1 2 m o nt hs f oll o wi n g c o m pleti o n of t he trial.
9. 2
S u bject I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prere q uisite f or eac h s u bject pri or t o partici pati o n i n t he trial is writte n i nf or me d 
c o nse nt , w hic h m ust be gi ve n bef ore a n y trial-relate d acti vities are carrie d o ut. A de q uate 
i nf or mati o n m ust t heref ore be gi ve n t o t he s u bject b y  the I n vesti gat or or a n a p pr o priate desi g nee 
(if l ocal re g ulati o ns per mit) bef ore i nf or me d c o nse nt is o btai ne d. 
A s u bject i nf or mati o n s heet m ust be pre pare d i n t he l ocal la n g ua ge i n acc or da nce wit h I CH G C P
a n d will be pr o vi de d b y t he S p o ns or f or t he p ur p ose of o btai ni n g i nf or me d c o nse nt. I n a d diti o n t o 
pr o vi di n g t his writte n i nf or mati o n t o a p ote ntial s u bject, t he I n vesti gat or or a desi g nate will i nf or m 
t he s u bject ver ball y of all perti ne nt as pects of t he trial, usi n g la n g ua ge c h ose n s o t hat t he 
i nf or mati o n ca n be f ull y a n d rea dil y un derst o o d b y  la ypers o ns. T he s u bject will be gi ve n s ufficie nt 
ti me t o rea d t he i nf or mati o n a n d t he o p p ort u nit y  to as k q uesti o ns a n d t o re q uest a d diti o nal 
i nf or mati o n a n d clarificati o n.
If per mitte d b y nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or ma y  inf or m t he s u bject 
a b o ut t he trial a n d si g n t he I CF, as a b o ve.
After t he i nf or mati o n is pr o vi de d b y  the I n vesti gat or, t he IC F m ust be si g ne d a n d date d b y  the 
s u bject a n d t he I n vesti gat or. 
T he si g ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he I n vesti gat or’s site, a n d 
m ust be safel y arc hi ve d s o t hat t he f or ms ca n be retrie ve d at a n y t i me f or m o nit ori n g, a u diti n g a n d 
i ns pecti o n p ur p oses. A c o p y of t he si g ne d a n d date d i nf or mati o n a n d IC F s h o ul d be pr o vi de d t o 
t he s u bject pri or t o partici pati o n.
W he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y  be rele va nt t o i nf or me d c o nse nt, 
t he I nvesti gat or will re vise t he s u bject i nf or mati o n s heet a n d a n y ot her writte n i nf or mati o n t o be
pr o vi de d t o t he s u bjects a n d s u b mit t he m t o t he I E C/I RB f or re vie w a n d o pi ni o n. Usi n g t he 
a p pr o ve d re vise d s u bject i nf or mati o n s heet a n d ot her writte n i nf or mati o n, T he I nvesti gat or will 
e x plai n t he c ha n ges t o t he pre vi o us versi o n t o eac h trial s u bject a n d o btai n ne w writte n c o nse nt f or 
c o nti n ue d partici pati o n i n t he trial. T he s u bject wi ll be gi ve n s ufficie nt ti me t o rea d t he i nf or mati o n 
a n d t he o p p ort u nit y  t o as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d clarificati o n a b o ut 
t he c ha n ges.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 4 9
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject at i ncl usi o n , i m me diatel y after i nf or me d 
c o nse nt has bee n o btai ne d. T his n u m ber will ser ve as t he s u bject’s i de ntifier i n t he trial as well as 
i n t he cli nical trial data base.
All s u bject data c ollecte d i n t he trial will be st ore d u n der t h e a p pr o priate s u b ject n u m ber. O nl y t he 
I n vesti gat or will be a ble t o li n k trial data t o a n i n di vi d ual s u bject via a n i de ntificati o n list ke pt at 
t he site. F or eac h s u bject, ori gi nal me dical data will be accessi ble f or t he p ur p oses of s o urce data 
verificati o n b y  the M o nit or,
a u dits a n d re g ulat or y ins pecti o ns, b ut s u bject c o nfi de ntialit y will be 
strictl y mai ntai ne d.
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, a n d 
st ori n g s u bject data. S u bjects will be i nf or me d acc or di n gl y, a n d will be re q ueste d t o gi ve t heir 
c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns.
Bl o o d a n d t u m or tiss ue sa m ples f or P G x a n d bi o mar kers will be st ore d f or u p t o 1 2 ye ars after trial 
c o m pleti o n. D uri n g t his ti me, t he sa m ples m a y be rea nal yz e d f or ne wl y i de ntifie d mar kers or wit h
n e w or i m pr o ve d tec h n ol o gy . After 1 2 ye ars, t he sa m ples will be destr o ye d or f ull y an o n y mize d 
or a ne w I E C/I R B a p pr o val a n d i nf or me d c o nse nt will be re q ueste d t o kee p t he sa m ples f or a n 
a d diti o nal peri o d. If t u m or tiss ue re mai ns, t he site will be n otifie d a n d t he t u m or tiss ue will be 
ret ur ne d t o t he site u p o n re q uest. If t he site d oes n ot re q uest t he ret ur n of t he t u m or tiss ue, it will 
be destr o ye d.
9. 4
E mer ge nc y Me dic al S u p p ort a n d S u bject C ar d
S u bjects e nr olle d i n t his cli nical trial will be pr o vi de d wit h E mer ge nc y  Me dical S u p p ort car ds 
d uri n g t heir trial partici pati o n, w hic h will be f ur nis he d b y  the S p o ns or. T he E mer ge nc y  Me dical 
S u p p ort car d is base d o n t he nee d t o pr o vi de cli nical trial s u bjects wit h a wa y  of i de ntif yi n g 
t he msel ves as partici pati n g i n a cli nical trial, a n d s u bse q ue ntl y to gi ve healt h care pr o vi ders access 
t o t he i nf or mati o n a b o ut t his partici pati o n t hat ma y  be nee de d t o deter mi ne t he c o urse of t he 
s u bject’s me dical treat me nt.
T his ser vice is desi g ne d t o pr o vi de i nf or mati o n t o healt h care pr o vi ders w h o are n ot part of t he 
cli nical trial; a n d t his ma y i ncl u de t he p ossi bilit y  of e mer ge nc y un bli n di n g if nee de d, i n case of 
bli n de d trials.
Cli nical trial In vesti gat ors, w h o are alrea d y a ware of t he cli nical trial pr ot oc ol a n d treat me nt, ha ve 
ot her mea ns of accessi n g t he necessar y  me dical i nf or mati o n f or t he ma na ge me nt of e mer ge ncies 
occ urri n g i n t heir s u bjects.
T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical trial I n vesti gat or cari n g f or t he 
affecte d s u bject. T he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact i nf or mati o n o n 
t he car d f or t his p ur p ose. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y s ubse q ue nt acti o n will 
f oll o w t he sta n dar d pr ocess esta blis he d f or 
I n vesti gat ors.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 4 9
I n cases w here t he I n vesti gat or is n ot a vaila ble, Merc k 
Ser o n o/ E M D Ser o n o pr o vi des t he 
a p pr o priate mea ns t o c o ntact a S p o ns or p h y sicia n. T his i ncl u des t he pr o visi o n of a 2 4- h o u r c o ntact 
n u m ber at a call ce nter, w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate 
S p o ns or p h y sicia n t o assist wit h t he me dical e mer ge nc y.
9. 5
Cli nic al Tri al I ns ur a nce a n d C o m pe ns ati o n t o S u bjects
I ns ura nce c o vera ge wi ll be pr o vi de d for eac h c o u ntr y partici pati n g t o t he trial. I ns ura nce c o n diti o ns 
s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d
Pri or t o c o m me nce me nt of t he trial at a gi ve n site, t his cli nical trial pr ot oc ol wil l be s u b mitte d 
t o get her wit h its ass ociate d d oc u me nts (e. g., IC F s) t o t he res p o nsi ble IE C or I RB f or its fa v ora ble 
o pi ni o n or a p pr o val , w hic h will be file d i n t he I nvesti gat or Site File . A c o p y will be file d i n t he
Trial Master File .
T he I E C or I RB will be as ke d t o d oc u me nt t he date of t he meeti n g at w hic h t he fa v ora ble o pi ni o n
or a p pr o val was gi ve n a n d t he me m bers a n d v oti n g me m bers prese nt. Writte n 
e vi de nce of 
fa v ora ble o pi ni o n or a p pr o val t hat clearl y i de ntifies t he trial, t he cli nical trial p r ot oc ol versi o n a n d 
t he S u bject I nf or mati o n a n d IC F versi o n re vie we d s h o ul d be pr o vi de d. W here p ossi ble, c o pies of 
t he meeti n g mi n utes s h o ul d be o btai ne d.
A me n d me nts t o t his cli nical trial pr ot oc ol will als o be s u b mitte d t o t he c o ncer ne d I E C or I R B, 
bef ore i m ple me ntati o n of s u bsta ntial c ha n ges (see Secti o n 1 0. 5 ). Rele va nt safety i nf or mati o n will 
be s u b mitte d t o t he I EC
or I RB d uri n g t he c o urse of t he trial i n acc or da nce wit h nati o nal 
re g ulati o ns a n d re q uire me nts.
9. 7
He alt h A ut h orities
T he cli nical trial pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n (f or e xa m ple, I M P D ossier, S u bject 
I nf or mati o n a n d IC F ) will be s u b mitte d or n otifie d t o t he Healt h A ut h orities i n acc or da nce wit h 
all l ocal a n d nati o nal re g ulati o ns f or eac h site.
1 0
Tri al M a n a ge me nt
1 0. 1
C ase Re p ort F or m H a n dli n g
Refer t o t he Ma n ual of o perati o ns f or e C R F ha n dli n g g ui deli nes.
T he mai n p ur p ose of the e C R F is t o o btai n data re q uire d b y  the cli nical trial pr ot oc ol i n a c o m plete, 
acc urate, le gi ble a n d ti mel y. T he data i n t he e C R F s h o ul d be c o nsiste nt wit h t he rele va nt s o urce 
d oc u me nts.
T he I n vesti gat or or desi g nee is res p o nsi ble f or e ns uri n g t hat t he d ata c ollecte d i n t he c o urse of t his 
trial is acc urate a n d d oc u me nte d a p pr o priatel y o n all a p plica ble f or ms. T he y  will t he n be 
pr ocesse d, e val uate d, a n d st ore d i n a n o n ym o us f or m i n acc or da nce wit h a p plica ble data pr otecti o n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 4 9
re g ulati o ns. T he I n vesti gat or m us t e ns ure t hat t he e C R Fs a n d a n y ot her ass ociate d d oc u me nts 
f or war de d t o S p o ns or or its desi g nate d or ga nizati o n c o ntai n n o me nti o n of a n y s u bject na mes.
T he data will be e ntere d i nt o a vali date d data base. T he C R Os Data Ma na ge me nt will be res p o nsi ble 
f or dat a pr ocessi n g, i n acc or da nce wit h t he C R Os sta n dar d o perati n g pr oce d ures . Data base l oc k 
will occ ur o nce q ualit y  co ntr ol pr oce d ure, a n d q ualit y  ass ura nce pr oce d ures (if a p plica ble) ha ve 
bee n c o m plete d. P D F files of t he e C R Fs will be pr o vi de d t o t he I n vesti ga t ors at t he c o m pleti o n of 
t he trial.
1 0. 2
S o urce D at a a n d S u bject Files
T he I n vesti gat or m ust kee p a file ( me dical file, ori gi nal me dical rec or ds) o n pa per or electr o nicall y 
f or e ver y s u bject i n t he trial. It m ust be p ossi ble t o i de ntif y eac h s u bject b y usi n g this s u bject file. 
T his file will c o ntai n t he de m o gra p hic a n d me dical i nf or mati o n f or t he s u bject liste d bel o w a n d 
s h o ul d be as c o m plete as p ossi ble. 

S u bject’s f ull na me, d ate of birt h, se x, h ei g ht, wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he trial)

Trial i de ntificati o n , t hat is, t he S p o ns or trial n u m ber f or t his cli nical trial, a n d s u bject n u m ber

Date s f or e ntr y i nt o t he trial (i nf or me d c o nse nt) a n d visits t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t his cli nical trial pr ot oc ol

All A E s

Date t hat t he s u bject left t he trial i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he trial or 
I M P (if a p plica ble).
A ll d oc u me nts c o ntai ni n g s o urce data m ust be file d, i nclu di n g C T or M RI  sca n i ma ges, E C G 
rec or di n gs, a n d la b orat or y res ults. S uc h d oc u me nts m ust bear t he s u bject n u m ber a n d t he date of
t he pr oce d ure. If p ossi ble, t his inf or mati o n s h o ul d be pri nte d b y  the i nstr u me nt use d t o perf or m 
t he assess me nt or meas ure me nt. As nec essar y, medical e val uati o n of s uc h rec or ds s h o ul d be 
perf or me d; all e val uati o ns s h o ul d be d oc u me nte d , si g ne d, a n d date d b y t he I n vesti gat or.
Electr o nic s u bject files will be pri nte d w he ne ver t he M o nit or perf or ms s o urce data verificati o n. 
Pri nt o uts m ust be si g ne d a n d date d b y  t he I n vesti gat or, c o u ntersi g ne d b y  t he M o nit or a n d ke pt i n 
a safe place at t he site.
1 0. 3
I n vesti g at or Site File a n d Arc hi vi n g
U p o n i nitiati o n of t he trial, the I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File 
c o ntai ni n g all necessar y  trial d oc u me nts , w hic h will be c o m plete d t hr o u g h o ut t he trial a n d u p date d 
as necessar y. T he file m ust be a vaila ble f or re vie w b y  t he M o nit or, d uri n g S p o ns or a u dit s a n d f or 
i ns pecti o n b y Healt h A ut h orities d uri n g a n d after t he trial, a n d m ust be safel y arc hi ve d f or at least 
1 5 ye ars ( or l o n ger, per l ocal re q uire me nts or as ot her wise n otifie d b y  the S p o ns or) after t he e n d 
of t he trial. T he d oc u me nts t o be arc hi ve d i ncl u de t he S u bject I de ntificati o n Li st a n d t he si g ne d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 4 9
s u bject IC F s. If arc hi vi n g of the I n vesti gat or Site File is n o l o n ger p ossi ble at t he site, t he 
I n vesti gat or m ust n otif y t he S p o ns or/ desi g nee.
All ori gi nal s u bject files ( me dical rec or ds) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, 
or practice) f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble re g ulati o ns, a n d/ or as per I CH 
G C P g ui deli nes, w hic he ver is l o n ger. I n a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o 
destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or.
1 0. 4
M o nit ori n g, 
Q u ali t y Ass ur a nce a n d I ns pecti o n b y He alt h 
A ut h orities
T his trial will be m o nit ore d i n acc or da nce wit h t he I C H G C P, a n d a n y ot her a p plica ble re g ulati o ns. 
T he site m o nit or will perf or m visits t o t he trial site at re g ular i nter vals.
T he cli nical trial pr ot oc ol, eac h ste p of t he data ca pt ure pr oce d ure, a n d t he ha n dli n g of t he data, 
i ncl u di n g t he fi nal cli nical trial re p ort, will be s u bject t o i n de pe n de nt Q ualit y Ass ura nce acti vities. 
A u dits ma y  be c o n d ucte d at a n y t i me d uri n g or after t he trial t o e ns ure t he vali di t y a n d i nte grit y of 
t he trial data. Re prese ntati ves of t he Q ualit y  Ass ura nce u nit fr o m t he S p o ns or or a desi g nate d 
or ga nizati o n, as well as Healt h A ut h orities, m ust be per mitte d t o access all trial d oc u me nts a n d 
ot her materials at t he site, i ncl u di n g t he In vesti gat or Site File, t he c o m plete d eC R Fs, all I MP a n d
I M P acc o u nta bilit y rec or ds, a n d t he ori gi nal me dical rec or ds or files f or eac h s u bject.
1 0. 5
C h a n ges t o t he Cli nic al Tri al Pr ot oc ol
C ha n ges t o t he cli nical trial pr ot oc ol will be d oc u me nte d i n writte n pr ot oc ol a me n d me nts. 
S u bsta nti ve a me n d me nts will us uall y  re q uire s u b missi o n t o t he Healt h A ut h orities a n d t o t he 
rele va nt I E C/I R B f or a p pr o val or fa v ora ble o pi ni o n. I n suc h cases, t he a me n d me nt will be 
i m ple me nte d o nl y after a p pr o val or fa v ora ble o pi ni o n has bee n o btai ne d.
Mi n or ( n o ns u bsta ntial) pr ot oc ol a me n d me nts, i ncl u di n g a d mi nistrati ve c ha n ges, will be file d b y  
t he S p o ns or a n d at t he site. T he y  will be s u b mitte d t o t he rele va nt I E C/IR B or t o Healt h A ut h orities 
o nl y  w here re q ueste d by perti ne nt re g ulati o ns. 
A n y  ame n d me nt t hat c o ul d affect t he s u bject’s a gree me nt t o partici pate i n t he trial re q uires
a d diti o nal i nf or me d c o nse nt pri or t o i m ple me ntati o n f oll o wi n g t he pr ocess as descri be d i n
Secti o n 9. 2.
1 0. 6
Cli nic al Tri al Re p ort a n d P u blic ati o n P olic y
1 0. 6. 1
Cli nic al Tri al Re p ort
After c o m pleti o n of t he trial, a cli nical trial re p ort will be writte n b y  the S p o ns or i n c o ns ultati o n 
wit h t he C o or di nati n g I nvesti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3 Str uct ure a n d C o nte nt 
of Cli nical St u d y  Re p orts ( 1 9 9 6).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 4 9
1 0. 6. 2 
P u blic ati o n
T he first p u blicati o n will i ncl u de t he res ults of t he a nal ysis of t he pri mar y  en d p oi nts a n d will 
i ncl u de data fr o m all trial sites.
T h e I n vesti gat or will i nf or m t he S p o ns or i n a d va nce a b o ut a n y pla ns t o p u blis h or prese nt data 
fr o m t he trial. A n y p u blicati o ns a n d prese ntati o ns of t he res ults (a bstracts i n j o ur nals or 
ne ws pa pers, oral prese ntati o ns, etc.), eit her i n w h ole or i n part, b y  In vesti gat ors or t heir 
re prese ntati ves will re q uire re vie w by t he S p o ns or bef ore s u b missi o n .
T he S p o ns or will n ot s u p press p u blicati o n, b ut mai ntai ns t he ri g ht t o dela y  p u blicati o n i n or der t o 
pr otect i ntellect ual pr o pert y  ri g hts.
P osti n g of data o n E u dra C T a n d Cli n icalTrials. g o v is pla n ne d a n d will occ ur 1 2 m o nt hs after t he 
last cli nic visit of t he fi nal trial s u bject or a n ot her a p pr o priate date t o meet a p plica ble re q uire me nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 4 / 1 4 9
1 1
Refere nces Cite d i n t he Te xt
1.
F o n g P C, B oss D S, Ya p T A, et al. I nhi biti o n of p ol y ( A D P-ri b ose) p oly m erase i n t u m ors fr o m 
B R C A m utati o n carriers. N E n gl J
Me d 2 0 0 9; 3 6 1( 2): 1 2 3 - 3 4.
2.
Far mer H, Mc Ca be N, L or d CJ, et al. Tar geti n g t he D N A re pair defect i n B R C A m uta nt cells 
as a t hera pe utic strate g y. Nat ure 2 0 0 5; 4 3 4( 7 0 3 5): 9 1 7- 2 1.
3.
A u de h M W, Car mic hael J, Pe ns o n R T, et al. Oral p ol y ( A D P-ri b ose) p ol y merase i n hi bit or 
ola pari b i n patie nts wit h B R C A 1 or B R C A 2 m utati o ns a n d rec urre nt o varia n ca ncer: a 
pr o of - of-c o nce pt trial. La ncet 2 0 1 0; 3 7 6( 9 7 3 7): 2 4 5- 5 1.
4.
S ha h B A, 
Q ures hi 
M M, 
L o g ue J M, et al. Assessi n g 
c u m ulati ve ac ute t o xicit y of 
c he m ora di ot hera p y i n hea d a n d nec k ca ncer wit h or wit h o ut i n d ucti o n c he m ot hera p y. A m J 
Ot olar y n g ol. 2 0 1 7; 3 8( 4): 4 5 6 - 6 1.
5.
I q bal M S, C ha w C, K o vari k J, et al. Pri mar y  co nc urre nt c he m ora diati o n i n hea d a n d nec k 
ca ncers wit h wee kl y cis plati n c he m ot hera p y:  a nal ysis of c o m plia nce, t o xicit y a n d s ur vi val. I nt 
Arc h Ot or hi n olar y n g ol. 2 0 1 7; 2 1( 2): 1 7 1- 7.
6.
H o m ma A, I na m ura N, Ori date N, et al. C o nc o mita nt wee kl y  cis plati n a n d ra di ot hera py f or 
hea d a n d nec k ca ncer. J p n J Cli n O n c ol. 20 1 1; 4 1( 8): 9 8 0 - 6.
7.
N or o n ha V, J os hi A, Patil V M, et al. O nce -a-wee k vers us o nce -e ver y- 3-wee ks cis plati n 
c he m ora diati o n f or l ocall y ad va nce d hea d a n d nec k ca ncer: a P hase III ra n d o mize d 
n o ni nferi orit y  trial. J Cli n O nc ol. 2 0 1 8; 3 6( 1 1): 1 0 6 4- 7 2.
8.
Das S, T h o mas S, Pal S K, et al. H y p ofracti o nate d palliati ve ra di ot hera p y  in l ocall y  ad va nce d 
i n o pera ble hea d a n d nec k ca ncer: C M C 
Vell ore 
e x perie nce. I n dia n J Palliat Care. 
2 0 1 3; 1 9( 2): 9 3 - 8.
9.
M osteller 
R D .
Si m plifie d 
Calc ulati o n 
of 
B o d y 
S urface 
Area. 
N 
E n gl 
J Me d 
1 9 8 7; 3 1 7( 1 7): 1 0 9 8 .
1 0. Dr u g De vel o p me nt a n d Dr u g I nteracti o ns. 
htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI ntera
cti o ns La beli n g/ uc m 0 8 0 4 9 9. ht m Accesse d o n 1 4 Ma y 2 0 1 5.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 5 / 1 4 9
1 2
A p pe n dices
A p pe n di x A:
Si g n at ure P a ges a n d Res p o nsi ble Pers o ns f or t he Tri al
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 4 9
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
A n O pe n La bel, P hase Ia/I b Trial of t he D N A -P K 
I n hi bit or M S C 2 4 9 0 4 8 4 A 
i n C o m bi nati o n 
wit h 
Ra di ot hera p y i n Patie nts 
wit h 
A d va nce d 
S oli d 
T u m ors
I N D N u m ber:
E u dr a C T N u m ber
2 0 1 5- 0 0 0 6 7 3- 1 2
Cli nic al Tri al Pr ot oc ol D ate / Versi o n
3 1 Ja n uar y 2 0 1 9 / Versi o n 9. 0
Ce nter N u m ber
Pri nci p al I n vesti g at or
I, t he u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he trial at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I nter nati o nal C o u ncil f or Har m o nisati o n G o o d Cli nical Practice ( T o pic E 6) a n d all 
a p plica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical trials t o 
o btai n a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I nvesti gati o nal Me dici nal 
Pr o d uct a n d a n y  ot her fi na ncial ties wit h the S p o ns or. T he S p o ns or will use a n y  s uc h i nf or mati o n 
s olel y for t he p ur p ose of c o m pl yi n g wit h t he re g ulat or y re q uire me nts. I t heref ore a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties 
i ncl u di n g t h ose of my s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet 
Healt h A ut h orit y  re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 4 9
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me
F u ncti o n
Bi ostatisticia n
I nstit uti o n
Merc k K Ga A
A d dress
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber
E- mail a d dress
Na me
F u ncti o n
Pri nci pal Cli nical Trial Lea d
I nstit uti o n
Merc k K Ga A
A d dress
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber
E- mail a d dress
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 4 9
A p pe n di x B :  
Res p o nse E v al u ati o n C riteri a i n S oli d T u m ors ( R E CI S T v 1. 1)
F or details, please refer t o t he f oll o wi n g pa per b y Eise n ha uer et al.
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
re vise d R E CIS T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5( 2): 2 2 8 - 4 7.
Defi niti o ns
At Baseli ne ( wit hi n 4 wee ks of i nitiati o n of treat me nt), t u m or lesi o ns/l ym p h n o des will be 
cate g orize d meas ura ble or n o n -meas ura ble as f oll o ws:
Me as ur a ble:

T u m or lesi o ns : M ust be acc uratel y meas ure d i n at least o ne di me nsi o n (l o n gest dia meter i n t he 
pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:

1 0 m m b y  C T sca n ( C T sca n slice t hic k ness ≤ 5 m m), 

1 0 m m cali per meas ure me nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y m eas ure d 
wit h cali pers s h o ul d be rec or de d as n o n -meas ura ble),

2 0 m m b y  c hest X-ra y.

M ali g n a nt ly m p h n o des : T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a l ym p h 
n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y  CT sca n ( C T sca n slice t hic k ness 
rec o m me n de d t o be ≤ 5 m m). At Baseli ne a n d i n f oll o w- u p, o nl y  the s h ort a xis will be meas ure d 
a n d f oll o we d. See als o n otes bel o w o n “ Baseli ne d oc u me ntati o n of tar get a n d n o ntar get lesi o ns” 
f or i nf or mati o n o n ly m p h n o de meas ure me nt.
N o n - me as ur a ble

All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l ym p h 
n o des wit h 1 0 t o < 1 5 m m s h ort a xis) as well as tr uly n o n- meas ura ble lesi o ns. Lesi o ns 
c o nsi dere d tr ul y n o n -meas ura ble i ncl u de le pt o me ni n geal disease, ascites, ple ural or pericar dial 
eff usi o n, i nfla m mat or y breast disease, l ym p ha n gitic 
i n v ol ve me nt of s ki n or l u n g, a n d 
a b d o mi nal masses/a b d o mi nal or ga n o me ga l y ide ntifie d b y  ph y sical e xa m t hat is n ot meas ura ble 
b y  re pr o d uci ble i ma gi n g tec h ni q ues.
S peci al c o nsi der ati o ns re g ar di n g lesi o n me as ur a bilit y
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y  treate d wit h l ocal t hera p y re q uire partic ular 
c o m me nt: 
B o ne lesi o ns:

B o ne sca n, p ositr o n e missi o n t o m o gra p hy sca n, or plai n fil ms are n ot c o nsi dere d a de q uate 
i ma gi n g tec h ni q ues t o meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m 
t he prese nce or disa p peara nce of b o ne lesi o ns. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 4 9

L yt ic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de ntifia ble s oft tiss ue c o m p o ne nts, t hat 
ca n be e val uate d b y  cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T, M RI, or ot her esta blis he d 
met h o ds ca n be c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he 
defi niti o n of meas ura bilit y descri be d a b o ve.

Blastic b o ne lesi o ns are n o n meas ura ble.
Cystic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be c o nsi dere d 
as mali g na nt lesi o ns ( neit her meas ura ble n or n o n meas ura ble) beca use t he y are, b y  defi niti o n, 
si m ple c ysts. 

‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble lesi o ns, 
if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. H o we ver, if n o nc ystic lesi o ns are 
pr ese nt i n t he sa me s u bject, t hese are preferre d f or selecti o n as tar get lesi o ns.
Lesi o ns wit h pri or l oc al tre at me nt:

T u m or lesi o ns sit uate d i n a pre vi o usl y  irra diate d area or ot her l oc ore gi o nal t hera py area are 
us uall y  not c o nsi dere d meas ura ble u nless t here has bee n de m o nstrate d pr o gressi o n i n t he lesi o n. 
Trial pr ot oc ols s h o ul d detail t he c o n diti o ns u n der w hic h s uc h lesi o ns w o ul d be c o nsi dere d 
meas ura ble.
Met h o ds of me as ure me nt

Meas ure me nt of lesi o ns
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, us i n g cali pers if cli nicall y assesse d. 
All baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d 
ne ver m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt.

Met h o d of assess me nt
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at Baseli ne a n d d uri n g f oll o w- u p. I ma gi n g base d e val uati o n 
s h o ul d al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d 
ca n n ot be i ma ge d b ut are assessa ble b y  cli nical e xa m. Cli nical lesi o ns: Cli nical lesi o ns will o nl y 
be c o nsi dere d meas ura ble w he n t he y are s u perficial a n d 1 0 m m dia meter as assesse d usi n g 
cali pers (e. g., s ki n n o d ules). F or t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y 
i ncl u di n g a r uler t o esti mate t he size of t he lesi o n is s u g geste d. As n ote d a b o ve, w he n lesi o ns 
ca n be e val uate d b y b ot h cli nical e xa m a n d i ma gi n g, i ma gi n g e val uati o n s h o ul d be u n derta ke n 
si nce it is m ore o bjecti ve a n d ma y als o be re vie we d at t he e n d of t he trial.

C hest X -r ay: C hest C T is preferre d o ver c hest X- ra y, partic ularl y w he n pr o gressi o n is a n 
i m p orta nt e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X- ra y, partic ularl y i n i de ntif yi n g ne w 
lesi o ns. H o we ver, lesi o ns o n c hest X- ra y ma y b e co nsi dere d meas ura b le if t he y are clearl y 
defi ne d a n d s urr o u n de d b y aerate d l u n g. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 4 9

C T, M RI : C T is t he best c urre ntl y availa ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns 
selecte d f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T 
sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve 
slice t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice 
t he slice t hic k ness. A n M RI is als o acce pta ble i n certai n sit uati o ns (e. g., f or b o d y scans).

Ultr as o u n d : Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as 
a met h o d of meas ure me nt.

E n d osc o py, l a p ar osc o py : T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n 
is n ot a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n 
bi o psies are o btai ne d or t o deter mi ne rela pse i n trials w here rec urre nce f oll o wi n g C R or 
s ur gical resecti o n is a n e n d p oi nt.

T u m or m arkers : T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. 

Cyt ol o gy, hist ol o gy : T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n 
rare cases if re q uire d b y pr ot oc ol (f or e xa m ple, resi d ual lesi o ns i n t u m or t y pes s uc h as ger m 
cell t u m ors, w here k n o w n resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n 
t o be a p ote ntial a d verse effect of treat me nt (e. g., wit h certai n ta xa ne c o m p o u n ds or 
a n gi o ge nesis i n hi bit ors), t he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n 
t hat a p pears or w orse ns d uri n g treat me nt ca n be c o nsi dere d if t he meas ura ble t u m or has met 
criteria f or res p o nse or sta ble disease i n or der t o differe ntiate bet wee n res p o nse ( or sta ble 
disease) a n d pr o gressi ve disease.
T u m or res p o nse ev al u ati o n
T o assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y  to esti mate t he o verall t u m or 
b ur de n at Baseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts. O nl y  s u bjects wit h 
meas ura ble disease at Baseli ne s h o ul d be i ncl u de d i n pr ot oc ols w here o bjecti ve t u m or res p o nse is 
t he pri mar y  en d p oi nt. Meas ura ble di sease is defi ne d b y  the prese nce of at least o ne meas ura ble 
lesi o n. Res p o nse criteria are liste d i n Ta ble E. 1 a n d Ta ble E. 2 . 
Res p o nse Criteri a
T a ble E. 1
E v al u ati o n of t ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R)  
Di s a p p e ar a n c e of all t ar g et l e si o n s. A n y p at h ol o gi c al l y m p h n o d e s ( w h et h er t ar g et or 
n o nt ar g et) m u st h a v e r e d u cti o n i n s h ort a xi s t o < 1 0 m m.
P arti al R e s p o n s e ( P R)
At l e a st a 3 0 % d e cr e a s e i n t h e s u m of di a m et er s of t ar g et l e si o n s, t a ki n g a s 
r ef er e n c e t h e b a s eli n e s u m di a m et er s.
Pr o gr e s si v e Di s e a s e 
At l e a st a 2 0 % i n cr e a s e i n t h e s u m of di a m et er s of t ar g et l e si o n s, t a ki n g a s r ef er e n c e 
t h e s m all e st s u m o n tri al (t hi s i n cl u d e s t h e b a s eli n e s u m if t h at i s t h e s m all e st o n 
tri al). I n a d diti o n t o t h e r el ati v e i n cr e a s e of 2 0 %, t h e s u m m u st al s o d e m o n str at e a n 
a b s ol ut e i n cr e a s e of at l e a st 5 m m. ( N ot e: t h e a p p e ar a n c e of o n e or m or e n e w 
l e si o n s i s al s o c o n si d er e d pr o gr e s si o n).
St a bl e Di s e a s e 
N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f o r P R n or s uffi ci e nt i n cr e a s e t o q u alif y f or 
pr o gr e s si v e di s e a s e, t a ki n g a s r ef er e n c e t h e s m all e st s u m di a m et er s w hil e o n tri al
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 4 9
T a ble E. 2
E v al u ati o n of n o nt ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R)
Di s a p p e ar a n c e of all n o nt ar g et l e si o n s a n d n or m ali z ati o n of t u m or m ar k er l e v el. All 
l y m p h n o d e s m u st b e n o n p at h ol o gi c al i n si z e ( < 1 0 m m s h ort a xi s).
St a bl e Di s e a s e 
P er si st e n c e of o n e or m or e n o nt ar g et l e si o n( s) a n d/ or m ai nt e n a n c e of t u m or m ar k er 
l e v el a b o v e t h e n or m al li mit s.
Pr o gr e s si v e Di s e a s e 
U n e q ui v o c al pr o gr e s si o n ( s e e c o m m e nt s b el o w) of e xi sti n g n o nt ar g et l e si o n s. ( N ot e: 
t h e a p p e ar a n c e of o n e or m or e n e w l e si o n s i s al s o c o n si d er e d pr o gr e s si o n).
N ot e: Alt h o u g h a cl e ar pr o gr e s si o n of “ n o nt ar g et” l e si o n s o nl y i s e x c e pti o n al, i n s u c h cir c u m st a n c e s, t h e o pi ni o n of 
t h e tr e ati n g p h y si ci a n s h o ul d pr e v ail a n d t h e pr o gr e s si o n st at u s s h o ul d b e c o nfir m e d l at er o n b y t h e r e vi e w p a n el 
( or tri al c h air).
E v al u ati o n of best o ver all res p o nse
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a res p o nse assess me nt occ urs.  Ta ble E- 3
bel o w pr o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at eac h ti me p oi nt f or s u bjects 
w h o ha ve meas ura ble disease at baseli ne.
T a ble E - 3
T ar g et l e si o n s
N o nt ar g et l e si o n s
N e w  l e si o n s
O v er all r e s p o n s e
C R
C R
N o
C R
C R
N o n -C R/ n o n -pr o gr e s si v e 
di s e a s e
N o
P R
C R
N ot e v al u at e d
N o
P R
P R
N o n - pr o gr e s si v e di s e a s e 
or n ot all e v al u at e d
N o
P R
St a bl e di s e a s e
N o n - pr o gr e s si v e di s e a s e 
or n ot all e v al u at e d
N o
St a bl e di s e a s e
N ot all e v al u at e d
N o n pr o gr e s si v e di s e a s e
N o
N E
Pr o gr e s si v e di s e a s e
A n y
Y e s or N o
Pr o gr e s si v e di s e a s e
A n y
Pr o gr e s si v e di s e a s e
Y e s or N o
Pr o gr e s si v e di s e a s e
A n y
A n y
Y e s
Pr o gr e s si v e di s e a s e
A b br e vi ati o n s: C R = c o m pl et e r e s p o n s e, N E = n ot e v al u a bl e; P R = p arti al r e s p o n s e.
T he best o verall res p o nse is deter mi ne d o nce all t he data f or t he s u bject is k n o w n.
Best res p o nse deter mi nati o n i n trials w here c o nfir mati o n of C R or P R I S N O T re q uire d: Best 
res p onse i n t hese trials is defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e xa m ple, a s u bject 
w h o has sta ble disease at first assess me nt, P R at sec o n d assess me nt, a n d pr o gressi ve disease o n 
last assess me nt has a best o verall res p o nse of P R). W he n sta ble disease is belie ve d t o be best 
res p o nse, it m ust als o meet t he pr ot oc ol s pecifie d mi ni m u m ti me fr o m baseli ne. If t he mi ni m u m 
ti me is n ot met w he n sta ble disease is ot her wise t he best ti me p oi nt res p o nse, t he s u bject’s best 
res p o nse de pe n ds o n t he s u bse que nt assess me nts. F or e xa m ple, a s u bject w h o has sta ble disease at 
first assess me nt, pr o gressi ve disease at sec o n d a n d d oes n ot meet mi ni m u m d urati o n f or sta ble 
disease, will ha ve a best res p o nse of pr o gressi ve disease. T he sa me s u bject l ost t o f oll o w -u p a fter 
t he first sta ble disease assess me nt w o ul d be c o nsi dere d n ot e val ua ble.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 4 9
Best res p o nse deter mi nati o n i n trials w here c o nfir mati o n of C R or P R I S re q uire d: C o m plete or 
partial res p o nses ma y be clai me d o nl y if t he criteria f or eac h are met at a s u bse q ue nt ti me p oi nt as 
s pecifie d i n t he pr ot oc ol (at least 4 wee ks a part). I n this circ u msta nce, t he best o verall res p o nse 
ca n be i nter prete d as i n  Ta ble E - 4.
T a ble E -4
O v er all r e s p o n s e  
O v er all r e s p o n s e
B E S T o v er a ll r e s p o n s e
Fir st ti m e p oi nt
S u b s e q u e nt ti m e p oi nt
C R
C R
C R
C R
P R
St a bl e di s e a s e, pr o gr e s si v e di s e a s e, or P R a
C R
St a bl e di s e a s e
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e, pr o gr e s si v e di s e a s e
C R
Pr o gr e s si v e di s e a s e
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e, pr o gr e s si v e di s e a s e
C R
N E
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e N E
P R
C R
P R
P R
P R
P R
P R
St a bl e di s e a s e
St a bl e di s e a s e
P R
Pr o gr e s si v e di s e a s e
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e, pr o gr e s si v e di s e a s e
P R
N E
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e N E
N E
N E
N E
A b br e vi ati o n s: C R = c o m pl et e r e s p o n s e, N E = n ot e v al u a bl e, P R = p arti al r e s p o n s e, 
a
If a C R i s tr ul y m et at fir st ti m e p oi nt, t h e n a n y di s e a s e s e e n at a s u b s e q u e nt ti m e p oi nt, e v e n di s e a s e 
m e eti n g P R crit eri a r el ati v e t o b a s eli n e, m a k e s t h e di s e a s e pr o gr e s si v e di s e a s e at t h at p oi nt ( si n c e di s e a s e m u st 
h a v e r e a p p e ar e d aft er C R). B e st r e s p o n s e w o ul d d e p e n d o n w h et h er mi ni m u m d ur ati o n f or st a bl e di s e a s e w a s 
m et. H o w e v er, s o m eti m e s ‘ C R’ m a y b e cl ai m e d w h e n s u b s e q u e nt s c a n s s u g g e st s m all l e si o n s w er e li k el y still 
pr e s e nt a n d i n f a ct t h e s u bj e ct h a d P R, n ot C R at t h e fir st ti m e p oi nt. U n d er t h e s e cir c u m st a n c e s, t h e ori gi n al C R 
s h o ul d b e c h a n g e d t o P R a n d t h e b e st r e s p o n s e i s P R.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 4 9
A p pe n di x D:
O utli ne of I nte nsit y -m o d ul ate d R a di ot her a p y
I n t he pla n ni n g of R T, i nte nsit y mo d ulate d R T (I M R T) m ust be use d. T he d ose pla n ni n g ca n be 
C T or p ositr o n e missi o n t o m o gra p h y- C T ( P E T - C T) acc or di n g t o i nstit uti o nal g ui deli nes.
T he use of dail y i ma ge g ui de d R T (I G R T) is rec o m me n de d.
F or patie nts wit h S C C H N, t he t otal d ose of R T is 6 6 t o 7 0 G y  gi ve n i n 3 3 t o 3 5 fracti o ns a n d f or 
patie nts wit h N S C L C, t he t otal d ose of R T is 6 6 G y gi ve n i n 3 3 fracti o ns. Si m ulta ne o us i nte grate d 
or se q ue ntial b o ost s h o ul d be gi ve n acc or di n g t o i nstit uti o nal g ui deli nes.
Or g a ns at ris k t o be c o nt o ure d
S C C H N:
P ar oti d gl a n d
R e q uir e d
S pi n al c or d
R e q uir e d
O pti c c hi a s m
R e q uir e d
Br ai n st e m
R e q uir e d
Or al c a vit y
F a c ult ati v e
Br a c hi al pl e x u s
F a c ult ati v e
M a n di bl e
F a c ult ati v e
P h ar y n g e al c o n stri ct or m u s cl e
F a c ult ati v e
C o c hl e a
F a c ult ati v e
E s o p h a g u s
F a c ult ati v e
L u n g s
F a c ult ati v e
E xt er n al b or d er of p ati e nt s
F a c ult ati v e
N S C L C:
S pi n al c or d
R e q uir e d
Br a c hi al pl e x u s
F a c ult ati v e
H e art
R e q uir e d
C or o n ar y art eri e s
R e q uir e d
St o m a c h, li v er a n d k i d n e y (if i n cl u d e d i n 
fi el d)
R e q uir e d
E s o p h a g u s
R e q uir e d
L u n g s
R e q uir e d
E xt er n al b or d er of p ati e nt s
R e q uir e d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 4 9
A p pe n di x E:
C o ntr ace pti ve G ui d a nce a n d W o me n of C hil d be ari n g P ote nti al
Defi niti o ns
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y 
sterile. 
Per ma ne nt 
sterilizati o n 
met h o ds 
i ncl u de h ys terect o my, 
bilateral 
sal pin gect o m y , a n d bilateral o o p h orect o my.
W o me n i n t he f oll o wi n g c ate g ories are n ot c o nsi dere d W O C B P
1.
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:

D oc u me nte d h ys terect o m y

D oc u me nte d bilateral sal pi n gect o m y

D oc u me nte d bilateral o o p h orect o m y
N ote:  Doc u me ntati o n ca n c o me fr o m t he site pers o n nel’s: re vie w of partici pa nt’s me dical 
rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w.
2.
Pre me narc hal
3.
P ost me n o pa usal fe male

Fe males w h o are p ost me n o pa usal (a ge-relate d a me n orr hea ≥1 2 c o nsec uti ve m o nt hs a n d 
i ncrease d f ollicle-sti m ulati n g h or m o ne [ F S H] > 4 0 mI U/ m L), or w h o ha ve u n der g o ne 
h y sterect o my or bilateral o o p h orect o m y  are e xe m pt fr o m pre g na nc y testi n g. If necessar y t o 
c o nfir m p ost me n o pa usal stat us, a n F S H will be dra w n at Scr ee ni n g.

Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of t he 
n o n- h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T 
d uri n g t he trial. Ot her wise, 
t he y 
must disc o nti n ue H R T 
t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore trial e nr oll me nt.
C o ntr ace pti ve G ui d a nce
Hi g hl y  Eff e cti v e C o ntr a c e pti v e M et h o d s T h at Ar e U s er D e p e n d e nt 
F ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 

C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g ) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n b

or al 

i ntr a v a gi n al 

tr a n s d er m al 

Pr o g e st o g e n -o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n b

or al 

i nj e ct a bl e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 9 / 1 4 9
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er I n d e p e n d e nt 

I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n b

I ntr a ut eri n e d e vi c e (I U D)

I ntr a ut eri n e h or m o n e -r el e a si n g s y st e m (I U S)

bil at er al t u b al o c cl u si o n

V a s e ct o mi z e d p art n er 
( A v a s e ct o mi z e d p art n er i s a hi g hl y eff e cti v e c o ntr a c e pti o n m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e m al e s e x u al 
p art n er of t h e W O C B P a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. If n ot, a n a d diti o n al hi g hl y eff e cti v e m et h o d of 
c o ntr a c e pti o n s h o ul d b e u s e d. )

S e x u al a b sti n e n c e 
( S e x u al a b sti n e n c e i s c o n si d er e d a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m h et er o s e x u al i nt er c o ur s e 
d uri n g t h e e ntir e p eri o d of ri s k a s s o ci at e d wit h t h e tri al dr u g. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e 
e v al u at e d i n r el ati o n t o t h e d u r ati o n of t h e tri al a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e p arti ci p a nt.) 
N O T E S: 
a) T y pi c al u s e f ail ur e r at e s m a y diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. U s e s h o ul d b e c o n si st e nt wit h 
o c al r e g ul ati o n s r e g ar di n g t h e u s e of c o ntr a c e p ti v e m et h o d s f or p arti ci p a nt s p arti ci p ati n g i n cli ni c al st u di e s. 
b) H or m o n al c o ntr a c e pti o n m a y b e s u s c e pti bl e t o i nt er a cti o n wit h t h e tri al dr u g, w hi c h m a y r e d u c e t h e effi c a c y of t h e 
c o ntr a c e pti v e m et h o d. I n t hi s c a s e 2 hi g hl y eff e cti v e m et h o d s of c o ntr a c e pti o n s h o ul d b e utili z e d d uri n g t h e tr e at m e nt 
p eri o d a n d f or at l e a st 9 0 d a y s aft er t h e l a st d o s e of tri al tr e at m e nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI