Clinical trial NCT04882917
Conditions: Advanced Solid Tumors
Keywords: M4076 Maximum tolerated dose Pharmacokinetics Pharmacodynamics
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2021-05-24; Completion date: 2023-03-31
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) (if reached) and early signs of efficacy of M4076 monotherapy in participants with solid tumors in dose escalation (Part 1A). Once the recommended dose for expansion (RDE) was declared in Part 1A, a preliminary food effect cohort, Part 1B, will follow at the RDE determined from Part 1A.

Detailed description:

Arms: arm 1: Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study arm 2: Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. arm 3: Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. arm 4: Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study.
Interventions: intervention 1: M4076
Intervention descriptions: intervention 1: M4076 was administered orally.

Protocol documents:
Prot_000.pdf: 
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 
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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 
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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 
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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 
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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  
 
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I N F O R M A T I O N 
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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 
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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.  
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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:  
  
 
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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

SAP_001.pdf: 
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                                                                                                                                      v 2. 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 9  
 
 
 
I nte gr ate d A n al ysis Pl a n  
St u d y N u m ber:  
M S 2 0 1 5 1 2 _ 0 0 1 0  
Cli nic al St u d y Pr ot oc ol 
Title:  
A  First -i n-h u ma n,  P h ase  I,  O p e 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  
St u d y P h ase : 
P hase I  
Merc k C o m p o u n d : 
M 4 0 7 6  
Pr ot oc ol V ersi o n:  
2 7  Oct o ber  2 0 2 2 / V ersi o n 4 . 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or : 
 
C o or di n ati n g A ut h or  
 
 
C hri sti n e Hi c ki n g  
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
 
 
 
 
 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n : 
1 9 Dece m b er 2 0 2 2 / Versi o n 2. 0  
I nte gr ate d A n al ysis Pl a n 
Re vie wers : 
F u n cti o n  
N a m e  
 
 
 
 
 
 
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C o nfi de nti al  
T his d o c u me nt is t h e pr o p ert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o n e of its affiliate d c o m p a nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or p art - be p asse d o n, re pr o d u ce d, p u blis h e d or use d wit h o ut 
e x press p er missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p y ri g ht © 2 0 2 1  b y Merc k K G a A, D a r mst a dt, Ger m a n y o r its affili ate. All ri g hts reser v e d.  
P P D
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M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
2/69 
 
 
Approval Page  
 
Integrated Analysis Plan: MS201512_0010 
A First-in-human, Phase I, Open-label Study of the ATM inhibitor M4076 in Participants with 
Advanced Solid Tumors. 
 
 
Approval of the IAP by all Merck Data Analysis Responsible has to be documented within 
Veeva Vault (BREEZE) via eSignature. With the approval, the Merck responsible for each of 
the analysis also takes responsibility that all reviewers’ comments are addressed adequately. 
By using eSignature, the signature will appear at the end of the document. 


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/69 
 
 
1 
Table of Contents  
                               Approval Page .......................................................................................2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................6 
3 
Modification History ............................................................................9 
4 
Purpose of the Integrated Analysis Plan ...............................................9 
5 
Objectives and Estimands .....................................................................9 
6 
Overview of Planned Analyses ...........................................................11 
6.1 
Analyses for SMC meetings ...............................................................12 
6.2 
Primary Analysis for dose escalation and food effect cohort (Part 
1A and Part 1B) ..................................................................................12 
6.3 
Final Analysis for dose escalation and food effect cohort (Part 1A 
and Part 1B) ........................................................................................12 
7 
Changes to the Planned Analyses in the Clinical Study Protocol ......12 
8 
Analysis Sets and Subgroups ..............................................................12 
8.1 
Definition of Analysis Sets .................................................................12 
9 
General Specifications for Data Analyses ..........................................14 
9.1 
Data handling after Cut-off Date ........................................................17 
9.2 
Definition of Baseline and Change from Baseline .............................18 
9.3 
Study Day / Study Intervention Day ...................................................19 
9.4 
Conversion Factors .............................................................................19 
9.5 
Date of Last Contact ...........................................................................19 
9.6 
Definition of On-treatment Period ......................................................20 
9.7 
Exposure time .....................................................................................20 
9.8 
Imputation of Missing Data ................................................................20 
9.9 
Age at Time of an Event .....................................................................24 
9.10 
Laboratory Toxicity grading ...............................................................24 
10 
Study Participants ...............................................................................24 
10.1 
Disposition of Participants and Discontinuations ...............................24 
10.2 
Protocol Deviations / Exclusion from Analysis Sets ..........................26 
10.2.1 
Important Protocol Deviations ............................................................26 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................28 
11 
Demographics and Other Baseline Characteristics .............................28 


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/69 
 
 
11.1 
Demographics .....................................................................................28 
11.2 
Medical History ..................................................................................29 
11.3 
Other Baseline Characteristics ............................................................29 
11.4 
Baseline Tumor Assessment  ..............................................................30 
11.5 
Prior Anti-cancer Therapy ..................................................................30 
12 
Previous or Concomitant Therapies/Procedures .................................31 
13 
Study Intervention: Compliance and Exposure ..................................32 
14 
Efficacy Analyses ...............................................................................33 
14.1 
Primary Estimand ...............................................................................33 
14.2 
Further Estimands ...............................................................................33 
14.2.1 
Secondary Endpoint: Objective Response (OR).................................33 
14.2.2 
Secondary Endpoint: Progression Free Survival (PFS) ......................36 
14.2.3 
Secondary Endpoint: Duration of Response (DoR) ............................37 
15 
Safety Analyses ..................................................................................38 
15.1 
Dose Limiting Toxicities (DLT) Analysis ..........................................38 
15.2 
Adverse Events ...................................................................................39 
15.2.1 
All Adverse Events .............................................................................40 
15.2.2 
Adverse Events Leading to Discontinuation, Interruption or Dose 
Reduction of Study Intervention .........................................................42 
15.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................43 
15.3.1 
Deaths .................................................................................................43 
15.3.2 
Serious Adverse Events ......................................................................43 
15.3.3 
Other Significant Adverse Events ......................................................43 
15.4 
Clinical Laboratory Evaluation ...........................................................44 
15.5 
Vital Signs ..........................................................................................48 
15.6 
Other Safety or Tolerability Evaluations ............................................49 
15.6.1 
ECOG Performance Status .................................................................49 
15.6.2 
Electrocardiogram (ECG) ...................................................................49 
16 
Analyses of Other Endpoints/Estimands ............................................51 
16.1 
Pharmacokinetics ................................................................................51 
16.1.1 
Descriptive Statistics of PK Concentration Data ................................51 
16.1.2 
Descriptive Statistics of PK Parameter Data ......................................51 


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                                                                                                                                      v 2. 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 9  
 
 
1 6. 1. 3  
Statistical A nal ysis of P K Para meter Data  ......................................... 5 2 
1 6. 1. 4  
Ge ner al S pecificati o ns f or P K C o nce ntrati o n a n d P K Para meter 
Data  ..................................................................................................... 5 3 
1 6. 1. 5  
Esti mati o n of P har mac o ki netic Para meters  ........................................ 5 4 
1 6. 1. 5. 1  
Esti mati o n of P har mac o ki netic Para meters i n Plas ma  ....................... 5 4 
1 6. 1. 5. 2  
Esti mati o n of P har mac o ki netic Para meters i n Uri n e  .......................... 5 7 
1 6. 1. 6  
Prese ntati o n of P K C o nce ntrati o n a n d P K Para m eter Data ................ 5 8  
1 6. 1. 6. 1  
Listi n gs a n d Ta bles ............................................................................. 5 8  
1 6. 1. 6. 2  
Gra p hical S u m maries a n d I n di vi d ual pl ots ( P K A nal ysis Set) ........... 6 0  
 
 
 
 
 
 
1 7  
Refere n ces  ........................................................................................... 6 5 
1 8  
A p pe n dices ......................................................................................... 6 6  
1 8. 1  
A p pe n di x 1 – N CI - C T C Gra da ble a n d N o n-Gra d a ble Safet y 
La b orat or y T est Para met ers a n d Directi o n(s) of A b n or malit y  ........... 6 6 
1 8. 2  
A p pe n di x 2 – I A P f or I D M C/ S M C .................................................... 6 9 
 
P P D


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/69 
 
 
2 
List of Abbreviations and Definition of Terms  
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
aPTT  
activated Partial Thromboplastin Time 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical classification  
ATM 
Ataxia-telangiectasia Mutated 
AUC 
Area under the curve 
BLRM  
Bayesian 2-parameter Logistic Regression Model 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
COVID-19 
Coronavirus disease 2019 
CMH 
Cochran-Mantel-Haenszel 
CALCIO 
Corrected Calcium and Ionized Calcium 
CR 
Complete Response 
(e)CRF 
(electronic) Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CV 
Coefficient of Variation 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/69 
 
 
ECOG 
Eastern Co-operative Oncology Group 
eDISH 
Drug-Induced Serious Hepatotoxicity 
FAS 
Full Analysis Set 
FU 
Follow-up 
GCP 
Good Clinical Practice 
γ-H2AX 
Gamma Histone Family Member X 
HR 
Hazard Ratio 
HRQoL 
Health-related quality of life 
IAP 
Integrated Analysis Plan 
ICE 
Intercurrent Event 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
ICD-O 
International Classification of Diseases for Oncology 
IPD 
Important Protocol Deviation 
IRC 
Independent Review Committee 
ITT 
Intention To Treat 
IVRS 
Interactive Voice Response System 
KM 
Kaplan-Meier 
LLN 
Lower Limit of Normal 
LLOQ 
The lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mantel-Haenszel 
MTD 
Maximum Tolerated Dose 
NA 
Not Applicable 
nd 
Not done 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
OR 
Objective Response  
ORR 
Objective Response Rate 
OS 
Overall Survival 
p-ATM 
Phosphorylated Ataxia-Telangiectasia Mutated 
Pd 
Pharmacodynamics 


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                                                                                                                                      v 2. 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 9  
 
 
 
P D  
Pr o gressi ve Diseas e or Pr ot oc ol De viati o n or P har mac o d y na mics  
P F S  
Pr o gressi o n Fr ee S ur vi val  
P T  
Preferre d Ter m  
P G x  
P har mac o ge n etics/ P har mac o ge n o mics  
P K  
P har mac o ki netics  
P K A S  
P har mac o ki netic A n al ysis Set  
P R  
Partial Res p o nse  
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 ose f or E x pa nsi o n  
S A E  
Seri o us A d verse E v e nt  
S A F  
Safet y A nal ysis Set  
S C R  
Scree ni n g a n al ysis set  
S M C  
Safet y M o nit ori n g C o m mittee  
S D  
Sta ble Disease or Sta n dar d De viati o n  
S D T M  
St u d y Data Ta b ulati o n M o del  
S M C  
Safet y M o nit ori n g C o m mittee  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
U L N  
U p per Li mit of N or mal  
W B C  
W hite Bl o o d Cell C o u n t 
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
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                                                                                                                                      v 2. 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 9  
 
 
3  
M o dific ati o n Hist or y   
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
1. 0  
0 9  N o v e m b er  
2 0 2 1  
 
I niti al V er si o n 
2. 0  
1 9 D e c e m b er 
2 0 2 2  
 
O nl y fi n al a n al y si s will b e p erf or m e d.  
D L T s will b e pr e s e nt e d o nl y b y D L T a n al y si s s et . 
N o n -r el e v a nt a n al y s e s r e m o v e d: 
•  
T a bl e o n b a s eli n e t u m or a s s e s s m e nt  
•  
E C O G s hift t a bl e  
•  
S u b s e q u e n c e a nti -c a n c er t h er a p y  
•  
Pri or A nti -c a n c er T h er a p y b y A T C a n d P T  
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n  
T he  p ur p ose  of  t his  I nt e grate d  A nal ysis  Pla n  (I A P)  is  t o  d oc u me nt  t ec h nical  a n d  detaile d  
s pecificati o ns f or all t he a nal yses of data c ollecte d f or pr ot oc ol M S 2 0 1 5 1 2 _ 0 0 1 0 i ncl u di n g P art 
1 A ( d ose es calati o n) a n d  P art 1 B (preli mi nar y f o o d effect c o h ort).  
Res ults of t he a nal yses d escri be d i n t his I A P will b e i ncl u de d  i n t he Cli nical St u d y Re p ort ( C S R) 
or i n se par ate r e p orts . A d diti o nall y, t he pla n ne d a n al yses i de ntifie d i n t his I A P ma y  be i ncl u de d i n 
re g ulat or y s u b missi o ns or f ut ure ma n uscri pts. A n y p ost- h oc, or u n pla n ne d a nal yses perf or me d t o 
pr o vi de res ults f or i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y 
i de ntifie d i n t he CS R.  
T he I A P is base d o n Secti o n 9  ( Statistical c o nsi derati o ns) of t he pr ot oc ol a me n d me nt versi o n 4. 0 
date d 2 7  Oct o ber  2 0 2 2 a n d  is  pre pare d  i n  c o m plia nce  wit h  I nter nati o nal  C o nfere n ce  o n  
Har m o nizati o n  (I C H E 9). It descri b es a nal yses pla n ne d i n t he pr ot oc ol a n d pr ot oc ol a me n d me nts. 
Details of t he Safet y M o nit ori n g C o m mittee ( S M C) a nal yses f or re g ular re vie w of t h e partici p a nts’ 
safet y ar e pr o vi de d i n a p pe n di x. 
5  
O bjecti ves a n d Esti m a n ds   
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 Ass ess me nt ( Part  1 B)  
P P D
P P D


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
10/69 
 
 
Objectives 
Estimands Attributes  
IAP section 
Primary 
 
To determine dose-toxicity relationship 
and MTD (if reached) of M4076 
monotherapy in participants with 
advanced solid tumors. 
Endpoints: 
• 
Occurrence of Dose Limiting Toxicities 
(DLTs). 
• 
Occurrence of adverse events (AEs) and 
treatment-related AEs. 
• 
Occurrence of clinically significant changes in 
vital signs, laboratory parameters, and 12-lead 
electrocardiogram (ECG) findings. 
 
Strategy for handling intercurrent events:   
For DLTs:  
• 
Discontinuation of treatment (> 20% planned 
treatment missed during DLT period) to prevent 
a DLT: composite strategy (to be considered a 
DLT).  
• 
Discontinuation treatment administrations not 
due to DLT or preventing a DLT (> 20% of 
planned treatment missed during DLT period): 
participant not considered in DLT analysis. 
 
For other endpoints: 
All available data from participants in safety 
analysis set will be used. 
 
Population:  
Patients with advanced solid tumors, who are 
intolerant or have no effective standard therapies 
available to them. 
 
Population level summary:  
• 
DLT probability as estimated using BLRM and 
credibility interval (only applicable for DLTs). 
• 
Standard summary statistics. 
 
Section 15.1 
Section 15.2, 15.3 
Section 15.4, 15.5, 15.6  
 
 
Secondary 
 
To determine the recommended dose 
for expansion (RDE) of M4076 
monotherapy in participants with 
advanced solid tumors. 
Endpoints: 
• 
In addition to safety and tolerability, changes 
from baseline for the following Pd biomarkers 
may be considered for determining the RDE:  
ATM pathway readouts such as, but not limited 
to, p-ATM, γ-H2AX and p-CHK2 in blood and 
tumor. 
• 
In addition, pharmacokinetic (PK) data will be 
used to support determination of the RDE. 
Section 15 
Section 16.1  
 
To characterize the PK profile of 
M4076 monotherapy in participants 
with advanced solid tumors. 
Endpoints: 
• 
PK parameters of M4076 in plasma after single 
dose and multiple doses.  
• 
Urine PK parameters (e.g., renal clearance) will 
be characterized in Part 1B if data permits. 
Section 16.1 


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                                                                                                                                      v 2. 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 9  
 
 
O bjecti ves  
Esti m a n ds Attri b utes  
I A P secti o n 
T o e val uate preli mi n ar y cli nical 
acti vit y para meters of M 4 0 7 6 
m o n ot hera p y i n p artici p a nts wit h 
a d va nce d s oli d t u m ors. 
E n d p oi nts:  
•  
O bjecti v e res p o nse ( O R) acc or di n g t o 
R E CI S T 1. 1 assesse d b y I n v esti gat or.  
•  
D urati o n of res p o nse ( D o R) acc or di n g t o 
R E CI S T 1. 1 assesse d b y I n v esti gat or.  
•  
Pr o gressi o n Free S ur vi v al ( P F S) acc or di n g t o 
R E CI S T 1. 1 assesse d b y I n v esti gat or.  
Secti o n 1 4  
T o assess t he effect of f o o d o n t he P K 
of M 4 0 7 6 a d mi nistere d as a si n gle d ose 
u n der fe d/fasti n g c o n diti o ns i n a c o h ort 
of partici pa nts wit h a d v a n ce d s oli d 
t u m ors at t he R D E fr o m Part 1 A.  
E n d p oi nts:  
Fe d/faste d rati o of M 4 0 7 6 plas ma P K p ara meters: 
A U C 0-- tlast, A U C0- ∞ a n d, C ma x w h e n a d mi nistere d as 
a si n gle d ose wit h or wit h o ut f o o d.  
Secti o n 1 6. 1  
 
T o assess c ha n g es i n p h ar mac o d y n a mic 
mar kers of M 4 0 7 6 acti 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 hera p y.  
E n d p oi nts:  
A bs ol ute a n d relati v e c h a n g es o ver ti me  fr o m 
b aseli n e of A T M p at h wa y rea d o uts, s u c h as, b ut n ot 
li mite d t o p-A T M, p -C H K 2 a n d γ-H 2 A X.   
Secti o n 1 6. 2  
6  
O ver vie w of Pl a n ne d A n al yses   
T he f oll o wi n g a nal yses are pla n ne d f or t his trial: 
•  Safet y M o nit ori n g C o m mittee  ( S M C) anal yses ( See I A P f or S M C i n A p pe n di x 1 8. 3 ) 
•  Fi nal a nal ysis f or d os e es calati o n a n d f o o d effect c o h ort ( Part 1 A a n d Part 1 B) 
Statistical a nal yses  (e xce pt f or S M Cs) will be perf or me d o n t he basis of C DI S C S D T M data. T hes e 
S D T M data  c o ntai n as cl ea n as p ossi ble e C R F dat a as well as e xter nal data f or ce ntral la b orat or y  
bi o mar ker dat a, t u m or assess me nt res ults b y I n vesti gat or a n d D L T decisi o ns fr o m S M C. 
C CI


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Statistical analyses for SMCs will be performed on the basis of eCRF/external data. 
A data review meeting will be held prior to any database lock. In addition, no database can be 
locked until this IAP has been approved (except for emergency). 
All planned analyses identified in the Clinical Study Protocol and in this IAP will be performed. 
6.1 
Analyses for SMC meetings  
Details of analyses for SMC meetings will be specified in a separate IAP, provided in Appendix 
18.2. 
6.2 
Primary Analysis for dose escalation and food effect cohort 
(Part 1A and Part 1B)  
The cutoff for the primary analysis of the safety, available PK, available Pd and preliminary 
antitumor activity data from Part 1A and Part 1B will be triggered when all participants have 
reached either the first on-treatment tumor assessment, or experienced death or premature 
withdrawal for any reason, whichever comes first. 
All trial data up to the primary analysis cutoff date will need to be in-house, all data queries 
resolved, and the database locked for primary analysis. 
This analysis will be the main analysis. All planned analyses as specified in the TLF table of 
contents for primary analysis will be performed. 
6.3 
Final Analysis for dose escalation and food effect cohort (Part 
1A and Part 1B)  
Final analyses to report further efficacy and safety data will be performed once the End of Study 
has been reached. Please refer to the study protocol for details on when participants are considered 
to have completed the study.  
All planned analyses as specified in the TLF table of contents for final analysis will be performed. 
7 
Changes to the Planned Analyses in the Clinical Study 
Protocol  
There are no changes to the planned analyses in the clinical study protocol.  
8 
Analysis Sets and Subgroups  
8.1 
Definition of Analysis Sets  
Screening Analysis Set (SCR) 
The Screening analysis set includes all participants who signed the informed consent. 


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Full Analysis Set (FAS) / Safety Analysis Set (SAF) 
The analysis set will include all screened participants, who received at least one dose of any study 
intervention. Analyses will consider participants as treated. 
Participants will be classified according to the dose actually received.  See Section 9 for details on 
determination of actual dose level. The Full Analysis Set (FAS) and the Safety Analysis Set (SAF) 
are identical. In outputs this analysis set will be denoted by ‘FAS/SAF’. Analyses of safety and 
efficacy will be based on this analysis set.  
Dose Limiting Toxicity Analysis Set (DLT)  
The DLT Set will include all participants who received at least one dose of study intervention and 
meet at least one of the following criteria: 
• Experienced at least one DLT during the DLT period, regardless of the administered number 
of doses of study intervention/completion in the DLT period 
• Received at least 80% of the planned cumulative dose during the DLT period of each study 
intervention and completed the DLT period 
• Additionally, participants who did not receive 80% of the planned total dose of study 
intervention, but at least 80% dosing of a different dose cohort and finished the DLT period 
are eligible for the DLT analysis set to be analyzed in the highest dose cohort for which they 
received 80% of dosing. 
The final decision on evaluability for dose escalation analysis will be made by the SMC (e.g. 
considering relevant deviations from dosing schedule). 
PK Analysis Set (PKAS)  
The Pharmacokinetic (PK) Analysis Set (PKAS) is a subset of the FAS/SAF and will consist of all 
participants, who receive at least one dose of study intervention, and provide at least one 
measurable post-dose concentration. A measurement below lower limit of quantification (BLQ) is 
considered a valid measurement. Participants will be analyzed per the actual study intervention 
they received. All PK analyses will be based on the PK Analysis Population. 
Pd Analysis Set  
The pharmacodynamics (Pd) Analysis Set will consist of all participants, who receive at least one 
dose of study intervention, have no clinically important protocol deviations or important events 
affecting Pd, and provide the baseline and at least one measurable Pd endpoint postdose. 
Participants will be analyzed per the actual study intervention they received. All Pd analyses will 
be based on this analysis population. 
Analyses per Analysis Set 
The following table summarizes the use of the analysis sets in the different analyses.  


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Analyses 
DLT 
FAS/SAF 
PKAS 
Pd 
DLT: Primary 
 
 
 
 
Safety and Tolerability 
 
 
 
 
Baseline Characteristics 
 
 
 
 
Previous and Concomitant Therapies 
 
 
 
 
Compliance and Exposure 
 
 
 
 
Efficacy  
 
 
 
 
Pharmacokinetic 
 
 
 
 
Pharmacodynamic 
 
 
 
 
DLT = Dose Limiting Toxicity; FAS = Full Analysis Set; SAF = Safety Analysis Set; PK = Pharmacokinetic Analysis 
Set; Pd = Pharmacodynamic 
Note: Safety, PK and Pd will be described by actual dose which might differ from planned dose. 
All other analyses will be described by planned dose, according to Intention-to-Treat principle. 
For more details, see Section 9. 
9 
General Specifications for Data Analyses  
The results of this study will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by study part (Part 1A and Part 1B), dose level (and 
regimen if different regimens tested), and by dietary status (“Fed” and “Fasted”) and/or scheduled 
time point, as applicable.   
Definition of actual dose 
Unless otherwise specified, analyses of safety, efficacy and PK parameters will be conducted by 
actual dose. In this open label, unblinded study, actual dose is determined by considering study 
drug compliance during the DLT evaluation period (first 21 days from first dose of M4076) and 
whether the subject experienced a DLT (as per SMC determination). If a different regimen is 
tested, all subjects remain in the regimen to which they were assigned (i.e. subjects cannot be 
assigned to a different pre-specified dose level with a different dosing scheme).  
In this context, compliance is defined as the cumulative actual dose taken by the subject divided 
by the cumulative cohort-level planned dose the subject was expected to receive. The planned dose 
level will be taken from the electronic case report form (eCRF) “Cohort”. The following table will 
be used to determine actual dose level: 


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                           First-in-human Study of M4076 in Advanced Solid Tumors  
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Table 1 Actual Dose Assignment  
Compliance of 
planned dose 
DLT Status 
Compliance relative to other pre-
specified dose levels 
Actual dose 
> 100% 
Any 
≥ 80% a higher pre-specified dose 
level 
Higher pre-
specified dose level 
> 100% 
Any 
< 80% a higher pre-specified dose 
level (or no higher dose level) 
Planned dose level 
≤ 100% 
 
DLT 
Any 
Planned dose level 
≥ 80% and ≤ 100% 
 
No DLT 
Any 
Planned dose level 
< 80% 
No DLT 
≥ 80% of a lower pre-specified 
dose level 
Lower pre-
specified dose level 
< 80% 
No DLT 
< 80% of the lowest pre-specified 
dose level (or no lower dose level) 
Lowest received 
pre-specified dose 
level*  
*Patient is not evaluable for DLT analysis set 
Note: In case a subject received >120% cumulative dose of the planned dose but ≤ 80% of the next 
higher pre-specified dose the data of this subject will not be considered in Pd and efficacy summary 
outputs. The data will be displayed in listings and line plots but with a footnote stating the actual 
cumulative dose. 
In the event there are subjects whose ‚actual‘ dose differs from the planned dose, disposition, 
compliance and exposure will be described by both planned and ‚actual‘ dose. 


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Period definition for Part 1B (Food effect Cohort) 
For analyses related to food effect assessments, the following timepoints are defined and mapped 
to the visit days in the Schedule of Activities for the preliminary food effect assessments in the 
protocol: 
Table 2 Definition of Periods including preliminary food effect assessments  
Food Effect Assessment 
Period -Fasted 
Food Effect Assessment 
Period -Fed*  
Part 1A Schedule 
Analysis 
Day 
Visit Day 
mapped from 
Schedule of 
Activities 
Analysis 
Day 
Visit Day 
mapped from 
Schedule of 
Activities 
Analysis 
Day 
Visit Day 
mapped 
from 
Schedule of 
Activities 
Fasted Day 1 
Day -7 or Day 1 
Fed Day 1 
Day -7 or Day 1 
Period 1 
Day 5 
Day 5 
Fasted Day 2 
Day -6 or Day 2 
Fed Day 2 
Day -6 or Day 2 
Period 1 
Day 6 
Day 6 
Fasted Day 3 
Day -5 or Day 3 
Fed Day 3 
Day -5 or Day 3 
Period 1 
Day 7 
Day 7 
Fasted Day 4 
Day -4 or Day 4 
Fed Day 4 
Day -4 or Day 4 
Period 1 
Day 8 
Day 8 
*The fed meal condition is planned to be a standard low-fat meal. 
Note, that Food Effect Assessment is defined until Day 4 pre-dose. After Day 4, assessments are 
continued according to Part 1A Schedule of Activities (Period 1 Day 8, Period 1 Day 15, etc.). All 
cross-over design related analysis in Part 1B refers to the data collected within the timeframe of 
food effect assessment only (Day -7 until Day 4 per Schedule of Activities for Part 1B). 
Listings 
In the individual participant data listing all individual data for each study part (Part 1A and Part 
1B) will be listed as measured. Repeated and unscheduled measurements will be included in the 
listings. All listings will be sorted by dose level, participant ID, and/or nominal time point, as 
appropriate. Data which are measured before administration of the administration of study 
intervention will be sorted by participant number and nominal time point (if appropriate). 
Tables and Descriptive Statistics 
All data will be summarized by study part (Part 1A and Part 1B), dose level (and regimen if 
different regimens are tested), dietary status(“Fed” and “Fasted”), day, and/or nominal time point, 
as appropriate Different dose levels will generally be presented in increasing order. A total column 
is also presented. Repeated and unscheduled measurements included in the listings will not be used 


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for statistical analyses or summaries, unless the repeated measurement was performed due to 
unreliable values/technical reasons, e.g., clotted samples.  
Presentation of continuous and qualitative variables 
Unless otherwise specified, continuous variables will be summarized using descriptive statistics, 
i.e. the number of participants with non-missing values (n), mean, standard deviation, median, 25th 
percentile (Q1) and 75th percentile (Q3), minimum, and maximum, 95% CIs for the mean, as 
appropriate.  
Mean, median, Q1, Q3, Min, and Max will have the same precision as collected in SDTM datasets 
for non-derived data. Standard deviation will be presented with one digit more than the mean. 
Percentage and percent change from baseline will be reported using one decimal digit, if not 
specified otherwise. Derived data such as duration and “time since” variables (see Section 9.3) 
will be displayed with one decimal digit, unless stated otherwise. 
If there are no missing values, the number of participants with missing values should be indicated 
by a 0. 
Qualitative variables will be summarized by frequency counts and percentages. Unless otherwise 
stated the calculation of proportions will be based on the number of participants in the analysis set 
of interest. Therefore, counts of missing observations will be included in the denominator and 
presented as a separate category.  
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants still present in the trial at that visit, unless otherwise specified. 
Descriptive statistics by nominal visit or time point, e.g. for laboratory measurements, will include 
only data from scheduled visits. Unscheduled visits will be included in the derivation of baseline 
or worst on-treatment values. 
Significance level: 
All statistical tests mentioned in this IAP are to be regarded as exploratory. No formal statistical 
hypothesis will be tested. If confidence intervals are to be calculated, these will be two-sided with 
a confidence probability of 95%, unless otherwise specified in this IAP. 
Software 
All analyses will be performed using SAS® Software version 9.4 or higher or R (www.r 
project.org), Version 3.5.1 or higher. 
9.1 
Data handling after Cut-off Date  
By its nature, data after cut-off may be incomplete and subject to further change and will not be 
used for summary statistics, statistical analyses, listings or imputations.  


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Stop dates are not affected by this rule, e.g. a stop date of Adverse Events (AEs), which starts prior 
to the cut-off, but stops after date of cut-off, will not be changed. 
These rules will be applied to all analyses performed for the primary analysis. For the final (follow-
up) analysis no cut-off date will be applied: the analysis will be performed only after all the data 
have been collected, fully cleaned and the database has been locked. 
9.2 
Definition of Baseline and Change from Baseline  
Definition of baseline: 
Part 1A: 
In general, the last non-missing measurement prior to the first study intervention administration 
will be used as the baseline measurement.  
Part 1B:  
In general (if not otherwise specified), the last non-missing measurement prior to the first study 
intervention administration will serve as the baseline measurement for efficacy as well as for safety 
analyses (irrespective of dietary status). 
For food effect analyses on pre-defined endpoints, the ‘baseline’ refers to the last scheduled 
measurement before administration of study intervention in each food effect assessment period. 
However, if a participant is missing the baseline collection, the previous non-missing evaluation 
could become the baseline value (e.g. from screening/admission). If no baseline value exists, then 
the baseline value and the respective change from baseline will be treated as missing. 
If an assessment that is planned to be performed before study intervention per protocol is 
performed on the same day as the start of study intervention, but the assessment time is not 
available, it will be assumed that it was performed prior and will be considered as baseline.  
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be analyzed similar to an unscheduled post-dose measurement. 
Definition of change from baseline 
absolute change from baseline = visit value – baseline value 
percent change from baseline = 100 * (visit value – baseline value) / baseline value 


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9.3 
Study Day / Study Intervention Day  
Part 1A: 
Day 1 is the day of start of study intervention, the day before is Day -1 (no Day 0 is defined). Study 
day / Study intervention day is defined relative to Day 1. 
Part 1B: 
Day 1 is the day of start of study intervention, the day before is Day -1 (no Day 0 is defined). Study 
day / Study intervention day is defined relative to Day 1 (irrespective of dietary status), if not 
otherwise specified.  
Definition of Duration and ‘Time Since’ Variables  
Durations in days will be calculated by the difference of start and stop date + 1 (e.g. survival time 
(days) = date of death – date of first study intervention + 1) if not otherwise specified. 
The time since an event (e.g. time since first diagnosis) will be calculated as reference date minus 
date of event. 
9.4 
Conversion Factors  
The following conversion factors will be used to convert days into months or years:  
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
9.5 
Date of Last Contact  
The date of last contact will be derived for participants not known to have died at the analysis 
cut-off using the latest complete date prior to or at the data cut-off date among the following: 
Participants off study intervention: 
Last known to be alive date collected on the ‘Survival Follow-up’ eCRF Participants on study 
intervention: 
• AE start and end dates 
• Date of last study intervention 
• Date of last tumor assessment 
• All participant assessment dates (blood draws [laboratory and PK], vital signs, performance 
status, ECG) 
• Date of discontinuation on disposition eCRF pages (unless reason for discontinuation is lost to 
follow-up). 


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• Start and End date of Concomitant Medication and Procedures eCRF pages 
Only dates associated with actual examinations of the participant reported in the eCRF will be 
used in the derivation.  Dates associated with a technical operation unrelated to participant status 
such as the date a blood sample was processed will not be used. Assessment dates after the cut-off 
date will not be applied to derive the last contact date. 
9.6 
Definition of On-treatment Period  
The on-treatment period is defined as the time from the first dose of study intervention day to the 
last administration day of study intervention + 30 days, or the cut-off date or death, whichever 
occurs first. 
9.7 
Exposure time  
Duration of exposure to study intervention = date of last dose of study intervention –date of 
first dose of study intervention +1. 
9.8 
Imputation of Missing Data  
Unless otherwise specified, all data will be evaluated as observed, and no imputation method for 
missing values will be used. 
In all participant data listings, imputed values will be presented, and imputed information will be 
flagged. 
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”. For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”. 
Where tables are presented over different time points, the total of missing and non-missing 
observations at each time point should reflect the population still in the trial at that time. This does 
not apply when imputations are made beyond trial withdrawal. For example, if a participant is still 
in the trial at the time-point but with missing data, they should be counted in the number of missing 
observations. 
The following table for imputation rules will be considered: 
 
Disease history 
Incomplete dates for disease history (e.g. initial diagnosis date, date of 
documented, locally advanced, inoperable or metastatic disease diagnosis, 
date of response or progression in prior treatment) will be imputed as 
follows: 
• If the day is missing, it will be imputed to the 15th day of the month.  
• If both day and month are missing and the year is prior to the year of the 
first study intervention, the month and day will be imputed as July 1st. 


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• If both day and month are missing and the year is same as the year of 
the first study intervention, the month and day will be imputed as 
January 1st.  
• If the date is completely missing, no imputation will be performed. 
 
Adverse events 
Incomplete AE-related dates will be imputed as follows:  
• In case the onset date is missing completely or missing partially but the 
onset month and year, or the onset year are equal to the start of study 
intervention then the onset date will be imputed by the minimum of start 
of study intervention and AE resolution date (if not missing). 
• In all other cases, the missing onset day or missing onset month will be 
imputed by 1.  
• Incomplete stop dates will be imputed by the last day of the month (if 
day is missing only), if not resulting in a date later than the date of 
participant’s death. In the latter case, the date of death will be used to 
impute the incomplete stop date. 
• In all other cases, the incomplete stop date will not be imputed. 
Previous and 
concomitant 
medication 
For identification of previous or concomitant medications/procedures, no 
formal imputation will be performed on missing or incomplete dates. Rules 
presented in Table 3 will be used to define if a medication/procedure is 
considered as a previous, concomitant or both previous and concomitant 
medication/procedure.  
Table 3 
Imputation rules for medication/procedure end dates  
End date of medication/procedure 
Imputation rule 
Day 
Month 
Year 
  
UNK 
UNK 
UNK 
After study intervention start (ongoing) 
UNK 
UNK 
< Study intervention start (year) 
Before study intervention start 
UNK 
UNK 
≥  Study intervention start (year) 
After study intervention start 
UNK 
< Study intervention start (month and year) 
Before study intervention start 
UNK 
≥  Study intervention start (month and year) 
After study intervention start 
< Study intervention start (complete date) 
Before study intervention start 
≥  Study intervention start (complete date) 
After study intervention start 
UNK = Unknown 


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Table 4 
Rules to define previous and/or concomitant medications  
Start date of medication/procedure 
Imputation rule  
(see Table 3) 
Medication/ 
procedure 
Day 
Month 
Year 
  
  
UNK 
UNK 
UNK 
Before study intervention start 
Previous 
UNK 
UNK 
UNK 
After study intervention start 
Previous and 
concomitant 
UNK 
UNK 
≤  Study intervention start (year) 
Before study intervention start 
Previous 
UNK 
UNK 
≤  Study intervention start (year) 
After study intervention start 
Previous and 
concomitant 
UNK 
UNK 
> Study intervention start (year) and 
≤  Study intervention end + 30 days 
(year) 
After study intervention start 
Concomitant 
UNK 
≤  Study intervention start (month and year) 
Before study intervention start 
Previous 
UNK 
≤  Study intervention start (month and year) 
After study intervention start 
Previous and 
concomitant 
UNK 
> Study intervention start (month and year) 
and ≤  Study intervention end + 30 days 
(month and year) 
After study intervention start 
Concomitant 
≤  Study intervention start (date) 
Before study intervention start 
Previous 
≤  Study intervention start (date) 
After study intervention start 
Previous and 
concomitant 
> Study intervention start (date) and ≤  Study 
intervention end + 30 days (date) 
After study intervention start 
Concomitant 
UNK = Unknown 
 
Dates 
of 
study 
intervention 
Start date of study interventions: 
•  No imputation will be done. 
End date of study interventions: 
• In case the last date of study intervention is missing or incomplete 
the date of last administration of study intervention will be taken 
from the treatment termination eCRF pages. 
• If the last date of study intervention is completely missing and there 
is no Treatment Termination eCRF page and no death date the 
participant should be considered to be ongoing and use the cut-off 
date for the analysis as the last dosing date 
• If the last date of study intervention is completely or partially 
missing and there is EITHER and Treatment Termination eCRF 
page OR a death date available (within the cut-off date) then imputed 
last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min 
(EOT date, death date) 


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= Last day of the month, if both Year and Month are available and 
Year = Year of min (EOT date, death date) and Month < the month 
of min (EOT date, death date) 
= min (EOT date, death date), for all other cases 
Death date 
 
For the purpose of survival analyses partially missing death dates will 
be imputed as follows: 
If only the day is missing, the death date will be imputed to the 
maximum of the (non-imputed) day after the date of last contact and the 
15th day of the month.  
Otherwise, it will not be imputed. 
 
Tumor assessments 
All investigation dates (e.g. X-ray, CT scan) must be completed with 
day, month and year. 
If there are multiple scan dates associated with an evaluation, i.e., 
radiological assessments occur over a series of days rather than the 
same day, the choice of date of assessment could impact the date of 
progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated 
with the evaluation will be used as the date of assessment. 
If one or more investigation dates for an evaluation are incomplete but 
other investigation dates are available, the incomplete date(s) are not 
considered for calculation of the assessment date and assessment date 
is calculated as the earliest of all investigation dates (e.g. X-ray, CT-
scan).   
If all measurement dates for an evaluation have no day recorded, the 1st 
of the month is used.  
If the month is not completed, for any of the investigations for an 
evaluation, the respective assessment will be considered to be at the 
date which is exactly between the previous and the following 
assessment. If both a previous and following assessments are not 
available, this assessment will not be used for any calculations. 
 
Dates of subsequent 
anti-cancer therapy 
Incomplete dates for start date of subsequent anti-cancer therapy (drug 
therapy, radiation, surgery) will be imputed as follows and will be used 
for determining censoring dates for efficacy analyses and in the 
derivation of the end of on-treatment period.  
If only day is missing, it will be imputed as the last day of the month 
unless the end date of subsequent anti-cancer therapy is before that date. 
In that case, the incomplete anti-cancer therapy start date will be 
imputed as the end date of the anti-cancer therapy. 


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If both day and month are missing, no imputation will be performed.  
Incomplete subsequent anti-cancer therapy stop dates will not be 
imputed. 
 
9.9 
Age at Time of an Event  
If age at the time of an Event is derived, the following algorithm will be used for the derivation 
• Year of event minus year of birth 
9.10 
Laboratory Toxicity grading  
In NCI-CTCAE v5.0 (see Section 18.1) the following parameters are not gradable at baseline as 
grading implies dependencies to baseline (e.g. ALT grade 1: >ULN - 3.0 x ULN if baseline was 
normal; 1.5 - 3.0 x baseline if baseline was abnormal): 
• Eosinophilia (added term, grade 1 depends on baseline) 
• Alanine aminotransferase increased 
• Alkaline phosphatase increased 
• Aspartate aminotransferase increased 
• Blood total bilirubin increased 
• Creatinine increased  
• GGT increased 
• INR increased (dependent on baseline also in v4.03) 
In addition, in v5.0 the term ‘Hyperglycemia’ does not depend on glucose laboratory 
measurements anymore and is thus excluded from laboratory analyses and part of AE reporting 
only.  
For the term ‘Hemoglobin increased’ the dependency to baseline is removed in v5.0. ‘INR 
increased’ is dependent on baseline values and intake of anticoagulants in both versions. 
10 
Study Participants  
The subsections in this section include specifications for reporting participant disposition and 
study intervention/study discontinuations. Additionally, procedures for reporting protocol 
deviations are provided. 
10.1 
Disposition of Participants and Discontinuations  
The number and percentage of participants in each of the below disposition categories will be 
presented as indicated in section 9. Percentages will be presented with respect to the number of 
participants in FAS/SAF analysis set. 


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Participant disposition will be summarized as follows: 
• Number of participants in each analysis population (SCR, FAS/SAF, DLT, PKAS, Pd) 
• Number of participants who discontinued from the study prior to study intervention overall and 
grouped by the main reason for discontinuation:  
o Participant did not meet all eligibility criteria 
o Withdrew consent 
o Other (COVID-19-related and COVID-19-non-related) 
The end of study intervention status will be summarized by: 
• Number of participants who received at least one dose of study intervention 
• Number and percentage of treated participants with ongoing study intervention 
• Number and percentage of treated participants who completed study intervention (overall and 
by reason): 
o Death 
o Progressive disease 
• Number and percentage of treated participants who discontinued the study intervention (overall 
and by primary reason): 
o Adverse event 
o Lost to follow-up 
o Protocol non-compliance 
o Death 
o Withdrew consent 
o Other (COVID-19-related and COVID-19-non-related) 
This table will be produced twice if there are participants with differing planned dose and actual 
dose, one by planned dose and one by actual dose. 
The end of study status will be summarized by: 
• Number and percentage of participants with ongoing study intervention  
• Number and percentage of participants off-treatment and in follow-up 
• Number and percentage of participants who completed the study (overall and by primary 
reason): 
o Progressive disease 
o Death 
• Number and percentage of participants who prematurely discontinued the study (overall and by 
primary reason) 


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o Adverse event 
o Lost to follow-up 
o Protocol non-compliance 
o Death 
o Progressive disease 
o Withdrew consent 
o Other (COVID-19-related and COVID-19-non-related) 
Additionally, the number of participants screened, and enrolled in each analysis set (SCR, 
FAS/SAF, DLT, PK and Pd) will be provided overall by region, by country within region and by 
site. 
Disposition of participants by allocated study intervention dose will be presented in a CONSORT 
Flow Diagram. 
10.2 
Protocol Deviations / Exclusion from Analysis Sets  
10.2.1 
Important Protocol Deviations  
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. 
Important protocol deviations include: 
• Participants enrolled and dosed on the study who did not satisfy enrolment criteria 
• Participants that develop withdrawal criteria whilst on the study but are not withdrawn 
• Participants that receive an incorrect dose 
• Participants that receive a prohibited concomitant medication 
• Failure to collect data necessary to interpret primary endpoints 
• Failure to collect necessary key safety data 
• Deviation from Good Clinical Practice (GCP) 
• Any other protocol deviation that might significantly affect the completeness, accuracy, and/or 
reliability of the study data or that might significantly affect a participant's rights, safety, or 
well-being. 
Important protocol deviations will be identified for all participants by either site monitoring, 
medical review processes or programming and confirmed prior to or at the Data Review Meeting 
at the latest. Any important protocol deviations are documented in SDTM datasets whether 
identified through site monitoring, medical review processes or programming. The management 
of protocol deviations is outside of this IAP document. 


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Clinically important protocol deviations (CIPDs) are a subset of important protocol deviations that 
could impact the key objectives of the study and that would lead to the exclusion of a participant 
from an analysis set (see Section 8.1 Definition of Analysis Sets).     
CIPDs may be identified during the course of the study but will not require amendments to this 
IAP.   
Important protocol deviations or important events that might have an effect on PK include, but 
may not be limited to the following: 
• Adverse events, diarrhea etc. (these instances will be discussed on a case-by case basis) 
• Impact of vomiting after oral administration but before 2x of median tmax (e.g. excluding the 
participant) will be assessed on a case-to-case basis for the impact on the overall result.   
• Sample processing errors that may lead to inaccurate bioanalytical results 
• Inaccurate dosing or dosing errors (e.g. dose administration delayed, dose change or missed 
doses) 
• Pre-dose or trough sample collected after the actual dosing 
• Non-compliance with food and drink requirements (e.g. non-fasted, incomplete meal 
consumption, caffeine intake) 
• Concomitant medication, vitamins, dietary or herbal supplements  
Should one or more of these events be available at the Data Review Meeting, its implication for 
PK evaluation will be discussed and agreed amongst relevant study team members (e.g. Sponsor 
Clinical Pharmacology/Biostatistics/Clinical Pharmacokinetics & Pharmacodynamics team 
representative). Appropriate action will be taken such as flagging individual values to be excluded 
from analysis.  
The protocol deviations recorded in the Clinical Trial Management System (CTMS) may utilize 
different terminology. The table below displays how the terminology used in CTMS translates to 
the terminology used in the IAP, the SDTM and ADaM datasets, and ultimately the CSR: 
CTMS 
IAP 
SDTM 
ADaM 
Non-important 
Non-important 
(only 
for 
protocol deviations related to 
COVID-19) 
Only protocol deviations 
related to COVID-19 are 
included 
Only protocol deviations related to 
COVID-19 are included 
Important 
Important 
Flagged with PDEVXXX 
code 
Flagged with PDEVXXX code 
Clinically Important Clinically important 
Mapped to Important 
Mapped to Important 


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                                                                                                                                      v 2. 0 
 
 
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A f ull list of p ote ntial pr ot oc ol de viati o ns i ncl u di n g defi niti o n a n d cate g orizati o n is mai ntai ne d b y 
 i n t he “ St u d y S pecific Pr ot oc ol  De viati o n List” attac he d t o t h e Pr ot oc ol  De viati o n  
Ma na ge me nt Pla n.  
A fre q ue n c y ta ble as well as a listi n g of i m p orta nt pr ot oc ol de viati o ns, will be pr o vi de d base d o n 
t he F A S/ S A F.  
Referri n g t o F D A , a listi n g of all p artici pa nts affecte d b y t he C O VI D-1 9 relate d st u d y disr u pti o n 
will be pr o d uce d b y u ni q ue s u bject n u m ber i de ntifier a n d b y i n vesti gati o nal site, a n d a  descri pti o n 
of h o w t he i n di vi d ual’s partici pati o n was altere d f or t he Part 1 A a n d P art 1 B.  
1 0. 2. 2  
Re as o ns Le a di n g t o t he E xcl usi o n fr o m a n A n al ysis Set   
A fre q ue n c y ta ble or ga nize d acc or di n g t o reas o n f or e xcl usi o n fr o m t he  D L T  a nal ysis set, as well 
as a listi n g, will be pr o vi de d. M ore det ails ca n be f o u n d i n Secti o n  8. 1 . 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics   
De m o gra p hic data a n d ot her bas eli ne c h aracteristi cs will be prese nte d f or t he F A S/ S A F a n al ysis 
set usi n g s u m mar y statistics f or c o nti n u o us varia bles a n d fre q ue nc y statistics (i.e. c o u nts a n d 
perce nt a ges) f or cate g ori cal varia bl es. Res ults will be pres e nte d as i n dicate d i n S ecti o n 9 .   
Listi n gs s h o wi n g de m o gra p hic data a n d ot her baseli ne c haracteristics will be prese nte d f or t he 
F A S . 
1 1. 1  
De m o gr a p hics   
De m o gra p hic c haract eristics a n d p h ysical meas ure me nts will be s u m marize d descri pti vel y usi n g 
t he f oll o wi n g i nf or mati o n fr o m t he Scree ni n g Visit eC R F pa ges.  
T he f oll o wi n g de m o gra p hic c har acteristics will be i ncl u de d:  
•  Se x: male, fe male  
•  Race: W hite, B lac k or Africa n A m erica n, Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve 
Ha waiia n or Ot her Pacific Isla n der, M ore t ha n o n e race , N ot c ollecte d at t his site, O t her 
•  Et h nic ori gi n: His pa nic or Lati n o/ N ot His pa nic or Lati n o 
•   A ge ( years)  
•  A ge cat e g ories: < 6 5 y ears, ≥ 6 5 years  
•  P o ole d Re gi o n: N ort h A merica 
•  Wei g ht ( k g) at Bas eli ne  
•  B MI ( k g/ m 2) at Baseli ne  
•  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce stat us ( 0, 1, 2, 3, 4) 
•  T o bacc o us e stat us  (f or m er/c urr e nt/ ne ver) 
P P D


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Specifications for computation: 
Age [years] 
• Date of birth is: (date of given informed consent - date of birth + 1) / 365.25  
• In case of missing day for at least one date, but month and year available for both dates: 
• For the derivation of age, the day of informed consent and the day of birth will be set to 1 and 
the formula above will be used 
• In case of missing month for at least one date, but year available for both dates: 
• For the derivation of age, the day and the month of informed consent and the day and month of 
birth will be set to 1 and the formula above will be used 
• The integer part of the calculated age will be used for reporting purposes. 
Specifications for computation:  
BMI [kg/m²] = 
weight [kg] 
height[cm]2 × 10000 
Site codes will be used for the determination of the participant’s geographic region. 
11.2 
Medical History  
The medical history will be summarized from the “Medical History” eCRF page, using the most 
recent MedDRA version at time of database lock, preferred term as event category and system 
organ class (SOC) body term as Body System category. Each participant will be counted only once 
within each preferred term (PT) or SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order. 
11.3 
Other Baseline Characteristics  
Information on disease characteristics collected at baseline will be summarized and listed. 
Summary statistics will be presented for:  
• ECOG Performance Status 
• Site of Primary Tumor by International Classification of Diseases for Oncology (ICD-O)  
• Time since initial cancer diagnosis (years) = (date of start of study treatment – date of initial 
cancer diagnosis + 1) / 365.25 
• Time since documented locally advanced, inoperable or metastatic disease diagnosis (years) = 
(date of start of study treatment – date of documented locally advanced, inoperable or 
metastatic disease diagnosis + 1) / 365.25 
• Tumor histopathologic type: Adenocarcinoma / Squamous cell carcinoma / Other 
• Disease stage at initial diagnosis 


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• Disease stage at study entry 
Incomplete dates for initial cancer diagnosis and documented inoperable or metastatic disease 
diagnosis will be handled as specified in Section 9.8. 
Baseline 
characteristics 
with 
respect 
to 
vital 
signs, 
physical 
examinations, 
and 
hematology/biochemistry will be part of Section 15 (Safety Evaluation). 
11.4 
Baseline Tumor Assessment  
Information collected by the Investigator on the baseline tumor assessment collected at the 
screening visit on the “Tumor Assessment (according to RECIST 1.1)” eCRF pages and “Sum of 
Diameters (according to RECIST 1.1)” eCRF page will be presented in a listing.  
11.5 
Prior Anti-cancer Therapy  
The prior anti-cancer therapies are collected under the “Prior Anti-Cancer Drug Therapies 
Details”, “Prior Anti-Cancer Radiotherapy Details” and “Prior Anti-Cancer Surgeries Details”, 
eCRF pages. 
The number and percentage of participants in each of the following anti-cancer therapy categories 
will be tabulated: 
• Participants with at least one type of prior anti-cancer treatment 
• Participants with at least one prior anti-cancer drug therapy 
• Participants with at least one prior anti-cancer radiotherapy 
• Participants with at least one prior anti-cancer surgery 
 
Prior anti-cancer drug therapy will be summarized as follows based on the number and percentage 
of participants with the following: 
• At least one prior anti-cancer drug therapy 
• Number of prior anti-cancer therapy regimens: 1 / 2 / 3 / ≥ 4  
• Prior anti-cancer therapy regimens for metastatic or locally advanced disease 
• Type of prior anti-cancer therapy 
• Intent of Therapy: Neo-Adjuvant / Adjuvant / Metastatic or Locally advanced 
• Best response to last prior treatment: Complete Response (CR) / Partial Response (PR) / Stable 
Disease (SD) / Progressive Disease (PD) / Not assessable / Unknown / Not applicable. Best 
response is derived from the last treatment regimen 
Listings of prior anti-cancer treatments and procedures will be provided as follows. These will 
include the participant identification number, and all the relevant collected data fields on the 
corresponding eCRF pages. 


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• Listing of prior anti-cancer drug therapies  
• Listing of prior anti-cancer radiotherapy  
• Listing of prior anti-cancer surgeries 
12 
Previous or Concomitant Therapies/Procedures  
The following analyses will be performed based on the FAS/SAF analysis set and presented as 
indicated in Section 9.   
Concomitant medications are medications, other than study intervention, which are taken by 
participants any time during the on-treatment period, see Section 9.7. 
Previous medications are medications, other than study intervention and pre-medications for 
study interventions, which started before first administration of study interventions.  
A medication may be classified as both concomitant and previous. The respective flags will be 
derived based on start and end date. To derive these flags in case of missing or partial dates, see 
Section 9.8.  
Concomitant and previous medication each will be summarized by number and percentage of 
participants from the “Concomitant medications” eCRF. ATC-2nd level (Anatomical Therapeutic 
Chemical classification class) and PT (Preferred Term) will be summarized as given from the 
World Health Organization-Drug Dictionary (WHO-DD) most current version.  
If any previous or concomitant medication is classified into multiple ATC classes, the medication 
will be summarized separately under each of these ATC classes.   
The summary tables will be sorted by decreasing frequency of drug class and decreasing frequency 
of preferred term in a given drug class. In case of equal frequency regarding ATC classification 
level 2 or preferred term, alphabetical order will be used.  
In case any specific medication does not have an ATC classification level 2 coded term, it will be 
summarized under “Unavailable ATC classification” category. Each participant will only be 
counted once, even if he/she received the same medication at different times. 
Any medication recorded on the “Concomitant Medications Details” eCRF page will be listed with 
an indication of whether the medication was previous, concomitant or both.  
All concomitant procedures, which were undertaken during the on-treatment period will be 
summarized according to the CRF page “Concomitant Procedures Details”. Concomitant 
procedures will be presented according to MedDRA SOC and PT, or in case of analyses of specific 
interest as classified by medical review. Number and percentage of participants with concurrent 
procedures (Prior, on or after the first day of study intervention or within 30 days after last dose of 
study intervention) overall and by type of procedure (as classified by medical review) will be 
presented. 


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A listing with the relevant information about concurrent procedures will also be produced. A flag 
will be added to indicate whether the procedure is: 
• Prior: the procedure started before the first dose of study treatment 
• Concurrent: as defined above   
• Post: the procedure started after the on-treatment period or during the on-treatment period but 
was still ongoing at the end of it.  
A procedure could therefore be prior and concurrent as well as concurrent and post-treatment. 
13 
Study Intervention: Compliance and Exposure  
The following analyses will be performed based on the safety analysis set by dose level (and 
regimen if different regimens are tested) and study part.  
All dosing calculations and summaries will be based on “M4076 Administration” eCRFs page.  
No imputation of missing start dates of study interventions will be done. In case the last date of 
study intervention is incomplete the date of last study intervention administration will be taken 
from the M4076 Termination page. 
A dose is regarded as administered if the actual dose received is > 0. 
Cumulative dose (mg) is the sum of the actual doses of study intervention received overall. 
Exposure duration (in weeks) is defined by: 
 
൬date of last dose of study intervention– date of first dose of study intervention + 1
7
൰ 
Dose intensity (mg/3 weeks period) is defined as: ቀ
Cumulative dose in mg
( Duration (weeks)/3) ቁ 
Relative Dose Intensity 
The relative dose intensity (%) is calculated based on 3-weeks period by dividing the dose intensity 
by the planned 3-weekly cumulative dose. 
The summary of study intervention exposure will include the following information: 
• Exposure duration (in weeks): overall distribution and by categories of < 1 period, ≥ 1 period 
to < 2 periods, ≥ 2 period to < 3 periods, and ≥ 3 periods. Categories may be updated based on 
observed treatment duration. Counts of participants who discontinued during each period 
(Period 1, Period 2, Period ≥ 3) will be provided along with reason for treatment 
discontinuation. 
• Cumulative dose (mg): overall distribution 
• Dose intensity (mg/3 week): overall distribution 


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• Relative dose intensity (%) by categories of < 60%, ≥ 60% to < 80%, ≥ 80% to < 90%, ≥ 90% 
to ≤ 120%, and > 120% 
• Number and percentage of participants with at least one dose reduction (overall and by primary 
reason): 
o Due to adverse event 
o Due to other reason 
• Number and percentage of participants with at least one missed dose (overall and by primary 
reason): 
o Due to adverse event 
o Due to other reason 
• Number of missed doses per cycles (Cycle 1, Cycle 2, Cycle ≥ 3) by categories of: 1 to 4 missed 
doses; 5 to 10 missed doses; ≥ 11 missed doses. 
Note: Cycles are calculated as treatment periods of 3 weeks (21 days) in length. 
A listing will be provided for all study intervention administrations. In Part B1, information on 
meal intake will be provided in addition to the study intervention administration details. 
14 
Efficacy Analyses  
The following analyses will be performed based on the FAS/SAF by dose level (in increasing 
order) and summarized by study part, except when otherwise stated.  In case a participant received 
> 120% cumulative dose of the planned dose, the data of this participant will not be included in 
efficacy summary outputs. The data will be displayed in listings and figures but with a footnote 
stating the actual cumulative dose. 
14.1 
Primary Estimand  
No primary efficacy estimand is specified. 
14.2 
Further Estimands  
No further estimands are specified. 
14.2.1 
Secondary Endpoint: Objective Response (OR)  
Tumor assessments are collected on the CRF pages: “Tumor Assessment - Target Lesions”, “Sum 
of Diameters”, “Tumor Assessment - Non-Target Lesions”, “Tumor Assessment - New Lesions” 
and “Assessment of Disease based on Imaging.” 
Best Overall response (BOR) will be assessed based on reported overall responses at different 
evaluation time points from the study intervention start date until documented disease progression 


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in accordance to RECIST v1.1 by investigator, taking requirements for confirmation into account 
as detailed below. 
Only tumor assessments performed before the start of any subsequent anti-cancer therapies will be 
considered in the assessment of BOR. If a tumor assessment was performed on the same day as 
start of new anti-cancer therapy, it will be assumed that the tumor assessment was performed prior 
to the start of the new anti-cancer therapy, therefore the tumor assessment will be included in the 
assessment of BOR. 
Clinical deterioration will not be considered as documented disease progression. In the case of 
multiple dates of scans within the same tumor assessment, the earliest scan date will be used as the 
date of tumor assessment. The order to obtain the BOR is the following: CR, PR, SD, PD, NE. If 
a participant has no post-baseline tumor assessments before starting new anticancer therapy, BOR 
will be NE.  
When SD is believed to be the best response, it must also occur after a minimum of 6 weeks from 
the start of study treatment. If the minimum time is not met, the participant’s BOR depends on the 
subsequent assessments. For example, a participant who has SD at the first assessment, PD at the 
second assessment, and does not meet the minimum duration for SD, the BOR will be PD. If the 
same participant is lost to follow-up after the first SD assessment, BOR would be considered NE. 
BOR Based on Confirmed Responses: 
• Complete Response (CR) = at least two determinations of CR at least 4 weeks apart (with no 
PD in between)  
• Partial Response (PR) = at least two determinations of PR or better (PR followed by PR or PR 
followed by CR) at least 4 weeks apart (and not qualifying for a CR), with no PD in between  
• Stable Disease (SD) = at least one SD assessment (or better) ≥ 6 weeks after start date (and not 
qualifying for CR or PR). 
• Non-CR/non-PD (applicable only to participants with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after start date (and not 
qualifying for CR or PR). 
• Progressive Disease (PD) = PD ≤ 12 weeks after start date of study treatment (and not 
qualifying for CR, PR, non-CR/non-PD or SD). 
• Not Evaluable (NE):  all other cases. 
Confirmation of response is not necessarily required at the next scan, but could be at any 
subsequent scan before PD. For instance, if a participant has PR-SD-PR or PR-NE-PR at 
consecutive tumor assessments, the best overall response will qualify for PR.  
SD can follow PR only in the rare case that tumor increases by less than 20% from the nadir, but 
enough that a previously documented 30% decrease from baseline no longer holds.  If this occurs 
the sequence PR-SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would 
be a best response of SD if the minimum duration for SD definition has been met. 
Confirmed Objective Response (OR) is defined as a confirmed best overall response of complete 
response (CR) or partial response (PR) according to RECIST v1.1. 


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Participants who do not have an on-treatment radiographic tumor assessment due to early 
progression, who receive anti-tumor treatments other than the study intervention prior to reaching 
confirmed CR or PR, or who die, progress, or drop out for any reason prior to reaching confirmed 
CR or PR will be counted as non-responders in the assessment of OR. Each participant will have 
an objective response status (0: ‘no OR’; 1: ‘OR’).   
OR rate (ORR) is the proportion of participants with OR in the analysis set. No formal statistical 
hypotheses will be tested. 
The number and percentage of participants with unconfirmed and confirmed BOR of CR, PR, SD, 
on-CR/non-PD, PD, and NE will be tabulated.  
The unconfirmed and confirmed ORR by dose level will be presented along with the two-sided 
95% CI using the Clopper-Pearson method (1934) (exact CI for a binomial proportion as computed 
by default by the SAS FREQ procedure using the EXACT option).  
A swimmer plot displaying some key radiological milestones will be produced by dose level. For 
each subject, the time on treatment will be represented. In addition, the following information will 
be displayed: time to confirmed BOR (CR, PR or SD), time to progression, and status at the end 
of the follow-up (alive or dead). 
Tumor shrinkage (%) is defined as the percent change from baseline in target lesions (sum of 
longest diameter for non-nodal lesions and short axis for nodal lesions as reported in the “Sum of 
diameters (according to RECIST 1.1)” eCRF page)) per time point. The tumor response will be 
based on the Investigator assessment. It will be derived as:  
൬Sum of target lesions at Week XX –  sum of target lesions at baseline 
Sum of target lesions at baseline
൰x 100 
The maximum tumor shrinkage (%) will be derived across all the post-baseline assessments until 
documented disease progression, excluding assessments after start of new anticancer therapy, as: 
          𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀൭൬Sum of target lesions at Week XX –  sum of target lesions at baseline
Sum of target lesions at baseline
൰x 100൱ 
 
The tumor shrinkage as well as the first occurrence of a new lesion and participant off study 
intervention will be displayed against time point (months) in a line plot (spider plot). 
In addition, the percent change from baseline in target lesions per time point as well as other 
relevant information will be presented in a data listing.  
A waterfall plot of maximum tumor shrinkage will be created including all participants with 
measurable disease at baseline and at least one valid post-baseline assessment. The confirmed 
BOR will also be presented as an annotation on each vertical bar. 
In addition, Subject data listings of tumor assessments and responses will be provided, including 
lesion number, description and location, type of lesion, imaging date, assessment method, diameter 
(mm), sum of diameter of target lesions (mm), confirmed BOR and best percent change in sum of 


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diameters (as recorded from the “Target Lesions”, “Sum of Diameters”, “Non-Target Lesions”, 
“New Lesions” and “Assessment of disease based on imaging” eCRF pages). 
14.2.2 
Secondary Endpoint: Progression Free Survival (PFS)  
Progression Free Survival (PFS) time is defined as the time (months) from start date to the date 
of the first documentation of objective PD or death due to any cause, whichever occurs first. The 
tumor response will be determined according to RECIST 1.1 and assessed by Investigator. 
PFS time (in months) = (Date of PD or death – start date + 1)/ 30.4375 (months) 
 
PFS data will be censored on the date of the last adequate tumor assessment for participants who 
do not have an event (PD or death), or with an event after two or more missing tumor assessments. 
Participants who do not have a baseline tumor assessment or who do not have any post-baseline 
tumor assessments will be censored on the start date unless death occurred on or before the time 
of the second planned tumor assessment in which case the death will be considered an event.  
The last adequate tumor assessment is defined as the last tumor assessment result that is not “NE” 
or “NA”. 
The censoring and event date options to be considered for the PFS analysis is presented in Table 
5.  
Table 5 Progression-free Survival Event / Censoring  
PFS Event Status 
Censoring 
Date of event / censoring 
Progressed or 
died 
 
Before any planned tumor 
assessment or within two 
subsequent scheduled tumor 
assessments after last response 
assessment of CR, PR or SD  
Event 
Minimum (Date of PD, Date of 
death) 
Otherwise 
Censored 
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
first dose of study intervention, 
whatever is later 
Neither progressed nor died 
Censored 
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
first dose of study intervention, 
whatever is later 
 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary of 
associated statistics including the median PFS time with two-sided 95% CIs.  In particular, the 
PFS rate at 3, 6 and 12 months and estimates for every 6 months will be estimated with 
corresponding two-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points defined 
above will be derived using the log-log transformation according to Kalbfleisch and Prentice 
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI on the 


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untransformed scale. The estimate of the standard error will be computed using Greenwood’s 
formula.   
The PFS time or censoring time and the reasons for censoring will also be presented in a participant 
listing. 
14.2.3 
Secondary Endpoint: Duration of Response (DoR)  
DoR is defined, for participants with confirmed objective response only, as the time (months) from 
first documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a participant has not had an event (PD or death), DoR is censored at the 
date of last adequate tumor assessment. The censoring rules for DoR are as described for PFS 
(Section 14.2.2). 
The last adequate tumor assessment is defined as the last tumor assessment result that is not “NE” 
or “NA”. 
DoR (months) = [date of event or censoring– first date of OR +1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary of 
associated statistics including the median DoR time with two-sided 95% CIs. In particular, DoR 
rate at 3, 6, 12 months and estimates for every 6 months thereafter will be estimated with 
corresponding two-sided 95% CIs. The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982) and CIs for the survival function estimates at the time points 
defined will be derived using the log-log transformation according to Kalbfleisch and Prentice 
(1980) (conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood's formula.  
DoR will be displayed graphically and analyzed using Kaplan-Meier methodology analogous to 
that used for PFS as described in Section 14.2.2. If the number of participants with OR is small, 
the Kaplan-Meier method may not provide reliable estimates.  In this case, only descriptive 
statistics or listings will be provided. 


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15 
Safety Analyses  
This section includes specifications for summarizing safety endpoints that are common across 
clinical studies such as adverse events, laboratory tests and vital signs. 
The DLT analysis will be performed on the DLT analysis set. All other safety analyses will be 
performed on the SAF analysis set. 
15.1 
Dose Limiting Toxicities (DLT) Analysis  
Of note, DLT as per SMC decision will be available in the table “Review of data” in the SMC 
minutes. In case a new DLT appears after the DLT period, the minutes will be updated. 
For primary analysis, a table will display the following (per dose level (and regimen if different 
regimens are tested)) and in total for Part 1A and Part 1B) for the DLT analysis set: 
• Number and percentage of participants with a DLT per investigator’s judgement as recorded 
in eCRF (using DLT flag from the AE CRF page) 
• Number and percentage of participants with a DLT per SMC decision 
A listing of DLTs (per investigator and/or per SMC) will be provided by dose level and participant, 
including whether it was judged to be a DLT by investigator and/or by SMC. 
This listing will additionally contain age, sex, site of primary tumor, SOC, PT, verbatim, CTCAE 
grade, SAE (yes/no), DLT per investigator (yes/no), DLT per SMC, relatedness to M4076 
(yes/no), start date (+treatment day), stop date (+treatment day), duration (in days), action taken 
with M4076, if treatment was stopped before start of AE: days since stop of treatment, and 
outcome. 
In addition, the following will be presented: 
• Mean and Quantiles (2.5%, 25%, 50%, 75%, 95% and 97.5%) for the posterior probability of 
a participant experiencing a DLT at each of the dose levels used in the study according to the 
same Bayesian Logistic Regression Model (BLRM) as described in the SMC IAP (see 
Appendix18.2) or SMC charter (if change occurred). For this analysis either SAS or R (using 
the package bcrm or crmPack) will be used. 
 
MTD suggestion from the Bayesian two-parameter logistic regression model 
The MTD as suggested from the modeling will be derived as follows: 
(1) The BLRM will be updated with all DLT data (SMC decision) from the dose escalation. 
(2) The dose with targeted toxicity probability of 30% will be identified for each of the MCMC 
samples. The median of all the “30% doses” over the MCMC samples will be the fitted dose 
for MTD. 


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(3) The next lower tested dose with the upper bound of the one-sided 95% credible interval ≤ 40% 
and with estimated DLT probability ≥ 17% and ≤ 30% will be selected as suggested MTD. 
(4) If none of the tested doses fulfill the criteria in 3), there is no MTD suggestion from the model. 
This information from items (3) and (4) will be forwarded to the SMC that will decide on the 
determination of the MTD. 
Additionally, the SMC will receive the estimated DLT probability and associated probability 
quantiles for all other doses tested. 
The fitted dose with 30% DLT probability (from item (2)) and the two-sided 95% credibility 
interval will be tabulated. 
For above analysis either SAS or R (using the package bcrm or crmPack) will be used. 
Frequentist MTD suggestion  
As second approach, the MTD as suggested by the frequentist estimation will also be derived:  
(1) All DLT data from the dose escalation will be included in a two-parameter logistic regression 
model (intercept and slope over log of the scaled dose, no prior; if the model does not converge, 
it will be reported as not calculable; the program code for this analysis can be found in the TLF 
shells).  
(2) The dose with targeted toxicity probability of 30% will be identified.  
(3) The next lower tested dose will be selected as suggested MTD.  
The fitted dose with 30% DLT probability (from item (2)) and the two-sided 95% confidence 
interval will be tabulated. 
Additionally, a table will be produced, providing the estimated probability for DLT with a 95% 
confidence interval, based on the frequentist logistic model.  
The models will be based on DLTs as identified by SMC. 
15.2 
Adverse Events  
Adverse Events (AE) will be analyzed among the Safety analysis set and presented by dose level 
(and regimen if different regimens are tested) and overall, and by study part, if not otherwise 
specified. 
Part 1A: 
Treatment-emergent adverse events (TEAEs) are those events with onset or worsening dates 
occurring within the on-treatment periods as defined in Section 9.7. 
This also includes AEs ongoing at baseline, which first improve under study intervention and then 
worsen irrespective of baseline.  Adverse events with changes in toxicity grade/severity, 
seriousness or outcome of AEs are recorded as separate entries in the eCRF with associated end 
and start dates (start date equals end date of previous entry, supported in eCRF v8.4 by 


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‘AECHGID’ in SUPPAE). Records of the same AE will be considered as one event in the analysis. 
If the severity of the reported event worsens after start of treatment, the TEAE flag will be re-
evaluated for the worse and the subsequent records as per the TEAE definition. If the worse record 
starts outside of the on-treatment period, it will not appear on the summaries/listings of TEAEs, 
unless otherwise specified. These events will be kept as separate records in the database in order 
to maintain the full detailed history of the events. The overall outcome of the adverse event is the 
outcome of the last event in the sequence. When such AEs are listed, start, end date and outcome 
should be provided together with change date, toxicity grade/severity and seriousness per episode.  
Adverse events related to study intervention are those events with relationship missing, unknown 
or yes. 
Part 1B- Cross-over design: 
Treatment-emergent AEs (TEAEs) are those events with onset dates on or after the first 
administration of study intervention in the first food effect assessment period. Any AE occurring 
before the administration of study intervention on Day 1 of the first food effect assessment period 
and resolved before administration of study intervention or not worsening after administration of 
study intervention in the first food effect assessment period will be included in the AE listings, but 
will not be included in the summary tables (unless otherwise stated). These will be referred to as 
“pre-treatment” AEs.  An AE occurring after administration of study intervention will be counted 
towards the last treatment received before the onset, even if the event is not resolved at the 
beginning of the following food effect assessment period.  An AE that worsens during a later food 
effect assessment period will be counted towards both treatments. 
In case AE-related dates are partial, the available information will be used in a conservative 
approach to determine whether the AE is treatment-emergent. All analyses described in Section 
15.2 will be based on TEAEs if not otherwise specified. The AE listings will include all AEs 
(whether treatment-emergent or not). AEs outside the on-treatment period will be flagged in the 
listings. 
Unless otherwise specified, TEAEs will be summarized by number and percentage of participants 
with the TEAE in the category of interest by primary System Organ Class (SOC) and Preferred 
Term (PT) in alphabetic order. 
Each participant will be counted only once within each SOC or PT. If a participant experiences 
more than one AE within a SOC or PT for the same summary period, only the AE with the strongest 
relationship or the worst severity, as appropriate, will be included in the summaries of relationship 
and severity.  
15.2.1 
All Adverse Events  
Adverse Event information is collected on the “Adverse Events Details” eCRF page. 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 5.0) per 
participant, using the latest version of MedDRA preferred term (PT) as event category and 
MedDRA primary system organ class (SOC).  


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If a qualifying AE is reported for a given participant more than once during study intervention, the 
worst toxicity and the worst relationship to study intervention will be tabulated. In case a 
participant had events with missing and non-missing grades, the maximum of the non-missing 
grades will be displayed. No imputation of missing grades will be performed. 
Incomplete AE-related dates will be handled as specified in Section 9.9. 
The following tables will be created, split by dose level and overall, and by study part: 
• The number and percentage of participants with: 
• Any TEAEs 
• Any TEAEs by worst NCI-CTCAE severity grade (≥ 3, ≥ 4) 
• Any M4076 related TEAEs 
• Any M4076 related TEAEs by worst NCI-CTCAE severity grade (≥ 3, ≥ 4)  
• Any M4076 related TEAEs leading to permanent discontinuation of study intervention 
• Any Serious TEAEs 
• Any non-serious TEAEs  
• Any related serious TEAEs  
• Any treatment-emergent AE of special interest (AESI) Cytopenia (as reported in the eCRF) 
• Any treatment-emergent AESI Cytopenia by worst NCI-CTCAE severity grade (≥ 3, ≥ 4) 
(as reported in the eCRF) 
• Any TEAEs leading to death (AEs with Grade 5 or outcome “fatal” if grade 5 not applicable) 
• Any related TEAEs leading to death 
In addition, all AEs will be tabulated by dose level and regimen (if different regimens tested) and 
overall and presented by PT and primary SOC in alphabetical order. 
For Part 1B the following tables will be created in addition, split by dietary status (“Fed” and 
“Fasted”) and overall:  
• The number and percentage of participants with at least one TEAE by worst NCI-CTCAE 
severity grade (any grade vs. Grade ≥ 3), SOC and PT.  
A horizontal mirror bar chart will be produced to display TEAEs by worst NCI-CTCAE severity 
grade. The figure will be split into two time periods (TEAEs occurring during Period 1 vs. TEAEs 
occurring on or after Period ≥ 2). AE preferred terms will be displayed along the vertical axis and 
the absolute number of participants with an AE in each preferred term will be displayed on the 
horizontal axis. The horizontal axis will be split by time (Period 1 vs. Period ≥ 2), with incidence 
of 0 in the center of the axis. Any TEAEs with start date during Period 1 will be displayed on the 
left side of the mirror plot and any TEAEs with start date on or after Period 2 will be displayed on 
the right side of the mirror plot. The worst grade will always be displayed, i.e. in case a change in 
grade occurs within a specified time period, the worst grade will be displayed. Events that occurred 


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in Period 1 and continued to Period ≥ 2 will be displayed on both time periods. If an event improves 
during Period 1 but continues to Period ≥ 2, this event will only be displayed at the left side of the 
mirror plot (Period 1). 
Display of NCI-CTC severity grade will also differ in color. Within each bar, incidence of TEAEs 
of toxicity Grades 3 to 5 will be shown in a darker shade and TEAEs of toxicity Grades 1 to 2 will 
be displayed in a lighter shade. Only TEAEs occurring in at least two participants or with 
frequency higher than 10% across all dose levels, whichever is greater, will be included in the 
figure. Preferred terms will be sorted in order of descending frequency of incidence among 
participants in Period 1. 
A listing of all AEs (whether treatment-emergent or not) will be provided. This listing will be 
sorted by study part, dose level and participant. This listing will additionally contain age, sex, site 
of primary tumor, SOC, PT, verbatim, CTCAE grade, SAE (yes/no), DLT per investigator 
(yes/no), DLT per SMC, relatedness to M4076 (yes/no), start date (+treatment day), stop date 
(+treatment day), duration (in days), action taken with M4076, if treatment was stopped before 
start of AE: days since stop of treatment, and outcome. 
Similarly, a listing of all adverse events Grade ≥ 3 (including non TEAEs) will be provided. 
15.2.2 
Adverse Events Leading to Discontinuation, Interruption or 
Dose Reduction of Study Intervention  
The frequency (number and percentage) of participants with each of the following will be 
presented in a summary table: 
• Any TEAEs leading to temporary discontinuation of M4076 
• Any related TEAEs leading to temporary discontinuation of M4076 
• Any TEAEs leading to permanent discontinuation of M4076 
• Any related TEAEs leading to permanent discontinuation of M4076 
• Any TEAEs leading to dose reduction of M4076* 
• Any related TEAEs leading to dose reduction of M4076* 
All TEAEs will be tabulated by dose level and total in a table displaying in separate columns and 
showing the incidence of TEAEs by SOC and PT (both sorted alphabetically).A listing of TEAEs 
leading to treatment discontinuation, interruption, or dose reduction of study intervention will be 
provided. This listing, sorted by study part, dose level and participant, will also include age, sex, 
site of primary tumor, SOC, PT, verbatim, CTCAE grade, SAE (yes/no), DLT per investigator 
(yes/no), DLT per SMC, relatedness to M4076 (yes/no), start date (+treatment day), stop date 
(+treatment day), duration (in days), action taken with M4076, outcome, if treatment was stopped 
before start of AE: days since stop of treatment, and outcome. 
* Note, dose reduction here is as a response to the eCRF AE page item “Action(s) taken with 
M4076”. 


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15.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events  
15.3.1 
Deaths  
All deaths, deaths within 30 days after last dose of study intervention, death within 60 days after 
first dose, as well as reason for death until end of study, will be tabulated based on information 
from the “Death” and “Survival Follow-Up” CRFs. 
• Number of Deaths 
•  Number of Deaths within 30 days after last dose of M4076 
• Number of Deaths within 60 days after first dose of M4076 
• Primary Reason of Death 
• Progressive disease and/or disease related condition 
 
• Event unrelated to M4076 
• Event related to M4076 
• Unknown 
In addition, a listing of Deaths will be provided, defined as any AE with Grade 5, or outcome 
“fatal” if grade 5 not applicable. This will be sorted by study part, dose level and participant. This 
listing will additionally contain age, sex, site of primary tumor, SOC, PT, verbatim, CTCAE  grade, 
SAE (yes/no), DLT per investigator (yes/no), DLT per SMC, relatedness to M4076 (yes/no), start 
date (+treatment day), stop date (+treatment day), duration (in days), action taken with M4076, if 
treatment was stopped before start of AE: days since stop of treatment, outcome, as well as a flag 
for death within 30 days of last dose of study intervention and a flag for death within 60 days of 
first dose of study intervention. 
15.3.2 
Serious Adverse Events  
The frequency tables as listed in Section 15.2.1 will be prepared for serious adverse events (SAEs). 
The listings of SAEs will also be provided with the relevant information with a flag for SAEs with 
onset outside of the on-treatment period. 
15.3.3 
Other Significant Adverse Events  
Other safety observations - Cytopenia 
The MedDRA search list for Cytopenia is based on the standardized MedDRA query (SMQ) 
‘Haematopoietic cytopenias SMQ broad scope. 
 


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This SMQ will be summarized overall and PT, 
- 
by worst NCI-CTCAE severity grade (any grade vs. Grade ≥ 3) 
- 
related according to Investigator. 
A listing of AESIs as reported in the eCRF, and a listing of SMQ ‘Haematopoietic cytopenias 
SMQ broad scope’ will be provided. These listings will be sorted by study part, dose level and 
participant. These listings will additionally contain age, sex, site of primary tumor, SOC, PT, 
verbatim, CTCAE grade, SAE (yes/no), DLT per investigator (yes/no), DLT per SMC, relatedness 
to M4076 (yes/no), start date (+treatment day), stop date (+treatment day), duration (in days), 
action taken with M4076, if treatment was stopped before start of AE: days since stop of treatment, 
and outcome. 
15.4 
Clinical Laboratory Evaluation  
All laboratory values will be reported in SI units. 
Laboratory values (including corresponding normal ranges) from local laboratories will be used 
for summary statistics and shift tables. In case both central and local labs are collected, summary 
statistics will be based on central lab collected data, while summaries of worst on-treatment 
abnormalities will be based on both local and central lab data.  
All protocol-required clinical laboratory assessments can be found in Table 7 (see Appendix 18.1). 
Laboratory results will be classified according to the NCI-CTCAE v5.0 (see Appendix 18.1). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to the 
categories: below normal limit, within normal limits and above normal limit (according to the 
laboratory normal ranges). 
For the definition of baseline measurement please see Section 9.2. 
Values below the detection limit will be imputed by half of the detection limit.  
In case just a text value with an “> x” is reported it will be analyzed as +1 significant digit, e.g 
“> 7.2 mmol” will be analyzed as 7.3. 
Quantitative data will be summarized using descriptive statistics presenting baseline value, 
maximum on treatment, and minimum on treatment as well as their changes to baseline. 
Qualitative data based on reference ranges will be described according to the categories (i.e. Low, 
Normal, and High).  
Abnormalities classified according to NCI-CTCAE toxicity grading version will be described 
using the worst on-treatment grade. For those parameters which are graded with two directions of 
toxicities such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized 
separately. Low direction toxicity (e.g., hypokalemia) grades at baseline and post baseline will be 
set to 0 when the variables are derived for summarizing high direction toxicity (e.g., 


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hyperkalemia), and vice versa. The same applies for non-gradable parameter, and description of 
changes from N/L to H and N/H to L will be provided, accordingly.   
For WBC differential counts (total neutrophil, lymphocyte, monocyte, eosinophil, and basophil 
counts), the absolute value will be used when reported.  When only percentages are available (this 
is mainly important for neutrophils and lymphocytes, because the CTCAE grading is based on the 
absolute counts), the absolute value is derived as follows:  
Derived differential absolute count = (WBC count) * (Differential %value / 100) 
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows:  
• Lymphocyte count decreased:   
o derived absolute count does not meet Grade 2-4 criteria, and 
o % value < % LLN value, and 
o derived absolute count ≥ 800/mm3 
• Neutrophil count decreased:  
o derived absolute count does not meet Grade 2-4 criteria, and 
o % value < % LLN value, and 
o derived absolute count ≥ 1500/mm3 
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium (CALCIO), if 
available. Corrected Calcium is calculated from Albumin and Calcium as follows 
Corrected calcium (mmol/L) =  
measured total Calcium (mmol/L) + 0.02 (40 - 
serum albumin [g/L]) 
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios of test 
result over upper limit of normal (ULN) will be calculated and classified for these three parameters 
during the on-treatment period. 
Parameters with NCI-CTC grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of participants and 
percentages) during the on-treatment period.  The denominator to calculate percentages for each 
laboratory parameter is the number of participants evaluable for CTCAE grading (i.e. those 
participants with normal values or for whom a Grade 1, 2, 3 or 4 can be derived). Grade 0 is not 
defined per NCI-CTCAE but will be used in derivations for simplicity to indicate that evaluable 
measurements are available. 


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• The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of participants with Grade 1, 2, 3, 4, 3/4, and any grade (1 to 4), laboratory 
abnormalities during the on-treatment period.   
• The shift table will summarize baseline CTCAE grade versus the worst on-treatment CTCAE 
grade. The highest CTCAE grade during the on-treatment period is considered as the worst 
grade for the summary.  
o In case of gradings involving baseline measurements (see Section 9.10) for the 
identification of grades during the on-treatment period, the shift table will present 
baseline normal and abnormal. Normal will include measurements below and within 
normal range (direction increase), or measurements within and above normal range 
(direction decrease). 
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, i.e.: 
Hematology:  
• Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte count 
increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil count 
decreased), Platelet Count (PLT) (platelet count decreased). 
Serum Chemistry: 
• Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), Alanine 
Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), Aspartate 
Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin increased, 
Creatinine (creatinine increased), Creatine Kinase (CPK increased), Potassium (hypokalemia/ 
hyperkalemia), 
Sodium 
(hyponatremia/ 
hypernatremia), 
Calcium 
(hypocalcemia/ 
hypercalcemia), Glucose (hypoglycemia/hyperglycemia), Gamma Glutamyl Transferase 
(GGT) (GGT increased), Lipase (lipase increased). 
Please see Appendix 1 for a list of the NCI-CTC -gradable parameters. 
Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and row percentage) of participants with:  
• Summary by worst on-treatment value (low/normal/high/missing/overall) 
• Shifts from baseline normal to at least one result above normal during on-treatment period  
• Shifts from baseline normal to at least one result below normal during on-treatment period 
In this study, these apply to the following parameters:  
Hematology:  


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• Hematocrit, Reticulocytes, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular 
Volume (MCV). 
Serum Chemistry:  
• Blood Urea Nitrogen (BUN), Total Protein, Total Urea.  
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF.  
• Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time (INR). 
• Urinalysis: all urinalysis parameters 
• Serum and urine human chorionic gonadotropin pregnancy test 
Serology (with no preclinical signs of hepatotoxicity, hepatitis B surface antigen, hepatitis C virus 
antibody and HIV screening).Following figures will be provided:  
eDISH plot 
A plot (eDISH) of peak ALT and AST versus peak total bilirubin, both relative to the upper limit 
of normal (ULN) will be provided. This eDISH plot (evaluation of drug-induced serious 
hepatotoxicity) will have reference lines at 3×ULN for ALT and AST and at 2×ULN for total 
bilirubin. 
Line plots: 
Graphical display (line plots) of platelet count, hemoglobin, Reticulocytes / Erythrocytes (% of 
RBC), 
neutrophils, 
lymphocytes, 
monocytes, 
creatinine, 
lipase, 
amylase, 
aspartate 
aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin and INR will be 
provided by actual time in days and by part and dose level for all analyses (with x-axis time, y-
axis lab value), using different colors per dose level and different line types to identify participants. 
Where feasible, reference lines for CTCAE grades should be added to graphical displays. 
The listings of laboratory results will be provided for all laboratory parameters. The listings will 
be sorted by parameters and assessment dates or visits for each participant. Laboratory values that 
are outside the normal range will be flagged in the data listings, along with corresponding normal 
ranges and CTCAE grades. 
In addition, listings of clinically significant Hematology and Biochemistry values (≥ Grade 3) will 
be provided.  
For the cross-over design in Part 1B, laboratory parameters will be summarized indicating the 
dietary status at the respective time-point using descriptive statistics for absolute values and change 
from baseline over time. Tables will be produced for Hematology and Biochemistry laboratory 
parameters. 


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15.5 
Vital Signs  
Vital sign summaries will include all vital sign assessments from the on-treatment period. All vital 
sign assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, Q1, 
Q3, minimum, and maximum) presenting baseline value, maximum on treatment, and minimum 
on treatment as well as their changes to baseline.  
The maximum changes of vital sign measurements screening/baseline to maximum changes after 
start of 1st study intervention will be grouped as follows:  
Body temperature increase 
< 1°C , 1-<2°C , 2-<3°C, ≥ 3 °C 
Heart rate increase from baseline  
<100 bpm ; ≥ 100 bpm 
≤20 bpm, >20 – 40 bpm, >40 bpm 
Heart rate decrease from baseline  
<100 bpm ; ≥ 100 bpm 
≤20 bpm, >20 – 40 bpm, >40 bpm 
SBP increase from baseline  
<140 mmHg; ≥ 140 mmHg  
≤20 mmHg, >20 – 40 mmHg, >40 mmHg 
SBP decrease from baseline  
<140 mmHg; ≥ 140 mmHg, 
≤20 mmHg, >20 – 40 mmHg, >40 mmHg 
DBP increase from baseline  
<90 mmHg; ≥ 90 mmHg  
≤20 mmHg, >20 – 40 mmHg, >40 mmHg 
DBP decrease from baseline  
<90 mmHg; ≥ 90 mmHg, 
≤20 mmHg, >20 – 40 mmHg, >40 mmHg 
Respiration rate increase from baseline <20 
bpm ; ≥ 20 bpm 
≤5 bpm, >5 – 10 bpm, >10 bpm 
Respiration rate decrease from baseline <20 
bpm ; ≥ 20 bpm 
≤5 bpm, >5 – 10 bpm, >10 bpm 
For each participant the worst on-treatment value will be calculated. For the definition of baseline 
values see Section 9.2. Missing values will define a separate category. 
The following summaries will be prepared for vital sign parameters as grouped above:  
• Maximal shifts (changes in categories) 
• Listing of highest change per participant 
An additional participant data listing will present all changes from baseline reported in the highest 
categories. 
For the cross-over design in Part 1B, vital signs will be summarized for absolute values and 
changes from baseline by time-point and dietary status using descriptive statistics. 


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15.6 
Other Safety or Tolerability Evaluations  
15.6.1 
ECOG Performance Status  
ECOG Performance Status information is collected on the “ECOG Performance Status” eCRF 
page and as described in the following table: 
Table 6 
Eastern Cooperative Oncology Group Performance Status  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, for example, light housework, office work 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities; up and 
about > 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair > 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
ECOG Performance Status will be provided in a listing.  
15.6.2 
Electrocardiogram (ECG)  
Standard 12-Lead ECG 
12-Lead ECG information will come from the “ELECTROCARDIOGRAM - (Single) Local” 
eCRF page. 
ECG summaries will include all 12-lead ECG assessments from the on-treatment period.  All 
12-lead ECG assessments will be listed, and those collected outside the on-treatment period will 
be flagged in the listing.   
The  following analyses will be performed for each applicable ECG parameters (HR, and QT, 
QTcF, QRS, PR intervals) by dose level, overall, and study part during the treatment period. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the analysis 
of notable ECG changes and the shift table analysis of notable QT parameters. 
• 
For each of the ECG parameters (HR, QT, QTcF, QRS, PR intervals), descriptive statistics 
at baseline, at each post-baseline time point and changes from baseline at each post-
baseline time point.  
• 
Frequency (number and percentage) of participants with notable ECG values according to 
the following categories: 
o QTcF* increase from baseline > 30 ms, > 60 ms 
o QTcF* > 450 ms, > 480 ms, > 500 ms 


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o HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm 
o HR ≥ 120 bpm and increase from baseline ≥ 20 bpm 
o PR ≥ 220 ms and increase from baseline ≥ 20 ms 
o QRS ≥ 120 ms 
The denominator to calculate percentages for each category is the number of participants 
evaluable for the category. 
• 
Frequency (number and percentage) of participants with post-baseline qualitative ECG 
abnormalities (morphology) will be presented as a shift table showing baseline versus the 
worst on-treatment result (Normal, Abnormal (not clinically significant), Abnormal 
(clinically significant)).  
For the cross-over design in Part 1B, ECG data will be summarized in addition by dietary status 
(“Fed” and “Fasted”) and time-point using descriptive statistics for absolute values and change 
from baseline over time. *The QTcF (corrected by the Fridericia’s formula) value will be collected 
in the eCRF page;  
Triplicate 12-lead ECG (Digital ECG) 
Triplicate 12-lead ECG will be also obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT and QTcF intervals. Electrocardiogram (ECG) results 
will be read locally, and all the three results will be reported in the eCRF.  
Listings of all ECG triplicates will be provided with all relevant information such as visit, date/time 
of assessment, measurement and results. 
The average of the replicate measurements should be determined after the derivation of the 
individual parameter at each time point and will be used for summaries as defined in the standard 
12-lead ECG section above.  
Relationship of PK concentration to change from baseline QTc will be explored by concentration-
QT analysis. This analysis will be described by a separate analysis plan. Results of this analysis 
will not be reported in CSR and may be reported as a separate analysis report. 


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16 
Analyses of Other Endpoints/Estimands  
16.1 
Pharmacokinetics  
All statistical analyses and descriptive summaries of PK data will be performed on the PKAS. 
16.1.1 
Descriptive Statistics of PK Concentration Data  
Plasma PK measurements will be listed and descriptively summarized using: number of subjects 
(N), number of non-missing observations (n), arithmetic mean (Mean), standard deviation (SD), 
coefficient of variation (CV%), minimum (Min), median (Median) and maximum (Max).  
Missing statistics, e.g. when they cannot be calculated, should be presented as “NC”. “ND” will 
be used if a PK sample was not taken. 
Descriptive statistics will only be calculated for n>2 in which a measurement of BLQ represents a 
valid measurement and will be taken as zero for summary statistics of PK concentration data. 
Values below the LLOQ will be treated as zero for the calculation of summary statistics and 
graphical presentations 
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data and rounded for reporting purposes only. In export datasets, as well as 
in the SDTM PC domain, PK concentrations will be provided with full precision and will not be 
rounded. 
The following conventions will be applied when reporting descriptive statistics of PK 
concentration data: 
N, n 
0 decimal place 
Mean, Min, Median, Max:  
3 significant digits 
SD: 
4 significant digits 
CV%: 
1 decimal place 
Urine concentrations and volumes will be listed but not be summarized. 
16.1.2 
Descriptive Statistics of PK Parameter Data  
PK parameter data will be descriptively summarized using: number of subjects (N), number of 
non-missing observations (n), arithmetic mean (Mean), standard deviation (SD), coefficient of 
variation (CV%), minimum (Min), median (Median), maximum (Max), geometric mean 
(GeoMean), the geometric coefficient of variation (GeoCV) and the 95% confidence interval for 
the GeoMean (LCI 95% GM, UCI 95% GM). For PK parameters related to time (e.g. tmax tlast), 
only n, Min, Median, and Max may be reported.  


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Descriptive statistics will only be calculated for a PK parameter when n>2.  
PK parameters read directly from the measurements (i.e. Cmax) will be reported with the same 
precision as the source data. All other PK parameters will be reported to 3 significant figures. In 
export datasets, as well as in the SDTM PP domain, PK parameters will be provided with full 
precision and will not be rounded. Descriptive statistics of PK parameter data will be calculated 
using full precision values and rounded for reporting purposes only. 
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data: 
N, n 
0 decimal place  
Mean, Min, Median, Max, GeoMean, 95% CI:  3 significant digits 
SD: 
4 significant digits 
CV%, GeoCV%: 
1 decimal place 
16.1.3 
Statistical Analysis of PK Parameter Data  
Dose proportionality will be provided separately for AUC0-∞, AUCτ, AUC0-tlast and Cmax on study 
day 1 and 8 for Part 1A using a power model. The power model will have the form: 
Y = a*(dose)b 
where Y is the PK parameter, and a and b are the coefficient and exponent, respectively, of the 
power equation. By taking the natural logarithm (ln), the power model can be analysed using linear 
regression and has the form: 
ln(Y) = ln(a)+b*ln(dose) + error 
=α + β*ln(dose) + error, 
where α is the intercept, and β is the slope, and ln(dose) is based on the dose size for each subject. 
For each PK parameter, the point estimate of slope β and its 95% CI will be provided. In addition, 
the estimated regression line will be overlaid on the individual points in the corresponding scatter 
plot (log-log scale). 
Dose proportionality will be declared if the 90% confidence interval (CI) for 𝛽𝛽 is entirely contained 
within the critical region, 
(1 + 
ln (0.50)
ln (𝑟𝑟) , 1 + 
ln (2.00)
ln (𝑟𝑟)  ) 
where 𝑟𝑟 is the ratio of the highest and the lowest dose in a given part of the study. Dose 
proportionality for participants who were administered the study intervention will be tested for 
Cmax and AUC0-∞, AUCτ, AUC0-tlast on Day 1 and at steady state. 


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Since the study is neither optimally designed nor powered to confirm the presence or absence of 
meaningful departures from dose proportionality, these results should be interpreted with caution. 
In addition, graphical assessment would also be considered to understand dose proportionality.   
If the samples remain above LLOQ for the whole dosing interval, then AUC0-tlast will be the same 
as AUCτ for Part 1A as there is another dose after 24 hours 
A statistical analysis will be conducted to investigate the food effect on the treatment by comparing 
(fed) treatment to (fasted) treatment for Part 1B. 
The natural log (ln)-transformed AUC0-∞, AUCτ , AUC0-tlast and Cmax will be analyzed using a 
mixed effect model. The model will include planned treatment sequence, period, and actual 
treatment as fixed effects, and subject within planned treatment sequence as a random effect. 
For each PK parameter separately, the least squares mean (LSM) for each treatment, difference in 
LSMs between the fed and fasted treatments, and corresponding 90% confidence intervals (CIs) 
will be calculated; these values will then be back-transformed to give the geometric least square 
mean (GLSM), ratio of GLSMs, and corresponding 90% CIs;  
Additionally, the pooled estimate (across treatments) of the within-subject coefficient of 
variation (CV) will be calculated, and residual plots will be produced to assess the adequacy of 
the model(s) fitted.  
16.1.4 
General Specifications for PK Concentration and PK 
Parameter Data  
Predose samples that occur before the first or subsequent drug administration will be assigned a 
time of 0 hours, as if the sample had been taken simultaneously with the study intervention 
administration.  
Predose or trough samples which have been taken after the subsequent dosing will be reported as 
a protocol deviation. The resulting concentrations will be included in concentration listings but 
excluded from descriptive statistics of concentrations and from PK parameter estimation.  
Values below the lower limit of quantification (BLQ) will be taken as zero for summary statistics 
of PK concentration data, PK parameter estimation (e.g. AUC) and for graphical presentations.  
In case profiles have a measurable pre-dose concentration less than or equal to 5% of its Cmax 
value, the participant’s data will be included in the PK and statistical analyses without any 
adjustments. If the pre-dose value is greater than 5% of the Cmax, the participant’s data for the 
affected profile will be included in the PK evaluation but excluded from descriptive and further 
statistical evaluation after agreement with the sponsor.  
Missing concentrations (e.g. no sample, insufficient sample volume for analysis, no result or result 
not valid) will be reported and used generally as “N.R.”. A participant who withdraws prior to the 
last planned observation will be included in the analyses up to the time of discontinuation. 


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Samples that are collected outside with a time deviation of > 10% from the protocol-scheduled 
time will be included in the PK parameter estimation (NCA) but will be excluded from the 
concentration summary and mean/median concentration plots.  
PK concentrations which are erroneous due to a sampling processing or analytical error (as 
documented in the bioanalytical report) may be excluded from the PK analysis if agreed by the 
Sponsor. In this case the rationale for exclusion will be provided in the CSR. Any other PK 
concentrations that appear implausible to the Clinical Pharmacologist/Clinical PK/PD Scientist 
will generally not be excluded from the analysis and data handling will be agreed with the sponsor 
clinical pharmacologist/PK scientist. Any implausible data will be documented in the CSR. 
If important protocol deviations occurred likely to affect the PK profile of participants as specified 
in Section 10.2.1, the impacted concentrations and PK parameters will be excluded from summary 
statistics and further statistical evaluation.  
Any PK concentrations or PK parameters excluded from summary statistics will be included in 
participant’s listings and flagged; a reason for exclusion will be detailed in the CSR (e.g. a footnote 
or a table of exclusions). Any flags should be included in the study specific CDISC data sets. 
PK concentrations and PK parameters excluded from summary statistics will not be included in 
mean/median figures. Mean/median plots will only contain values where n>2; if a cohort size is 
less than 2 individual data will be included in this plot. Footnote with details will be added. 
In case of missing or incomplete urine/feces samples, affected urine/feces PK parameters will be 
flagged in the listings and excluded from descriptive statistics if calculated. 
16.1.5 
Estimation of Pharmacokinetic Parameters  
The computer program Phoenix® WinNonlin® version 6.4, or higher (Certara, L.P., 1699 S 
Hanley Road, St Louis, MO 63144, USA) will be used to derive PK parameters applying non-
compartmental analysis (NCA).  
The statistical software SAS® (Statistical Analysis System, SAS-Institute, Cary NC, USA, 
windows version 9.1 or higher) may be used to generate additional PK parameters, produce tables, 
listings and figures.  
16.1.5.1 
Estimation of Pharmacokinetic Parameters in Plasma  
PK parameters analysis will be calculated using the actual elapsed time since dosing, with the 
exception of the interim analysis for SMC. In cases where the actual sampling time is missing, 
calculations may be performed using the scheduled time. Details (e.g. number of samples, 
participants affected) will be described in the CSR. In cases actual dosing time is missing, 
scheduled time might be used for NCA after performance of adequate plausibility checks and 
agreement with the sponsor. Decision and rationale should be included in the CSR.  
The following plasma PK parameters will be calculated for M4076 where appropriate  


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Symbol 
Definition 
AUC0-tlast 
The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last 
sampling time (tlast) at which the concentration is at or above the lower limit of quantification. 
Calculated using the mixed log-linear trapezoidal rule (linear up, log down). 
AUC0-tlast/Dose 
The Dose normalized AUC from time zero to the last sampling time (tlast) at which the 
concentration is at or above the lower limit of quantification. Normalized using the actual 
dose, using the formula AUC0-tlast /Dose. 
AUCτ 
The AUC over the dosing interval from T1=0 h to T2=τh. Calculated using the mixed 
log-linear trapezoidal rule (linear up, log down). For single dose, AUCτ is calculated as a 
partial area with the defined time range. In multiple dose profiles AUCτ is calculated at steady 
state from one pre-dose time point to the dosing interval time. In cases where the actual 
observation time is not equal to the scheduled observation time AUCτ will be calculated 
based on the estimated concentration at τhours, and not the concentration at the actual 
observation time where a regression has been performed. 
AUCτ /Dose 
The dose normalized AUC over the interval from T1=0 h to T2= τ h. Normalized using actual 
dose, using the formula AUCτ /Dose. 
AUC0-72 
The AUC from time zero (= dosing time) to 72 hours post-dose. Calculated using the mixed 
log-linear trapezoidal rule (linear up, log down). In cases where the actual observation time is 
not equal to the scheduled observation time (72 hours), AUC0-72 will be calculated based on 
the estimated concentration at 72 hours, and not the concentration at the actual observation 
time (Part 1B only). 
AUC0-72/Dose 
The dose normalized AUC from time zero (= dosing time) to 72 hours post-dose. Normalized 
using actual dose, using the formula AUC0-72 /Dose. (Part 1B only) 
AUC0-∞ 
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value 
for the concentration at tlast, as estimated using the linear regression from λz determination. 
AUC0-∞ = AUC0-tlast +Clast pred/ λz (single dose only) 
AUC0-∞/Dose 
The dose normalized AUC from time zero extrapolated to infinity. Normalized using actual 
dose, using the formula AUC0-∞ /Dose. (single dose only) 
CL/F 
The apparent total body clearance of study intervention following extravascular 
administration. CL/F= Dose p.o. /AUC0-∞. (single dose) 
Cmax 
Maximum observed concentration 
Cmax/Dose 
The dose normalized maximum concentration. Normalized using the actual dose, and the 
formula Cmax /Dose. 
Ctrough 
The concentration observed immediately before next dosing (Part 1A only) 
LI 
The linearity index after repeated administration calculated as LI= (AUCτ after multiple dose) 
/ (AUC0-∞ after single dose) (Part 1A, Day 8 only) 
Racc(AUCτ) 
The accumulation ratio after repeated administration calculated as Racc(AUCτ) = (AUCτ after 
multiple dose) / (AUCτ after single dose) (Part 1A, Day 8 only) 
Racc(Cmax) 
The accumulation factor to assess the increase in maximum concentration until steady state is 
reached. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose) (Part 1A, Day 8 only) 
t1/2 
Apparent terminal half-life. t1/2 = ln (2)/λz 
tlast 
The last sampling time at which the concentration is at or above the lower limit of 
quantification 


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tmax 
The time to reach the maximum observed concentration collected during a dosing interval 
(unless otherwise defined, take the 1st occurrence in case of multiple/identical Cmax values) 
Vz/F 
The apparent volume of distribution during the terminal phase following extravascular 
administration. Vz/F = Dose/(AUC0-∞*λz) following single dose.  
The following urine PK parameters will be calculated where appropriate  
Symbol 
Definition 
Aet1-t2 
Total amount excreted between times t1 (= start) and t2 (= end) of the current collection 
interval. Calculated by interval Aet1-t2 = Conc * Vu(t1-t2) and cumulative. 
fet1-t2 % 
Fraction of administered drug that is excreted unchanged in urine between times t1 (= start) 
and t2 (= end) of the current collection interval. Calculated by interval fet1-t2 = Aet1-t2/Dose 
and cumulative. 
CLR 
The renal clearance of study intervention. CLR = Ae0-t/AUC0-t. 
Additional PK parameters may be calculated where appropriate.  
Units for PK parameter output will be based on concentration and dose units used in the study, 
unless otherwise specified.  In case concentration data units change within the study, PK 
parameters will be reported using consistent units throughout study outputs. In such cases, the 
Sponsor will specify relevant units for reporting before the final PK evaluation.  
The parameters Cmax, tlast, and tmax will be obtained directly from the concentration-time profiles. 
If Cmax occurs at more than one timepoint, tmax will be assigned to the first occurrence of Cmax. 
In cases where the actual observation time is not equal to the scheduled observation time, AUCτ 
and AUC0-72, other partial areas will be calculated based on the estimated concentration at τ hours, 
72h, and not the concentration at the actual observation time.  
The following rules might be applied for calculation of AUCτ, AUC0-72, after agreement with the 
Sponsor: 
• In case suitable regression cannot be performed, partial areas may be calculated using the 
actual sampling time provided it is within 10% of the actual sampling time.  
• In cases BLQ concentrations occur at the end of the collection interval, these concentrations 
might be set to missing for calculations of partial AUCs. This is an exemption to the general 
BLQ handling rule and should be applied in case its application would result in estimation of 
implausible partial AUC values. Implausibility is considered in cases partial AUCs were 
greater than AUC0-∞.  
• At steady state, the pre-dose concentration may be duplicated and used as the trough 
concentration for calculation of AUCτ if the sample prior to the next dose is missing and vice 
versa. 


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The following PK parameters will be calculated for diagnostic purposes and listed, but will not be 
summarized: 
Symbol 
Definition 
λz low 
First (λz low) time point of the time interval of the log-linear regression to determine λz. 
λz up 
Last (λz up) time point of the time interval of the log-linear regression to determine λz. 
Nλ  
Number of data points (Nλ) included in the log-linear regression analysis to determine λz. 
Rsq, adj 
Adjusted goodness of fit statistic (adjusted Rsq) for calculation of λz 
AUCextra% 
AUC from time tlast extrapolated to infinity given as percentage of AUC0-∞. (AUCextra%) 
Span ratio 
Span ratio of interval over which t1/2 was estimated/t1/2 
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin “best fit” methodology will be used as standard. If warranted, further adjustment may 
be made by the pharmacokineticist, after agreement with the Sponsor. The last quantifiable 
concentration >LLOQ should always be included in the regression analysis, while the 
concentration at tmax and any concentrations BLQ which occur after the last quantifiable data point 
>LLOQ should not be used.  
If AUCextra%>20% and/or the coefficient of correlation (Rsq adj) of λz is <0.8 and/or the 
observation period over which the regression line is estimated (span ratio) is less than 2-fold the 
resulting t1/2, the rate constants and all derived parameters (e.g. t1/2, AUC0-∞, CL/F etc.) will be 
listed, flagged and included in the parameter outputs and excluded from descriptive statistics and 
further statistical evaluation.  
If AUC0-∞ cannot be determined reliably for all subjects and/or dose levels/treatments, an 
alternative AUC measure, such as AUC to a fixed timepoint or AUC0-tlast, may be used in the 
statistical analysis of dose proportionality and/or food effect.   
16.1.5.2 
Estimation of Pharmacokinetic Parameters in Urine  
For urine samples, which are collected within a time range the nominal start and end of collections 
times will be used for PK evaluation. 
Urine concentrations which are BLQ will be set to zero. 
The following urine PK parameters will be calculated for M4076 where appropriate  
Symbol 
Definition 
Aet1-t2 
Total amount excreted between times t1 (= start) and t2 (= end) of the current collection 
interval. Calculated by interval Aet1-t2 = Conc * Vu(t1-t2) and cumulative. 


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fet1-t2 % 
Fraction of administered drug that is excreted unchanged in urine between times t1 (= start) 
and t2 (= end) of the current collection interval. Calculated by interval fet1-t2 = Aet1-t2/Dose 
and cumulative. 
CLR 
The renal clearance of study intervention. CLR = Ae0-t/AUC0-t. 
Additional PK parameters may be calculated where appropriate.  
16.1.6 
Presentation of PK Concentration and PK Parameter Data  
“Dose level” in the PK TFLs description refer to schedule and dose. 
“Day” in the PK TFLs description refer to single dose or steady state. 
16.1.6.1 
Listings and Tables  
The following PK tables will be produced (PK Analysis Set): 
Part 1A + Part 1B (Day 4 predose onwards) 
• Descriptive statistics of concentrations of M4076 in plasma by part, day, and dose level  
• Descriptive statistics of plasma PK parameters for M4076 by part, day, and dose level (do not 
include diagnostic parameters).   
• Descriptive statistics of dose normalized plasma PK parameters for M4076 by part, day and 
dose level.  
• Descriptive statistics of plasma trough concentrations (Ctrough) by part and dose level, using 
standard descriptive statistics for Days 2, 8, 9, 22 and predose samples for subsequent cycles 
Part 1B (Food effect assessment period up to Day 4 predose) 
• Descriptive statistics of concentrations of M4076 in plasma by dietary status 
• Descriptive statistics of plasma PK parameters and CLR for M4076 by dietary status (do not 
include diagnostic parameters). 
• Descriptive statistics of dose normalized plasma PK parameters for M4076 by dietary status 
• Descriptive statistics of amount and fraction excreted in urine by interval and cumulatively by 
dietary status. 
 
 
 


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The following PK Listings will be produced (Safety Analysis Set): 
Part 1A + Part 1B (Day 4 predose onwards) 
• Individual plasma concentrations of M4076  by part, day and dose level 
• Individual plasma PK parameters for M4076 by part, day and dose level 
• Individual dose normalized plasma PK parameters for M4076 by part, day and dose level  
• Trough plasma concentrations (Ctrough) of M4076 by part and dose level, Days 2, 8, 9, 22 and 
predose samples for subsequent cycles. 
• Plasma PK diagnostic parameters for M4076 by part, day and dose level  
• Plasma M4076 PK sampling date, actual time, nominal time, deviation from time, percentage 
time deviation, concentration by participant, part and dose level status sorted in chronological 
order 
Part 1B (Food effect assessment period up to Day 4 predose) 
• Individual plasma concentrations of M4076 by dietary status 
• Individual urine concentrations of M4076 by dietary status 
• Individual plasma PK parameters and CLR (Part 1B) for M4076 by dietary status 
• Individual dose normalized plasma PK parameters for M4076 by dietary status. 
• Individual amount and fraction excreted in urine, by interval and cumulatively and dietary 
status. 
• Plasma PK diagnostic parameters for M4076 by dietary status. 
• Plasma M4076 PK sampling date, actual time, nominal time, deviation from time, percentage 
time deviation, concentration by participant, and dietary status sorted in chronological order 
• Urine M4076 PK sampling date, start and end time and date of collection interval, urine 
volume, concentration, excreted amount by participant and dietary status sorted in 
chronological order 
• Phoenix WinNonlin NCA Core Output 
 
 


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
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16.1.6.2 
Graphical Summaries and Individual plots (PK Analysis Set)  
Part 1A + Part 1B (Day 4 predose onwards)  
• Individual plasma concentration versus time plots by day, and dose level; linear and semi-log; 
using the actual time points. If any post-dose concentration is BLQ the line representing LLOQ 
may be added to the semi-log plots.   
• Overlaid individual (single dose and steady-state) plasma concentration versus time plots by 
participant, dose level, on linear and semi-log scale. If any post-dose concentration is BLQ the 
line representing LLOQ will be added to the semi-log plots.  
• Arithmetic mean and median M4076 plasma concentration time plots; linear (±SD for 
arithmetic mean) and semi-log; using scheduled (nominal) time points by day grouped by dose 
level. If any post-dose concentration is BLQ the line representing LLOQ will be added to the 
semi-log plots 
• Scatter Plot of individual dose-normalized AUC0-∞, AUCτ and Cmax versus Dose on a linear 
scale by day (single dose and steady state). Include GeoMean. 
• Scatter Plot of individual AUC0-∞, AUCτ and Cmax versus Dose on a log-log scale.  A linear 
regression line will be overlaid, with a pointwise confidence band for the regression line for 
Part 1A, Day 1 and Day 8. 
• Individual Ctrough values will be plotted against study day on a linear scale, for all participants 
by dose level on Days 2, 8, 9, 22 and predose samples for subsequent cycles.  
• Mean Ctrough ±SD will be plotted by dose level, on a linear scale Days 2, 8, 9, 22 and predose 
samples for subsequent cycles. 
Part 1B (Food effect assessment period up to Day 4 predose) 
• Individual plasma concentration versus time plots by dietary status; linear and semi-log; using 
the actual time points. If any post-dose concentration is BLQ the line representing LLOQ may 
be added to the semi-log plots.   
• Overlaid individual plasma concentration versus time plots (fasted and low-fat meal); linear 
and semi-log; using the actual time points. If any post-dose concentration is BLQ the line 
representing LLOQ may be added to the semi-log plots.   
• Arithmetic mean and median M4076 plasma concentration time plots; linear (±SD for 
arithmetic mean) and semi-log; using scheduled (nominal) time points by dietary status. If any 
post-dose concentration is BLQ the line representing LLOQ will be added to the semi-log plots 
• Box plot of dose-normalized AUC0-∞, AUC0-tlast, AUCτ and Cmax by dietary status. 


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                                                                                                                                      v 2. 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 /6 9  
 
 
•  Pl ot of Mea n ( +/ - S D) C u m ulati ve A m o u nt of M 4 0 7 6 E xcrete d i n Uri ne vers us Mi d ti me 
i nter val o n a Li near Scal e b y dietar y stat us  
•  Pl ot of I n di vi d ual C u m ulati ve A m o u nt of M 4 0 7 6 E xcrete d i n Uri n e vers us Mi d ti me i nter val  
o n a Li near Scale  b y diet ar y stat us  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C C I
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                                                                                                                                      v 2. 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 /6 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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                                                                                                                                      v 2. 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 /6 9  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
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                                                                                                                                      v 2. 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 /6 9  
 
 
 
 
C CI


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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17 
References  
Brookmeyer, R., and Crowley, J. (1982). “A Confidence Interval for the Median Survival Time.” 
Biometrics 38:29–41.  
Clopper, C. J., and Pearson, E. S. (1934). “The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial.” Biometrika 26:404–413.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009;45: 228-247.  
James D. Brierley (Editor), Mary K. Gospodarowicz (Editor), Christian Wittekind (Editor). TNM 
Classification of Malignant Tumours, 8th Edition, ISBN: 978-1-119-26357-9, January 2017, 
Wiley-Blackwell, 272 Pages  
Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New 
York: John Wiley & Sons.  


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
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18 
Appendices  
18.1 
Appendix 1 – NCI-CTC Gradable and Non-Gradable Safety 
Laboratory 
Test 
Parameters 
and 
Direction(s) 
of 
Abnormality  
Table 7 
Protocol-Required Clinical Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
Mean corpuscular volume 
(MCV) 
White Blood Cell Count 
with absolute and 
percentage (%): 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Reticulocytes 
Hemoglobin 
Mean corpuscular 
hemoglobin (MCH) 
Hematocrit 
 
Coagulation 
INR, prothrombin time, partial 
thromboplastin time (aPTT) 
 
 
Biochemistry 
Blood Urea 
Nitrogen and/or 
Urea 
Potassium 
Aspartate 
aminotransferase 
Bilirubin (total and direct) 
 
Creatinine 
Sodium 
Alanine aminotransferase 
Protein and albumin  
 
Glucose 
Calcium 
Alkaline phosphatase 
 
 
Gamma 
glutamyltransferase 
(gGT) 
Lipase 
Amylase 
 
Details of liver chemistry stopping criteria and required actions are given in protocol Section 6.6.1 and Appendix 5 
of the protocol. 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• 
Serum and urine human chorionic gonadotropin pregnancy test (as needed for women of 
childbearing potential). 
Serology (with no preclinical signs of hepatotoxicity, hepatitis B surface antigen, hepatitis C 
virus antibody) to rule out active infection will be performed at the Investigator’s discretion. 
HIV screening is optional at the Investigator’s discretion unless required locally. 
All study-required laboratory assessments will be performed by a central laboratory, except 
for safety laboratory assessments. 
 
 


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
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Table 8 
NCI-CTC gradable parameters 
Laboratory Assessment 
Parameters  
Name in NCI-CTC 
Direction(s) of 
abnormality 
Hematology 
Hemoglobin 
Anemia/Hemoglobin increased 
Low/High 
 
Leukocytes (WBC) 
White blood cell decreased / Leukocytosis  
Low/High 
 
Neutrophils 
Neutrophil count decreased  
Low 
 
Lymphocytes 
Lymphocyte count decreased / increased 
Low/High 
 
Eosinophils 
Eosinophila [a] 
High 
 
Platelets 
Platelet count decreased 
Low 
Biochemistry 
Albumin 
Hypoalbuminemia  
Low 
 
Alanine Aminotransferase 
(ALT) 
Alanine Aminotransferase increased [a] 
High 
 
Aspartate Aminotransferase 
(AST) 
Aspartate Aminotransferase increased [a] 
High 
 
Alkaline Phosphatase 
Alkaline Phosphatase increased [a] 
High 
 
Gamma Glutamyl Transferase 
(GGT) 
GGT increased [a] 
High 
 
Total Bilirubin 
Blood bilirubin increased [a] 
High 
 
Amylase 
Serum amylase increased  
High 
 
Lipase 
Lipase increased  
High 
 
Creatinine 
Creatinine increased [a] 
High 
 
Sodium 
Hyponatremia / Hypernatremia 
Low / High 
 
Potassium 
Hypokalemia / Hyperkalemia 
Low / High 
 
Calcium 
Hypocalcemia / Hypercalcemia 
Low / High 
 
Glucose 
Hypoglycemia / Hyperglycemia 
Low / High 
Coagulation 
Activated Partial 
Thromboplastin Time 
Activated Partial Thromboplastin Time 
prolonged 
High 
 
Prothrombin Intl. Normalized 
Ration (INR) 
INR increased 
High 
Note: parameters with both Low and High directions of abnormality are going to be split. For example, Calcium is going to be 
split in Calcium Low and Calcium High. 
a on-treatment grading dependent on baseline status. 
 
 
 


M4076                     
                           First-in-human Study of M4076 in Advanced Solid Tumors  
MS201512_0010                                                                                                                                      v2.0 
 
 
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Table 9 
NCI-CTC non-gradable parameters 
Laboratory Assessment 
Parameters  
Hematology 
Hematocrit  
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
Reticulocytes 
 
Reticulocytes/Erythrocytes 
 
Neutrophils/Leukocytes (%)  
 
Lymphocytes/Leukocytes (%) 
 
Basophils 
 
Basophils/Leukocytes (%) 
 
Eosinophils/Leukocytes (%) 
 
Monocytes 
 
Monocytes/Leukocytes (%) 
Biochemistry 
Total Protein 
 
Urea Nitrogen (BUN) 
 
Serum cystatin C 
Coagulation 
Prothrombin Time 
 
Prothrombin Time/Standard 
Urinalysis 
Blood 
 
Bacteria (Microscopic analysis) 
 
Casts (Microscopic analysis) 
 
Crystals (Microscopic analysis) 
 
Epithelial Cells (Microscopic analysis) 
 
Bilirubin 
 
Glucose in Urine 
 
Urobilinogen 
 
Ketones 
 
Nitrite 
 
pH 
 
Proteins in Urine 
 
Erythrocytes in Urine (Microscopic analysis) 
 
Leukocytes esterase 
 
Leukocytes in Urine (Microscopic analysis) 
 
Specific gravity 
 
 
 


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                                                                                                                                      v 2. 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 /6 9  
 
 
1 8. 2  
A p pe n di x 2 – I A P f or I D M C/ S M C  
 
P P D
P P D
C CI
P P D
P P D
P P D
P P D