A First-in-human, Phase I, Open-label Study of the ATM Inhibitor M4076 in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 410)
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: EMD Serono Research & Development Institute, Inc.

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2  
 
 
Cli nic al St u d y Pr ot oc ol   
Title P a ge   
Cli nic al St u d y Pr ot oc ol Title:  
A First -i n-h u ma n, P has e 1 , O pe n-la bel St u d y of t h e 
A T M i n hi bit or 
M 4 0 7 6 i n 
Partici pa nts 
wit h 
A d va nce d S oli d T u m ors   
St u d y N u m ber:  
M S 2 0 1 5 1 2 _ 0 0 1 0  
Pr ot oc ol V ersi o n:  
2 7  O ct o ber 2 0 2 2 / V ersi o n 4 . 0 
Merc k C o m p o u n d : 
M 4 0 7 6  
Merc k Re gistere d C o m p o u n d N a me i n 
J a p a n : 
N ot A p plica ble  
St u d y P h ase:  
P hase 1  
S h ort Title:  
First -i n-h u ma n St u d y of M 4 0 7 6 i n A d va nce d S oli d 
T u m ors  
Acr o n y m or A b bre vi ati o n:  
D D Ri ver S oli d  T u m ors 4 1 0  
C o or di n ati n g I n vesti g at or : 
 
 
 
  
  
 
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:  
S p o ns or:  
Affiliates of Merc k K Ga A, Dar msta dt, Ger ma n y  
F or all c o u ntri es, e x ce pt t he U S a n d Ca na d a:  
Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y  
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y  
Fra n kf urter Str. 2 5 0  
6 4 2 9 3 Dar msta dt, Ger ma n y  
I n t he U S a n d Ca na d a: 
E M D Ser o n o Researc h & De v el o p me nt I nstit ute, 
I n c. 
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y  
4 5 A Mi d dlese x T ur n pi ke  
Billerica, M A, 0 1 8 2 1, U S A  
 
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:  
I N D n u m ber 
 
Gl o bal Versi o n I D: 
P P D
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
Pr ot oc ol A me n d me nt S u m m a r y of C h a n ges  
Pr ot oc ol Hist or y  
 
V er si o n N u m b er  
T y p e  
V er si o n D at e  
1. 0  
Ori gi n al Pr ot o c ol  
0 1  F e b  2 0 2 1  
2. 0  
Gl o b al  A m e n d m e nt  
0 7  A pr  2 0 2 1  
3. 0  
Gl o b al A m e n d m e nt  
2 5  O ct 2 0 2 1  
4. 0  
Gl o b al A m e n d m e nt  
2 7  O ct 2 0 2 2  
Pr ot oc ol V ersi o n 4 . 0 (2 7  O ct o ber 2 0 2 2 ) 
O ver all R ati o n ale f or t he A me n d me nt  
T he o verall rati o nale f or t his a me n d me nt is t o u p date t he ris k classificati o n i n t he pr ot oc ol base d 
o n ne w a vaila bl e cli nical data fr o m t his st u d y . 
S e cti o n # a n d N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
Titl e p a g e  
Titl e p a g e m o difi c ati o n s i n 
pl a c e m e nt of v er si o n r e p orti n g a n d 
r e m o v al of ot h er i nf or m ati o n. 
T o f oll o w i nt er n al q u alit y st a n d ar d s f or 
cli ni c al st u d y pr ot o c ol s.  
1. 1  S y n o p si s  
U p d at e d n u m b er of p arti ci p a nt s t o 
4 0 i n P art  1 A  
T o r e cr uit a d diti o n al c o h ort s, if n e e d e d.  
1. 3. 1 P art  1 A –  M 4 0 7 6 
M o n ot h e r a p y D o s e 
E s c al ati o n ( D ail y D o si n g)  
 
T a bl e  1 S c h e d ul e of 
A cti viti e s: M 4 0 7 6 
M o n ot h er a p y D o s e 
E s c al ati o n  ( D ail y D o si n g), 
P art  1 A.  
S af et y F oll o w -u p vi sit wi n d o w 
u p d at e d b y a d di n g mi n u s 7 d a y s.  
 
P h y si c al e x a mi n ati o n o n D a y 8 
w a s d el et e d.  
 
N ot e s  f or s t u d y s it e v i sit s a n d 
fr e s h p air e d t u m or bi o p si e s w a s 
u p d at e d.  
U p d at e s d o n e f or cl arit y.  
1. 3. 2  P art  1 B –  Pr eli mi n ar y 
F o o d Eff e ct A s s e s s m e nt  
 
T a bl e  2 S c h e d ul e of 
A cti viti e s: Pr eli mi n ar y F o o d 
Eff e ct A s s e s s m e nt, P art 
1 B  
Ar c hi v al t u m or bi o p s y r o w w a s 
d el et e d.  
 
N ot e f or fr e s h p air e d t u m or 
bi o p si e s w a s u p d at e d  
F or si m pli cit y it w a s d el et e d.  
 
 
U p d at e d  f or cl arit y. 
1. 3. 3  P art s 1 A a n d 1 B –  
P h ar m a c o ki n eti c, E C G, 
a n d 
 
 S a m pli n g 
S c h e d ul e  
 
T a bl e  3 P art 1 A M 4 0 7 6 
M o n ot h er a p y D o s e 
E s c al ati o n: 
P h ar m a c o ki n eti c, E C G a n d 
 
 
Vi sit wi n d o w o n D a y 8 w a s 
d el et e d . 
 
P K s a m pli n g f o ot n ot e w a s 
u p d at e d.  
F or c o n si st e n c y wit h T a bl e 1.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
S e cti o n # a n d N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
2. 3  B e n efit/ Ri s k 
A s s e s s m e nt  
A d d e d n e w i d e ntifi e d a n d 
i m p ort a nt p ot e nti al ri s k s (r a s h a n d 
h y p er s e n siti vit y, r e s p e cti v el y) . 
 
Ri s k a s s o ci at e d wit h D DI 
i nf or m ati o n w a s u p d at e d. 
B a s e d o n t h e n e w a v ail a bl e cli ni c al d at a fr o m 
t hi s st u d y, n e w ri s k s h a v e b e e n a d d e d. 
 
B a s e d o n t h e D DI a s s e s s m e nt u si n g i n vitr o 
d at a . 
4. 1  O v er all D e si g n  
Fl e xi bl e w or di n g a d d e d f or P art  1 B 
of t h e st u d y.  
U p d at e d f or cl arit y a n d fl e xi bilit y.  
5. 2  E x cl u si o n Crit eri a  
U p d at e d pri or/ c o n c o mit a nt t h er a p y 
crit eri o n.  
B a s e d o n t h e D DI a s s e s s m e nt u si n g i n vitr o 
d at a . 
6. 5. 3  Pr o hi bit e d M e di ci n e s  
Ri s k a s s o ci at e d wit h D DI 
i nf or m ati o n w a s u p d at e d.  
B a s e d o n t h e D DI a s s e s s m e nt u si n g i n vitr o 
d at a . 
6. 6. 2. 1  D o s e I nt err u pti o n s 
a n d M o difi c ati o n s  
A d d e d n e w i d e ntifi e d a n d 
i m p ort a nt p ot e nti al ri s k s (r a s h a n d 
h y p er s e n siti vit y, r e s p e cti v el y).  
 
T a bl e 1 0 u p d at e d wit h 3 0 0  m g 
r el at e d i nf or m ati o n. 
B a s e d o n t h e n e w a v ail a bl e cli ni c al d at a fr o m 
t hi s st u d y, n e w ri s k s h a v e b e e n a d d e d. 
 
 
U p d at e d f or c o m pl et e n e s s . 
8. 2. 2  Vit al Si g n s  
S e mi -s u pi n e c h a n g e d t o 
s e mi -r e c u m b e nt. 
U p d at e d f or c o n si st e n c y wit h e C R F d e si g n.  
9. 2  S a m pl e Si z e 
D et er mi n ati o n  
U p d at e d n u m b er of p arti ci p a nt s t o 
4 0 i n P art  1 A . 
T o r e cr uit a d diti o n al c o h ort s, if n e e d e d.  
9. 4. 2  S af et y A n al y s e s  
D el et e d i nt eri m a n al y si s fr o m P art 
1 A.  
U p d at e d f or cl arit y.  
9. 4. 4  S e q u e n c e of 
A n al y s e s  
Pri m ar y a n al y si s will b e d o n e o nl y 
f or d o s e e s c al ati o n p art of t h e 
st u d y.  
U p d at e d f or cl arit y.  
A p p e n di x  1 3  Pr ot o c ol 
A m e n d m e nt Hi st or y  
U p d at e r el at e d t o V 3. 0 c o pi e d t o 
t hi s s e cti o n. 
U p d at e d f or c o m pl et e n e s s.  
T hr o u g h o ut  
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s. 
Mi n or; t h er ef or e, h a v e n ot b e e n s u m m ari z e d.  
D DI = dr u g -dr u g i nt er a cti o n; E C G = el e ctr o c ar di o gr a m; e C R F = el e ctr o ni c c a s e r e p ort f or m . 
 
- C o nfi d e nti al –  
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot –  i n f ull or p art –  b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 2  b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.  
 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
T a ble of C o nte nts   
Title Pa ge  
 ..............................................................................................................1  
Ta ble of C o nte nts   ..............................................................................................................4  
1  
Pr ot oc ol S u m mar y  ................................................................................9  
1. 1  
S y n o psis  ................................................................................................9  
1. 2  
Sc he ma  ................................................................................................1 2  
1. 3  
Sc he d ule of A cti vities  .........................................................................1 3  
1. 3. 1  
Part 1 A –  M 4 0 7 6 M o n ot hera p y D os e Escal ati o n ( Dail y D osi n g)  ......1 4  
1. 3. 2  
Part  1 B –  Preli mi nar y F o o d Effect Ass ess me nt  .................................1 9  
1. 3. 3  
Parts  1 A a n d 1 B –  P har mac o ki netic, E C G, a n d 
P har mac o d y na mics Bi o mar ker Sa m pli n g Sc he d ule  ...........................2 4  
2  
I ntr o d u cti o n .........................................................................................2 9  
2. 1  
St u d y R ati o nale  ...................................................................................2 9  
2. 1. 1  
M 4 0 7 6 M o n ot hera p y  ..........................................................................2 9  
2. 2  
Bac k gr o u n d  .........................................................................................3 0  
2. 3  
Be nefit/ Ris k Assess me nt  ....................................................................3 0  
2. 3. 1  
Ris k Assess me nt  .................................................................................3 1  
2. 3. 2  
Be nefit Assess me nt  .............................................................................3 3  
2. 3. 3  
O verall Be nefit: Ris k C o ncl usi o n  .......................................................3 3  
3  
O bjecti ves a n d Esti ma n ds  ...................................................................3 4  
4  
St u d y Desi g n  .......................................................................................3 6  
4. 1  
O verall Desi g n  ....................................................................................3 6  
4. 1. 1  
Part 1 A –  M 4 0 7 6 M o n ot hera p y D os e Escal ati o n  ...............................3 8  
4. 1. 2  
Part  1 B –  Preli mi nar y F o o d Effect Ass ess me nt  .................................3 9  
4. 2  
J ustificati o n f or D ose ..........................................................................4 0  
4. 3  
Scie ntific Rati o nale f or St u d y Desi g n  ................................................4 1  
4. 4  
E n d of St u d y Defi niti o n  ......................................................................4 1  
5  
St u d y P o p ulati o n  .................................................................................4 2  
5. 1  
I n cl usi o n Criteria ................................................................................4 2  
5. 2  
E x cl usi o n Criteria  ...............................................................................4 4  
5. 3  
Lif est yle C o nsi derati o ns  .....................................................................4 7  
5. 4  
Scree n Fail ures  ....................................................................................4 7  
6  
St u d y I nter v e nti o n(s)  ..........................................................................4 7  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
6. 1  
St u d y I nter v e nti o n A d mi nistrati o n  .....................................................4 7  
6. 2  
St u d y I nter v e nti o n(s) Pre parati o n, Ha n dli n g, St ora ge , a n d 
Acc o u nta bilit y  .....................................................................................4 8  
6. 3  
Meas ures t o Mi ni mize Bias: St u d y I nter v e nti o n Assi g n me nt a n d 
Bli n di n g  ..............................................................................................4 9  
6. 3. 1  
St u d y I nter v e nti o n Assi g n me nt  ..........................................................4 9  
6. 3. 2  
Bli n di n g  ..............................................................................................4 9  
6. 4  
St u d y I nter v e n ti o n C o m plia nce ..........................................................4 9  
6. 5  
C o nc o mita nt T hera p y  .........................................................................5 0  
6. 5. 1  
Resc ue Me dici ne  .................................................................................5 0  
6. 5. 2  
Per mitte d Me dici nes  ...........................................................................5 0  
6. 5. 3  
Pr o hi bite d Me dici nes  ..........................................................................5 0  
6. 5. 4  
Ot her I nter v e nti o ns  .............................................................................5 2  
6. 6  
D ose Selecti o n a n d M o dificati o n  ........................................................5 2  
6. 6. 1  
Safet y M o nit ori n g C o m mittee  ............................................................5 2  
6. 6. 2  
D ose -li miti n g T o xicities –  Defi niti o n a n d Criteria  .............................5 3  
6. 6. 2. 1  
D ose I nterr u pti o ns a n d M o dificati o ns  ................................................5 4  
6. 7  
St u d y I nter v e nti o n after t he E n d of t he St u d y  ....................................5 6  
7  
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici p a nt 
Disc o nti n uati o n/ Wit h dra wal  ...............................................................5 7  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................5 7  
7. 2  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ...................5 7  
7. 3  
L ost t o F oll o w -U p ...............................................................................5 8  
8  
St u d y Assess me nts a n d Pr oce d ures  ....................................................5 8  
8. 1  
Efficac y Assess me nts a n d Pr oce d ures  ................................................5 9  
8. 2  
Safet y Assess me nts a n d Pr oce d ures  ...................................................5 9  
8. 2. 1  
P h ysical E x a mi nati o ns  ........................................................................6 0  
8. 2. 2  
Vital Si g ns  ..........................................................................................6 0  
8. 2. 3  
Electr ocar di o gra ms  .............................................................................6 0  
8. 2. 3. 1  
Sta n dar d Si n gle 1 2 -l ea d Electr ocar di o gra ms ......................................6 0  
8. 2. 3. 2  
Di gital Tri plicate Electr o car di o gra m s ................................................6 0  
8. 2. 4  
Cli nical Safet y La b orat or y Assess me nts  ............................................6 1  
8. 3  
A d verse E v e nts a n d Seri o us A d verse E v e nts  .....................................6 1  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
8. 3. 1  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E v e nt I nf or mati o n  ....................................................6 1  
8. 3. 2  
Met h o d of Dete cti n g A d verse E ve nts a n d Seri o us A d verse E v e nts  ...6 2  
8. 3. 3  
F oll o w -u p of A d v erse E v e nts a n d Seri o us A d verse E ve nts  ...............6 2  
8. 3. 4  
Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  .....6 2  
8. 3. 5  
Pre g n a nc y  ...........................................................................................6 3  
8. 3. 6  
A d verse E v e nts of S peci al I nt erest  .....................................................6 4  
8. 4  
Treat me nt of O v er d ose  .......................................................................6 5  
8. 5  
P har mac o ki netics  ................................................................................6 5  
8. 9  
I m m u n o ge nicit y Assess me nts ............................................................6 9  
8. 1 0  
Healt h Ec o n o mics  ...............................................................................6 9  
9  
Statistical C o nsi derati o ns  ....................................................................6 9  
9. 1  
Statistical H y p ot heses  .........................................................................6 9  
9. 2  
Sa m ple Siz e Deter mi nati o n  ................................................................7 0  
9. 3  
P o p ulati o ns f or A nal ys es  ....................................................................7 1  
9. 4  
Statistical A nal yses  .............................................................................7 1  
9. 4. 1  
Efficac y A nal yses  ...............................................................................7 2  
9. 4. 2  
Safet y A nal yses  ..................................................................................7 3  
9. 4. 2. 1  
Part 1 A: D ose Escal ati o n  ....................................................................7 4  
9. 4. 2. 2  
Part 1 B: Preli mi nar y F o o d Effect Ass ess me nt  ...................................7 6  
9. 4. 3  
Ot her A nal yses  ....................................................................................7 7  
9. 4. 4  
Se q ue nce of A nal yses  .........................................................................7 8  
1 0  
Refere n ces  ...........................................................................................7 9  
1 1  
A p pe n dices  .........................................................................................8 0  
A p pe n di x  1  
A b bre viati o ns  ......................................................................................8 1  
A p pe n di x  2  
St u d y G o ver na nce  ...............................................................................8 3  
A p pe n di x  3  
C o ntrace pti o n  ......................................................................................9 0  
A p pe n di x  4  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g  ................................................9 2  
A p pe n di x  5  
Li ver Safet y: S u g geste d Acti o ns a n d F oll o w -u p Assess me nts  ...........9 8  
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A p pe n di x  6  
Cli nical La b orat or y Tests  ...................................................................9 9  
A p pe n di x  7  
P ote ntial Variati o ns i n St u d y I nter ve nti o n Sc he d ul es a n d 
Sc he d ules of Acti vities  .....................................................................1 0 0  
A p pe n di x  8  
E x a m ple of L o w -fat Me al f or F o o d Effect C o h ort ( Part 1 B)  ...........1 0 2  
A p pe n di x  9  
Res p o nse E val uati o n  Criteria i n S oli d T u m ors ( R E CI S T) 
Versi o n  1. 1  ........................................................................................1 0 3  
A p pe n di x  1 0  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce S tat us ..............1 1 2  
 
 
A p pe n di x  1 2  
M o del f or Ba yesia n D ose Escalati o n  ................................................1 1 4  
A p pe n di x  1 3  
Pr ot oc ol A me n d me nt Hist or y  ...........................................................1 1 6  
A p pe n di x  1 4  
S p o ns or Si g nat ure Pa ge  ....................................................................1 2 0  
A p pe n di x  1 5  
C o or di nati n g I n vesti gat or Si g nat ur e Pa ge  ........................................1 2 1  
A p pe n di x  1 6  
Pri nci pal I n v esti gat or Si g nat ure Pa ge  ...............................................1 2 2  
T a ble of I n -te xt T a bles 
Ta ble  1  
Sc he d ule of A cti vities: M 4 0 7 6 M o n ot hera p y D ose Escalati o n 
( Dail y D osi n g), Part 1 A ......................................................................1 4  
Ta ble  2  
Sc he d ule of A cti vities: Preli mi nar y F o o d Effect Assess me nt, Part 
1 B  ........................................................................................................1 9  
Ta ble  3  
Part 1 A M 4 0 7 6 M o n ot hera p y D ose Es calati o n: P har mac o ki netic, 
E C G a n d P har mac o d y n a mics Bi o mar ker Assess m e nts  ......................2 4  
 
 
 
Ta ble  5  
I d e ntifie d a n d P ote ntial Ris ks of t he St u d y I nter v e nti o ns a n d 
Pr oce d ures  ...........................................................................................3 2  
Ta ble  6  
O bjecti ves a n d Esti ma n ds: M 4 0 7 6 M o n ot hera p y D ose Escalati o n 
( Part 1 A) a n d Preli mi nar y F o o d Effect Assess me nt ( Part  1 B)  ...........3 5  
Ta ble  7  
S u m mar y of O v erall St u d y Desi g n  .....................................................3 7  
Ta ble  8  
St u d y I nter v e nti o n Details  ..................................................................4 7  
Ta ble  9  
Cli nical E x a m ples of Str o n g C Y P 3 A a n d P -g p I n hi bit ors a n d 
C Y P 3 A I n d ucers a n d s e nsiti ve C Y P 3 A 4 s u bstrates wit h narr o w 
t hera pe utic i n de x .................................................................................5 1  
Ta ble  1 0  
M 4 0 7 6 Rec o m me n de d D ose M o dificati o ns f or Gra de  3 
He mat ol o gi c a n d N o n he mat ol o gic A D Rs  ..........................................5 5  
Ta ble  1 1  
A d verse E v e nts of S peci al I nt erest  .....................................................6 5  
Ta ble  1 2  
Assess me nt of Bl o o d P h ar mac o ki netic Para meters  ............................6 5  
Ta ble  1 3  
Assess me nt of Uri ne P har mac o ki netic Para meters  ............................6 7  
Gl o bal Versi o n I D: C CI
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
Ta ble  1 4  
8 0 % C o vera ge I nter v al f or t he 9 0 % C o nfi de nce I nter vals f or 
Esti mate d Fe d/ Faste d Rati o, n  =  6 per Se q ue nce ( 1 2 i n t otal) ............7 0  
Ta ble  1 5  
P o p ulati o ns f or A nal ys es  ....................................................................7 1  
Ta ble  1 6  
Part 1 A Efficac y A nal ys es  ..................................................................7 2  
Ta ble  1 7  
Safet y A nal yses  ..................................................................................7 3  
Ta ble  1 8  
Pri or Distri b uti o n of Pr o ba bilit y f or D L T  ..........................................7 5  
Ta ble  1 9  
Part 1 - Ot her A n al ys es  .......................................................................7 7  
Ta ble  2 0  
Pr ot oc ol -Re q uire d Cli nical La b orat or y Assess me nts  .........................9 9  
Ta ble  2 1  
S u m mar y of Alter nate Sc he d ules of M 4 0 7 6  ....................................1 0 0  
Ta ble  2 2  
T o xicit y I nter vals  ..............................................................................1 1 4  
T a ble of I n -te xt Fi g ures 
Fi g ure  1  
St u d y Sc h e ma O v er vie w  .....................................................................1 2  
Fi g ure  2  
Part 1 A - M 4 0 7 6 M o n ot hera p y D os e Escal ati o n Sc he ma  ..................1 2  
Fi g ure  3  
Escalati o n Tree: E x a m ples of D ose Rec o m me n dati o ns Base d o n 
t he Ba yesia n M o del f or t he First 3 C o h orts ........................................7 6  
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
1  
Pr ot oc ol S u m m ar y   
1. 1  
S y n o psis   
Pr ot oc ol Title: A First -i n-h u ma n, P hase 1 , O pe n -la bel St u d y of t he A T M i n hi bit or M 4 0 7 6 i n 
Partici pa nts wit h A d va nce d S oli d T u m ors  
S h ort Title: First -i n-h u ma n St u d y of M 4 0 7 6 i n A d va nce d S oli d T u m ors  
R ati o n ale: T he p ur p ose of t his st u d y is t o esta blis h t he safet y, t olera bilit y a n d p har mac o ki netic 
(P K ) pr ofile ( wit h a n d wit h o ut f o o d), 
ma xi m u m t olerate d d ose ( M T D; if o bser ve d) a n d 
rec o m me n de d d ose f or e x pa nsi o n ( R D E) f or M 4 0 7 6 i n patie nts wit h a d va nce d s oli d t u m ors f or 
w hic h n o sta n dar d t hera p y is a vaila bl e.  
O bjecti ves a n d E n d p oi nts:   
T he f oll o wi n g t a ble s u m marizes t he o bjecti ves a n d esti ma n ds of t he st u d y. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
O bjecti ves a n d E sti m a n ds: M 4 0 7 6 M o n ot her a p y D ose Esc al ati o n ( P art 1 A) a n d Preli mi n ar y 
F o o d Effect Assess me nt  ( P a rt 1 B)  
O bj e cti v e s  
E sti m a n d s attri b ut e s  
Pri m ar y  
T o d et er mi n e d o s e -t o xi cit y r el ati o n s hi p a n d 
M T D (if 
r e a c h e d) 
of 
M 4 0 7 6 
m o n ot h er a p y i n 
p ati e nt s wit h 
a d v a n c e d s oli d t u m or s  
E n d p oi nt s : 
•  
O c c urr e n c e of D o s e Li miti n g T o xi citi e s ( D L T s).  
•  
O c c urr e n c e of a d v er s e e v e nt s ( A E s) a n d 
tr e at m e nt-r el at e d A E s. 
•  
O c c urr e n c e of cli ni c all y si g nifi c a nt c h a n g e s i n vit al 
si g n s, l a b or at or y p ar a m et er s, a n d 1 2 -l e a d 
el e ctr o c ar di o gr a m ( E C G) fi n di n g s.  
 
Str at e g y f or h a n dli n g i nt er c urr e nt e v e nt s:   
F or D L T s:  
•  
Di s c o nti n u ati o n of tr e at m e nt ( >  2 0 % pl a n n e d 
tr e at m e nt mi s s e d d uri n g D L T p eri o d) t o pr e v e nt a 
D L T: c o m p o sit e  str at e g y (t o b e c o n si d er e d a D L T)  
•  
Di s c o nti n u ati o n of  tr e at m e nt a d mi ni str ati o n s  n ot d u e 
t o D L T or pr e v e nti n g a D L T ( > 2 0 % of pl a n n e d 
tr e at m e nt mi s s e d d uri n g D L T p eri o d): p arti ci p a nt n ot 
c o n si d er e d i n D L T a n al y si s . 
 
F or ot h er e n d p oi nt s:  
All a v ail a bl e d at a fr o m p arti ci p a nt s i n s af et y a n al y si s s et 
will b e u s e d.  
 
P o p ul ati o n:  
P ati e nt s  wit h a d v a n c e d s oli d tu m or s, w h o ar e i nt ol er a nt 
or h a v e n o eff e cti v e st a n d ar d t h er a pi e s a v ail a bl e t o 
t h e m. 
 
P o p ul ati o n l e v el s u m m ar y:  
•  
D L T pr o b a bilit y a s e sti m at e d u si n g B L R M a n d 
cr e di bilit y i nt er v al  ( o nl y a p pli c a bl e f or D L T s). 
•  
St a n d ar d s u m m ar y st ati sti c s . 
S e c o n d ar y  
T o d et er mi n e t h e r e c o m m e n d e d d o s e f or e x p a n si o n 
( R D E) of M 4 0 7 6 m o n ot h er a p y i n p arti ci p a nt s wit h 
a d v a n c e d s oli d t u m or s  
•  
I n a d diti o n t o s af et y a n d t ol er a bilit y, c h a n g e s fr o m 
b a s eli n e f or t h e f oll o wi n g P d bi o m ar k er s m a y b e 
c o n si d er e d f or d et er mi ni n g t h e R D E:  A T M p at h w a y 
r e a d o ut s s u c h a s, b ut n ot li mit e d t o, p-A T M, −H 2 A X  
a n d p -C H K 2 i n bl o o d a n d t u m or.  
•  
I n a d diti o n, p h ar m a c o ki n eti c ( P K) d at a will b e u s e d t o 
s u p p ort d et er mi n a ti o n of t h e R D E. 
T o c h ar a ct eri z e t h e P K pr ofil e of M 4 0 7 6 m o n ot h er a p y i n 
p arti ci p a nt s wit h a d v a n c e d s oli d t u m or s  
•  
P K p ar a m et er s of M 4 0 7 6 i n pl a s m a aft er si n gl e d o s e 
a n d m ulti pl e d o s e s .  
•  
Uri n e P K p ar a m et er s ( e. g., r e n al cl e ar a n c e) will b e 
c h ar a ct eri z e d i n P art 1 B d at a p er mitt e d . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
O bj e cti v e s  
E sti m a n d s attri b ut e s  
T o e v al u at e pr eli mi n ar y cli ni c al a cti vit y p ar a m et er s of 
M 4 0 7 6 m o n ot h er a p y i n p arti ci p a nt s wit h a d v a n c e d s oli d 
t u m or s 
E n d p oi nt s  
•  
O bj e cti v e r e s p o n s e ( O R) a c c or di n g t o R E CI S T  1. 1 
a s s e s s e d b y I n v e sti g at or . 
•  
D ur ati o n of r e s p o n s e ( D o R) a c c or di n g t o R E CI S T  1. 1 
a s s e s s e d b y I n v e sti g at or . 
•  
Pr o gr e s si o n Fr e e S ur vi v al ( P F S) a c c or di n g t o 
R E CI S T  1. 1 a s s e s s e d b y I n v e sti g at or . 
T o a s s e s s t h e eff e ct of f o o d o n t h e P K of M 4 0 7 6 
a d mi ni st er e d a s a si n gl e d o s e u n d er f e d/f a sti n g 
c o n diti o n s i n a c o h ort of p arti ci p a nt s wit h a d v a n c e d s oli d 
t u m or s at t h e R D E fr o m P art  1 A . 
E n d p oi nt s  
F e d/f a st e d r ati o of M 4 0 7 6 pl a s m a P K p ar a m et er s:  
A U C 0 -tl a st, A U C0 -∞ a n d, C m a x w h e n a d mi ni st er e d a s a 
si n gl e d o s e wit h or wit h o ut f o o d.  
T o a s s e s s c h a n g e s i n p h ar m a c o d y n a mi c m ar k er s of 
M 4 0 7 6 a cti vit y i n t u m or a n d bl o o d d uri n g M 4 0 7 6 
m o n ot h er a p y  
E n d p oi nt s  
A b s ol ut e a n d r el ati v e c h a n g e s o v er ti m e fr o m b a s eli n e of 
A T M p at h w a y r e a d o ut s, s u c h a s, b ut n ot li mit e d t o 
p -A T M , p-C H K 2  a n d -H 2 A X.   
A E = a d v er s e e v e nt; A T M  =  at a xi a -t el a n gi e ct a si a mut at e d ; A U C =  ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ; 
B L R M  =  B a y e si a n 2 -p ar a m et er L o gi sti c R e gr e s si o n M o d el ; D L T =  d o s e li miti n g t o xi cit y;  D o R = d ur ati o n of r e s p o n s e; 
E C G  =  el e ctr o c ar di o gr a m;  γ -H 2 A X  =  g a m m a hi st o n e f a mil y m e m b er X ; M T D =  m a xi m u m t ol er at e d d o s e; 
O R  =  o bj e cti v e r e s p o n s e; P d  =  p h ar m a c o d y n a mi c s;  p -A T M = p h o s p h or yl at e d at a xi a -t el a n gi e ct a si a m ut at e d; p -C H K 2  
=  c h e c k p oi nt ki n a s e 2 pr ot ei n ; P F S = pr o gr e s si o n fr e e s ur vi 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 D E = r e c o m m e n d e d d o s e f or e x p a n si o n .  
O ver all Desi g n: T his is a n o p e n -la bel, P hase 1 , cli nical st u d y of M 4 0 7 6. Part 1 A  is a M 4 0 7 6 
m o n ot hera p y 
d ose 
escalati o n 
desi g ne d t o 
deter mi ne t he 
s afet y, t olera bilit y, 
P K, 
p har mac o d y n a mics  a n d earl y si g ns of efficac y i n partici pa nts wit h s oli d t u m ors. O nce a n R D E is 
declare d i n Part  1 A, a preli mi nar y f o o d effect c o h ort , Part 1 B, ma y  f oll o w a n d will be c o n d ucte d  
at t he R D E or a l o wer d ose t ha n R D E  d eter mi ne d fr o m Part  1 A.  Part  1 B is a ra n d o mi ze d, 
2 -se q ue nce, 2-peri o d, cr oss -o ver desi g n .  
Discl os ure St ate me nt:  T his is a n u n bli n de d  se q ue ntial treat me nt st u d y wit h 2 parts: d ose 
escalati o n ( Part  1 A) a n d f o o d effect st u d y ( Part 1 B) . 
N u m ber of Ar ms: N ot a p plica ble.  
Bli n di n g:  N o bli n di n g  
N u m ber of P artici p a nts: A p pr o xi matel y  4 0  p artici pa nts are pla n ne d t o  be assi g n e d t o st u d y 
i nter ve nti o n, i ncl u di n g 2 2 t o 2 8  partici pa nts i n Part  1 A (pla n ne d 4  p ote ntial d ose le vels ) a n d 
1 2  partici pa nts i n Part  1 B; the sa m ple siz e f or t he M T D a n d/ or R D E d ose  l e vel nee ds t o be at least 
6  partici pa nts .  
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: It is esti mate d t hat partici p a nts will be o n t he st u d y 
f or a n a p pr o xi mate d urati o n of 1 0 5 da ys/ 1 5  wee ks .  
I n v ol ve me nt of S peci al C o m mittee(s): Safet y M o nit ori n g C o m mittee.   
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
1. 2  
Sc he m a   
Fi g ure  1  prese nts a st u d y sc he ma o ver vie w of t h e st u d y.  
•  Part  1 A: D ose escalati o n of M 4 0 7 6 m o n ot hera p y ( Fi g ure  2 ). 
•  Part  1 B: Preli mi nar y f o o d effect c o h ort will f oll o w at t he rec o m me n de d d ose f or 
e x pa nsi o n ( R D E ) esta blis he d i n Part  1 A.  
Fi g ure  1  
St u d y Sc he m a O ver vie w   
 
T he c o h ort siz e pla n ne d i n Part  1 A is 3  partici pa nts per D ose Le v el ( D L ). T h e pr o p ose d D Ls  
re pres e nte d i n Fi g ure  2  ma y be a dj uste d bas e d o n Safet y M o nit ori n g C o m mittee ( S M C ) decisi o n 
t o reac h e x p os ures ass oci ate d wit h precli nical effi cac y w hile b ala nci n g safet y a n d t olera bilit y.  
After ma xi m u m t olerate d d ose ( M T D ) a n d/ or R D E ha ve bee n deter mi ne d i n Part  1 A, a n a d diti o nal 
c o h ort of 1 2  partici pa nts ma y b e e nr olle d i n Part  1 B at t his d ose t o ass ess preli mi nar y effect of 
f o o d o n M 4 0 7 6 m o n ot hera p y.  
Fi g ure  2  
P art 1 A - M 4 0 7 6 M o n ot her a p y D ose Esc al ati o n Sc he m a   
 
N ote: A D L  of 3 0 0  m g was als o a d mi nistere d orall y o nce dail y.  
D L  =  d ose le vel; M T D  =  ma xi m u m t olerate d d ose; R D E  =  rec o m me n de d d ose f or e x pa nsi o n; S M C =  safet y 
m o nit ori n g c o m mittee.  
P art 1 A:   
M 4 0 7 6 M o n ot h er a p y D o s e E s c al ati o n  
( N =2 2 t o 2 8 p arti ci p a nt s)  
P art 1 B:   
M 4 0 7 6  Pr eli mi n ar y F o o d Eff e ct  
( N = 1 2 p arti ci p a nt s)  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
1. 3  
Sc he d ule of Acti vities   
T he Sc he d ule of Acti vities  f or Part 1 A ( M 4 0 7 6 M o n ot hera p y D ose Es calati o n) d ail y d osi n g 
sc he d ule of t his st u d y is pr o vi de d i n Ta ble  1 . A d diti o nal assess me nts ma y b e perf or me d at 
u nsc he d ule d ti me p oi nts if cli nicall y i n dicat e d at t he I n vesti gat or’s discreti o n. T o facilitate ti mel y 
a d mi nistrati o n of st u d y i nter ve nti o n, safet y la b orat or y sa m ples ma y b e o btai ne d u p t o 3 d a ys 
bef ore d osi n g. If la b orat or y sa m ples are dra w n bef ore t he da y of d osi n g, t he y s h o ul d be rec or de d 
i n t he cas e re p ort f or ms  (C R F ) c orres p o n di n g t o t he da y of pla n ne d M 4 0 7 6 a d mi nistrati o n. T he 
Part  1 A p har mac o ki n etic ( P K ), electr o car di o gra m ( E C G ) a n d p har mac o d y na mic ( P d ) bi o mar ker 
assess me nts  sc he d ule is detaile d i n Ta ble  3 .  
T he Sc he d ule of Acti vities  f or Part 1 B ( p reli mi nar y F o o d Effect Assess me nt) is pr o vi de d i n 
Ta ble  2 . T he Part  1 B P K, E C G, a n d P d bi o mar ker assess me nts sc he d ule is detaile d i n Ta ble  4 . 
F or Part  1 A , p ote ntial variati o ns i n st u d y i nter ve nti o n sc he d ules a n d s c he d ule of acti vities d ue t o 
alter nati ve d osi n g sc h e d ules are f o u n d A p pe n di x  7 . Please see Secti o ns 4. 1. 1  a n d 4. 1. 2 , a n d 
A p pe n di x  1 2  f or details o n m o del f or Ba yesia n d os e escal ati o n . 
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
1. 3. 1  
P art 1 A –  M 4 0 7 6 M o n ot her a p y D ose  Esc al ati o n ( D ail y D osi n g)   
T he sc he d ule of e ve nts f or Part  1 A are pr o vi de d i n Ta ble  1 . 
T he Part 1 A fasti n g wi n d o w is defi ne d as: 2 h o urs pre d ose t o 1 -h o ur p ost d ose i n ge neral, a n d  h o urs pre d ose t o 4 h o urs p ost d ose o n 
da ys w here P K -ti me matc he d tri plicate E C Gs are c ollecte d.  
T a ble  1  
Sc he d ule of Acti vitie s: M 4 0 7 6 M o n ot her a p y D ose Esc al ati o n ( D ail y D osi n g), P art 1 A  
A s s e s s m e nt s a n d 
Pr o c e d ur e s  
S cr e e n 
( D -2 8 
t o -1)  
D L T P eri o d 
( 2 1 d a y s)  
S u b s e q u e nt 3 -w e e k 
P eri o d s ( 2 1 d a y s)  
E n d of St u d y 
I nt er v e nti o n 
Vi sit  
S af et y  
F oll o w u p/  
Di s c o nti n u ati o n 
Vi sit  
N ot e s  
D a y  
 
1  
2  
8  
9  
1 5  
1  
8  
1 5  
Wit hi n 7  d a y s 
aft er l a st d o s e  
3 0  d a y s aft er l a st 
d o s e   
 
Vi sit Wi n d o w 
( d a y s) 
 
-1  
 
 
 
 
 
 
 
+ 7  
+ /- 7  
D a y  1 a s s e s s m e nt s t h at c o ul d 
b e c o m pl et e d o n D a y  -1 ar e 
li mit e d t o p h y si c al e x a mi n ati o n, 
h ei g ht/ w ei g ht, a n d E C O G 
p erf or m a n c e st at u s.  
St u d y Sit e Vi sit s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
St arti n g C y cl e 4, vi sit s at D a y 8 
a n d D a y 1 5 ar e o pti o n al  
Writt e n 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  
 
 
 
 
 
 
 
 
 
 
 
M e di c al Hi st or y 
(i n cl u d e s s u b st a n c e 
u s a g e); 
D e m o gr a p h y  
X  
 
 
 
 
 
 
 
 
 
 
S u b st a n c e s: t o b a c c o u s e o nl y.  
H e p atiti s B a n d C 
t e st s 
X  
 
 
 
 
 
 
 
 
 
 
T o r ul e o ut a cti v e i nf e cti o n, 
p erf or m e d at t h e I n v e sti g at or’ s 
di s cr eti o n. S e e A p p e n di x  6  f or 
d et ail s.  
O pti o n al HI V 
S cr e e ni n g  
X  
 
 
 
 
 
 
 
 
 
 
HI V t e sti n g i s o pti o n al at t h e 
I n v e sti g at or’ s di s cr eti o n u nl e s s 
r e q uir e d l o c all y. 
Gl o bal Versi o n I D: C CI
C
C
I

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt s a n d 
Pr o c e d ur e s  
S cr e e n 
( D -2 8 
t o -1)  
D L T P eri o d 
( 2 1 d a y s)  
S u b s e q u e nt 3 -w e e k 
P eri o d s ( 2 1 d a y s)  
E n d of St u d y 
I nt er v e nti o n 
Vi sit  
S af et y  
F oll o w u p/  
Di s c o nti n u ati o n 
Vi sit  
N ot e s  
D a y  
 
1  
2  
8  
9  
1 5  
1  
8  
1 5  
Wit hi n 7  d a y s 
aft er l a st d o s e  
3 0  d a y s aft er l a st 
d o s e   
 
Vi sit Wi n d o w 
( d a y s) 
 
-1  
 
 
 
 
 
 
 
+ 7  
+ /- 7  
D a y  1 a s s e s s m e nt s t h at c o ul d 
b e c o m pl et e d o n D a y  -1 ar e 
li mit e d t o p h y si c al e x a mi n ati o n, 
h ei g ht/ w ei g ht, a n d E C O G 
p erf or m a n c e st at u s.  
S er u m Pr e g n a n c y 
T e st ( W O C B P o nl y)  
X  
 
 
 
 
 
 
 
 
X  
 
S e e S e cti o n  8. 3. 5 . 
Uri n e Pr e g n a n c y 
T e st ( W O C B P o nl y)  
 
X  
 
 
 
 
X  
 
 
 
 
Uri n e β -h C G r e s ult s m u st b e 
a v ail a bl e pri or t o M 4 0 7 6 d o si n g.  
P h y si c al 
E x a mi n ati o n  
X  
X  
 
 
X  
X  
X  
 
 
X  
X  
S e e S e cti o n  8. 2. 1 . 
H ei g ht a n d W ei g ht  
X  
X  
 
 
 
 
X  
 
 
X  
X  
C oll e ct h ei g ht at S cr e e ni n g 
o nl y.  
I m a gi n g Di s e a s e 
A s s e s s m e nt 
( C T/ M RI) 
X  
X ( at t h e e n d of e v er y 6  w e e k s f or t h e fir st 
2 4  w e e k s, t h e n e v er y 1 2  w e e k s)  
X  
 
T u m or a s s e s s m e nt a c c or di n g 
t o R E CI S T 1. 1 u ntil di s e a s e 
pr o gr e s si o n, e n d of st u d y, or 
d e at h, w hi c h e v er i s e arli er. S e e 
S e cti o n  8. 1  f or d et ail s of 
i m a gi n g. 
Vit al si g n s   
X  
X  
 
X  
 
X  
X  
 
 
X  
X  
I n t h e fir st 6 w e e k s o n st u d y 
tr e at m e nt, vit al si g n s ar e 
m e a s ur e d a s f oll o w s:  
•  
Pr e d o s e ( wit hi n 
a p pr o xi m at el y 3 0 t o 
6 0  mi n ut e s pri or)  
•  
4  h o ur s ( ± 1  h o ur) p o st d o s e 
o n D a y  1 a n d D a y  8. Aft er 
6  w e e k s, vit al si g n s t o b e 
m e a s ur e d pr e d o s e.  
St a n d ar d 1 2 -l e a d 
E C G  
X  
 
 
 
 
 
X  
p o st 
d o si n g  
 
 
X  
X  
 
Tri pli c at e di git al 
E C G  
 
X  
X  
X  
 
 
 
 
 
 
 
S e e T a bl e  3  f or tri pli c at e E C G 
d et ail s.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt s a n d 
Pr o c e d ur e s  
S cr e e n 
( D -2 8 
t o -1)  
D L T P eri o d 
( 2 1 d a y s)  
S u b s e q u e nt 3 -w e e k 
P eri o d s ( 2 1 d a y s)  
E n d of St u d y 
I nt er v e nti o n 
Vi sit  
S af et y  
F oll o w u p/  
Di s c o nti n u ati o n 
Vi sit  
N ot e s  
D a y  
 
1  
2  
8  
9  
1 5  
1  
8  
1 5  
Wit hi n 7  d a y s 
aft er l a st d o s e  
3 0  d a y s aft er l a st 
d o s e   
 
Vi sit Wi n d o w 
( d a y s) 
 
-1  
 
 
 
 
 
 
 
+ 7  
+ /- 7  
D a y  1 a s s e s s m e nt s t h at c o ul d 
b e c o m pl et e d o n D a y  -1 ar e 
li mit e d t o p h y si c al e x a mi n ati o n, 
h ei g ht/ w ei g ht, a n d E C O G 
p erf or m a n c e st at u s.  
E C O G p erf or m a n c e 
st at u s  
X  
X  
 
 
 
 
X  
 
 
X  
X  
S e e A p p e n di x  1 0 . 
A E, A E SI a n d S A E 
a s s e s s m e nt  
C o nti n u o u s  
Fr o m ti m e of si g ni n g t h e I C F 
t hr o u g h t h e S af et y F oll o w-u p 
Vi sit, a n d u ntil c o m pl eti o n of t h e 
st u d y. S A E s a n d A E SI s s h o ul d 
b e f oll o w e d u ntil r e s ol uti o n, 
st a bili z ati o n, t h e e v e nt i s 
ot h er wi s e e x pl ai n e d, or t h e 
p arti ci p a nt i s l o st t o f oll o w -u p 
( s e e S e cti o n 8. 3. 3 ). 
C o n c o mit a nt 
m e di c ati o n s a n d 
pr o c e d ur e s 
(i n cl u di n g c oll e cti o n 
of s u b s e q u e nt 
a nti c a n c er t h er a p y)  
 
 
S er u m C h e mi str y  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
F or Vi sit  1/ D 1, s a m pl e c a n b e 
c oll e ct e d u p t o 7 2  h o ur s pri or t o 
d o si n g. D 8 a n d D 1 5 
a s s e s s m e nt s ar e o pti o n al aft er 
W e e k  9. S e e A p p e n di x  6  f or 
d et ail s.  
H e m at ol o g y a n d 
C o a g ul ati o n ( P T, 
a P T T, I N R)  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
F or Vi sit  1/ D 1, s a m pl e c a n b e 
c oll e ct e d u p t o 7 2  h o ur s pri or t o 
d o si n g. D 8 a n d D 1 5 
a s s e s s m e nt s ar e o pti o n al aft er 
W e e k  9. S e e A p p e n di x  6  f or 
d et ail s.  
Uri n al y si s  
X  
X  
 
 
 
X  
X  
 
 
X  
 
S e e A p p e n di x  6  f or d et ail s.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt s a n d 
Pr o c e d ur e s  
S cr e e n 
( D -2 8 
t o -1)  
D L T P eri o d 
( 2 1 d a y s)  
S u b s e q u e nt 3 -w e e k 
P eri o d s ( 2 1 d a y s)  
E n d of St u d y 
I nt er v e nti o n 
Vi sit  
S af et y  
F oll o w u p/  
Di s c o nti n u ati o n 
Vi sit  
N ot e s  
D a y  
 
1  
2  
8  
9  
1 5  
1  
8  
1 5  
Wit hi n 7  d a y s 
aft er l a st d o s e  
3 0  d a y s aft er l a st 
d o s e   
 
Vi sit Wi n d o w 
( d a y s) 
 
-1  
 
 
 
 
 
 
 
+ 7  
+ /- 7  
D a y  1 a s s e s s m e nt s t h at c o ul d 
b e c o m pl et e d o n D a y  -1 ar e 
li mit e d t o p h y si c al e x a mi n ati o n, 
h ei g ht/ w ei g ht, a n d E C O G 
p erf or m a n c e st at u s.  
Ar c hi v al t u m or 
bi o p s y c oll e cti o n  
X  
 
 
 
 
 
 
 
 
 
 
If i n s uffi ci e nt ti s s u e i s a v ail a bl e 
fr o m a n ar c hi v e d s p e ci m e n, or 
if t h e bi o p s y w a s o bt ai n e d 
>  1 2  m o nt h s b ef or e S cr e e ni n g, 
a fr e s h bi o p s y s a m pl e m a y b e 
r e q u e st e d d uri n g s cr e e ni n g 
( pri or t o D 1) u nl e s s 
c o ntr ai n di c at e d f or m e di c al 
r e a s o n s.  
St u d y I nt er v e nti o n A d mi ni str ati o n 
M 4 0 7 6 M o n ot h er a p y  
 
D ail y d o si n g. ( F a sti n g wi n d o w: 2 hr s pr e d o s e t o 1 hr 
p o st d o s e i n g e n er al, a n d 2 hr s pr e d o s e t o 4 hr s 
p o st d o s e o n d a y s w h er e P K -ti m e m at c h e d tri pli c at e 
E C G s ar e c oll e ct e d.)  
 
 
S e e a d diti o n al p ot e nti al 
tr e at m e nt s c h e d ul e s i n 
A p p e n di x  7 .  
P h ar m a c o ki n eti c A s s e s s m e nt s  
Bl o o d - P K bl o o d 
s a m pl e s M 4 0 7 6  
 
X  
X  
X  
X  
 
X  
 
 
 
 
S e e T a bl e  3  f or P K s a m pl e 
d et ail s.  
Bi o m ar k er A s s e s s m e nt s  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C
C
I

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /1 2 2  
 
 
A s s e s s m e nt s a n d 
Pr o c e d ur e s  
S cr e e n 
( D -2 8 
t o -1)  
D L T P eri o d 
( 2 1 d a y s)  
S u b s e q u e nt 3 -w e e k 
P eri o d s ( 2 1 d a y s)  
E n d of St u d y 
I nt er v e nti o n 
Vi sit  
S af et y  
F oll o w u p/  
Di s c o nti n u ati o n 
Vi sit  
N ot e s  
D a y  
 
1  
2  
8  
9  
1 5  
1  
8  
1 5  
Wit hi n 7  d a y s 
aft er l a st d o s e  
3 0  d a y s aft er l a st 
d o s e   
 
Vi sit Wi n d o w 
( d a y s) 
 
-1  
 
 
 
 
 
 
 
+ 7  
+ /- 7  
D a y  1 a s s e s s m e nt s t h at c o ul d 
b e c o m pl et e d o n D a y  -1 ar e 
li mit e d t o p h y si c al e x a mi n ati o n, 
h ei g ht/ w ei g ht, a n d E C O G 
p erf or m a n c e st at u s.  
Fr e s h P air e d t u m or 
bi o p si e s  
X  
 
X  
 
 
 
 
 
 
 
 
O pti o n al.  
T h e fir st of t w o p air e d bi o p si e s 
s h o ul d b e c oll e ct e d a n yti m e 
d uri n g s cr e e ni n g. T h e s e c o n d 
bi o p s y s h o ul d b e c oll e ct e d  o n 
D 2 fr o m 2 t o 4  h o ur s aft er st u d y 
i nt er v e nti o n a d mi ni str ati o n. N o 
b o n e bi o p si e s ar e all o w e d.  T h e 
fir st bi o p s y c a n r e pl a c e t h e 
ar c hi v al t u m or bi o p s y.  
Pl a s m a –  Cir c ul ati n g 
T u m or D N A S a m pl e  
 
X  
 
 
 
 
X  
 
 
X  
 
C oll e ct pr e d o s e  o n d o si n g 
d a y s.  
Bl o o d –  I m m u n o-
p h e n ot y pi n g  
 
X  
 
 
 
 
X  
D 2 2 
o nl y  
 
 
 
 
C oll e ct pr e d o s e.  
S er u m/ pl a s m a –  
Cir c ul ati n g f a ct or s 
( c yt o ki n e s) 
 
X  
 
 
 
 
X  
D 2 2 
o nl y  
 
 
 
 
C oll e ct pr e d o s e.  
A E  = a d v er s e e v e nt; a P T T = a cti v at e d p arti al t hr o m b o pl a sti n ti m e;  β -h C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n; C T = c o m p ut e d t o m o gr a p h y; D  =  D a 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  =  E a st er n C o o p er ati v e O n c ol o g y Gr o u p; −H 2 A X  = g a m m a hi st o n e f a mil y m e m b er X ; HI V = h u m a n 
i m m u n o d efi ci e n c y vir u s; I C F =  i nf or m e d c o n s e nt f or m; I N R = i nt er n ati o n al n or m ali z e d r ati o; 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; P T  =  pr ot hr o m bi n ti m e; 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; S A E = s eri o u s a d v er s e e v e nt; W O C B P  =  w o m a n of 
c hil d b e ari n g p ot e nti al.  
 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
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 2 2  
1. 3. 2  
P art  1 B –  Preli mi n ar y F o o d Effect Assess me nt  
Part  1 B (t he preli mi nar y f o o d effect assess me nt) will be assesse d b y a pre defi ne d sc h e d ule i n Ta ble  2  fr o m Da y -7 u ntil Da y  3 . T he 
fasti n g wi n d o w is defi ne d i n Part 1 B as 1 0 h o urs pre d ose t o 4 h o urs p ost d ose. F or assess me nts after Da y  4 see Part  1 A Sc he d ule of 
Acti vities  (Ta ble  1 ).  
N ote: After M 4 0 7 6 P K is esta blis he d, t he mi ni m u m re q uire d ti me i nter val ( was h o ut) b et wee n t h e first 2  a d mi nistrati o ns of M 4 0 7 6 ma y 
be a dj uste d ( mi ni m u m of 5  ti mes t he half-life of M 4 0 7 6, b ut at least 1 da y a n d n ot >  6  da ys). A d diti o nall y, if t he half -life of M 4 0 7 6 is 
s u bsta ntiall y l o n ger t ha n ori gi nall y pre dicte d, a n a d diti o nal P K ti me p oi nt o n Da y -5 ma y b e a d de d a n d earlier ti me p oi nt(s) re m o ve d s o 
t hat t he t otal n u m ber of bl o o d dra ws is not i ncreas e d.  
T a ble  2  
Sc he d ule of Acti vities: Preli mi n ar y F o o d Effect Assess me nt, P a rt 1 B  
A s s e s s m e nt a n d 
Pr o c e d ur e s  
S cr e e n 
F o o d Eff e ct A s s e s s m e nt  
Tr e at m e nt  
N ot e s  
D a y  
D -2 8 t o
-8
-7
-6
-5
-4
-3 t o -1
1  
2  
3  
4 
Vi sit Wi n d o w  ( d a ys ) 
-1
D a y  1 a s s e s s m e nt s t h at 
c o ul d b e c o m pl et e d o n D a y -1 
ar e li mit e d t o p h y si c al 
e x a mi n ati o n, h ei g ht/ w ei g ht, 
a n d E C O G p erf or m a n c e 
st at u s.  
St u d y Sit e Vi sit s  
X  
X  
X  
X  
X  
W a s h o ut d a y s  
X  
X  
X  
S e e T a bl e  1  
Aft er D a y 4  p arti ci p a nt s will 
c o nti n u e t o b e tr e at e d a s p er 
T a bl e  1  (S c h e d ul e of 
A cti viti e s  f or P art  1 A ). 
Writt e n 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  
M e di c al hi st or y  
(i n cl u d e s s u b st a n c e 
u s a g e) ; D e m o gr a p h y 
X  
S u b st a n c e s: t o b a c c o u s e 
o nl y . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt a n d 
Pr o c e d ur e s  
S cr e e n  
F o o d Eff e ct A s s e s s m e nt  
Tr e at m e nt  
N ot e s  
D a y  
D -2 8 t o 
-8  
-7  
-6  
-5  
-4  
-3 t o -1  
1  
2  
3  
4  
 
Vi sit Wi n d o w  ( d a ys ) 
 
 
 
 
 
 
-1  
 
 
 
D a y  1 a s s e s s m e nt s t h at 
c o ul d b e c o m pl et e d o n D a y -1 
ar e li mit e d t o p h y si c al 
e x a mi n ati o n, h ei g ht/ w ei g ht, 
a n d E C O G p erf or m a n c e 
st at u s.  
H e p atiti s B a n d C 
t e st s 
X  
 
 
 
 
 
 
 
 
 
T o r ul e o ut a cti v e i nf e cti o n, 
p erf or m e d at t h e 
I n v e sti g at or’ s di s cr eti o n. 
O pti o n al HI V 
S cr e e ni n g  
X  
 
 
 
 
 
 
 
 
 
HI V t e sti n g i s o pti o n al at t h e 
I n v e sti g at or’ s di s cr eti o n. 
Pr e g n a n c y T e st 
( W O C B P o nl y) 
X  
X  
 
 
 
 
X  
 
 
 
S er u m t e st at S cr e e ni n g, 
uri n e t e st ot h er wi s e.  
Uri n e pr e g n a n c y r e s ult s m u st 
b e a v ail a bl e pri or t o M 4 0 7 6 
d o si n g.  
E C O G p erf or m a n c e 
st at u s  
X  
X  
 
 
 
 
X  
 
 
 
S e e A p p e n di x  1 0 . 
S af et y A s s e s s m e nt s  
P h y si c al E x a mi n ati o n  
X  
 
 
 
 
 
X  
 
 
 
R ef er t o S e cti o n  8. 2. 1 . 
H ei g ht a n d W ei g ht  
X  
 
 
 
 
 
X  
 
 
 
C oll e ct h ei g ht at s cr e e ni n g 
o nl y.  
I m a gi n g Di s e a s e 
A s s e s s m e nt 
( C T/ M RI) 
X  
 
 
 
 
 
 
 
 
 
 
Vit al Si g n s  
X  
X  
 
 
 
 
X  
 
 
 
Vit al si g n s ar e t o b e 
m e a s ur e d a s f oll o w s:  
•  
D a y -7 a n d D a y 1, at 
pr e d o s e ( wit hi n 
a p pr o xi m at el y 3 0 t o 
6 0  mi n ut e s pri or) a n d  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt a n d 
Pr o c e d ur e s  
S cr e e n  
F o o d Eff e ct A s s e s s m e nt  
Tr e at m e nt  
N ot e s  
D a y  
D -2 8 t o 
-8  
-7  
-6  
-5  
-4  
-3 t o -1  
1  
2  
3  
4  
 
Vi sit Wi n d o w  ( d a ys ) 
 
 
 
 
 
 
-1  
 
 
 
D a y  1 a s s e s s m e nt s t h at 
c o ul d b e c o m pl et e d o n D a y -1 
ar e li mit e d t o p h y si c al 
e x a mi n ati o n, h ei g ht/ w ei g ht, 
a n d E C O G p erf or m a n c e 
st at u s.  
•  
4  h o ur s ( ± 1  h o ur) 
p o st d o s e   
S er u m C h e mi str y  
X  
X  
 
 
 
 
X  
 
 
 
S e e A p p e n di x  6  f or d et ail s. 
H e m at ol o g y a n d 
C o a g ul ati o n ( P T, 
a P T T, I N R)  
X  
X  
 
 
 
 
X  
 
 
 
S e e  A p p e n di x  6  f or d et ail s. 
Uri n al y si s  
X  
X  
 
 
 
 
X  
 
 
 
S e e  A p p e n di x  6  f or d et ail s. 
St a n d ar d 1 2 -l e a d 
E C G  
X  
 
 
 
 
 
 
 
 
 
 
Tri pli c at e di git al E C G  
 
X  
 
 
 
 
X  
 
 
 
E C G s h o ul d o nl y b e c oll e ct e d 
f or p arti ci p a nt s d o s e d i n t h e 
f a st e d st at e. S e e T a bl e  4  f or 
tri pli c at e E C G d et ail s. 
A E a n d S A E 
a s s e s s m e nt  
C o nti n u o u s  
 
C o n c o mit a nt 
m e di c ati o n s a n d 
pr o c e d ur e s r e vi e w  
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt a n d 
Pr o c e d ur e s  
S cr e e n  
F o o d Eff e ct A s s e s s m e nt  
Tr e at m e nt  
N ot e s  
D a y  
D -2 8 t o 
-8  
-7  
-6  
-5  
-4  
-3 t o -1  
1  
2  
3  
4  
 
Vi sit Wi n d o w  ( d a ys ) 
 
 
 
 
 
 
-1  
 
 
 
D a y  1 a s s e s s m e nt s t h at 
c o ul d b e c o m pl et e d o n D a y -1 
ar e li mit e d t o p h y si c al 
e x a mi n ati o n, h ei g ht/ w ei g ht, 
a n d E C O G p erf or m a n c e 
st at u s.  
St u d y I nt er v e nti o n a n d Tr e at m e nt  
L o w -f at M e al or 
O v er ni g ht F a sti n g  
( F a sti n g wi n d o w: 
1 0  h o ur s pr e d o s e t o 
4 h o ur s p o st d o s e)  
 
X  
X  
 
 
 
X  
 
 
 
P arti ci p a nt s i n P art  1 B will b e 
r a n d o ml y a s si g n e d o n a 1: 1 
b a si s t o 1 of 2  st u d y 
i nt er v e nti o n s e q u e n c e s: 
( 1) f a st e d f oll o w e d b y f e d, or 
( 2) f e d f oll o w e d b y f a st e d.  
Aft er c o m pl eti o n of f o o d eff e ct 
a s s e s s m e nt s , p arti ci p a nt s 
m a y c o nti n u e t o r e c ei v e st u d y 
i nt er v e nti o n at R D E fr o m D 4 
o n w ar d ( o n a n e m pt y 
st o m a c h) a n d f oll o w 
a s s e s s m e nt s a s p er T a bl e  1  
fr o m D 8 o n w ar d s.  
M 4 0 7 6 A d mi ni str ati o n 
( si n gl e d o s e) 
 
X  
 
 
 
 
X  
 
 
X  
Aft er D 4 , M 4 0 7 6 d o si n g 
s h o ul d c o nti n u e at t h e R D E 
a n d t h er e aft er f oll o w 
a s s e s s m e nt s a s p er T a bl e  1 . 
P h ar m a c o ki n eti c  A s s e s s m e nt s:   
 
Bl o o d –  P K bl o o d 
s a m pl e s M 4 0 7 6  
 
X  
X  
X  
X  
 
X  
X  
X  
X  
S e e T a bl e  4  f or P K s a m pl e 
d et ail s.   
Uri n e P K C oll e cti o n  
 
X  
X  
X  
X  
 
X  
X  
X  
X  
S e e T a bl e  4  f or uri n e P K 
s a m pl e d et ail s . 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
A s s e s s m e nt a n d 
Pr o c e d ur e s  
S cr e e n  
F o o d Eff e ct A s s e s s m e nt  
Tr e at m e nt  
N ot e s  
D a y  
D -2 8 t o 
-8  
-7  
-6  
-5  
-4  
-3 t o -1  
1  
2  
3  
4  
 
Vi sit Wi n d o w  ( d a ys ) 
 
 
 
 
 
 
-1  
 
 
 
D a y  1 a s s e s s m e nt s t h at 
c o ul d b e c o m pl et e d o n D a y -1 
ar e li mit e d t o p h y si c al 
e x a mi n ati o n, h ei g ht/ w ei g ht, 
a n d E C O G p erf or m a n c e 
st at u s.  
Pl a s m a –  Cir c ul ati n g 
T u m or D N A S a m pl e  
 
X  
 
 
 
 
 
 
 
 
C oll e ct pr e d o s e.  
Fr e s h P air e d T u m or 
Bi o p si e s  
X  
 
 
 
 
 
 
 
 
X  
M a n d at or y c oll e cti o n, if n ot 
c o ntr ai n di c at e d f or m e di c al 
r e a s o n s. T h e fir st of t w o 
p air e d bi o p si e s m u st b e 
c oll e ct e d a n yti m e d uri n g 
s cr e e ni n g. T h e s e c o n d bi o p s y 
m u st b e c oll e ct e d o n D 4  fr o m 
2 t o 4  h o ur s aft er st u d y 
i nt er v e nti o n. N o b o n e 
bi o p si e s ar e all o w e d.  
Bl o o d - I m m u n e 
P h e n ot y pi n g  
 
X  
 
 
 
 
 
 
 
 
C oll e ct pr e d o s e.  
S er u m/ pl a s m a –  
Cir c ul ati n g F a ct or s  
 
X  
 
 
 
 
 
 
 
 
C oll e ct pr e d o s e.  
A E  =  a d v er s e e v e nt; a P T T = a cti v at e d p arti al t hr o m b o pl a sti n ti m e; C T = c o m p ut e d t o m o gr a p h y; D = D a y; D N A  =  d e o x yri b o n u cl ei c a ci d; E C G  =  el e ctr o c ar di o gr a m;  
E C O G  =  E a st er n C o o p er ati v e O n c ol o g y Gr o u p; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; I N R = i nt er n ati o n al n or m ali z e d r ati o; 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; P K  =  p h ar m a c o ki n eti c; P T = pr ot hr o m bi n ti m e; R D E  =  r e c o m m e n d e d d o s e f or e x p a n si o n; S A E = s eri o u s a d v er s e e v e nt;  
W O C B P  =  w o m a n of c hil d b e ari n g p ot e nti al.   
 
 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /1 2 2  
 
 
1. 3. 3  
P arts  1 A a n d 1 B –  P h ar m ac o ki netic, E C G, a n d 
a m pli n g 
Sc he d ule   
T a ble  3  
P art 1 A M 4 0 7 6 M o n ot h er a p y D ose Esc al ati o n: P h ar m a c o ki netic, E C G a n d 
 
Assess me nts   
St u d y D a y  
M 4 0 7 6 D o si n g  
P K S a m pli n g Ti m e  
E C G b  
P air e d Bi o p si e s  
S cr e e ni n g ( D – 2 8 t o -1)  
 
 
 
X  
D a y 1  
X  
Pr e d o s e a  
X  
 
 
0. 5 h o ur  ± 1 0 mi n ut e s  
p o st d o s e  
 
 
 
1 h o ur  ± 1 0 mi n ut e s  p o st d o s e  
 
 
 
2 h o ur s  ± 1 0 mi n ut e s  
p o st d o s e  
X  
 
 
3 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
 
4 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
 
6 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
 
8 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
D a y 2  
 
X  
Pr e d o s e a  
X  
 
2 h o ur s -4  h o ur s p o st d o s e c 
 
X c 
D a y 8  
 
X  
Pr e d o s e a  
X  
 
 
1 h o ur  ± 1 0 mi n ut e s  p o st d o s e  
X  
 
 
 
2 h o ur s  ± 1 0 mi n ut e s  
p o st d o s e  
X  
 
 
 
3 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
St u d y D a y  
M 4 0 7 6 D o si n g  
P K S a m pli n g Ti m e  
E C G b  
P air e d Bi o p si e s  
 
 
4 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
 
 
6 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
 
 
 
 
8 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
X  
 
 
D a y 9  
X  
Pr e d o s e a  
 
 
 
D a y 2 2  
X  
Pr e d o s e a  
 
 
X  
 
 
2 h o ur s  ± 1 0 mi n ut e s  
p o st d o s e  
 
 
X  
 
 
4 h o ur s  ± 2 0 mi n ut e s  
p o st d o s e  
 
 
X  
All s u b s e q u e nt D a y  1 of 
e v er y 3  w e e k tr e at m e nt 
p eri o d  
X  
Pr e d o s e a  
 
 
 
N ot e: T h e f a sti n g wi n d o w i n P art 1 A i s d efi n e d a s: 2 h o ur s pr e d o s e t o 1 -h o ur p o st d o s e i n g e n er al, a n d 2 h o ur s pr e d o s e t o 4 h o ur s p o st d o s e o n d a y s w h er e P K -
ti m e m at c h e d tri pli c at e E C G will b e c oll e ct e d.  
E C G  =  el e ctr o c ar di o gr a m; γ -H 2 A X = g a m m a hi st o n e f a mil y m e m b er X; 
; P K =  p h ar m a c o ki n eti c.  
a 
All pr e d o s e s a m pl e s h a v e a wi n d o w of -6 0  mi n ut e s  pri or t o d o si n g . 
b  
T h e wi n d o w p eri o d f or E C G i s t h e s a m e a s n ot e d f or P K s a m pli n g . 
c 
Eff ort s s h o ul d b e m a d e t o c oll e ct bl o o d f or P K a n d 
 a n d bi o p s y s a m pl e s  ar o u n d si mil ar ti m e p oi nt s  ( ± 2 0  mi n ut e s ). 
P eri o d  1 D a y 8/ 9 P K s a m pli n g m a y b e c o n d u ct e d o n D a y 1 5/ 1 6, or P eri o d  2 D a y  1/ 2, if r e q uir e d f or l o gi sti c al r e a s o n s a n d/ or i n c a s e st u d y i nt er v e nti o n w a s 
i nt err u pt e d a n d r e s u m e d. I n t hi s c a s e, ti mi n g of a s s o ci at e d tri pli c at e E C G m e a s ur e m e nt s s h o ul d b e r e s c h e d ul e d a c c or di n gl y, a n d t h e S p o n s or n otifi e d i n a d v a n c e. 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C
CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
T a ble  4  
P art 1 B Preli mi n ar y F o o d Effect Assess me nt: P h ar m ac o ki netic, E C G a n d 
 
Assess me nts   
St u d y D a y  
M 4 0 7 6 
D o si n g  
P K S a m pli n g Ti m e  
Uri n e C oll e cti o n f or P K  
E C G b  
P air e d Bi o p si e s  
S cr e e ni n g ( D -2 8 t o -8)  
 
 
 
 
X  
-7  
X  
Pr e d o s e a  
X ( 1  h o ur , 0) 
X  
 
 
0. 5 h o ur  ± 1 0 mi n ut e s  p o st d o s e  
X ( 0 t o 4 h o ur s)  
 
 
 
1 h o ur  ± 1 0 mi n ut e s  p o st d o s e  
X  
 
 
2 h o ur s  ± 1 0 mi n ut e s  p o st d o s e  
X  
 
 
3 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X  
 
 
4 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X ( 4 t o 8 h o ur s)  
X  
 
 
6 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X  
 
 
8 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X ( 8 t o 2 4 h o ur s)  
X  
 
 
1 0 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
 
 
-6  
 
2 4 h o ur s  ± 2 h o ur s  p o st d o s e  
X ( 2 4 t o 4 8  h o ur s)  
 
 
-5  
 
4 8 h o ur s  ± 2 h o ur s  p o st d o s e  
X ( 4 8 t o 7 2 h o ur s)  
 
 
 
-4  
 
7 2 h o ur s  ± 2 h o ur s  p o st d o s e  
 
 
 
 
D a y -3 t o -1 W a s h o ut  
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
St u d y D a y  
M 4 0 7 6 
D o si n g  
P K S a m pli n g Ti m e  
Uri n e C oll e cti o n f or P K  
E C G b  
P air e d Bi o p si e s  
D a y 1  
X  
Pr e d o s e a   
 
X  
 
 
0. 5 h o ur  ± 1 0 mi n ut e s  p o st d o s e  
X ( 0 t o 4 h o ur s)  
 
 
 
1 h o ur  ± 1 0 mi n ut e s  p o st d o s e  
 
 
 
2 h o ur s  ± 1 0 mi n ut e s  p o st d o s e  
X  
 
 
3 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X  
 
4 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X ( 4 t o 8 h o ur s)  
X  
 
 
6 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X  
 
 
8 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
X ( 8 t o 2 4 h o ur s)  
X  
 
 
1 0 h o ur s  ± 2 0 mi n ut e s  p o st d o s e  
 
 
D a y 2  
 
2 4 h o ur s  ± 2 h o ur s  p o st d o s e  
X ( 2 4 t o 4 8  h o ur s)  
 
 
D a y 3  
 
4 8 h o ur s  ± 2 h o ur s  p o st d o s e  
X ( 4 8 t o 7 2 h o ur s)  
 
 
D a y 4 d  
X  
Pr e d o s e a  
 
 
 
 
1 h o ur s ± 1 0 mi n ut e s p o st d o s e  
 
 
 
 
3 h o ur s ± 6 0 mi n ut e s p o st d o s e  
 
 
 
X c 
 
 
 
 
 
 
 
6 h o ur s ± 2 0 mi n ut e s p o st d o s e  
 
 
 
 
 
8 h o ur s ± 2 0 mi n ut e s p o st d o s e  
 
 
 
 
E C G  =  el e ctr o c ar di o gr a m; γ -H 2 A X = g a m m a hi st o n e f a mil y m e m b er X; P d  =  p h ar m a c o d y n a mi c; P K  =  p h ar m a c o ki n eti c; R D E = r e c o m m e n d e d d o s e f or e v al u ati o n.  
a  
All pr e d o s e s a m pl e s h a v e a wi n d o w of –  6 0  mi n ut e s  pri or t o n e xt d o si n g . 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
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 2 2  
 
 
b  
Tri pli c at e E C G c oll e cti o n i s o nl y a p pli c a bl e t o p arti ci p a nt s d o s e d i n t h e f a st e d st at e . T h e f a sti n g wi n d o w i n P art 1 B i s d efi n e d a s 1 0 h o ur s pr e d o s e t o 
4  h o ur s p o st d o s e .  
c 
T h e bi o p s y c a n b e c oll e ct e d a n yti m e b et w e e n 2 a n d 4  h o ur s aft er tr e at m e nt a d mi ni str ati o n . Eff ort s s h o ul d b e m a d e t o c oll e ct P K a d P d bl o o d  a n d bi o p s y 
s a m pl e s  ar o u n d si mil ar ti m e p oi nt s ( ± 2 0  mi n ut e s ). 
d  
Aft er c o m pl eti o n of P art  1 B a s s e s s m e nt s, p arti ci p a nt s m a y c o nt i n u e t o r e c ei v e st u d y i nt er v e nti o n at R D E fr o m D 4 o n w ar d ( o n a n e m pt y st o m a c h) a n d f oll o w 
a s s e s s m e nt s a s p er T a bl e  3  fr o m D 8 o n w ar d s.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
2  
I ntr o d ucti o n  
M 4 0 7 6 ( M S C 2 5 8 5 8 2 3 A)  is a p ote nt, selecti ve a n d orall y  bi o a vaila ble a de n osi ne tri p h os p hate  
c o m petiti ve i n hi bit or  of ata xia -tela n giectasia m utate d ( A T M) ki nase. A T M pla ys a ce ntral r ole i n 
t he de o x yri b o n u cleic aci d (D N A ) da ma ge res p o nse a n d A T M i n hi bit ors e n ha nce t he c yt ot o xic 
effects of D N A d a ma gi n g t hera pies s u c h as ra di ot hera p y a n d D N A d o u ble -stra n d brea k 
( D S B)-i n d u ci n g c he m ot h era pies. M 4 0 7 6  als o has m o n ot hera p y a nti t u m or acti vities i n a s u bset of 
ca ncer cell m o dels.  
Detaile d i nf or mati o n o n t he c he mistr y, p har m ac ol o g y, efficac y, a n d safet y of  M 4 0 7 6 is i n t he 
M 4 0 7 6 I n v esti gat or’s Br oc h ure (I B) . 
2. 1  
St u d y R ati o n ale   
T he p ur p ose of t his st u d y is t o esta blis h t he safet y, t olera bilit y a n d P K pr ofile ( wit h a n d wit h o ut 
f o o d), M T D (if o bser ve d) a n d R D E f or M 4 0 7 6 i n partici pa nts wit h a d va nce d s oli d t u m ors f or 
w hic h n o sta n dar d t hera p y is a vaila bl e.  
T he f oll o wi n g s ecti o ns c o ntai n t he rati o nale f or c o n d ucti n g t he 
M 4 0 7 6 m o n ot hera p y. F or 
disc ussi o n of t he scie ntifi c rati o nale f or st u d y d esi g n, see Secti o n  4. 3 , a n d f or j ustificati o n of d ose, 
see Secti o n 4. 2 . 
2. 1. 1  
M 4 0 7 6 M o n ot her a p y   
T he rati o nale f or Part 1 of t his st u d y ( M 4 0 7 6 m o n ot hera p y), w hi c h i ncl u des partici pa nts wit h 
a d va nce d s oli d t u m ors f or w hic h n o a p pr o ve d/esta blis he d effecti ve treat me nt o pti o ns e xist, is t hat 
A T M i n hi bit ors ha ve s h o w n a ntit u m or effects i n s u bsets of ca nce r m o dels i n vitr o a n d i n vi v o. 
S pecificall y, M 4 0 7 6 d ecreases cell via bilit y i n vitr o i n a s u bset of 1 6/ 9 3 ca ncer cell li nes t este d 
( GI 5 0 <  5 u M) a n d i n vi v o ca use d t u m or gr o wt h i n hi biti o n i n m ulti ple patie nt deri ve d t u m or P D X 
m o dels deri ve d fr o m gastric, o v aria n, tri ple n e gati ve breast ca ncer a n d p a n creatic ca n cers.  
T he a ntit u m or effects are belie ve d t o o cc ur b y t he c o nce pt of s y nt hetic l et halit y: t w o ge n es are 
s y nt heticall y l et hal if m utati o n of eit her ge n e al o ne is c o m pati ble wit h cell via bilit y w hilst a 
m utati o n ( or tar geti n g) of b ot h ge nes lea ds t o cell deat h. It h as bee n de m o nstrate d t hat ca n cers wit h 
m utati o ns i n Fa nc o ni ane mia ge n es are se nsiti ve t o A T M i n hi bit ors si nce t he A T M a n d Fa nc o ni 
ane mia  re pair pat h w a ys are i m p orta nt f or fait hf ul re pair of d o ubl e -stra n de d D N A brea ks a n d 
i ntra-stra n d 
D N A cr oss-li n ks via t he h o m ol o g o us rec o m bi nati o n pr ocess (Ke n n e d y  2 0 0 7 ; 
Cai  2 0 2 0 ). I n a d diti o n, si m ulta ne o us i nacti vati o n of A T M a n d t he t u m or s up press or p h os p hatase 
a n d te nsi n h o m ol o g ( P T E N) has bee n re p orte d t o b e s y nt heticall y let hal ( M c Ca be  2 0 1 5 ; Cai  2 0 2 0 ). 
T he P T E N i na cti vati o n i ncreas e d t he l e vel of reacti ve o x y ge n s pecies-i n d uce d D N A d a ma ge, 
w hic h li kel y re q uires 
A T M f or re p air. 
C o nse q ue ntl y, c he mical i n hi biti o n of 
A T M i n 
P T E N -deficie nt cells res ulte d i n cell c ycle arrest, c hr o m os o mal a berrati o ns, a n d a p o pt osis. 
M olec ular c haract erizati o n of t he se nsiti ve t u m or m o de ls i n vitr o a n d i n vi v o a n d i n vesti gati o n of 
t heir u n derl yi n g ge netic dis p ositi o ns a n d p ote ntial s y nt hetic let halit y tar gets are u n der e val u ati o n. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
2. 2  
B ac k gr o u n d   
I n hi biti n g t he D N A Da ma ge Res p o nse ( D D R) has bec o me a n attracti ve t hera pe utic c o n ce pt i n 
ca ncer t hera p y, si nce resista nce t o ge n ot o xic t hera pies has bee n ass ociate d wit h i ncrease d D D R 
si g nali n g, a n d m a n y ca ncers ha v e defects i n certai n c o m p o ne nts of t he D D R re n deri n g t h e m hi g hl y 
de pe n de nt o n t he re mai ni n g D D R p at h wa ys f or s ur vi val.  
T o e ns ure t he fait hf ul tra ns missi o n of t heir ge neti c i nf or mati o n t o t he pr o ge n y, ma m malia n cells 
ha ve e v ol ve d a n el a b orate m olec ular mac hi ner y f or d etecti n g a n d re p airi n g D N A lesi o ns. A 
m ultit u de of  D N A re p air mec ha nis ms are des cri be d i n h u ma n cells ( C urti n  2 0 1 2 ). P h ysical or 
c he mical a ge nts t hat ge n erate brea ks i n D N A are a m o n g t h e m ost wi del y use d classes of ca ncer 
t hera pe utics t o da y. Ra di ot hera p y, f or e x a m ple, i nd uces m ulti ple brea ks i n cell ular D N A i n cl u di n g 
D S Bs. W he n left u nre paire d, D S Bs ca n l ea d t o i n d ucti o n of cell c ycle arrest a n d ulti matel y cell 
deat h. T o re pair D S Bs, or ga nis ms ha ve de vel o pe d a c o m ple x res p o nse t hat i ncl u des rec o g niti o n 
of t he d a ma ge d D N A,  cell ular si g nali n g i n cl u di n g c o ntr ol of t he cell c ycl e, a n d ulti matel y re pair 
of t he D N A l esi o n. T w o maj or pat h wa ys me di ate t he re pair of D S Bs i n m a m malia n cells ter me d 
h o m ol o g o us rec o m bi nati o n ( H R) a n d n o n h o m ol o g o us e n d -j oi ni n g ( N H EJ). T he A T M acts as a n  
u pstrea m si g nali n g ki nas e, w hic h re g ul ates s e veral as pects of D N A re p air i ncl u di n g H R, N H EJ, 
a n d t he cell c ycl e. T he H R re pair acts wit h hi g h fi delit y, relies o n t he i ntact sister c hr o mati d as a 
te m plate, a n d is acti ve i n t he S a n d G 2 p hase of t he cell c ycl e, w hile N H EJ is err or -pr o ne a n d 
acti ve t hr o u g h o ut all p hases of t he cell c ycle.  
M 4 0 7 6 (s u bsta nce c o d e M S C 2 5 8 5 8 2 3 A), a s mall m olec ule, is a hi g hl y p ot e nt a n d selecti ve A T M 
ki nase i n hi bit or. I n li ne wit h its pr o p ose d mec ha nis m of acti o n, i n hi biti o n of A T M  ki nase acti vit y 
b y M 4 0 7 6 e n h a nce d t he t hera pe utic effect of D N A D S B -i n d uci n g treat me nt m o dalities i ncl u di n g 
ra di ot hera p y, c he m ot hera p y a n d tar gete d a ge nts li ke A T R i n hi bit ors, t o p ois o merase i n hi bit ors a n d 
p ol y A D P ri b ose p ol y m erase i n hi bit ors i n vitr o a n d  i n vi v o. T his p ote ntiati o n ca n b e attri b ute d t o 
i n hi biti o n of A T M-de pe n de nt D S B re pair as well as i n hi biti o n of A T M -c o ntr olle d cell c ycl e 
c hec k p oi nts.  
Base d o n rece nt fi n di n gs, A T M i n hi biti o n is e x pecte d t o be nefit patie nts har b ori n g D D R 
m utati o ns, f or e x a m ple, 
m utati o ns i n Fa nc o ni ane mia ge nes ( Ke n n e d y  2 0 0 7 ; Cai  2 0 2 0 ). 
Ca ncer -s p ecific alterati o ns i n t he D D R mac hi n er y re pres e nt t he basis of s y nt h eticall y let hal 
i nteracti o ns wit h i n hi bitors of D N A da m a ge res p o nse. Si m ulta ne o us i nacti vati o n of A T M a n d 
P T E N has bee n re p orte d t o be s y nt heticall y let hal ( Mc Ca be  2 0 1 5 _ Mc Ca b e _ N, _ Ha n na ; Cai  2 0 2 0 ). 
T he P T E N i na cti vati o n i ncreas e d t he l e vel of reacti ve o x y ge n s pecies -i n d uce d D N A d a ma ge, 
w hic h ma y re q uir e A T M acti vati o n f or re pair. Testi n g of 
M 4 0 7 6 i n ca ncer cell li nes a n d  
patie nt -deri ve d x e n o graft m o dels of h u ma n ca ncer ( gastri c, tri ple ne gati ve breast ca n cer , o v aria n, 
pa ncreas) de m o nstr ate d si n gle a ge nt a ntit u m or acti vit y. 
F or details r efer t o t he c urre nt M 4 0 7 6 I B.  
2. 3  
Be nefit/ Ris k Assess me nt   
M ore detaile d i nf or mati o n  a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o n a bl y 
e x pecte d a d vers e e v e nts of  M 4 0 7 6  ma y b e f o u n d i n t he M 4 0 7 6 I B.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Base d o n t he a vaila ble  n o ncli nical a n d cli nical data t o date, t he c o n d uct of t he st u d y, as s pecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble.  
2. 3. 1  
Ris k Assess me nt   
Precli nical safet y e val uati o n of M 4 0 7 6 i n dicates t hat treat me nt wit h t his c o m p o u n d ma y  b e  
ass ociate d wit h  i ncreas e d heart rate, c yt o p e nia a n d ris ks s uc h as l y m p h oc yt o pe nia a n d i nf ecti o ns, 
a n d dr u g -dr u g i nteracti o ns w he n c o nc o mita ntl y a d mi nistere d wit h str o n g i n hi bit ors or i n d ucers of 
c yt o c hr o me P 4 5 0 ( C Y P )3 A 4 or P -gl yc o pr otei n  ( P-g p) , a n d ge n ot o xicit y (see Ta ble  5 ). 
C o nc o mita nt a d mi nistrati o n wit h se nsiti ve cli nical s u bstrates of U G T 1 A 1 or P -g p, wit h p ote ntiall y 
narr o w t hera pe utic i n de x or k n o w n safet y ris ks are pr o hi bite d, s pecificall y iri n otec a n, di g o xi n, a n d 
oral direct t hr o m bi n i n hi bit ors. T heref ore, re g ular la b orat or y m o nit ori n g f or h e mat ol o gi cal 
para meters a n d E C G assess me nts are b uilt i nt o t he c urre nt pr ot oc ol. I n a d diti o n, all t he sta n dar d 
safet y assess me nts i ncl u di n g ser u m bi oc he mistr y, c oa g ul ati o ns a n d uri ne a nal ys es are perf or me d 
o n a re g ular b asis ( See Sc he d ule of A cti vities  i n Secti o n 1. 3 ). F urt her, strict use of c o ntrace pti o n 
is re q uire d, a n d mal e partici pa nts i nf or me d t hat fertilit y mi g ht be i m paire d l o n g-ter m. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
T a ble  5  
I de ntifie d a n d  P ote nti al Ris ks  of t he St u d y I nter ve nti o ns a n d Pr oce d ures  
P ot e nti al Ri s k s  
S u m m ar y of D at a/ R ati o n al e f or 
Ri s k  
Miti g ati o n Str at e g y  
St u d y I nt er v e nti o n M 4 0 7 6  
I d e ntifi e d Ri s k ( n o n i m p ort a nt) 
R a s h  
R ef er t o S e cti o n 6. 1 of t h e 
M 4 0 7 6 I B.  
Gr a d e 2 r a s h ( wit h o ut s y st e mi c s y m pt o m s) 
- I nt err u pt tr e at m e nt a n d tr e at wit h t o pi c al 
a n d/ or s y st e mi c st er oi d s.  
Gr a d e 2 a n d Gr a d e 3 r a s h ( wit h o ut 
s y st e mi c s y m pt o m s) - m a n a g e wit h 
tr e at m e nt i nt err u pti o n a n d s u p p orti v e 
m e di c ati o n s, i n cl u di n g t o pi c al or or al 
st er oi d s.  
R a s h wit h a s s o ci at e d s y st e mi c s y m pt o m s 
( e. g., f e v er) - st o p tr e at m e nt i m m e di at el y 
a n d d o n ot  r e c h all e n g e wit h a n y d o s e of 
M 4 0 7 6.   
All c a s e s of r a s h s h o ul d b e di s c u s s e d wit h 
t h e m e di c al m o nit or. 
Im p ort a nt P ot e nti al Ri s k  
H y p er s e n siti vit y  
R ef er t o S e cti o n 6. 1 of t h e 
M 4 0 7 6 I B.  
P arti ci p a nt s  w h o e x p eri e n c e r a s h a n d 
s y st e mi c s y m pt o m s ( e. g., f e v er , v o miti n g, 
di arr h e a ), or ot h er si g n s of h y p er s e n siti vit y 
s h o ul d h a v e M 4 0 7 6 di s c o nti n u e d 
i m m e di at el y, a n d ar e n ot t o b e 
r e c h all e n g e d wit h a n y d o s e of M 4 0 7 6.  
P ot e nti al Ri s k s  
C yt o p e ni a, l y m p h o p e ni a  
+/ - i nf e cti o n s 
R ef er t o S e cti o n  6. 1 of t h e 
M 4 0 7 6 I B.  
E x cl u si o n of p arti ci p a nt s wit h i n s uffi ci e nt 
b o n e m arr o w f u n cti o n. R e g ul ar m o nit ori n g 
of l a b or at or y e v al u ati o n s f or h e m at ol o g y 
a n d vit al si g n s. C o nti n u o u s m o nit ori n g of 
A E s wit h cli ni c al m a n a g e m e nt a s 
i n di c at e d, i n cl u di n g st u d y i nt er v e nti o n 
i nt err u pti o n, d o s e m o difi c ati o n or 
di s c o nti n u ati o n.  
I n cr e a s e d h e art r at e 
R ef er t o S e cti o n 6. 1 of t h e 
M 4 0 7 6 I B.  
E x cl u si o n of s u bj e ct s wit h si g nifi c a nt 
c ar di a c c o n d u cti o n a b n or m aliti e s. R e g ul ar 
m o nit ori n g of E C G a n d vit al si g n s. 
C o nti n u o u s m o nit ori n g of a d v er s e e v e nt s 
wit h cli ni c al m a n a g e m e nt a s i n di c at e d, 
i n cl u di n g st u d y i nt er v e nti o n i nt err u pti o n, 
d o s e m o difi c ati o n or di s c o nti n u ati o n.  
Birt h d ef e ct s a n d a b orti o n s  
I n vitr o a n d i n vi v o g e n ot o xi cit y 
i n v e sti g ati o n s s h o w ed M 4 0 7 6 t o 
c a u s e g e n ot o xi cit y. R ef er t o 
S e cti o n  4. 3. 3 of M 4 0 7 6 I B.  
Stri ct c o ntr a c e pti o n f or p arti ci p a nt s a n d 
t h eir p art n er s a s i n cl u si o n crit eri a, d uri n g 
tr e at m e nt, a n d t h er e aft er 6 m o nt h s f or 
f e m al e s a n d 3 m o nt h s f or m al e s, i n cl u di n g 
r efr ai ni n g fr o m s p er m d o n ati o n s.  
Ri s k s a s s o ci at e d wit h dr u g -dr u g 
i nt er a cti o n s 
N o f or m al dr u g -dr u g i nt er a cti o n 
st u di e s h a v e b e e n c o n d u ct e d 
wit h M 4 0 7 6 i n h u m a n s.  
R ef er t o S e cti o n  4. 2. 9 of M 4 0 7 6 
I B. 
C o n c o mit a nt a d mi ni str ati o n wit h str o n g 
i n hi bit or s or i n d u c er s of C Y P 3 A 4 or 
P -gl y c o pr ot ei n a g e nt s i s pr o hi bit e d . 
C o n c o mit a nt a d mi ni str ati o n wit h s e n siti v e 
cli ni c al s u b str at e s of U G T 1 A 1 or P -g p, wit h 
p ot e nti all y n arr o w t h er a p e uti c i n d e x or 
k n o w n s af et y ri s k s ar e pr o hi bit e d, 
s p e cifi c all y iri n ot e c a n, di g o xi n, a n d or al 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
dir e ct t hr o m bi n i n hi bit or s. Cli ni c al 
s u b str at e s of C Y P 3 A 4 wit h n arr o w 
t h er a p e uti c i n d e x ar e pr o hi bit e d. Cli ni c al 
s e n siti v e s u b str at e s a n d m o d er at e 
i n hi bit or s of C Y P 3 A 4 s h o ul d b e a v oi d e d 
a n d if p er mitt e d, s h o ul d b e u s e d wit h 
c a uti o n.  
St u d y Pr o c e d ur e s  
A s s e s s m e nt  
S u m m ar y of D at a/ R ati o n al e f or 
Ri s k  
Miti g ati o n Str at e g y  
Bl o o d S a m pli n g  
Bl o o d s a m pli n g i s r e q uir e d f or 
p arti ci p a nt s a s d et ail e d i n t h e 
S c h e d ul e 
of 
A cti viti e s 
a n d i s 
c o n si d er e d 
e s s e nti al 
f or 
t h e 
st u d y’ s s ci e ntifi c o bj e cti v e s. Bl o o d 
s a m pli n g c arri e s a ri s k of A E s 
i n cl u di n g p ai n, br ui si n g, bl e e di n g, 
r e d n e s s 
a n d 
s w elli n g 
of t h e 
sit e/ v ei n, a n d i nf e cti o n.  
Mi ni mi z ati o n 
of 
bl o o d 
s a m pli n g 
w a s 
t h o u g htf ull y 
c o n si d er e d 
d uri n g 
pr ot o c ol 
d e v el o p m e nt w ei g hi n g ri s k t o p arti ci p a nt s 
v er s u s a c hi e v e m e nt of t h e st u d y’ s s ci e ntifi c 
o bj e cti v e s.  
T u m or bi o p si e s  
Fr e s h t u m or bi o p si e s ar e r e q uir e d 
f or s u b s et s of p arti ci p a nt s a s 
d et ail e d i n t h e 
S c h e d ul e 
of 
A cti viti e s a n d i n cl u si o n crit eri a 
a n d ar e c o n si d er e d e s s e nti al f or 
t h e st u d y’ s s ci e ntifi c o bj e cti v e s. 
Bi o p si e s c arr y 
a ri s k 
of 
A E s 
i n cl u di ng bl e e di n g a n d i nf e cti o n.  
I n v e sti g at or s ar e t o u s e cli ni c al j u d g e m e nt 
a n d n ot pr o c e e d wit h bi o p s y if hi g h ri s k of 
a d v er s e e v e nt s. Pr ot o c ol all o w s o mi s si o n of 
bi o p si e s if 
c o ntr ai n di c at e d f or 
m e di c al 
r e a s o n s ( s e e S e cti o n 8. 6 ). 
A E  =  a d v er s e e v e nt; C Y P = c yt o c hr o m e P; E C G  =  el e ctr o c ar di o gr a m; I B  =  i n v e sti g at or’ s br o c h ur e.  
2. 3. 2  
Be nefit Assess me nt   
Precli nical p har mac ol o g y d ata s h o w t h at M 4 0 7 6, a hi g hl y p ot e nt a n d sel ecti ve i n hi bit or of A T M, 
e x hi bits a ntica ncer acti vit y as a m o n ot hera p y i n a s u bset of ca ncer m o dels.  
2. 3. 3  
O ver a ll Be nefit: Ris k C o ncl usi o n  
Base d o n t he precli nic al e val uati o n f or t o xicit y, meas ures are ta ke n t o mi ni mize ris k t o partici pa nts 
i n t his st u d y. Gi ve n t he precli nical e v al uati o n f or p ote ntial efficac y a n d t o xicit y (see Secti o n  2. 1 ), 
t he c o n d uct of t his first-i n-h u ma n st u d y i n p atie nts wit h a d va nce d s oli d t u m ors f or w hic h n o 
sta n dar d of care e xists is j ustifie d. Cli nical safet y a n d t olera bilit y data will be re vie we d o n o n g oi n g 
basis a n d f urt h er ris k mi ni miz ati o n meas ures if re q uire d will be i m ple me nte d.  As per n e w cli nical 
data  fr o m t his st u d y ras h was c o nsi dere d as an  i d e ntifie d ris k a n d h y perse nsiti vit y as i m p orta nt 
p ote ntial ris k ( F or details refer t o Secti o n 6. 1 of t h e I B).  
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o n a bl y 
e x pecte d a d vers e e v e nts of  M 4 0 7 6 ma y b e f o u n d i n Secti o n 4. 3  a n d t he I B. 
Base d o n t he a v aila ble  n o ncli nical data t o date, t he c o n d uct of t he st u d y, as s p ecifie d i n t his 
pr ot oc ol, is c o nsi dere d j ustifia ble.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
3  
O bjecti v es a n d E sti m a n ds  
Ta ble  6  s u m marizes t he o bjecti ves  a n d esti ma n ds of t he st u d y. T he st atistical as pects of t he 
e n d p oi nts are o utli ne d i n Secti o n  9 . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
T a ble  6  
O bjecti ves a n d E sti m a n ds: M 4 0 7 6 
M o n ot her a p y D ose Esc al ati o n 
( P a rt 1 A) a n d Preli mi n ar y F o o d Effect Assess me nt ( P art  1 B )  
O bj e cti v e s  
E sti m a n d s attri b ut e s  
Pri m ar y  
T o d et er mi n e d o s e -t o xi cit y r el ati o n s hi p a n d M T D (if 
r e a c h e d) of M 4 0 7 6 m o n ot h er a p y i n p ati e nt s wit h 
a d v a n c e d s oli d t u m or s . 
E n d p oi nt s : 
•  
O c c urr e n c e of D o s e Li miti n g T o xi citi e s ( D L T s).  
•  
O c c urr e n c e of a d v er s e e v e nt s ( A E s) a n d 
tr e at m e nt-r el at e d A E s . 
•  
O c c urr e n c e of cli ni c all y si g nifi c a nt c h a n g e s i n vit al 
si g n s, l a b or at or y p ar a m et er s, a n d 1 2 -l e a d 
el e ctr o c ar di o gr a m ( E C G) fi n di n g s.  
 
Str at e g y f or h a n dli n g i nt er c urr e nt e v e nt s:   
F or D L T s:  
•  
Di s c o nti n u ati o n of tr e at m e nt ( >  2 0 % pl a n n e d 
tr e at m e nt mi s s e d d uri n g D L T p eri o d) t o pr e v e nt a 
D L T: c o m p o sit e str at e g y (t o b e c o n si d er e d a D L T) .  
•  
Di s c o nti n u ati o n tr e at me nt a d mi ni str ati o n s n ot d u e t o 
D L T or pr e v e nti n g a D L T ( > 2 0 % of pl a n n e d 
tr e at m e nt mi s s e d d uri n g D L T p eri o d): p arti ci p a nt n ot 
c o n si d er e d i n D L T a n al y si s . 
 
F or ot h er e n d p oi nt s:  
All a v ail a bl e d at a fr o m p arti ci p a nt s i n s af et y a n al y si s s et 
will b e u s e d.  
 
P o p ul ati o n:  
P a ti e nt s wit h a d v a n c e d s oli d tu m or s, w h o ar e i nt ol er a nt 
or h a v e n o eff e cti v e st a n d ar d t h er a pi e s a v ail a bl e t o 
t h e m. 
 
P o p ul ati o n l e v el s u m m ar y:  
•  
D L T pr o b a bilit y a s e sti m at e d u si n g B L R M a n d 
cr e di bilit y i nt er v al ( o nl y a p pli c a bl e f or D L T s).  
•  
St a n d ar d s u m m ar y st ati sti c s . 
S e c o n d ar y  
T o d et er mi n e t h e r e c o m m e n d e d d o s e f or e x p a n si o n 
( R D E) of M 4 0 7 6 m o n ot h er a p y i n p arti ci p a nt s wit h 
a d v a n c e d s oli d t u m or s . 
•  
I n a d diti o n t o s af et y a n d t ol er a bilit y, c h a n g e s fr o m 
b a s eli n e f or t h e f oll o wi n g P d bi o m ar k er s m a y b e 
c o n si d er e d f or d et er mi ni n g t h e R D E:  A T M p at h w a y 
r e a d o ut s s u c h a s, b ut n ot li mit e d t o, p-A T M, γ -H 2 A X  
a n d p -C H K 2 i n bl o o d a n d t u m or.  
•  
I n a d diti o n, p h ar m a c o ki n eti c ( P K) d at a will b e u s e d t o 
s u p p ort d et er mi n ati o n of t h e R D E . 
T o c h ar a ct eri z e t h e P K pr ofil e of M 4 0 7 6 m o n ot h er a p y i n 
p arti ci p a nt s wit h a d v a n c e d s oli d t u m or s . 
•  
P K p ar a m et er s of M 4 0 7 6 i n pl a s m a aft er si n gl e d o s e 
a n d m ulti pl e d o s e .  
•  
Uri n e P K p ar a m et er s ( e. g., r e n al cl e ar a n c e) will b e 
c h ar a ct eri z e d i n P art 1 B d at a p er mitt e d . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
O bj e cti v e s  
E sti m a n d s attri b ut e s  
T o e v al u at e pr eli mi n ar y cli ni c al a cti vit y p ar a m et er s of 
M 4 0 7 6 m o n ot h er a p y i n p arti ci p a nt s wit h a d v a n c e d s oli d 
t u m or s. 
E n d p oi nt s  
•  
O bj e cti v e r e s p o n s e ( O R) a c c or di n g t o R E CI S T  1. 1 
a s s e s s e d b y I n v e sti g at or . 
•  
D ur ati o n of r e s p o n s e ( D o R) a c c or di n g t o R E CI S T  1. 1 
a s s e s s e d b y I n v e sti g at or. 
•  
Pr o gr e s si o n Fr e e S ur vi v al ( P F S) a c c or di n g t o 
R E CI S T  1. 1 a s s e s s e d b y I n v e sti g at or . 
T o a s s e s s t h e eff e ct of f o o d o n t h e P K of M 4 0 7 6 
a d mi ni st er e d a s a si n gl e d o s e u n d er f e d/f a sti n g 
c o n diti o n s i n a c o h ort of p arti ci p a nt s wit h a d v a n c e d s oli d 
t u m or s at t h e R D E fr o m P art 1 A.  
E n d p oi nt s  
F e d/f a st e d r ati o of M 4 0 7 6 pl a s m a P K p ar a m et er s: 
A U C 0 --tl a st, A U C0 -∞ a n d, C m a x w h e n a d mi ni st er e d a s a 
si n gl e d o s e wit h or wit h o ut f o o d.  
T o a s s e s s c h a n g e s i n p h ar m a c o d y n a mi c m ar k er s of 
M 4 0 7 6 a cti vit y i n t u m or a n d bl o o d d uri n g M 4 0 7 6 
m o n ot h er a p y . 
E n d p oi nt s  
A b s ol ut e a n d r el ati v e c h a n g e s o v er ti m e fr o m b a s eli n e of 
A T M p at h w a y r e a d o ut s, s u c h a s, b ut n ot li mit e d t o 
p -A T M , p-C H K 2  a n d -H 2 A X.   
A E = a d v er s e e v e nt; A T M = at a xi a -t el a n gi e ct a si a m ut at e d; A U C = ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e; 
B L R M  =  B a y e si a n 2 -p ar a m et er L o gi sti c R e gr e s si o n M o d el; D L T = d o s e li miti n g t o xi cit y; D o R  =  d ur ati o n of 
r e s p o n s e; E C G = el e ctr o c ar di o gr a m; γ -H 2 A X = g a m m a hi st o n e f a mil y m e m b er X; M T D = m a xi m u m t ol er at e d d o s e; 
O R  =  o bj e cti v e r e s p o n s e; 
; p-A T M = p h o s p h or yl at e d at a xi a -t el a n gi e ct a si a m ut at e d; 
p -C H K 2 = c h e c k p oi nt ki n a s e 2 pr ot ei n; P F S = pr o gr e s si o n fr e e s ur vi 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 D E = r e c o m m e n d e d d o e f or e x p a n si o n.  
4  
St u d y Desi g n   
4. 1  
O ver all Desi g n   
T his is a n o pe n -la bel, m ultice nter, P hase 1 , cli nical st u d y of M 4 0 7 6 (see Ta ble  7 ).  
Part  1 A  is a M 4 0 7 6 m o n ot hera p y d ose escalati o n desi g ne d t o deter mi ne t h e safet y, t olera bilit y, 
P K, P d a n d earl y si g ns of efficac y i n partici pa nts wit h s oli d t u m ors. O nce a n R D E is declare d i n 
Part  1 A, a preli mi nar y f o o d effect c o h ort, Part  1 B, ma y  f oll o w a n d will be c o n d ucte d  at t he R D E 
or a l o wer d ose t ha n R D E  deter mi ne d fr o m Part  1 A.  Part  1 B is a ra n d o mize d, 2 -se q ue nce, 
2 -peri o d, cr oss -o ver desi g n.  
Gl o bal Versi o n I D: C CI
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
T a ble  7  
S u m m ar y of O ver all St u d y Desi g n   
St u d y P art  
P o p ul ati o n  
D e si g n  
St u d y 
I nt er v e nti o n 
P art  1 A  
All p a ti e nt s wit h a d v a n c e d 
s oli d t u m or s  
D o s e e s c al ati o n e nr olli n g p a ti e nt s i n s e q u e nti al 
c o h ort s at i n cr e a si n g d o s e l e v el s.  
M 4 0 7 6 
m o n ot h er a p y  
P art  1 B  
All p a ti e nt s wit h a d v a n c e d 
s oli d t u m or s  
O n c e a n  R D E i s d et er mi n e d  i n P art 1 A, a 
pr eli mi n ar y f o o d eff e ct a s s e s s m e nt will b e 
i n cl u d e d ( 2 ×  2 r a n d o mi z e d cr o s s o v er) . 
M 4 0 7 6 
m o n ot h er a p y  
R D E = r e c o m m e n d e d d o s e f or e x p a n si o n. 
In di vi d ual p artici pa nts will f oll o w st u d y pr oce d ures a n d ass ess me nts as s h o w n i n t he S c he d ule 
o f A ssess me nt i n Secti o n 1. 3 . Secti o n 1. 2  prese nts t he St u d y Sc h e ma f or t h e st u d y.  F or Part  1 A, 
p ote ntial variati o ns i n st u d y i nter ve nti o n sc he d ul es a n d sc he d ule of acti vities d ue t o alter nati ve 
d osi n g sc he d ul es are f o u n d i n  A p pe n di x  7 . 
D ur ati o n of St u d y:  
F or eac h partici pa nt i n P art 1 A, t he st u d y will i ncl u de a S cree ni n g peri o d l asti n g u p t o 2 8  d a ys . 
Partici pa nts will be treate d u ntil disease pr o gressi o n , deat h, or E n d of S t u d y. It is esti mate d t hat 
partici pa nts will be o n t h e st u d y f or a n a p pr o xi mate d urati o n of 1 0 5  da ys/ 1 5  wee ks. T h ere will 
als o be a n E n d of St u d y I nter ve nti o n Visit ( wit hi n 7  da ys aft er l ast d ose), a n d a Safet y F oll o w -u p 
peri o d of 3 0  da ys ( ± 7 d a ys) after t h e las t st u d y i nt er ve nti o n i nta ke.  
F or eac h partici pa nt i n Part 1 B, t he st u d y will i ncl u de a scree ni n g peri o d lasti n g u p t o 2 1  da ys, a 
preli mi nar y f o o d effect assess me nt of 7  d a ys f oll o we d b y st u d y i nter ve nti o n wit h 
M 4 0 7 6 
m o n ot hera p y u ntil diseas e pr o gressi o n o r e n d of st u d y. Fr o m Da y 5  o n war d, partici p a nts will 
c o nti n ue t o be treat e d as f or Part  1 A wit h sa me visits.  
Scree ni n g:  
Scree ni n g will be perf or me d wit hi n 2 8  da ys pri or t o Da y 1 of M 4 0 7 6 a d mi nistrati o n . If t here are 
n o cli nicall y si g nifica nt fi n di n gs d uri n g  Scree ni n g a n d t he i n di vi d ual 
meets all t he 
pr ot oc ol -defi ne d i n cl usi o n a n d n o ne of t he e x cl usi o n criteria, t he i n di vi d ual will be c o nsi dere d 
eli gi ble f or p artici pati o n i n t he st u d y. Scree ni n g f or t he ne xt c o h ort ma y  be p erf or me d bef ore t he 
S M C has ta ke n t he decisi o n o n t he ne xt d ose. T he eli gi ble p artici pa nts s cree n e d f or t h e ne xt 
c o h ort will, h o we ver, o nl y b e treate d after t he decisi o n f or t he ne xt c o h ort h as bee n t a ke n  b y t he 
S M C . 
I n di vi d uals w h o fail t o start st u d y i nter ve nti o n, f or i nsta nce d ue t o u n met pr ot oc ol -s pecifie d 
criteria or c o nse nt wit h dra wal, will be c o nsi dere d Scree ni n g Fail ures.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
St u d y I nter ve nti o n Peri o d:  
All partici pa nts will recei ve st u d y i nter ve nti o n u ntil disease pr o gressi o n (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 V ersi o n 1. 1 , see A p pe n di x  9 ), deat h, A E lea di n g t o 
disc o nti n uati o n of st u d y i nter ve nti o n(s), or wit h dra wal of c o ns e nt, w hic he v er occ urs first.  
F oll o w -u p:  
All partici pa nts are t o be f oll o we d u p after e n d of st u d y i nter ve nti o n, i ncl u di n g a n E n d of St u d y 
I nter ve nti o n Visit assess me nt  ( wit hi n 7 da ys of last d ose) . A Safet y F oll o w-u p Visit will occ ur 
3 0  ( ± 7) da ys after t he last d ose of M 4 0 7 6 f or all partici pa nts w h o disc o nti n ue d t he st u d y 
i nter ve nti o n per ma n e ntl y.  
See Secti o n  4. 3  f or E n d of St u d y defi niti o n.  
A ss u m pti o ns a n d pr ojecti o ns a b o ut t he li kel y d urati o n of t he st u d y i nter ve nti o n a n d effi cac y 
p hases are pr o vi de d i n Secti o n  9 . 
4. 1. 1  
P art 1 A –  M 4 0 7 6 M o n ot her a p y D ose Esc al ati o n   
Part  1 A of t he st u d y will defi ne t he M T D a n d/ or R D E of M 4 0 7 6 m o n ot hera p y i n partici pa nts 
wit h a d va nce d s oli d t u m ors f or w hic h n o sta n d ar d t hera p y is a vaila bl e.  
T he first d os e es calati o n c o h ort of 3  partici pa nts will recei ve M 4 0 7 6 m o n ot hera p y at t he starti n g 
d ose of 1 0 0  m g a d mi nistere d orall y  o nce dail y u n der fasti n g c o n diti o ns  (see Secti o n 6. 1  f or 
fasti n g wi n d o w i nf or m ati o n). F or f urt h er d ose escalati o n c o h orts, a n S M C will meet a n d re vie w 
all a vaila ble safet y, P K a n d P d data t o pr o vi de rec o m me n dati o ns o n t he D L  f or t he ne xt c o h ort. 
A Ba yesia n d ose -t o xicit y m o del (A p pe n di x  1 2 ) will assist t he S M C i n d ose rec o m me n d ati o ns. 
F or details of statistical c o nsi derati o ns, see Secti o n  9 .  
P ote ntial D L s are: 1 0 0 m g (starti n g d ose), 2 0 0 m g, 3 0 0 m g, 4 0 0 m g, 6 0 0  m g. A D L  of 5 0  m g 
will be e x pl ore d i n case t he starti n g d ose of 1 0 0  m g is n ot t olerate d. De pe n di n g o n t he o bser ve d 
t o xicit y pr ofile a n d a v aila ble P K a n d P d, t he S M C ma y deci de o n d oses differe nt t o, or hi g h er or 
l o wer fr o m w hat is pres p ecifie d. T he S M C ma y als o rec o m me n d c ha n gi n g t he d osi n g re gi me n 
t o e. g. t hri ce w ee kl y ( dail y d osi n g o n Da ys 1, 3, a n d 5 of eac h wee k), t wice wee kl y ( dail y d osi n g 
o n Da ys  1 a n d 4 of eac h wee k), a n d/ or sc h e d ules wit h h oli da ys fr o m  st u d y i nt er ve nti o n (e. g., 
3  da ys o n/ 4  da ys off, 7 da ys o n/ 1 4 da ys off, 1 4 d a ys o n/ 7 da ys off). M ore details o n t he S M C 
a n d d ose escalati o n ca n b e f o u n d i n Secti o n  6. 6. 1 . T he S M C o perati o nal det ails will be pr o vi de d 
i n a n S M C C harter, w hi c h will be esta blis he d pri or t o t he start of recr uit me nt. T he d etails will 
i ncl u de, b ut n ot li mite d t o S M C me m bers hi p, meeti n g fre q u e ncies, mi ni m u m re q uire m e nts f or 
dat a re vie w, a n d res p o nsi bilities.  
D ose escalati o n will pr ocee d acc or di n g t o S M C rec o m me n dati o n u ntil M T D a n d/ or a safe R D E 
is deter mi ne d a n d/ or t he S M C rec o m me n ds e n di n g d os e es calati o n. T h e M T D a n d R D E are 
defi ne d b y t he S M C. Tar get D L T pr o ba bilit y f or t he M T D deter mi nati o n is 3 0 %.  I n deter mi ni n g 
t he R D E, t he S M C will als o c o nsi der P K, P d a n d i nf or mati o n o n t he s afet y a n d t olera bilit y of 
t he st u d y i nter ve nti o n be y o n d t he D L T peri o d.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
At least 6  partici pa nts are re q uire d t o be treate d at t he M T D a n d/ or R D E.  
R D E ca n n ot e x cee d M T D. If s u g geste d R D E is b el o w M T D, d ose escalati o n will c o nti n ue u ntil 
M T D is reac h e d (if a p plica ble) or S M C deci des e n di n g d ose escalati o n.  
At t he discreti o n of t he S M C, if t he t o xicit y a n d t ol era bilit y pr ofile of M 4 0 7 6 re mai ns a m bi g u o us 
at a n y D L , i ncl u di n g t he M T D or if a d diti o nal P K/ P d data are felt necess ar y at a n y D L  bel o w 
t he 
M T D, a d diti o nal partici pa nts ma y b e st u die d at t hat D L  t o better defi ne t he t o xicit y, 
t olera bilit y, P K, a n d P d. T he st u d y pr oce d ures f or t hese a d diti o nal partici p a nt(s)/c o h ort(s) will 
be t he sa me as t h at s pecifie d f or ot her st u d y partici pa nts/c o h orts.  
T his st u d y p art will als o i n vesti gate t he p har mac o d y n a mics of M 4 0 7 6 as a s ec o n dar y o bjecti ve. 
Paire d t u m or bi o psies ( o pti o nal) a n d serial bl o o d sa m ples ( ma n dat or y) will be c ollecte d t o 
e val uate mar kers of A T M i n hi biti o n.  
If n ecess ar y, t he Sc he d ul e of Acti vities  will be a dj uste d, e. g. t o e ns ure t hat P K a n d P d sa m ples 
are c ollecte d at t he a p pr o priate ti me p oi nts.  
O nce t he M T D a n d/ or R D E is deter mi ne d i n Part 1 A, t h e R D E fr o m Part 1 A will be use d f or t he 
f o o d effect c o h ort i n Part 1 B.  
I ntr a partici p a nt D ose Escalati o n: N o i ntra p artici pa nt d ose es calati o n is all o we d. H o we ver, u p o n 
declarati o n of safet y a n d t olera bilit y of t he M T D or R D E b y t he S M C, partici pa nts w h o are still 
recei vi n g o n g oi n g st u d y i nter ve nti o n at d oses l o wer t ha n t he R D E ma y b e s witc he d t o t he R D E 
if partici pa nts ha ve n ot e x perie nce d a n y tr eat me nt -e mer ge nt relate d A Es greater t ha n  Gra d e  1.  
4. 1. 2  
P art  1 B –  Preli mi n ar y F o o d Effect Assess me nt   
Part  1 B ma y b e gi n e nr olli n g o nce t he M T D or R D E is defi ne d i n Part  1 A a n d will f oll o w a 
ra n d o mize d, 2-se q ue n ce, 2-peri o d, cr oss -o ver d esi g n wit h a t ar get s a m ple si ze of 1 2  partici pa nts. 
Partici pa nts will be ra n d o mize d b y t he I nt eracti ve ( p h o ne a n d we b) Res p o ns e S yste m (I X R S) t o 
1 of 2 se q ue n ces. All o cati o n assi g n me nt will be d o ne o n a 1: 1 b asis: ( 1) faste d f oll o we d b y fe d, 
or ( 2) fe d f oll o we d b y faste d.   
Partici pa nts will visit t he cli nic fr o m Da y  -7 t o Da y -4 d uri n g w hic h t he y will recei ve a si n gl e 
M 4 0 7 6 d ose wit h P K sa m ples c ollecte d as o utli ne d i n Ta ble  2 . Partici pa nts will recei ve a n ot her 
d ose o n Da y  1 t o e ns ure a n a p pr o xi mate o ne -wee k was h o ut peri o d bet w ee n a d mi nistrati o ns. 
O nce t he P K of M 4 0 7 6 is c haracterize d, t he mi ni m u m was h o ut peri o d ma y b e c h a n ge d t o 
5  half -li ves at t h e discreti o n of t he S p o ns or, if warra nte d. T he fe d meal c o n diti o n is pla n ne d t o 
be a sta n dar d l o w -fat me al (see A p pe n di x  8 ). P K sa m ples will be c ollecte d f or b ot h fe d a n d faste d 
st u d y i nter ve nti o ns. Tri plicate E C G sa m ples will be c ollecte d o nl y f or parti ci pa nts d ose d i n t he 
faste d state (see Secti o n 6. 1 f or details re gar di n g t he fasti n g wi n d o w). A d diti o nall y, if t he 
half -life of M 4 0 7 6 is s u bsta ntiall y l o n ger t ha n ori gi nall y pre dicte d, t he P K sa m pli n g ti me p oi nts 
after t he first d ose o n Da y  -7 ma y be a dj uste d, as descri be d i n t he Sc he d ule of Acti vities 
(Secti o n  1. 3. 2 ). 
T he S M C will c o nti n ue t o m o nit or t he safet y of M 4 0 7 6 a n d ma y rec o m me n d c o nti n ui n g at t he 
sa me d ose, c ha n ge t he d ose ( n ot hi g her t ha n 
M T D defi ne d i n Part  1 A), or st o p Part  1 B. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
U nacce pta ble t o xicit y f or Part  1 B will be A Es t hat f ulfil l t he D L T criteria (as defi n e d i n 
Secti o n  6. 6 ) re gar dl ess of w he n t he y occ ur d uri n g treat me nt. A d verse e v e nts will be c ollecte d 
a n d re p orte d i n si mila r m a n ner t o Part 1 A of t h e st u d y. T he S M C d ecisi o ns i n Part  1 B will als o 
be s u p p orte d b y a Ba yesia n M o del.  Refer t o Secti o n  9. 4. 4  f or details.  
T he P d of M 4 0 7 6 will als o be i n vesti gate d i n Part  1 B . Paire d t u m or bi o psies a n d serial peri p heral 
bl o o d m o n o n uclear cells sa m ples will be c ollecte d t o e val u ate mar kers of A T M act i vati o n a n d 
i n hi biti o n, as well as of D N A d a ma ge. T he c ollecti o n of p aire d t u m or bi o psies is ma n dat or y, 
u nless c o ntrai n dicate d f or me dical reas o ns. If i ns ufficie nt paire d t u m or bi o psies are o btai ne d, 
a d diti o nal partici pa nts c o nse nti n g t o pr o vi d e paire d t u m or bi o psies ma y b e a d d e d at t h e 
discreti o n of t he S p o ns or.  
If necessar y, t he Sc he d ul e of A cti vities  will be a dj uste d, e. g., t o e ns ure t hat P K a n d P d sa m ples 
are c ollecte d at t he a p pr o priate ti me p oi nts.  
After c o m pleti o n of t he Part 1 B assess me nts, partici p a nts will c o nti n ue t o be tr eate d u n der t h e 
sa me sc he d ule as partici p a nts i n t he d ose escal ati o n c o h orts of Part 1 A starti n g fr o m D a y  5 .  
Base d o n t he res ults of Part 1 B ass ess me nts, fasti n g restricti o ns ma y b e m o difie d f or re m ai ni n g 
a n d a d diti o nal st u d y pa rtici pa nts i n s o me or all st u d y parts at t he discreti o n of t he S M C. 
4. 2  
J ustific ati o n f or D ose   
T he starti n g d ose of 
M 4 0 7 6 f or t h is first-i n-h u ma n st u d y was det er mi ne d base d o n t he 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) G ui deli ne S 9 ‘ N o ncli nical E val uati o n f or 
A ntica ncer P har mace uticals’ ( 2 0 0 9) 
t he F D A g ui da nce ( F o o d a n d 
Dr u g a d mi nistrati o n: 
G ui da nce f or I n d ustr y: Esti mati n g t he Ma xi m u m Safe Starti n g D ose i n i nitial Cli nical Tri als f or 
T hera p e utics i n A d ult Healt h y V ol u nteers, 2 0 0 5) a n d t o o k i nt o c o nsi derati o n t he se verel y t o xic 
d ose ( S T D) a n d hi g hest n o n -S T D  as well as t he pre di cte d h u ma n e x p os ure a n d t he 
P K/ p har mac o d y na mic m o deli n g of t he pre dict e d p har mac ol o gical acti ve d ose ra n ge i n h u ma ns. 
C o m plete d G o o d La b orat or y Practice 4 -wee k re peat -d os e t o xicit y st u dies i n rats a n d d o gs 
s u p p ort t he calc ulati o n of t he starti n g d ose. A p pl yi n g t he c o m m o n a p pr oac h of a 1 0 -f ol d safet y 
mar gi n t o t he S T D 1 0 ( >  1 0 0  m g/ k g/ da y) i n rats ( m ost se ns iti ve s pecies) it c orres p o n ds t o a 
h u ma n e q ui vale nt d ose of 9 6  m g per da y ( G ui da nce I C H S 9 2 0 1 0); ass u mi n g 6 0  k g b o d y wei g ht 
a n d b o d y s urface area c orrecti o n, w hic h h as bee n r o u n de d t o 1 0 0  m g.  
At t he 1 0 0  m g 
M 4 0 7 6 d ose, u n b o u n d A U C m ulti ples ( o bser ve d t o xi c o ki netic e x p os ure/ 
pre dicte d h u ma n e x p os ure rati o) of a p pr o xi matel y 3. 0 a n d 1. 5 relati ve t o t h e t o xic d ose i n 1 0 % 
of t he a ni mals i n rat a n d hi g hest n o n -se verel y t o xic d ose ( n o n-S T D) i n d o g, res p ecti vel y, are 
e x pecte d base d o n t he pre dicte d h u ma n P K. U n b o u n d C ma x  m ulti ples of a p pr o xi matel y 6. 0 a n d 
5. 5  relati ve t o t he t o xic d ose i n 1 0 % of t he a ni mals i n rat a n d hi g hest n o n-s e verel y t o xic d ose i n 
d o g, res pecti vel y, are esti mate d base d o n t he pre dicte d h u ma n P K. T he fi n di n gs of pri mar y 
i nterest i n t he re peat dose t o xicit y st u dies i n esta blis hi n g t he starti n g d ose were i ncreas e d heart 
rate a n d l y m p h atic a n d he mat ol o gical t o xicit y. Base d o n t he nat ure of t hese fi n di n gs a n d t heir 
a bilit y t o be m o nit or e d cli nicall y, t he pr o p ose d e x p os ure mar gi ns were c o nsi dere d acc e pta ble i n 
t he i nterest of mi ni mizi n g t he e x p os ure of partici p a nts t o p ote ntiall y i neffecti ve t hera p y. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Base d o n precli nical i n vi v o st u dies i n setti n gs rele va nt t o p har m ac ol o gicall y e val uat e t he 
s pecific effect of a n A T M i n hi bit or, M 4 0 7 6 is e x pecte d t o be p har mac ol o gicall y acti ve at t he 
starti n g d ose of 1 0 0 m g.  
Part 1 B (t he preli mi nar y f o o d effect ass ess me nt) will be c o n d ucte d wit h t w o si n gle d oses of 
M 4 0 7 6 of t he s a me a m o u nt. T he d ose of M 4 0 7 6 t o be a d mi nistere d is pla n ne d t o be t he R D E, 
alt h o u g h a l o w er d ose m a y b e use d at t he discreti o n of t he S M C. Base d o n n o ncli nical data a n d 
pre dicte d hi g h d e gree of a bs or pti o n t hat is e x pecte d t o be d ose -li near u p t o 6 0 0 m g, a cli nicall y 
rele va nt f o o d effect is n ot a ntici pate d. Base d o n n o ncli nical re p eat d ose t o xicity a n d 
p har mac o ki netic st u dies of M 4 0 7 6, i ncrease d e x p os ure as a res ult of c oa d mi nistrati o n wit h f o o d 
f or a si n gle d ose is n ot e x pecte d t o s u bsta ntiall y alter t he ris k.  
See Secti o n  6. 6  f or i nf or mati o n o n d ose selecti o n a n d m o dificati o ns. 
4. 3  
Scie ntific R ati o n ale f or St u d y Desi g n   
T he P hase 1 , d ose-escalati o n st u d y is desi g ne d t o esta blis h a safe a n d t olera ble d ose of M 4 0 7 6 
m o n ot hera p y ( Part 1 A) a n d t o i n vesti gate P K, P d, a n d earl y si g ns of efficac y i n p artici pa nts wit h 
a d va nce d s oli d t u m ors f or w hic h n o sta n dar d t hera p y is a vaila bl e.  
Rati o nale f or t he cr oss o ver desi g n f or t h e pre li mi nar y f o o d effect assess me nt ( Part 1 B): T he 
2 -se q ue nce cr oss o ver d esi g n, as c o m pare d t o a n alter nati ve parallel desi g n, mi ni mizes t he 
n u m ber of st u d y partici pa nts re q uir e d t o i de ntif y t he effect of f o o d o n t he P K of M 4 0 7 6 si nce 
eac h p artici pa nt ser ves as t heir o w n c o ntr ol. T he select e d was h o ut peri o d will s ufficie ntl y 
re m o ve M 4 0 7 6 fr o m t he s yste mic cir c ulati o n t o eli mi nate t he ris k of carr y o v er effects w hic h ca n 
be deleteri o us t o t he st u d y’s o utc o m e a n d i nter pretati o n.  
Partici pa nt i n v ol ve me nt i n de vel o p me nt of t he st u d y desi g n was n ot s o u g ht.  
4. 4  
E n d of St u d y Defi niti o n   
E n d of St u d y f or a n I n di vi d ual Partici pa nt:  A partici pa nt has c o m plete d t h e st u d y if he/s he h as 
c o m plete d all st u d y parts, i ncl u di n g E n d of St u d y I nter ve nti o n Visit  a n d Safet y F oll o w -u p Visit  
(see Secti o n 1. 3 ) or o ne of t he f oll o wi n g criteri a a p plies: 
•  Wit h dra wal of c o nse nt t o st u d y  
•  L ost t o F oll o w -u p  
•  Die d  
All partici pa nts w h o d o n ot f ulfil o ne of t he pri or t hree criteria s h o ul d b e f oll o we d u ntil t he last 
partici pa nt has c o m plete d t he Safet y F oll o w -u p Visit or tra nsferre d t o st u d y i nter ve nti o n access 
o uts i de of t his st u d y. 
E n d of St u d y O v erall:  T he e n d of t he st u d y is defi ne d as t he date of c o m pleti o n  of st u d y 
i nter ve nti o n b y all parti ci pa nts a n d all re q uire d st u d y acti vities/ visits (i ncl u di n g t he Safet y 
F oll o w -u p Visit).  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
P ost  St u d y I nter ve nti o n f or a n I n di vi d ual Partici pa nt:  After t he o bjecti ves of t he st u d y are 
ac hie ve d p artici pa nts recei vi n g o n g oi n g st u d y i nt er ve nti o n ma y b e offere d t he i n vesti gati o nal 
dr u g  o utsi de of t his st u d y u n der o bser vati o n of l ocal re g ulati o ns.  
T he S p o ns or ma y ter mi nate t he st u d y at a n y ti me o nce access t o st u d y i nter ve nti o n f or 
partici pa nts still be nefiti n g is pr o visi o ne d via a r oll o ver st u d y, e x pa n d e d access, mar ket e d 
pr o d uct or a n ot her mec h a nis m of access , as a p pr o priate.  
5  
St u d y P o p ul ati o n   
T he criteria i n Secti o n s 5. 1  a n d 5. 2  are desi g ne d t o e nr oll o nl y partici p a nts, w h o are a p pr o pri ate 
f or t he st u d y; t here b y, e ns uri n g t he st u d y f ulfills its o bjecti ves. All rele va nt me dical a n d 
n o n me dical c o n diti o ns are c o nsi der e d w he n deci di n g w het her a partici p a nt is s uita ble f or t his 
st u d y. 
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e x cl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
Bef ore perf or mi n g a n y st u d y assess me nts t hat are n ot  part of t he partici pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will c o nfir m t hat t he partici pa nt or t he partici pa nt’s le gal re pres e ntati ve 
(w here all o we d b y l oc al la ws a n d re g ulati o ns) has pr o vi de d writte n i nf or me d c o nse nt, as 
i n dicate d i n A p pe n di x  2 . 
5. 1  
I ncl usi o n Criteri a  
T he f oll o wi n g criteri a a p pl y f or Part 1 A a n d 1 B of t his st u d y.  
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:  
A ge  
1.  Are  ≥ 1 8  years of a ge at t he ti me of si g ni n g t he i nf or me d c o nse nt.  
T y pe of P artici p a nt a n d Dise ase C h ar acteristi cs  (i ncl u di n g or g a n f u ncti o n) 
2.  Pa tie nts wit h a d va nce d s oli d t u m ors, f or w h o m n o sta n dar d of care t hera p y e xists or f or 
w h o m is n ot c o nsi dere d s ufficie ntl y effecti ve, or w h o ca n n ot t olerate st a n dar d of care. 
3.  Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce stat us 0 or 1 . 
4.  A de q uate h e mat ol o gi cal f u ncti o n defi ne d b y  a bs ol ute ne utr o p hil c o u nt, ≥ 1. 5 ×  1 0 9/ L, 
platelet c o u nt ≥ 1 0 0  ×  1 0 9/ L, a n d h e m o gl o bi n ≥ 9 g/ d L, a n d wit h o ut gr o wt h fact or treat me nt 
or bl o o d tra nsf usi o n wit hi n 2 wee ks bef ore t he st u d y i nter ve nti o n start.  
5.  A de q uate h e patic f u ncti o n defi ne d b y  t otal bilir u bi n le vel ≤ 1. 5 × u p per li mit of n or mal 
( U L N), as partate a mi n otr a nsferase le vel ≤ 3 × U L N, a n d a n ala ni ne a mi n otra nsferase ( A L T) 
le vel ≤ 3 × U L N. F or pati e nts wit h li ver metastases, as partate a mi n otra nsferase  ≤ 5. 0 × U L N, 
A L T  ≤ 5. 0 × U L N, a n d t otal bilir u bi n ≤ 3. 0 × U L N is acce pta ble.  F or patie nt s wit h Gil bert’s 
disease, t otal bilir u bi n ≤ 2. 0 m g/ d L or direct bilir u bi n ≤ 1 × U L N is acce pta ble.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
6.  A de q uate re n al f u ncti o n defi ne d b y a n esti mate d gl o mer ular filtrati o n rate >  6 0  m L/ mi n 
acc or di n g t o t he C oc kcr oft -Ga ult e q uati o n:  (G l o mer ular filtrati o n rate =  { (( 1 4 0– a ge) x 
wei g ht)/( 7 2 x S Cr) }  x 0. 8 5 (if fe male) . 
7.  Partici pa nts i n Part 1 B (t he preli mi nar y f o o d effect assess me nt) m ust a gree t o pr o vi de paire d 
t u m or bi o psies if n ot c o ntrai n dicate d f or me dical r eas o ns.  
Se x  
8.  Are m ale a n d/ or fe m ale  
9.  C o ntrace pti ve us e b y 
males or fe males will be c o nsiste nt wit h l ocal re g ulati o ns o n 
c o ntrace pti o n met h o ds f or t h ose partici pati n g i n cli nical st u dies.  
Male partici pa nts:  
A gree t o t he f oll o wi n g d uri n g t h e st u d y i nter ve nti o n peri o d a n d f or at l east 3  m o nt hs  after 
t he last d ose of st u d y i nter ve nti o n: 
•  Refrai n fr o m d o n ati n g s p er m.  
P L U S, eit her:  
•  A bstai n fr o m a n y acti vit y t hat all o ws f or e x p os ure t o ejac ulate.  
O R  
•  Use a male c o n d o m:  
W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial ( W O C B P) 
a n d a d vise her t o use a hi g hl y-effecti ve c o ntrace pti ve met h o d wit h a fail ure rate of 
<  1 % per year, as des cri b e d i n A p pe n di x  3  si nce a c o n d o m ma y brea k or lea k. 
W he n e n ga gi n g i n a n y acti vit y t hat all o ws f or e x p os ure t o ejac ulate t o a n ot her pers o n.  
•  Male partici pa nts m ust use a male c o n d o m wit h pre g na nt fe m ale part ners d uri n g t he 
st u d y. 
Fe male p artici pa nts:  
Are n ot pre g n a nt or breastfee di n g, a n d at least 1 of t he f oll o wi n g c o n diti o ns a p plies:  
•  N ot a W O C B P  
O R  
•  If a W O C B P, use a hi g hl y effecti ve c o ntrace pti ve met h o d (i.e., wit h a fail ure rate of 
<  1 % per year), prefera bl y wit h l o w user de p e n de n c y, as des cri be d i n A p pe n di x  3  f or 
t he f oll o wi n g ti me peri o ds: 
o  Bef ore t he first d ose of t h e st u d y i nter ve nti o n(s), if usi n g h or m o nal c o ntr ace pti o n: 
▪ Has c o m plete d at least o ne 4 -wee k c ycl e of a n oral c o ntrace pti o n pill a n d 
eit her ha d or has be g u n h er me nses  
O R  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
▪ Has use d a d e p ot c o ntrace pti ve or e xte n de d  c ycl e oral c o ntrace pti ve f or at 
least 2 8 da ys a n d has a d oc u me nte d ne gati ve pre g na nc y test usi n g a hi g hl y 
se nsiti ve assa y. 
o  D uri n g t h e i nter ve nti o n p eri o d  
o  After t he st u d y i nter ve nti o n peri o d (i.e., after t he l ast d ose of st u d y i nter ve nti o n 
is a d mi nistere d) f or at least 6  m o nt hs  after t he last d ose  of st u d y i nter ve nti o n a n d 
a gree n ot t o d o nat e e g gs ( o va, o oc ytes) f or re pr o d ucti o n d uri n g t his peri o d  
T he I n vesti gat or e v al uat es t he effecti ve ness of t h e c o ntrace pti ve met h o d i n relati o ns hi p t o t he 
first d ose of st u d y i nter ve nti o n 
o  Ha ve a ne gati ve uri n e pr e g na nc y test, as re q uir e d b y l o cal re g ulati o ns, wit hi n 
2 4  h o urs bef ore t he first d ose of st u d y i nter ve nti o n  
o  W o me n s h o ul d n ot breastfee d d uri n g t he st u d y a n d f or at least 1  m o nt h after t h e 
st u d y peri o d, (i.e., aft er t he last d ose of st u d y i nter ve nti o n is a dmi nistere d).  
A d diti o nal re q uire m e nts f or pre g n a nc y t esti n g d uri n g a n d after st u d y i nter ve nti o n are i n 
Secti o n  8. 3. 5 .  
T he I n vesti gat or re vie ws t he me dical hist or y, me nstr ual hist or y, a n d rece nt se x ual acti vit y t o 
decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y u n detecte d pre g na nc y.  
I nf or me d C o nse nt 
1 0.  Ca pa ble of gi vi n g  si g n e d i nf or me d c o nse nt, as i n dicate d i n A p pe n di x  2 , w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m (I C F) 
a n d t his pr ot oc ol.  
5. 2  
E xcl usi o n Criteri a   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
Me dic al C o n diti o ns  
1.  Cli nicall y si g nifica nt (i.e., acti ve) u nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d 
t o: 
•  A cti ve i nfecti o n (i. e., re q uiri n g s yste mic a nti bi otics  or a ntif u n gals ) 
•  U nc o ntr olle d arteri al h y perte nsi o n (i.e., s yst olic bl o o d press ure  > 1 5 0  m m H g, diast olic 
bl o o d press ure  >  1 0 0  m m H g)  
•  S y m pt o matic c o n gesti ve heart fail ure ( ≥ Ne w Y or k Heart Ass ociati o n Classificati o n 
Class  II), u nsta ble a n gi na, 
m y o car dial i nfarcti o n or a c or o nar y re v asc ularizati o n 
pr oce d ure wit hi n 1 8 0  da ys of st u d y e ntr y  
•  Calc ulate d a v era ge 
Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula ( Q Tc F ) of 
>  4 5 0  msec f or males a n d >  4 7 0 msec f or fe mal es.  
•  A hist or y of a d diti o nal ris k fact ors f or T orsa d es de P oi ntes (e. g., cli nicall y rele va nt 
h y p o kal e mia, fa mil y hist or y of L o n g Q T S y n dr o me)  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  T he use of c o nc o mita nt me dicati o ns t hat pr ol o n g t he Q T/ Q Tc i nter val  
•  Se vere car diac arr h yt h mia re q uiri n g me dicati o n  
•  Cere bral v asc ular acci de nt/ str o ke 
•  Cli nicall y si g nifica nt li ver di sease c o nsiste nt wit h C hil d P u g h Class B or C; a n d/ or 
•  A n y ps yc hiatric ill ness/s ocial sit uati o ns t hat 
w o ul d li mit c o m plia nce 
wit h st u d y 
re q uire me nts.  
2.  Prese nce of brai n metast ases u nless cli nicall y sta ble ( wit h o ut e vi de nce of pr o gressi o n b y 
i ma gi n g f or at least f o ur wee ks pri or t o t h e first d ose of st u d y i nt er ve nti o n a n d a n y ne ur ol o gic 
s y m pt o ms ha ve ret ur ne d t o baseli ne), n o e vi de nce of ne w brai n metastas es, a n d o n a sta bl e 
or decreasi n g d ose or wit h o ut ster oi ds f or at l east 1 4  da ys pri or t o st u d y i nter ve nti o n. 
Partici pa nts wit h carci n o mat o us me ni n gitis are e x cl u de d re gar dless of cli nical sta bilit y. 
Ce ntral ner v o us s yste m  i ma gi n g at Scree ni n g is n ot ma n dat or y. 
3.  Has a k n o w n a d diti o nal mali g na n c y t hat is pr o gressi n g a n d/ or re q uires acti ve treat me nt. I n 
a d diti o n,  partici pa nts are e x cl u de d w h o were dia g n ose d wit h a n ot her mali g na nc y wit hi n 
3  years of starti n g st u d y i nter ve nti o n. E x ce pti o ns i ncl u de f ull y res ecte d bas al cell carci n o m a 
of t he s ki n or s q ua m o us cell carci n o ma of t he s ki n, i n sit u cer vical ca n cer, f ull y r esecte d 
d uctal carci n o ma i n sit u, a n d S ta ge I A n o ni n vasi v e gra d e I e n d o metri oi d e n d o metrial ca ncer, 
t hat has u n der g o ne c urati ve t hera p y. Partici pa nts wit h ot her l ocalize d mali g na n cies treate d 
wit h c urati ve i nte nt nee d t o be disc usse d wit h t he Me dical M o nit or. Partici pa nt m ust n ot ha ve 
a n y k n o w n hist or y of m yel o d ys plastic s y n dr o m e or ac ute m yel oi d le u ke mia.  
4.  Has k n o w n ata xia tela n gi ectasia  
5.  Pa rtici pa nts wit h  t u m ors har b ori n g pre vi o usl y i de ntifie d A T M m utati o ns  
6.  I n di vi d uals wit h k n o w n h u ma n i m m u n o deficie nc y vir us a n d/ or acti ve viral he patitis ( B 
a n d/ or C), a n d i n di vi d uals o n  viral h e patitis B t hera p y  are e x cl u de d. H o we ver, i n di vi d ual 
wit h He patitis C treate d wit h c urati ve t hera p y are n ot c o nsi dere d acti vel y i nfecte d.  
7.  Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, a n d/ or la b orat or y a b n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he trial, i nterfere wit h t he partici p a nt’s partici pati o n f or 
t he f ull d urati o n of t he tri al, a n d/ or is n ot i n t he best i nterest of t he partici pa nt t o partici pate, 
i n t he o pi ni o n of t he treati n g i n vesti gat or.  
G astr oi ntesti n al C o n diti o ns  
8.  Seri o us gastr oi ntesti nal blee di n g 
wit hi n 3  m o nt hs, refract or y n a usea a n d v o miti n g, 
u nc o ntr olle d diarr hea, k n o w n mala bs or pti o n, si g nifica nt s mall b o wel res ecti o n or gastric 
b y pass s ur ger y, us e of fee di n g t u bes, ot her c hr o nic gastr oi ntesti nal disease (i n cl u di n g 
e x ocri ne pa ncreatic i ns ufficie nc y re q uiri n g pa n creatic e nz y me re pl ace me nt t hera p y) a n d/ or 
ot her sit uati o n t hat ma y precl u de a de q uat e a bs or pti o n of oral me dicati o ns  
Pri o r/ C o nc o mit a nt T her a p y  
9.  Partici pa nts w h o ma y ha ve recei v e d a n y of t he f oll o wi n g a ntica ncer t hera p y(i es) , or 
c o nc o mita nt me dicati o ns wit hi n t he f oll o wi n g wi n d o ws per t he first d a y of st u d y i nter ve nti o n 
a d mi nistrati o n:  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  He mat o p oietic gr o wt h fact ors (i ncl u di n g er yt hr o p oieti n, dar be p oeti n, gra n ul oc yte -c ol o n y 
sti m ulati n g fact or, gra n ul oc yte 
macr o p ha ge-c ol o n y sti m ulati n g fact or, a n d plat elet 
sti m ulat ors [e. g. eltr o m b o pa g, r o mi pl osti m, or I L-1 1] ) a n d bl o o d tra nsf usi o ns wit hi n 
2  wee ks.  
•  A ntica ncer treat me nt wit hi n 2 8  da ys or 5  h alf -li ves, w hic he v er is s h orter, e x ce pt f or 
nitr os o ureas or mit o m yci n C ( wit hi n 6  wee ks).  
•  Partici pa nts recei vi n g pri or treat me nt wit h a n A T M i n hi bit or. 
•  Pri or c urati ve -i nte nt ra di ot hera p y 
wit hi n 4 wee ks. Pri or palliati ve ra di ot hera p y t o 
metastatic lesi o n(s) is per mitte d pr o vi de d it was c o m plete d >  2  wee ks pri or t o st u d y 
e nr oll me nt a n d t o xicities ha ve rec o vere d t o Gra de ≤ 1.  
•  Maj or s ur ger y wit hi n 4  wee ks a n d n ot rec o v ere d f or si de effects Gra d e ≤ 1, acc or di n g t o 
i n vesti gat or’s j u d g me nt. 
•  A n y ot her t y pe of a ntica n cer t hera p y, n ot liste d a b o ve, wit hi n 4 wee ks.  
•  Cli nical s u bstrates of C Y P 3 A 4 wit h narr o w t hera p e utic i n de x . St o p at least 1 wee k bef ore 
st u d y i nter ve nti o n u ntil safet y f oll o w-u p visit.  
•  Str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4 or P -g p t hat ca n n ot b e disc o nti n u e d  as o utli ne d 
i n Secti o n 6. 5. 3 . E x a m ples of str o n g i n hi bit ors of C Y P 3 A 4 a n d P -g p i n hi bit ors or str o n g 
i n d ucers of C Y P 3 A are pr o vi de d i n Ta ble  9 . 
•  A d diti o nal e x cl u de d c o n c o mita nt me dicati o ns i n cl u de iri n oteca n, oral direct t hr o m bi n 
i n hi bit ors, a n d di g o xi n. St o p at least 1 wee k bef ore st u d y i nter ve nti o n u n til safet y 
f oll o w-u p visit . 
•  C o nc o mita nt treat me nt wit h pr ot o n p u m p i n hi bit ors is pr o hi bite d. T h e a d mi nistrati o n of 
H 2-rece pt or a nta g o nists will be per mitte d as l o n g as t he y are n ot a d mi nistere d f or 1 2 h o urs 
bef ore or 2 h o urs after t he d osi n g of M 4 0 7 6. A nta ci ds ca n n ot be a d mi nistere d 2 h o urs 
bef ore or 2 h o urs after t h e d osi n g of M 4 0 7 6.  
1 0.  Partici pa nts n ot rec o vere d fr o m A Es (i. e., Gra de ≤ 1) of pri or a ntica ncer t hera pies. 
E x ce pti o n: Gra de  2 A Es n ot c o nstit uti n g a safet y ris k, base d o n t he I n vesti gat or’s j u d ge m e nt, 
m ust be c o ns ulte d wit h t he S p o ns or pri or t o e nr ol me nt . 
Pri o r/ C o nc urre nt Cli nic al St u d y E x perie nce  
1 1.  Is c urre ntl y partici pati n g a n d recei vi n g st u d y t hera p y or has partici pate d i n a st u d y of a n 
i n vesti gati o nal a ge nt a n d recei v e d st u d y t hera p y a n d/ or use d a n i n vesti gati o n al de vice wit hi n 
4  wee ks of t he first M 4 0 7 6 a d mi nistrati o n  of st u d y i nter ve nti o n or l o n g er if descri be d 
else w here.  
1 2.  H y p erse nsiti vit y t o t he acti ve s u bsta nce or t o a n y of t he e x ci pie nts of M 4 0 7 6.  
Ot her E xcl usi o ns  
1 3.  Pre g n a nt or breastfee di n g.  
1 4.  Part 1 B o nl y (f o o d effect c o h ort): partici pa nts u na ble t o c o ns u me a l o w -fat meal as s pecifi e d 
i n A p pe n di x  8 . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
5. 3  
Lifest yle C o nsi der ati o ns   
N o s pecific lifest yle or di etar y restricti o ns are re q uire d t hr o u g h o ut t he st u d y. T o bacc o use  stat us, 
e. g., f or mer, c urrent or n e ver , will be c ollecte d at scree ni n g a n d rec or de d i n t he eC R F.   
Refer t o A p pe n di x  8  f or ti mi n g of meals i n Parts 1 A a n d 1 B.  
5. 4  
Scree n F ail ures   
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y b e 
rescree ne d o n ce  after t he reas o n f or scree ni n g fail ure has bee n a d dresse d. Rescree n e d 
partici pa nts will be rec o nse nte d a n d assi g n e d a ne w partici pa nt n u m ber a n d will u n der g o 
Scree ni n g pr oce d ures as pla n ne d b y t he pr ot oc ol.  A n y pre vi o us s cree ni n g t ests ca n b e use d f or 
rescree ni n g, pr o vi de d t h e y are wit hi n t he ne w s cree ni n g wi n d o w.  
6  
St u d y I nter ve nti o n(s )  
St u d y i nter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), place b o, or 
me dical de vic e(s) i nte n de d t o be a d mi nistere d t o a st u d y p artici pa nt p er  t he st u d y pr ot oc ol. St u d y 
i nter ve nti o n is use d i nstea d of “st u d y dr u g, I nvesti gati o nal 
M e dici nal Pr o d uct, or st u d y 
treat me nt”. 
6. 1  
St u d y I nter ve nti o n A d mi nistr ati o n   
Partici pa nts are pla n ne d t o c o nti n ue wit h st u d y i nter ve nti o n (see Ta ble  8 ) u ntil d oc u me nte d 
disease pr o gressi o n, disc o nti n uati o n d ue t o a d verse e ve nts, deat h or wit h dr a wal fr o m t h e st u d y, 
w hic he ver occ urs earlier.  
F asti n g Wi n d o w Defi niti o n  
F or Part 1 A - T he fasti n g wi n d o w is defi ne d as: 2 h o urs pre -d ose t o 1 -h o ur p ost -d ose i n ge neral, 
a n d 2 h o urs pre -d ose t o 4 h o urs p ost -d ose o n da ys w here P K -ti me matc he d tri plicate E C G will 
be c ollecte d. T his fasti n g strate g y facilitates m ore fre q ue nt dail y d osi n g re gi me ns a n d alle viates 
p ote ntial disc o mf ort f or a d va nce d ca ncer patie nts d uri n g t he d os e escalati o n p hase.  
F or Part 1 B - T h e fasti n g wi n d o w is defi ne d as: 1 0 h o urs pre -d os e t o 4 h o urs p ost -d ose.  
T a ble  8  
St u d y I nter ve nti o n Det ails   
I nt er v e nti o n N a m e 
M 4 0 7 6  
T y p e  
Dr u g  
D o s e F or m ul ati o n  
Fil m -c o at e d t a bl et s  
U nit D o s e Str e n gt h s  
5 0 m g  
D o s e A m o u nt  
M 4 0 7 6 will b e a d mi ni st er e d or all y, a s pl a n n e d, o n c e d ail y p er  t h e d o s e 
e s c al ati o n s c h e m a ( Fi g ur e  2 ) a n d a s d et er mi n e d b y t h e S M C b a s e d 
o n s af et y, t ol er a bilit y, a n d pr eli mi n ar y P K a n d, if a p pr o pri at e, P d d at a . 
M T D/ R D E t o b e d et er mi n e d .  
S e e S e cti o n s  4. 1. 1  a n d 6. 6  f or m or e i nf or m ati o n. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Fr e q u e n c y  
O n c e d ail y; s c h e d ul e s m a y b e a d a pt e d  
R o ut e of A d mi ni str ati o n  
Or al  
U s e  
E x p eri m e nt al  
I M P/NI M P  
I M P 
S o ur ci n g  
Pr o vi d e d c e ntr all y b y t h e S p o n s or . 
P a c k a gi n g a n d L a b eli n g  
St u d y I nt er v e nti o n will b e pr o vi d e d i n p arti ci p a nt kit s c o nt ai ni n g M 4 0 7 6 
t a bl et s i n bli st er s. E a c h kit  will b e l a b el e d p er c o u ntr y r e q uir e m e nt . 
I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; M T D = m a xi m u m t ol er at e d d o s e; NI M P = n o n i n v e sti g ati o n al m e dici n al 
pr o d u ct; 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; R D E = r e c o m m e n d e d d o s e f or e v al u ati o n ; S M C =  s af et y 
m o nit ori n g c o m mitt e e . 
6. 2  
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y   
T he In vesti gat or, i nstit uti o n, or t he hea d of t h e me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
•  U p o n recei pt of t he st u d y i nter ve nti o n(s), t he In vesti gat or or desi g nee will  c o nfir m 
a p pr o priate te m perat ure c o n diti o ns ha ve b ee n 
mai ntai ne d d uri n g tr a nsit a n d a n y 
discre pa n cies ar e re p orte d a n d res ol ve d bef ore use.  Als o, t he res p o nsi ble pers o n will c hec k 
f or acc urate d eli ver y. F urt her g ui da nce a n d i nf or mati o n f or st u d y i nter ve nti o n 
acc o u nta bilit y are pr o vi d e d i n t he P har mac y M a n ual.  
•  O nl y p artici pa nts e nr olle d i n t he st u d y m a y recei ve st u d y i nter ve nti o n(s) a n d o nl y 
a ut h orize d site staff ma y s u p pl y it.  All st u d y i nter ve nti o n(s) will  be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr oll e d , a n d m o nit ore d ( m a n ual or a ut o mate d) area, per  t he la bele d 
st ora ge c o n diti o ns, a n d wit h access li mite d to t he In vesti gat or a n d a ut h orize d site staff.  
•  Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nt a bilit y f or ms s o t hat acc urat e 
rec or ds will be a vaila ble f or verifi cati o n at eac h m o nit ori n g visit. 
•  St u d y i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:  
o  C o nfir mati o n of 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 p erat ur e ra n ge.  
o  T he i n ve nt or y pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.  
o  T he d ose(s) eac h partici p a nt use d d uri n g t he st u d y.  
o  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 us e d st u d y i nter ve nti o n(s). 
o  Dates, q ua ntities, b atc h n u m bers, me dicati o n  n u m bers, e x pir y dates, a n d t he partici p a nt 
n u m bers.  
•  T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y d o c u me nts t h at partici pa nt s 
were pr o vi d e d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d 
were f ull y rec o n cile d.  
•  U n use d st u d y i nter ve nti o n(s) will  n ot b e disc ar de d or use d f or a n y p ur p ose ot her t ha n t he 
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y b e re -dis pe nse d 
t o a differe nt partici pa nt. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  A St u d y M o nit or will peri o dicall y c ollect t he st u d y i nter ve nti o n(s) acc o u nt a bilit y f or ms.  
•  F urt her g ui da n ce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o n(s) 
are pr o vi d e d i n t he P har mac y  Ma n ual.  
6. 3  
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g   
6. 3. 1  
St u d y I nter ve nti o n Assi g n me nt   
T he I X R S will be use d t o assi g n u ni q ue partici pa nt n u m bers, all ocate partici pa nts t o st u d y 
i nter ve nti o n gr o u p at t he ra n d o mizati o n visit, a n d st u d y i nter ve nti o n t o partici pa nts at eac h st u d y 
i nter ve nti o n visit. 
Bef ore t he st u d y is i nitiate d, t he directi o ns f or t he I X R S will be pr o vi de d t o eac h site. T he site 
will c o ntact t he I X R S pri or t o starti n g st u d y i nter ve nti o n a d mi nistrati o n f or eac h p artici pa nt.  
F or Part  1 B, after c o nfir ma ti o n of partici pa nt’s eli gi bilit y pri or t o st u d y i nter ve nti o n 
a d mi nistrati o n, partici pa nts will be ce ntrall y all ocate d t o eit her ( 1) faste d f oll o we d b y fe d, or ( 2) 
fe d f oll o we d b y faste d i n a 1: 1 rati o usi n g a n IX R S  a n d per a c o m p uter -ge nerate d ra n d o mizati o n 
list. 
6. 3. 2  
Bli n di n g   
T his is a n o pe n -la b el st u d y. Partici pa nts a n d I n v esti gat ors will be a ware of st u d y i nter ve nti o n 
assi g n me nts.  
Re d ucti o n of bias is miti gate d b y t he ra n d o mize d desi g n i n Part  1 B ( preli mi nar y f o o d effect 
assess me nt), w hic h will use a n I X R S t o assist i n ra n d o mizati o n t o fe d/fasti n g sc he d ules. T he 
I X R S will als o be use d f or st u d y i nter ve nti o n assi g n me nt. 
6. 4  
St u d y I nter ve nti o n C o m pli a nce   
W he n partici pa nts are d ose d at t h e site, t h e y will recei ve st u d y i nt er ve nti o n directl y fr o m t he 
I n v esti gat or or d esi g n ee, u n der me dical s u per visi o n. T he date a n d ti me of eac h d ose a d mi nistere d 
i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he C R F. T he d os e of 
st u d y i nter ve nti o n a n d st u d y partici pa nt i de ntificati o n will be c o nfir me d at t he ti me of d osi n g b y 
a me m ber of t h e st u d y sit e staff ot her t ha n t he pers o n a d mi nisteri n g t he st u d y i nt er ve nti o n.  
W he n partici pa nts self -a d mi nister st u d y i nter ve nti o n(s) at h o me, c o m plia nce wit h st u d y 
i nter ve nti o n will be assesse d at eac h visit. C o m plia nce will be assesse d b y direct q uesti o ni n g, 
c o u nti n g ret ur n e d ta blets  d uri n g t he site visits a n d d oc u me nte d i n t he s o urce d oc u me nts a n d 
C R F. A n y d e viati o n(s) fr o m t he prescri be d d os a ge re gi me n are rec or de d i n t he C R F.  
A rec or d of t he n u m b er of ta blets dis pe nse d t o a n d ta ke n b y eac h partici pa nt will be mai ntai ne d 
a n d rec o n cile d wit h st u d y i nter ve nti o n a n d c o m pl ia nce rec or ds. I nter v e nti o n start a n d st o p dates, 
i ncl u di n g dates f or i nter ve nti o n dela ys a n d/ or d ose re d ucti o ns will als o be rec or de d i n t he C R F. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
6. 5  
C o nc o mit a nt T her a p y   
Rec or d i n t he C R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d 
fr o m t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g 
a n y c h a n ges.  F or pres cri pti o n a n d o ver -t he-c o u nter me dici n es, vacc i nes, vita mi ns, a n d her bal 
s u p ple me nts, rec or d t h e na me, reas o n f or us e, dat es a d mi nistere d, a n d d osi n g i nf or m ati o n.  
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n  c o nc o mita nt or pri or t h era p y.  
6. 5. 1  
Resc ue Me dici ne   
T here is n o s pecific treat me nt or me dici n e a v aila ble t o c o u nteract t he i n hi biti o n of A T M i nte n d e d 
b y M 4 0 7 6. F or a n y u n w a nte d e ve nts d uri n g st u d y i nter ve nti o n wit h M 4 0 7 6, t he o nc ol o gical 
sta n dar ds i n s u p p orti ve care s h o ul d be a p plie d.  
6. 5. 2  
Per mitte d Me dici nes   
A n y me di ci nes t hat are c o nsi dere d necessar y t o pr otect t he partici pa nt’s welfare i n e mer ge n cies 
ma y b e gi ve n at t he I n v esti gat or’s discreti o n, re g ar dless if it res ults i n a pr ot oc ol de viati o n.  
O utsi de t he D L T o bser vati o n peri o d i n Part  1 A of t he st u d y, pr o p h ylactic or t hera pe utic use of 
he mat o p oietic gr o wt h fact ors is per mitte d t o pre ve nt t o xicities re q uiri n g st u d y i nter ve nti o n 
i nterr u pti o n or disc onti n uati o n. D uri n g t he D L T o bs er vati o n p eri o d, pr o p h yl actic us e is 
pr o hi bite d. T hera pe utic use, if d ee me d necessar y  b y t he I n vesti gat or, is all o we d a n d ma y 
c o nstit ute a D L T (see Secti o n  6. 6. 2  f or details of D L T criteri a). 
T he a d mi nistrati o n of H 2-rece pt or a nta g o nists is per mitte d as l o n g as t he y are n ot a d mi nistere d 
f or 1 2 h o urs bef ore or 2 h o urs aft er t he d osi n g of M 4 0 7 6. A ntaci ds ca n n ot be a d mi nistere d 
2  h o urs bef ore or 2 h o urs after t he d osi n g of M 4 0 7 6.  
T he c o nti n uati o n of h or m o ne t hera p y is all o we d t hr o u g h o ut t he st u d y if t he partici pa nt has b ee n 
o n sta ble treat me nt f or t he last 3  m o nt hs pri or t o e nr oll me nt a n d t he I n v esti gat or rec o m me n ds 
t he nee d t o c o nti n ue t his d uri n g t he st u d y. 
6. 5. 3  
Pr o hi bite d Me dici nes   
Pr o hi bite d me dicati o ns d uri n g t he scree ni n g peri o d are as defi ne d i n t he pri or/c o nc o mita nt 
t hera p y e x cl usi o n criteria i n Secti o n  5. 2 .  
C o nc o mita nt a d mi nistrati o n of M 4 0 7 6 wit h iri n oteca n, oral direct t hr o m bi n i n hi bit ors, di g o xi n, 
a n d pr ot o n p u m p i n hi bit ors is pr o h i bite d.  
C o nc o mita nt a d mi nistrati o n of 
M 4 0 7 6 wit h cli nical s u bstrates of C Y P 3 A 4 wit h narr o w 
t hera pe utic i n de x is pr o hi bite d.  
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
E x a m ples of str o n g i n hi bit ors of C Y P 3 A 4  a n d P -g p i n hi bit ors or str o n g i n d ucers of C Y P 3 A 4  are 
pr o vi de d i n Ta ble  9 . I n or der t o be e nr olle d, partici pa nts m ust st o p bef ore st u d y i nter ve nti o n 
a d mi nistrati o n:  
•  Str o n g i n hi bit ors of C Y P 3 A 4  or P -g p, st o p at least 1 wee k  bef ore st u d y i nte r ve nti o n 
a d mi nistrati o n . 
•  Str o n g i n d ucers of C Y P 3 A 4 , st o p at least 2 wee ks bef ore st u d y i nter ve nti o n a d mi nistrati o n. 
•  Cli nical s u bstrates of C Y P 3 A 4 wit h narr o w t h era pe utic i n de x , st o p at least 1 wee k b ef ore 
st u d y i nter ve nti o n u ntil safet y f oll o w-u p visit . 
T a ble  9  
Cli nic al E x a m ples of Str o n g C Y P 3 A a n d P -g p I n hi bit ors a n d C Y P 3 A 
I n d ucers a n d se ns iti ve C Y P 3 A 4 s u bstr ates wit h n arr o w t her a pe utic 
i n de x 
Tr a n s p ort er  
Str o n g I n hi bit or  
 
P -g p  
a mi o d ar o n e, c ar v e dil ol, 
cl arit hr o m y ci n, dr o n e d ar o n e, 
itr a c o n a z ol e, l a p ati ni b, l o pi n a vir 
a n d rit o n a vir, pr o p af e n o n e, 
q ui ni di n e, r a n ol a zi n e, rit o n a vir, 
s a q ui n a vir a n d rit o n a vir, t el a pr e vir, 
ti pr a n a vir a n d rit o n a vir, v er a p a mil. 
 
E n z y m e  
Str o n g I n hi bit or s  
Str o n g I n d u c er s  
C Y P 3 A  
b o c e pr e vir, c o bi ci st at, d a n o pr e vir 
a n d rit o n a vir, el vit e gr a vir a n d 
rit o n a vir, gr a p efr uit j ui c e, i n di n a vir 
a n d rit o n a vir, itr a c o n a z ol e, 
k et o c o n a z ol e, l o pi n a vir a n d 
rit o n a vir, p arit a pr e vir a n d rit o n a vir 
a n d ( o m bit a s vir a n d/ or d a s a b u vir), 
p o s a c o n a z ol e, rit o n a vir, s a q ui n a vir 
a n d rit o n a vir, t el a pr e vir, ti pr a n a vir 
a n d rit o n a vir, t elit hr o m y ci n, 
tr ol e a n d o m y ci n, v ori c o n a z ol e. 
a p al ut a mi d e, c ar b a m a z e pi n e, 
e n z al ut a mi d e, mit ot a n e, p h e n yt oi n, 
rif a m pi n, St. J o h n’ s w ort 
(H y p eri c u m  p erf or at u m ). 
E n z y m e  
Cli ni c al s u b str at e s of C Y P 3 A 4 wit h 
n arr o w t h er a p e uti c i n d e x  
 
- 
C Y P 3 A  
A st e mi z ol e, C y cl o s p ori n e, 
E v er oli m u s, Pi m o zi d e, sir oli m u s, 
t a cr oli m u s 
- 
S o u rc e: htt p s:// w w w.f d a. g o v/ dr u g s/ dr u g -i nt er a cti o n s-l a b eli n g/ dr u g-d e v el o p m e nt -a n d -dr u g -i nt er a cti o n s-t a bl e-
s u b str at e s -i n hi bit or s-a n d -i n d u c er s # T a bl e 3-2  
C Y P 3 A = c yt o c hr o m e P 4 5 0; P -g p = P -gl y c o pr ot ei n.  
N ot e : M o st P-g p i n hi bit or s al s o i n hi bit C Y P 3 A . 
If t h e 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 st u d y 
i nter ve nti o n peri o d, e. g., d ue t o A Es, st u d y i nter ve nti o n m ust be i nterr u pte d, a n d per ma n e nt 
disc o nti n uati o n s h o ul d be disc usse d wit h me dical m o nit or.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
6. 5. 4  
Ot her I nter ve nti o ns   
Ra diati o n t hera p y is n ot all o we d o n t his st u d y e x ce pt f or p alliati ve treat m e nt of lesi o ns t hat are 
prese nt at baseli ne a n d ca use s y m pt o ms t hat ca n n ot be a de q uatel y c o ntr olle d b y ot her mea ns e. g. 
a nal gesics. If ra diati o n t hera p y is re q uire d, t h e st u d y i nter ve nti o n s h o ul d be wit h hel d f or at l east 
4  half -li ves bef ore t he a d mi nistrati o n of ra diati o n a n d ma y be res u me d o nce t o xicities are 
Gra de  ≤ 1  (refer t o t he M 4 0 7 6 I B f or m ore d etails). In a d diti o n, t he I n vesti gat or s h o ul d e ns ure 
t hat t u m or assess me nts are rece ntl y o btai ne d a n d re p orte d as p er R E CI S T 1. 1  (A p pe n di x  9 ), 
bef ore i nitiati o n of ra diati o n t hera p y. 
6. 6  
D ose Selecti o n a n d M o dific ati o n   
T he rec o m me n dati o n i n Part 1 A t o pr ocee d t o t he ne xt D L  (i ncl u di n g w hat D L ), or t o d ecreas e 
t he d ose i n t he n e xt c o h ort or t o e x pa n d t he c urre nt D L  t o i ncl u d e a d diti o nal partici pa nts  will b e 
ma de b y t h e S M C base d o n safet y, t olera bilit y, a n d preli mi nar y P K a n d, if a p pr o priate, P d data. 
T he S M C recei ves o ut p uts of a Ba yesia n d ose -t o xicit y m o del wit h esti mate d D L T pr o ba bilities 
f or p ote ntial ne xt D Ls  t o s u p p ort t he decisi o n ma ki n g of t he S M C . T he Ba yesia n m o del 
(A p pe n di x  1 2 ) will be base d o n pri or  i nf or mati o n, o bser ve d n u m ber of e val ua ble partici pa nts 
a n d n u m ber of partici pa nts wit h D L T. F urt her d etails o n t he Ba yesi a n m o del are pr o vi de d i n 
Secti o n  9. 4. 2 . F urt her det ails o n t he S M C are pr o vi de d i n Secti o n 6. 6. 1 . 
Partici pa nts are eli gi ble f or t he Ba yesia n d ose -t o xicit y m o d el f or D L T pr o b a bilit y, if t he y f ulfill 
t he criteria of t he D L T a nal ysis set, defi ne d i n Secti o n 9. 3 . 
Detaile d j ustificati o n of t he starti n g d ose f or M 4 0 7 6 is pr o vi de d i n Secti o n  4. 2 . Details of t h e 
d ose escal ati o n sc he ma i n Secti o n  1. 2 . 
6. 6. 1  
S afet y M o nit ori n g C o m mittee   
D uri n g t he d ose -es calati o n part ( Part 1 A)  of t h e st u d y, t he S M C will e val uate t he s afet y 
(i ncl u di n g D L Ts), t olera bilit y, a n d a v aila ble P K, t o i ncl u de at least pre defi ne d P K of t he p re vi o us 
c o h ort, a n d a v aila ble P d data. T he S M C will deci d e o n d ose escalati o n, de -escalati o n, a d diti o nal 
e nr ol me nt o n sa me D L , M T D, or s us pe nsi o n of e nr ol me nt. I n cases w here e nr oll me nt of t he last 
partici pa nt i n a d osi n g c o h ort is si g nifica ntl y dela ye d, t he S M C ma y deci d e ( base d o n a v aila ble 
data) u p o n e nr ol me nt a n d d ose f or t he ne xt d osi n g c o h ort bef ore all partici p a nts i n a c o h ort ha v e 
c o m plete d t he D L T peri o d. F or t his partici pa nt, t he S M C will c o nsi der all a v aila ble data a n d a n y 
s u bse q ue nt e mer gi n g data at a s u bse q ue nt meeti n g. A n a d -h o c meeti n g will be c o n ve ne d if t his 
partici pa nt e x perie nces a D L T.  
T he S M C ca n rec o m me n d m o dif yi n g t he sc h e d ule of a d mi nistrati o n. S M C will re vie w P K t o 
deter mi ne if a dj ust me nt of sc he d ule (t o pre d efi ne d alter nati ve sc h e d u les as defi ne d i n 
A p pe n di x  7 ) is a p pr o priate d uri n g t he d ose escalati o n base d o n t he c ollecte d data. T he us ual 
c o h ort siz e is 3  partici pa nts, b ut t he S M C ca n d eci de t o c ha n ge t he siz e of c o h orts. Base d o n t he 
o bser ve d t o xicit y  pr ofile a n d a vaila ble P K a n d P d, D L (s) t hat are differe nt t o, or hi g her or l o wer 
t ha n t he pres pecifi e d d os es ma y b e teste d. T he S M C ma y als o rec o m me n d c ha n gi n g t he d osi n g 
re gi me n. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
D uri n g t h e Part  1 B  of t he st u d y, t he S M C will m o nit or t he safet y a n d ma y rec o m me n d b y 
c o nse ns us o n c o nti n uati o n, e x pa nsi o n, a n d m o dificati o ns of t he st u d y. T he S M C ma y m o dif y t h e 
fre q ue n c y of meeti n gs as dee me d a p pr o priate d uri n g t he st u d y. 
T he s pecific w or ki n g pr oce d ures w ill be descri be d i n a n S M C C harter, w hic h will be esta blis he d 
bef ore first i nf or me d c o nse nt si g ne d . 
6. 6. 2  
D ose -li miti n g T o xicities –  Defi niti o n a n d Criteri a   
A D L T is d efi ne d as a n y of t he f oll o wi n g A Es acc or di n g t o t he Nati o nal Ca ncer I nstit ute 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI -C T C A E ) Versi o n  5. 0 assesse d b y t he 
I n v esti gat or a n d/ or t he S p o ns or at a n y d ose, j u d ge d n ot t o be relate d t o t he u n derl yi n g dise ase or 
a n y pre vi o us or c o nc o mita nt me dicati o n or c o nc urre nt c o n diti o n,  occ urri n g d uri n g t he D L T 
o bser vati o n peri o d, w hi c h f or Part  1 A starts o n t he first da y of st u d y i nter ve nti o n ( Da y  1) a n d 
has a d urati o n of 2 1  d a ys.  
St u d y accr ual will be halte d, pe n di n g disc ussi o ns wit h t he S M C or t he st u d y S p o ns or, if t here is 
a n occ urre n ce of a Gra d e  5 t o xicit y b y t he N CI -C T C A E Versi o n 5. 0 attri b uta ble t o t he tr eat me nt 
re gi me n or if m or e t ha n 1 D L T is see n i n D L  1  i n Part 1 A . 
T he treat me nt of t o xicities wit h tra nsf usi o ns or gr o wt h fact ors (e. g., gra n ul oc yte -c ol o n y 
sti m ulati n g fact or, er yt hr o p oeti n) is n ot per mitte d d uri n g t he D L T p eri o d a n d if it occ urs will be 
c o nsi dere d a D L T.  
A Es j u d ge d as D L T  will  i ncl u de: 
•  A n y Gra d e ≥ 3 n o n -he m at ol o gic  A E wit h e xce pti o n  of:  
•  Si n gle la b orat or y val u es o ut of n or mal ra n ge t hat ha ve n o cli nical c orrelat e a n d res ol ve t o 
Gra de ≤ 1 or t o baseli ne 
wit hi n 7 da ys 
wit h a de q uate 
me dical 
ma na ge me nt or 
as y m pt o matic Gra d e 3 li pase or a m ylas e el e vati o n ( > 5 U L N) n ot ass ociat e d wit h cli nical 
ma nifestati o n of pa ncreatitis.  
•  I nf usi o n-relat e d reacti o n res ol vi n g wit hi n 6 h o urs fr o m t he e n d of i nf usi o n a n d c o ntr olle d 
wit h me dical ma na ge me nt (f or i v c o m p o u n ds o nl y)  
•  Diarr hea persisti n g < 7 2 h o urs after i nitiati o n of me dical ma na ge m e nt  
•  Na usea a n d  v o miti n g of ≤ 7 2 h d urati o n wit h a de q uate a n d o pti mal t hera p y  
•  Tra nsie nt ( ≤ 7 2 h) fati g ue, l ocal reacti o ns, fl u -li ke s y m pt o ms, fe ver, hea dac he, 
h y perte nsi o n t hat res ol ves t o Gra de ≤ 1 wit h a de q uate treat me nt  
•  Gra de 3 n o n -rec urre nt s ki n t o xicit y t hat res ol ves t o Gra d e ≤ 1 i n l ess t h a n 7 da ys after 
i nitiati o n of me dical ma na ge me nt 
•  T u m or flare p h e n o me n o n defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at sites of 
k n o w n or s us pecte d t u m or t hat res ol ve t o Gra de ≤ 2 wit hi n 6  da ys  
•  A n y d eat h clearl y d ue t o t he u n derl yi n g dis ease or e xtra ne o us ca uses  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  Gra de  ≥ 3 ne utr o pe nia wit h cli nical si g ns/s y m pt o ms, s uc h as fe ver >  3 8. 5 °C (e. g., f or fe brile 
ne utr o pe nia, a n A N C  <  1 0 0 0/ m m 3 wit h si n gle te m p of 3 8. 3 °C [ 1 0 1  °F] or a s ustai ne d 
te m perat ur e of ≥3 8 °C [ 1 0 0. 4  °F] f or m ore t ha n o ne h o ur)  
•  Gra de ≥ 3 t hr o m b oc yt o p e nia wit h me dicall y c o ncer ni n g bl ee di n g  
•  A n y Gra d e ≥ 4 he mat ol o gic A E, e x ce pt:  
o  Is olat e d Gra d e 4 l y m p h o pe nia wit h o ut cli nical c orrelate 
o  A n y Gra d e 4 n e utr o pe ni a of < 7 da ys ’ d urati o n n ot ass ociate d wit h a n y cli nical 
sy m pt o ms  
•  All e ve nts of A L T ≥ 3 × u p per li mit of n or mal ( U L N) a n d bilir u bi n ≥ 2 × U L N ( >  3 5 % direct 
bilir u bi n) or A L T >  3 × U L N a n d i nter nati o nal n or malize d rati o (I N R) >  1. 5, if I N R meas ure d, 
ma y i n dicat e p ote ntial se vere li ver i nj ur y ( p ossi ble H y’s La w) , will re q uir e pr o m pt per ma ne nt 
disc o nti n uati o n fr o m t he st u d y, a n d will be re p ort e d as a n S A E (e x cl u di n g st u dies of he patic 
i m pair me nt or cirr h osis): 
•  Wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m A L P).  
•  I n t he a bse n ce of ot her reas o ns t ha n dr u g t o xicit y t o e x plai n t he la b orat or y c o nstellati o n 
(e. g., viral he p atitis A, B, C or c o-me dicati o n).  
•  I n t he a bse n ce of ot her reas o ns t ha n dr u g t o xicit y t o e x plai n t he la b orat or y c o nstellati o n. 
•  A n y A E le a di n g t o t he i na bilit y t o deli ver at least 8 0 % of t he pla n n e d t otal d ose f or t he D L T 
peri o d, e x ce pt i n sit uati o ns ot her t ha n t o xicit y, e. g. p artici pa nt n o nc o m pli a nce or l o gistical 
iss ues wit h st u d y i nter ve nti o n deli ver y . 
•  Deat h n ot cle arl y attri b ute d t o u n derl yi n g dis ease or alter nati ve ca use.  
•  A d diti o nall y, t he S M C  ma y i d e ntif y as a D L T:  
•  A T E A E  (i nsi de or o utsi de of t he D L T peri o d) 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 n ce s uc h t hat f urt her d ose escalati o n w o ul d e x p ose partici pa nts t o 
u nacce pta ble ris k  
T he S M C m ust c o nfir m a n y D L T.  
If a n y c h a n ge is ma de t o t he gra d e or ca usalit y of a n A E d uri n g t he st u d y t hat ma y alter its D L T 
stat us, t he S p o ns or m ust be i nf or me d i m me diatel y as t his ma y affect d ose escalati o n decisi o ns.  
A d diti o nall y, partici pa nts e x cl u de d fr o m t he D L T a nal ysis set ma y be re place d; t he decisi o n will 
be ma de b y t he S M C.  
6. 6. 2. 1  
D ose I nterr u pti o ns a n d M o dific ati o ns   
Partici pa nts w h o e x perie nce a n A E meeti n g D L T criteria d uri n g t he D L T assess me nt peri o d nee d 
t o i nterr u pt M 4 0 7 6 (Ta ble  1 0 ). N o d ose m o dificati o ns of M 4 0 7 6 s h o ul d be ma de d uri n g t he D L T 
assess me nt peri o d f or t he d ose escal ati o n part of t he st u d y ( Pa rt 1 A). 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Partici pa nts w h o e x perie nce ras h a n d s yst e mic s y m pt o ms (e. g., fe v er, v o miti n g, diarr hea), or 
ot her si g ns of h y perse nsiti vit y s h o ul d ha ve M 4 0 7 6 disc o nti n ue d i m me diatel y a n d are n ot t o be 
rec halle n ge d wit h a n y d ose of M 4 0 7 6. Gra de 2 a n d Gra de 3 ras h ( wit h o ut s yste mic s y m pt o ms) 
s h o ul d be ma na ge d wit h treat me nt i nterr u pti o n a n d s u p p orti ve me dicati o ns, i ncl u di n g t o pical or 
oral ster oi ds.  
D ose m o dificati o ns o utsi de t he D L T p eri o d  are all o we d. Partici pa nts w h o e x perie nce a Gra de  4 
dr u g -relat e d t o xicit y s h oul d disc o nti n ue treat me nt pr o m ptl y. F or a Gra d e 3 dr u g -relat e d t o xicit y, 
M 4 0 7 6 treat me nt s h o ul d be i nterr u pte d a n d ma y  res u me at a re d uce d d ose pr o vi de d t he t o xicit y 
has res ol ve d t o Baseli ne val ue or Gra d e ≤ 1 wit hi n 2 wee ks. At t he first i nsta nce of a Gra d e  3 
t o xicit y, st u d y i nter ve nti o n will be h el d, a n d all o we d t o res u me wit h a 2 5 % d ose re d ucti o n o n ce 
sai d t o xicit y rec o vers t o Gra de ≤ 1. S h o ul d a st u d y partici p a nt de vel o p a rec urre nt Gra de  3 
dr u g -relat e d t o xicit y, st u d y i nter ve nti o n will o nce a gai n be he l d, a n d all o we d t o res u me wit h a 
5 0 % d ose re d ucti o n o nce sai d t o xicit y rec o v ers t o Gra de ≤ 1.  S u bse q ue nt rec urre n ces of Gra de  3 
t o xicit y will pr o m pt disc o nti n uati o n of st u d y treat me nt, i.e., n o m or e t ha n 2 d ose re d ucti o ns will 
be per mitte d.  Base d o n e mer gi n g data (i. e. t o xicit y, P K, P d)  a n d ta blet stre n gt h a vaila bilit y , 
differe nt d os e re d u cti o ns ma y b e rec o m me n de d as a gree d bet wee n S p o ns or a n d i n vesti gat or, 
s uc h as alter nati ve d ose re d ucti o n ste ps or differe nt d osi n g re gi me n. Rec o m me n de d d ose 
re d ucti ons f or eac h p ot e ntial D L  are pr o vi d e d i n  T a ble  1 0 . 
O nce t he d ose of M 4 0 7 6 has bee n re d uce d i n a n i n di vi d ual partici pa nt, it m ust n ot be escalate d 
bac k  t o t he ori gi nal d ose le vel. If m ore t ha n 2 d ose re d ucti o ns of > 5 0 % d ose decrease are 
i n dicate d, t he p artici pa nt will be per m a ne ntl y disc o nti n ue d fr o m st u d y i nter ve nti o n. C o ns ultati o n 
bet wee n I n v esti gat or a n d S p o ns or a b o ut d ose re d u cti o n is e nc o ura ge d.  
T a ble  1 0  
M 4 0 7 6 Rec o m me n de d D ose 
M o dific ati o ns  f or Gr a de 3 He m at ol o gic 
a n d N o n he m at ol o gic A D Rs   
P ot e nti al D L s –  
St arti n g d o s e s  
Gr a d e 3 H e m at ol o gi c a n d N o n h e m at ol o gi c A D R s  
1 st  o c c urr e n c e  
D R of 2 5 %  
2 n d  o c c urr e n c e  
D R of 5 0 %  
3r d o c c ur e n c e  
1 0 0 m g  
5 0 * 
Di s c o nti n u e d  
N A  
2 0 0 m g  
1 5 0  
1 0 0  
D i s c o nti n u e d 
3 0 0 m g  
2 0 0  
1 5 0  
Di s c o nti n u e d  
4 0 0 m g  
3 0 0  
2 0 0  
D i s c o nti n u e d 
6 0 0 m g  
4 5 0  
3 0 0  
D i s c o nti n u e d 
A D R = a d v er s e dr u g r e a cti o n; D L = d o s e l e v el; D R = d o s e r e d u cti o n ; N A = n ot a p pli c a bl e. 
* re d u cti o n i s 5 0 % b a s e d o n a v ail a bl e t a bl et str e n gt h s . 
F or d ela ys i n st u d y i nt er ve nti o n e x cee di n g 2  wee ks, t h e i nter ve nti o n will be p er ma ne ntl y 
disc o nti n ue d, e x ce pt f or a sit uati o n w here t he partici pa nt has be n efitte d fr o m st u d y i nter ve nti o n 
wit h M 4 0 7 6 bef ore t he a d mi nistrati o n dela y a n d is e x pecte d t o c o nti n ue t o be nefit fr o m res u me d 
st u d y i nter ve nti o n after t he i nterr u pti o n. 
See Secti o n  7  f or i nf or m ati o n re gar di n g disc o nti n uati o n of st u d y i nter ve nti o n a n d partici p a nt 
disc o nti n uati o n/ wit h dra wal.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /1 2 2  
 
 
6. 7  
St u d y I nter ve nti o n after t he E n d of t he St u d y   
Partici pa nts still be nefitti n g fr o m st u d y tr eat me nt will be offere d c o nti n ue d access t o t he 
treat me nt t he y recei ve d d uri n g t he st u d y after t he e n d of t he st u d y, w he n a p pr o priate, wit hi n 
defi ne d li mitati o ns a n d as descri be d bel o w.  
A r oll -o ver st u d y or Si n gle Patie nt P ost -st u d y Access ma y be i m ple me nte d. U n der t his 
mec ha nis m, i n di vi d ual partici pa nts w h o c o m pl ete d t he st u d y ma y b e pr o vi de d wit h t heir 
assi g ne d tr eat me nt o utsi de of t he cli nical st u d y u n d er t he res p o nsi bilit y of t h e treati n g p h ysicia n. 
T his treat me nt s h o ul d c o m pl y wit h a n y le gal a n d re g ulat or y re q uire me nt as t here are n o 
a p pr o priate alter nati ve tr eat me nts a vaila ble.  
Data o n safet y e ve nts c o nti n ue t o be c ollecte d per a safet y re p orti n g a gree m e nt wit h t he 
partici pa nts treati n g p h ysicia n.  
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o partici pa nts after t h e y lea v e t he st u d y 
beca use s u c h care w o ul d n ot differ fr o m w hat is n or mall y e x pecte d f or patie nts wit h a d va nce d 
s oli d t u m ors. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /1 2 2  
 
 
7  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al   
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n   
T he partici pa nt m ust be wit h dra w n fr o m st u d y i nt er ve nti o n i n t he e v e nt of a n y of t h e f oll o wi n g:  
•  At his/ her re q uest ( wit h dra wal of c o nse nt of st u d y i nter ve nti o n) . 
•  De vel o p me nt of u nacce pta ble t o xicit y . 
•  Occ urre nce of pr o gressi v e  disease acc or di n g t o R E CI S T  1. 1  (A p pe n di x  9 ). St u d y i nter ve nti o n 
ma y c o nti n ue past t he deter mi nati o n of pr o gressi ve disease if dee me d i n dicate d b y t he 
I n v esti gat or a n d disc usse d wit h t he S p o ns or.  
•  I nitiati o n of a n y ot her a ntica ncer t hera p y, e x ce pt f or palliati ve ra diati o n t hera p y (see 
Secti o n  6. 5. 4 ). 
•  Occ urre nce of a n e x cl usi o n criteri o n t hat is cli nicall y rele va nt a n d  affects t he partici pa nt’s 
safet y, if disc o nti n uati o n is c o nsi dere d necessar y b y t he I n v esti gat or a n d/ or S p o ns or .  
•  Occ urre nce of pre g na n c y . 
•  Use of a n o n p er mitte d c o nc o mita nt dr u g (i ncl u di n g a n y ot her dr u g wit h k n o w n a ntica ncer 
acti vit y u nless s pecifie d ot h er wise).  
•  N o nc o m plia nce t h at 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 partici pa nt 
safet y or st u d y i nte grit y. 
I n rare i nsta nces, it ma y be necess ar y f or a parti ci pa nt t o per ma ne ntl y disc o nti n ue ( defi niti ve 
disc o nti n uati o n) st u d y i nter ve nti o n. If st u d y i nter ve nti o n is defi niti vel y dis c o nti n ue d, t he 
partici pa nt will  re mai n i n t he st u d y t o be e val uate d f or a n E n d of St u d y I nt er ve nti o n Visit . T he 
Sc he d ule of A cti vities  i n dicates data t o be c ollecte d at t he ti me of disc o nti n uati o n of st u d y 
i nterve nti o n a n d f oll o w -u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.  
Pre g n a nc y:  
F or i nf or m ati o n re gar di n g pre g na nc y, s ee Secti o n  8. 3. 5 . 
T he Sc he d ule of Assess me nts s pecifies t he d ata t o c ollect at st u d y i nter ve nti o n disc o nti n uati o n 
a n d f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be c o m plet e d.  
7. 2  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y   
•  A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or f or safet y, be ha vi oral c o m plia nce, 
or a d mi nistrati ve reas o ns.  
•  At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a disc o nti n uati o n visit will be 
c o n d ucte d, as liste d i n t he Sc he d ule of Acti vities . T he Sc he d ule of Acti vities  s pecifies t he 
data t o c ollect at st u d y disc o nti n uati o n a n d f oll o w -u p, a n d a n y a d diti o nal e val uati o ns t hat 
nee d t o be c o m plet e d.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /1 2 2  
 
 
•  If t h e partici pa nt wit h dra ws c o nse nt f or f ut ure i n v ol ve me nt i n t he st u d y, a n y data c ollecte d 
u p t o t hat p oi nt ma y still be use d, b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gi cal 
sa m ples c ollecte d will be destr o ye d. 
•  A partici p a nt has t he ri g ht at a n y ti me t o re q uest d estr ucti o n of a n y bi ol o gical sa m ples t a ke n. 
T he In vesti gat or will  d oc u me nt t his i n t he site st u d y rec or ds.  
A d diti o nal partici pa nts m a y be e nr olle d f or eac h p artici pa nt w h o wit h dra ws fr o m t he st u d y after 
si g ni n g c o nse nt a n d s uccessf ull y meeti n g e ntr y criteria b ut di d n ot recei ve st u d y i nter ve nti o n. 
A d diti o nall y, partici pa nts e x cl u de d fr o m t he D L T a nal ysis s et ma y b e re place d.  
T he I n v es ti gat or will be res p o nsi ble f or t h e safet y of t he st u d y partici p a nts a n d ma ke e v er y 
atte m pt t o c ollect data. See Secti o n  7. 3  f or f urt her details. 
7. 3  
L ost t o F oll o w -U p   
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns will  be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:  
•  T he site will  atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y.  
•  Bef ore a partici pa nt is dee me d “l ost t o f oll o w-u p ”, the In vesti gat or or desi g nee will  ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 3 tel e p h o ne 
calls; 2) if necessar y, s e n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he 
partici pa nt’s last k n o w n maili n g a d dress , a n d 3) if a partici p a nt has gi ve n t he a p pr o priat e 
c o nse nt, c o ntact t he partici pa nt’s ge n eral practiti o ner f or i nf or mati o n.  T hese c o ntact 
atte m pts will  be d oc u me nte d i n t he partici pa nt’s me dical rec or d.  
•  If t he p artici pa nt c o nti n ues t o be u nreac ha ble, he/s h e will be dee me d as “l ost t o f oll o w -u p” . 
8  
St u d y Assess me nts a n d Pr oce d ures   
•  St u d y ass ess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Sc he d ul e of 
Acti vities . 
•  N o  pr ot oc ol wai vers or e x e m pti o ns are all o we d.  
•  I m me diat e safet y c o ncer ns are disc uss e d wit h t he S p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y i nter ve nti o n.  
•  A d here n ce t o t he st u d y desi g n re q uir e me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Acti vities , is esse ntial a n d re q uire d f or st u d y c o n d uct. 
•  All scree ni n g e v al uati o ns 
will  be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y crit eria. T he In v esti gat or will mai ntai n a scree ni n g l o g t o 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
rec or d details of all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d 
reas o ns f or scree ni n g fail ure. 
•  Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t h e I n vesti gat or will o btai n writte n i nf or me d c o nse nt as s pecifie d i n A p pe n di x  2 . 
•  Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g n i n g of t he I C F ma y b e use d f or scree ni n g or b aseli ne p ur p oses pr o vi de d 
t he pr oce d ures met t he pr ot oc ol-s pecifie d criteria a n d were p erf or m e d wit hi n t he ti me fra me 
defi ne d i n t he Sc he d ule of Acti vities . 
8. 1  
Effic ac y Assess me nts a n d Pr oce d ures   
Ra di o gra p hic i ma ges a n d p h ysical fi n di n gs ( p h ysical assess me nts) will be use d b y t h e 
I n v esti gat ors f or t he l o cal deter mi nati o n of disease pr o gressi o n a n d partici pa nt treat me nt 
decisi o ns. Refer t o t he R E CI S T 1. 1 p u blicati o n f or a d diti o nal i nf or mati o n ( Eise n ha uer  2 0 0 9 ). 
W he ne ver a vaila ble, t he l o n gest dia met er meas ure me nt of eac h tar get l esi o n a n d s h ort a xis f or 
n o des deri ve d fr o m  hist orical c o m p uterize d t o m o gra p h y ( C T)/ ma g netic res o na nce i ma gi n g 
( M RI) sca ns o v er a peri o d of u p t o 1 0 0 da ys pri or t o e nr oll me nt s h o ul d be c ollecte d i n or der t o 
assess t u m or gr o wt h d y n a mics pri or t o st u d y e nr oll me nt. F or c o m para bilit y, tar get lesi o ns i n  
b ot h hist orical a n d o n -treat me nt sca ns s h o ul d matc h, if p ossi ble. Partici pa nts will ha ve a c hest 
a n d a b d o mi nal i ma gi n g sca n (e. g., c o m p ute d t o m o gra p h y, ma g n etic res o na nce i ma gi n g ) as 
a p pr o priate a n d, if cli nic all y i n dicate d, i ma gi n g s ca ns of ot h er b o d y ar eas (e. g., b o n e, pel vis). 
Partici pa nts s h o ul d ha ve a re peat i ma gi n g s ca n as descri be d i n t he Sc h e d ule of Acti vities  i n 
Secti o n  1. 3 . All i ma gi n g sca ns t o assess dise ase pr o gressi o n s h o ul d be perf or me d usi n g si milar 
i ma gi n g platf or ms a n d i ma gi n g tec h ni q ues, i ncl u di n g t he use or a bse n ce of c o ntrast, a n d s h o ul d 
be of c o nsiste nt a nat o mi c l ocati o ns wit h pri or i ma gi n g sca ns, w he n e ver p ossi ble. At E n d of 
St u d y  I nter v e nti o n visit, t he t u m or assess me nt s h o ul d o nl y b e perf or me d if n o diseas e 
pr o gressi o n was pr e vi o usl y d oc u me nt e d.  
I ma gi n g sca ns will be l o call y rea d f or all p arts of t he st u d y. T h e a p plica ble o verall res p o nse 
cate g or y f or eac h visit t hat i ncl u des di sease assess me nt, base d o n e val uati o n of i ma gi n g sca n, 
will be rec or de d i n t he C R F. Deter mi nati o n of p artici pa nt st u d y dis p ositi o n (i.e.,  disc o nti n uati o n 
or e xte nsi o n of t hera p y) will be base d o n disease pr o gressi o n as i nter prete d fr o m t he l ocal 
e val uati o n  of t he i ma gi n g sca n.  
F or assess me nt  ti me p oi nts a n d pr oce d ures f or pri mar y, sec o n dar y, a n d tertiar y/ e x pl orat or y 
effic ac y e n d p oi nts, se e Sc he d ule of Acti vities  (Secti o n  1. 3 ).  
8. 2  
S afet y Assess me nts a n d Pr oce d ures   
T he safet y pr ofile of t he st u d y i nter ve nti o n 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 b aseli ne me dical c o n diti o ns, a d verse e ve nts ( A Es), p h ysic al e x a mi nati o n fi n di n gs, 
vital si g ns, electr ocar di o gra ms, Easter n C o o perati ve O nc ol o g y G r o u p perf or ma nce stat us (see 
A p pe n di x  1 0 ), a n d la b orat or y tests.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
C o m pre he nsi ve assess m e nt of a n y p ot e ntial t o xicit y e x perie nce d b y eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
In v esti gat or will re p ort a n y A Es, w het her o bser ve d b y t he I n v esti gat or o r re p orte d b y t he 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n  8. 3. 1 . 
8. 2. 1  
P h ysic al E x a mi n ati o ns   
•  A c o m plete p h ysical e x a mi nati o n 
will i ncl u de, at a 
mi ni m u m, assess me nts of t he 
car di o vas c ular, res pirat or y, g astr oi ntesti nal a n d n e ur ol o gical s yste ms.  
•  A brief p h ysical e x a mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car di o vas c ular s yste m, a n d a b d o me n (li ver a n d s plee n).  
•  I n v esti gat ors will  pa y s pecial atte nti o n t o cli nical si g ns relat e d t o pre vi o us seri o us ill nesses.  
8. 2. 2  
Vit al Si g ns   
•  Hei g ht at s cree ni n g  a n d wei g ht will be m eas ure d a n d rec or de d  as per ti me p oi nts n ote d i n t he 
Sc he d ule of Assess me nts . 
•  Oral te m perat ure, p ulse rate, res pir at or y rat e, a n d bl o o d press ure will be assesse d.  
•  Bl o o d press ur e a n d p ulse meas ure me nts will be asse sse d i n a s u pi ne p ositi o n wit h a 
c o m pletel y a ut o mate d de vice. Ma n u al tec h ni q u es will be use d o nl y if a n a ut o mate d de vice is 
n ot a vaila ble.  
•  Bl o o d press ure a n d p ulse meas ure m e nts will  be prece d e d b y at l east 5 mi n utes of rest f or t he 
partici pa nt i n a q uiet s etti n g wit h o ut distracti o ns (e. g., tele visi o n, cell p h o nes).  
•  Vital si g ns will be m eas ur e d i n a se mi -rec u m be nt p ositi o n after 5 mi n utes rest a n d will i ncl u d e 
te m perat ur e, s yst olic a n d diast olic bl o o d press ure, a n d p ulse.  
8. 2. 3  
Electr oc ar di o gr a ms   
8. 2. 3. 1  
St a n d ar d Si n gle 1 2 -le a d Electr oc ar di o gr a ms  
Si n gle 1 2 -lea d E C Gs will be o btai ne d as o utli ne d i n t he Sc he d ule of Acti vities  usi n g a n E C G 
mac hi ne t hat a ut o maticall y cal c ulates t he h eart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc F 
i nter vals. 
8. 2. 3. 2  
Di git al Tri plic ate Electr oc ar di o gr a ms   
Tri plicate 1 2 -l ead E C G will be o btai ne d as o utli ne d i n t he Sc he d ule of Acti vities  usi n g a n E C G 
mac hi ne t hat a ut o maticall y cal c ulates t he h eart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc F 
i nter vals.  
At eac h ti me p oi nt at w hic h tri plicate E C G are re q uire d o utsi de of H olter c oll ecti o n, 3 i n di vi d ual 
E C G traci n gs will b e o bt ai ne d as cl osel y as p ossi ble i n s uccessi o n, b ut n o m ore t ha n 2  mi n utes 
a part. T h e f ull set of tri plicates will be c o m plet e d i n less t ha n 4  mi n utes  a n d will occ ur i n a 
resti n g state wit h o ut pri or pr oce d ure s uc h as bl o o d dra w. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
8. 2. 4  
Cli nic al S afet y L a b or at or y Assess me nts   
•  Bl o o d a n d uri n e sa m ples will be c ollecte d f or t he cli nical la b orat or y tests liste d i n A p pe n d i x 6  
at t he ti me p oi nts liste d i n t he Sc he d ule of Acti vities . All sa m ples will  be clearl y i de ntifie d. 
See Ta ble  2 0 . 
•  A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y, as d eter mi ne d necessar y b y 
t he In v esti gat or or re q uir e d b y l o cal re g ul ati o ns.  
•  T he tests will be perf or me d b y l o cal la b orat or y.  
•  T he S p o ns or will  recei ve a list of t h e l ocal la b orat or y n or mal ran ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y will  be f or war de d t o t he S p o ns or.  
•  T he In vesti gat or will  re vie w eac h la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c h a n ges occ urri n g d uri n g t h e st u d y i n t he A E secti o n of t he C R F.  T he 
la b orat or y re p orts will  be file d wit h t he s o urce d o c u me nts.  
A d diti o nal ser u m or hi g hl y se nsiti ve uri ne pre g n a nc y tests ma y b e c o n d u cte d, as deter mi ne d 
necessar y b y t he i n v esti gat or or re q uire d b y l ocal re g ul at i o n, t o esta blis h t he a bse nce of 
pre g na nc y at a n y ti me d uri n g t he st u d y.  
8. 3  
A d verse E ve nts a n d Seri o us A d verse E ve nts   
T he defi niti o ns of a n A d verse E ve nt ( A E) a n d a Seri o us A d v erse E ve nt ( S A E) are i n A p pe n di x  4 . 
T he I n v esti gat or a n d a n y q u alifie d d esi g n ees (e. g., S u b -In v esti gat ors) are res p o nsi ble f or 
detecti n g, d oc u me nti n g, a n d rec or di n g e v e nts t hat meet t he defi niti o n of a n A E or S A E. T he 
I n v esti gat or re mai ns res p o nsi ble f or f oll o wi n g u p A Es t hat are seri o us or t hat ca use d t he 
partici pa nt t o disc o nti n ue t he st u d y i nter ve nti o n or st u d y, as s pecifie d i n Secti o n  8. 3. 3 . 
Re q uests f or f oll o w -u p will us uall y b e ma de vi a t he S t u d y M o nit or, alt h o u g h i n e x ce pti o nal 
circ u msta nc es t he gl o b al patie nt  safet y de p art me nt ma y c o ntact t he I n vesti gat or directl y t o o btai n 
f urt her i nf or m ati o n or t o disc uss t he e ve nt. 
T he met h o d of rec or di n g, e val u ati n g, a n d ass essi n g ca us alit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mit ti n g S A E re p orts are i n A p pe n di x 4.  
8. 3. 1  
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt 
a n d Seri o us A d verse E ve nt I nf or m ati o n   
All S A Es will be c ollecte d fr o m t h e si g ni n g of t h e I C F u ntil t he safet y f oll o w-u p visit at t h e ti me 
p oi nts s pecifie d i n t he Sc he d ule of Acti vities  ( Secti o n 1. 3 ). Be y o n d t his re p orti n g peri o d, a n y 
ne w u ns olicite d S A Es t hat t he I n v esti gat or s p o nta ne o usl y re p orts t o t he S p o ns or will be c ollecte d 
a n d pr ocess e d.  
All A E s will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he safet y f oll o w-u p visit at t he ti me 
p oi nts s pecifie d i n t he Sc he d ule of Acti vities . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A Es/ S A Es t hat be gi n bef ore t he start of st u d y i nter ve nti o n b ut after o bt ai ni n g I C F will be 
rec or de d o n t he Me dic al Hist or y/ C urre nt Me dical C o n diti o ns C RF, n ot o n t he A E C R F.  
All S A Es will be rec or de d a n d re p orte d t o t he S p o ns or or desi g nee i m me diatel y a n d u n der n o 
circ u msta nce will t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x  4 . T he I n v esti gat or will s u b mit 
a n y u p d ate d S A E data t o t he S p o ns or wit hi n 2 4  h o urs of it bei n g a vaila ble usi n g t he sa me 
pr oce d ure t hat was us e d f or t he i nitial re p ort.  
I n v esti gat ors are n ot o bli gat e d t o acti vel y s olicit A Es or S A Es after t h e e n d of st u d y partici pati o n. 
H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i n cl u di n g a deat h, at a n y ti me after a partici pa nt 
has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be reas o n a bl y relate d t o 
t he st u d y i nter ve nti o n or st u d y partici p ati o n, t he I n vesti gat or will  pr o m ptl y n otif y t he S p o ns o r. 
8. 3. 2  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts   
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n .  
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n-e n d e d a n d 
n o n -lea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut A E 
occ urre nces.  
T he met h o d of rec or di n g, e val u ati n g, a n d ass essi n g ca us alit y of A E s a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts are i n A p pe n di x  4 . 
8. 3. 3  
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts   
After t he i nitial A E/ S A E re p ort, t he In v esti gat or is re q uire d t o pr oacti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es  a n d a d verse e ve nts of s pecial i nterest ( A E SIs ) (as defi ne d 
i n Secti o n 8. 3. 6 ), will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, 
or t he partici p a nt is l ost t o f oll o w -u p (as d efi ne d i n Secti o n  7. 3 ). Reas o na ble atte m pts t o o btai n 
t his i nf or mati o n will  be ma de a n d d oc u me nte d. It is als o t he I n vesti gat or’s res p o nsi bilit y t o 
e ns ure t hat a n y n ecess ar 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. F urt h er i nf or mati o n o n f oll o w -u p pr oce d ures is i n  A p pe n di x  4 . 
8. 3. 4  
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts   
Pr o m pt n otificati o n b y t he I n v esti gat or t o t he S p o ns or of a n S A E ( partic ularl y life -t hr eate ni n g 
a n d deat hs) is ess e ntial s o t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of 
partici pa nts a n d t he safet y of a st u d y i nter ve nti o n  u n der cli nical i n vesti gati o n are met.  
T he S p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T he 
S p o ns or will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uir e me nts relati n g t o s afet y re p orti n g 
t o t he re g ulat or y a ut h orit y, I nstit uti o nal Re vie w B oar ds (I R B)/I n de p e n de nt Et hics C o m mittees 
(I E C), a n d In v esti gat ors.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
I n di vi d ual Case Safet y Re p orts will  be pre pare d f or s us pecte d u ne x pec te d seri o us a d verse 
reacti o ns ( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire m e nts a n d S p o ns or p olic y a n d 
f or war de d t o In vesti gat ors, as necess ar y.  
A n In v esti gat or w h o recei ves a n I n di vi d ual Case Safet y Re p ort descri bi n g a S U S A R or ot her 
s pecific safet y i nf or mati o n (e. g., E mer gi n g Safet y Iss ue Re p ort, s u m mar y or listi n g of 
S A Es/ S U S A Rs) fr o m t he S p o ns or will re vie w a n d t he n file it al o n g wit h t he I n v esti gat or 
Br oc h ure i n t he I n v esti gat or’s Site File a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o 
l ocal re q uir e me nts. 
I n t his gl o bal cli nical m ultice nter st u d y, t he S p o ns or is i n t he best p ositi o n t o deter mi ne a n 
u na ntici pate d pr o bl e m (as defi n e d i n U S R e g ulati o ns 2 1 C F R 3 1 2. 6 6). T he S p o ns or will 
i m me diatel y n otif y all I n v esti gat ors of fi n di n gs t hat c oul d a d versel y affect t he safet y of 
partici pa nts, i m pact t he c o n d uct of t he st u d y or alter t he I R B’s a p pr o val/fa v ora bl e o pi ni o n t o 
c o nti n ue t he st u d y. A n u na ntici pate d pr o ble m is a seri o us a d verse e v e nt t hat b y its nat ure, 
i nci de nce, se v erit y, or o utc o me has n ot bee n i d e ntifie d i n t he c urre nt versi o n of t he ris k a nal ysis 
re p ort, s pecifie d i n Secti o n 2. 3  
8. 3. 5  
Pre g n a nc y   
•  Details of all pre g na n cies i n fe male partici pa nts a n d, if i n dicate d, fe m ale part ners of mal e 
partici pa nts will be c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil 2 8  da ys after t he 
last st u d y i nter ve nti o n a d mi nistrati o n. I na d v erte nt pre g na n cies will b e f oll o we d-u p as per 
l ocal/c o u ntr y ( healt h a ut h orities) g ui deli nes.  
•  If a pre g n a nc y is re p orte d, t he In v esti gat or will i nf or m t he S p o ns or wit hi n 2 4  h o urs of lear ni n g 
of t he pre g na n c y a n d will f oll o w t he pr oce d ures s pecifie d bel o w  f or c ollecti o n of pre g n a nc y 
i nf or mati o n. 
•  A b n or mal pre g na n c y o ut c o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g n a nc y) are c o nsi dere d S A Es.  
C ollecti o n of Pre g n a nc y I nf or m ati o n  
Male partici pa nts wit h part ners w h o bec o me pre g n a nt  
•  T he In v esti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y mal e partici pa nt’s 
fe male part ner, w h o bec o mes pre g n a nt w hile t he partici pa nt is i n t his st u d y. T his a p plies 
o nl y t o partici pa nts w h o recei v e  st u d y i nter ve nti o n. 
•  After o bt ai ni n g si g n e d c o nse nt fr o m t he pre g n a nt f e male part ner directl y, t h e In vesti gat or 
will rec or d t he pre g n a nc y i nf or mati o n o n t he a p pr o priate f or m a n d s u b mit it t o t he S p o ns or 
wit hi n 2 4  h o urs  of l e ar ni n g of t he pre g na nc y. T he fe male part ner will als o be f oll o we d t o 
deter mi ne t he o utc o me of t he pre g n a nc y. I nf or m ati o n o n t he stat us of t he m ot her a n d c hil d 
will be f or war de d t o t he S p o ns or. Ge n erall y, t h e f oll o w -u p will b e n o l o n ger t ha n 6 t o 
8  wee ks f o ll o wi n g t he esti mate d deli ver y date. A n y ter mi nati o n of t he pre g na n c y will be 
re p orte d re gar dless of fet al stat us ( prese nce or a bs e nce of a n o malies) or i n dicati o n f or t he 
pr oce d ure.  
Fe male Partici pa nts w h o bec o me pre g na nt  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  T he In v esti gat or will c ollect pre g n a nc y i nf or m ati o n o n a n y fe male partici pa nt w h o 
bec o mes pre g n a nt w hile s he is i n t he st u d y. T he i nitial i nf or mati o n will be rec or de d o n t he 
a p pr o priate f or m a n d s u b mitte d t o t he S p o ns or wit hi n 2 4  h o urs  of lear ni n g of t he 
pre g na nc y.  
•  T he partici p a nt will be  f oll o we d t o det er mi ne t he o utc o me of t he pre g na nc y. T he 
In v esti gat or will c ollect f oll o w -u p i nf or mati o n o n t he partici pa nt a n d t h e ne o nate,  a n d t h e 
i nf or mati o n will be f or war de d t o t h e S p o ns or. Ge nerall y, f oll o w -u p will n ot be re q uire d 
f or l o n ger t ha n 6 to 8 wee ks b e y o n d t he esti mate d deli ver y date. A n y ter mi nati o n of 
pre g na nc y will be re p ort e d, re gar dless of fet al stat us ( prese n ce or a bse n ce of a n o malies) 
or i n dicati o n f or t he pr oce d ure.  
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g n a nc y c o m plicati o n 
or electi ve ter mi nati o n of a pre g na n c y f or me dical reas o ns will be re p ort e d as a n A E or 
S A E.  
•  A s p o nta ne o us a b orti o n ( occ urri n g at <  2 2 wee ks gestati o nal a ge) or still birt h ( occ urri n g 
at > 2 2 wee ks gestati o nal a ge) is al w a ys c o nsi dere d t o be a n S A E a n d will be re p ort e d as 
s uc h. 
•  A n y p ost -st u d y pre g na nc y relate d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y 
i nter ve nti o n b y t h e In vesti gat or 
will be re p orte d t o t he S p o ns or as s pecifie d i n 
Secti o n  8. 3. 4 . W hile t he In v esti gat or is n ot o bli gate d t o acti vel y s ee k t his i nf or mati o n i n 
f or mer st u d y partici pa nts, he or s he ma y lear n of a n S A E t hr o u g h s p o nta n e o us re p orti n g. 
•  A n y fe mal e partici pa nt  w h o bec o mes pre g n a nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y i nter ve nti o n . 
8. 3. 6  
A d verse E ve nts of S peci al I nterest   
F or t his st u d y, A E SIs i ncl u de o nl y t he f oll o wi n g:  
•  C yt o pe nia 
(l y m p h o pe nia, 
le u k o pe nia / ne utr o p e nia, 
t hr o m b oc yt o p e ni a, 
a ne mia), 
Gra de  ≥ 3 or 
wit h c o m plicati o ns, e. g., ne utr o pe nia 
wit h fe ver or i nfecti o n or 
t hr o m b oc yt o pe ni a wit h me dicall y c o ncer ni n g blee di n g. 
A n A E SI (seri o us or n o nseri o us reacti o n) is o ne of scie ntific a n d me dical c o ncer n s pecific t o t he 
st u d y i nter ve nti o n, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y t he I n v esti gat or 
t o t he S p o ns or is re q uire d. S uc h e ve nts of i nterest ma y re q uir e f urt her i n vesti gati o n or i n-de pt h 
e val uati o ns t o bet ter c haracterize a n d u n derst a n d t he ass ociati o n bet w ee n t he A E  a n d M 4 0 7 6 . 
Base d o n n o n cli nical dat a, t he f oll o wi n g A Es will be c o nsi dere d A E SI (T a ble  1 1 ).  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
T a ble  1 1  
A d verse E ve nts of S peci al I nterest   
A E  
M a n a g e m e nt  
C yt o p e ni a s ( l y m p h o p e ni a, 
l e u k o/ n e utr o p e ni a, t hr o m b o c yt o p e ni a, 
a n e mi a), Gr a d e ≥ 3 or wit h c o m pli c ati o n s, 
e. g.  n e utr o p e ni a wit h f e v er or i nf e cti o n or 
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.  
R e p e at bl o o d t e st wit hi n 7 2 h o ur s  of r e c ei vi n g t h e a b n or m al l a b r e s ult . 
C o nti n u o u s m o nit ori n g of A E s wit h cli ni c al m a n a g e m e nt a s i n di c at e d, 
i n cl u di n g 
st u d y i nt er v e nti o n i nt err u pti o n, 
d o s e 
m o difi c ati o n 
or 
di s c o nti n u ati o n  (s e e T a bl e  1 0 ). 
A E = A d v er s e e v e nt.  
T he I n v esti gat or m ust c o m plete t he A E SI Re p ort F or m a n d c o m m u nicate wit h t he S p o ns or 
wit hi n 2 4  h o urs of occ urre nce of A E SI. Seri o us A E SI ( base d o n S A E re p orti n g criteri a) s h o ul d 
al wa ys be re p orte d as S A E as o utli ne d i n Secti o n  8. 3. 4 . 
8. 4  
Tre at me nt of O ver d ose   
F or t his st u d y, a n y d os e of M 4 0 7 6  greater t h a n t h e s pecifi e d d ose f or eac h st u d y c o h ort will be 
c o nsi dere d a n o ver d os e.  
T he S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose , ot her t ha n s y m pt o matic 
treat me nt of A Es as dee me d necess ar y .  
E ve n if n ot ass o ciate d wit h a n A E or a n  S A E, a n y o ver d ose is rec or de d i n t he C R F a n d re p ort e d 
t o g l o bal p atie nt safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n an  S A E a n d O ver d ose 
Re p ort F or m, f oll o wi n g t he pr oce d ure i n  A p pe n di x  4 , t he secti o n o n Re p orti n g S A Es.   
8. 5  
P h ar m ac o ki netics   
Sa m pli n g ti mes f or t he deter mi nati o n of M 4 0 7 6 ca n be f o u n d i n Ta ble  3  f or Part 1 A a n d Ta ble  4  
f or Part 1 B.  T he P K sa m pli n g sc he d ule  m a y b e m o difie d u p o n a gree me nt of t he cli nical 
p har mac ol o gist , i n vesti gat ors, a n d S M C t o o pti mize t he defi niti o n of t he p har mac o ki neti c 
pr ofiles b ut will n ot i ncrease t he n u m ber of P K dra ws.  
T he f oll o wi n g P K p ara meters 
will be calc ul ate d, 
w he n a p pr o priate  (see Ta ble  1 2 ). 
A 
n o n -c o m part me ntal a nal ysis ( N C A) will be perf or me d t o esti mate t hese P K para meters f or 
M 4 0 7 6.  
T a ble  1 2  
Assess me nt of Bl o o d P h ar m ac o ki ne tic P ar a meters  
S y m b ol  
D efi niti o n  
A U C 0 -tl a st 
T h e ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o ( = d o si n g 
ti m e) t o t h e l a st s a m pli n g ti m e (tl a st) at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e 
t h e l o w er li mit of q u a ntifi c ati o n. C al c ul at e d u si n g t h e mi x e d l o g-li n e ar 
tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
A U C 0 -tl a st/ D o s e 
T h e D o s e n or m ali z e d A U C fr o m ti m e z er o t o t h e l a st s a m pli n g ti m e (t l a st) at 
w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n. 
N or m ali z e d u si n g t h e a ct u al d o s e, u si n g t h e f or m ul a A U C 0 -tl a st / D o s e. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
S y m b ol  
D efi niti o n  
A U C  
T h e A U C o v er t h e d o si n g i nt er v al fr o m T 1  =  0 h t o T 2  =  h. C al c ul at e d u si n g t h e 
mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, lo g d o w n). F or si n gl e d o s e, A U C  i s 
c al c ul at e d a s a p arti al ar e a wit h t h e d efi n e d ti m e r a n g e. I n m ulti pl e d o s e 
pr ofil e s A U C  i s c al c ul at e d at st e a d y st at e fr o m o n e pr e-d o s e ti m e p oi nt t o t h e 
d o si n g i nt er v al ti m e. I n c a s e s w h er e t h e a ct u al o b s er v ati o n ti m e i s n ot e q u al t o 
t h e s c h e d ul e d o b s er v ati o n ti m e A U C will b e c al c ul at e d b a s e d o n t h e 
e sti m at e d c o n c e ntr ati o n at h o ur s, a n d n ot t h e c o n c e ntr ati o n at t h e a ct u al 
o b s er v ati o n ti m e.  
A U C  / D o s e 
T h e d o s e n or m ali z e d A U C o v er t h e i nt er v al fr o m T 1  =  0 h t o T 2  =   h. 
N or m ali z e d u si n g a ct u al d o s e, u si n g t h e f or m ul a A U C  / D o s e. 
A U C 0 -7 2  
T h e A U C fr o m ti m e z er o ( = d o si n g ti m e) t o 7 2  h o ur s  p o st -d o s e. C al c ul at e d 
u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). I n c a s e s 
w h er e t h e a ct u al o b s er v ati o n ti m e i s n ot e q u al t o t h e s c h e d ul e d o b s er v ati o n 
ti m e ( 7 2 h o ur s ), A U C0 -7 2  will b e c al c ul at e d b a s e d o n t h e e sti m at e d 
c o n c e ntr ati o n at 7 2  h o ur s, a n d n ot t h e c o n c e ntr ati o n at t h e a ct u al o b s er v ati o n 
ti m e. 
A U C 0 -7 2 / D o s e 
T h e d o s e n or m ali z e d A U C fr o m ti m e z er o ( = d o si n g  ti m e) t o 7 2 h o ur s  
p o st -d o s e. N or m ali z e d u si n g a ct u al d o s e, u si n g t h e f or m ul a A U C 0 -7 2 / D o s e. 
A U C 0 - 
T h e A U C fr o m ti m e z er o ( d o si n g ti m e) e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e 
pr e di ct e d v al u e f or t h e c o n c e ntr ati o n at t l a st, a s e sti m at e d u si n g t h e li n e ar 
re gr e s si o n fr o m λ z d et er mi n ati o n. A U C 0 -∞ =  A U C 0 -tl a st + C l a st pr e d/ λz 
A U C 0 -/ D o s e 
T h e d o s e n or m ali z e d A U C fr o m ti m e z er o e xtr a p ol at e d t o i nfi nit y. N or m ali z e d 
u si n g a ct u al d o s e, u si n g t h e f or m ul a A U C 0 -∞ / D o s e. 
C L/ F  
T h e a p p ar e nt t ot al b o d y cl e ar a n c e of st u d y i nt er v e nti o n f oll o wi n g e xtr a v a s c ul ar 
a d mi ni str ati o n.  C L/ F  =  D o s e p. o. / A U C0 -∞. 
C m a x  
M a xi m u m o b s er v e d c o n c e ntr ati o n  
C m a x/ D o s e  
T h e d o s e n or m ali z e d m a xi m u m c o n c e ntr ati o n. N or m ali z e d u si n g t h e a ct u al 
d o s e, a n d t h e f or m ul a C m a x / D o s e. 
C tr o u g h 
T h e c o n c e ntr ati o n o b s er v e d i m m e di at el y b ef or e n e xt d o si n g  
LI  
T h e li n e arit y i n d e x aft er r e p e at e d a d mi ni str ati o n c al c ul at e d a s LI  =  ( A U C aft er 
m ulti pl e d o s e ) / ( A U C0 -∞ aft er si n gl e d o s e)  
R a c c( A U C ) 
T h e a c c u m ul ati o n r ati o aft er r e p e at e d a d mi ni str ati o n c al c ul at e d a s 
R a c c( A U C ) =  ( A U C aft er m ulti pl e d o s e) / ( A U C  aft er si n gl e d o s e)  
R a c c( C m a x)  
T h e a c c u m ul ati o n f a ct or t o a s s e s s t h e i n cr e a s e i n m a xi m u m c o n c e ntr ati o n 
u ntil st e a d y st at e i s r e a c h e d. R a c c( C m a x)  =  ( Cm a x  aft er m ulti pl e d o s e)/ ( C m a x aft er 
si n gl e d o s e)  
t1/ 2  
A p p ar e nt t er mi n al h alf -lif e. t1/ 2  =  l n ( 2)/ λz 
tl a st 
T h e l a st s a m pli n g ti m e at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit 
of q u a ntifi c ati o n  
tm a x  
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a 
d o si n g i nt er v al ( u nl e s s ot h er wi s e d efi n e d, t a k e t h e 1 st o c c urr e n c e i n c a s e of 
m ulti pl e/i d e nti c al C
m a x  v al u e s)  
V z/ F 
T h e a p p ar e nt v ol u m e of di stri b uti o n d uri n g t h e t er mi n al p h a s e f oll o wi n g 
e xtr a v a s c ul ar a d mi ni str ati o n. V z/ F = D o s e/( A U C0 -∞* λ z) f oll o wi n g si n gl e d o s e. 
V z/ F =  D o s e/( A U C * λz) f oll o wi n g m ulti pl e d o s e. 
 
•  W h ole bl o o d sa m ples 
(of a p pr o xi matel y 2  m L ) a n d uri ne sa m ples ( Part 1 B o nl y)  will be 
c ollecte d f or me as ur e me nt of plas ma a n d uri ne c o nce ntrati o ns  of M 4 0 7 6 . C ollecti o n ti mes 
are s pecifie d i n t he Sc he d ule of Acti vities  (Ta ble  3  f or Part 1 A a n d Ta ble  4  f or Part 1 B) . T h e 
act ual d ate a n d ti me ( 2 4 -h o ur cl oc k) of eac h s a m ple will be rec or de d t o cal c ulate act ual ti me 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
ela pse d si nc e t he pri or d ose a d mi nistrati o n. T he s a m pli n g ti mi n g ma y b e altere d d uri n g t he 
st u d y b ase d o n ne wl y a v aila ble data (e. g., t o o btai n data cl oser t o t he ti me of pea k plas ma 
c o nce ntr ati o ns) t o e ns ure a p pr o priate m o nit ori n g. I n a d diti o n, act ual d ate a n d ti me of start 
a n d e n d of t he uri ne c ollecti o n fracti o n a n d t he v ol u me of eac h uri ne c oll ecti o n fracti o n will 
be rec or de d i n t he C R F.   
•  T he q ua ntificati o n o f M 4 0 7 6 c o nce ntrati o ns i n plas ma a n d uri ne will be perf or me d usi n g 
vali date d bi oa nal ytical met h o ds a n d will be re p orte d i n a se p arate bi oa nal yti cal re p ort.  
C o nce ntrati o ns will be use d t o e val uate t he P K  of M 4 0 7 6.  
•  Re mai ni n g s a m ples  c ollecte d f or t he a nal ysi s of M 4 0 7 6 plas ma  a n d uri ne c o nce ntrati o n s ma y 
be use d t o e val uat e safet y or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or aft er t he 
st u d y, w hic h will be re p orte d o utsi de of t he cli nical st u d y re p ort ( C S R ).  
•  T he f oll o wi n g p har mac o ki netic para meters  will be esti mate d fr o m uri ne c o nce ntrati o n of 
M 4 0 7 6  i n Part 1 B  (Ta ble  1 3 ), w here p ossi ble: 
T a ble  1 3  
Assess me nt of Uri ne P h ar m ac o ki netic P ar a meters   
S y m b ol  
D efi niti o n  
A e t 1-t 2 
T ot al a m o u nt e x cr et e d b et w e e n ti m e s t 1 ( = st art) a n d t 2 ( = e n d) of t h e c urr e nt 
c oll e cti o n i nt er v al.  
C al c ul at e d b y i nt er v al A et 1-t 2 = C o n c * V u (t 1-t 2) a n d c u m ul ati v e.  
f et 1-t 2 %   
Fr a cti o n of a d mi ni st er e d dr u g t h at i s e x cr et e d u n c h a n g e d i n uri n e b et w e e n 
ti m e s t 1 ( = st art) a n d t 2 ( = e n d) of t h e c urr e nt c oll e cti o n i nt er v al.  
C al c ul at e d b y i nt er v al f e t 1-t 2 = A e t 1-t 2/ D o s e a n d c u m ul ati v e.   
C L R  
T h e r e n al cl e ar a n c e of st u d y i nt er v e nti o n. C L R  = A e 0 -t/ A U C0 -t. 
A d diti o nal para meters ma y b e calc ulate d if a p pr o priate.  
Met h o d ol o g y f or t he calc ulati o n of p har mac o ki netic para meters will be detaile d i n t he I nte grat e d 
A nal ysis Pla n (i A P).  
•  Details o n pr ocess es f or c ollecti o n a n d ha n dli n g of t hese sa m ples are i n t he La b orat or y 
Ma n ual. Rete nti o n ti me a n d p ossi ble a nal yses of s a m ples after t he e n d of st u d y are s pecifie d 
i n t he res pecti ve I C F. 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 8 /1 2 2  
 
 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
8. 9  
I m m u n o ge nicit y Assess me nts  
N ot a p pli ca ble  
8. 1 0  
He alt h Ec o n o mics   
N ot a p plica ble  
9  
St atistic al C o nsi der ati o ns   
A nal ysis of all data, i ncl u di n g safet y a n d P K d ata will be perf or me d b y t he S p o ns or or its 
desi g nee. T h e res ults of all st u d y p arts will be re p orte d i n t he C S R . Details of t he a n al ysis of 
safet y, efficac y, P K, P d, a n d bi o mar ker data will be prese nt e d i n t he i A P. 
9. 1  
St atistic al H y p ot hes es  
N o f or mal h y p ot hesis testi n g will be perf or me d. T his is a n e x pl orat or y st u d y.  
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 0 /1 2 2  
 
 
9. 2  
S a m ple Size Deter mi n ati o n   
Part 1 A –  D ose E scalati o n 
A 
Ba yesia n 
2 -para met er 
L o gistic 
Re gressi o n 
M o del 
will assist t he 
S M C i n d ose 
rec o m me n dati o ns. T h e pl a n ne d c o h ort siz e is a p pr o xi matel y 3 p artici pa nts. T he t otal sa m ple siz e 
will de pe n d o n t he n u m ber of c o h orts t o b e e val uate d . A p pr o xi matel y 4 0  partici pa nts are pla n ne d 
t o be assi g n e d t o st u d y i nter ve nti o n, i ncl u di n g 2 2 t o 2 8  partici pa nts i n Part  1 A ( pla n ne d 
4  p ote ntial D Ls of 1 0 0, 2 0 0, 4 0 0, a n d 6 0 0  m g), a n d 1 2  partici pa nts i n Part 1 B; t he sa m ple siz e 
f or t he M T D a n d/ or R D E D L n ee ds t o be at least 6 partici pa nts.  
Part 1 B –  Preli mi nar y F o o d Effect Ass ess me nt Sa m ple Size J ustificati o n  
F or a preli mi nar y assess me nt of t he effect of f o o d o n t he s yste mic e x p os ure of 
M 4 0 7 6, 
1 2  partici pa nts will be ra n d o mize d 1: 1 i n a ra n d o mize d , 2 -se q ue nce, 2 -peri o d , cr oss-o ver desi g n 
t o recei ve a si n gle d ose M 4 0 7 6 u n der a fe d c o n diti o n i n 1 of t he f oll o wi n g se q ue nces 1) faste d 
f oll o we d b y fe d, or 2) fe d f oll o we d by faste d. T he d ose of M 4 0 7 6 will be t he R D E fr o m Part  1 A.  
T his sa m ple siz e is e x pecte d t o res ult i n s uffi cie nt precisi o n f or t he esti mate of t he rati o bet wee n 
P K para meters u n der fe d a n d faste d c o n diti o ns i n or der t o g ui d e f urt her d e vel o p me nt. Ass u mi n g 
t hat t he wit hi n-s u bject c oefficie nt of vari ati o n ( C V ) f or A U C0 -2 4 h a n d C ma x  is bet wee n 1 0 % a n d 
3 0 %, t he 2 -si de d 9 0 % c o nfi de nce i nter val ( CI) f or t he ge o metric mea n rati o ( G M R) will be 
c o ntai ne d i n t he b o u n dari es prese nte d i n T a ble  1 4 , wit h 8 0 % pr o ba bilit y. 
F or e x a m ple, if t he wit hi n -s u bject C V is 2 0 %, a n d a G M R of 5 0 % is o bs er ve d, t he n t he 9 0 % CI  
f or t he G M R will be c o nt ai ne d i n [ 3 5. 6 %; 7 0. 2 %] wit h 8 0 % pr o ba bilit y. Wit h a C V of 3 0 % a n d 
a n o bser ve d G M R of 1 0 0 %, t he c orres p o n di n g b o u n daries are [ 6 0. 5 %; 1 6 5 %].  
T a ble  1 4  
8 0 % 
C o ver a ge I nter v al f or t he 9 0 % 
C o nfi de nce I nter v als f or  
Esti m ate d Fe d/ F aste d R ati o, n  =  6 per Se q ue nce ( 1 2 i n t ot al )  
C V  
G M R  
8 0 % C o v er a g e I nt er v al  
n  =  6 p er S e q u e n c e  
 
F e d v er s u s F a st e d  
L o w er B o u n d  
U p p er B o u n d  
1 0 %  
0. 5 0  
4 2. 1 %  
5 9. 3 %  
2 0 %  
0. 5 0  
3 5. 6 %  
7 0. 2 %  
3 0 %  
0. 5 0  
3 0. 2 %  
8 2. 7 %  
 
1 0 %  
1. 0 0  
8 4. 3 %  
1 1 9 %  
2 0 %  
1. 0 0  
7 1. 2 %  
1 4 0 %  
3 0 %  
1. 0 0  
6 0. 5 %  
1 6 5 %  
 
1 0 %  
2. 0 0  
1 6 9 %  
2 3 7 %  
2 0 %  
2. 0 0  
1 4 2 %  
2 8 1 %  
3 0 %  
2. 0 0  
1 2 1 %  
3 3 1 %  
C V  =  c o effi ci e nt of v ari ati o n ; G M R = G e o m etri c m e a n r ati o.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
T h e s e c al c ul ati o n s w er e p erf or m e d u si n g t h e m o d ul e M T C 1 1 of t h e s oft w ar e n Q u er y A d vi s or ® 7. 0 f or n at ur al 
l o g arit h m tr a n sf or m e d d at a, a n d b a c k-tr a n sf or m e d t o t h e ori gi n al s c al e. 
9. 3  
P o p ul ati o ns f or A n al yses   
T he a nal ysis p o p ulati o ns are s pecifie d bel o w ( Ta ble  1 5 ). T h e fi nal d ecisi o n t o e x cl u de 
partici pa nts fr o m a n y a n al ysis p o p ulati o n will be ma de d uri n g a d ata re vie w meeti n g pri or t o 
data base l o c k. H o we ver, f or t he D L T a nal ysis set, t he decisi o n o n e val ua bilit y will be ma de b y 
t he S M C. 
T a ble  1 5  
P o p ul ati o ns f or A n al yses   
A n al y si s S et  
D e s cri pti o n  
S cr e e ni n g ( S C R)  
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt.  
F ull A n al y si s S et ( F A S) 
/ S af et y A n al y si s S et 
( S A F) 
All S C R p arti ci p a nt s, w h o r e c ei v e d at l e a st o n e d o s e of a n y st u d y i nt er v e nti o n.  
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d .  
D L T  
All F A S/ S A F p arti ci p a nt s w h o m e et at l e a st o n e of t h e f oll o wi n g crit eri a:  
•  
E x p eri e n c e d at l e a st o n e D L T d uri n g t h e D L T p er i o d, r e g ar dl e s s of t h e 
a d mi ni st er e d n u m b er of d o s e s of st u d y i nt er v e nti o n/ c o m pl eti o n of t h e D L T p eri o d . 
•  
R e c ei v e d at l e a st 8 0 % of t h e pl a n n e d c u m ul ati v e d o s e d uri n g t h e D L T p eri o d of 
e a c h st u d y i nt er v e nti o n a n d c o m pl et e d t h e D L T p eri o d . 
•  
A d diti o n all y, p arti c i p a nt s w h o di d n ot r e c ei v e 8 0 % of t h e pl a n n e d t ot al d o s e of 
st u d y i nt er v e nti o n, b ut at l e a st 8 0 % d o si n g of a diff er e nt d o s e c o h ort a n d fi ni s h e d 
t h e D L T p eri o d ar e eli gi bl e f or t h e D L T a n al y si s s et t o b e a n al y z e d i n t h e hi g h e st 
d o s e c o h ort f or w hi c h t h e y r e c ei v e d 8 0 % of d o si n g.  
T h e fi n al d e ci si o n o n e v al u a bilit y f or d o s e e s c al ati o n a n al y si s will b e m a d e b y t h e S M C 
( e. g. c o n si d eri n g r el e v a nt d e vi ati o n s fr o m d o si n g s c h e d ul e). 
P K ( P K A S) 
All p arti ci p a nt s w h o r e c ei v e at l e a st o n e d o s e of st u d y i nt er v e nti o n a n d pr o vi d e at l e a st 
o n e m e a s ur a bl e p o st -d o s e c o n c e ntr ati o n. A m e a s ur e m e nt b el o w l o w er li mit of 
q u a ntifi c ati o n ( B L Q) i s c o n si d er e d a v ali d m e a s ur e m e nt. P arti ci p a nt s will b e a n al y z e d 
a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e d. All P K a n al y s e s will b e b a s e d  o n t h e 
P K A n al y si s P o p ul ati o n.  
P d  
All p arti ci p a nt s, w h o r e c ei v e at l e a st o n e d o s e of st u d y i nt er v e nti o n, h a v e n o cli ni c all y 
i m p ort a nt pr ot o c ol d e vi ati o n s or i m p ort a nt e v e nt s aff e cti n g P d, a n d pr o vi d e at l e a st 
o n e m e a s ur a bl e P d e n d p oi nt p o st d o s e.  
P arti ci p a nt s will b e a n al y z e d p er t h e a ct u al st u d y i nt er v e nti o n t h e y r e c ei v e d. All P d 
a n al y s e s will b e b a s e d o n t hi s a n al y si s p o p ul ati o n.  
D L T = d o s e li miti n g t o xi cit y; 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 K A S = p h ar m a c o ki n eti c a n al y si s 
s et .  
9. 4  
St atistic al  A n al yses   
All a nal yses will be pre p are d b y D L a n d will be descri be d i n detail i n t he i A P. E x ce pt f or t he 
a nal ysis of D L Ts, all a n al yses will be perf or me d o n t he Safet y A nal ysis p o p ulati o n.  
T he f oll o wi n g statistics will be use d t o s u m marize t he st u d y dat a (e. g. bas eli ne c haracteristics) 
u nless ot her wise s pecifie d:  
•  C o nti n u o us v ari a bles : n u m ber of n o n -missi n g o bser vati o ns, mea n, sta n d ar d de viati o n, 
me dia n, 2 5 % Perce ntile t o 7 5 % Perce ntile ( Q 1  t o Q 3), mi ni m u m, a n d ma xi m u m, 9 5 %  CIs 
f or t he mea n, as a p pr o priate. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  C ate g oric al v a ri a bles:  fre q ue nci es a n d perce nt a ges. 
T he calc ul ati o n of pr o p orti o ns will be base d o n t he n u m ber of p artici pa nts i n t he a nal ysis set of 
i nterest, u nless ot her wise s pecifie d i n t he st u d y i A P. 
B aseli ne  is defi ne d as last n o n-missi n g val ue pri or t o first a d mi nistrati o n of st u d y i nter ve nti o n  
O n -tre at me nt v al ues are defi ne d a s t h ose meas ure d d uri n g t he st u d y i nter ve nti o n peri o d. 
Besi des t he d etails o utli ne d bel o w, m ore details will be s pecifie d i n t he i A P fi nalize d bef ore 
data base l oc k.  
9. 4. 1  
Effic ac y A n al yses   
All efficac y a n al ys es will be perf or me d o n t he F ull A nal ysis Set  p o p ulati o n u nless ot her wise 
s pecifie d (T a ble  1 6 ). 
T a ble  1 6  
P art 1 A  Effic ac y A n al yses   
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
P art 1 A  
Pri m ar y  
N o pri m ar y effi c a c y e n d p oi nt i s s p e cifi e d . 
S e c o n d ar y  
O bj e cti v e r e s p o n s e a c c or di n g t o 
R E CI S T  1. 1 a s s e s s e d b y I n v e sti g at or  
O R R will b e d et er mi n e d a s t h e pr o p orti o n of p arti ci p a nt s wit h a 
c o nfir m e d o bj e cti v e r e s p o n s e of P R or C R. C o nfir m ati o n of t h e  
r e s p o n s e a c c or di n g t o R E CI S T 1. 1 will b e r e q uir e d n o s o o n er t h a n 
4  w e e k s aft er t h e i niti al d o c u m e nt ati o n of C R or P R.  
 
T h e n u m b er a n d pr o p orti o n of o v er all r e s p o n s e ( d efi n e d a s C R + P R) 
will b e t a b ul at e d.  
T h e 9 5 % CI f or t h e O R R will b e c al c ul at e d u si n g t h e Cl o p p er -P e ar s o n 
m et h o d.  
D o R a c c or di n g t o R E CI S T  1. 1 
a s s e s s e d b y I n v e sti g at or  
D o R i s d efi n e d a s t h e ti m e ( m o nt h s) fr o m fir st d o c u m e nt ati o n of 
o bj e cti v e r e s p o n s e ( C R or P R) t o t h e d at e of fir st d o c u m e nt ati o n of P D 
or d e at h d u e t o a n y c a u s e, w hi c h e v er o c c u r s fir st.  
 
D ur ati o n of r e s p o n s e d at a will b e c e n s or e d o n t h e d at e of t h e l a st n o n -
mi s si n g t u m or a s s e s s m e nt f or p arti ci p a nt s w h o d o n ot h a v e a n e v e nt 
( P D or d e at h) or f or p arti ci p a nt s f or w hi c h t h e e v e nt i s r e p ort e d aft er 
t w o or m or e mi s s e d s u b s e q u e nt s c h ed ul e d t u m or a s s e s s m e nt s. 
P arti ci p a nt s w h o d o n ot h a v e a b a s eli n e t u m or a s s e s s m e nt or w h o d o 
n ot h a v e a n y p o st b a s eli n e t u m or a s s e s s m e nt s will b e c e n s or e d at t h e 
d at e of t h e st art of st u d y i nt er v e nti o n.  
 
K a pl a n -M ei er e sti m at e s ( pr o d u ct -li mit e sti m at e s) will b e pr e s e nt e d f or 
t h e a n al y si s of D o R t o g et h er wit h a s u m m ar y of a s s o ci at e d st ati sti c s 
( m e di a n D o R  a n d r e s p o n s e r at e e sti m at e s at 3, 6, 1 2 m o nt h s a n d 
e v er y 6 m o nt h s t h er e aft er if a p pli c a bl e) i n cl u di n g t h e c orr e s p o n di n g 
2 -si d e d 9 5 % CI s.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 3 /1 2 2  
 
 
P F S a c c or di n g t o R E CI S T  1. 1 
a s s e s s e d b y I n v e sti g at or  
P F S i s d efi n e d a s t h e ti m e (i n m o nt h s) fr o m d at e of fir st a d mi ni str ati o n 
of st u d y i nt er v e nti o n t o t h e d at e of t h e fir st d o c u m e nt ati o n of P D or 
d e at h d u e t o a n y c a u s e, w hi c h e v er o c c ur s fir st. T h e c e n s ori n g r ul e s 
f or P F S ar e a s d e s cri b e d a b o v e f or D o R. 
 
K a pl a n -M ei er e sti m at e s ( pr o d u ct -li mit e sti m at e s) will b e pr e s e nt e d f or 
t h e a n al y si s of P F S  t o g et h er wit h a s u m m ar y of a s s o ci at e d st ati sti c s 
( m e di a n P F S ti m e  a n d P F S r at e  e sti m at e s at 3, 6, 1 2  m o nt h s a n d 
e v er y 6 m o nt h s t h er e aft er if a p pli c a bl e) i n cl u di n g t h e c orr e s p o n di n g 2 -
si d e d 9 5 % CI s.  
T erti ar y/ E x pl or at or y  
Will b e s p e cifi e d i n t h e I nt e gr at e d A n al y si s Pl a n, fi n ali z e d b ef or e 
d at a b a s e l o c k.  
CI  =  c o nfi d e n c e i nt er v al; C R  =  c o m pl et e r e s p o n s e; D o R  =  d ur ati o n of r e s p o n s e; O R R  =  o bj e cti v e r e s p o n s e r at e; 
P D  =  di s e a s e pr o gr e s si o n ; P F S  =  pr o gr e s si o n -fr e e s ur vi v al; P R =  p arti al r e s p o n s e; 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.  
9. 4. 2  
S afet y A n al yses   
T he D L T a n al ysis will be perf or me d o n t he D L T A nal ysis p o p ulati o n. All ot her safet y a nal yses 
will be perf or me d o n t h e Safet y A nal ysis p o p ulati o n.  See Ta ble  1 7 . 
T a ble  1 7  
S afet y A n al yses   
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
P art 1 A   
Pri m ar y  
D L T  
A E s cl a s sifi e d a s D L T s a s a s s e s s e d b y S M C will b e e v al u at e d.  
B a y e si a n d o s e t o xi cit y  a n al y si s . 
At pri m ar y a n al y si s f or P art 1 A , t h e n u m b er a n d pr o p orti o n of p arti ci p a nt s 
e x p eri e n ci n g D L T s will b e r e p ort e d b y d o s e l e v el, b a s e d o n o b s er v ati o n s d uri n g t h e 
fir st st u d y i nt er v e nti o n e v al u ati o n  ( 2 1 d a y s) . P o st eri or pr o b a biliti e s ( 2. 5 %, 2 5 %, 5 0 %, 
7 5 %, a n d 9 7. 5 % q u a ntil e s) f or D L T r at e s at s el e ct e d d o s e s will b e e sti m at e d fr o m t h e 
B a y e si a n d o s e t o xi cit y m o d el.  
S e n siti vit y a n al y si s u si n g fr e q u e nti st m o d eli n g ( wit h o ut pri or).  
R e g ar di n g i nt er c urr e nt e v e nt s: T h e s e ar e c o n si d er e d i n t h e d efi niti o n of D L T s a n d 
D L T a n al y si s s et.  
S e c o n d ar y  
A E  
A E s will b e c o d e d a c c or di n g t o t h e l at e st a v ail a bl e v er si o n of M e d D R A. S e v erit y of 
A E s will b e gr a d e d u si n g t h e N CI -C T C A E ( V er si o n  5. 0). Mi s si n g cl a s sifi c ati o n s 
c o n c er ni n g st u d y i nt er v e nti o n r el ati o n s hi p s will b e c o n si d er e d r el at e d t o t h e st u d y 
i nt er v e nti o n. T E A E s ar e d efi n e d a s A E s e m er gi n g or w or s e ni n g aft er st art of st u d y 
i nt er v e nti o n u ntil 3 0 d a y s aft er t h e e n d of st u d y i nter v e nti o n p eri o d.  
F oll o wi n g T E A E s will b e pr e s e nt e d i n s u m m ari e s b y i n ci d e n c e a n d t y p e a c c or di n g t o 
M e d D R A S y st e m Or g a n Cl a s s e s a n d Pr ef err e d T er m s:  
•  
T E A E s .  
•  
S A E s .  
•  
T E A E s r el at e d t o st u d y i nt er v e nti o n s . 
•  
N CI -C T C A E  Gr a d e  3 or hi g h er T E A E s . 
•  
N CI -C T C A E  Gr a d e  3 or hi g h er r el at e d T E A E s . 
•  
T E A E s l e a di n g t o i nt err u pti o n s, d o s e m o difi c ati o n s of st u d y i nt er v e nti o n s . 
•  
T E A E s l e a di n g t o p er m a n e nt di s c o nti n u ati o n of st u d y i nt er v e nti o n s . 
•  
T E A E s l e a di n g t o d e at h . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 4 /1 2 2  
 
 
D e at h  
C o u nt s a n d p er c e nt a g e s.  
C h a n g e s i n l a b or at or y 
m e a s ur e m e nt s  
S u m m ar y st ati sti c s a n d b o x pl ot s.  
L a b or at or y r e s ult s will al s o b e cl a s sifi e d b y Gr a d e a c c or di n g t o N CI -C T C A E. W or st 
o n -tr e at m e nt gr a d e s a s w ell a s s hift s t o w or st o n tr e at m e nt gr a d e s will b e 
s u m m ari z e d. M e a s ur e m e nt s wit h o ut N CI -C T C A E gr a di n g wi ll b e s u m m ari z e d b y 
a b o v e, wit hi n a n d b el o w n or m al li mit s.  
Vit al si g n s a n d E C O G 
p erf or m a n c e st at u s  
B a s eli n e a n d o n -tr e at m e nt v al u e s will b e s u m m ari z e d. 
S u m m ar y st ati sti c s : 
I n cr e a s e/ d e cr e a s e i n vit al si g n s ( b o d y t e m p er at ur e, h e art r at e, bl o o d pr e s s ur e a n d 
r e s pir at or y r at e), E C O G p erf or m a n c e st at u s a n d b o d y w ei g ht will b e c at e g ori z e d a n d 
s u m m ari z e d d e s cri pti v el y i n s hift t a bl e s fr o m b a s eli n e t o mi ni m u m a n d m a xi m u m 
o n -tr e at m e nt v al u e s. 
E C G s  
Cli ni c all y si g nifi c a nt, a b n or m al fi n di n g s fr o m 1 2 -l e a d E C G s d uri n g t h e tr e at m e nt p h a s e 
will b e pr e s e nt e d d e s cri pti v el y. C h a n g e fr o m b a s eli n e t o w or st o n -tr e at m e nt v al u e will 
b e s u m m ari z e d d e s cri pti v el y f or t h e Q T c F i nt er v al i n a c c or d a n c e t o I C H E 1 4 crit eri a.  
 
 
A E  =  a d v er s e e v e nt; 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  =  E a st er n C o o p er ati v e 
O n c ol o g y Gr o u p; I C H  =  I nt er n ati o n al Co u n cil  f or H ar m o ni s ati o n; M e d D R A  =  M e di c al Di cti o n ar y f or R e g ul at or y 
A cti viti e s; N CI -C T C A E  =  N ati o n al C a n c er I n stit ut 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; Q T c F  =  Q T 
i nt er v al c orr e ct e d u si n g Fri d eri ci a’ s f or m ul a; S A E =  s eri o u s a d v er s e e v e nt; S M C  =  s af et y m o nit ori n g c o m mitt e e; 
T E A E  =  tr e at m e nt e m er g e nt a d v er s e e v e nt. 
9. 4. 2. 1  
P art 1 A : D ose Esc al ati o n   
A nal ys es t o deci de o n d ose escalati o n will be perf or me d o n t he D L T set a n d will be base d o n 
a vaila ble safet y a n d preli mi nar y P K data. T o s u p p ort t he decisi o n o n d ose escalati o n, t he S M C 
will recei ve res ults of a Ba yesi a n d ose -t o xicit y m o del, i ncl u di n g t he rec o m me n dati o n of n e xt 
D L . T his Ba yesi a n d ose-t o xicit y 
m o del (Ne u e nsc h wa n d er  2 0 0 8 ) is f urt her s pecifie d i n 
A p pe n di x  1 2 . F or eac h S M C meeti n g, t he m o del will be u p date d wit h t he n u m ber of D L Ts a n d 
e val ua ble p artici pa nts per D L . 
P ote ntial D L s are: 1 0 0 m g (starti n g d ose), 2 0 0 m g, 4 0 0 m g, 6 0 0 m g . H o we ver, t he S M C ma y 
deci de t o ha ve differe nt, or a d diti o nal D L s or s ki p D L s (t otal dail y d ose i ncreases m ust n ot 
e x cee d 1 0 0 % of t he hi g hest t otal dail y D L  c urre ntl y c o nsi d ere d safe). Base d o n t he o bser ve d 
t o xicit y pr ofile a n d a v aila ble P K a n d P d, D L (s) t h at are differe nt t o, or hi g her or l o w er t ha n t he 
pres pecifi e d D L s ma y be teste d. 
T he d ose s u g gest e d b y t h e m o del f or t he ne xt c o h ort will be base d o n mi ni mizi n g t he Ba yesia n 
Ris k.  
T he S M C ma y c h o ose a differe nt d ose t ha n s u g gest e d b y t he Ba yesia n escal ati o n a p pr oac h. Als o, 
t he S M C ma y d eci de t o c ha n ge t he d osi n g re gi me n. I n s uc h a case t he d ose-t o xicit y m o del will 
be e xte n de d, or a se parat e m o del will be set u p  usi n g t he i nf or mati o n fr o m pre vi o us c o h orts t o 
defi ne a n e w pri or i nf or m ati o n f or t he ne w sc h e d ule.  
T he M T D will be defi n e d b y t he S M C. T he tar get D L T pr o ba bilit y f or t he M T D is 3 0 % . 
Us uall y , decisi o ns o n d ose es calati o n are ta ke n o nce all partici p a nts of t he m ost rece nt c o h ort 
ha ve c o m plete d t he D L T peri o d  or dr o p pe d o ut . I n e x ce pti o nal cases, h o we ver, t he S M C ma y 
deci de o n t he ne xt c o h ort earlier, i .e., bef ore t he l ast partici pa nt of a c o h ort has fi nis he d t he D L T 
Gl o bal Versi o n I D: 
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 5 /1 2 2  
 
 
peri o d (c o nsi deri n g t he m o del rec o m me n dati o n).  Per defi niti o n of t he D L T a nal ysis  s et, 
partici pa nts w h o h a ve n ot c o m plete d t he D L T peri o d are n ot i ncl u de d f or u p date of t h e m o del, 
u nless t he y e x perie n ce d a D L T.  H o we ver, d ata of s uc h partici p a nts will be i n cl u de d at ne xt S M C.  
Details o n a nal yses f or S M C will be descri be d i n t he S M C iA P.  
Bef ore first d osi n g, t he ass u me d  relati o ns hi p bet wee n D L  a n d t o xicit y is s pecifie d t hr o u g h t he 
pri or distri b uti o n. T he pri or distri b uti o n c h ose n f or t his st u d y c orres p o n ds t o t he f oll o wi n g  
(Ta ble  1 8 ): 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D L T = D o s e li miti n g t o xi cit y.  
I n Fi g ure  3  se veral e x a m ples of d ose es calati o n rec o m me n d ati o ns b y t h e m o del f or t he first 
3  c o h orts (eac h wit h 3  partici pa nts) de pe n di n g o n t he n u m ber of e x perie nce d D L Ts ( fr o m 0  t o 3) 
are s h o w n:  
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Fi g ure  3  
Esc al ati o n T ree: E x a m ples of D ose R ec o m me n d ati o ns B ase d o n t he 
B a yesi a n M o del f or t he F irst 3 C o h orts   
 
T h e r e c o m m e n d ati o n s ill u str at e d i n t h e d e ci si o n  tr e e ar e n ot bi n di n g. T h e S M C m a y c h o o s e a diff er e nt d o s e t h a n 
s u g g e st e d b y t h e B a y e si a n e s c al ati o n a p pr o a c h.  
Details of t he m o del, i ncl u di n g t he pri or distri b uti o n are i n A p pe n di x  1 2 . 
9. 4. 2. 2  
P art 1 B: Preli mi n ar y F o o d Effect Assess me nt   
Part  1 B ma y start o nce t he R D E has bee n d efi ne d i n Part  1 A. M 4 0 7 6 will be a d mi nistere d at a 
d ose a n d sc he d ul e t hat w as deter mi ne d as t he R D E i n Part  1 A.  
T he S M C will c o nti n ue t o m o nit or t he safet y of M 4 0 7 6 d uri n g Part  1 B. T he S M C will be 
s u p p orte d b y t he res ults of t he Ba yesia n m o d el us e d i n Part 1 A. D uri n g Part 1 B, t he m o d el will 
s u p p ort t he S M C e. g. w h e n a c ha n ge i n d ose is c o nsi dere d b y pr o vi di n g t o xicit y esti mates f or 
t he d oses. U nacce pt a ble t o xicit y i n t he f o o d effect c o h ort is defi ne d as A Es t hat meet t he D L T 
criteria (as defi n e d i n Secti o n  6. 6 ) re gar dless of whe n t he y occ ur d uri n g treat me nt.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
9. 4. 3  
Ot her A n al yses   
Details o n t he P K,  
 a n d  
 bi o mar ker a nal ys es will be i n t h e i A P t hat will be fi nalize d 
bef ore d ata base l oc k. I nt e grate d a n al ys es acr oss st u dies, s uc h as the p o p ulati o n P K a nal ysis a n d 
P D a nal ys es will be pres e nte d se paratel y fr o m t he mai n C S R.  
P K  para met ers will be calc ulate d usi n g sta n d ar d n o n -c o m part me ntal met h o ds a n d t he act ual 
a d mi nistere d d ose. P K para meters  will be calc ulate d usi n g t he act ual ela pse d ti me p ost d ose, wit h 
t he e x ce pti o n of P K a nal ysis f or S M C re vie w, w hic h will be calc ulate d usi n g sc he d ule d sa m pli n g 
ti mes (see Ta ble  1 9 ). 
W here t he act ual sa m pli n g ti me is missi n g t he calc ulati o ns ma y b e 
perf or me d usi n g t he s c he d ule d sa m pli n g ti mes.  
N o nc o m part me ntal a n al ysis will be perf or me d usi n g P h oe ni x  Wi n N o nli n  ( Certara, L. P., 
1 6 9 9, S Ha nle y R o a d, St L o ui s, M O, 6 3 1 4 4, U S A) V ersi o n 6. 3 or hi g her.  
T he statistical s oft ware S A S  ( Statistical A nal ysis S yste m, S A S-I nstit ute, Car y, N C, U S A 
wi n d o ws V ersi o n 9.4  or hi g her) ma y be us e d t o pr o d uce ta bles listi n gs a n d fi g ures.  
T a ble  1 9  
P art 1 - Ot her A n al yses   
Ot h er A n al y s e s  
P art 1 A : D o s e E s c al ati o n  
C m a x , C m a x / D o s e, tm a x , A U C0 -tl a st, 
A U C 0 -tl a st/ D o s e, A U C 0 -∞, 
A U C 0 -∞/ D o s e, t1/ 2 , A U C , A U C  
/ D o s e, C L/ F, V z/ F Ctr o u g h, 
R a c c (A U C ), Ra c c (C m a x ), LI, tl a st 
P K p ar a m et er s of M 4 0 7 6 (i n pl a s m a) aft er si n gl e a n d m ulti pl e d o s e 
( m o n ot h er a p y) will b e c al c ul at e d b y n o n c o m p art m e nt al a n al y si s.  
S u m m ar y st ati sti c s of P K p ar a m et er s a n d a s s o ci at e d P K c o n c e ntr ati o n s will 
b e d et er mi n e d a n d r e p ort e d.  
A n al y s e s will b e p erf or m e d o n t h e P K A S . 
 
P art 1 B: Pr eli mi n ar y F o o d Eff e ct A s s e s s m e nt  
A U C 0 -tl a st, Cm a x , A U C0 -∞  
P K p ar a m et er s of M 4 0 7 6 will b e c al c ul at e d aft er si n gl e d o s e u si n g 
n o n c o m p art m e nt al a n al y si s.  
A mi x e d m o d el wit h st u d y i nt er v e nti o n, p eri o d a n d s e q u e n c e a s fi x e d eff e ct s 
a n d a r a n d o m eff e ct f or p arti ci p a nt wit hi n s e q u e n c e will b e a p pli e d t o 
l o g-tr a n sf or m e d P K p ar a m et er s Cm a x  a n d A U C . 
A n al y s e s will b e b a s e d o n t h e P K A S . 
C m a x / D o s e, tm a x , A U C0 -tl a st/ D o s e, 
A U C 0 -∞/ D o s e, t1/ 2 , A U C , A U C  
/ D o s e, A U C 0 -7 2, A U C 0 -7 2 / D o s e, 
C L/ F, V z/ F Ctr o u g h,, Ra c c ( A U C), 
R a c c( C m a x ), LI, tl a st, C L R , A e(t 1 -t 2), 
fe(t 1 -t 2) 
A d diti o n al M 4 0 7 6 P K p ar a m et er s ( pl a s m a a n d uri n e) a n d s u m m ar y st ati sti c s.  
C o n c e ntr ati o n -Q T c  
R el ati o n s hi p of ti m e m at c h e d P K c o n c e ntr ati o n t o c h a n g e fr o m b a s eli n e Q T c 
will b e e x pl or e d b y c o n c e ntr ati o n -Q T a n al y si s. T hi s a n al y si s m a y i n cl u d e P K 
ti m e-m at c h e d Q T c d at a fr o m ot h er M 4 0 7 6 cli ni c al st u di e s . T h e d et ail s of t hi s 
a n al y si s  will b e d e s cri b e d i n a s e p ar at e a n al y si s pl a n , a n d t h e r e s ult s r e p orte d 
s e p ar at el y fr o m t h e  C S R.  
F A S = f ull a n al y si s s et; P K  =  p h ar m a c o ki n eti c; P K A S = p h ar m a c o ki n eti c a n al y si s s et; Q T c  =  c orr e ct e d Q T i nt er v al; 
R a c c  =  a c c u m ul ati o n r ati o . 
Gl o bal Versi o n I D: C CI
C C
I
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
9. 4. 4  
Se q ue nce of A n al yses   
S M C f or P art 1 A:  T he S M C will re vie w a vaila bl e data d uri n g st u d y c o n d uct. T he c ut -off f or 
d ose escalati o n assess me nts b y t he S M C will us uall y b e tri g gere d b y t h e c o m pleti o n of t he D L T 
peri o d ( or dr o p o ut) of t he last partici p a nt i n t he res pecti ve d ose escal ati o n c o h ort of us uall y 
3  partici pa nts.  W he n e nr ol me nt of last p artici pa nt i n a d osi n g c o h ort is del a ye d, t he S M C ma y 
deci de ( base d o n  a vaila bl e data) u p o n e nr ol me nt a n d d ose f or t he ne xt d osi n g c o h ort bef ore all 
partici pa nts i n a c o h ort h a ve c o m plete d 2 1  da ys . T he Ba yesia n m o del will t he n be u p date d wit h 
t he a vaila ble dat a, a n d t h e data fr o m t he partici pa nt n ot ha vi n g c o m plete d t h e D L T peri o d at ti me 
of S M C will be c o nsi dere d i n t he ne xt S M C. I n t hese cas es, c ut-off ca n b e earlier (after D L T 
peri o d of t he first 2 s u bje cts is fi nis he d or t he y e x perie nce d a D L T).  
S M C f or P art 1 B:  T he c ut -off of t he S M C will be tri g gere d w he n  t he 6t h partici pa nt  has bee n 
treate d f or 28  da ys ( or has dr o p pe d o ut ). T he S M C will be s u p p orte d b y t he res ults of  t he 
Ba yesi a n m o del use d i n Part 1 A.  
Pri m ary  a n alysis f or d ose esc al ati o n  
T he c ut -off f or a n e x pl orat or y a n al ysis of t he safet y, a vaila ble P K, a vaila ble P d a n d preli mi nar y 
a ntit u m or acti vit y data fr o m Part 1 A will be tri g gere d w he n all partici pa nts ha ve reac h e d eit her 
t he first o n-treat me nt t u m or assess me nt, or e x perie nce d d eat h or pre m at ur e wit h dra wal f or a n y 
reas o n, w hic h e ver c o mes first. 
Fi n al  A n alysis f or P art 1 A a n d 1 B  
F oll o w -u p a nal yses t o re p ort f urt her efficac y , safet y, a n d P K data  if a p pli ca ble f or Part 1 A a n d 
all a nal ys es f or Part 1 B will be perf or me d o n ce t he E n d of St u d y h as bee n reac h e d.  
A d diti o n al A n alyses  
F urt her a nal yses ma y b e perf or me d, e. g. f or p u blicati o n p ur p oses or decisi o n -ma ki n g p ur p oses.  
M ore details will be descri be d i n t he i A P. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
1 0  
Refere nces   
B o vé D, Ye u n g 
W Y, Paler m o G, et al. 
M o del -Bas e d D ose Escal ati o n Desi g ns i n R wit h 
cr m Pac k. J o ur nal of Statistical S oft ware. 2 0 1 9; 8 9: 1 0 .  
Cai M Y, D u n n C E, C h e n 
W, et al. C o o perati o n of t he A T M a n d Fa n c o ni A ne mia/ B R C A 
Pat h wa ys i n D o u bl e -Stra n d Brea k E n d Resecti o n. Cell Re p. 2 0 2 0; 3 0: 2 4 0 2 -1 5.e 5 .  
C urti n NJ. D N A re pair d ysre g ulati o n fr o m ca ncer dri ver t o t hera pe utic tar get. Nat Re v Ca ncer. 
2 0 1 2; 1 2: 8 0 1 -1 7 .  
Eise n ha uer E A, T h erasse 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 CI S T g ui deli n e (V ersi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5: 2 2 8 -4 7.   
Ke n ne d y R D, C h e n C C, St uc kert P, et al. Fa nc o ni a ne mia pat h w a y -d eficie nt t u m or cells are 
h y perse nsiti ve t o i n hi biti o n of ata xia tela n gi ectasi a m utate d. J Cli n I n vest. 2 0 0 7; 1 1 7: 1 4 4 0-4 9 .  
Mc Ca be N, H a n na C, Wal ker S M, et al. M ec ha nisti c Rati o nale t o Tar get P T E N -Deficie nt T u m or 
Cells 
wit h I n hi bit ors of t he 
D N A 
Da ma ge 
Res p o nse 
Ki n ase 
A T M. 
Ca ncer 
Res. 
2 0 1 5; 7 5: 2 1 5 9 -6 5 .  
Ne ue nsc h wa n der B, Bra ns o n M, Gs p o ner T. Critical as pects of t he Ba yesia n a p pr oac h t o p hase  I 
ca ncer trials. Stat Me d. 2 0 0 8; 2 7: 2 4 2 0 -3 9 .  
Sc h wartz L H, Litiere S, de Vri es E, et al. R E CI S T 1. 1 -U p date a n d Clarificati o n  : Fr o m t h e 
R E CI S T C o m mittee. E ur J Ca ncer 6 2 ( 2 0 1 6) 1 3 2e 1 3 7 .  
S weeti n g M, M a n der A, Sa bi n T. Ba yesi a n C o nti n ual Rassess me nt Met h o d Desi g ns f or P hase 1 
D ose -Fi n di n g Tri als. J Stat S oft ware. 2 0 1 3; 5 4( 1 3 ).  
Ya p T A, Ta n D S, Ter b uc h A, et al. First -i n-H u m a n Trial of t he Oral Ata xia Tela n giect asia a n d 
Ra d 3 -Relate d I n hi bit or B A Y 1 8 9 5 3 4 4 i n Patie nts wit h A d va nce d S oli d T u m ors. Ca ncer Disc o v. 
2 0 2 0: C D -2 0 -0 8 6 8. O nli ne a hea d of pri nt.   
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
1 1  
A p pe n dices   
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  1  
A b bre vi ati o ns   
 
A E  
ad verse eve nt  
A E SI  
a d verse e ve nt of s p ecial i nterest  
A L T  
ala ni ne a mi n otra nsferas e  
a P T T 
acti vate d partial t hr o m b o plasti n ti me  
A T M  
ata xia-tela n gi ectasia m ut ate d 
A T R  
ata xia-tela n gi ectasia a n d ra d 3-relate d 
B L R M  
Ba yesi a n 2 -para meter L o gistic Re gressi o n M o del  
CI  
c o nfi de nce i nter val  
C R F  
case re p ort for m  
C S R  
cli nical st u d y re p ort  
C V  
c oeffi cie nt of variati o n  
C Y P  
c yt o c hr o me P 4 5 0  
D D R  
D N A Da ma ge Res p o nse  
D L  
d ose le vel  
D N A  
de o x yri b o n ucleic aci d  
D S B  
d o u ble -stra n d brea k 
E C G  
electr ocar di o gra m 
F A S  
f ull a nal ysis set  
γ-H 2 A X  
ga m ma hist o ne fa mil y m e m ber X  
G C P  
G o o d Cli nical Practice  
G M R  
ge o m etric mea n rati o  
H R  
h o m ol o g o us rec o m bi nati o n  
i A P 
i nte grate d a n al ysis pla n 
I B 
I n v esti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I X R S 
I nteracti ve ( p h o ne a n d we b) Res p o nse S yste m  
M T D  
ma xi m u m t olerate d d ose  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts  
N H EJ  
n o n h o m o l o g o us e n d-j oi ni n g 
p -A T M  
p h os p h or ylat e d ata xia -tel a n gi ectasia m utate d 
P D  
disease pr o gressi o n  
P d  
p har mac o d y n a mics  
P -g p  
P -gl yc o pr ot ei n  
P K  
p har mac o ki netics  
P K A S  
p har mac o ki netic a nal ysis set  
P T E N  
p h os p hatase a n d te nsi n h o m ol o g  
Q Tc F  
Q T i nter val c orrecte d usi n g Fri deri cia’s f or m ula  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R D E  
rec o m me n de d d os e f or e x pa nsi o n 
S A E  
seri o us ad vers e ev e nt  
S A F  
safet y a n al ysis set 
S C R  
scree ni n g a nal ysis set 
S M C  
Safet y M o nit ori n g C o m mittee  
S T D  
se verel y t o xic d ose 
U L N  
u p per li mit of n or mal  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  2  
St u d y G o ver n a nce   
Fi n a nci al Discl os ure  
I n v esti gat ors a n d S u b-I n vesti gat ors will pr o vi de t he S p o ns or wit h e n o u g h , acc urate fi n a ncial 
i nf or mati o n, as re q uest e d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priat e re g ul at or y a ut h oriti es. T his 
i nf or mati o n is re q uire d d uri n g t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y. 
I nf or me d C o nse nt Pr ocess 
•  T he I n v esti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt or his/ her le gall y a ut h orize d re prese nt ati ve (w here all o we d b y l ocal la ws a n d 
re g ulati o ns) a n d a ns wer all q uesti o ns o n t he st u d y.  
•  Partici pa nts will  be i nf or m e d t hat t heir partici pati o n is v ol u ntar y.  
•  Partici pa nts or t heir le gall y -a ut h orize d re prese ntati ve (w here all o we d b y l ocal la ws a n d 
re g ulati o ns) will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of 2 1 C F R 5 0; l ocal re g ulati o ns; I C H g ui deli nes; Healt h I ns ura nce P orta bilit y 
a n d Acc o u nta bilit y Act ( HI P A A) re q uire me nts, w here a p plica ble; a n d t he I R B/I E C or 
st u d y ce nt er. 
•  T he me dical rec or d will  i ncl u de a stat e me nt t hat writte n i nf or me d c o nse nt was o btai n e d 
bef ore t he partici pa nt  w as e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h orize d pers o n o btai ni n g t h e i nf or me d c o nse nt will  als o si g n t he I C F.  
•  If t h e I C F is u p date d d uri n g t heir partici pati o n i n t he st u d y, partici pa nts will  be 
re-c o ns e nte d t o t he m ost c urre nt, a p pr o ve d v ersi o n.  
•  A c o p y of t he I C F(s) will  be pr o vi de d t o t he partici pa nt or t he parti ci pa nt’s le gall y 
a ut h orize d re pres e ntati ve.  
•  T he ori gi nal si g ne d a n d date d c o ns e nt will re m ai n at t he I n vesti gat or’s site a n d will  be 
safel y arc hi ve d s o t hat it ca n be retrie ve d at a n y ti 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. 
Partici pa nts w h o are rescree ne d are re q uir e d t o rec o nse nt. 
D at a Pr otecti o n  
•  T he S p o ns or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir i nf or me d 
c o nse nt . A n y partici pa nt rec or ds or d atasets t hat are tra nsferre d t o t he S p o ns or will c o ntai n 
t he i de ntifier o nl y; partici pa nt na mes or a n y i de ntifia ble i nf or mati o n will n ot b e 
tra nsferre d. 
•  T he S p o ns or will  i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d d ata will be use d per 
l ocal data pr otecti o n a n d pri vac y la ws. T h e le vel of discl os ure will  als o be e x plai ne d t o t he 
partici pa nt  a n d pre g na nt part ners (if a p plica ble) , w h o will be re q uire d t o gi ve c o nse nt f or 
t heir data t o be use d, as s pecifie d i n t he i nf or m ed c o nse nt . 
•  T he partici pa nt will  be i nf or me d t hat his/ her me dical rec or ds ma y be e x a mi ne d b y Cli nical 
Q ualit y 
Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
a p pr o priate I R B/I E C me m bers, a n d b y re g ulat or y a ut h orit y i ns pe ct ors. All s u c h pers o ns 
will strictl y m ai ntai n partici pa nts’ c o nfi de ntialit y.  
St u d y A d mi nistr ati ve  
•  T he C o or di nati n g I n vesti gat or liste d o n t he title pa ge re prese nts all I n v esti gat ors f or d ecisi o ns 
a n d disc ussi o ns o n t his st u d y, per I C H G C P. T he C o or di nati n g  I n vesti gat or will pr o vi de 
e x pert me dical i n p ut a n d a d vice o n t he st u d y d esi g n a n d e x ec uti o n a n d is res p o nsi ble f or t he 
re vie w a n d si g n off of t he cli nical st u d y re p ort. 
T he st u d y will a p p ear i n t he f oll o wi n g cli nical st u dies re gistr y : Cli nical Tri als. g o v . 
Sa fet y M o nit ori n g C o m mittee 
A Safet y M o nit ori n g C o m mittee ( S M C ) will be f or me d i n t his st u d y.  T h e S M C c o nsists of 
S p o ns or re prese nt ati ves (i ncl u di n g, b ut n ot li mite d t o t he Me dical Res p o nsi ble, t he Patie nt Safet y 
Strate g y Lea d, t h e Bi ostatisticia n, a n d t he P K e x pert) a n d I n vesti gat ors. T he Me dical M o nit or 
fr o m t he C o ntract Researc h Or ga nizati o n ma y  be a S M C me m ber.  T h e S M C ma y m o dif y t h e 
fre q ue n c y of meeti n gs as dee me d a p pr o pri ate d uri n g t he st u d y. Refer t o Secti o n s 4. 1. 1 , 4. 1. 2 , 
a n d 6. 6. 1 , f or m or e details.  
T he Cli nical Researc h Or ga niz ati o n, 
 will be res p o nsi ble f or t he f oll o wi n g acti vities:  
o  
 ce ntr al la b ser vi ces  
o  Cli nical data ma na ge me nt st u d y desi g n a n d pr o gra m mi n g  
o  Cli nical a ncillar y s u p plies ser vices  
o  Cli nical data ma na ge me nt  
o  Cli nical o perati o ns  
o  Feasi bilit y  
o  Gl o bal re g ulat or y ser vices  
o  Gl o bal site ser vices 
o  Me dical writi n g  
o  Me dical m o nit ori n g  
o  O perati o nal strat e g y a n d pla n ni n g  
o  P har mac o vi gila nce a n d Dr u g safet y s er vices  
o  Pr oject fi na ncial a nal ysts  
o  Pr oject ma na ge me nt  
o  Pr oject ve n d or ma n a ge m e nt  
o  Statistical a nal ysis  
o  Statistical pr o gra m mi n g  
Gl o bal Versi o n I D: C CI
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  Fis her is res p o nsi ble f or dr u g s u p pl y a n d distri b uti o n res p o nsi bilities (e. g., us e of re gi o nal 
distri b uti o n ce nters) . 
•  T he I X R S will be use d t o assi g n u ni q ue partici pa nt n u m bers, all ocate partici pa nts t o st u d y 
i nter ve nti o n gr o u p at t he ra n d o mizati o n visit, a n d st u d y i nt er ve nti o n t o partici pa nts at eac h 
st u d y i nter ve nti o n visit. 
•  T he S p o ns or is res p o nsi ble f or s u p pl y a n d ma n ufact ure of M 4 0 7 6 a n d f or st u d y o versi g ht.  
•  T he st u d y will b e c o n d ucte d at a p pr o xi matel y 4  st u d y sites i n N ort h A merica, i ncl u di n g 
a p pr o xi matel y 2  st u d y sit es i n t he U S.  
•  Details of str u ct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parat e 
Pr oject 
Ma na ge me nt Pla n . 
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
•  T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d t he f oll o wi n g:  
•  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui d eli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical 
Scie nces ( CI O M S) I nter n ati o nal Et hical G ui deli nes  
•  A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli nes  
•  A p plica ble la ws a n d re g ulati o ns  
•  T he I n v esti gat or will  s u b mit t he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I C F, 
I n v esti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts (e. g., a d vertise me nts) t o a n I R B/I E C a n d 
t he I R B/I E C will  re vie w a n d a p pr o ve t h e m bef ore t he st u d y is i nitiate d. 
•  A n y pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nt e d i n writi n g a n d 
re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e x ce pt f or c h a n ges necessar y t o 
eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n a p plica ble, a me n d me nts will be 
s u b mitte d t o t he a p pr o priate Healt h A ut h orities. 
•  T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
•  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or m ore 
fre q ue ntl y per t he I R B’s/I E C’s re q uire m e nts, p olicies, a n d pr o ce d ures. 
•  N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs, as re q uire d b y 
I R B/I E C pr oce d ures 
•  Pr o vi di n g o versi g ht of t he st u d y c o n d uct at t he site a n d a d here nce t o re q uire me nts of 
2 1 C F R, I C H  g ui deli nes, t he I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical 
st u dies (if a p plica ble), a n d all ot her a p plica ble l o cal re g ulati o ns  
•  T he pr ot oc ol a n d a n y a p plica ble d oc u me nt ati o n 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.  
E mer ge nc y Me dic al S u p p ort  
•  T he S p o ns or or desi g n ee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts f or 
use d uri n g t he st u d y. T hese pr o vi de t he mea ns f or partici pa nts t o i de ntif y t he msel ves as 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
p artici pati n g i n a cli nic al st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y 
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 det er mi ne t he c o urse of m e dical 
treat me nt f or t he partici p a nt. T he i nf or mati o n o n t he E mer ge n c y M e dical S u p p ort car d ma y 
i ncl u de t he pr ocess f or e mer ge nc y u n bli n di n g (if a p plica ble). 
•  T he first p oi nt of c o ntact f or all e mer ge n cies will be t he cli nical st u d y I n vesti gat or cari n g f or 
t he partici pa nt. C o nse q ue ntl y, t he I n v esti gat or a grees t o pr o vi de his or her e mer ge nc y c o ntact 
i nf or mati o n o n t he car d. If t he I n vesti gat or is a vaila ble w he n a n e v e nt occ urs, t he y will a ns wer 
a n y q uesti o ns. A n y s u bs e q ue nt acti o n (e. g., u n bli n di n g) will f oll o w t he sta n dar d pr ocess 
esta blis he d f or I n v esti gat ors.  
•  W he n t he I n vesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a p pr o priate mea ns t o c o ntact 
a S p o ns or ( or d esi g n ee) p h ysicia n. T his i ncl u des pr o visi o n of a 2 4 -h o ur c o ntact n u m ber at a 
call ce nter, w here b y t h e healt h care pr o vi ders will be gi v e n access t o t he a p pr o priate S p o ns or 
( or desi g nee) p h ysicia n t o assist wit h t he me dical e mer ge n c y.  
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts  
•  I ns ura nce c o v era ge will be pr o vi de d f or eac h c o u ntr y p artici pati n g i n t h e st u d y. I ns ura n ce 
c o n diti o ns will  meet g o o d l ocal sta n dar ds, as  a p plica ble.  
Cli nic al St u d y Re p ort  
•  After st u d y c o m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
C o or di nati n g I n vesti gat or.  
P u blic ati o n  
•  T he res ults of t his st u d y m a y b e p u blis he d or prese nte d at scie ntific meeti n gs. If t hi s is 
f oresee n, t he I n v esti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore 
s u b missi o n. T his all o ws Merc k t o pr otect pr o priet ar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
•  T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y i n t h eir e ntiret y a n d n ot as i n di vi d ual site data. I n t his cas e, a c o or di nati n g 
I n v esti gat or will be desi g nate d b y a gree me nt.  
•  A ut h ors hi p will be deter mi ne d b y a gree me nt a n d i n li ne wit h I nter n ati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire m e nts.  
Disse mi n ati o n of Cli nic al St u d y D at a  
•  After c o m pleti o n of t he st u d y, a cli nical st u d y re p ort  will be writte n b y t he 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 n vesti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3 a n d 
will be s u b mitte d i n acc or da nce wit h l ocal re g ul ati o ns.  
D at a Q u alit y Ass ur a nce  
•  All partici pa nt st u d y data will be rec or de d o n pri nt e d or el ectr o nic C R Fs o r tra ns mitte d t o t he 
S p o ns or or desi g nee ele ctr o nicall y (e. g., la b orat or y data). T h e I n v esti gat or is res p o nsi ble f or 
verif yi n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y b y p h ysicall y or 
electr o nicall y si g ni n g t he C R F. Details f or ma na gi n g C R Fs are i n t he Data Ma na ge me nt Pla n . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  T he I n v esti gat or will  mai ntai n acc urat e d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he C R F. 
•  T he I n v esti gat or will  per mit st u d y -relate d m o nit ori n g, q u alit y ass ura n ce a u dits, I R B/I E C 
re vie w, a n d re g ul at or y a ge n c y i ns pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d 
s o urce dat a. 
•  M o nit ori n g det ails descri bi n g str ate g y (e. g., ris k -base d i nitiati ves i n o perati o ns a n d q ualit y 
s uc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gi es a n d A nal yti cal Ris k -Base d M o nit ori n g), 
met h o ds, res p o nsi bilities a n d re q uire m e nts, i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n -site m o nit ori n g) are i n t he M o nit ori n g Pla n. 
•  T he S p o ns or or desi g nee is res p o nsi ble f or data m a na ge me nt of t his st u d y, i ncl u di n g q ualit y 
c hec ki n g of t he d ata a n d mai ntai ni n g a vali dat e d data base. Data bas e l oc k will occ ur o nce 
q ualit y c o ntr ol a n d q ualit y ass ur a nce pr oce d ures ha ve bee n c o m plete d. Detai ls will be 
o utli ne d i n Data Ma na ge me nt d oc u me nts a n d pr o ce d ures.  
•  St u d y M o nit ors will perf or m o n g oi n g s o urce d ata verificati o n t o c o nfir m t hat data i n t he C R F 
are acc urate, c o m plete, a n d verifia ble; t hat t he safet y a n d ri g hts of parti ci pa nts are bei n g 
pr ote cte d; a n d t hat t he st u d y is bei n g c o n d ucte d p er t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y 
ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
•  T he I n v esti gat or will retai n r ec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t h e 
c o n d uct of t his st u d y f or 1 5 years after st u d y c o m pleti o n, u nless l ocal re g ulati o ns, i nstit uti o nal 
p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds ma y be d estr o ye d d uri n g t he 
rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut t he S p o ns or’s writte n n otificati o n.  
S o urce D oc u me nts  
•  S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. 
•  T he I n v esti gat or will  kee p a pa p er or electr o nic fil e ( me dical file a n d ori gi n al me dical rec or ds) 
at t he site f or eac h st u d y partici p a nt. T he file will  i de ntif y eac h partici pa nt, c o ntai n t he 
f oll o wi n g d e m o gra p hic a n d me dical i nf or mati o n f or t he p artici pa nt, a n d will  be as c o m plete 
as p ossi ble:  
•  Partici pa nt’s f ull na me, d ate of birt h, se x, hei g ht, a n d wei g ht  
•  Me dical hist or y a n d c o n c o mita nt diseases  
•  Pri or a n d c o nc o mita nt t h era pies (i n cl u di n g c ha n ges d uri n g t h e st u d y)  
•  St u d y i d e ntifier (i.e. , t h e S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber.  
•  Dates of e ntr y i nt o t he st u d y (i.e., si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h visit 
t o t he site 
•  A n y me di cal e x a mi nati o ns a n d cli nical fi n di n gs pre defi n e d i n t he pr ot oc ol  
•  All A Es  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  Date t hat t he partici pa nt l ef t t he st u d y, 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 
st u d y or st u d y i nter ve nti o n, if a p plica ble. 
•  All s o urce data will  be file d (e. 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). Eac h d o c u me nt will  ha ve t he partici p a nt n u m ber a n d t he pr oce d ure d ate; i deall y, 
pri nte d b y t he i nstr u me nt use d f or t he pr oce d ure. As necessar y, me dical e val uati o n of t hes e 
rec or ds will  be perf or me d, d oc u me nte d, si g n e d a n d date d b y t he I n vesti gat or.  
•  Data rec or de d o n pri nte d or electr o nic C R Fs t hat are t ra nscri b e d fr o m s o urce d oc u me nts will  
be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa n cies will  be e x plai ne d. T he 
I n v esti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tr a nsfer rec or ds, de pe n di n g o n 
t he st u d y. Als o, c urre nt me dical rec or ds w ill be a vaila ble.  
•  T he St u d y M o nit ors will use pri nt o uts of electr o nic files f or s o urce data v erificati o n. T hes e 
pri nt o uts will  be si g ne d a n d date d b y t he I n v esti gat or  a n d ke pt i n t he st u d y file.  Pri nti n g t he 
files will n ot be necessar y if t he st u d y m o nit or is per mitte d t o access a n d re vie w electr o ni c 
partici pa nt files or ot her electr o nic st u d y rec or ds at I n v esti gat or sites, pr o vi de d t hat t he y are 
gi ve n t heir o w n u ni q ue access a n d is “ R ea d O nl y”.  
•  S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y t h e 
a p plica ble re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic h e ver is l o n ger. T he 
I n v esti gat or e ns ures t hat n o destr ucti o n of m e dical rec or ds is perf or me d wit h o ut t he S p o ns or’s 
writte n a p pr o val.  
•  Defi niti o n of w hat c o nstit utes s o ur ce data is fo u n d i n M o nit ori n g Pla n . 
St u d y a n d Site St art a n d Cl os ure  
•  First Act of Re cr uit me nt  
•  T he st u d y start date is t he date w h e n t he cli nical st u d y will be o pe n f or recr uit me nt.  
•  T he first act of recr uit me nt is w he n t he first site is o pe ne d  a n d will be t he st u d y start date.  
•  St u d y Cl os ur e a n d Site T er mi nati o n  
•  T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y ti me 
a n d f or a n y reas o n. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is 
c o nsi dere d  cl ose d w h e n all re q uire d d o c u me nts a n d st u d y s u p plies h a ve b ee n c ollecte d a n d 
a site cl os ure visit has bee n c o m plete d.  
•  T he I n v esti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d e n o u g h n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
•  Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n v esti gat or ma y i ncl u d e:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes  
•  I n a de q uat e recr uit me nt of partici pa nts b y t he I n v esti gat or 
•  Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d  
•  If t he st u d y is pre mat urel y ter mi nat e d or s us pe n de d, t he S p o ns or will  pr o m ptl y i nf or m t he 
I n v esti gat ors, t he I E Cs/I R Bs, t he re g ul at or y a ut h orities, a n d a n y c o ntract res earc h 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
or ga niz ati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d 
b y t he a p plica ble re g ul at or y re q uir e me nts. T he I n v esti gat or will pr o m ptl y i nf or m t he 
partici pa nts a n d as s ur e a p pr o priate partici pa nt t hera p y a n d/ or f oll o w-u p.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  3  
C o ntr ace pti o n   
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, as s pecifie d bel o w.  
If fertilit y is u n clear (e. g., a me n orr hea i n a d oles ce nts or at hletes) a n d a me nstr ual c ycl e ca n n ot 
be c o nfir me d b ef ore t he first d ose of st u d y i nter ve nti o n, c o nsi der  a d diti o nal e val uati o n.  
A W O C B P is n ot : 
1.  
Pre me narc hal  
2.  
A pre me n o pa usal fe mal e wit h 1 of t he f oll o wi n g:  
•  D oc u me nte d h ysterect 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  
 
D oc 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 t h e fe mal e’s me dical 
rec or ds, me di cal e x a mi nati o n, or me dical hist or y i nter vie w. 
 
F or a fe male wit h per ma ne nt i nfertilit y d ue t o a n alter nate me di cal ca use ot her t ha n t he 
a b o ve, (e. g., m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n a p plies 
t o deter mi ne st u d y e ntr y. 
3.  
A p ost me n o pa usal fe mal e  
•  A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca us e.  
•  A hi g h f ollicle -sti m ulati n g h or m o n e ( F S H) le vel i n t he p ost me n o pa usal ra n ge 
ma y b e use d t o c o nfir m a p ost me n o pa usal state i n a fe male n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o n al re place me nt t hera p y ( H R T). H o we v er, i n t he a bse nce 
of 1 2 m o nt hs of a me n orr hea, m ore t ha n 1 F S H meas ure me nt is re q uir e d i n t he 
p ost me n o pa usal ra n ge.  
•  A fe male 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 -estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he 
wis hes t o c o nti n ue her H R T d uri n g t he st u d y. Ot h er wise, s he m ust 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 st u d y e nr oll me nt.  
C o ntr ace pti o n G ui d a nce:  
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:  
Hi g hl y Effecti ve M et h o ds T h at H a ve L o w User De pe n de nc y  
•  
I m pla nta ble pr o gest o ge n-o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
I ntra uteri ne de vice (I U D) 
•  
I ntra uteri ne h or m o ne-releasi n g s yste m (I U S) 
•  
Bilateral t u bal occl usi o n  
•  
V asect o mize d part n er: a hi g hl y effe cti ve c o ntrace pti ve met h o d pr o vi d e d t h at t he part n er is t he s ole se x ual part n er of a 
W O C B P a n d t h e a bse nce of s per m has bee n 
c o nfir me d. Ot her wise, use a n a d diti o nal hi g hl y effecti ve met h o d of 
c o ntrace pti o n. T he s per mat o ge nesis c ycle is a p pr o xi mat el y 9 0 da ys.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Hi g hl y Effecti ve M et h o ds T h at Are User D e pe n de nt  
▪ 
C o m bi n e d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n a ss ociate d wit h i n hi biti o n of o v ulati o n 
•  
Oral  
•  
I ntra va gi n al 
•  
Tra ns der mal  
•  
I njecta ble 
▪ 
Pr o gest o ge n -o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
Oral  
•  
I njecta ble 
▪ 
Se x ual a bsti n e nce: a hi g hl y effecti ve met h o d o nl y  if defi n e d as refr ai ni n g fr o m i nterc o urse d uri n g t he e ntire peri o d of 
ris k ass ociate d wit h t h e st u d y i nter ve nti o n. T he relia bilit y of se x ual a bsti n e nce is e val u ate d i n relati o n t o t h e d urati o n of  
t h e st u d y. 
Acce pt a ble M et h o ds  
▪ 
Pr o gest o ge n -o nl y oral h or m o n al c o ntrace pti o n w here i n hi biti o n of o v ulati o n is n ot t h e pri mar y m o de of acti o n  
▪ 
Male or fe male c o n d o m wit h or wit h o ut s per mici de.  Male c o n d o m a n d fe male c o n d o m ca n n ot be use d t o get h er ( d ue t o 
ris k of fail ure wit h fricti o n) 
▪ 
Cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici de  
▪ 
A c o m bi n ati o n of mal e c o n d o m wit h eit her cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici de ( d o u ble -barrier met h o ds)  
C o ntrace pti ve use b y me n or w o me n is c o nsiste nt wit h l o cal re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or t h ose 
partici p ati n g i n cli nical st u dies.  
Hi g hl y effecti ve met h o ds h a ve a fail ure rate of <  1 % per year w he n use d c o nsiste ntl y a n d c orrectl y. T y pical use fail ure rates 
differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y.  
H or m o nal c o ntrace pti o n ma y be s us ce pti ble t o i nteracti o n wit h t h e st u d y i nter ve nti o n(s), w hic h ma y re d uce t h e effic ac y of 
t h e c o ntrace pti ve met h o d. As s uc h, male c o n d o ms m ust b e use d i n a d diti o n t o h or m o nal c o ntrace pti o n. If l o call y re q uire d, i n 
acc or da nce wit h Cli nical Trial Facilitati o n Gr o u p g ui deli nes, acce pta ble c o ntrace pti ve met h o ds are li mite d t o t h ose w hic h 
i n hi bit o v ulati o n as t he pri mar y m o de of acti o n. 
Ac ce pta ble met h o ds are c o nsi dere d effecti ve, b ut n ot  hi g hl y effecti ve (i.e., ha ve a fail ure rate of ≥ 1 % per year). P eri o dic 
a bsti ne nce (cale n dar, s y m pt ot h er mal, p ost -o v ulati o n met h o ds), wit h dra wal (c oit us i nterr u pt us), s per mici des o nl y, a n d 
lactati o nal a me n orr h oea met h o d are n ot  a cce pta ble met h o ds of c o ntrace pti o n . 
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  4  
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g   
A E Defi niti o n  
A E Defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical st u d y p artici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her c o nsi dere d relate d t o 
t he st u d y i nter ve nti o n or n ot . 
•  A n A E ca n t h eref ore b e a n y u nfa v ora bl e a n d u ni nt e n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e x acer bate d) te m p orall y ass ociate d 
wit h t he use of st u d y i nter ve nti o n. F or s ur gi cal or dia g n ostic pr o ce d ures, t h e 
c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is c o nsi dere d as t he A E rat her t ha n t he 
pr oce d u re itself. 
E ve nts Meeti n g  t he A E Defi niti o n 
•  A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e. g., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w ors e n fr o m baseli ne, a n d are j u d ge d t o be m ore se v ere t ha n 
e x pecte d f or t he p artici pa nt’s c o n diti o n  are c o nsi d ere d cli nicall y si g nifica nt i n t he 
me dical a n d scie ntific j u d g me nt of t he In vesti gat or ( e. g., n ot rel ate d t o pr o gressi o n of 
u n derl yi n g dise ase , le a di n g t o st u d y i nter ve nti o n disc o nti n uati o n). 
•  E x acer bati o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  Ne w c o n diti o ns detect e d or dia g n os e d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve b ee n prese nt bef ore t he start of t he st u d y.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
i nter ve nti o n or a c o n c o mita nt me dicati o n. 
•  “ Lac k of efficac y” or “fail ure of e x p ecte d p har mac ol o gical acti o n” p er se will n ot be 
re p orte d as a n A E or an  S A E. H o we ver, t h e si g ns, s y m pt o ms, a n d/ or cli nical se q uelae 
res ulti n g fr o m lac k of efficac y will be re p orte d as a n A E or an  S A E if t h e y f ulfil t he 
defi niti o n of a n A E or S A E.  
E ve nts N O T  Meeti n g t he A E Defi niti o n  
•  U nless j u d ge d b y t h e In v esti gat or t o b e m ore se v ere t ha n e x pecte d f or t he partici pa nt’s 
c o n diti o n, a n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs, ot her a b n or mal safet y 
assess me nts t hat are ass o ciate d wit h t he u n derl yi n g diseas e, t he diseas e/ dis or der bei n g 
st u die d wit hi n t he e x pecte d ness f or p artici pa nt’s c o n diti o n, as j u d ge d b y t h e I n vesti gat or . 
•  Me dical or s ur gic al pr oce d ure (e. g., e n d os c o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds 
t o t he pr oce d ure is t he A E. 
•  Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  A ntici pate d da y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w orse n.  
A E/ 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 dise ase/ dis or der bei n g st u die d assesse d b y meas ure m e 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 y m pt o ms (i ncl u di n g 
la b orat or y a b nor m alities) will n ot be re p orte d as A Es/ S A Es, u nless t he partici pa 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 his/ her  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 E  re p orti n g peri o d, as d efi ne d i n Secti o n 8. 3. 1 . 
S A E Defi niti o n  
If a n e ve nt is n ot a n A E per t he defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met (e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y, deat h 
d ue t o pr o gressi o n of dis ease).  
 
A n  S A E is defi ne d as a n y u nt o w ar d me dic al o cc urre nce t h at, at a n y d ose:  
•  Res ults i n de at h  
•  Is lif e-t hre ate ni n g 
T he ter m 'life -t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e v e nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h 
h y p ot hetic all y mi g ht ha v e ca use d d eat h, if it were m ore se vere.  
•  Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
•  I n ge n eral, h os pitaliz ati o n si g nifies t hat t he partici pa nt has bee n det ai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysici a n’s offic e or  
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are 
A Es. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfils a n y ot her seri o us criteri a, t he e ve nt is 
seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t h e A E 
will  be c o nsi dere d seri o us.  
•  H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n fr o m 
baseli ne is n ot c o nsi dere d a n A E.  
•  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 pitaliz ati o n m ust be d oc u me nte d a n d re p orte d as S A Es.  
•  Res ults i n persiste nt dis a bilit y/i nc a p acit y  
T he ter m dis a bilit y me a ns a s u bsta ntial disr u pti o n of a p ers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
T his defi niti o n is n ot  i nte n de d t o i ncl u de ex perie nces of relati vel y mi n or me dical si g nifica n ce 
s uc h as u nc o m plicate d h ea dac h e, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de nt al tra u ma 
(e. g., s pr ai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt e ver y da y life f u ncti o ns b ut d o n ot 
c o nstit ute a s u bs ta ntial disr u pti o n. 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  Is a c o n ge nit al a n o m al y/ birt h defect 
•  Ot her sit u ati o ns  
•  Me dical or scie ntific j u d g me nt will  be e x ercise d i n deci di n g w het her S A E re p orti n g is 
a p pr o priate i n ot her sit uati o ns , s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
partici pa nt 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 ot her 
o utc o mes liste d i n t he a b o ve defi niti o n. T hese e v e nts are us uall y c o nsi dere d as seri o us. 
•  E x a m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca n cers, i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n h os pitaliz ati o n, or de vel o p me nt of dr u g d e pe n d e nc y or dr u g a buse.  
A n y s us pe cte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y i nter ve nti o n is als o c o nsi dere d 
a n S A E f or re p orti n g p ur p oses, as s pecifi e d bel o w f or re p orti n g S A Es or D L Ts.  
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E  
A E a n d S A E Rec or di n g  
•  W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he 
In v esti gat or t o re vie w all 
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts) 
relate d t o t he e v e nt. 
•  T he In vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or ma ti o n i n t he C R F. 
•  As nee d e d, S p o ns or  m a y as k f or c o pi es of certai n me dical rec or ds (e. g., a ut o ps y re p orts, 
s u p ple me ntal la b re p orts, d oc u me nts o n 
me dical hist or y/c o nc o mita nt 
me dicati o ns, 
disc har ge letters), as s u p p orti n g s o urce d oc u me nt ati o n. All partici p a n t i de ntifiers, e x ce pt 
t he partici pa nt n u m ber, will be re dact e d o n t hese c o pies bef ore s u b missi o n t o S p o ns or . 
•  T he In v esti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot h er cli nical i nf or mati o n. W h e ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
•  If a n A E c o nstit utes a D L T t his is d oc u me nte d acc or di n gl y. 
•  S pecific g ui da nce is i n t he 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.  
 
Assess me nt of I nte nsit y  
I n v esti gat ors will refere n ce t he Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y Criteria f or 
A Es ( C T C A E), V ersi o n 5. 0  ( p u blicati o n date: 2 7 N o v 2 0 1 7 ), 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 v erit y/i nte nsit y; hereafter referre d t o as s e verit y) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere n ce d d o c u me nt, a n d s pecific e v e nt gra d es are als o pr o vi de d.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
If t he se v erit y f or a n A E is n ot s pecificall y gra de d b y N CI-C T C A E, t he I n v esti gat or is t o use 
t he ge n eral NCI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best me dical 
j u d g me nt. 
T he 5 ge neral gra d es are:  
•  Gra de 1 or Mil d  
•  Gra de 2 or M o derate  
•  Gra de 3 or Se vere  
•  Gra de 4 or Life -t hreat e ni n g 
•  Gra de 5 or Deat h  
A n y cli nical A E wit h se verit y 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 d e 4, s uc h as a ne mi a or ne utr o p e 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 s pecifie d bel o w. 
If d eat h occ urs, t he pri m ar y ca use of deat h or e ve nt lea di n g t o deat h will  be rec or de d a n d 
re p orte d as a n S A E. “ Fat al” will be rec or de d as t h e o utc o me of t his s pecifi c e ve nt a n d d eat h 
will n ot be rec or de d as se parate e ve nt. O nl y, if n o ca use of d eat h ca n be re p orte d (e. g., s u d d e n 
deat h, u ne x plai ne d de at h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.  
 
Assess me nt of C a us alit y  
•  T he I n vesti gat or will assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h A E/ S A E 
occ urre nce:  
•  U nrelate d: N ot reas o na bl y relate d t o t he st u d y i nter ve nti o n. A E c o ul d n ot me dicall y 
( p har mac ol o gi call y/ cli nicall y) be attri b ute d t o t he st u d y i nter ve nti o n. A reas o na bl e 
alter nati ve e x pla nati o n will  be a vaila ble.  
•  Relate d: 
Reas o na bl y relate d t o t he st u d y i nt er ve nti o n. 
A E c o ul d 
me dicall y 
( p har mac ol o gi call y/ cli nicall y) be attri b ute d t o t he st u d y i nter ve nti o n. 
•  A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat h er t ha n a rela ti o ns hi p ca n n ot be r ule d o ut. 
•  T he I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
•  Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as 
well as t h e te m p oral relati o ns hi p of t he e ve nt t o stu d y i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.  
•  T he I n v esti gat or 
will als o c o ns ult t he I n v esti gat or Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mati o n, f or mar kete d pr o d ucts, i n his/ her ass ess me nt. 
•  F or eac h A E/ S A E, t he I n vesti gat or will  d oc u me nt  i n t he me dical n otes t hat he/s he has 
re vie we d t h e A E/ S A E a n d assesse d ca usalit y.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  T here ma y b e sit uati o ns w he n a n S A E has occ urre d , a n d t h e I n v esti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he S p o ns or or its desi g nee. T o meet t he 
re p orti n g ti meli ne, t he ca usalit y assess me nt is n ot re q uire d f or t he i nitial re p ort. 
•  T he In vesti gat or ma y c ha n ge his/ her ca us alit y assess me nt after c o nsi d eri n g f oll o w -u p 
i nf or mati o n a n d se n d an  S A E f oll o w -u p re p ort wit h t he u p date d ca us alit y assess me nt.  
•  T h e ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts. 
 
F oll o w -u p of A Es a n d S A Es  
•  T he In vesti gat or will perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal meas ure me nts 
a n d/ or e v al uati o ns, as m e dicall y i n dicate d or as re q ueste d b y S p o ns or  t o el uci date t h e 
nat ure a n d/ or ca us alit y of t he A E or S A E, as f ull y as p ossi ble. T his ma y i ncl u de a d diti o nal 
la b orat or y t ests or i n v esti gati o ns, hist o pat h ol o gi cal e x a mi nati o ns, or c o ns ultati o n wit h 
ot her healt h care pr ofessi o nals.  
•  Ne w or u p d ate d i nf or mati o n will be rec or de d i n t he ori gi n all y c o m plete d C R F.  
•  T he In vesti gat or will s u b mit a n y u p date d S A E dat a t o S p o ns or  wit hi n 2 4 h o urs of recei pt 
of t he i nf or mati o n.  
Re p orti n g of S A Es  
S A E Re p orti n g b y  a n Electr o nic D at a C ollecti o n T o ol  
•  T he pri mar y me c ha nis m f or re p orti n g a n S A E i n m ultice nter st u dies t o t he S p o ns or or its 
desi g nee will be t he el ectr o nic data c ollecti o n t o ol.  
•  If t he electr o nic s yst e m is u na vaila ble, t he n t he site will use t he pa p er S A E f or m, s pecifie d 
bel o w, t o re p ort t he e ve nt wit hi n 2 4 h o urs. 
•  T he site will e nt er t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes a vaila ble.  
•  After t he st u d y is c o m plete d at a site, t he electr o nic data c ollecti o n t o ol will be ta ke n 
off -li ne t o pre v e nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data. 
•  If a site recei ves a re p ort of a ne w S A E fr o m a st u d y p artici pa nt or recei ves u p date d dat a 
o n a pre vi o usl y re p orte d S A E aft er t h e el ectr o nic data c ollecti o n t o ol has bee n ta ke n 
off -li ne, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m or t o t he S p o ns or’s 
safet y de p art me nt. 
•  B y e x ce pti o n, a n S A E ( or f oll o w -u p i nf or mati o n) ma y be re p ort e d b y t e le p h o ne. T he site 
will c o m plete t he electr o nic S A E data e ntr y i m me diatel y t hereafter.  
S A E Re p orti n g b y a P a per F o r m  
•  S A E re p orti n g o n a pa p er re p ort f or m  is use d as a bac k -u p met h o d f or a n E D C s yste m 
fail ure. T h e f or m i ncl u des  c o m pleti o n i nstr ucti o ns f or t he I n v esti gat or, na mes, a d dresses, 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
a n d tele p h o ne a n d fa x n u m bers . All i nf or mati o n fr o m t he pa per f or m will  be tra nscri be d 
i nt o t he electr o nic f or m as s o o n as t he s yste m b ec o mes a vaila ble. 
•  Facsi mile tra ns missi o n (fa x t o mail) of t he pa per f or m or a n y f oll o w -u p i nf or mati o n is t he 
preferre d met h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or or its 
desi g nee.  
•  I n rare cir c u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y tele p h o n e 
is acce pta bl e wit h a c o p y of t he f or m se nt b y o ver ni g ht mail or c o uri er ser vice.  
•  I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he In v esti gat or t o c o m plete 
a n d si g n t he f or m  wit hi n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.  
•  A d diti o nal d oc u me nts (e. g. l a b orat or y re p orts, a ut o ps y re p ort, h os pital disc h ar ge l etter) a n d 
rele va nt p a ges fr o m t he C R F ma y be re q uir e d i n a d diti o n (e. g. m e dical hist or y, c o nc o mita nt 
me dicati o n). T he d ata pr o vi de d will  be c o nsiste nt wit h t he i nf or mati o n i n t he C R F. 
Re c or di n g a n d Re p orti n g of D L Ts  
•  Eac h e v e nt t hat meets t he D L T criteria, as s p ecifi e d i n Secti o n 6. 6. 2 , will  be rec or de d i n 
t he C R F wit hin 2 4 h o urs  after a ware ness of t h e e v e nt.  
•  Seri o us D L Ts will  be re p orte d i n a n e x pe dite d ma n ner, usi n g t he S A E re p orti n g pr ocess, 
as s pecifie d a b o ve.  
•  N otificati o n of eac h D L T relate d e ve nt ( n o n -s eri o us a n d seri o us) will  be re p orte d t o t he 
S p o ns or or its desi g nee wit hi n 2 4 h o urs fr o m t he date of a ware ness.  
Re p orti n g of A E SIs  
•  F or a n o n -seri o us A E SI, t he site will c o m plete t he s pecific A E SI re p ort f or m a n d n otif y t he 
S p o ns or i m me diatel y ( wit hi n 2 4 h o urs), usi n g t he sa me process f or re p orti n g S A E s, as 
s pecifie d a b o v e. 
•  F or a s eri o us A E SI, t he site will c o m plete a n S A E re p ort f or m, usi n g t he S A E re p orti n g 
pr ocess , s pecifie d a b o v e. 
Re p orti n g of Pre g n a ncies  
•  Pre g n a nc y will  be re p ort e d w het her relat e d t o t he st u d y i nter ve nti o n usi n g t he a p plica ble 
pa per f or m.  
•  T he a p plica bl e f or m will be  use d t o re p ort if a n a b n or mal o utc o me of t h e pre g na n c y occ urs 
a n d t he c hil d/fet us s ustai ns a n e ve nt.  
•  Facsi mile tra ns missi o n (fa x t o mail) of  t he pa per f or m or a n y f oll o w-u p i nf or mati o n is t he 
preferre d met h o d f or tra ns missi o n a n d will be d o n e wit hi n 2 4 h o urs t o t h e S p o ns or or its 
desi g nee . 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  5  
Li ver S afet y: S u g geste d Acti o ns a n d F oll o w -u p Assess me nts   
If a st u d y p artici pa nt is n ote d t o ha ve ala ni ne a mi n otra nsferas e  or as partate a mi n otra nsferas e  
ele vate d 3  ti mes or great er a b o ve u p per li mit of n or mal ( U L N ; n e w or w orse ni n g of pree xisti n g), 
t he a b n or malit y s h o ul d be rec or de d as a n a d v erse e ve nt , re gar dless if cli nical s y m pt o ms are 
prese nt or n ot. If a st u d y p artici pa nt is n ote d t o ha ve ala ni ne a mi n otra nsferas e  or as partate 
a mi n otra nsferase  3  ti mes or greater a b o v e U L N a n d t otal bilir u bi n > 2 U L N f or w hic h a n 
alter nati ve eti ol o g y has n ot bee n i de ntifie d, t he e ve nt s h o ul d b e re p orte d as a seri o us a d v erse 
e ve nt. T he I n vesti gat or m ust c o ntact t he S p o ns or Me dical Res p o nsi ble f or disc ussi o n  (see 
Secti o n  7. 1  f or details). 
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  6  
Cli nic al L a b or at or y Tests   
T a ble  2 0  
Pr ot oc ol -R e q uire d Cli nic al L a b or at or y Assess me nts   
L a b or at or y 
A s s e s s m e nt s  
P ar a m et er s  
H e m at ol o g y  
Pl at el et c o u nt  
M e a n c or p u s c ul ar v ol u m e 
( M C V) 
W hit e Bl o o d C ell C o u nt 
wit h a b s ol ut e a n d / or 
p er c e nt a g e ( %) : 
•  
N e utr o p hil s  
•  
L y m p h o c yt e s  
•  
M o n o c yt e s  
•  
E o si n o p hil s  
•  
B a s o p hil s  
R eti c ul o c yt e s  
H e m o gl o bi n  
M e a n c or p u s c ul ar 
h e m o gl o bi n ( M C H)  
H e m at o crit  
 
C o a g ul ati o n  
I N R, pr ot hr o m bi n ti m e, p arti al 
t hr o m b o pl a sti n ti m e (a P T T)  
 
 
Bi o c h e mi str y  
Bl o o d Ur e a 
Nitr o g e n or Ur e a  
P ot a s si u m  
A s p art at e 
a mi n otr a n sf er a s e  
Bilir u bi n (t ot al a n d dir e ct) 
 
Cr e ati ni n e  
S o di u m  
Al a ni n e a mi n otr a n sf er a s e  
Pr ot ei n a n d al b u mi n  
 
Gl u c o s e  
C al ci u m  
Al k ali n e p h o s p h at a s e  
 
 
G a m m a 
gl ut a m yltr a n sf er a s e 
( g G T) 
Li p a s e  
A m yl a s e  
 
D et ail s of li v er c h e mi str y st o p pi n g crit eri a a n d r e q uir e d a cti o n s ar e gi v e n i n S e cti o n  6. 6. 1  a n d A p p e n di x  5 . 
R o uti n e U ri n al y si s 
•  
S p e cifi c gr a vit y  
•  
p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s b y di p sti c k  
•  
Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n or m al)  
Ot h er S cr e e ni n g 
T e st s  
•  
S er u m a n d uri n e h u m a n c h ori o ni c g o n a d otr o pi n pr e g n a n c y t e st ( a s n e e d e d f or w o m e n of 
c hil d b e ari n g p ot e nti al).  
S er ol o g y ( wit h n o pr e cli ni c al si g n s of h e p at ot o xi cit y, h e p atiti s B s urf a c e a nti g e n, h e p atiti s C 
vir u s a nti b o d y) t o r ul e o ut a cti v e i nf e cti o n will b e p erf or m e d at t h e I n v e sti g at or’ s di s cr eti o n. 
HI V s cr e e ni n g i s o pti o n al  at t h e I n v e sti g at or’ s di s cr eti o n u nl e s s r e q uir e d  l o c all y. 
All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y a c e ntr al l a b or at or y, e x c e pt 
f or s af et y l a b or at or y a s s e s s m e nt s. 
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  7  
P ote nti al V ari ati o ns i n St u d y I nter ve nti o n Sc he d ules a n d 
Sc he d ules of Acti vities   
A d diti o nal sc he d ules ma y als o be e val uat e d at t he discreti o n of t he S p o ns or a n d S M C.  
S u m mar y of alter nate sc he d ules of M 4 0 7 6 a n d c ha n ges t o t he Sc he d ule of Acti vities  i n Part 1 A  
(Ta ble  2 1 ): 
T a ble  2 1  
S u m m ar y of Alter n ate Sc he d ules of M 4 0 7 6   
P art 1 A  
T wi c e w e e kl y  
 Cli ni c vi sit s  
N o c h a n g e  
 M 4 0 7 6 
 a d mi ni str ati o n  
M 4 0 7 6 d o si n g i s t wi c e d ail y o n D a y s 1 a n d 4 of e a c h w e e k ( e. g., M o n, T h u).  
 P K s a m pli n g  
N o c h a n g e  
T hr e e ti m e s w e e kl y  
 Cli ni c vi sit s  
N o c h a n g e  
 M 4 0 7 6 
 a d mi ni str ati o n  
M 4 0 7 6 d o si n g i s o n D a y s 1, 3 a n d 5 of e v er y w e e k ( e. g., M o n, W e d, Fri).  
 P K s a m pli n g  
-D L T P eri o d D a y s 1 a n d 1 2: pr e d o s e at 0 h o ur s, p o st d o s e at 0. 5, 1, 2, 3, 4, 6, 8 h o ur s.  
-D L T P eri o d D a y s  2 a n d 1 3: 2 4 h o ur  (± 4 h o ur ) p o st d o s e o n D 1 a n d D 1 2  
-3 -w e e k P eri o d s D a y 1  a n d s u b s e q u e ntl y e v er y ot h er 3 -w e e k P eri o d : t a k e t w o 
s a m pl e s at st art a n d e n d of vi sit, at l e a st 1 h o ur  a p art . 
4 d a y s o n/ 3 d a y s off  
 Cli ni c vi sit s  
N o c h a n g e  
 M 4 0 7 6 
 a d mi ni str ati o n  
M 4 0 7 6 d o si n g i s o n 4 c o n s e c uti v e d a y s of a w e e k ( e. g., M o n, T u e, W e d, T h u)  
 P K s a m pli n g  
-D L T P eri o d D a y s 1 a n d 1 1: pr e d o s e at 0 h o ur s, p o st d o s e at 0. 5, 1, 2, 3, 4, 6, 8 h o ur s.  
-D L T P eri o d D a y s  2 a n d 1 2: 2 4 h o u r ( ± 4 ho u r) p o st d o s e o n D 1 a n d D 1 1 (t o b e t a k en  
pri or t o n e xt d o si n g) . 
-3 -w e e k P eri o d s D a y 1  a n d s u b s e q u e ntl y e v er y ot h er 3 -w e e k  P eri o d : t a k e t w o 
s a m pl e s at st art a n d e n d of vi sit, at l e a st 1 h o ur  a p art . 
7 d a y s o n/ 7 d a y s off  
 Cli ni c vi sit s  
N o c h a n g e  
 M 4 0 7 6 
 a d mi ni str ati o n  
M 4 0 7 6 d o si n g o n D a y s 1 -7 f oll o w e d b y a 7 -d a y dr u g h oli d a y.  
 P K s a m pli n g  
F or D L T p eri o d st arti n g wit h o n w e e k s:  
-D L T P eri o d D a y s 1 a n d 2 1: pr e d o s e at 0 h o ur s, p o st d o s e at 0. 5, 1, 2, 3, 4, 6, 8 h o ur s.  
-D L T P eri o d D a y s  2 a n d 2 2: 2 4 h o u r (± 4 h o u r) p o st d o s e o n D 1 a n d D 2 1 (t o b e t a k e 
pri or n e xt d o si n g) . 
-3 -w e e k P eri o d s D a y 1  a n d s u b s e q u e ntl y e v er y ot h er 3 -w e e k P eri o d : t a k e t w o 
s a m pl e s at st art a n d e n d of vi sit, at l e a st 1 h o ur  a p art . 
 
It i s a d vi s a bl e t o h a v e all D L T p eri o d s f or t hi s s c h e m e t o st art wit h 7 d o si n g d a y s.  
 
H o w e v er, f or p ati e nt s w h o st art wit h 7 d a y s off, t h e f ol l o wi n g s a m pli n g str at e g y 
a p pli e s:  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
-D L T P eri o d D a y 8, D a y 1 5: pr e d o s e at 0 h o ur s, p o st d o s e at 0. 5, 1, 2, 3, 4, 6, 8 h o ur s.  
-D L T P eri o d D a y 9: 2 4 h o ur ( ± 4 h o ur) p o st d o s e o n D 8 (t o b e t a k e n pri or t o n e xt 
d o si n g) . 
-3 -w e e k P eri o d s D a y 8 a n d s u b s e q u e ntl y e v er y  ot h er 3 -w e e k P eri o d: t a k e 2  s a m pl e s 
at st art a n d e n d of vi sit, at l e a st 1 h o ur a p art . 
1 4 d a y s o n/ 1 4 d a y s off  
 Cli ni c vi sit s  
D a y s 1, 2, 1 4, a n d 1 5  
 M 4 0 7 6 
 a d mi ni str ati o n  
M 4 0 7 6 d o si n g o n D a y s 1 -1 4 f oll o w e d b y a 1 4 -d a y dr u g h oli d a y.  
 P K s a m pli n g  
-D L T P eri o d D a y s 1 a n d 1 4: pr e d o s e at 0 h o ur s, p o st d o s e at 0. 5, 1, 2, 3, 4, 6, 8 h o ur s.  
-D L T P eri o d D a y s  2 a n d 1 5: 2 4 h o u r (± 4 h o u r) p o st d o s e o n D 1 a n d D 1 4 (t o b e t a k en  
pri or n e xt d o si n g) . 
-3 -w e e k P eri o d s D a y 1  a n d s u b s e q u e ntl y e v er y ot h er 3 -w e e k  P eri o d : t a k e t w o 
s a m pl e s at st art a n d e n d of vi sit, at l e a st 1 h o ur  a p art . 
 
It i s a d vi s a bl e t o h a v e all D L T p eri o d s f or t hi s s c h e m e t o st art wit h 1 4 d o si n g d a y s.  
 
H o w e v er, f or p ati e nt s w h o st art wit h 1 4 d a y s off, t h e f oll o wi n g s a m pli n g str at e g y 
a p pli e s:  
-D L T P eri o d D a y s 1 5 a n d 2 1: pr e d o s e at 0 h o ur s, p o st d o s e at 0. 5, 1, 2, 3, 4, 6, 8 
h o ur s.  
-D L T P eri o d D a y 1 6: 2 4 h o ur ( ± 4 h o ur) p o st d o s e o n D 1 5 (t o b e t a k e n pri or n e xt 
d o si n g) . 
-3 -w e e k P eri o d s D a y 1 5 a n d s u b s e q u e ntl y e v er y ot h er 3 -w e e k P eri o d: t a k e t w o 
s a m pl e s at st art a n d e n d of vi sit, at l e a st 1 h o ur a p art . 
D = D a y; D L T = d o s e li miti n g t o xi cit y; P K  =  p h ar m a c o ki n eti c.  
Uri n e P K p ar a m et er s will b e a s s e s s e d i n P art 1 B o nl y  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  8  
E x a m ple of L o w -f at Me al f or F o o d Effect C o h ort ( P art 1 B )  
Per F D A’s “ Assessi n g t he Effects of F o o d o n Dr u gs i n I N Ds a n d N D As —  Cli nical 
P har mac ol o g y C o nsi derati o ns G ui da nce f or I n d ustr y”, t he c o m p ositi o n of a l o w -fat meal 
i ncl u des 4 0 0 t o 5 0 0 cal ories of w hic h 2 5 % or 1 1 t o 1 4 gra ms c o me fr o m fat. A n e x a m ple of a 
l o w-fat brea kfast liste d b y t he a ge nc y c o nsists of t he f oll o wi n g: ei g ht o u nces of mil k ( 1 % fat), 
o ne b oile d e g g, a n d o n e pac ket of fla v ore d i nsta nt oat meal ma de wit h w ater.  
T he meal s h o ul d be c o ns u me d wit hi n a p pr o xi matel y 3 0 mi n utes, a n d t he M 4 0 7 6 d osa ge f or m 
s h o ul d be a d mi nistere d at 3 0 mi n utes after t he start of t he meal f or t he fe d state.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  9  
Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors ( R E CI S T) 
Versi o n  1. 1   
T he te xt bel o w was o btai ne d fr o m Eise n ha u er  2 0 0 9  a n d Sc h wartz  2 0 1 6 . 
Defi niti o ns  
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he i nter nati o nal criteria pr o p os e d 
b y t h e R E CI S T C o m mittee ( Versi o n  1. 1).  C ha n ges i n o nl y t h e lar gest dia m eter ( u ni di me nsi o nal 
meas ure me nt) of t he t u m or lesi o ns are us e d i n t he R E CI S T criteria. N ote: Lesi o ns are eit her 
meas ura ble or n o n -m eas ura ble usi n g t he criteria pr o vi de d bel o w. T he ter m “e val u a ble” i n 
refere nce t o meas ur a bilit y will n ot be use d beca use it d oes n ot pr o vi de a d diti o nal mea ni n g or 
acc urac y.  
Meas ura ble Diseas e  
T u m or lesi o ns: M ust be acc urate l y meas ure d i n at least 1 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 (irres pecti ve of sca n ner t y p e) a n d M RI ( n o less t ha n d o u ble t he slice 
t hic k ness a n d a mi ni m u m of 1 0 m m) 
•  1 0 m m cal i per meas ur e m e nt b y cli nical e xa m ( w h e n s u perfici al) 
•  2 0 m m b y c hest X -ra y (if clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g). 
M ali g n a nt ly m p h n o des : T o be c o nsi dere d p at h ol o gicall y e nlar ge d a n d meas ura ble, a l y m p h n o d e 
m ust be ≥ 1 5  m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice t hic k ness rec o m me n d e d 
t o be n o greater t ha n 5 m m). At bas eli ne a n d i n f oll o w-u p, o nl y t he s h ort a xis will be meas ure d 
a n d f oll o we d.  
N o n -meas ur a ble Dise ase  
All ot her lesi o ns ( or sites of disease), i ncl u di n g s m all lesi o ns ( l o n gest dia meter ≥ 1 0 t o <  1 5  m m 
wit h c o n ve nti o nal tec h ni q ues or <  1 0 m m usi n g s piral C T sca n), are c o nsi dere d n o n -m eas ura ble 
disease. 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 y m p ha n gitic i n v ol ve me nt o f s ki n or l u n g, a b d o mi nal masses/a b d o mi nal or ga n o me gal y 
i de ntifie d b y p h ysical e x a mi nati o n 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 
are all n o n -m eas ur a ble.  
B o ne lesi o ns:  
•  B o ne sca n, P E T sca n, or plai n fil ms are n ot c o nsi dere d a de q u ate 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 us e d t o c o nfir m t he prese nce or 
disa p peara nce of b o ne lesi o ns.  
•  L ytic 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 o ss-secti o nal i ma gi n g tec h ni q ues s uc h as C T or M RI ca n be c o nsi dere d 
as meas ura bl e 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.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  Blastic b o ne lesi o ns are n o n -meas ura bl e.  
Cystic lesi o ns:  
•  Lesi o ns t hat meet t he cri teria f or ra di o gra p hicall y defi n e 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) si nce 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 pres e nt c ystic m etastas es ca n be c o nsi dere d as m e as ura bl e lesi o ns, 
if t he y meet t he defi niti o n of meas ura bilit y des cri be d a b o ve. H o we ver, if n o nc ystic lesi o ns 
are prese nt i n t he sa me p artici pa nt, t hese are preferre d f or selecti o n as t ar 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 uat e d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her l ocal 
re gi o nal t hera p y, are us u all y n ot c o nsi dere d meas ura ble u nless t here has b ee n de m o nstrate d 
pr o gressi o n i n t he lesi o n. St u d y 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.  
Tar get Lesi o ns  
All meas ura bl e lesi o ns u p t o a m a xi m u m of 2 lesi o ns per or ga n a n d 5 lesi o ns i n t otal, s h o ul d be 
i de ntifie d as t ar g et l esi o ns a n d rec or de d a n d meas ure d at b aseli ne. T ar get lesi o ns s h o ul d b e 
selecte d o n th e basis of t heir siz e (lesi o ns wit h t he l o n gest dia meter), be re pres e ntati ve of all 
i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble re p eate d 
meas ure me nts.  
L y m p h n o des merit s peci al me nti o n si nce t he y are n or mal a nat o mical str u ct ures w hic h ma y b e 
visi ble b y i ma gi n g e v e n if n ot i n v ol ve d b y t u m or. Pat h ol o gical n o des w hic h are defi ne d as 
meas ura ble a n d m a y be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort a xis of 
≥ 1 5  m m b y C T sca n. O nl y t he s h ort a x is of t hese n o des will c o ntri b ute t o t he baseli ne s u m. T h e 
s h ort a xis of t he n o de is t he dia meter n or mall y use d b y ra di ol o gists t o j u d ge if a n o de is i n v ol ve d 
b y s oli d t u m or. N o d al siz e is n or mall y re p orte d as 2 di me nsi o ns i n t he pla ne i n w hic h t he i ma ge 
is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; f or M RI t h e pla ne of ac q uisiti o n 
ma y be a xial, sa gittal, or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. F or e x a m ple, 
a n a b d o mi nal n o d e w hic h is re p ort e d as b ei n g 2 0 m m x 3 0 m m ha s a s h ort a xis of 2 0 m m a n d 
q ualifies as a mali g na nt, meas ura bl e n o de. I n t his e x a m ple, 2 0  m m s h o ul d be rec or de d as t he 
n o de meas ure m e nt. All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥ 1 0  m m b ut <  1 5  m m) 
s h o ul d be c o nsi dere d n o n-tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0  m m are c o nsi dere d 
n o n -pat h ol o gic al a n d s h o ul d n ot be rec or de d or f oll o we d.  
A s u m of t h e dia met ers (l o n gest f or n o n -n o dal l esi o ns, s h ort a xis f or n o d al l esi o ns) f or all tar get 
lesi o ns will be calc ul ate d a n d re p orte d as t he b aseli ne s u m dia meters. If l y m p h n o des are t o be 
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t h e s h ort a xis is a d de d i nt o t he s u m. T he baseli ne 
s u m dia meters will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve t u m or re gressi o n 
i n t he meas ura ble di me nsi o n of t he disease.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
N o n -tar get Lesi o ns 
All ot her lesi o ns ( or sites of disease) i ncl u di n g p at h ol o gical l y m p h n o d es s h o ul d be i de ntifie d as 
n o n -tar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne. Meas ure me nts are n ot re q uir e d, a n d 
t hese lesi o ns s ho ul d b e f oll o we d as ‘ pres e nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n’ 
( m ore details t o f oll o w). I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n-tar get lesi o ns i n v ol vi n g 
t he sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e. g., ‘ m ulti ple e nlar ge d p el vic l y m p h 
n o des’ or ‘ m ulti ple li ver metastases’).  
G UI D E LI N E S F O R E V A L U A TI O N O F M E A S U R A B L E DI S E A S E  
All meas ure me nts s h o ul d be rec or de d i n metri c n ot ati o n, usi n g cali pers if cli nicall y assesse d. All 
baseli ne e v al 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 v er 
m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he tr eat me nt.  
T he sa me met h o d of ass ess 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 ollo w -u p. I m a gi n g bas e d e v al uati o n s h o ul d 
al wa ys be d o ne rat her t h a n cli nical e x a 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 bl e b y cli nical e xa mi nati o n. 
N o p h ot o gra p hs, n o s ki n lesi o n meas ure m e nt b y cali pers a n d n o meas ure me n ts o n c hest X-ra y 
will be d o ne i n t his st u d y.  
C T, M RI:  C T is t he best c urre ntl y a v aila 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 d efi 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 h at C T slice t hic k ness is 5 m m or less. As is d escri be d i n A p pe n di x II of t h e 
ori gi nal s o ur ce article cite d a b o ve  (Eise n ha uer  2 0 0 9 ), w he n C T sca ns h a ve slice t hic k ness greater 
t ha n 5 m m, t he mi ni m u m siz e f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. M RI 
is als o acce pt a ble i n certai n sit uati o ns (e. g., f or b o d y sca ns).  
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 siz e a n d s h o ul d n ot be use d as a 
met h o d of meas ure me nt. Ultras o u n d e x a mi n ati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vie w at a later date a n d, beca us e t he y are o p erat or de p e n de nt, it ca n n ot be 
g uara nte e d t hat t he sa m e tec h ni q ue a n d m eas ure me nts will be ta ke n fr o m 1 assess me nt t o t he 
ne xt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n b y C T 
or M RI is a d vise d. If t here is c o ncer n a b o ut r a diati o n e x p os ure at C T, M RI ma y be use d i nstea d 
of C T i n selecte d i nsta nces.  
E n d osc o p y, l a p ar osc o p y:  T he utilizati o n of t hese tec h ni q u es f or o bjecti v e t u m or e v al uati o n is 
n ot a d vise d. H o we v er, t he y ca n b e 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 n e d or t o deter mi ne rela pse i n st u dies w here rec urre nce f oll o wi n g c o m plete 
res p o nse ( C R) or s ur gi cal resecti o n is a n e n d p oi nt.  
T u m or m ar kers:  T u m or mar k ers al o n e ca n n ot b e use d t o assess o bjecti ve t u m or res p o nse. If 
mar kers are i nitiall y a b o ve t he u p per n or mal li mit; h o we ver, t he y m ust n or malize f or a 
partici pa nt t o be c o nsi dere d i n c o m plete res p o nse. Beca use t u m or mar kers are diseas e s pecific,  
i nstr ucti o ns f or t heir me as ure me nt s h o ul d b e i nc or p orate d i nt o pr ot oc ols o n a dise ase s p ecific 
basis. S pecific g ui deli nes f or b ot h C A -1 2 5 res p o nse (i n rec urre nt o v aria n ca ncer) a n d pr ostat e -
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
s pecific a nti ge n res p o ns e (i n rec urre nt pr ostate ca ncer), h a ve b e e n p u blis he d. I n a d diti o n, t he 
G y n ec ol o gic Ca n cer I nt er gr o u p h as de v el o pe d C A -1 2 5 pr o gressi o n crit eria w hi c h are t o be 
i nte grate d wit h o bjecti ve t u m or assess me nt f or use i n 1st-li ne st u dies i n o varia n ca ncer. 
C yt ol o g y, hist ol o g y:  T hese tec h ni q ues ca n be us e d t o differe ntiate bet w ee n partial res p o nse 
( P R) a n d C R i n rare cases if re q uir e d b y pr ot oc ol (e. g., 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 b e 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 vers e e ve nt ( A E) of treat me nt (e. g., wit h certai n ta x a 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 m ati 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 tr eat me nt ca n b e 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 st a ble disease ( S D) i n or der t o differe ntiat e bet wee n res p o nse ( or S D) a n d 
pr o gressi ve dise ase ( P D).  
R E S P O N S E C RI T E RI A  
E val uati o n of Tar get Lesi o ns  
C R: Disa p peara n ce of all tar get lesi o ns. A n y pat h ol o gical l y m p h n o des ( w het her t ar get  or n o n -
tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m.  
Partial res p o nse: At le ast a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as 
refere nce t he bas eli ne s u m dia meters.  
P D: At least a 2 0 % i ncrease i n t he s u m of di a meters of tar ge t lesi o ns, t a ki n g as refere n ce t h e 
s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if t hat is t he s mallest o n st u d y). I n a d diti o n 
t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 
5  m m. ( N ote: t he a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).  
S D: Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncreas e t o q ualif y f or P D, ta ki n g 
as refere n ce t he s mallest s u m dia meters w hile o n st u d y.  
Ly m p h n o des.  L y m p h n o des i de ntifie d  as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e x a mi nati o n), 
e ve n if t he n o des re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l y m p h n o des are 
i ncl u de d as tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot be zer o e ve n if C R criteria are m et, si nc e 
a n or mal l y m p h n o d e is defi ne d as ha vi n g a s h ort a xis of <  1 0 m m. Case re p ort f or ms ( C R Fs) or 
ot her data c ollecti o n met h o ds ma y t heref ore be desi g ne d t o ha ve tar get n o d al les i o ns rec or de d i n 
a se parate secti o n w here, i n or der t o q u alif y f or C R, eac h n o de m ust ac hie ve a s h ort a xis 
<  1 0  m m. F or P R, S D, a n d P D, t he act ual s h ort a xis meas ure me nt of t h e n o des is t o be i ncl u de d 
i n t he s u m of tar get lesi o ns. 
T ar get lesi o ns t h at bec o m e ‘t o o s m all t o me as ure’.  W hile o n st u d y, all lesi o ns ( n o dal a n d 
n o n -n o dal) rec or de d at baseli ne s h o ul d ha ve t h eir act ual meas ure m e nts rec or de d at eac h 
s u bse q ue nt e val uati o n, e ve n w he n v er y s mall (e. g., 2 m m). H o we ver, s o meti mes lesi o ns or 
l y m p h n o des w hich are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat 
t he ra di ol o gist ma y n ot feel c o mf orta bl e assi g ni n g a n e x act meas ure a n d ma y re p ort t he m as 
bei n g ‘t o o s mall t o me as ure’. W he n t his occ urs , it is i m p orta nt t hat a val u e be rec or de d o n t he 
C R F. If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y dis a p peare d, t he meas ure me nt 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o 
s mall t o meas ur e, a defa ult val ue of 5 m m s h o ul d be  assi g n e d. ( N ote: It is less li kel y t hat t his 
r ule will be use d f or l y m p h n o des si nce t he y us uall y h a ve a defi na ble siz e w he n n or mal a n d are 
fre q ue ntl y s urr o u n de d b y fat, s uc h as i n t he retr o perit o ne u m; h o we v er, if a l y m p h n o de is 
belie ve d t o b e prese nt a n d is fai ntl y see n b ut t o o s m all t o meas ure, a defa ult v al ue of 5  m m s h o ul d 
be assi g ne d i n t his circ u msta nce as well). T his defa ult val ue is deri ve d fr o m t he 5  m m C T slice 
t hic k ness ( b ut s h o ul d n ot be c h a n ge d wit h var yi n g C T slice t hic k n ess). T he meas ure me nt of 
t hese lesi o ns is p ote ntiall y n o n-re pr o d uci ble; t heref ore, pr o vi di n g t his defa ult val ue will pre ve nt 
false res p o nses or pr o gressi o ns base d u p o n meas ure me nt err or. T o reiterate, h o we ver, if t he 
ra di ol o gist is a ble t o pr o vi de a n act ual meas ure, t hat s h o ul d be rec or de d, e ve n if it is bel o w 5 m m.  
Lesi o ns t h at s plit or c o alesce o n tre at me nt.  W he n n o n -n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nt e d p orti o ns s h o ul d be a d d e d t o get her t o calc ulate t h e tar get lesi o n s u m. 
Si milarl y, as lesi o ns c o alesce, a pla ne bet wee n t he m ma y be mai ntai n e d t hat w o ul d ai d i n 
o btai ni n g ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr ul y 
c oalesce d s uc h t hat t he y are n o l o n ger se p ara ble, t he vect or of t he l o n gest dia meter i n t his 
i nstance s h o ul d be t he m a xi mal l o n gest dia meter f or t he ‘c o alesce d l esi o n’.  
E val uati o n of N o n -tar get Lesi o ns 
W hile s o me n o n -tar get lesi o ns ma y act uall y be meas ura ble, t h e y nee d n ot be meas ure d a n d 
i nstea d s h o ul d be assesse d o nl y q ualitati vel y at t he ti me p oi nts s pecifie d i n t he pr ot oc ol.  
C R: Disa p peara nce of all n o n -tar get lesi o ns a n d n or malizati o n of t u m or mar ker le vel. All l y m p h 
n o des m ust be n o n -pat h ol o gical i n size ( <  1 0 m m s h ort a xis).  
N o n -C R/ N o n -P D: Persiste nce of 1 or m ore n o n -tar get lesi o n(s) a n d/ or mai nte na nce of t u m or 
mar ker le v el a b o ve t he n or mal li mits.  
P D: U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n -tar get lesi o ns. ( N ote: t he 
a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).  
W h e n t he p artici p a nt als o h as me as ur a ble dise ase.  I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal 
pr o gressi o n’ o n t he basis of t he n o n -tar get dise ase, t here m ust be a n o verall le vel of s u bsta ntial 
w orse ni n g i n n o n -tar get disease s uc h t h at, e ve n i n t he pres e nce of S D or P R i n tar get diseas e, t he 
o ver all t u m or b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y. A m o dest 
‘i ncrease’ i n t he siz e of 1 or m ore n o n-tar get lesi o ns is us uall y n ot s ufficie nt t o q ualit y f or 
u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall pr o gressi o n  s olel y o n t he basis of 
c ha n ge i n n o n -tar get dise ase i n t he face of S D or P R of tar get disease will t heref ore be e xtre mel y 
rare. 
W h e n t he p artici p a nt h as o nly n o n -me as ur a ble dise ase.  T his circ u msta nce arises i n s o me P hase 
3  st u dies w he n it is n ot a criteri o n of st u d y e ntr y t o ha ve meas ura ble diseas e. T he sa me ge neral 
c o nce pt a p plies here as n ote d a b o ve; h o we ver, i n t his i nsta nce t here is n o meas ura ble diseas e 
assess me nt t o fact or i nt o t he i nter pretati o n of a n i ncreas e i n n o n -meas ura ble disease b ur de n . 
Beca use w orse ni n g i n n o n -tar get diseas e ca n n ot b e easil y q u a ntifie d ( b y defi niti o n: if all lesi o ns 
are tr ul y n o n -meas ur a ble), a usef ul test t hat ca n be a p plie d w he n assessi n g partici pa nts f or 
u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o v er all diseas e b ur de n base d o n t he 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
c ha n ge i n n o n -meas ur a ble disease is c o m p ara bl e i n ma g nit u de t o t he i ncrease t hat w o ul d be 
re q uire d t o declare P D f or meas ura ble diseas e: i.e., a n i ncrease i n t u m or b ur de n re prese nti n g a n 
a d diti o nal 7 3 % i ncrease i n ‘ v ol u me’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a 
meas ura ble lesi o n). E x a m ples i ncl u de a n i ncrease i n a ple ural eff usi o n fr o m ‘trace’ t o ‘lar ge’, a n 
i ncreas e i n l y m p h a n gitic disease fr o m l ocalize d t o wi des prea d, or ma y be descri be d i n pr ot oc ols 
as ‘s ufficie nt t o re q uire a c ha n ge i n t hera p y’. If ‘ u ne q ui v ocal pr o gressi o n’ is see n, t he partici p a nt 
s h o ul d be c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it w o ul d be i deal t o ha ve 
o bjecti ve criteria t o a p pl y t o n o n -me as ura bl e disease, t he v er y n at ure o f t hat disease ma kes it 
i m p ossi ble t o d o s o; t heref ore, t h e i ncrease m ust be s u bsta ntial. 
Ne w Lesi o ns  
T he a p peara n ce of ne w 
mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt. T here are n o s pec ific criteria f or t he 
i de ntificati o n of ne w ra di o gra p hi c lesi o ns; h o we ver, t he fi n di n g of a n e w lesi o n s h o ul d be 
u ne q ui v ocal: i .e., n ot attri b uta ble t o differe n ces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g 
m o dalit y, or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her t ha n t u m or (e. g., s o me ‘ ne w’ b o ne 
lesi o ns ma y b e si m pl y h eali n g or flare of pre-e xisti n g lesi o ns). T his is partic ularl y i m p orta nt 
w he n t he partici pa nt’s baseli ne lesi o ns s h o w partial or c o m plete res p o nse. F or e x a m ple, necr osis 
of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as a ‘ ne w’ c ystic lesi o n, w hic h it is n ot.  
A lesi o n i de ntifie d o n a f oll o w -u p st u d y i n a n a nat o m ical l ocati o n t hat was n ot sca n n e d at 
baseli ne is c o nsi dere d a ne w lesi o n a n d will i n dicate P D. A n e x a m ple of t his is t he partici pa nt 
w h o has visceral disease at baseli ne a n d w hile o n st u d y has a brai n C T or M RI or dere d w hic h 
re veals metastases. T he p artici pa nt’s brai n metastases are c o nsi dere d t o be e vi de nce of P D e ve n 
if he/s he di d n ot ha ve brai n i ma gi n g at baseli ne. 
If a ne w lesi o n is e q ui v ocal, e. g., beca use of its s mall size, c o nti n ue d t hera p y a n d f oll o w-u p 
e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re p eat sca ns c o nfir m t here is defi nitel y 
a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n.  
W hile fl u de o x y gl uc ose p ositr o n e missi o n t o m o gra p h y ( F D G -P E T) res p o nse assess me nts nee d 
a d diti o nal st u dies, it i s s o meti mes reas o na ble t o i nc or p orat e t he use of F D G-P E T sca n ni n g t o 
c o m ple me nt C T sca n ni n g i n assess me nt of pr o gressi o n ( partic ul arl y p ossi ble ‘ ne w’ diseas e). 
Ne w lesi o ns o n t he basis of F D G -P E T i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g 
al g orith m:  
a. Ne gati ve F D G -P E T at baseli ne, wit h a p ositi ve F D G -P E T at f oll o w -u p is a si g n of P D b ase d 
o n a ne w lesi o n.  
b.  N o F D G -P E T at baseli ne a n d a p ositi ve F D G -P E T at f oll o w -u p: If t he p ositi ve F D G -P E T at 
f oll o w-u p c orres p o n ds t o a ne w site of disease c o nfir me d b y C T, t his is P D. If t he p ositi ve 
F D G -P E T at f oll o w -u p is n ot c o nfir me d as a ne w site of disease o n C T, a d diti o nal f oll o w -u p 
C T sca ns are n ee d e d t o deter mi ne if t here is tr ul y pr o gressi o n occ urri n g at t hat site (if s o, t he 
date of P D will be t he date of t he i nitial a b n or mal F D G -P E T sca n). If t he p ositi ve F D G -P E T 
at f oll o w-u p c orres p o n ds t o a pre -e xisti n g site of disease o n C T t hat is n ot pr o gressi n g o n t he 
basis of t he a nat o mic i ma ges, t his is n ot P D.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
E val uati o n of Best O verall Res p o nse  
T he best o v eral l res p o nse ( B O R) is t he best res p o nse rec or de d fr o m t he start of t he st u d y 
i nter ve nti o n u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uir e me nt f or c o nfir mati o n. O n 
occasi o n, a res p o nse ma y n ot be d oc u me nte d u ntil after t he e n d of t hera p y, s o pr ot oc ols s h o ul d 
be cle ar if p ost treat me nt assess me nts are t o b e c o nsi dere d i n d eter mi nati o n of B O R. Pr ot oc ols 
m ust s pecif y h o w a n y n e w t hera p y i ntr o d uce d b ef ore pr o gressi o n will affect b est res p o nse 
desi g nati o n. T he p artici p a nt’s B O R assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d 
n o n -tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara n ce of ne w lesi o ns. 
F urt her m ore, d e pe n di n g o n t he n at ure of t he st u d y a n d t h e pr ot oc ol re q uire me nts, it ma y als o 
re q uire c o nfir mat or y me as ure me nt. S pecifi call y, i n n o n-ra n d o mize d st u dies w here res p o ns e is 
t he pri mar y e n d p oi nt, c o nfir mati o n of P R or C R is nee de d t o dee m eit her 1 t he ‘ B O R’.  
T he B O R is det er mi ne d o nce all t he d ata f or t he partici pa nt is k n o w n. Best res p o nse 
deter mi nati o n i n st u dies w here c o nfir m ati o n of c o m plete or P R I S N O T re q uire d: Best res p o ns e 
i n t hese st u dies is defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e x a m ple, a partici pa nt 
w h o has S D at first assess me nt, P R at sec o n d assess me nt, a n d P D o n last assess me nt has a B O R 
of P R).  W he n S D 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 bas eli ne. If t he mi ni m u m ti me is n ot met w he n S D is ot her wise t he best 
ti me p oi nt res p o nse, t he partici pa nt’s b est res p o nse de p e n ds o n t h e s u bse q ue nt assess me nts. F or 
e x a m ple, a partici pa nt w h o has S D at first ass ess me nt, P D at sec o n d a n d d o es n ot meet mi ni m u m 
d urati o n f or S D, will ha v e a b est res p o nse of P D. T he sa me p artici pa nt l ost t o f oll o w -u p after t he 
first S D assess me nt w o ul d be c o nsi dere d i ne val ua ble. 
 
T ar g et L e si o n s  
N o n -t 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  
C R  
N o n -C R/ n o n -P D  
N ot E v al u at e d  
N o  
N o  
P R  
P R  
P R  
N o n -P D or n ot all e v al u at e d  
N o  
P R  
S D  
 
N ot all e v al u at e d  
N o n -P D or n ot all e v al u at e d  
N o n -P D  
N o  
 
N o  
S D  
 
N E  
P D  
A n y  
Y e s or N o  
P D  
A n y  
P D  
Y e s or N o  
P D  
A n y  
A n y  
Y e s  
P D  
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; P D = pr o gr e s si v e di s e a s e ; S D = st a bl e 
di s e a s e . 
S e e t e xt f or m or e d et ail s.  
N ote:  
W he n n o dal diseas e is i n cl u de d i n t he s u m of t ar get lesi o ns a n d t he n o des decrease t o ‘ n or m al’ 
siz e ( < 1 0 m m), t he y ma y still ha ve a meas ure m e nt re p ort e d o n sca ns. T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o versta t e pr o gressi o n s h o ul d it be 
base d o n i ncreas e i n siz e of t he n o des. As n ote d earlier, t his mea ns t hat p arti ci pa nts wit h C R ma y 
n ot ha ve a t otal s u m of ‘zer o’ o n t he C R F.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
I n st u dies w here c o nfir m ati o n of res p o nse is re q uire d, re peate d ‘ N E’ ti me p oi nt assess me nts ma y 
c o m plicate best res p o ns e deter mi nati o n. T he a n al ysis pla n f or t he st u d y m ust a d dress h o w 
missi n g data/assess me nts will be a d dresse d i n det er mi nati o n of res p o nse a n d pr o gressi o n. F or 
e x a m ple, i n m ost st u dies, it is reas o na ble t o c o nsi der a partic i pa nt wit h ti me p oi nt res p o nses of 
partial res p o nse -N E -p arti al res p o nse as a c o nfir me d res p o nse.  
Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de n ce of P D at t hat ti me s h o ul d be re p orte d as ‘s y m pt o matic deteri or ati o n’. 
E ver y eff ort s h o ul d b e ma de t o d oc u me nt o bjecti ve pr o gressi o n e v e n after disc o nti n uati o n of 
treat me nt. S y m pt o matic deteri orati o n is n ot a des cri pt or of a n o bjecti ve res p o nse; it is a reas o n 
f or st o p pi n g st u d y t hera p y.  
C o n diti o ns t hat defi ne ‘earl y pr o gressi o n, earl y deat h, a n d i ne val ua bilit y’ are st u d y -s pecific a n d 
s h o ul d be clearl y des cri be d i n eac h pr ot oc ol ( de pe n di n g o n tr eat me nt d urati o n, a n d treat me nt 
peri o dicit y).  
I n s o me circ u msta n ces it ma y be diffic ult t o disti n g uis h resi d ual dise ase fr o m n or mal tiss ue. 
W he n t he e val uati o n of C R de pe n ds u p o n t his deter mi nati o n, it is rec o m me n de d t hat t he resi d ual 
lesi o n be i n vesti gate d (fi ne nee dle as pir ate/ bi o ps y) bef ore assi g ni n g a stat us of C R. T he use of 
F D G -P E T m a y be use d t o u p gra de a res p o nse t o a C R i n a ma n ner si milar t o a bi o ps y i n cases 
w here a resi d ual ra di o gra p hi c a b n or malit y is t h o u g ht t o re prese nt fi br osis or scarri n g. T he us e of 
F D G -P E T i n t his circ u msta nce s h o ul d be pr os pecti vel y descri be d i n t he pr ot oc ol a n d s u p p orte d 
b y diseas e s pecific me dical literat ure f or t he i n dicati o n. H o we ver, it m ust be ac k n o wle d ge d t hat 
b ot h a p pr oac h es ma y le a d t o false p ositi ve C R d ue t o li mitati o ns of F D G -P E T a n d bi o ps y 
res ol uti o n/se nsiti vit y. 
F or e q ui v ocal fi n di n gs of pr o gressi o n (e. g., ver y s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me n t ma y c o nti n ue u ntil t he ne xt sc he d ule d assess me nt. If 
at t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he d ate of pr o gressi o n s h o ul d be t he 
earlier date w h e n pr o gressi o n was s us pecte d.  
C O N FI R M A T O R Y M E A S U R E M E N T/ D U R A TI O N O F R E S P O N S E  
C o nfir mati o n  
I n n o n-ra n d o mize d st u dies w here res p o nse is t he pri mar y e n d p oi nt, c o nfir mati o n of P R a n d C R 
is re q uire d t o e ns ure t he res p o nses i de ntifie d are n ot t he res ult of meas ure me nt err or. T his will 
als o per mit a p pr o priate i nter pretati o n of res ults i n t he c o nte xt of hist orical data w here res p o ns e 
has tra diti o nall y re q uire d c o nfir mati o n i n s uc h st u dies. H o we ver, i n all ot her circ u msta n ces, i .e., 
i n ra n d o mize d st u dies ( P hase 2  or 3 ) or st u dies w here S D or pr o gressi o n are t he pri mar y 
e n d p oi nts, c o nfir mati o n of res p o ns e is n ot re q uire d si nce it will n ot a d d val ue t o t he i nter pretati o n 
of t he st u d y res ults. H o we ver, eli mi nati o n of t he re q uire me nt f or res p o nse c o nfir mati o n ma y 
i ncreas e t he i m p orta nce of ce ntral re vie w t o pr otect a gai nst bias, i n partic ular i n st u dies w hich 
are n ot bli n de d.  
I n t h e case of S D, m eas ure me nts m ust ha ve met t he S D criteri a at least o nce after st u d y e ntr y at 
a mi ni m u m i nter val (i n ge neral n ot less t ha n 6 t o 8 wee ks) t hat is defi ne d i n t he st u d y pr ot oc ol.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
D urati o n of O verall Res p o nse  
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met 
f or C R/ P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec urre nt or P D is o bjecti vel y 
d oc u me nte d (ta ki n g as refere n ce f or P D t he s mallest meas ure me nts rec or de d o n s t u d y). 
T he d urati o n of o verall C R is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or C R 
u ntil t he first date t hat rec urre nt disease is o bjecti vel y d o c u me nte d.  
D urati o n of Sta ble Disease  
Sta ble disease is meas ur e d fr o m t he start of t he treat me nt (i n ra n d o mize d st u dies, fr o m date of 
ra n d o mizati o n) u ntil t he criteria f or pr o gressi o n are met, ta ki n g as refere n ce t he s mallest s u m o n 
st u d y (if t he b aseli ne s u m is t he s mallest, t his is t he refere n ce f or calc ulati o n of P D).  
T he cli nical rele v a n ce of t he d urati o n of S D v aries i n differe nt st u dies a n d diseases. If t h e 
pr o p orti o n of p artici pa nts ac hie vi n g S D f or a mi ni m u m peri o d of ti me is a n e n d p oi nt of 
i m p orta nce i n a partic ular st u d y, t he pr ot oc ol s h o ul d s pecif y t he mi ni mal ti me i nter val re q uired 
bet wee n 2  me as ure m e nts f or deter mi nati o n of S D.  
N ote: T he d urati o n of res p o nse a n d S D as well as t he pr o gressi o n -free s ur vi val are i nfl ue nce d 
b y t he fre q ue n c y of f oll o w -u p after b aseli ne e val u ati o n. It is n ot i n t he s c o p e of t his g ui deli ne t o 
defi ne a st a n d ar d f oll o w -u p fre q ue nc y. T he fre q ue nc y s h o ul d ta ke i nt o acc o u nt ma n y para meters 
i ncl u di n g diseas e t y pes a n d sta ges, treat me nt peri o dicit y, a n d sta n dar d practice. H o we ver, t hese 
li mitati o ns of t he precisi o n of t he meas ure d e n d p oi nt s h o ul d be ta ke n i nt o acc o u nt if c o m paris o ns 
bet wee n st u dies are t o be ma de.  
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  1 0  
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us   
 
Gr a d e  
D e s cri pti o n  
0  
F ull y a cti v e, a bl e t o c arr y o n all pr e -di s e a s e p erf or m a n c e wit h o ut r e stri cti o n  
1  
R e stri ct e d i n p h y si c all y str e n u o u s a cti vit y b ut a m b ul at or y a n d a bl e t o c arr y o ut w or k of a li g ht or 
s e d e nt ar y n at ur e, f or e x a m pl e, li g ht h o u s e w or k, offi c e w or k  
2  
A m b ul at or y a n d c a p a bl e of all s elf -c ar e, b ut u n a bl e t o c arr y o ut a n y w or k a cti viti e s; u p a n d 
a b o ut  >  5 0 % of w a ki n g h o ur s  
3  
C a p a bl e of o nl y li mit e d s elf -c ar e, c o nfi n e d t o b e d or c h air > 5 0 % of w a ki n g h o ur s  
4  
C o m pl et el y di s a bl e d; c a n n ot c arr y o n a n y s elf -c ar e; t ot all y c o nfi n e d t o b e d or c h air  
5  
D e a d  
 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  1 2  
M o del f or B a yesi a n D ose E sc al ati o n  
T he Ba yesia n m o del res ults are base d o n t he n u m ber of D L Ts a n d e v al ua ble partici pa nts p er 
d ose le vel  ( D L). T he S M C will recei v e res ults of a Ba yesia n t w o-para meter l o gistic re gressi o n 
m o del 
u p date d 
wit h t he 
o bser ve d 
D L T 
d ata ( Ne ue nsc h wa n der  2 0 0 8 ), i ncl u di n g 
a 
rec o m me n dati o n f or t he ne xt d ose. F or a D L  d j, t he relati o ns hi p bet w ee n d ose a n d pr o ba bilit y of 
t o xicit y P ( D L T) is defi ne d b y: 
𝑃( 𝐷𝐿𝑇|𝑑𝑗,𝛼,𝛽) =
𝑒𝑥𝑝( 𝛼+ 𝑒𝑥𝑝(𝛽)∗𝑙𝑜𝑔(
𝑑𝑗
𝑑𝑟𝑒𝑓) )
1 + 𝑒𝑥𝑝( 𝛼+ 𝑒𝑥𝑝(𝛽)∗𝑙𝑜𝑔(
𝑑𝑗
𝑑𝑟𝑒𝑓) )
, 
wit h bi variate n or mall y distri b ute d para meters ( α, β)  usi n g t he f oll o wi n g para meterizati o n:  
•  Pre -select e d D L  d j ε {5 0  m g, 1 0 0  m g, 2 0 0  m g, 4 0 0  m g, 6 0 0  m g }  
•  Refere n ce d os e d ref =  8 0 0  m g  
 
 
 
 
 
 
T he f oll o wi n g t o xicit y re gi o ns (Ta ble  2 2 ) will be defi ne d:  
T a ble  2 2  
T o xicit y Inter v als   
T o xi cit y i nt er v al s  
Pr o b a bilit y of D L T  
L o s s t er m 
( w ei g ht i n l o s s f u n cti o n)  
U n d er -D o si n g  
[ 0. 0, 0. 2 0) 
1  
T ar g et t o xi cit y  
[ 0. 2 0, 0. 3 5] 
0  
E x c e s si v e t o xi cit y  
( 0. 3 5, 0. 6 0] 
1  
U n a c c e pt a bl e t o xi cit y  
( 0. 6 0, 1. 0 0] 
1. 5  
D L T = d o s e li miti n g t o xi cit y.  
T he m o del -base d rec o m me n dati o n f or t he ne xt D L  is t he D L  t hat mi ni mizes t he l oss f u ncti o n. 
T he l oss f u ncti o n is defi ne d as t he s u m of pr o d ucts of t h e pr o ba bilit y t o lie wit hi n eac h of t he 
t o xicit y re gi o ns, a n d t h e ass ociate d l oss ter m: 
•  1 × P ( U n der -D osi n g) + 0 × P (tar gete d t o xicit y) + 1 × P (e x cessi ve t o xicit y ) +  
1. 5 × P ( u nacce pta ble t o xicit y).  
•  I n crease of D L s is li mite d b y 1 0 0 % of t he hi g hest c urre nt t otal dail y D L . 
T he m o del will be pr o vi de d wit h t he f oll o wi n g pre -selecte d D L s: 5 0 m g, 1 0 0 m g, 2 0 0 m g, 
4 0 0  m g, 6 0 0 m g. T he set of d oses ca n b e c h a n ge d a n y ti me b y t he S M C.  
T he tar get D L T pr o ba bilit y f or t h e M T D is 3 0 %.  
T he S M C will be n otifie d of a p ot e ntial M T D o nce t he esti mate f or D L T pr o ba bilit y of a p ote ntial 
M T D reac hes s ufficie nt precisi o n, i.e.:  
Gl o bal Versi o n I D: C CI
C
C
I

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
•  T he u p per b o u n d of t he o ne -si de d 9 5 % cre di ble i nter val is n ot m ore t ha n 4 0% ,  
•  a n d t he esti mate d D L T pr o ba bilit y f or t h e s u g gest e d M T D is i n [ 1 7 % -3 0 %] . 
I n case i nf or mati o n arises fr o m ot her st u dies t hat c ha n ges c urre nt k n o wle d ge o n t he d ose t o xicit y 
relati o ns hi p, t he pri or distri b uti o n will be u p date d pri or t o t he first partici pa nt bei n g treate d i n 
t his st u d y. T his c ha n ge will be d oc u me nt e d i n t h e S M C c harter. If c ha n ges are nee de d d u e t o a 
c ha n ge i n re gi me n, t hese will als o be d oc u me nte d i n t he S M C c harter pri or t o first S M C wit h 
partici pa nts wit h ne w re gi me n.  
T he Ba yesia n m o del use d i n Part 1 A will be use d c o nti n u o usl y t o als o m o nit or t he t o xicit y res ults 
i n Part 1 B wit h all partici pa nts. U nacce pta ble t o xicit y i n t he f o o d effect c o h ort is defi ne d as A Es 
t hat meet t he D L T criteria (as defi n e d i n Secti o n 6. 6 ) re gar dless of w he n t he y occ ur d uri n g 
treat me nt.  
P osteri or distri b uti o n a n d t he rec o m me n de d ne xt D L  s u ggeste d b y t he m o del will be calc ul ate d 
usi n g S A S V ersi o n 9. 4 or hi g h er, E A S T V ersi o n 6. 5 or hi g her, or R V ersi o n 3. 5. 1 or hi g her wit h 
li brar y pac k a ge b cr m (S weeti n g  2 0 1 3 ) or p ac ka ge C R M pac k (B o vé  2 0 1 9 ). 
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  1 3  
Pr ot oc ol A me n d me nt Hist or y   
T he i nf or mati o n f or t he c urre nt a me n d m e nt is o n t he title pa ge.  
Pr ot oc ol V ersi o n 3 . 0 (2 5 -Oct -2 0 2 1)  
T he o verall rati o nale f or t his a me n d me nt is base d o n t he nee d t o u p date t he a d verse e ve nts of 
s pecial i nterest ( A E SI) i nf or mati o n i n t his pr ot oc ol. 
S e cti o n # a n d N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
Titl e p a g e  
Titl e p a g e m o difi c ati o n s i n 
pl a c e m e nt of v er si o n r e p orti n g a n d 
r e m o v al of ot h er i nf or m ati o n. 
T o f oll o w i nt er n al q u alit y st a n d ar d s f or 
cli ni c al st u d y pr ot o c ol s.  
1. 3. 1  
T a bl e  1 S c h e d ul e of 
A cti viti e s: M 4 0 7 6 
M o n ot h er a p y D o s e 
E s c al ati o n  ( D ail y D o si n g), 
P art  1 A.  
 
 
 
 
1. 3. 2  
T a bl e 2: S c h e d ul e of 
A cti viti e s: Pr eli mi n ar y F o o d 
Eff e ct A s s e s s m e nt, 
P art  1 B.  
F or D L T P eri o d D a y  1, a wi n d o w 
p eri o d of ‘ - 1  d a y ’ w a s a d d e d t o 
s p e cifi c a s s e s s m e nt s.  
A d diti o n al t e xt w a s a d d e d t o t h e 
M e di c al hi st or y r e g ar di n g t h e 
c oll e cti o n of i nf or m ati o n p ert ai ni n g 
to t o b a c c o u s e.  
A d d e d r e q uir e m e nt f or e xt e n d e d 
f oll o w-u p of S A E s a n d A E SI s.  
 
Pr o hi biti o n of ti s s u e s a m pl e s of 
b o n e bi o p si e s f or 
 
s u b mi s si o n.  
A Vi sit wi n d o w w a s a d d e d f or p arti ci p a nt 
fl e xi bilit y. 
 
T o pr o vi d e tr a n s p ar e n c y a n d cl arit y t h at  t hi s 
i nf or m ati o n i s b ei n g c oll e ct e d f or p ot e nti al 
u s e i n P K a s s e s s m e nt.  
 
 
F or c o n si st e n c y wit h S e cti o n  8. 3. 6 . 
 
Li mit e d t u m or c ell ul arit y i n bi o p si e s o bt ai n e d 
fr o m b o n e( s) i s i n s uffi ci e nt t o p erf or m 
 
 a n al y si s. 
1. 3. 3  
T a bl e  4 P art  1 B 
Pr eli mi n ar y F o o d Eff e ct 
A s s e s s m e nt: P K, E C G a n d 
 
A s s e s s m e nt s  
Uri n e c oll e cti o n i nt er v al f or P K 
w a s f urt h er s p e cifi e d.  
Cl arifi c ati o n.  
2. 1  
St u d y R ati o n al e  
2. 2  
B a c k gr o u n d  
2. 3. 2  
B e n efit A s s e s s m e nt  
R e m o v e d m e nti o n of at a xi a -
t el a n gi e ct a si a a n d r a d 3 -r el at e d 
(A T R i) c o m bi n ati o n.  
N o l o n g er n e e d e d i n t hi s pr ot o c ol.  
2. 3  
B e n efit/ Ri s k A s s e s s m e nt  
A d d e d r e q uir e d t e xt p er M er c k 
pr ot o c ol st a n d ar d s.  
T o f oll o w i n t er n al q u alit y st a n d ar d s f or 
cli ni c al st u d y pr ot o c ol s.  
5  
St u d y P o p ul ati o n  
A p p e n di x  2  
St u d y G o v er n a n c e 
(I nf or m e d C o n s e nt 
Pr o c e s s)  
T e xt u al c h a n g e s r e g ar di n g l e g al or 
l e g all y a ut h ori z e d r e pr e s e nt ati v e. 
T o f oll o w i nt er n al q u alit y st a n d ar d s f or 
cli ni c al st u d y pr ot o c ol s.  
5. 3  
Lif e st yl e C o n si d er ati o n s  
A d d e d t h at t o b a c c o u s e  st at u s 
(f or m er, c urr e nt , n e v er) will b e 
c oll e ct e d at s cr e e ni n g a n d 
r e c or d e d i n t h e e C R F. 
T o e v al u at e p ot e nti al i m p a ct of t o b a c c o u s e 
o n P K, effi c a c y, a n d s af et y.  
Gl o bal Versi o n I D: C CI
C CI
C
CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
S e cti o n # a n d N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
6. 6. 2. 1  
T a bl e  1 0 M 4 0 7 6 
R e c o m m e n d e d D o s e 
M o difi c ati o n s  
‘Gr a d e  3 H e m at ol o gi c a n d 
N o n h e m at ol o gi c A D R s ’ w a s 
a d d e d i n t h e T a bl e titl e a n d 
‘ h e m at ol o gi c’ w a s a d d e d i n t h e 
T a bl e h e a d er.  
T o i n cl u d e h e m at ol o gi c t o xi citi e s f or cl arit y 
a n d c o n si st e n c y wit h t h e r e q uir e m e nt s 
alr e a d y st at e d i n t hi s se cti o n . 
S e cti o n  8. 3  
A d v er s e E v e nt s a n d 
S eri o u s A d v er s e E v e nt s 
(A E /S A E  d et e cti o n 
m et h o d)  
A d d e d s e nt e n c e r ef er e n ci n g t o 
A p p e n di x  4 f or i nf or m ati o n 
r e g ar di n g r e c or di n g, e v al u ati n g, 
a n d a s s e s si n g c a u s alit y of A E s 
a n d S A E s a n d pr o c e d ur e s f or 
c o m pl eti n g a n d tr a n s mitti n g S A E 
r e p ort s. 
T o f oll o w i nt er n al q u alit y st a n d ar d s f or 
cli ni c al st u d y pr ot o c ol s.  
8. 3. 6  
A d v er s e E v e nt s of S p e ci al 
I nt er e st 
A d d e d d efi niti o n of A E SI s of 
c yt o p e ni a.  
T o all o w cl o s er m o nit ori n g of A E s c o n si st e nt 
wit h t h e p ot e nti al r i s k of c yt o p e ni a. 
9. 4. 3  
Ot h er A n al y s e s  
T a bl e  1 9 P art 1 Ot h er 
A n al y s e s  
C o n c e ntr ati o n -Q T c  a n al y si s 
d et ail s ar e s p e cifi e d.  
Cl arifi c ati o n.  
A p p e n di x  4  
A d v er s e E v e nt s: 
D efi niti o n s a n d Pr o c e d ur e s 
f or R e c or di n g, E v al u ati n g, 
F oll o w -u p, a n d r e p orti n g 
( a d v er s e e v e nt/ s eri o u s 
a d v er s e e v e nt d et e cti o n 
m et h o d)  
U p d at e of t e xt r e g ar di n g g ui d a n c e 
t o t h e Pri n ci p al I n v e sti g at or. 
T o f oll o w i nt er n al q u alit y st a n d ar d s f or 
cli ni c al st u d y pr ot o c ol s a n d c l arifi c ati o n s t o 
t h e t e xt f or b ett er u n d er st a n di n g of g ui d a n c e 
of a d v er s e e v e nt s/ s eri o u s a d v er s e e v e nt s 
d efi niti o n.  
T hr o u g h o ut  
R e m o v al of O v er al l S ur vi v al a n d 
m e nti o n of  S ur vi v al F oll o w -u p.  
T o ali g n wit h st a n d ar d P h a s e 1  st u d y d e si g n  
t e m pl at e, w h er e n o o v er all s ur vi v al i s 
i n cl u d e d. 
T hr o u g h o ut  
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s. 
Mi n or; t h er ef or e, h a v e n ot b e e n s u m m ari z e d.  
A D R = a d v er s e dr u g r e a cti o n; A E = a d v er s e e v e nt; A E SI = a d v er s e e v e nt of s p e ci al i nt er e st; A T R = at a xi a 
t el a n gi e ct a si 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 R F = el e ctr o ni c c a s e r e p ort f or m; P D = 
p h ar m a c o d y n a mi c; P K  =  p h ar m a c o ki n eti c;  Q T c = C orr e ct e d Q T I nt er v al ; S A E  =  s eri o u s a d v er s e e v e nt . 
Pr ot oc ol V ersi o n 2. 0 ( 0 7 -A pr -2 0 2 1)  
O ver all R ati o n ale f or t he A me n d me nt  
T he o verall rati o nale f or t his a me n d me nt is b ase d o n t he fact t hat t he f ull t o xicit y pr ofile of 
M 4 0 7 6 re mai ns u n k n o w n i n h u ma ns; t heref ore, meas ures re gar di n g c o n c o mita nt me dicati o ns 
a n d d ose m o dificati o ns were a d o pte d.  
Gl o bal Versi o n I D: C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
S e cti o n # a n d 
N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
1. 3. 1 P art 1 A –  
M 4 0 7 6 
M o n ot h er a p y D o s e 
E s c al ati o n ( D ail y 
D o si n g)  
A d d e d t h e P art 1 A f a sti n g wi n d o w 
i nf or m atio n  
F or cl arit y  
1. 3. 2 P art 1 B  
A d d e d t h e P art 1 B f a sti n g wi n d o w 
i nf or m ati o n 
F or cl arit y  
T a bl e 1: P art 1 A 
S c h e d ul e of 
A cti viti e s  
F a sti n g wi n d o w a d d e d t o t h e “ St u d y 
I nt er v e nti o n A d mi ni str ati o n” r o w. 
F or cl arit y  
T a bl e 2: P art 1 B 
S c h e d ul e of 
A cti viti e s  
F a sti n g wi n d o w a d d e d i n t h e “ L o w -f at 
M e al or O v er ni g ht F a sti n g” r o w.  
Vit al si g n s a s s e s s m e nt s ti mi n g n ot e 
a d d e d.  
F or cl arit y  
T a bl e 3: P art 1 A 
M 4 0 7 6 
M o n ot h er a p y D o s e 
E s c al ati o n: 
P h ar m a c o ki n eti c, 
E C G a n d 
P h ar m a c o d y n a mi c s 
Bi o m ar k er 
A s s e s s m e nt s  
A d d e d a f o ot n o t e o utli ni n g f a sti n g 
wi n d o w.  
F or cl arit y  
T a bl e 4: P art 1 B 
Pr eli mi n ar y F o o d 
Eff e ct A s s e s s m e nt: 
P h ar m a c o ki n eti c, 
E C G a n d 
P h ar m a c o d y n a mi c s 
Bi o m ar k er 
A s s e s s m e nt s  
A d d e d a f o ot n ot e o utli ni n g E C G f a sti n g 
wi n d o w.  
F or cl arit y  
4. 1. 1 P art 1 A –  
M 4 0 7 6 
M o n ot h er a p y D o s e 
E s c al ati o n  
A d d e d r ef er e n c e t o f a sti n g wi n d o w 
i nf or m ati o n i n S e cti o n 6. 1. 
A d d e d n ot e t h at, i n d et er mi ni n g t h e 
R D E, t h e S M C will a d diti o n all y 
c o n si d er P K a n d P d i nf or m ati o n.  
R e m o v e d t h e f oll o wi n g s e nt e n c e: If 
M T D i s n ot r e a c h e d, t h e S M C m a y 
d efi n e t h e R D E b a s e d o n t h e P K, P d, 
a n d s af et y pr ofil e.  
F or c o m pl et e n e s s a n d cl arit y  
4. 1. 2 P art 1 B - 
Pr eli mi n ar y F o o d 
Eff e ct A s s e s s m e nt  
A d d e d r ef er e n c e t o f a sti n g wi n d o w 
i nf or m ati o n i n S e cti o n 6. 1. 
F or cl arit y.  
5. 1 I n cl u si o n 
Crit eri a  
U p d at e d I n cl u si o n Crit eri o n of C L cr 
fr o m 3 0 m L/ mi n t o 6 0 m L/ mi n b y 
C o c k cr oft -G a ult e q u ati o n  
S af et y m e a s ur e i n t hi s FI H st u d y.  
5. 2 E x cl u si o n 
Crit eri a  
A d d e d t h e f oll o wi n g b ull et s:  
•  
A 
hi st or y 
of 
a d diti o n al ri s k 
f a ct or s f or T or s a d e s d e P oi nt e s 
( e. g.,  
cli ni c all y  
r el e v a nt 
h y p o k al e mi a, f a mil y hi st or y of 
L o n g Q T S y n dr o m e)  
A s a d diti o n al s af et y m e a s ur e s.  
Gl o bal Versi o n I D: C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
S e cti o n # a n d 
N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
•  
T h e  
u s e  
of  
c o n c o mit a nt 
m e di c ati o n s t h at pr ol o n g t h e 
Q T/ Q T c i nt er v al  
5. 2 E x cl u si o n 
Crit eri a;  
6. 5. 2 P er mitt e d 
M e di ci n e s;  
6. 5. 3 Pr o hi bit e d 
M e di ci n e s  
A s a p pr o pri at e i n r e s p e cti v e s e cti o n s, 
a d d e d i nf o r m ati o n r e g ar di n g e x cl u si o n 
of iri n ot e c a n, or al dir e ct t hr o m bi n 
i n hi bit or s, di g o xi n, a n d pr ot o n p u m p 
i n hi bit or s wit h ti m e wi n d o w c a v e at s f or 
a c c e pt a bl e a d mi ni str ati o n of H 2 -
r e c e pt or a nt a g o ni st s a n d a nt a ci d s 
F or cl arit y a n d t o a v oi d p ot e nti al eff e ct of 
c o n c o mit a nt a d mi ni str ati o n.  
6. 1 St u d y 
I nt er v e nti o n 
A d mi ni str ati o n  
A d d e d P art s 1 A a n d 1 B f a sti n g wi n d o w 
i nf or m ati o n 
F or cl arit y  
6. 6. 2 D o s e -li miti n g 
T o xi citi e s –  
D efi niti o n a n d 
Crit eri a  
A d d e d t h at t h e p o s si bilit y of H y’ s L a w 
p ar a m et er s a s li st e d will r e q uir e p r o m pt 
p er m a n e nt di s c o nti n u ati o n fr o m t h e 
st u d y.  
A s a d diti o n al s af et y m e a s ur e  
6. 6. 2. 1 D o s e 
I nt err u pti o n s a n d 
M o difi c ati o n s; 
T a bl e 1 0  
M o difi e d a s f oll o w s a s it p ert ai n s t o t e xt 
a n d T a bl e  1 0:  
•  
T o r e q uir e p er m a n e nt 
di s c o nti n u ati o n of M 4 0 7 6 f or 
Gr a d e 4 dr u g -r el at e d t o xi cit y. 
Pr o vi d e j u stifi c ati o n f or a n y 
e x c e pti o n s.  
•  
T o pr o vi d e g ui d eli n e s f or 
r e c urr e nt Gr a d e 3 e v e nt s. 
•  
T o r e q uir e p er m a n e nt 
di s c o nti n u ati o n f or c a s e s 
m e eti n g H y’ s l a w crit eri a. 
Alt er n ati v el y pr o vi d e 
j u stifi c ati o n f or w h y t hi s i s n ot 
n e c e s s ar y.  
A s a d diti o n al s af et y m e a s ur e s  
7. 1 Di s c o nti n u ati o n 
of St u d y 
I nt er v e nti o n 
D el et e d t e xt r ef erri n g t o I n v e sti g at or 
d et er mi n ati o n of w h et h er or n ot t o 
di s c o nti n u e st u d y i nt er v e nti o n s f or li v er 
i nj ur y or c ar di a c c h a n g e s  
A s t h er e i s i n s uffi ci e nt i nf or m ati o n t o s u p p ort 
e vi d e n c e -b a s e d d e ci si o n s b y t h e I n v e sti g at or s.  
9. 4. 2. 1 P art 1 A: 
D o s e E s c al ati o n  
A d d e d t h at t h e t ot al d ail y d o s e 
i n cr e a s e d m u st n ot e x c e e d 1 0 0 % of 
t h e hi g h e st t ot al d ail y d o s e l e v el 
c o n si d er e d s af e.  
F or cl arit y  
A p p e n di x 6 Cli ni c al 
L a b or at or y T e st s; 
T a bl e 1 9  
I n t h e T a bl e r o w of “ Ot h er S cr e e ni n g 
T e st s”, cl arifi e d t h at e x c e pt f or s af et y 
l a b or at or y a s s e s s m e nt s, all 
st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s 
will b e p erf or m e d b y a c e ntr al 
l a b or at or y. 
F or cl arit y  
T hr o u g h o ut  
Mi n or a d mi ni str ati v e, e dit ori al, a n d 
d o c u m e nt f or m atti n g r e vi si o n s  
Mi n or; t h er ef or e, h a v e n ot b e e n s u m m ari z e d  
 
 
Gl o bal Versi o n I D: C CI

P P D
P P D
P P D
P P D
P P D
P P D
P P D

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  1 5  
C o or di n ati n g I n vesti g at or Si g n at ure P a ge   
St u d y Title:  
A First -i n-h u ma n, P has e I, O pe n -la bel St u d y of t h e A T M 
i n hi bit or M 4 0 7 6 i n Partici pa nts wit h A d va nce d S oli d 
T u m ors  
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:  
I N D n u m ber 
 
Cli nic al St u d y Pr ot oc ol Versi o n:  2 7  Oct o ber  2 0 2 2 /4 . 0 
Site N u m ber:  
2 0 1  
I a p pr o ve t he desi g n of t h e cli nical st u d y, a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site 
a n d u n dersta n d a n d will c o n d uct it per t he cli nical st u d y 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 n ati 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 uir e me nts a n d nati o nal la ws.  
_ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat
Date of Si g nat ure  
 
N a me, ac a de mi c 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:  
  
 
Gl o bal Versi o n I D: 
O ct o b er 2 8, 2 0 2 2
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P
D
P P D
C CI
C CI

M 4 0 7 6  
First -i n-h u m a n St u d y of M 4 0 7 6 i n A d v a nce d S oli d T u m ors  
M S 2 0 1 5 1 2 _ 0 0 1 0  
 
 
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 2 2  
 
 
A p pe n di x  1 6  
Pri nci p al I n vesti g at or Si g n at ure P a ge   
St u d y Title:  
A First -i n-h u ma n, P has e 1 , O pe n-la bel St u d y of t he 
A T M i n hi bit or M 4 0 7 6 i n Partici pa nts wit h A d va nce d 
S oli d T u m ors  
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:  
I N D n u m ber 1 3 8 6 9 4  
Cli nic al St u d y Pr ot oc ol Versi o n:  2 7  Oct o ber  2 0 2 2 /4 . 0 
Site N u m ber:  
 
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site a n d u n dersta n d a n d will c o n d uct it per 
t he cli nical st u d y 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 bl e 
He alt h 
A ut h orit y 
re q uire me nts a n d n ati o nal la ws. 
I als o u n d ersta n d t hat H ealt h A ut h orities ma y re q uire t he S p o ns ors of cli nical st u dies t o o btai n 
a n d s u p pl y d etails a b o ut o w ners hi p i nterests i n t he S p o ns or or I n v esti gati o nal Me dici nal Pr o d uct 
a n d a n y ot h er fi n a ncial ti es wit h t he S p o ns or. T h e S p o ns or will use a n y s u c h i nf or mati o n s olel y 
f or c o m pl yi n g wit h t h e re g ul at or y re q uire me nts. T heref ore, I a gree t o s u p pl y t he S p o ns or wit h 
a n y necessar y i nf or m ati o n re gar di n g o w ners hi p i nterest a n d fi na n cial ties i ncl u di n g t h os e of m y 
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. 
 
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_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
Date of Si g nat ure  
 
N a me, ac a de mi c 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:  
 
 
Gl o bal Versi o n I D: C CI